Journal: Circulation

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Abstract

Time-Restricted Salutary Effects of Blood Flow Restoration on Venous Thrombosis and Vein Wall Injury in Mouse and Human Subjects.

Li W, Kessinger CW, Orii M, Lee H, ... Henke PK, Jaffer FA

Up to 50% of patients with proximal deep venous thrombosis (DVT) will develop the post-thrombotic syndrome (PTS) characterized by limb swelling and discomfort, hyperpigmentation, skin ulcers, and impaired quality-of-life. While catheter-based interventions enabling restoration of blood flow (RBF) have demonstrated little benefit on PTS, the impact on the acuity of the thrombus and mechanisms underlying this finding remain obscure. Here in experimental and clinical studies, we examined whether RBF has a restricted time window for improving DVT resolution.First, experimental stasis DVT was generated in C57/BL6 mice (N=291) by inferior vena cava ligation. To promote RBF, mice underwent mechanical de-ligation with or without intravenous recombinant tissue plasminogen activator (rtPA), administered two days after de-ligation. RBF was assessed over time by ultrasonography and intravital microscopy. Resected thrombosed IVC specimens underwent thrombus and vein wall histological and gene expression assays. Next, in a clinical study, we conducted a post-hoc analysis of the ATTRACT pharmacomechanical catheter-directed thrombolysis (PCDT) trial (NCT00790335) to assess the effects of PCDT on VEINES quality-of-life (VEINES-QoL) and Villalta scores for specific symptom-onset-to-randomization (SOR) timeframes.Mice that developed RBF by day 4, but not later, exhibited reduced day 8 thrombus burden parameters and reduced day 8 vein wall fibrosis and inflammation, compared to controls. In mice without RBF, rtPA administered at day 4, but not later, reduced day 8 thrombus burden and vein wall fibrosis. Notably, in mice already exhibiting RBF by day 4, rtPA administration did not further reduce thrombus burden or vein wall fibrosis. In the ATTRACT trial, patients receiving PCDT in an intermediate SOR timeframe of 4-8 days demonstrated maximal benefits in VEINES-QoL and Villalta scores (between group difference=8.41 and 1.68 respectively, p<0.001 vs. patients not receiving PCDT). PCDT did not improve PTS scores for patients having an SOR time of <4 days or >8 days.Taken together, these data illustrate that within a restricted therapeutic window, RBF improves DVT resolution, and PCDT may improve clinical outcomes. Further studies are warranted to examine the value of time-restricted RBF strategies to reduce PTS in DVT patients.



Circulation: 14 Jan 2021; epub ahead of print
Li W, Kessinger CW, Orii M, Lee H, ... Henke PK, Jaffer FA
Circulation: 14 Jan 2021; epub ahead of print | PMID: 33445952
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Abstract

Clinical Efficacy and Safety of Alirocumab after Acute Coronary Syndrome According to Achieved Level of Low-Density Lipoprotein Cholesterol: A Propensity Score-Matched Analysis of the ODYSSEY OUTCOMES Trial.

Schwartz GG, Steg PG, Bhatt DL, Bittner VA, ... Szarek M, ODYSSEY OUTCOMES Committees and Investigators

Recent international guidelines have lowered recommended target levels of low-density lipoprotein-cholesterol (LDL-C) for patients at very high risk for major adverse cardiovascular events (MACE). However, uncertainty persists whether additional benefit results from achieved LDL-C levels below conventional targets. Inferences from prior analyses are limited because patients who achieve lower versus higher LDL-C on lipid-lowering therapy differ in other characteristics prognostic for MACE and because few achieved very low LDL-C levels. To overcome these limitations, we performed a propensity score matching (PSM) analysis of the ODYSSEY OUTCOMES trial which compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome (ACS) receiving intensive or maximum-tolerated statin treatment.Patients on alirocumab were classified in prespecified strata of LDL-C achieved at 4 months of treatment: <25 (n=3357), 25-50 (n=3692) or >50 mg/dL (n=2197). For each stratum, MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) after month 4 was compared in patients receiving placebo with similar baseline characteristics and adherence, using 1:1 PSM.Across achieved LDL-C strata of the alirocumab group patients differed by baseline LDL-C, lipoprotein(a), use of intensive statin therapy, study medication adherence, and other demographic, medical history, biometric, and laboratory criteria. After PSM, characteristics were similar in corresponding patients of the alirocumab and placebo groups. Treatment hazard ratio (HR), 95% confidence interval (CI), and absolute risk reduction (ARR, number per 100 patient-years) for MACE were similar in those with achieved LDL-C <25 mg/dL (HR, 0.74; 95% CI, 0.62 to 0.89; ARR, 0.92) or 25-50 mg/dL (HR, 0.74; 95% CI, 0.64 to 0.87; ARR, 1.05). Patients with achieved LDL-C >50 mg/dL had poorer adherence and derived less benefit (HR, 0.87; 95% CI, 0.73 to 1.04; ARR, 0.62). No safety concerns were associated with a limited period of LDL-C levels <15 mg/dL.After accounting for differences in baseline characteristics and adherence, patients treated with alirocumab who achieved LDL-C levels <25 mg/dL did not appear to derive further reduction in the risk of MACE compared to those who achieved LDL-C levels of 25-50 mg/dL.URL: https://www.clinicaltrials.gov Unique identifier: NCT01663402.



Circulation: 12 Jan 2021; epub ahead of print
Schwartz GG, Steg PG, Bhatt DL, Bittner VA, ... Szarek M, ODYSSEY OUTCOMES Committees and Investigators
Circulation: 12 Jan 2021; epub ahead of print | PMID: 33438437
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Abstract

Cell-Free DNA to Detect Heart Allograft Acute Rejection.

Agbor-Enoh S, Shah P, Tunc I, Hsu S, ... Valantine HA, GRAfT Investigators

After heart transplantation, Endomyocardial biopsy (EMBx) is used to monitor for acute rejection (AR). Unfortunately, EMBx is invasive and its conventional histologic interpretation has limitations. This is a validation study to assesses the performance of a sensitive blood biomarker- percent donor-derived cell-free DNA (%ddcfDNA) - for detection of AR in cardiac transplant recipients.This multicenter, prospective cohort study recruited heart transplant subjects and collected plasma samples contemporaneously with EMBx for %ddcfDNA measurement by shotgun sequencing. Histopathology data was collected to define AR, its two phenotypes (acute cellular rejection, ACR, and antibody-mediated rejection, AMR) and controls without rejection. The primary analysis was to compare %ddcfDNA levels (median and interquartile range - IQR) for AR, AMR and ACR to controls and to determine %ddcfDNA test characteristics using receiver-operator characteristics analysis.The study included 171 subjects with median post-transplant follow-up of 17.7 months (IQR: 12.1-23.6), with 1,392 EMBx, and 1,834 ddcfDNA measures available for analysis. Median %ddcfDNA levels decayed after surgery to 0.13% (0.03-0.21) by 28 days. %ddcfDNA increased again with AR compared to controls values (0.38, IQR=0.31-0.83, vs. 0.03, IQR=0.01-0.14 p<0.001). The rise was detected 0.5 and 3.2 months before histopathological diagnosis of ACR and AMR. The area-under-the- receiver-operator characteristics curve (AUROC) for AR was 0.92. A 0.25 %ddcfDNA threshold had a negative predictive value (NPV) for AR of 99% and would have safely eliminated 81% of EMBx. %ddcfDNA showed distinctive characteristics comparing AMR to ACR, included 5-fold higher levels (pAMR ≥2 1.68, IQR=0.49-2.79 vs. ACR grade ≥2R 0.34, IQR=0.28-0.72), higher AUROC (0.95 vs. 0.85), higher guanosine-cytosine content, and higher percentage of short ddcfDNA fragments.%ddcfDNA detected AR with a high AUROC and NPV. Monitoring with ddcfDNA, demonstrated excellent performance characteristics for both ACR and AMR and led to earlier detection than the EMBx-based monitoring. This study supports the use of %ddcfDNA to monitor for AR in heart transplant patients and paves the way for a clinical utility study.URL: http://clinicaltrials.gov Unique Identifier: NCT02423070.



Circulation: 12 Jan 2021; epub ahead of print
Agbor-Enoh S, Shah P, Tunc I, Hsu S, ... Valantine HA, GRAfT Investigators
Circulation: 12 Jan 2021; epub ahead of print | PMID: 33435695
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Abstract

Current Indications for Transcatheter Mitral Valve Replacement Using Transcatheter Aortic Valves: Valve-in-Valve, Valve-in-Ring, and Valve-in-Mitral Annulus Calcification.

Urena M, Vahanian A, Brochet E, Ducrocq G, Iung B, Himbert D

Use of transcatheter mitral valve replacement (TMVR) using transcatheter aortic valves in clinical practice is limited to patients with failing bioprostheses and rings or mitral valve disease associated with severe mitral annulus calcification. Whereas the use of valve-in-valve TMVR appears to be a reasonable alternative to surgery in patients at high surgical risk, much less evidence supports valve-in-ring and valve-in-mitral annulus calcification interventions. Data on the results of TMVR in these settings are derived from small case series or voluntary registries. This review summarizes the current evidence on TMVR using transcatheter aortic valves in clinical practice from the characteristics of the TMVR candidates, screening process, performance of the procedure, and description of current results and future perspectives. TMVR using dedicated devices in native noncalcified mitral valve diseases is beyond the scope of the article.



Circulation: 11 Jan 2021; 143:178-196
Urena M, Vahanian A, Brochet E, Ducrocq G, Iung B, Himbert D
Circulation: 11 Jan 2021; 143:178-196 | PMID: 33428433
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Abstract

Cardiomyocyte Krüppel-like Factor 5 Promotes De Novo Ceramide Biosynthesis and Contributes to Eccentric Remodeling in Ischemic Cardiomyopathy.

Hoffman M, Palioura D, Kyriazis ID, Cimini M, ... Drakos SG, Drosatos K

We previously showed that cardiomyocyte Krüppel-like factor (KLF)-5 regulates cardiac fatty acid oxidation. As heart failure has been associated with altered fatty acid oxidation, we investigated the role of cardiomyocyte KLF5 in lipid metabolism and pathophysiology of ischemic heart failure.Using rtPCR and Western Blot, we investigated the KLF5 expression changes in a myocardial infarction (MI) mouse model and heart tissue from patients with ischemic heart failure. Using 2D-echocardiography, we evaluated the effect of KLF5 inhibition after MI using pharmacological KLF5 inhibitor ML264 and mice with cardiomyocyte specific KLF5 deletion (αMHC-KLF5). We identified the involvement of KLF5 in regulating lipid metabolism and ceramide accumulation after MI using liquid-chromatography-tandem-mass-spectrometry, and Western Blot and rtPCR analysis of ceramide-metabolism-related genes. We lastly evaluated the effect of cardiomyocyte-specific KLF5 overexpression (αMHC-rtTA-KLF5) on cardiac function and ceramide metabolism, and rescued the phenotype using myriocin to inhibit ceramide biosynthesis.KLF5 mRNA and protein levels were higher in human ischemic heart failure samples and in rodent models 24h, 2- and 4-weeks post-permanent left coronary artery ligation. αMHC-KLF5 mice and mice treated with ML264 had higher ejection fraction and lower ventricular volume and heart weight after MI. Lipidomic analysis showed that αMHC-KLF5 mice with MI had lower myocardial ceramide levels compared with littermate control mice with MI although basal ceramide content of αMHC-KLF5 mice was not different from control mice. KLF5 ablation suppressed the expression of serine-palmitoyl-transferase-long-chain-base-subunit (SPTLC)1 and SPTLC2, which regulate de novo ceramide biosynthesis. We confirmed our previous findings that myocardial SPTLC1 and SPTLC2 levels are increased in heart failure patients. Consistently, αMHC-rtTA-KLF5 mice showed increased SPTLC1 and SPTLC2 expression, higher myocardial ceramide levels, and systolic dysfunction beginning 2-weeks after KLF5 induction. Treatment of αMHC-rtTA-KLF5 mice with myriocin that inhibits SPT, suppressed myocardial ceramide levels and alleviated systolic dysfunction.KLF5 is induced during the development of ischemic heart failure in humans and mice and stimulates ceramide biosynthesis. Genetic or pharmacological inhibition of KLF5 in mice with MI prevents ceramide accumulation, alleviates eccentric remodeling, and increases ejection fraction. Thus, KLF5 emerges as a novel therapeutic target for the treatment of ischemic heart failure.



Circulation: 11 Jan 2021; epub ahead of print
Hoffman M, Palioura D, Kyriazis ID, Cimini M, ... Drakos SG, Drosatos K
Circulation: 11 Jan 2021; epub ahead of print | PMID: 33430631
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Abstract

Prognostic Value of Non-Ischemic Ring-Like Left Ventricular Scar in Patients with Apparently Idiopathic Non-Sustained Ventricular Arrhythmias.

Muser D, Nucifora G, Pieroni M, Castro SA, ... Marchlinski FE, Santangeli P

Left ventricular (LV) scar on late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) has been correlated with life-threatening arrhythmic events in patients with apparently idiopathic ventricular arrhythmias (VA). We investigated the prognostic significance of a specific LV-LGE phenotype characterized by a ring-like pattern of fibrosis.686 patients with apparently idiopathic non-sustained VA underwent contrast enhanced CMR. A ring-like pattern of LV scar was defined as LV subepicardial/midmyocardial LGE involving at least 3 contiguous segments in the same short-axis slice. The endpoint of the study was time to the composite outcome of all cause death, resuscitated cardiac arrest due to ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT) and appropriate implantable cardioverter defibrillator therapy.A total of 28 (4%) patients had a ring-like pattern of scar (Group A), 78 (11%) a non ring-like pattern (Group B), and 580 (85%) had normal CMR with no LGE (Group C). Group A patients were younger compared to Group B and Group C (median age 40 vs. 52 vs. 45 years, p<0.01), more frequently males (96% vs. 82% vs. 55%, p<0.01) with a higher prevalence of family history of sudden cardiac death/cardiomyopathy (39% vs. 14% vs. 6%; p<0.01), and more frequent history of unexplained syncope (18% vs. 9% vs. 3%, p<0.01). All patients in Group A showed VA with a right bundle branch block morphology vs. 69% in Group B and 21% in Group C (p<0.01). Multifocal VA were observed in 46% of Group A patients compared to 26% of Group B and 4% of Group C (p<0.01). After a median follow-up of 61 (34-84) months, the composite outcome occurred in 14 patients (50%) in Group A vs. 15 (19%) in Group B and 2 (0.3%) in Group C (p<0.01). After multivariable adjustment, the presence of LGE with ring-like pattern remained independently associated with increased risk of the composite endpoint (HR 68.98, 95% CI 14.67-324.39, p<0.01).In patients with apparently idiopathic non-sustained VA, nonischemic LV scar with a ring-like pattern is associated with malignant arrhythmic events.



Circulation: 05 Jan 2021; epub ahead of print
Muser D, Nucifora G, Pieroni M, Castro SA, ... Marchlinski FE, Santangeli P
Circulation: 05 Jan 2021; epub ahead of print | PMID: 33401956
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Abstract

PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) Enhances Platelet Activation, Thrombosis, and Myocardial Infarct Expansion by Binding to Platelet CD36.

Qi Z, Hu L, Zhang J, Yang W, ... Ding Z, Ge J
Background
PCSK9 (proprotein convertase subtilisin/kexin 9), mainly secreted by the liver and released into the blood, elevates plasma low-density lipoprotein cholesterol by degrading low-density lipoprotein receptor. Pleiotropic effects of PCSK9 beyond lipid metabolism have been shown. However, the direct effects of PCSK9 on platelet activation and thrombosis, and the underlying mechanisms, as well, still remain unclear.
Methods
We detected the direct effects of PCSK9 on agonist-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, α-granule release, spreading, and clot retraction. These studies were complemented by in vivo analysis of FeCl-injured mouse mesenteric arteriole thrombosis. We also investigated the underlying mechanisms. Using the myocardial infarction (MI) model, we explored the effects of PCSK9 on microvascular obstruction and infarct expansion post-MI.
Results
PCSK9 directly enhances agonist-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, P-selectin release from α-granules, spreading, and clot retraction. In line, PCSK9 enhances in vivo thrombosis in a FeCl-injured mesenteric arteriole thrombosis mouse model, whereas PCSK9 inhibitor evolocumab ameliorates its enhancing effects. Mechanism studies revealed that PCSK9 binds to platelet CD36 and thus activates Src kinase and MAPK (mitogen-activated protein kinase)-extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase, increases the generation of reactive oxygen species, and activates the p38MAPK/cytosolic phospholipase A2/cyclooxygenase-1/thromboxane A signaling pathways downstream of CD36 to enhance platelet activation, as well. Using CD36 knockout mice, we showed that the enhancing effects of PCSK9 on platelet activation are CD36 dependent. It is important to note that aspirin consistently abolishes the enhancing effects of PCSK9 on platelet activation and in vivo thrombosis. Last, we showed that PCSK9 activating platelet CD36 aggravates microvascular obstruction and promotes MI expansion post-MI.
Conclusions
PCSK9 in plasma directly enhances platelet activation and in vivo thrombosis, and MI expansion post-MI, as well, by binding to platelet CD36 and thus activating the downstream signaling pathways. PCSK9 inhibitors or aspirin abolish the enhancing effects of PCSK9, supporting the use of aspirin in patients with high plasma PCSK9 levels in addition to PCSK9 inhibitors to prevent thrombotic complications.



Circulation: 04 Jan 2021; 143:45-61
Qi Z, Hu L, Zhang J, Yang W, ... Ding Z, Ge J
Circulation: 04 Jan 2021; 143:45-61 | PMID: 32988222
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Abstract

Primary Results From the Understanding Outcomes With the S-ICD in Primary Prevention Patients With Low Ejection Fraction (UNTOUCHED) Trial.

Gold MR, Lambiase PD, El-Chami MF, Knops RE, ... Boersma LVA,
Background
The subcutaneous (S) implantable cardioverter-defibrillator (ICD) is safe and effective for sudden cardiac death prevention. However, patients in previous S-ICD studies had fewer comorbidities, had less left ventricular dysfunction, and received more inappropriate shocks (IAS) than in typical transvenous ICD trials. The UNTOUCHED trial (Understanding Outcomes With the S-ICD in Primary Prevention Patients With Low Ejection Fraction) was designed to evaluate the IAS rate in a more typical, contemporary ICD patient population implanted with the S-ICD using standardized programming and enhanced discrimination algorithms.
Methods
Primary prevention patients with left ventricular ejection fraction ≤35% and no pacing indications were included. Generation 2 or 3 S-ICD devices were implanted and programmed with rate-based therapy delivery for rates ≥250 beats per minute and morphology discrimination for rates ≥200 and <250 beats per minute. Patients were followed for 18 months. The primary end point was the IAS-free rate compared with a 91.6% performance goal, derived from the results for the ICD-only patients in the MADIT-RIT study (Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy). Kaplan-Meier analyses were performed to evaluate event-free rates for IAS, all-cause shock, and complications. Multivariable proportional hazard analysis was performed to determine predictors of end points.
Results
S-ICD implant was attempted in 1116 patients, and 1111 patients were included in postimplant follow-up analysis. The cohort had a mean age of 55.8±12.4 years, 25.6% were women, 23.4% were Black, 53.5% had ischemic heart disease, 87.7% had symptomatic heart failure, and the mean left ventricular ejection fraction was 26.4±5.8%. Eighteen-month freedom from IAS was 95.9% (lower confidence limit, 94.8%). Predictors of reduced incidence of IAS were implanting the most recent generation of device, using the 3-incision technique, no history of atrial fibrillation, and ischemic cause. The 18-month all-cause shock-free rate was 90.6% (lower confidence limit, 89.0%), meeting the prespecified performance goal of 85.8%. Conversion success rate for appropriate, discrete episodes was 98.4%. Complication-free rate at 18 months was 92.7%.
Conclusions
This study demonstrates high efficacy and safety with contemporary S-ICD devices and programming despite the relatively high incidence of comorbidities in comparison with earlier S-ICD trials. The inappropriate shock rate (3.1% at 1 year) is the lowest reported for the S-ICD and lower than many transvenous ICD studies using contemporary programming to reduce IAS. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02433379.



Circulation: 04 Jan 2021; 143:7-17
Gold MR, Lambiase PD, El-Chami MF, Knops RE, ... Boersma LVA,
Circulation: 04 Jan 2021; 143:7-17 | PMID: 33073614
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Abstract

Reduction in Revascularization With Icosapent Ethyl: Insights From REDUCE-IT Revascularization Analyses.

Peterson BE, Bhatt DL, Steg PG, Miller M, ... Ballantyne CM,
Background
Patients with elevated triglycerides despite statin therapy have increased risk for ischemic events, including coronary revascularizations.
Methods
REDUCE-IT (The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients with elevated triglycerides (135-499 mg/dL), controlled low-density lipoprotein (41-100 mg/dL), and either established cardiovascular disease or diabetes plus other risk factors to receive icosapent ethyl 4 g/d or placebo. The primary and key secondary composite end points were significantly reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.
Results
A total of 8179 randomly assigned patients were followed for 4.9 years (median). First revascularizations were reduced to 9.2% (22.5/1000 patient-years) with icosapent ethyl versus 13.3% (33.7/1000 patient-years) with placebo (hazard ratio, 0.66 [95% CI, 0.58-0.76]; <0.0001; number needed to treat for 4.9 years=24); similar reductions were observed in total (first and subsequent) revascularizations (negative binomial rate ratio, 0.64 [95% CI, 0.56-0.74]; <0.0001), and across elective, urgent, and emergent revascularizations. Icosapent ethyl significantly reduced percutaneous coronary intervention (hazard ratio, 0.68 [95% CI, 0.59-0.79]; <0.0001) and coronary artery bypass grafting (hazard ratio, 0.61 [95% CI, 0.45-0.81]; =0.0005).
Conclusions
Icosapent ethyl reduced the need for first and subsequent coronary revascularizations in statin-treated patients with elevated triglycerides and increased cardiovascular risk. To our knowledge, icosapent ethyl is the first non-low-density lipoprotein-lowering treatment that has been shown to reduce coronary artery bypass grafting in a blinded, randomized trial. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.



Circulation: 04 Jan 2021; 143:33-44
Peterson BE, Bhatt DL, Steg PG, Miller M, ... Ballantyne CM,
Circulation: 04 Jan 2021; 143:33-44 | PMID: 33148016
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Abstract

Review of Cardiac Involvement in Multisystem Inflammatory Syndrome in Children.

Alsaied T, Tremoulet AH, Burns JC, Saidi A, ... de Ferranti S, Friedman KG

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with substantial cardiovascular implications. Although infection with SARS-CoV-2 is usually mild in children, some children later develop a severe inflammatory disease that can have manifestations similar to toxic shock syndrome or Kawasaki disease. This syndrome has been defined by the US Centers for Disease Control and Prevention as multisystem inflammatory syndrome in children. Although the prevalence is unknown, >600 cases have been reported in the literature. Multisystem inflammatory syndrome in children appears to be more common in Black and Hispanic children in the United States. Multisystem inflammatory syndrome in children typically occurs a few weeks after acute infection and the putative etiology is a dysregulated inflammatory response to SARS-CoV-2 infection. Persistent fever and gastrointestinal symptoms are the most common symptoms. Cardiac manifestations are common, including ventricular dysfunction, coronary artery dilation and aneurysms, arrhythmia, and conduction abnormalities. Severe cases can present as vasodilatory or cardiogenic shock requiring fluid resuscitation, inotropic support, and in the most severe cases, mechanical ventilation and extracorporeal membrane oxygenation. Empirical treatments have aimed at reversing the inflammatory response using immunomodulatory medications. Intravenous immunoglobulin, steroids, and other immunomodulatory agents have been used frequently. Most patients recover within days to a couple of weeks and mortality is rare, although the medium- and long-term sequelae, particularly cardiovascular complications, are not yet known. This review describes the published data on multisystem inflammatory syndrome in children, focusing on cardiac complications, and provides clinical considerations for cardiac evaluation and follow-up.



Circulation: 04 Jan 2021; 143:78-88
Alsaied T, Tremoulet AH, Burns JC, Saidi A, ... de Ferranti S, Friedman KG
Circulation: 04 Jan 2021; 143:78-88 | PMID: 33166178
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Abstract

VEGF-B Promotes Endocardium-Derived Coronary Vessel Development and Cardiac Regeneration.

Räsänen M, Sultan I, Paech J, Hemanthakumar KA, ... Kivelä R, Alitalo K
Background
Recent discoveries have indicated that, in the developing heart, sinus venosus and endocardium provide major sources of endothelium for coronary vessel growth that supports the expanding myocardium. Here we set out to study the origin of the coronary vessels that develop in response to vascular endothelial growth factor B (VEGF-B) in the heart and the effect of VEGF-B on recovery from myocardial infarction.
Methods
We used mice and rats expressing a VEGF-B transgene, VEGF-B-gene-deleted mice and rats, apelin-CreERT, and natriuretic peptide receptor 3-CreERT recombinase-mediated genetic cell lineage tracing and viral vector-mediated VEGF-B gene transfer in adult mice. Left anterior descending coronary vessel ligation was performed, and 5-ethynyl-2\'-deoxyuridine-mediated proliferating cell cycle labeling; flow cytometry; histological, immunohistochemical, and biochemical methods; single-cell RNA sequencing and subsequent bioinformatic analysis; microcomputed tomography; and fluorescent- and tracer-mediated vascular perfusion imaging analyses were used to study the development and function of the VEGF-B-induced vessels in the heart.
Results
We show that cardiomyocyte overexpression of VEGF-B in mice and rats during development promotes the growth of novel vessels that originate directly from the cardiac ventricles and maintain connection with the coronary vessels in subendocardial myocardium. In adult mice, endothelial proliferation induced by VEGF-B gene transfer was located predominantly in the subendocardial coronary vessels. Furthermore, VEGF-B gene transduction before or concomitantly with ligation of the left anterior descending coronary artery promoted endocardium-derived vessel development into the myocardium and improved cardiac tissue remodeling and cardiac function.
Conclusions
The myocardial VEGF-B transgene promotes the formation of endocardium-derived coronary vessels during development, endothelial proliferation in subendocardial myocardium in adult mice, and structural and functional rescue of cardiac tissue after myocardial infarction. VEGF-B could provide a new therapeutic strategy for cardiac neovascularization after coronary occlusion to rescue the most vulnerable myocardial tissue.



Circulation: 04 Jan 2021; 143:65-77
Räsänen M, Sultan I, Paech J, Hemanthakumar KA, ... Kivelä R, Alitalo K
Circulation: 04 Jan 2021; 143:65-77 | PMID: 33203221
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Abstract

Comparison of Self-Expanding Bioprostheses for Transcatheter Aortic Valve Replacement in Patients With Symptomatic Severe Aortic Stenosis: SCOPE 2 Randomized Clinical Trial.

Tamburino C, Bleiziffer S, Thiele H, Scholtz S, ... Hengstenberg C, Capodanno D
Background
Few randomized trials have compared bioprostheses for transcatheter aortic valve replacement, and no trials have compared bioprostheses with supra-annular design. The SCOPE 2 trial (Safety and Efficacy Comparison of Two TAVI Systems in a Prospective Randomized Evaluation 2) was designed to compare the clinical outcomes of the ACURATE neo and CoreValve Evolut bioprostheses for transcatheter aortic valve replacement.
Methods
SCOPE 2 was a randomized trial performed at 23 centers in 6 countries between April 2017 and April 2019. Patients ≥75 years old with an indication for transfemoral transcatheter aortic valve replacement as agreed by the heart team were randomly assigned to receive treatment with either the ACURATE neo (n=398) or the CoreValve Evolut bioprostheses (n=398). The primary end point, powered for noninferiority of the ACURATE neo bioprosthesis, was all-cause death or stroke at 1 year. The key secondary end point, powered for superiority of the ACURATE neo bioprosthesis, was new permanent pacemaker implantation at 30 days.
Results
Among 796 randomized patients (mean age, 83.2±4.3 years; mean Society of Thoracic Surgeons Predicted Risk of Mortality score, 4.6±2.9%), clinical follow-up information was available for 778 (98%) patients. Within 1 year, the primary end point occurred in 15.8% of patients in the ACURATE neo group and in 13.9% of patients in the CoreValve Evolut group (absolute risk difference, 1.8%, upper 1-sided 95% confidence limit, 6.1%; =0.0549 for noninferiority). The 30-day rates of new permanent pacemaker implantation were 10.5% in the ACURATE neo group and 18.0% in the CoreValve Evolut group (absolute risk difference, -7.5% [95% CI, -12.4 to -2.60]; =0.0027). No significant differences were observed in the components of the primary end point. Cardiac death at 30 days (2.8% versus 0.8%; =0.03) and 1 year (8.4% versus 3.9%; =0.01), and moderate or severe aortic regurgitation at 30 days (10% versus 3%; =0.002) were significantly increased in the ACURATE neo group.
Conclusions
Transfemoral transcatheter aortic valve replacement with the self-expanding ACURATE neo did not meet noninferiority compared with the self-expanding CoreValve Evolut in terms of all-cause death or stroke at 1 year, and it was associated with a lower incidence of new permanent pacemaker implantation. In secondary analyses, the ACURATE neo was associated with more moderate or severe aortic regurgitation at 30 days and cardiac death at 30 days and 1 year. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03192813.



Circulation: 21 Dec 2020; 142:2431-2442
Tamburino C, Bleiziffer S, Thiele H, Scholtz S, ... Hengstenberg C, Capodanno D
Circulation: 21 Dec 2020; 142:2431-2442 | PMID: 33054367
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Abstract

Exercise Training-Induced Repolarization Abnormalities Masquerading as Congenital Long QT Syndrome.

Dagradi F, Spazzolini C, Castelletti S, Pedrazzini M, ... Crotti L, Schwartz PJ
Background
The diagnosis of long QT syndrome (LQTS) is rather straightforward. We were surprised by realizing that, despite long-standing experience, we were making occasional diagnostic errors by considering as affected subjects who, over time, resulted as not affected. These individuals were all actively practicing sports-an observation that helped in the design of our study.
Methods
We focused on subjects referred to our center by sports medicine doctors on suspicion of LQTS because of marked repolarization abnormalities on the ECG performed during the mandatory medical visit necessary in Italy to obtain the certificate of eligibility to practice sports. They all underwent our standard procedures involving both a resting and 12-lead ambulatory ECG, an exercise stress test, and genetic screening.
Results
There were 310 such consecutive subjects, all actively practicing sports with many hours of intensive weekly training. Of them, 111 had a normal ECG, different cardiac diseases, or were lost to follow-up and exited the study. Of the remaining 199, all with either clear QTc prolongation and/or typical repolarization abnormalities, 121 were diagnosed as affected based on combination of ECG abnormalities with positive genotyping (QTc, 482±35 ms). Genetic testing was negative in 78 subjects, but 45 were nonetheless diagnosed as affected by LQTS based on unequivocal ECG abnormalities (QTc, 472±33 ms). The remaining 33, entirely asymptomatic and with a negative family history, showed an unexpected and practically complete normalization of the ECG abnormalities (their QTc shortened from 492±37 to 423±25 ms [<0.001]; their Schwartz score went from 3.0 to 0.06) after detraining. They were considered not affected by congenital LQTS and are henceforth referred to as \"cases.\" Furthermore, among them, those who resumed similarly heavy physical training showed reappearance of the repolarization abnormalities.
Conclusion
It is not uncommon to suspect LQTS among individuals actively practicing sports based on marked repolarization abnormalities. Among those who are genotype-negative, >40% normalize their ECG after detraining, but the abnormalities tend to recur with resumption of training. These individuals are not affected by congenital LQTS but could have a form of acquired LQTS. Care should be exercised to avoid diagnostic errors.



Circulation: 21 Dec 2020; 142:2405-2415
Dagradi F, Spazzolini C, Castelletti S, Pedrazzini M, ... Crotti L, Schwartz PJ
Circulation: 21 Dec 2020; 142:2405-2415 | PMID: 33073610
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Abstract

Redox-Resistant SERCA [Sarco(endo)plasmic Reticulum Calcium ATPase] Attenuates Oxidant-Stimulated Mitochondrial Calcium and Apoptosis in Cardiac Myocytes and Pressure Overload-Induced Myocardial Failure in Mice.

Goodman JB, Qin F, Morgan RJ, Chambers JM, ... Cohen RA, Colucci WS
Background
SERCA [sarco(endo)plasmic reticulum calcium ATPase] is regulated by oxidative posttranslational modifications at cysteine 674 (C674). Because sarcoplasmic reticulum (SR) calcium has been shown to play a critical role in mediating mitochondrial dysfunction in response to reactive oxygen species, we hypothesized that SERCA oxidation at C674 would modulate the effects of reactive oxygen species on mitochondrial calcium and mitochondria-dependent apoptosis in cardiac myocytes.
Methods
Adult rat ventricular myocytes expressing wild-type SERCA2b or a redox-insensitive mutant in which C674 is replaced by serine (C674S) were exposed to HO (100 µmol/Lμ). Free mitochondrial calcium concentration was measured in adult rat ventricular myocytes with a genetically targeted fluorescent probe, and SR calcium content was assessed by measuring caffeine-stimulated release. Mice with heterozygous knock-in of the SERCA C674S mutation were subjected to chronic ascending aortic constriction.
Results
In adult rat ventricular myocytes expressing wild-type SERCA, HO caused a 25% increase in mitochondrial calcium concentration that was associated with a 50% decrease in SR calcium content, both of which were prevented by the ryanodine receptor inhibitor tetracaine. In cells expressing the C674S mutant, basal SR calcium content was decreased by 31% and the HO-stimulated rise in mitochondrial calcium concentration was attenuated by 40%. In wild-type cells, HO caused cytochrome c release and apoptosis, both of which were prevented in C674S-expressing cells. In myocytes from SERCA knock-in mice, basal SERCA activity and SR calcium content were decreased. To test the effect of C674 oxidation on apoptosis in vivo, SERCA knock-in mice were subjected to chronic ascending aortic constriction. In wild-type mice, ascending aortic constriction caused myocyte apoptosis, LV dilation, and systolic failure, all of which were inhibited in SERCA knock-in mice.
Conclusions
Redox activation of SERCA C674 regulates basal SR calcium content, thereby mediating the pathologic reactive oxygen species-stimulated rise in mitochondrial calcium required for myocyte apoptosis and myocardial failure.



Circulation: 21 Dec 2020; 142:2459-2469
Goodman JB, Qin F, Morgan RJ, Chambers JM, ... Cohen RA, Colucci WS
Circulation: 21 Dec 2020; 142:2459-2469 | PMID: 33076678
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Abstract

Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase.

Xiao L, Salem JE, Clauss S, Hanley A, ... Ellinor PT, Milan DJ
Background
Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood.
Methods
We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF.
Results
We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7; <0.0001).
Conclusions
These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215.



Circulation: 21 Dec 2020; 142:2443-2455
Xiao L, Salem JE, Clauss S, Hanley A, ... Ellinor PT, Milan DJ
Circulation: 21 Dec 2020; 142:2443-2455 | PMID: 33092403
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Abstract

Association of Baseline and Longitudinal Changes in Body Composition Measures With Risk of Heart Failure and Myocardial Infarction in Type 2 Diabetes: Findings From the Look AHEAD Trial.

Patel KV, Bahnson JL, Gaussoin SA, Johnson KC, ... Pandey A,
Background
Intentional weight loss is associated with lower risk of heart failure (HF) and atherosclerotic cardiovascular disease among patients with type 2 diabetes. However, the contribution of baseline measures and longitudinal changes in fat mass (FM), lean mass (LM), and waist circumference (WC) to the risk of HF and myocardial infarction (MI) in type 2 diabetes is not well established.
Methods
Adults from the Look AHEAD trial (Action for Health in Diabetes) without prevalent HF were included. FM and LM were predicted using validated equations and compared with dual-energy x-ray absorptiometry measurements in a subgroup. Adjusted Cox models were used to evaluate the associations of baseline and longitudinal changes in FM, LM, and WC over 1- and 4-year follow-up with risk of overall HF, HF with preserved ejection fraction (EF; EF ≥50%), HF with reduced EF (EF <50%), and MI.
Results
Among 5103 participants, there were 257 incident HF events over 12.4 years of follow-up. Predicted and measured FM/LM were highly correlated (=0.87-0.90; n=1369). FM and LM decreased over 4-year follow-up with greater declines in the intensive lifestyle intervention arm. In adjusted analysis, baseline body composition measures were not significantly associated with HF risk. Decline in FM and WC, but not LM, over 1 year were each significantly associated with lower risk of overall HF (adjusted hazard ratio per 10% decrease in FM, 0.80 [95% CI, 0.68-0.95]; adjusted hazard ratio per 10% decrease in WC, 0.77 [95% CI, 0.62-0.95]). Decline in FM was significantly associated with lower risk of both HF subtypes. In contrast, decline in WC was significantly associated with lower risk of HF with preserved EF but not HF with reduced EF. Similar patterns of association were observed for 4-year changes in body composition and HF risk. Longitudinal changes in body composition were not significantly associated with risk of MI.
Conclusions
In adults with type 2 diabetes, a lifestyle intervention is associated with significant loss of FM and LM. Declines in FM and WC, but not LM, were each significantly associated with lower risk of HF but not MI. Furthermore, decline in WC was significantly associated with lower risk of HF with preserved EF but not HF with reduced EF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00017953.



Circulation: 21 Dec 2020; 142:2420-2430
Patel KV, Bahnson JL, Gaussoin SA, Johnson KC, ... Pandey A,
Circulation: 21 Dec 2020; 142:2420-2430 | PMID: 33164570
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Abstract

2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

, Ommen SR, Mital S, Burke MA, ... Semsarian C, Sorajja P

Aim This executive summary of the hypertrophic cardiomyopathy clinical practice guideline provides recommendations and algorithms for clinicians to diagnose and manage hypertrophic cardiomyopathy in adult and pediatric patients as well as supporting documentation to encourage their use. Methods A comprehensive literature search was conducted from January 1, 2010, to April 30, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases. Structure Many recommendations from the earlier hypertrophic cardiomyopathy guidelines have been updated with new evidence or a better understanding of earlier evidence. This summary operationalizes the recommendations from the full guideline and presents a combination of diagnostic work-up, genetic and family screening, risk stratification approaches, lifestyle modifications, surgical and catheter interventions, and medications that constitute components of guideline directed medical therapy. For both guideline-directed medical therapy and other recommended drug treatment regimens, the reader is advised to follow dosing, contraindications and drug-drug interactions based on product insert materials.



Circulation: 21 Dec 2020; 142:e533-e557
, Ommen SR, Mital S, Burke MA, ... Semsarian C, Sorajja P
Circulation: 21 Dec 2020; 142:e533-e557 | PMID: 33215938
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Abstract

Circular RNA CircMAP3K5 Acts as a MicroRNA-22-3p Sponge to Promote Resolution of Intimal Hyperplasia via TET2-Mediated SMC Differentiation.

Zeng Z, Xia L, Fan S, Zheng J, ... Liu R, Tang WH

Aberrant expression of circular RNA (CircRNA) contributes to human diseases. CircRNAs regulate gene expression by sequestering specific microRNAs (miRNAs). In this study, we investigated whether CircMAP3K5 could act as a competing endogenous miR-22-3p sponge and regulate neointimal hyperplasia.CircRNA profiling from genome-wide RNA sequencing data was compared between human coronary artery smooth muscle cells (HCASMCs) treated with or without PDGF. Expression levels of circular MAP3K5 (CircMAP3K5) was assessed in human coronary arteries from autopsies on patients with dilated cardiomyopathy (DCM) or coronary heart disease (CHD). The role of CircMAP3K5 in intimal hyperplasia was further investigated in mice with AAV9-mediated CircMAP3K5 transfection. SMC-specific Tet2 knockout mice and global miR-22-3p knockout mice were used to delineate the mechanism by which CircMAP3K5 attenuated neointimal hyperplasia using the femoral arterial wire injury model.RNA sequencing demonstrated that treatment with PDGF-BB significantly reduced expression of CircMAP3K5 in HCASMCs. Wire-injured mouse femoral arteries and diseased arteries from CHD patients (where PDGF-BB is increased) confirmed in vivo downregulation of CircMAP3K5 associated with injury and disease. Lentivirus-mediated overexpression of CircMAP3K5 inhibited the proliferation of HCASMCs. In vivo AAV9-mediated transfection of CircMap3k5 specifically inhibited SMC proliferation in the wire-injured mouse arteries, resulting in reduced neointima formation. Using a luciferase reporter assay and RNA pull-down, CircMAP3K5 was found to sequester miR-22-3p, which in turn inhibited the expression of TET2. Both in vitro and in vivo results demonstrate that the loss of miR-22-3p recapitulated the anti-proliferative effect of CircMap3k5 on VSMCs. In SMC-specific Tet2 knockout mice, loss of Tet2 abolished the CircMap3k5-mediated anti-proliferative effect on VSMCs.We identify CircMAP3K5 as a master regulator of TET2-mediated VSMC differentiation. Targeting the CircMAP3K5/miR-22-3p/TET2 axis may provide a potential therapeutic strategy for diseases associated with intimal hyperplasia including restenosis and atherosclerosis.



Circulation: 18 Dec 2020; epub ahead of print
Zeng Z, Xia L, Fan S, Zheng J, ... Liu R, Tang WH
Circulation: 18 Dec 2020; epub ahead of print | PMID: 33207953
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Abstract

Central Command and the Regulation of Exercise Heart Rate Response in Heart Failure with Preserved Ejection Fraction.

Sarma S, Howden E, Lawley J, Samels M, Levine BD

Chronotropic incompetence (CI) is common in HFpEF and is linked to impaired aerobic capacity. Whether upstream autonomic signaling pathways responsible for raising exercise heart rate (HR) are impaired in HFpEF is unknown. We investigated the integrity of central command and muscle metaboreceptor function, two predominant mechanisms responsible for exertional increases in HR, in HFpEF and senior control subjects.Fourteen healthy, senior controls (7M,7F) and 20 carefully screened HFpEF patients (8M,12F) underwent cardiopulmonary exercise testing (peak VO) and static handgrip exercise at 40% of maximal voluntary contraction (MVC) to fatigue with post-exercise circulatory arrest (PECA) for 2 minutes to assess central command and metaboreceptor function respectively.Peak VO (13.1 ± 3.4 vs 22.7 ± 4.0 ml/kg/min; p<0.001) and HR (122 ± 20 vs 155 ± 14 bpm; p<0.001) were lower in HFpEF than senior controls. There were no significant differences in peak HR response during static handgrip between groups (HFpEF vs controls: 90 ± 13 vs 93 ± 10 bpm; p=0.49). Metaboreceptor function defined as mean arterial blood pressure at the end of PECA was also not significantly different between groups.Central command (vagally mediated) and metaboreceptor function (sympathetically mediated) in patients with HFpEF were not different from healthy senior controls despite significantly lower peak whole-body exercise heart rates. These results demonstrate key reflex autonomic pathways regulating exercise heart rate responsiveness are intact in HFpEF.



Circulation: 17 Dec 2020; epub ahead of print
Sarma S, Howden E, Lawley J, Samels M, Levine BD
Circulation: 17 Dec 2020; epub ahead of print | PMID: 33205661
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Abstract

BMP9 and BMP10 Act Directly on Vascular Smooth Muscle Cells for Generation and Maintenance of the Contractile State.

Wang L, Rice M, Swist S, Kubin T, ... Schneider A, Braun T

Vascular smooth muscle cells (VSMCs) show a remarkable phenotypic plasticity allowing acquisition of contractile or synthetic states but critical information is missing about the physiological signals, promoting formation and maintenance of contractile VSMCs . BMP9 and BMP10 are known to regulate endothelial quiescence after secretion from the liver and right atrium, whereas a direct role in the regulation of VSMCs was not investigated. Here, we studied the role of BMP9 and BMP10 for controlling formation of contractile VSMCs.We generated several cell type-specific loss- and gain-of-function transgenic mouse models to investigate the physiological role of BMP9, BMP10, ALK1 and SMAD7 . Morphometric assessments, expression analysis, blood pressure measurements, single molecule fluorescencehybridization (FISH) were performed together with analysis of isolated pulmonary VSMCs to unravel phenotypic and transcriptomic changes in response to absence or presence of BMP9 and BMP10.Concomitant genetic inactivation ofin the germ line andin the right atrium led to dramatic changes in vascular tone and diminution of the VSMC layer with attenuated contractility and decreased systemic as well as right ventricular systolic pressure (RVSP). , overexpression ofin endothelial cells (ECs) of adult mice dramatically enhanced formation of contractile VSMCs and increased systemic blood pressure as well as RVSP. Likewise, BMP9/10 treatment induced an ALK1-dependent phenotypic switch from synthetic to contractile in pulmonary VSMCs. SMC specific overexpression ofcompletely suppressed differentiation and proliferation of VSMCs and reiterated defects observed in adultdouble mutants. Deletion ofin VSMCs recapitulated thephenotype in pulmonary but not in aortic and coronary arteries. Bulk expression analysis and single molecule RNA-FISH uncovered vessel bed-specific, heterogeneous expression of BMP type 1 receptors, explaining phenotypic differences in differentmutant vessel beds.Our study demonstrates that BMP9 and BMP10 act directly on VSMCs for induction and maintenance of their contractile state. Surprisingly, the effects of BMP9/10 in VSMCs are mediated by different combinations of BMP type 1 receptors in a vessel bed specific manner, offering new opportunities to manipulate blood pressure in the pulmonary circulation.



Circulation: 17 Dec 2020; epub ahead of print
Wang L, Rice M, Swist S, Kubin T, ... Schneider A, Braun T
Circulation: 17 Dec 2020; epub ahead of print | PMID: 33334130
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Abstract

Phospholemman Phosphorylation Regulates Vascular Tone, Blood Pressure and Hypertension in Mice and Man.

Boguslavskyi A, Tokar S, Prysyazhna O, Rudyk O, ... Fuller W, Shattock MJ

Background: While it has long been recognized that smooth muscle Na/K ATPase (NKA) modulates vascular tone and blood pressure (BP), the role of its accessory protein phopholemman (PLM) has not been characterized. The aim of this study was to test the hypothesis that PLM phosphorylation regulates vascular toneand this mechanism plays an important role in modulation of vascular function and BP in experimental modelsand in man. : PLM knock-in mice (PLM), in which PLM is rendered unphosphorylatable, were used to assess the role of PLM phosphorylation in vitro in aortic and mesenteric vessels using wire myography and membrane potential measurements.BP and regional blood flow were assessed using Doppler flow and telemetry in young (14-16 weeks) and old (57-60 weeks) wild-type (WT) and transgenic mice. : We searched human genomic databases for mutations in PLM in the region of the phosphorylation sites and performed analyses within two human data cohorts (UK Biobank and GoDARTS) to assess the impact of an identified SNP on BP. This SNP was expressed in HEK cells and its effect on PLM phosphorylation determined using Western Blotting.PLM phosphorylation at Ser63 and Ser68 limited vascular constriction in response to phenylephrine. This effect was blocked by ouabain. Prevention of PLM phosphorylation in the PLM mouse profoundly enhanced vascular responses to PE bothand . In ageing WT mice PLM was hypophosphorylated and this correlated with the development of ageing-induced essential hypertension. In man we identified a non-synonymous coding variant, single nucleotide polymorphism rs61753924, which causes the substitution R70C in PLM. In HEK cells the R70C mutation prevented PLM phosphorylation at Ser68. This variant\'s rare allele is significantly associated with increased BP in middle-aged men.These studies demonstrate the importance of PLM phosphorylation in the regulation of vascular tone and BP and suggest a novel mechanism, and therapeutic target, for ageing-induced essential hypertension in man.



Circulation: 17 Dec 2020; epub ahead of print
Boguslavskyi A, Tokar S, Prysyazhna O, Rudyk O, ... Fuller W, Shattock MJ
Circulation: 17 Dec 2020; epub ahead of print | PMID: 33334125
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Abstract

An Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction: The EPIC-HF Trial.

Allen LA, Venechuk G, McIlvennan CK, Page Ii RL, ... Buttrick P, Matlock DD

Major gaps exist in the routine initiation and dose up-titration of guideline-directed medical therapies (GDMT) for patients with heart failure with reduced ejection fraction (HFrEF). Without novel approaches to improve prescribing, the cumulative benefits of HFrEF treatment will be largely unrealized. Direct-to-consumer marketing and shared decision making reflect a culture where patients are increasingly involved in treatment choices, creating opportunities for prescribing interventions that engage patients.The Electronically delivered, Patient-activation tool for Intensification of medications for Chronic Heart Failure with reduced ejection fraction (EPIC-HF) trial randomized patients with HFrEF from a diverse health system to usual care versus patient-activation tools-a 3-minute video and 1-page checklist-delivered electronically 1 week prior, 3 days prior and 24 hours prior to a cardiology clinic visit. The tools encouraged patients to work collaboratively with their clinicians to \"make one positive change\" in HFrEF prescribing. The primary endpoint was the percent of patients with GDMT medication initiations and dose intensifications from immediately preceding the cardiology clinic visit to 30 days, compared to usual care during the same period.EPIC-HF enrolled 306 patients, 290 of whom attended a clinic visit during the study period: 145 were sent the patient-activation tools and 145 were controls. Median age was 65 years, 29% female, 11% black, 7% Hispanic, median ejection fraction 32%. Pre-clinic data revealed significant GDMT opportunities, with no patients on target doses of beta-blocker, sacubitril/valsartan, and mineralocorticoid receptor antagonists. From immediately preceding the cardiology clinic visit to 30 days later, 49.0% in the intervention and 29.7% in control experienced an initiation or intensification of their GDMT (p=0.001). The majority of these changes were made at the clinician encounter itself and involved dose uptitrations. There were no deaths, and no significant differences in hospitalization or emergency department visits at 30 days between groups.A patient-activation tool delivered electronically prior to a cardiology clinic visit improved clinician intensification of GDMT.URL: https://clinicaltrials.gov Unique Identifier: NCT03334188.



Circulation: 16 Dec 2020; epub ahead of print
Allen LA, Venechuk G, McIlvennan CK, Page Ii RL, ... Buttrick P, Matlock DD
Circulation: 16 Dec 2020; epub ahead of print | PMID: 33201741
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Abstract

2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

Otto CM, Nishimura RA, Bonow RO, Carabello BA, ... Thompson A, Toly C
Aim
This executive summary of the valvular heart disease guideline provides recommendations for clinicians to diagnose and manage valvular heart disease as well as supporting documentation to encourage their use.
Methods
A comprehensive literature search was conducted from January 1, 2010, to March 1, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, Cochrane, Agency for Healthcare Research and Quality Reports, and other selected database relevant to this guideline.
Structure
Many recommendations from the earlier valvular heart disease guidelines have been updated with new evidence and provides newer options for diagnosis and treatment of valvular heart disease. This summary includes only the recommendations from the full guideline which focus on diagnostic work-up, the timing and choice of surgical and catheter interventions, and recommendations for medical therapy. The reader is referred to the full guideline for graphical flow charts, text, and tables with additional details about the rationale for and implementation of each recommendation, and the evidence tables detailing the data considered in developing these guidelines.



Circulation: 16 Dec 2020:CIR0000000000000932; epub ahead of print
Otto CM, Nishimura RA, Bonow RO, Carabello BA, ... Thompson A, Toly C
Circulation: 16 Dec 2020:CIR0000000000000932; epub ahead of print | PMID: 33332149
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Impact:
Abstract

Emulating Randomized Clinical Trials with Nonrandomized Real-World Evidence Studies: First Results from the RCT DUPLICATE Initiative.

Franklin JM, Patorno E, Desai RJ, Glynn RJ, ... Gautam N, Schneeweiss S

Regulators are evaluating the use of non-interventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT-DUPLICATE initiative uses a structured process to design RWE studies emulating randomized controlled trials (RCTs) and compare results. Here, we report findings of the first 10 trial emulations, evaluating cardiovascular outcomes of antidiabetic or antiplatelet medications.We selected 3 active-controlled and 7 placebo-controlled RCTs for replication. Using patient-level claims data from US commercial and Medicare payers, we implemented inclusion/exclusion criteria, selected primary endpoints, and comparator populations to emulate those of each corresponding RCT. Within the trial-mimicking populations, we conducted propensity score matching to control for >120 pre-exposure confounders. All study parameters were prospectively defined and protocols registered before hazard ratios (HRs) and 95% confidence intervals (CIs) were computed. Success criteria for the primary analysis were pre-specified for each replication.Despite attempts to emulate RCT design as closely as possible, differences between the RCT and corresponding RWE study populations remained. The regulatory conclusions were equivalent in 6 of 10. The RWE emulations achieved a HR estimate that was within the 95% CI from the corresponding RCT in 8 of 10 studies. In 9 of 10, either the regulatory or estimate agreement success criteria were fulfilled. The largest differences in effect estimates were found for RCTs where second-generation sulfonylureas were used as a proxy for placebo regarding cardiovascular effects. Nine of 10 replications had a standardized difference between effect estimates of <2, which suggests differences within expected random variation.Agreement between RCT and RWE findings varies depending on which agreement metric is used. Interim findings indicate that selection of active comparator therapies with similar indications and use patterns enhances the validity of RWE. Even in the context of active comparators, concordance between RCT and RWE findings is not guaranteed, partially because trials are not emulated exactly. More trial emulations are needed to understand how often and in what contexts RWE findings match RCTs.URL: https://clinicaltrials.gov Unique Identifiers: NCT03936049, NCT04215523, NCT04215536, NCT03936010, NCT03936036, NCT03936062, NCT03936023, NCT03648424, NCT04237935, NCT04237922.



Circulation: 16 Dec 2020; epub ahead of print
Franklin JM, Patorno E, Desai RJ, Glynn RJ, ... Gautam N, Schneeweiss S
Circulation: 16 Dec 2020; epub ahead of print | PMID: 33327727
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Abstract

Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque.

Drobni ZD, Alvi RM, Taron J, Zafar A, ... Hoffmann U, Neilan TG
Background
Immune checkpoint inhibitors (ICIs) treat an expanding range of cancers. Consistent basic data suggest that these same checkpoints are critical negative regulators of atherosclerosis. Therefore, our objectives were to test whether ICIs were associated with accelerated atherosclerosis and a higher risk of atherosclerosis-related cardiovascular events.
Methods
The study was situated in a single academic medical center. The primary analysis evaluated whether exposure to an ICI was associated with atherosclerotic cardiovascular events in 2842 patients and 2842 controls matched by age, a history of cardiovascular events, and cancer type. In a second design, a case-crossover analysis was performed with an at-risk period defined as the 2-year period after and the control period as the 2-year period before treatment. The primary outcome was a composite of atherosclerotic cardiovascular events (myocardial infarction, coronary revascularization, and ischemic stroke). Secondary outcomes included the individual components of the primary outcome. In addition, in an imaging substudy (n=40), the rate of atherosclerotic plaque progression was compared from before to after the ICI was started. All study measures and outcomes were blindly adjudicated.
Results
In the matched cohort study, there was a 3-fold higher risk for cardiovascular events after starting an ICI (hazard ratio, 3.3 [95% CI, 2.0-5.5]; <0.001). There was a similar increase in each of the individual components of the primary outcome. In the case-crossover, there was also an increase in cardiovascular events from 1.37 to 6.55 per 100 person-years at 2 years (adjusted hazard ratio, 4.8 [95% CI, 3.5-6.5]; <0.001). In the imaging study, the rate of progression of total aortic plaque volume was >3-fold higher with ICIs (from 2.1%/y before 6.7%/y after). This association between ICI use and increased atherosclerotic plaque progression was attenuated with concomitant use of statins or corticosteroids.
Conclusions
Cardiovascular events were higher after initiation of ICIs, potentially mediated by accelerated progression of atherosclerosis. Optimization of cardiovascular risk factors and increased awareness of cardiovascular risk before, during, and after treatment should be considered among patients on an ICI.



Circulation: 14 Dec 2020; 142:2299-2311
Drobni ZD, Alvi RM, Taron J, Zafar A, ... Hoffmann U, Neilan TG
Circulation: 14 Dec 2020; 142:2299-2311 | PMID: 33003973
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Impact:
Abstract

Epigenetic Reader BRD4 (Bromodomain-Containing Protein 4) Governs Nucleus-Encoded Mitochondrial Transcriptome to Regulate Cardiac Function.

Kim SY, Zhang X, Schiattarella GG, Altamirano F, ... Gillette TG, Hill JA
Background
BET (bromodomain and extraterminal) epigenetic reader proteins, in particular BRD4 (bromodomain-containing protein 4), have emerged as potential therapeutic targets in a number of pathological conditions, including cancer and cardiovascular disease. Small-molecule BET protein inhibitors such as JQ1 have demonstrated efficacy in reversing cardiac hypertrophy and heart failure in preclinical models. Yet, genetic studies elucidating the biology of BET proteins in the heart have not been conducted to validate pharmacological findings and to unveil potential pharmacological side effects.
Methods
By engineering a cardiomyocyte-specific BRD4 knockout mouse, we investigated the role of BRD4 in cardiac pathophysiology. We performed functional, transcriptomic, and mitochondrial analyses to evaluate BRD4 function in developing and mature hearts.
Results
Unlike pharmacological inhibition, loss of BRD4 protein triggered progressive declines in myocardial function, culminating in dilated cardiomyopathy. Transcriptome analysis of BRD4 knockout mouse heart tissue identified early and specific disruption of genes essential to mitochondrial energy production and homeostasis. Functional analysis of isolated mitochondria from these hearts confirmed that BRD4 ablation triggered significant changes in mitochondrial electron transport chain protein expression and activity. Computational analysis identified candidate transcription factors participating in the BRD4-regulated transcriptome. In particular, estrogen-related receptor α, a key nuclear receptor in metabolic gene regulation, was enriched in promoters of BRD4-regulated mitochondrial genes.
Conclusions
In aggregate, we describe a previously unrecognized role for BRD4 in regulating cardiomyocyte mitochondrial homeostasis, observing that its function is indispensable to the maintenance of normal cardiac function.



Circulation: 14 Dec 2020; 142:2356-2370
Kim SY, Zhang X, Schiattarella GG, Altamirano F, ... Gillette TG, Hill JA
Circulation: 14 Dec 2020; 142:2356-2370 | PMID: 33113340
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Impact:
Abstract

Call to Action: Structural Racism as a Fundamental Driver of Health Disparities: A Presidential Advisory From the American Heart Association.

Churchwell K, Elkind MSV, Benjamin RM, Carson AP, ... Williams O,

Structural racism has been and remains a fundamental cause of persistent health disparities in the United States. The coronavirus disease 2019 (COVID-19) pandemic and the police killings of George Floyd, Breonna Taylor, and multiple others have been reminders that structural racism persists and restricts the opportunities for long, healthy lives of Black Americans and other historically disenfranchised groups. The American Heart Association has previously published statements addressing cardiovascular and cerebrovascular risk and disparities among racial and ethnic groups in the United States, but these statements have not adequately recognized structural racism as a fundamental cause of poor health and disparities in cardiovascular disease. This presidential advisory reviews the historical context, current state, and potential solutions to address structural racism in our country. Several principles emerge from our review: racism persists; racism is experienced; and the task of dismantling racism must belong to all of society. It cannot be accomplished by affected individuals alone. The path forward requires our commitment to transforming the conditions of historically marginalized communities, improving the quality of housing and neighborhood environments of these populations, advocating for policies that eliminate inequities in access to economic opportunities, quality education, and health care, and enhancing allyship among racial and ethnic groups. Future research on racism must be accelerated and should investigate the joint effects of multiple domains of racism (structural, interpersonal, cultural, anti-Black). The American Heart Association must look internally to correct its own shortcomings and advance antiracist policies and practices regarding science, public and professional education, and advocacy. With this advisory, the American Heart Association declares its unequivocal support of antiracist principles.



Circulation: 14 Dec 2020; 142:e454-e468
Churchwell K, Elkind MSV, Benjamin RM, Carson AP, ... Williams O,
Circulation: 14 Dec 2020; 142:e454-e468 | PMID: 33170755
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Impact:
Abstract

BRD4 (Bromodomain-Containing Protein 4) Interacts with GATA4 (GATA Binding Protein 4) to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes.

Padmanabhan A, Alexanian M, Linares-Saldana R, González-Terán B, ... Jain R, Srivastava D
Background
Gene regulatory networks control tissue homeostasis and disease progression in a cell type-specific manner. Ubiquitously expressed chromatin regulators modulate these networks, yet the mechanisms governing how tissue specificity of their function is achieved are poorly understood. BRD4 (bromodomain-containing protein 4), a member of the BET (bromo- and extraterminal domain) family of ubiquitously expressed acetyl-lysine reader proteins, plays a pivotal role as a coactivator of enhancer signaling across diverse tissue types in both health and disease and has been implicated as a pharmacological target in heart failure. However, the cell-specific role of BRD4 in adult cardiomyocytes remains unknown.
Methods
We combined conditional mouse genetics, unbiased transcriptomic and epigenomic analyses, and classic molecular biology and biochemical approaches to understand the mechanism by which BRD4 in adult cardiomyocyte homeostasis.
Results
Here, we show that cardiomyocyte-specific deletion ofin adult mice leads to acute deterioration of cardiac contractile function with mutant animals demonstrating a transcriptomic signature characterized by decreased expression of genes critical for mitochondrial energy production. Genome-wide occupancy data show that BRD4 enriches at many downregulated genes (including the master coactivators , and their downstream targets) and preferentially colocalizes with GATA4 (GATA binding protein 4), a lineage-determining cardiac transcription factor not previously implicated in regulation of adult cardiac metabolism. BRD4 and GATA4 form an endogenous complex in cardiomyocytes and interact in a bromodomain-independent manner, revealing a new functional interaction partner for BRD4 that can direct its locus and tissue specificity.
Conclusions
These results highlight a novel role for a BRD4-GATA4 module in cooperative regulation of a cardiomyocyte-specific gene program governing bioenergetic homeostasis in the adult heart.



Circulation: 14 Dec 2020; 142:2338-2355
Padmanabhan A, Alexanian M, Linares-Saldana R, González-Terán B, ... Jain R, Srivastava D
Circulation: 14 Dec 2020; 142:2338-2355 | PMID: 33094644
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Abstract

Ticagrelor or Prasugrel in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

Aytekin A, Ndrepepa G, Neumann FJ, Menichelli M, ... Schüpke S, Kastrati A
Background
Data on the comparative efficacy and safety of ticagrelor versus prasugrel in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention are limited. We assessed the efficacy and safety of ticagrelor versus prasugrel in a head-to-head comparison in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention.
Methods
In this prespecified subgroup analysis, we included 1653 patients with ST-segment-elevation myocardial infarction randomized to receive ticagrelor or prasugrel in the setting of the ISAR REACT-5 trial (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5). The primary end point was the incidence of death, myocardial infarction, or stroke at 1 year after randomization. The secondary end point was the incidence of bleeding defined as BARC (Bleeding Academic Research Consortium) type 3 to 5 bleeding at 1 year after randomization.
Results
The primary end point occurred in 83 patients (10.1%) in the ticagrelor group and in 64 patients (7.9%) in the prasugrel group (hazard ratio, 1.31 [95% CI, 0.95-1.82]; =0.10). One-year incidence of all-cause death (4.9% versus 4.7%; =0.83), stroke (1.3% versus 1.0%; =0.46), and definite stent thrombosis (1.8% versus 1.0%; =0.15) did not differ significantly in patients assigned to ticagrelor or prasugrel. One-year incidence of myocardial infarction (5.3% versus 2.8%; hazard ratio, 1.95 [95% CI, 1.18-3.23]; =0.010) was higher with ticagrelor than with prasugrel. BARC type 3 to 5 bleeding occurred in 46 patients (6.1%) in the ticagrelor group and in 39 patients (5.1%) in the prasugrel group (hazard ratio, 1.22 [95% CI, 0.80-1.87]; =0.36).
Conclusions
In patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention, there was no significant difference in the primary end point between prasugrel and ticagrelor. Ticagrelor was associated with a significant increase in the risk for recurrent myocardial infarction. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01944800.



Circulation: 14 Dec 2020; 142:2329-2337
Aytekin A, Ndrepepa G, Neumann FJ, Menichelli M, ... Schüpke S, Kastrati A
Circulation: 14 Dec 2020; 142:2329-2337 | PMID: 33115278
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Abstract

Effects of n-3 Fatty Acid Supplements in Elderly Patients after Myocardial Infarction: A Randomized Controlled Trial.

Kalstad AA, Myhre PL, Laake K, Tveit SH, ... Arnesen H,

High intake of marine n-3 polyunsaturated fatty acids (PUFA) has been associated with reduced risk of cardiovascular events; however, this has not been confirmed in patients with a recent acute myocardial infarction (AMI). Elderly patients are at particularly increased cardiovascular risk after MI, but few trials address this group specifically. Omega-3 fatty acids hold the potential to reduce cardiovascular events with limited adverse effects in this vulnerable group. The hypothesis was that daily addition of 1.8g n-3 PUFA to standard of care secondary prophylaxis in elderly patients who have survived an AMI would reduce the risk of subsequent cardiovascular events during 2 years follow-up.The OMega-3 fatty acids in Elderly with Myocardial Infarction (OMEMI) trial is an investigator-initiated, multi-center, randomized clinical trial adding 1.8 g n-3 PUFA (930 mg EPA and 660 mg DHA) versus placebo (corn oil) daily to standard of care in 70-82 years old patients with recent (2-8 weeks) AMI. The primary endpoint was a composite of non-fatal AMI, unscheduled revascularization, stroke, all-cause death, heart failure hospitalization after two years. The secondary outcome was new atrial fibrillation. The safety outcome was major bleeding. Serum fatty acids were measured as biomarkers of adherence.In total, 1,027 patients were randomized. Follow-up data were available for 1,014 patients who were included in the intention-to-treat analysis. Mean ± SD age was 75±3.6 years, 294 (29%) were female and mean triglycerides were 111.4±61.9 mg/dL. The primary endpoint occurred in 108 (21.4%) patients on n-3 PUFA vs 102 (20.0%) on placebo (HR 1.08 [95%CI 0.82-1.41], p=0.60). The secondary endpoint occurred in 28 (7.2%) patients on n-3 PUFA vs 15 (4.0%) on placebo (1.84 [0.98 -3.45], p=0.06). Median changes in EPA and DHA were +87% and +16% for n-3 PUFA vs -13% and -8% for placebo. Major bleeding occurred in 54 (10.7%) and 56 (11.0%) in the n-3 PUFA and placebo groups, respectively (p=0.87). Similar results were found in per-protocol analysis (n=893).We could not detect reduction in clinical events in our elderly patients with a recent AMI, treated with 1.8 g n-3 PUFAs daily for 2 years.OMEMI Study; URL: https://clinicaltrials.gov Unique Identifier: NCT01841944.



Circulation: 14 Dec 2020; epub ahead of print
Kalstad AA, Myhre PL, Laake K, Tveit SH, ... Arnesen H,
Circulation: 14 Dec 2020; epub ahead of print | PMID: 33191772
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Abstract

Stroke Prevention in Atrial Fibrillation: Looking Forward.

Katsanos AH, Kamel H, Healey JS, Hart RG

Ischemic strokes related to atrial fibrillation are highly prevalent, presenting with severe neurologic syndromes and associated with high risk of recurrence. Although advances have been made in both primary and secondary stroke prevention for patients with atrial fibrillation, the long-term risks for stroke recurrence and bleeding complications from antithrombotic treatment remain substantial. We summarize the major advances in stroke prevention for patients with atrial fibrillation during the past 30 years and focus on novel diagnostic and treatment approaches currently under investigation in ongoing clinical trials. Non-vitamin K antagonist oral anticoagulants have been proven to be safer and equally effective compared with warfarin in stroke prevention for patients with nonvalvular atrial fibrillation. Non-vitamin K antagonist oral anticoagulants are being investigated for the treatment of patients with atrial fibrillation and rheumatic heart disease, for the treatment of patients with recent embolic stroke of undetermined source and indirect evidence of cardiac embolism, and in the prevention of vascular-mediated cognitive decline in patients with atrial fibrillation. Multiple clinical trials are assessing the optimal timing of non-vitamin K antagonist oral anticoagulant initiation after a recent ischemic stroke and the benefit:harm ratio of non-vitamin K antagonist oral anticoagulant treatment in patients with atrial fibrillation and history of previous intracranial bleeding. Ongoing trials are addressing the usefulness of left atrial appendage occlusion in both primary and secondary stroke prevention for patients with atrial fibrillation, including those with high risk of bleeding. The additive value of prolonged cardiac monitoring for subclinical atrial fibrillation detection through smartphone applications or implantable cardiac devices, together with the optimal medical management of individuals with covert paroxysmal atrial fibrillation, is a topic of intensive research interest. Colchicine treatment and factor XIa inhibition constitute 2 novel pharmacologic approaches that might provide future treatment options in the secondary prevention of cardioembolic stroke attributable to atrial fibrillation.



Circulation: 14 Dec 2020; 142:2371-2388
Katsanos AH, Kamel H, Healey JS, Hart RG
Circulation: 14 Dec 2020; 142:2371-2388 | PMID: 33315494
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Abstract

Effect of Prehospital Crushed Prasugrel Tablets in Patients With ST-Segment-Elevation Myocardial Infarction Planned for Primary Percutaneous Coronary Intervention: The Randomized COMPARE CRUSH Trial.

Vlachojannis GJ, Wilschut JM, Vogel RF, Lemmert ME, ... Van Mieghem NM, Smits PC
Background
Early treatment with a potent oral platelet P2Y inhibitor is recommended in patients presenting with ST-segment-elevation myocardial infarction scheduled to undergo primary percutaneous coronary intervention (pPCI). The impact on coronary reperfusion of crushed P2Y inhibitor tablets, which lead to more prompt and potent platelet inhibition, is unknown.
Methods
We conducted a randomized controlled, multicenter trial in the Netherlands, enrolling patients with ST-segment-elevation myocardial infarction scheduled to undergo pPCI. Patients were randomly allocated to receive in the ambulance, before transfer, a 60-mg loading dose of prasugrel either as crushed or integral tablets. The independent primary end points were thrombolysis in myocardial infarction (TIMI) 3 flow in the infarct-related artery at initial coronary angiography, and complete (≥70%) ST-segment resolution 1 hour after pPCI. The safety end points were TIMI major and Bleeding Academic Research Consortium ≥3 bleedings. Secondary end points included platelet reactivity and ischemic outcomes.
Results
A total of 727 patients were assigned to either crushed or integral tablets of prasugrel loading dose. The median time from study treatment to wire-crossing during pPCI was 57 (47-70) minutes. The primary end point TIMI 3 flow in the infarct-related artery before pPCI occurred in 31.0% in the crushed group versus 32.7% in the integral group (odds ratio, 0.92 [95% CI, 0.65-1.30], =0.64). Complete ST-segment resolution 1 hour after pPCI was present in 59.9% in the crushed group versus 57.3% in the integral group (odds ratio, 1.11 [95% CI, 0.78-1.58], =0.55). Platelet reactivity at the beginning of pPCI, measured as P2Y reactivity unit, differed significantly between groups (crushed, 192 [132-245] versus integral, 227 [184-254], ≤0.01). TIMI major and Bleeding Academic Research Consortium ≥3 bleeding occurred in 0% in the crushed group versus 0.8% in the integral group, and in 0.3% in the crushed group versus 1.1% in the integral group, respectively. There were no differences observed between groups regarding ischemic events at 30 days.
Conclusions
Prehospital administration of crushed prasugrel tablets does not improve TIMI 3 flow in the infarct-related artery before pPCI or complete ST-segment resolution 1 h after pPCI in patients presenting with ST-segment-elevation myocardial infarction scheduled for pPCI. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03296540.



Circulation: 14 Dec 2020; 142:2316-2328
Vlachojannis GJ, Wilschut JM, Vogel RF, Lemmert ME, ... Van Mieghem NM, Smits PC
Circulation: 14 Dec 2020; 142:2316-2328 | PMID: 33315489
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Abstract

Gender Based Differences in Outcomes among Resuscitated Patients with Out-of-Hospital Cardiac Arrest.

Mody P, Pandey A, Slutsky AS, Segar MW, ... Idris AH, Morrison L

Studies examining gender-based differences in outcomes of out-of-hospital cardiac arrest patients have demonstrated that despite a higher likelihood of return of spontaneous circulation, women do not have higher survival.Patients successfully resuscitated from out-of-hospital cardiac arrest enrolled in the Continuous Chest Compression trial were included. Hierarchical multivariable logistic regression models were constructed to evaluate the association between gender and survival after adjustment for age, gender, cardiac arrest rhythm, witnessed status, bystander cardiopulmonary resuscitation, episode location, epinephrine dose, emergency medical services response time and duration of resuscitation. Do Not Resuscitate (DNR) and withdrawal of life-sustaining therapy (WLST) order status were used to assess whether differences in post resuscitation outcomes were modified by baseline prognosis. The analysis was replicated among Amiodarone, Lidocaine, or Placebo Cardiac Arrest trial participants.Among 4,875 successfully resuscitated patients, 1,825 (37.4%) were women and 3,050 (62.6%) were men. Women were older (67.5 vs. 65.3 years), received less bystander cardiopulmonary resuscitation (49.1% vs. 54.9%), and had a lower proportion of cardiac arrests that were witnessed (55.1% vs. 64.5%) or had shockable rhythm (24.3% vs. 44.6%, p<0.001 for all). A significantly higher proportion of women received DNR orders (35.7% vs. 32.1%, p=0.009) and had WLST (32.8% vs. 29.8%, p=0.03). Discharge survival was significantly lower in women (22.5% vs. 36.3%, p<0.001, adjusted odds ratio [OR] 0.78, 95% confidence interval [C.I.] 0.66 - 0.93, p=0.005). The association between gender and discharge survival was modified by DNR and WLST order status such that women had significantly reduced discharge survival among patients who were not made DNR (31.3% vs. 49.9%, p=0.005, adjusted OR 0.74, 95% C.I. 0.60 - 0.91) or did not have WLST (32.3% vs. 50.7%, p=0.002, adjusted OR 0.73, 95% C.I. 0.60 - 0.89). In contrast, no gender difference in survival was noted among patients receiving a DNR order (6.7% vs. 7.4%, p=0.90) or had WLST (2.8% vs. 2.4%, p=0.93). Consistent patterns of association between gender and post-resuscitation outcomes were observed in the secondary cohort.Among resuscitated out-of-hospital cardiac arrest patients, discharge to survival was significantly lower in women compared with men especially among patients considered to have a favorable prognosis.



Circulation: 14 Dec 2020; epub ahead of print
Mody P, Pandey A, Slutsky AS, Segar MW, ... Idris AH, Morrison L
Circulation: 14 Dec 2020; epub ahead of print | PMID: 33317326
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Abstract

Coronary Optical Coherence Tomography and Cardiac Magnetic Resonance Imaging to Determine Underlying Causes of MINOCA in Women.

Reynolds HR, Maehara A, Kwong RY, Sedlak T, ... Zhong H, Hochman JS

Myocardial infarction with non-obstructive coronary arteries (MINOCA) occurs in 6-15% of MI and disproportionately affects women. Scientific statements recommend multi-modality imaging in MINOCA to define the underlying cause. We performed coronary optical coherence tomography (OCT) and cardiac magnetic resonance imaging (CMR) to assess mechanisms of MINOCA.In this prospective, multicenter, international, observational study, we enrolled women with a clinical diagnosis of MI. If invasive coronary angiography revealed <50% stenosis in all major arteries, multi-vessel OCT was performed, followed by CMR (cine imaging, late gadolinium enhancement, and T2-weighted imaging and/or T1 mapping). Angiography, OCT, and CMR were evaluated at blinded, independent core laboratories. Culprit lesions identified by OCT were classified as definite or possible. The CMR core laboratory identified ischemia-related and non-ischemic myocardial injury. Imaging results were combined to determine the mechanism of MINOCA, when possible.Among 301 women enrolled at 16 sites, 170 were diagnosed with MINOCA, of whom 145 had adequate OCT image quality for analysis; 116 of these underwent CMR. A definite or possible culprit lesion was identified by OCT in 46.2% (67/145) of participants, most commonly plaque rupture, intra-plaque cavity or layered plaque. CMR was abnormal in 74.1% (86/116) of participants. An ischemic pattern of CMR abnormalities (infarction or myocardial edema in a coronary territory) was present in 53.4% of participants undergoing CMR (62/116). A non-ischemic pattern of CMR abnormalities (myocarditis, takotsubo syndrome or non-ischemic cardiomyopathy) was present in 20.7% (24/116). A cause of MINOCA was identified in 84.5% of the women with multi-modality imaging (98/116), higher than with OCT alone (p<0.001) or CMR alone (p=0.001). An ischemic etiology was identified in 63.8% of women with MINOCA (74/116), a non-ischemic etiology was identified in 20.7% (24/116), and no mechanism was identified in 15.5% (18/116).Multi-modality imaging with coronary OCT and CMR identified potential mechanisms in 84.5% of women with a diagnosis of MINOCA, three-quarters of which were ischemic and one-quarter of which were non-ischemic, alternate diagnoses to MI. Identification of the etiology of MINOCA is feasible and has the potential to guide medical therapy for secondary prevention.URL: https://clinicaltrials.gov Unique Identifier: NCT02905357.



Circulation: 13 Dec 2020; epub ahead of print
Reynolds HR, Maehara A, Kwong RY, Sedlak T, ... Zhong H, Hochman JS
Circulation: 13 Dec 2020; epub ahead of print | PMID: 33191769
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Abstract

Mapping the Endothelial Cell -Sulfhydrome Highlights the Crucial Role of Integrin Sulfhydration in Vascular Function.

Bibli SI, Hu J, Looso M, Weigert A, ... Sigala F, Fleming I

In vascular endothelial cells, cysteine metabolism by the cystathionine γ lyase (CSE), generates hydrogen sulfide-related sulfane sulfur compounds (HS), that exert their biological actions via cysteine -sulfhydration of target proteins. This study set out to map the \"-sulfhydrome\" i.e. the spectrum of proteins targeted by HS in human endothelial cells.LC-MS/MS was used to identify S-sulfhydrated cysteines in endothelial cell proteins and β3 integrin intra-protein disulfide bond rearrangement. Functional studies included endothelial cell adhesion, shear stress-induced cell alignment, blood pressure measurements and flow-induced vasodilatation in endothelial cell-specific CSE knock out mice and a small collective of patients with endothelial dysfunction.Three paired sample sets were compared: (1) native human endothelial cells isolated from plaque-free mesenteric arteries (CSE activity high) and plaque-containing carotid arteries (CSE activity low), (2) cultured human endothelial cells kept under static conditions or exposed to fluid shear stress to decrease CSE expression, and (3) cultured endothelial cells exposed to shear stress to decrease CSE expression and treated with solvent or the slow-releasing HS donor, SG1002. The endothelial cell \"-sulfhydrome\" consisted of 3446 individual cysteine residues in 1591 proteins. The most altered family of proteins were the integrins and focusing on β3 integrin in detail we found that -sulfhydration affected intra-protein disulfide bond formation and was required for the maintenance of an extended-open conformation of the β leg. β3 integrin -sulfhydration was required for endothelial cell mechanotransductionas well as flow-induced dilatation in murine mesenteric arteries. In cultured cells, the loss of -sulfhydration impaired interactions between β3 integrin and Gα13, resulting in the constitutive activation of RhoA and impaired flow-induced endothelial cell realignment. In humans with atherosclerosis, endothelial function correlated with low HS generation, impaired flow-induced dilatation and a failure to detect β3 integrin -sulfhydration, all of which were rescued following the administration of an HS supplement.Vascular disease is associated with marked changes in the -sulfhydration of endothelial cell proteins involved in mediating responses to flow. Short term HS supplementation improved vascular reactivity in humans highlighting the potential of interfering with this pathway to treat vascular disease.



Circulation: 13 Dec 2020; epub ahead of print
Bibli SI, Hu J, Looso M, Weigert A, ... Sigala F, Fleming I
Circulation: 13 Dec 2020; epub ahead of print | PMID: 33307764
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Abstract

Effect of Empagliflozin on Left Ventricular Volumes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction (SUGAR-DM-HF).

Lee MMY, Brooksbank KJM, Wetherall K, Mangion K, ... Petrie MC, Sattar N

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF). However, their effects on cardiac structure and function in HFrEF are uncertain.We designed a multicenter randomized, double-blind, placebo-controlled trial to investigate the cardiac effects of empagliflozin in patients in NYHA functional class II to IV with a left ventricular (LV) ejection fraction ≤40% and type 2 diabetes or prediabetes. Patients were randomized 1:1 to empagliflozin 10 milligrams once daily or placebo, stratified by age (<65 and ≥65 years) and glycemic status (diabetes or prediabetes). The co-primary outcomes were change from baseline to 36 weeks in LV end-systolic volume indexed to body surface area (LVESVi) and LV global longitudinal strain (LV GLS) measured using cardiovascular magnetic resonance (CMR). Secondary efficacy outcomes included other CMR measures (LVEDVi, LVEF), diuretic intensification, symptoms (Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS)), 6-minute walk distance (6MWD), B-lines on lung ultrasound and biomarkers (including NT-proBNP).From April 2018 to August 2019, 105 patients were randomized: 77 (73.3%) male, mean age 68.7 [SD 11.1] years, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LVEF 32.5% [9.8%], and 81 (77.1%) NYHA II and 24 (22.9%) NYHA III. Patients received standard treatment for HFrEF. Compared with placebo, empagliflozin reduced LVESVi by 6.0 (-10.8 to -1.2) ml/m (p=0.015). There was no difference in LV GLS. Empagliflozin reduced LVEDVi by 8.2 (-13.7 to -2.6) ml/m (p=0.0042) and reduced NT-proBNP by 28 (2 to 47) %, p=0.038. There were no between-group differences in other CMR measures, KCCQ-TSS, 6MWD or B-lines.The SGLT2 inhibitor empagliflozin reduced LV volumes in patients with HFrEF and type 2 diabetes or prediabetes. Favorable reverse LV remodeling may be a mechanism by which SGLT2 inhibitors reduce HF hospitalization and mortality in HFrEF.URL: https://www.clinicaltrials.gov Unique Identifier: NCT03485092.



Circulation: 12 Dec 2020; epub ahead of print
Lee MMY, Brooksbank KJM, Wetherall K, Mangion K, ... Petrie MC, Sattar N
Circulation: 12 Dec 2020; epub ahead of print | PMID: 33186500
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Abstract

Myocardial Injury in Severe COVID-19 Compared to Non-COVID Acute Respiratory Distress Syndrome.

Metkus TS, Sokoll LJ, Barth AS, Czarny MJ, ... Trost JC, Hasan RK

Knowledge gaps remain in the epidemiology and clinical implications of myocardial injury in COVID-19. Our goal was to determine the prevalence and outcomes of myocardial injury in severe COVID-19 compared to acute respiratory distress syndrome (ARDS) unrelated to COVID-19.We included intubated COVID-19 patients from 5 hospitals between March 15 and June 11, 2020 with troponin levels assessed. We compared them to patients from a cohort study of myocardial injury in ARDS. We performed survival analysis with primary outcome of in-hospital death associated with myocardial injury. We performed linear regression to identify clinical factors associated with myocardial injury in COVID-19.Of 243 patients intubated with COVID-19, 51% had troponin levels > upper limit of normal (ULN). Chronic kidney disease, lactate, ferritin and fibrinogen were associated with myocardial injury. Mortality was 22.7% among COVID-19 patients with troponin < ULN and 61.5% for those with troponin levels > 10xULN (P< 0.001). The association of myocardial injury with mortality was not statistically significant after adjusting for age, sex and multi-system organ dysfunction. Compared to non-COVID ARDS patients, patients with COVID-19 were older with higher creatinine and less favorable vital signs. After adjustment, COVID-19 was associated with lower odds of myocardial injury compared to non-COVID ARDS (OR 0.55 95% CI 0.36-0.84, P=0.005).Myocardial injury in severe COVID-19 is a function of baseline comorbidities, advanced age and multisystem organ dysfunction similar to traditional ARDS. The adverse prognosis of myocardial injury in COVID-19 relates largely to multisystem organ involvement and critical illness.



Circulation: 12 Dec 2020; epub ahead of print
Metkus TS, Sokoll LJ, Barth AS, Czarny MJ, ... Trost JC, Hasan RK
Circulation: 12 Dec 2020; epub ahead of print | PMID: 33186055
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Abstract

Effect of Dapagliflozin on Clinical Outcomes in Patients with Chronic Kidney Disease, With and Without Cardiovascular Disease.

McMurray JJV, Wheeler DC, Stefánsson BV, Jongs N, ... Heerspink HJL,

Dapagliflozin reduces the risk of end-stage renal disease in patients with chronic kidney disease. We examined the relative risk of cardiovascular and kidney events in these patients and the effect of dapagliflozin on either type of event, taking account of history of cardiovascular disease.In the DAPA-CKD trial (Dapagliflozin And Prevention of Adverse Outcomes in Chronic Kidney Disease), 4304 participants with chronic kidney disease were randomized to dapagliflozin 10 mg once daily or placebo. The primary endpoint was a composite of sustained decline in estimated GFR ≥50%, end-stage kidney disease, or kidney or cardiovascular death. The secondary endpoints were a kidney composite outcome (primary endpoint, minus cardiovascular death), the composite of hospitalization for heart failure or cardiovascular death and all-cause death. In a prespecified subgroup analysis, we divided patients into primary and secondary prevention subgroups according to history of cardiovascular disease.Secondary prevention patients (n=1610; 37.4%) were older, more often male, had a higher blood pressure and body-mass index, and were more likely to have diabetes. Mean estimated glomerular filtration rate and median urinary albumin-to-creatinine ratio was similar in the primary and secondary prevention groups. The rates of adverse cardiovascular outcomes were higher in the secondary prevention group, but kidney failure occurred at the same rate in the primary and secondary prevention groups. Dapagliflozin reduced the risk of the primary composite outcome to a similar extent in both the primary (HR, 0.61 [95% CI, 0.48-0.78]) and secondary (0.61, 0.47-0.79) prevention groups (P-interaction=0.90). This was also true for the composite of heart failure hospitalization or cardiovascular death (0.67, 0.40-1.13 versus 0.70, 0.52-0.94, respectively, P-interaction=0.88), and all-cause (0.63, 0.41-0.98 versus 0.70, 0.51-0.95, respectively, P-interaction=0.71). Rates of adverse events were low overall and did not differ between patients with and without cardiovascular disease.Dapagliflozin reduced the risk of kidney failure, death from cardiovascular causes or hospitalization for heart failure, and prolonged survival, in people with chronic kidney disease, with or without type 2 diabetes, independently of the presence of concomitant cardiovascular diseaseURL: https://clinicaltrials.gov Unique Identifier: NCT03036150.



Circulation: 12 Dec 2020; epub ahead of print
McMurray JJV, Wheeler DC, Stefánsson BV, Jongs N, ... Heerspink HJL,
Circulation: 12 Dec 2020; epub ahead of print | PMID: 33186054
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Abstract

Clinical Application of a Novel Genetic Risk Score for Ischemic Stroke in Patients with Cardiometabolic Disease.

Marston NA, Patel PN, Kamanu FK, Nordio F, ... Sabatine MS, Ruff CT

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in five trials across the spectrum of cardiometabolic disease.Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48, SOLID-TIMI 52, SAVOR-TIMI 53, PEGASUS-TIMI 54, and FOURIER trials were included in this analysis. A set of 32 SNPs associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors.In 51,288 subjects across the five trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, increasing genetic risk was strongly and independently associated with increased risk for ischemic stroke (p-trend=0.009). When compared to individuals in the lowest third of genetic risk, individuals in the middle and top tertiles of genetic risk had adjusted hazard ratios of 1.15 (95% CI 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted HR for the top versus lowest tertile of 1.27 (95% CI 1.04-1.53), compared with an adjusted HR of 1.06 (95% CI 0.81-1.41) in subjects with prior stroke. In an exploratory analysis of patients with atrial fibrillation and CHADS-VASc of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHADS-VASc of 3.Across a broad spectrum of subjects with cardiometabolic disease, a 32-SNP GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHADS-VASc scores, the GRS identified patients with risk comparable to those with higher CHADS-VASc scores.



Circulation: 12 Dec 2020; epub ahead of print
Marston NA, Patel PN, Kamanu FK, Nordio F, ... Sabatine MS, Ruff CT
Circulation: 12 Dec 2020; epub ahead of print | PMID: 33185476
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Abstract

Oxidation of Protein Kinase A Regulatory Subunit PKARIα Protects Against Myocardial Ischemia-Reperfusion Injury by Inhibiting Lysosomal-Triggered Calcium Release.

Simon JN, Vrellaku B, Monterisi S, Chu SM, ... Eaton P, Casadei B

Kinase oxidation is a critical signalling mechanism through which changes in the intracellular redox state alter cardiac function. In the myocardium, type-1 protein kinase A (PKARIα) can be reversibly oxidized, forming interprotein disulfide bonds within the holoenzyme complex. However, the effect of PKARIα disulfide formation on downstream signaling in the heart, particularly under states of oxidative stress such as ischemia and reperfusion (I/R), remains unexplored.Atrial tissue obtained from patients before and after cardiopulmonary bypass and reperfusion and left ventricular (LV) tissue from mice subjected to I/R or sham surgery were used to assess PKARIα disulfide formation by immunoblot. To determine the impact of disulfide formation on PKARIα catalytic activity and sub-cellular localization, live-cell fluorescence imaging and stimulated emission depletion super-resolution microscopy were performed in prkar1 knock-out mouse embryonic fibroblasts, neonatal myocytes or adult LV myocytes isolated from \'redox dead\' (Cys17Ser) PKARIα knock-in mice and their wild-type littermates. Comparison of intracellular calcium dynamics between genotypes was assessed in fura2-loaded LV myocytes whereas I/R-injury was assessed ex vivo.In both humans and mice, myocardial PKARIα disulfide formation was found to be significantly increased (2-fold in humans, p=0.023; 2.4-fold in mice, p<0.001) in response to I/R in vivo. In mouse LV cardiomyocytes, disulfide-containing PKARIα was not found to impact catalytic activity, but instead led to enhanced A-kinase-anchoring protein (AKAP) binding with preferential localization of the holoenzyme to the lysosome. Redox-dependent regulation of lysosomal two pore channels (TPC) by PKARIα was sufficient to prevent global calcium release from the sarcoplasmic reticulum in LV myocytes, without affecting intrinsic ryanodine receptor leak or phosphorylation. Absence of I/R-induced PKARIα disulfide formation in \"redox dead\" knock-in mouse hearts resulted in larger infarcts (2-fold, p<0.001) and a concomitant reduction in LV contractile recovery (1.6-fold, p<0.001), which was prevented by administering the lysosomal TPC inhibitor Ned-19 at the time of reperfusion.Disulfide-modification targets PKARIα to the lysosome where it acts as a gatekeeper for TPC-mediated triggering of global calcium release. In the post-ischemic heart, this regulatory mechanism is critical for protecting from extensive injury and offers a novel target for the design of cardioprotective therapeutics.



Circulation: 12 Dec 2020; epub ahead of print
Simon JN, Vrellaku B, Monterisi S, Chu SM, ... Eaton P, Casadei B
Circulation: 12 Dec 2020; epub ahead of print | PMID: 33185461
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Abstract

Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status - Results from the EMPEROR-Reduced Trial.

Anker SD, Butler J, Filippatos G, Khan MS, ... Packer M,

Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events.Patients with class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes.Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (HbA1c 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio 0.72 [95% CI 0.60-0.87] and 0.78 [95% CI 0.64-0.97], respectively, interaction P =0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these endpoints, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (P-interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia.In the EMPEROR-Reduced trial, empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c.



Circulation: 10 Dec 2020; epub ahead of print
Anker SD, Butler J, Filippatos G, Khan MS, ... Packer M,
Circulation: 10 Dec 2020; epub ahead of print | PMID: 33175585
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Abstract

Role of IgE-FcεR1 in Pathological Cardiac Remodeling and Dysfunction.

Zhao H, Yang H, Geng C, Chen Y, ... Yan C, Wang J

Immunoglobulin E (IgE) belongs to a class of immunoglobulins involved in immune response to specific allergens. However, the roles of IgE and IgE receptor (FcεR1) in pathological cardiac remodeling and heart failure (HF) are unknown.Serum IgE levels and cardiac IgE receptor (FcεR1) expression were assessed in diseased hearts from human and mouse. The role of FcεR1 signaling in pathological cardiac remodeling was explored in vivo by FcεR1 genetic depletion, anti-IgE antibodies, and bone-marrow (BM) transplantation. The roles of IgE-FcεR1 pathway were further evaluated in vitro in primary cultured rat cardiomyocytes (CMs) and cardiac fibroblasts (CFs). RNA-seq and bioinformatic analyses were used to identify biochemical changes and signaling pathways that are regulated by IgE/FcεR1.Serum IgE levels were significantly elevated in patients with HF as well as in two mouse cardiac disease models induced by chronic pressure overload via transverse aortic contraction (TAC) and chronic angiotensin II (Ang II) infusion. Interestingly, FcεR1 expression levels were also significantly up-regulated in failing hearts from human and mouse. Blockade of the IgE-FcεR1 pathway by FcεR1 knockout alleviated TAC- or Ang II-induced pathological cardiac remodeling and/or dysfunction. Anti-IgE antibodies (including the clinical drug, omalizumab) also significantly alleviated Ang II-induced cardiac remodeling. BM transplantation experiments indicated that IgE-induced cardiac remodeling was mediated through non-BM-derived cells. FcεR1 was found to be expressed in both CMs and CFs. In cultured rat CMs, IgE-induced CM hypertrophy and hypertrophic marker expression were abolished by depleting FcεR1. In cultured rat CFs, IgE-induced CF activation and matrix protein production were also blocked by FcεR1 deficiency. RNA-seq and signaling pathway analyses revealed that transforming growth factor-β (TGF-β) may be a critical mediator and blocking TGF-β indeed alleviated IgE-induced cardiomyocyte hypertrophy and cardiac fibroblast activation .Our findings suggest that IgE induction plays a causative role in pathological cardiac remodeling, at least partially via the activation of IgE-FcεR1 signaling in CMs and CFs. Therapeutic strategies targeting the IgE-FcεR1 axis may be effective for managing IgE-mediated cardiac remodeling.



Circulation: 10 Dec 2020; epub ahead of print
Zhao H, Yang H, Geng C, Chen Y, ... Yan C, Wang J
Circulation: 10 Dec 2020; epub ahead of print | PMID: 33305586
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Abstract

Risk of Cardiovascular Outcomes in Type 2 Diabetes Patients Following Addition of SGLT2 Inhibitors Versus Sulfonylureas to Baseline GLP-IRA Therapy.

Dave CV, Kim SC, Goldfine AB, Glynn RJ, Tong A, Patorno E

Several glucagon-like peptide agonists (GLP-1RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2i) have demonstrated cardiovascular benefit in type 2 diabetes in large randomized controlled trials in patients with established cardiovascular disease or multiple risk factors. However, few trial participants were on both agents and it remains unknown whether the addition of SGLT2i to GLP-1RA therapy has further cardiovascular benefits.Patients adding either SGLT2i or sulfonylureas to baseline GLP-1RA were identified within 3 US claims datasets (2013-2018) and were 1:1 propensity score matched (PSM) adjusting for >95 baseline covariates. The primary outcomes were 1) composite cardiovascular endpoint (CCE; comprised of myocardial infarction, stroke, and all-cause mortality) and 2) heart failure hospitalization. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated in each dataset and pooled via fixed-effects meta-analysis.Among 12,584 propensity-score matched pairs (mean [SD] age 58.3 [10.9] year; male (48.2%)) across the 3 datasets, there were 107 CCE events [incidence rate per 1,000 person-years (IR) = 9.9; 95% CI: 8.1, 11.9] among SGLT2i initiators compared to 129 events [IR = 13.0; 95% CI: 10.9, 15.3] among sulfonylurea initiators corresponding to an adjusted pooled HR of 0.76 (95% CI: 0.59, 0.98); this decrease in CCE was driven by numerical decreases in the risk of MI (HR 0.71, 95% CI: 0.51, 1.003) and all-cause mortality (HR 0.68, 95% CI: 0.40, 1.14) but not stroke (HR 1.05, 95% CI: 0.62, 1.79). For the outcome of heart failure hospitalization, there were 141 events [IR = 13.0; 95% CI: 11.0, 15.2] among SGLT2i initiators versus 206 [IR = 20.8; 95% CI: 18.1, 23.8] events among sulfonylurea initiators corresponding to an adjusted pooled HR of 0.65 (95% CI: 0.50, 0.82).Risk of residual confounding cannot be fully excluded. Individual therapeutic agents within each class may have different magnitudes of effect. In this large real-world cohort of diabetic patients already on GLP-1RA, addition of SGLT2i - compared to addition of sulfonylurea - conferred greater cardiovascular benefit. The magnitude of the cardiovascular risk reduction was comparable to the benefit seen in cardiovascular outcome trials of SGLT2i versus placebo where baseline GLP-1RA use was minimal.



Circulation: 10 Dec 2020; epub ahead of print
Dave CV, Kim SC, Goldfine AB, Glynn RJ, Tong A, Patorno E
Circulation: 10 Dec 2020; epub ahead of print | PMID: 33302723
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Abstract

Treatment of Masked Hypertension with a Chinese Herbal Formula: A Randomized, Placebo-Controlled Trial.

Zhang DY, Cheng YB, Guo QH, Shan XL, ... Li Y, Wang JG
Background
Masked hypertension is associated with adverse cardiovascular outcomes. Nonetheless, no randomized controlled trials exist in the treatment of masked hypertension. The aim of this randomized, placebo-controlled trial was to investigate the efficacy and safety of blood pressure (BP)-lowering treatment with a Chinese herbal formula, gastrodia-uncaria granules, in patients with masked hypertension.
Methods
Patients with an office BP of <140/90 mm Hg and daytime ambulatory BP of 135 to 150 mm Hg systolic or 85 to 95 mm Hg diastolic were randomly assigned 1:1 to the treatment of gastrodia-uncaria granules or placebo 5 to 10 g twice daily for 4 weeks. The primary efficacy variable was the change in daytime ambulatory BP.
Results
At baseline, office and daytime BP of the 251 participants (mean age, 50.4 years; 53.4% men; mean body mass index 24.5 kg/m; and 2.8%, 1.6%, and 30.7% with cardiovascular disease, diabetes, and smoking, respectively) averaged 129/82 and 135/89 mm Hg, respectively. In the intention-to-treat analysis, daytime systolic/diastolic BP was reduced by 5.44/3.39 and 2.91/1.60 mm Hg in the gastrodia-uncaria granules and placebo groups, respectively. The between-group difference in BP reductions was significant for the daytime (2.52/1.79 mm Hg; ≤0.025) and 24-hour BP (2.33/1.49 mm Hg; ≤0.012), but not for the clinic and nighttime BPs (≥0.162). The per-protocol analysis in 229 patients produced similar results. Only 1 adverse event (sleepiness during the day) was reported, and no serious adverse event occurred.
Conclusions
BP-lowering treatment with Chinese traditional medicine gastrodia-uncaria granules is efficacious for patients with masked hypertension. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02156024.



Circulation: 09 Dec 2020; 142:1821-1830
Zhang DY, Cheng YB, Guo QH, Shan XL, ... Li Y, Wang JG
Circulation: 09 Dec 2020; 142:1821-1830 | PMID: 33019798
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Abstract

Assessing and Addressing Cardiovascular Health in LGBTQ Adults: A Scientific Statement From the American Heart Association.

Caceres BA, Streed CG, Corliss HL, Lloyd-Jones DM, ... Ross LM,

There is mounting evidence that lesbian, gay, bisexual, transgender, and queer or questioning (LGBTQ) adults experience disparities across several cardiovascular risk factors compared with their cisgender heterosexual peers. These disparities are posited to be driven primarily by exposure to psychosocial stressors across the life span. This American Heart Association scientific statement reviews the extant literature on the cardiovascular health of LGBTQ adults. Informed by the minority stress and social ecological models, the objectives of this statement were (1) to present a conceptual model to elucidate potential mechanisms underlying cardiovascular health disparities in LGBTQ adults, (2) to identify research gaps, and (3) to provide suggestions for improving cardiovascular research and care of LGBTQ people. Despite the identified methodological limitations, there is evidence that LGBTQ adults (particularly lesbian, bisexual, and transgender women) experience disparities across several cardiovascular health metrics. These disparities vary by race, sex, sexual orientation, and gender identity. Future research in this area should incorporate longitudinal designs, elucidate physiological mechanisms, assess social and clinical determinants of cardiovascular health, and identify potential targets for behavioral interventions. There is a need to develop and test interventions that address multilevel stressors that affect the cardiovascular health of LGBTQ adults. Content on LGBTQ health should be integrated into health professions curricula and continuing education for practicing clinicians. Advancing the cardiovascular health of LGBTQ adults requires a multifaceted approach that includes stakeholders from multiple sectors to integrate best practices into health promotion and cardiovascular care of this population.



Circulation: 09 Dec 2020; 142:e321-e332
Caceres BA, Streed CG, Corliss HL, Lloyd-Jones DM, ... Ross LM,
Circulation: 09 Dec 2020; 142:e321-e332 | PMID: 33028085
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Abstract

Endotoxinemia Accelerates Atherosclerosis via Electrostatic Charge-Mediated Monocyte Adhesion.

Schumski A, Ortega-Gómez A, Wichapong K, Winter C, ... Döring Y, Soehnlein O

Acute infection is a well-established risk factor of cardiovascular inflammation increasing the risk for a cardiovascular complication within the first weeks after infection. However, the nature of the processes underlying such aggravation remains unclear. Lipopolysaccharide (LPS) derived from Gram-negative bacteria is a potent activator of circulating immune cells including neutrophils, which foster inflammation through discharge of neutrophil extracellular traps (NETs). Here we utilize a model of endotoxinemia to link acute infection and subsequent neutrophil activation with acceleration of vascular inflammation.Acute infection was mimicked by injection of a single dose of LPS into hypercholesterolemic mice. Atherosclerosis burden was studied by histomorphometric analysis of the aortic root. Arterial myeloid cell adhesion was quantified by intravital microscopy.LPS treatment rapidly enhanced atherosclerotic lesion size by expansion of the lesional myeloid cell accumulation. LPS treatment led to the deposition of NETs along the arterial lumen and inhibition of NET release annulled lesion expansion during endotoxinemia, thus suggesting that NETs regulate myeloid cell recruitment. To study the mechanism of monocyte adhesion to NETs, we employedadhesion assays and biophysical approaches. In these experiments, NET-resident histone H2a attracted monocytes in a receptor-independent, surface charge-dependent fashion. Therapeutic neutralization of histone H2a by antibodies or bydesigned cyclical peptides enables us to reduce luminal monocyte adhesion and lesion expansion during endotoxinemia.Our study shows, that NET-associated histone H2a mediates charge-dependent monocyte adhesion to NETs and accelerates atherosclerosis during endotoxinemia.



Circulation: 09 Dec 2020; epub ahead of print
Schumski A, Ortega-Gómez A, Wichapong K, Winter C, ... Döring Y, Soehnlein O
Circulation: 09 Dec 2020; epub ahead of print | PMID: 33167684
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Abstract

Temporal Changes in Secondary Prevention and Cardiovascular Outcomes after Revascularization for Peripheral Arterial Disease in Denmark: A Nationwide Cohort Study.

Søgaard M, Nielsen PB, Skjøth F, Eldrup N, Larsen TB

Patients with peripheral arterial disease (PAD) are at increased risk of cardiovascular morbidity and mortality. Medical prevention with antithrombotic and statin therapies is a mainstay of treatment to prevent adverse outcomes; nevertheless, patients with PAD are often undertreated. This study described the temporal changes in medical prevention and adverse outcomes in a national cohort of patients with symptomatic PAD after revascularization.We identified all patients with a first open surgical or endovascular revascularization procedure in the lower extremities or abdomen in Denmark, from 2000 to 2016. We examined temporal changes in the use of aspirin, clopidogrel, and statins and one-year cause-specific hazard ratios (HR) for adverse clinical outcomes, after adjusting for procedure type, treatment indication, age, sex and cardiovascular risk factors. The analyses were performed overall, and within strata of index procedure (endovascular vs. surgical), treatment indication, age, sex, and high-risk comorbidities.Between 2000 and 2016, we identified 32,911 patients that underwent revascularization for symptomatic PAD. The mean age was 69 years and increased over time as did the burden of comorbidity. The cumulative incidence of medication use increased between 2000-2004 and 2013-2016, respectively, from 57.3% to 64.3% for aspirin, 3.6% to 24.8% for clopidogrel, and from 36.2% to 77.1% for statins. Concurrently, the one-year outcome rates declined. Compared with 2000-2004, the adjusted HRs in 2013-2016 were 0.73 (95% CI 0.62-0.84) for major adverse cardiovascular events, 0.92 (95% CI 0.85-1.00) for major adverse limb events, 0.60 (95% CI 0.48-0.74) for myocardial infarction, 0.94 (95% CI 0.75-1.18) for ischemic stroke, 0.92 (95% CI 0.75-1.12) for major bleeding, 0.54 (95% CI 0.39-0.76) for cardiovascular death, and 0.80 (95% CI 0.72-0.88) for all cause death. These improvements in prognosis were most prominent from 2000-2004 to 2005-2008, and occurred in all strata of index procedure, treatment indication, sex, age and comorbidity. In contrast, the adjusted HR for major amputations was 1.00 (95% CI 0.90-1.11), when comparing 2013-2016 to 2000-2004.Medical prevention of adverse events has increased considerably over time in patients that underwent revascularization for symptomatic PAD. This increase was accompanied by reductions in all adverse outcomes, except major amputations.



Circulation: 09 Dec 2020; epub ahead of print
Søgaard M, Nielsen PB, Skjøth F, Eldrup N, Larsen TB
Circulation: 09 Dec 2020; epub ahead of print | PMID: 33300375
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Abstract

Temporal Release of High-Sensitivity Cardiac Troponin T and I and Copeptin After Brief Induced Coronary Artery Balloon Occlusion in Humans.

Árnadottir Á, Pedersen S, Hasselbalch RB, Goetze JP, ... Bundgaard H, Iversen K

Cardiac troponins (cTns) are the cornerstone of diagnosing acute myocardial infarction (MI). There is limited knowledge on the duration of ischemia necessary to induce a measurable release of cTns or the very early release kinetics of cTns following an ischemic event. Copeptin may have a supplementary role in ruling out MI early. We investigated the release of cTns and copeptin in the first hours after experimental balloon-induced ischemia in humans.Thirty-four patients (median age, 60 years [IQR 51-64]; 15 males, 43%) with angiographically normal coronary arteries were randomized into four groups with different durations of induced myocardial ischemia (0, 30, 60, 90 seconds). Ischemia was induced by inflating a balloon in the left anterior descending artery (LAD) between the first and second diagonal branch. Blood was collected prior to balloon inflation (baseline) every 15 min for the first 3 h, and every 30 min for the next 3 h. The cTns were analyzed by three high-sensitivity assays: hs-cTnT (Roche), hs cTnI (Siemens), and hs-cTnI (Abbott). Copeptin was analyzed by a sandwich immunoluminometric assay.None of the patients had any complications. Increased cTn concentrations were detected by all three assays, and the magnitude of the increase was associated with the duration of ischemia. Increased hs-cTnI (Siemens) concentrations were first detectable 15 min after 90 s ischemia (median 43.7% increase) and increased more steeply and had a higher peak than the other assays. Copeptin levels did not significantly change. Using the cTnT, hs-cTnI (Siemens), and hs-cTnI (Abbott) concentrations at 0 min and 180 min, 1 (11%), 0, and 0 patients from the 60 s ischemia group and 5 (63%), 2 (25%), and 1 (11%) from the 90 s ischemia group, respectively, fulfilled criteria for a biochemical MI.This study is the first to report the early release kinetics of cTn concentrations following different durations of experimental coronary balloon occlusion in humans. All assays detected a cTn increase after only 30 seconds of ischemia. Hs-cTnI (Siemens) rose faster and reached a higher peak. Copeptin levels did not significantly change.URL: https://clinicaltrials.gov Unique Identifier: NCT03203057.



Circulation: 09 Dec 2020; epub ahead of print
Árnadottir Á, Pedersen S, Hasselbalch RB, Goetze JP, ... Bundgaard H, Iversen K
Circulation: 09 Dec 2020; epub ahead of print | PMID: 33297742
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Abstract

Cross-Priming Dendritic Cells Exacerbate Immunopathology after Ischemic Tissue Damage in the Heart.

Forte E, Perkins B, Sintou A, Kalkat HS, ... Rosenthal N, Sattler S

Ischemic heart disease is a leading cause of heart failure and despite advanced therapeutic options, morbidity and mortality rates remain high. Although acute inflammation in response to myocardial cell death has been extensively studied, subsequent adaptive immune activity and anti-heart autoimmunity may also contribute to the development of HF. After ischemic injury to the myocardium, dendritic cells (DC) respond to cardiomyocyte necrosis, present cardiac antigen to T cells and potentially initiate a persistent autoimmune response against the heart. Cross-priming DC have the ability to activate both CD4+ helper and CD8 cytotoxic T cells in response to necrotic cells and may thus be crucial players in exacerbating autoimmunity targeting the heart. This study investigates a role for cross-priming DC in post-MI myocardial impairment through presentation of self-antigen from necrotic cardiomyocytes to cytotoxic CD8 T cells.We induced type-2 myocardial infarction (MI)-like ischemic injury in the heart by treatment with a single high dose of the beta-adrenergic agonist isoproterenol. We characterized the DC population in the heart and mediastinal lymph nodes and analyzed long-term cardiac immunopathology and functional decline in wild type and -depleted mice lacking DC cross-priming function.A diverse DC population, including cross-priming DC, is present in the heart and activated after ischemic injury.mice deficient in DC cross-priming are protected from long-term immune-mediated myocardial damage and decline of cardiac function, likely due to dampened activation of cytotoxic CD8 T cells.Activation of cytotoxic CD8 T cells by cross-priming DC contributes to exacerbation of post-ischemic inflammatory damage of the myocardium and corresponding decline in cardiac function. Importantly, this provides novel therapeutic targets to prevent immune-mediated worsening of post-ischemic HF.



Circulation: 09 Dec 2020; epub ahead of print
Forte E, Perkins B, Sintou A, Kalkat HS, ... Rosenthal N, Sattler S
Circulation: 09 Dec 2020; epub ahead of print | PMID: 33297741
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Abstract

Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women.

Honigberg MC, Zekavat SM, Niroula A, Griffin GK, ... Ebert BL, Natarajan P

Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown.We included postmenopausal women from the UK Biobank (N=11,495) aged 40-70 years with whole exome sequences and from the Women\'s Health Initiative (WHI, N=8,111) aged 50-79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of (1) any CHIP and (2) CHIP with variant allele frequency (VAF) >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes mellitus, and hormone therapy use. Secondary analyses considered natural vs. surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease (CAD).The sample included 19,606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with vs. without a history of premature menopause was 8.8% vs. 5.5% (P<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: OR 1.36, 95% 1.10-1.68, P=0.004; CHIP with VAF >0.1: OR 1.40, 95% CI 1.10-1.79, P=0.007). Associations were larger for natural premature menopause (all CHIP: OR 1.73, 95% CI 1.23-2.44, P=0.001; CHIP with VAF >0.1: OR 1.91, 95% CI 1.30-2.80, P<0.001) but smaller and non-significant for surgical premature menopause. In gene-specific analyses, onlyCHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (HR associated with all CHIP: 1.36, 95% CI 1.07-1.73, P=0.012; HR associated with CHIP with VAF >0.1: 1.48, 95% CI 1.13-1.94, P=0.005).Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.



Circulation: 08 Dec 2020; epub ahead of print
Honigberg MC, Zekavat SM, Niroula A, Griffin GK, ... Ebert BL, Natarajan P
Circulation: 08 Dec 2020; epub ahead of print | PMID: 33161765
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Abstract

Acute Cardiovascular Manifestations in 286 Children with Multisystem Inflammatory Syndrome Associated with COVID-19 Infection in Europe.

Valverde I, Singh Y, Sanchez-de-Toledo J, Theocharis P, ... Miller O,

The aim of the study was to document cardiovascular clinical findings, cardiac imaging and laboratory markers in children presenting with the novel multisystem inflammatory syndrome (MIS-C) associated with COVID-19 infection.A real-time internet-based survey endorsed by the Association for European Paediatric and Congenital Cardiologists (AEPC) Working Groups for Cardiac Imaging and Cardiovascular Intensive Care. Inclusion criteria was children 0-18 years admitted to hospital between February 1 and June 6, 2020 with diagnosis of an inflammatory syndrome and acute cardiovascular complications.A total of 286 children from 55 centers in 17 European countries were included. The median age was 8.4 years (IQR 3.8-12.4 years) and 67% were males. The most common cardiovascular complications were shock, cardiac arrhythmias, pericardial effusion and coronary artery dilatation. Reduced left ventricular ejection fraction was present in over half of the patients and a vast majority of children had raised cardiac troponin (cTnT) when checked. The biochemical markers of inflammation were raised in majority of patients on admission: elevated CRP, serum ferritin, procalcitonin, NT-proBNP, IL-6 level and D-dimers. There was a statistically significant correlation between degree of elevation in cardiac and biochemical parameters and need for intensive care support (p <0.05). Polymerase chain reaction (PCR) for SARS-CoV-2 was positive in 33.6% while IgM and IgG antibodies were positive in 15.7% and IgG 43.6 % cases, respectively when checked. One child died in the study cohort.Cardiac involvement is common in children with multisystem inflammatory syndrome associated with Covid-19 pandemic. A majority of children have significantly raised levels of NT pro-BNP, ferritin, D-dimers and cardiac troponin in addition to high CRP and procalcitonin levels. Compared to adults with Covid-19, mortality in children with MIS-C is uncommon despite multi-system involvement, very elevated inflammatory markers and need for intensive care support.



Circulation: 08 Dec 2020; epub ahead of print
Valverde I, Singh Y, Sanchez-de-Toledo J, Theocharis P, ... Miller O,
Circulation: 08 Dec 2020; epub ahead of print | PMID: 33166189
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Abstract

Efficacy of Ertugliflozin on Heart Failure-Related Events in Patients With Type 2 Diabetes Mellitus and Established Atherosclerotic Cardiovascular Disease: Results of the VERTIS CV Trial.

Cosentino F, Cannon CP, Cherney DZI, Masiukiewicz U, ... McGuire DK,
Background
In patients with type 2 diabetes mellitus, sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure (HHF). We assessed the effect of ertugliflozin on HHF and related outcomes.
Methods
VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial), a double-blind, placebo-controlled trial, randomly assigned patients with type 2 diabetes mellitus and atherosclerotic cardiovascular (CV) disease to once-daily ertugliflozin 5 mg, 15 mg, or placebo. Prespecified secondary analyses compared ertugliflozin (pooled doses) versus placebo on time to first event of HHF and composite of HHF/CV death, overall and stratified by prespecified characteristics. Cox proportional hazards modeling was used with the Fine and Gray method to account for competing mortality risk, and Andersen-Gill modeling to analyze total (first+recurrent) HHF and total HHF/CV death events.
Results
A total of 8246 patients were randomly assigned to ertugliflozin (n=5499) or placebo (n=2747); n=1958 (23.7%) had a history of heart failure (HF) and n=5006 (60.7%) had pretrial ejection fraction (EF) available, including n=959 with EF ≤45%. Ertugliflozin did not significantly reduce first HHF/CV death (hazard ratio [HR], 0.88 [95% CI, 0.75-1.03]). Overall, ertugliflozin reduced risk for first HHF (HR, 0.70 [95% CI, 0.54-0.90]; =0.006). Previous HF did not modify this effect (HF: HR, 0.63 [95% CI, 0.44-0.90]; no HF: HR, 0.79 [95% CI, 0.54-1.15];interaction=0.40). In patients with HF, the risk reduction for first HHF was similar for those with reduced EF ≤45% versus preserved EF >45% or unknown. However, in the overall population, the risk reduction tended to be greater for those with EF ≤45% (HR, 0.48 [95% CI, 0.30-0.76]) versus EF >45% (HR, 0.86 [95% CI, 0.58-1.29]). Effect on risk for first HHF was consistent across most subgroups, but greater benefit of ertugliflozin was observed in 3 populations: baseline estimated glomerular filtration rate <60 mL·min·1.73 m, albuminuria, and diuretic use (eachinteraction <0.05). Ertugliflozin reduced total events of HHF (rate ratio, 0.70 [95% CI, 0.56-0.87]) and total HHF/CV death (rate ratio, 0.83 [95% CI, 0.72-0.96]).
Conclusions
In patients with type 2 diabetes mellitus, ertugliflozin reduced the risk for first and total HHF and total HHF/CV death, adding further support for the use of sodium-glucose cotransporter 2 inhibitors in primary and secondary prevention of HHF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01986881.



Circulation: 07 Dec 2020; 142:2205-2215
Cosentino F, Cannon CP, Cherney DZI, Masiukiewicz U, ... McGuire DK,
Circulation: 07 Dec 2020; 142:2205-2215 | PMID: 33026243
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Impact:
Abstract

Development of a Cardiac Sarcomere Functional Genomics Platform to Enable Scalable Interrogation of Human Variants.

Pettinato AM, Ladha FA, Mellert DJ, Legere N, ... Chen YS, Hinson JT
Background
Pathogenicvariants are a cause of hypertrophic and dilated cardiomyopathies, which promote heart failure by incompletely understood mechanisms. The precise functional significance for 87% ofvariants remains undetermined, in part, because of a lack of functional genomics studies. The knowledge of which and howvariants cause hypertrophic and dilated cardiomyopathies could improve heart failure risk determination, treatment efficacy, and therapeutic discovery, and provide new insights into cardiomyopathy pathogenesis, as well.
Methods
We created a toolkit of human induced pluripotent stem cell models and functional assays using CRISPR/Cas9 to studyvariant pathogenicity and pathophysiology. Using human induced pluripotent stem cell-derived cardiomyocytes in cardiac microtissue and single-cell assays, we functionally interrogated 51variants, including 30 pathogenic/likely pathogenic variants and 21 variants of uncertain significance. We used RNA sequencing to determine the transcriptomic consequences of pathogenicvariants and adapted CRISPR/Cas9 to engineer a transcriptional reporter assay to assist prediction ofvariant pathogenicity. We also studied variant-specific pathophysiology using a thin filament-directed calcium reporter to monitor changes in myofilament calcium affinity.
Results
Hypertrophic cardiomyopathy-associatedvariants caused increased cardiac microtissue contraction, whereas dilated cardiomyopathy-associated variants decreased contraction.variant-dependent changes in sarcomere contractile function induced graded regulation of 101 gene transcripts, including MAPK (mitogen-activated protein kinase) signaling targets, , and . We distinguished pathogenicvariants from wildtype controls using a sarcomere functional reporter engineered by inserting tdTomato into the endogenouslocus. On the basis of a combination ofreporter activity and cardiac microtissue contraction, our study provides experimental support for the reclassification of 2 pathogenic/likely pathogenic variants and 2 variants of uncertain significance.
Conclusions
Our study found that hypertrophic cardiomyopathy-associatedvariants increased cardiac microtissue contraction, whereas dilated cardiomyopathy-associated variants decreased contraction, both of which paralleled changes in myofilament calcium affinity. Transcriptomic changes, includinglevels, directly correlated with sarcomere function and can be used to predictvariant pathogenicity.



Circulation: 07 Dec 2020; 142:2262-2275
Pettinato AM, Ladha FA, Mellert DJ, Legere N, ... Chen YS, Hinson JT
Circulation: 07 Dec 2020; 142:2262-2275 | PMID: 33025817
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Abstract

Innate Immune Nod1/RIP2 Signaling Is Essential for Cardiac Hypertrophy but Requires Mitochondrial Antiviral Signaling Protein for Signal Transductions and Energy Balance.

Lin HB, Naito K, Oh Y, Farber G, ... Harper ME, Liu PP
Background
Cardiac hypertrophy is a key biological response to injurious stresses such as pressure overload and, when excessive, can lead to heart failure. Innate immune activation by danger signals, through intracellular pattern recognition receptors such as nucleotide-binding oligomerization domain 1 (Nod1) and its adaptor receptor-interacting protein 2 (RIP2), might play a major role in cardiac remodeling and progression to heart failure. We hypothesize that Nod1/RIP2 are major contributors to cardiac hypertrophy, but may not be sufficient to fully express the phenotype alone.
Methods
To elucidate the contribution of Nod1/RIP2 signaling to cardiac hypertrophy, we randomized Nod1, RIP2, or wild-type mice to transverse aortic constriction or sham operations. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice.
Results
Nod1 and RIP2 proteins were upregulated in the heart after transverse aortic constriction, and this was paralleled by increased expression of mitochondrial proteins, including mitochondrial antiviral signaling protein (MAVS). Nod1 and RIP2 mice subjected to transverse aortic constriction exhibited better survival, improved cardiac function, and decreased cardiac hypertrophy. Downstream signal transduction pathways that regulate inflammation and fibrosis, including NF (nuclear factor) κB and MAPK (mitogen-activated protein kinase)-GATA4/p300, were reduced in both Nod1 and RIP2 mice after transverse aortic constriction compared with wild-type mice. Coimmunoprecipitation of extracted cardiac proteins and confocal immunofluorescence microscopy showed that Nod1/RIP2 interaction was robust and that this complex also included MAVS as an essential component. Suppression of MAVS expression attenuated the complex formation, NF κB signaling, and myocyte hypertrophy. Interrogation of mitochondrial function compared in the presence or ablation of MAVS revealed that MAVS serves to suppress mitochondrial energy output and mediate fission/fusion related dynamic changes. The latter is possibly linked to mitophagy during cardiomyocytes stress, which may provide an intriguing link between innate immune activation and mitochondrial energy balance under stress or injury conditions.
Conclusions
We have identified that innate immune Nod1/RIP2 signaling is a major contributor to cardiac remodeling after stress. This process is critically joined by and regulated through the mitochondrial danger signal adapter MAVS. This novel complex coordinates remodeling, inflammatory response, and mitochondrial energy metabolism in stressed cardiomyocytes. Thus, Nod1/RIP2/MAVS signaling complex may represent an attractive new therapeutic approach toward heart failure.



Circulation: 07 Dec 2020; 142:2240-2258
Lin HB, Naito K, Oh Y, Farber G, ... Harper ME, Liu PP
Circulation: 07 Dec 2020; 142:2240-2258 | PMID: 33070627
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Abstract

Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization: Impact of Concomitant Clopidogrel on Efficacy and Safety.

Hiatt WR, Bonaca MP, Patel MR, Nehler MR, ... Szalay D, Bauersachs R
Background
The VOYAGER PAD trial (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) demonstrated superiority of rivaroxaban plus aspirin versus aspirin to reduce major cardiac and ischemic limb events after lower extremity revascularization. Clopidogrel is commonly used as a short-term adjunct to aspirin after endovascular revascularization. Whether clopidogrel modifies the efficacy and safety of rivaroxaban has not been described.
Methods
VOYAGER PAD was a phase 3, international, double-blind, placebo-controlled trial in patients with symptomatic PAD undergoing lower extremity revascularization randomized to rivaroxaban 2.5 mg twice daily plus 100 mg aspirin daily or rivaroxaban placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was TIMI (Thrombolysis in Myocardial Infarction) major bleeding, with International Society on Thrombosis and Haemostasis major bleeding a secondary safety outcome. Clopidogrel use was allowed at the discretion of the investigator for up to 6 months after the qualifying revascularization.
Results
Of the randomized patients, 3313 (50.6%) received clopidogrel for a median duration of 29.0 days. Over 3 years, the hazard ratio for the primary outcome of rivaroxaban versus placebo was 0.85 (95% CI, 0.71-1.01) with clopidogrel and 0.86 (95% CI, 0.73-1.01) without clopidogrel without statistical heterogeneity ( for interaction=0.92). Rivaroxaban resulted in an early apparent reduction in acute limb ischemia within 30 days (hazard ratio, 0.45 [95% CI, 0.14-1.46] with clopidogrel; hazard ratio, 0.48 [95% CI, 0.22-1.01] without clopidogrel;for interaction=0.93). Compared with aspirin, rivaroxaban increased TIMI major bleeding similarly regardless of clopidogrel use ( for interaction=0.71). With clopidogrel use >30 days, rivaroxaban was associated with more International Society on Thrombosis and Haemostasis major bleeding within 365 days (hazard ratio, 3.20 [95% CI, 1.44-7.13]) compared with shorter durations of clopidogrel ( for trend=0.06).
Conclusions
In the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use but with a trend for more International Society on Thrombosis and Haemostasis major bleeding with clopidogrel use >30 days than with a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization regardless of concomitant clopidogrel, with a short course (≤30 days) associated with less bleeding. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02504216.



Circulation: 07 Dec 2020; 142:2219-2230
Hiatt WR, Bonaca MP, Patel MR, Nehler MR, ... Szalay D, Bauersachs R
Circulation: 07 Dec 2020; 142:2219-2230 | PMID: 33138628
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Impact:
Abstract

Personal-Level Protective Actions Against Particulate Matter Air Pollution Exposure: A Scientific Statement From the American Heart Association.

Rajagopalan S, Brauer M, Bhatnagar A, Bhatt DL, ... Brook RD,

Since the publication of the last American Heart Association scientific statement on air pollution and cardiovascular disease in 2010, unequivocal evidence of the causal role of fine particulate matter air pollution (PM, or particulate matter ≤2.5 μm in diameter) in cardiovascular disease has emerged. There is a compelling case to provide the public with practical personalized approaches to reduce the health effects of PM. Such interventions would be applicable not only to individuals in heavily polluted countries, high-risk or susceptible individuals living in cleaner environments, and microenvironments with higher pollution exposures, but also to those traveling to locations with high levels of PM. The overarching motivation for this document is to summarize the current evidence supporting personal-level strategies to prevent the adverse cardiovascular effects of PM, guide the use of the most proven/viable approaches, obviate the use of ineffective measures, and avoid unwarranted interventions. The significance of this statement relates not only to the global importance of PM, but also to its focus on the most tested interventions and viable approaches directed at particulate matter air pollution. The writing group sought to provide expert consensus opinions on personal-level measures recognizing the current uncertainty and limited evidence base for many interventions. In doing so, the writing group acknowledges that its intent is to assist other agencies charged with protecting public health, without minimizing the personal choice considerations of an individual who may decide to use these interventions in the face of ongoing air pollution exposure.



Circulation: 07 Dec 2020; 142:e411-e431
Rajagopalan S, Brauer M, Bhatnagar A, Bhatt DL, ... Brook RD,
Circulation: 07 Dec 2020; 142:e411-e431 | PMID: 33150789
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Impact:
Abstract

Guidance to Reduce the Cardiovascular Burden of Ambient Air Pollutants: A Policy Statement From the American Heart Association.

Kaufman JD, Elkind MSV, Bhatnagar A, Koehler K, ... Turner JR,

In 2010, the American Heart Association published a statement concluding that the existing scientific evidence was consistent with a causal relationship between exposure to fine particulate matter and cardiovascular morbidity and mortality, and that fine particulate matter exposure is a modifiable cardiovascular risk factor. Since the publication of that statement, evidence linking air pollution exposure to cardiovascular health has continued to accumulate and the biological processes underlying these effects have become better understood. This increasingly persuasive evidence necessitates policies to reduce harmful exposures and the need to act even as the scientific evidence base continues to evolve. Policy options to mitigate the adverse health impacts of air pollutants must include the reduction of emissions through action on air quality, vehicle emissions, and renewable portfolio standards, taking into account racial, ethnic, and economic inequality in air pollutant exposure. Policy interventions to improve air quality can also be in alignment with policies that benefit community and transportation infrastructure, sustainable food systems, reduction in climate forcing agents, and reduction in wildfires. The health care sector has a leadership role in adopting policies to contribute to improved environmental air quality as well. There is also potentially significant private sector leadership and industry innovation occurring in the absence of and in addition to public policy action, demonstrating the important role of public-private partnerships. In addition to supporting education and research in this area, the American Heart Association has an important leadership role to encourage and support public policies, private sector innovation, and public-private partnerships to reduce the adverse impact of air pollution on current and future cardiovascular health in the United States.



Circulation: 07 Dec 2020; 142:e432-e447
Kaufman JD, Elkind MSV, Bhatnagar A, Koehler K, ... Turner JR,
Circulation: 07 Dec 2020; 142:e432-e447 | PMID: 33147996
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Impact:
Abstract

Is There a Sex Gap in Surviving an Acute Coronary Syndrome or Subsequent Development of Heart Failure?

Ezekowitz JA, Savu A, Welsh RC, McAlister FA, Goodman SG, Kaul P
Background
We hypothesized that disparities between sexes in the management of myocardial infarction (MI) may have changed over time, and thus altered the prognoses after MI, especially the risk for the development of heart failure.
Methods
Using a large population-based cohort of patients with MI between April 1, 2002, and March 31, 2016, we examined the incidence, angiographic findings, treatment (including revascularization), and clinical outcomes of patients with a first-time MI. To elucidate the differences between sexes, a series of multivariable models were created to explore all MI and non-ST-segment-elevation MI (NSTEMI) versus ST-segment-elevation MI (STEMI) over time.
Results
Between 2002 and 2016, 45 064 patients (13 878 [30.8%] women) were hospitalized with a primary diagnosis of first-time MI (54.9% NSTEMI and 45.1% STEMI). Women were older (median age, 72 versus 61 years), had more comorbidities, and had lower rates of diagnostic angiography than did men (women, 74%, versus men, 87%). When angiography was performed, women had a lower proportion of left main, 2-vessel disease with proximal left anterior descending or 3-vessel disease compared with men (33.4% versus 40.9%, <0.0001), and a higher frequency of 1-vessel disease or nonobstructive coronary artery disease (39.6% versus 29.1%, <0.0001). Women had a higher unadjusted rate of in-hospital mortality than did men in both patients with STEMI (women, 9.4%, versus men, 4.5%) and patients with NSTEMI (women, 4.7%, versus men, 2.9%). After adjustment, this difference remained significant in STEMI (adjusted odds ratio, 1.42 [95% CI, 1.24-1.64]) but not in NSTEMI (adjusted odds ratio, 0.97 [95% CI, 0.83-1.13]). After discharge, women developed heart failure after STEMI (women, 22.5%, versus men, 14.9%) as well as after NSTEMI (women, 23.2%, versus men, 15.7%). The adjusted relative risk for women versus men of developing the outcomes of mortality and heart failure remained similar across years, although the differences were nonsignificantly attenuated over 5 years of follow-up.
Conclusions
Although some attenuation of differences in clinical outcomes over time has occurred, women remain at higher risk than men of dying or developing heart failure in the subsequent 5 years after STEMI or NSTEMI, even after accounting for differences in angiographic findings, revascularization, and other confounders.



Circulation: 07 Dec 2020; 142:2231-2239
Ezekowitz JA, Savu A, Welsh RC, McAlister FA, Goodman SG, Kaul P
Circulation: 07 Dec 2020; 142:2231-2239 | PMID: 33249922
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Impact:
Abstract

Endothelial Cell Indoleamine 2, 3-Dioxygenase 1 Alters Cardiac Function Following Myocardial Infarction Through Kynurenine.

Melhem NJ, Chajadine M, Gomez I, Howangyin KY, ... Silvestre JS, Taleb S

Ischemic cardiovascular diseases, particularly acute myocardial infarction (MI) is one of the leading cause of mortality worldwide. Indoleamine 2, 3-dioxygenase 1 (IDO) catalyzes one rate-limiting step of L-Tryptophan (Trp) metabolism, and emerges as an important regulator of many pathological conditions. We hypothesized that IDO could play a key role to locally regulate cardiac homeostasis after MI.Cardiac repair was analyzed in mice harboring specific endothelial or smooth muscle cells or cardiomyocyte or myeloid cell deficiency of IDO and challenged with acute myocardial infarction.We show that Kynurenine (Kyn) generation through IDO is markedly induced after MI in mice. Total genetic deletion or pharmacological inhibition of IDO limits cardiac injury and cardiac dysfunction after MI. Distinct loss of function of IDO in smooth muscle cells, inflammatory cells, or cardiomyocytes does not impact cardiac function and remodeling in infarcted mice. In sharp contrast, mice harboring endothelial cell-specific deletion of IDO show an improvement of cardiac function, as well as cardiomyocyte contractility and reduction in adverse ventricular remodeling.Kyn supplementation in IDO-deficient mice abrogates the protective effects of IDO deletion. Notably, Kyn precipitates cardiomyocyte apoptosis through reactive oxygen species production in an aryl hydrocarbon receptor-dependent mechanism.These data suggest that IDO could constitute a new therapeutic target during acute MI.



Circulation: 03 Dec 2020; epub ahead of print
Melhem NJ, Chajadine M, Gomez I, Howangyin KY, ... Silvestre JS, Taleb S
Circulation: 03 Dec 2020; epub ahead of print | PMID: 33272024
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Impact:
Abstract

Achieving Optimal Population Cardiovascular Health Requires an Interdisciplinary Team and a Learning Healthcare System: A Scientific Statement From the American Heart Association.

Foraker RE, Benziger CP, DeBarmore BM, Cené CW, ... Roger VL,

Population cardiovascular health, or improving cardiovascular health among patients and the population at large, requires a redoubling of primordial and primary prevention efforts as declines in cardiovascular disease mortality have decelerated over the past decade. Great potential exists for healthcare systems-based approaches to aid in reversing these trends. A learning healthcare system, in which population cardiovascular health metrics are measured, evaluated, intervened on, and re-evaluated, can serve as a model for developing the evidence base for developing, deploying, and disseminating interventions. This scientific statement on optimizing population cardiovascular health summarizes the current evidence for such an approach; reviews contemporary sources for relevant performance and clinical metrics; highlights the role of implementation science strategies; and advocates for an interdisciplinary team approach to enhance the impact of this work.



Circulation: 02 Dec 2020:CIR0000000000000913; epub ahead of print
Foraker RE, Benziger CP, DeBarmore BM, Cené CW, ... Roger VL,
Circulation: 02 Dec 2020:CIR0000000000000913; epub ahead of print | PMID: 33269600
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Impact:
Abstract

Number of Social Determinants of Health and Fatal and Nonfatal Incident Coronary Heart Disease in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

Safford MM, Reshetnyak E, Sterling MR, Richman JS, ... Booth J, Pinheiro LC

Social determinants of health (SDH) are individually associated with incident coronary heart disease (CHD) events. Indices reflecting social deprivation have been developed for population management, but are difficult to operationalize during clinical care. We examined whether a simple count of SDH is associated with fatal incident CHD and nonfatal myocardial infarction (MI).We used data from the prospective longitudinal REasons for Geographic And Racial Differences in Stroke cohort study, a national population-based sample of community-dwelling Black and white adults age ≥45 years recruited from 2003-7. Seven SDH from the five Healthy People 2020 domains included social context (Black race, social isolation); education (educational attainment); economic stability (annual household income); neighborhood (living in a zip code with high poverty); and healthcare (lacking health insurance, living in one of the 9 US states with the least public health infrastructure). Outcomes were expert adjudicated fatal incident CHD and nonfatal MI.Of 22,152 participants free of CHD at baseline, 58.8% were women, 42.0% were Blacks, 20.6% had no SDH, 30.6% had 1, 23.0% had 2, and 25.8% had ≥3. There were 463 fatal incident CHD events and 932 nonfatal MIs over median 10.7 years [IQR 6.6-12.7]. Fewer SDH were associated with nonfatal MI than with fatal incident CHD. The age-adjusted incidence per 1000 person-years increased with the number of SDH for both fatal incident CHD (0 SDH 1.30, 1 SDH 1.44, 2 SDH 2.05, ≥3 SDH 2.86) and nonfatal MI (0 SDH 3.91, 1 SDH 4.33, ≥2 SDH 5.44). Compared to those without SDH, crude and fully adjusted hazard ratios (HR) for fatal incident CHD among those with ≥3 SDH were 3.00 (95% CI 2.17, 4.15) and 1.67 (95% CI 1.18, 2.37), respectively; and that for nonfatal MI among those with ≥2 SDH were 1.57 (95% CI 1.30, 1.90) and 1.14 (0.93, 1.41), respectively.A greater burden of SDH was associated with a graded increase in risk of incident CHD, with greater magnitude and independent associations for fatal incident CHD. Counting the number of SDH may be a promising approach that could be incorporated into clinical care to identify individuals at high risk of CHD.



Circulation: 02 Dec 2020; epub ahead of print
Safford MM, Reshetnyak E, Sterling MR, Richman JS, ... Booth J, Pinheiro LC
Circulation: 02 Dec 2020; epub ahead of print | PMID: 33269599
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Impact:
Abstract

Myocardial Infarction in the ISCHEMIA Trial: Impact of Different Definitions on Incidence, Prognosis, and Treatment Comparisons.

Chaitman BR, Alexander KP, Cyr DD, Berger JS, ... Hochman JS,

In ISCHEMIA, an initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality compared with a conservative strategy in patients with stable ischemic heart disease and moderate/severe myocardial ischemia. The most frequent component of composite cardiovascular endpoints was myocardial infarction.ISCHEMIA prespecified that the primary and major secondary composite endpoints of the trial be analyzed using two MI definitions. For procedural MI, the primary MI definition used CK-MB as the preferred biomarker whereas the secondary definition used cardiac troponin. Procedural thresholds were >5 times URL for PCI and >10 times for CABG. Procedural MI definitions included (i) a category of elevated biomarker only events with much higher biomarker thresholds (ii) new ST segment depression of ≥ 1mm for the primary and ≥ 0.5 mm for the secondary definition and (iii) new coronary dissections ≥ NHLBI grade 3. We compared MI type, frequency, and prognosis by treatment assignment using both MI definitions.Procedural MI\'s accounted for 20.1% of all MI events with the primary definition and 40.6% of all MI events with the secondary definition. Four-year MI rates in patients undergoing revascularization were more frequent with the invasive vs conservative strategy using the primary [2.7% vs. 1.1%; adjusted HR 2.98 (95% CI 1.87, 4.73)] and secondary [8.2% vs. 2.0%; adjusted HR 5.04 (95% CI 3.64, 6.97)] MI definitions. Type 1 MI\'s were less frequent with the invasive vs conservative strategy using the primary [3.40% vs. 6.89%; adjusted HR 0.53 (95% CI 0.41,0.69); p<0.0001], and secondary [3.48% vs 6.89%; adjusted HR 0.53 (95% CI 0.41, 0.69); p<0.0001] definitions. The risk of subsequent cardiovascular death was higher after a type 1 MI compared to no MI using the primary [adjusted HR 3.38 (95% CI 2.03,5.61); p<0.001] or secondary MI definition [adjusted HR 3.52 (2.11, 5.88); p<0.001].In ISCHEMIA, type 1 MI events using the primary and secondary definitions during 5-year follow-up were more frequent with an initial conservative strategy and associated with subsequent cardiovascular death. Procedural MI rates were greater in the invasive strategy and using the secondary MI definition.URL: https://clinicaltrials.gov Unique Identifier: NCT01471522.



Circulation: 02 Dec 2020; epub ahead of print
Chaitman BR, Alexander KP, Cyr DD, Berger JS, ... Hochman JS,
Circulation: 02 Dec 2020; epub ahead of print | PMID: 33267610
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Impact:
Abstract

Signalosome-Regulated Serum Response Factor Phosphorylation Determining Myocyte Growth in Width Versus Length as a Therapeutic Target for Heart Failure.

Li J, Tan Y, Passariello CL, Martinez EC, ... Rosenfeld MG, Kapiloff MS
Background
Concentric and eccentric cardiac hypertrophy are associated with pressure and volume overload, respectively, in cardiovascular disease both conferring an increased risk of heart failure. These contrasting forms of hypertrophy are characterized by asymmetrical growth of the cardiac myocyte in mainly width or length, respectively. The molecular mechanisms determining myocyte preferential growth in width versus length remain poorly understood. Identification of the mechanisms governing asymmetrical myocyte growth could provide new therapeutic targets for the prevention or treatment of heart failure.
Methods
Primary adult rat ventricular myocytes, adeno-associated virus (AAV)-mediated gene delivery in mice, and human tissue samples were used to define a regulatory pathway controlling pathological myocyte hypertrophy. Chromatin immunoprecipitation assays with sequencing and precision nuclear run-on sequencing were used to define a transcriptional mechanism.
Results
We report that asymmetrical cardiac myocyte hypertrophy is modulated by SRF (serum response factor) phosphorylation, constituting an epigenomic switch balancing the growth in width versus length of adult ventricular myocytes in vitro and in vivo. SRF Ser phosphorylation is bidirectionally regulated by RSK3 (p90 ribosomal S6 kinase type 3) and PP2A (protein phosphatase 2A) at signalosomes organized by the scaffold protein mAKAPβ (muscle A-kinase anchoring protein β), such that increased SRF phosphorylation activates AP-1 (activator protein-1)-dependent enhancers that direct myocyte growth in width. AAV are used to express in vivo mAKAPβ-derived RSK3 and PP2A anchoring disruptor peptides that block the association of the enzymes with the mAKAPβ scaffold. Inhibition of RSK3 signaling prevents concentric cardiac remodeling induced by pressure overload, while inhibition of PP2A signaling prevents eccentric cardiac remodeling induced by myocardial infarction, in each case improving cardiac function. SRF Ser phosphorylation is significantly decreased in dilated human hearts, supporting the notion that modulation of the mAKAPβ-SRF signalosome could be a new therapeutic approach for human heart failure.
Conclusions
We have identified a new molecular switch, namely mAKAPβ signalosome-regulated SRF phosphorylation, that controls a transcriptional program responsible for modulating changes in cardiac myocyte morphology that occur secondary to pathological stressors. Complementary AAV-based gene therapies constitute rationally-designed strategies for a new translational modality for heart failure.



Circulation: 29 Nov 2020; 142:2138-2154
Li J, Tan Y, Passariello CL, Martinez EC, ... Rosenfeld MG, Kapiloff MS
Circulation: 29 Nov 2020; 142:2138-2154 | PMID: 32933333
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Abstract

Dual Functional States of R406W-Desmin Assembly Complexes Cause Cardiomyopathy With Severe Intercalated Disc Derangement in Humans and in Knock-In Mice.

Herrmann H, Cabet E, Chevalier NR, Moosmann J, ... Lilienbaum A, Schröder R
Background
Mutations in the human desmin gene cause myopathies and cardiomyopathies. This study aimed to elucidate molecular mechanisms initiated by the heterozygous R406W-desmin mutation in the development of a severe and early-onset cardiac phenotype.
Methods
We report an adolescent patient who underwent cardiac transplantation as a result of restrictive cardiomyopathy caused by a heterozygous R406W-desmin mutation. Sections of the explanted heart were analyzed with antibodies specific to 406W-desmin and to intercalated disc proteins. Effects of the R406W mutation on the molecular properties of desmin were addressed by cell transfection and in vitro assembly experiments. To prove the genuine deleterious effect of the mutation on heart tissue, we further generated and analyzed R405W-desmin knock-in mice harboring the orthologous form of the human R406W-desmin.
Results
Microscopic analysis of the explanted heart revealed desmin aggregates and the absence of desmin filaments at intercalated discs. Structural changes within intercalated discs were revealed by the abnormal organization of desmoplakin, plectin, N-cadherin, and connexin-43. Next-generation sequencing confirmed thevariant c.1216C>T (p.R406W) as the sole disease-causing mutation. Cell transfection studies disclosed a dual behavior of R406W-desmin with both its integration into the endogenous intermediate filament system and segregation into protein aggregates. In vitro, R406W-desmin formed unusually thick filaments that organized into complex filament aggregates and fibrillar sheets. In contrast, assembly of equimolar mixtures of mutant and wild-type desmin generated chimeric filaments of seemingly normal morphology but with occasional prominent irregularities. Heterozygous and homozygous R405W-desmin knock-in mice develop both a myopathy and a cardiomyopathy. In particular, the main histopathologic results from the patient are recapitulated in the hearts from R405W-desmin knock-in mice of both genotypes. Moreover, whereas heterozygous knock-in mice have a normal life span, homozygous animals die at 3 months of age because of a smooth muscle-related gastrointestinal phenotype.
Conclusions
We demonstrate that R406W-desmin provokes its severe cardiotoxic potential by a novel pathomechanism, where the concurrent dual functional states of mutant desmin assembly complexes underlie the uncoupling of desmin filaments from intercalated discs and their structural disorganization.



Circulation: 29 Nov 2020; 142:2155-2171
Herrmann H, Cabet E, Chevalier NR, Moosmann J, ... Lilienbaum A, Schröder R
Circulation: 29 Nov 2020; 142:2155-2171 | PMID: 33023321
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Impact:
Abstract

Left Ventricular Unloading Is Associated With Lower Mortality in Patients With Cardiogenic Shock Treated With Venoarterial Extracorporeal Membrane Oxygenation: Results From an International, Multicenter Cohort Study.

Schrage B, Becher PM, Bernhardt A, Bezerra H, ... Wechsler L, Westermann D
Background
Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used to treat cardiogenic shock. However, VA-ECMO might hamper myocardial recovery. The Impella unloads the left ventricle. This study aimed to evaluate whether left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO was associated with lower mortality.
Methods
Data from 686 consecutive patients with cardiogenic shock treated with VA-ECMO with or without left ventricular unloading using an Impella at 16 tertiary care centers in 4 countries were collected. The association between left ventricular unloading and 30-day mortality was assessed by Cox regression models in a 1:1 propensity score-matched cohort.
Results
Left ventricular unloading was used in 337 of the 686 patients (49%). After matching, 255 patients with left ventricular unloading were compared with 255 patients without left ventricular unloading. In the matched cohort, left ventricular unloading was associated with lower 30-day mortality (hazard ratio, 0.79 [95% CI, 0.63-0.98]; =0.03) without differences in various subgroups. Complications occurred more frequently in patients with left ventricular unloading: severe bleeding in 98 (38.4%) versus 45 (17.9%), access site-related ischemia in 55 (21.6%) versus 31 (12.3%), abdominal compartment in 23 (9.4%) versus 9 (3.7%), and renal replacement therapy in 148 (58.5%) versus 99 (39.1%).
Conclusions
In this international, multicenter cohort study, left ventricular unloading was associated with lower mortality in patients with cardiogenic shock treated with VA-ECMO, despite higher complication rates. These findings support use of left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO and call for further validation, ideally in a randomized, controlled trial.



Circulation: 29 Nov 2020; 142:2095-2106
Schrage B, Becher PM, Bernhardt A, Bezerra H, ... Wechsler L, Westermann D
Circulation: 29 Nov 2020; 142:2095-2106 | PMID: 33032450
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Abstract

Growth Differentiation Factor 15 Provides Prognostic Information Superior to Established Cardiovascular and Inflammatory Biomarkers in Unselected Patients Hospitalized With COVID-19.

Myhre PL, Prebensen C, Strand H, Røysland R, ... Erik Berdal J, Omland T
Background
Growth differentiation factor 15 (GDF-15) is a strong prognostic marker in sepsis and cardiovascular disease (CVD). The prognostic value of GDF-15 in coronavirus disease 2019 (COVID-19) is unknown.
Methods
Consecutive, hospitalized patients with laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and symptoms of COVID-19 were enrolled in the prospective, observational COVID Mechanisms Study. Biobank samples were collected at baseline, day 3 and day 9. The primary end point was admission to the intensive care unit or death during hospitalization, and the prognostic performance of baseline and serial GDF-15 concentrations were compared with that of established infectious disease and cardiovascular biomarkers.
Results
Of the 123 patients enrolled, 35 (28%) reached the primary end point; these patients were older, more often had diabetes, and had lower oxygen saturations and higher National Early Warning Scores on baseline. Baseline GDF-15 concentrations were elevated (>95th percentile in age-stratified healthy individuals) in 97 (79%), and higher concentrations were associated with detectable SARS-CoV-2 viremia and hypoxemia (both <0.001). Patients reaching the primary end point had higher concentrations of GDF-15 (median, 4225 [IQR, 3197-5972] pg/mL versus median, 2187 [IQR, 1344-3620] pg/mL, <0.001). The area under the receiver operating curve was 0.78 (95% CI, 0.70-0.86). The association between GDF-15 and the primary end point persisted after adjusting for age, sex, race, body mass index, estimated glomerular filtration rate, previous myocardial infarction, heart failure, and atrial fibrillation (<0.001) and was superior and incremental to interleukin-6, C-reactive protein, procalcitonin, ferritin, D-dimer, cardiac troponin T, and N-terminal pro-B-type natriuretic peptide. Increase in GDF-15 from baseline to day 3 was also greater in patients reaching the primary end point (median, 1208 [IQR, 0-4305] pg/mL versus median, -86 [IQR, -322 to 491] pg/mL, <0.001).
Conclusions
GDF-15 is elevated in the majority of patients hospitalized with COVID-19, and higher concentrations are associated with SARS-CoV-2 viremia, hypoxemia, and worse outcome. The prognostic value of GDF-15 was additional and superior to established cardiovascular and inflammatory biomarkers. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04314232.



Circulation: 29 Nov 2020; 142:2128-2137
Myhre PL, Prebensen C, Strand H, Røysland R, ... Erik Berdal J, Omland T
Circulation: 29 Nov 2020; 142:2128-2137 | PMID: 33058695
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Abstract

Comprehensive Metabolic Phenotyping Refines Cardiovascular Risk in Young Adults.

Murthy VL, Reis JP, Pico AR, Kitchen R, ... Clish CB, Shah RV
Background
Whereas cardiovascular disease (CVD) metrics define risk in individuals >40 years of age, the earliest lesions of CVD appear well before this age. Despite the role of metabolism in CVD antecedents, studies in younger, biracial populations to define precise metabolic risk phenotypes are lacking.
Methods
We studied 2330 White and Black young adults (mean age, 32 years; 45% Black) in the CARDIA study (Coronary Artery Risk Development in Young Adults) to identify metabolite profiles associated with an adverse CVD phenome (myocardial structure/function, fitness, vascular calcification), mechanisms, and outcomes over 2 decades. Statistical learning methods (elastic nets/principal components analysis) and Cox regression generated parsimonious, metabolite-based risk scores validated in >1800 individuals in the Framingham Heart Study.
Results
In the CARDIA study, metabolite profiles quantified in early adulthood were associated with subclinical CVD development over 20 years, specifying known and novel pathways of CVD (eg, transcriptional regulation, brain-derived neurotrophic factor, nitric oxide, renin-angiotensin). We found 2 multiparametric, metabolite-based scores linked independently to vascular and myocardial health, with metabolites included in each score specifying microbial metabolism, hepatic steatosis, oxidative stress, nitric oxide modulation, and collagen metabolism. The metabolite-based vascular scores were lower in men, and myocardial scores were lower in Black participants. Over a nearly 25-year median follow-up in CARDIA, the metabolite-based vascular score (hazard ratio, 0.68 per SD [95% CI, 0.50-0.92]; =0.01) and myocardial score (hazard ratio, 0.60 per SD [95% CI, 0.45-0.80]; =0.0005) in the third and fourth decades of life were associated with clinical CVD with a synergistic association with outcome (=0.009). We replicated these findings in 1898 individuals in the Framingham Heart Study over 2 decades, with a similar association with outcome (including interaction), reclassification, and discrimination. In the Framingham Heart Study, the metabolite scores exhibited an age interaction (=0.0004 for a combined myocardial-vascular score with incident CVD), such that young adults with poorer metabolite-based health scores had highest hazard of future CVD.
Conclusions
Metabolic signatures of myocardial and vascular health in young adulthood specify known/novel pathways of metabolic dysfunction relevant to CVD, associated with outcome in 2 independent cohorts. Efforts to include precision measures of metabolic health in risk stratification to interrupt CVD at its earliest stage are warranted.



Circulation: 29 Nov 2020; 142:2110-2127
Murthy VL, Reis JP, Pico AR, Kitchen R, ... Clish CB, Shah RV
Circulation: 29 Nov 2020; 142:2110-2127 | PMID: 33073606
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Abstract

Prevention of Complications in the Cardiac Intensive Care Unit: A Scientific Statement From the American Heart Association.

Fordyce CB, Katz JN, Alviar CL, Arslanian-Engoren C, ... van Diepen S,

Contemporary cardiac intensive care units (CICUs) have an increasing prevalence of noncardiovascular comorbidities and multisystem organ dysfunction. However, little guidance exists to support the development of best-practice principles specific to the CICU. This scientific statement evaluates strategies to avoid the potentially preventable complications encountered within contemporary CICUs, focusing on those that are most applicable to the CICU environment. This scientific statement reviews evidence-based practices derived in non-CICU populations, assesses their relevance to CICU practice, and highlights key knowledge gaps warranting further investigation to attenuate patient risk.



Circulation: 29 Nov 2020; 142:e379-e406
Fordyce CB, Katz JN, Alviar CL, Arslanian-Engoren C, ... van Diepen S,
Circulation: 29 Nov 2020; 142:e379-e406 | PMID: 33115261
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Abstract

Antithrombotic Therapy for Atherosclerotic Cardiovascular Disease Risk Mitigation in Patients With Coronary Artery Disease and Diabetes Mellitus.

Capodanno D, Angiolillo DJ

Patients with diabetes mellitus (DM) are characterized by enhanced thrombotic risk attributed to multiple mechanisms including hyperreactive platelets, hypercoagulable status, and endothelial dysfunction. As such, they are more prone to atherosclerotic cardiovascular events than patients without DM, both before and after coronary artery disease (CAD) is established. In patients with DM without established CAD, primary prevention with aspirin is not routinely advocated because of its increased risk of major bleeding that largely offsets its ischemic benefit. In patients with DM with established CAD, secondary prevention with antiplatelet drugs is an asset of pharmacological strategies aimed at reducing the risk of atherosclerotic cardiovascular events and their adverse prognostic consequences. Such antithrombotic strategies include single antiplatelet therapy (eg, with aspirin or a P2Y inhibitor), dual antiplatelet therapy (eg, aspirin combined with a P2Y inhibitor), and dual-pathway inhibition (eg, aspirin combined with the vascular dose of the direct oral anticoagulant rivaroxaban) for patients with chronic ischemic heart disease, acute coronary syndromes, and those undergoing percutaneous coronary intervention. Because of their increased risk of thrombotic complications, patients with DM commonly achieve enhanced absolute benefit from more potent antithrombotic approaches compared with those without DM, which most often occurs at the expense of increased bleeding. Nevertheless, studies have shown that when excluding individuals at high risk for bleeding, the net clinical benefit favors the use of intensified long-term antithrombotic therapy in patients with DM and CAD. Several studies are ongoing to establish the role of novel antithrombotic strategies and drug formulations in maximizing the net benefit of antithrombotic therapy for patients with DM. The scope of this review article is to provide an overview of current and evolving antithrombotic strategies for primary and secondary prevention of atherosclerotic cardiovascular events in patients with CAD and DM.



Circulation: 29 Nov 2020; 142:2172-2188
Capodanno D, Angiolillo DJ
Circulation: 29 Nov 2020; 142:2172-2188 | PMID: 33253005
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Abstract

Menopause Transition and Cardiovascular Disease Risk: Implications for Timing of Early Prevention: A Scientific Statement From the American Heart Association.

El Khoudary SR, Aggarwal B, Beckie TM, Hodis HN, ... Allison MA,

Cardiovascular disease (CVD) is the leading cause of death in women, who have a notable increase in the risk for this disease after menopause and typically develop coronary heart disease several years later than men. This observation led to the hypothesis that the menopause transition (MT) contributes to the increase in coronary heart disease risk. Over the past 20 years, longitudinal studies of women traversing menopause have contributed significantly to our understanding of the relationship between the MT and CVD risk. By following women over this period, researchers have been able to disentangle chronological and ovarian aging with respect to CVD risk. These studies have documented distinct patterns of sex hormone changes, as well as adverse alterations in body composition, lipids and lipoproteins, and measures of vascular health over the MT, which can increase a woman\'s risk of developing CVD postmenopausally. The reported findings underline the significance of the MT as a time of accelerating CVD risk, thereby emphasizing the importance of monitoring women\'s health during midlife, a critical window for implementing early intervention strategies to reduce CVD risk. Notably, the 2011 American Heart Association guidelines for CVD prevention in women (the latest sex-specific guidelines to date) did not include information now available about the contribution of the MT to increased CVD in women. Therefore, there is a crucial need to discuss the contemporary literature on menopause and CVD risk with the intent of increasing awareness of the significant adverse cardiometabolic health-related changes accompanying midlife and the MT. This scientific statement provides an up-to-date synthesis of the existing data on the MT and how it relates to CVD.



Circulation: 29 Nov 2020:CIR0000000000000912; epub ahead of print
El Khoudary SR, Aggarwal B, Beckie TM, Hodis HN, ... Allison MA,
Circulation: 29 Nov 2020:CIR0000000000000912; epub ahead of print | PMID: 33251828
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Abstract

A Linear and Non-Linear Mendelian Randomization Analysis of the Association Between Diastolic Blood Pressure and Cardiovascular Events: The J Curve Revisited.

Arvanitis M, Qi G, Bhatt DL, Post WS, ... Battle A, McEvoy JW

Recent clinical guidelines support intensive blood pressure (BP) treatment targets. However, observational data suggest that excessive diastolic BP (DBP) lowering might increase the risk of myocardial infarction (MI); reflecting a J- or U-shaped relationship.We analyzed 47,407 participants from 5 cohorts (median age 60 years). First, to corroborate prior observational analyses, we used traditional statistical methods to test the shape of association between DBP and CVD. Second, we created polygenic risk scores (PRS) of DBP and SBP and generated linear Mendelian randomization (MR) estimates for the effect of DBP on CVD. Third, using novel non-linear MR approaches, we evaluated for non-linearity in the genetic relationship between DBP and CVD. Comprehensive MR interrogation of DBP required us to also model SBP, given the two are strongly correlated.Traditional observational analysis of our cohorts suggested a J-shaped association between DBP and MI. By contrast, linear MR analyses demonstrated an adverse effect of increasing DBP increments on CVD outcomes, including MI (MI Hazard ratio = 1.07 per unit mmHg increase in DBP, p<0.001). Furthermore, non-linear MR analyses found no evidence for a J-shaped relationship, instead confirming that MI risk decreases consistently per unit decrease in DBP, even among individuals with low values of baseline DBP.In this analysis of the genetic effect of DBP, we found no evidence for a non-linear J- or U-shaped relationship between DBP and adverse CVD outcomes; including MI.



Circulation: 29 Nov 2020; epub ahead of print
Arvanitis M, Qi G, Bhatt DL, Post WS, ... Battle A, McEvoy JW
Circulation: 29 Nov 2020; epub ahead of print | PMID: 33249881
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Abstract

Stem Cell Pluripotency Genes Klf4 and Oct4 Regulate Complex SMC Phenotypic Changes Critical in Late-Stage Atherosclerotic Lesion Pathogenesis.

Alencar GF, Owsiany KM, Karnewar S, Sukhavasi K, ... Bekiranov S, Owens GK
Background
Rupture and erosion of advanced atherosclerotic lesions with a resultant myocardial infarction or stroke are the leading worldwide cause of death. However, we have a limited understanding of the identity, origin, and function of many cells that make up late-stage atherosclerotic lesions, as well as the mechanisms by which they control plaque stability.
Methods
We conducted a comprehensive single-cell RNA sequencing of advanced human carotid endarterectomy samples and compared these with single-cell RNA sequencing from murine microdissected advanced atherosclerotic lesions with smooth muscle cell (SMC) and endothelial lineage tracing to survey all plaque cell types and rigorously determine their origin. We further used chromatin immunoprecipitation sequencing (ChIP-seq), bulk RNA sequencing, and an innovative dual lineage tracing mouse to understand the mechanism by which SMC phenotypic transitions affect lesion pathogenesis.
Results
We provide evidence that SMC-specific Klf4- versus Oct4-knockout showed virtually opposite genomic signatures, and their putative target genes play an important role regulating SMC phenotypic changes. Single-cell RNA sequencing revealed remarkable similarity of transcriptomic clusters between mouse and human lesions and extensive plasticity of SMC- and endothelial cell-derived cells including 7 distinct clusters, most negative for traditional markers. In particular, SMC contributed to a Myh11, Lgals3 population with a chondrocyte-like gene signature that was markedly reduced with SMC- knockout. We observed that SMCs that activate Lgals3 compose up to two thirds of all SMC in lesions. However, initial activation of Lgals3 in these cells does not represent conversion to a terminally differentiated state, but rather represents transition of these cells to a unique stem cell marker gene-positive, extracellular matrix-remodeling, \"pioneer\" cell phenotype that is the first to invest within lesions and subsequently gives rise to at least 3 other SMC phenotypes within advanced lesions, including Klf4-dependent osteogenic phenotypes likely to contribute to plaque calcification and plaque destabilization.
Conclusions
Taken together, these results provide evidence that SMC-derived cells within advanced mouse and human atherosclerotic lesions exhibit far greater phenotypic plasticity than generally believed, with Klf4 regulating transition to multiple phenotypes including Lgals3 osteogenic cells likely to be detrimental for late-stage atherosclerosis plaque pathogenesis.



Circulation: 23 Nov 2020; 142:2045-2059
Alencar GF, Owsiany KM, Karnewar S, Sukhavasi K, ... Bekiranov S, Owens GK
Circulation: 23 Nov 2020; 142:2045-2059 | PMID: 32674599
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Abstract

Single-Cell Genomics Reveals a Novel Cell State During Smooth Muscle Cell Phenotypic Switching and Potential Therapeutic Targets for Atherosclerosis in Mouse and Human.

Pan H, Xue C, Auerbach BJ, Fan J, ... Li M, Reilly MP
Background
Smooth muscle cells (SMCs) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC dedifferentiation, migration, and transdifferentiation into other cell types. Yet how SMCs contribute to the pathophysiology of atherosclerosis remains elusive.
Methods
To reveal the trajectories of SMC transdifferentiation during atherosclerosis and to identify molecular targets for disease therapy, we combined SMC fate mapping and single-cell RNA sequencing of both mouse and human atherosclerotic plaques. We also performed cell biology experiments on isolated SMC-derived cells, conducted integrative human genomics, and used pharmacological studies targeting SMC-derived cells both in vivo and in vitro.
Results
We found that SMCs transitioned to an intermediate cell state during atherosclerosis, which was also found in human atherosclerotic plaques of carotid and coronary arteries. SMC-derived intermediate cells, termed \"SEM\" cells (stem cell, endothelial cell, monocyte), were multipotent and could differentiate into macrophage-like and fibrochondrocyte-like cells, as well as return toward the SMC phenotype. Retinoic acid (RA) signaling was identified as a regulator of SMC to SEM cell transition, and RA signaling was dysregulated in symptomatic human atherosclerosis. Human genomics revealed enrichment of genome-wide association study signals for coronary artery disease in RA signaling target gene loci and correlation between coronary artery disease risk alleles and repressed expression of these genes. Activation of RA signaling by all-trans RA, an anticancer drug for acute promyelocytic leukemia, blocked SMC transition to SEM cells, reduced atherosclerotic burden, and promoted fibrous cap stability.
Conclusions
Integration of cell-specific fate mapping, single-cell genomics, and human genetics adds novel insights into the complexity of SMC biology and reveals regulatory pathways for therapeutic targeting of SMC transitions in atherosclerotic cardiovascular disease.



Circulation: 23 Nov 2020; 142:2060-2075
Pan H, Xue C, Auerbach BJ, Fan J, ... Li M, Reilly MP
Circulation: 23 Nov 2020; 142:2060-2075 | PMID: 32962412
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Abstract

Randomized Pilot Clinical Trial of Early Coronary Angiography Versus No Early Coronary Angiography After Cardiac Arrest Without ST-Segment Elevation: The PEARL Study.

Kern KB, Radsel P, Jentzer JC, Seder DB, ... Hsu CH, Noc M
Background
The benefit of emergency coronary angiography after resuscitation from out-of-hospital cardiac arrest is uncertain for patients without ST-segment elevation. The aim of this randomized trial was to evaluate the efficacy and safety of early coronary angiography and to determine the prevalence of acute coronary occlusion in resuscitated patients with out-of-hospital cardiac arrest without ST-segment elevation.
Methods
Adult (>18 years) comatose survivors without ST-segment elevation after resuscitation from out-of-hospital cardiac arrest were prospectively randomized in a 1:1 fashion under exception to informed consent regulations to early coronary angiography versus no early coronary angiography in this multicenter study. Early angiography was defined as ≤120 minutes from arrival at the percutaneous coronary intervention-capable facility. The primary end point was a composite of efficacy and safety measures, including efficacy measures of survival to discharge, favorable neurologic status at discharge (Cerebral Performance Category score ≤2), echocardiographic measures of left ventricular ejection fraction >50%, and a normal regional wall motion score of 16 within 24 hours of admission. Adverse events included rearrest, pulmonary edema on chest x-ray, acute renal dysfunction, bleeding requiring transfusion or intervention, hypotension (systolic arterial pressure ≤90 mm Hg), and pneumonia. Secondary end points included the incidence of culprit vessels with acute occlusion.
Results
The study was terminated prematurely before enrolling the target number of patients. A total of 99 patients were enrolled from 2015 to 2018, including 75 with initially shockable rhythms. Forty-nine patients were randomized to early coronary angiography. The primary end point of efficacy and safety was not different between the 2 groups (55.1% versus 46.0%; =0.64). Early coronary angiography was not associated with any significant increase in survival (55.1% versus 48.0%; =0.55) or adverse events (26.5% versus 26.0%; =1.00). Early coronary angiography revealed a culprit vessel in 47%, with a total of 14% of patients undergoing early coronary angiography having an acutely occluded culprit coronary artery.
Conclusions
This underpowered study, when considered together with previous clinical trials, does not support early coronary angiography for comatose survivors of cardiac arrest without ST elevation. Whether early detection of occluded potential culprit arteries leads to interventions that improve outcomes requires additional study.
Registration
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02387398.



Circulation: 23 Nov 2020; 142:2002-2012
Kern KB, Radsel P, Jentzer JC, Seder DB, ... Hsu CH, Noc M
Circulation: 23 Nov 2020; 142:2002-2012 | PMID: 32985249
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Abstract

Proteomic Evaluation of the Comorbidity-Inflammation Paradigm in Heart Failure With Preserved Ejection Fraction: Results From the PROMIS-HFpEF Study.

Sanders-van Wijk S, Tromp J, Beussink-Nelson L, Hage C, ... Lam CSP, Shah SJ
Background
A systemic proinflammatory state has been hypothesized to mediate the association between comorbidities and abnormal cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). We conducted a proteomic analysis to investigate this paradigm.
Methods
In 228 patients with HFpEF from the multicenter PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction), 248 unique circulating proteins were quantified by a multiplex immunoassay (Olink) and used to recapitulate systemic inflammation. In a deductive approach, we performed principal component analysis to summarize 47 proteins known a priori to be involved in inflammation. In an inductive approach, we performed unbiased weighted coexpression network analyses of all 248 proteins to identify clusters of proteins that overrepresented inflammatory pathways. We defined comorbidity burden as the sum of 8 common HFpEF comorbidities. We used multivariable linear regression and statistical mediation analyses to determine whether and to what extent inflammation mediates the association of comorbidity burden with abnormal cardiac structure/function in HFpEF. We also externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without heart failure.
Results
Comorbidity burden was associated with abnormal cardiac structure/function and with principal components/clusters of inflammation proteins. Systemic inflammation was also associated with increased mitral E velocity, E/e\' ratio, and tricuspid regurgitation velocity; and worse right ventricular function (tricuspid annular plane systolic excursion and right ventricular free wall strain). Inflammation mediated the association between comorbidity burden and mitral E velocity (proportion mediated 19%-35%), E/e\' ratio (18%-29%), tricuspid regurgitation velocity (27%-41%), and tricuspid annular plane systolic excursion (13%) (<0.05 for all), but not right ventricular free wall strain. TNFR1 (tumor necrosis factor receptor 1), UPAR (urokinase plasminogen activator receptor), IGFBP7 (insulin-like growth factor binding protein 7), and GDF-15 (growth differentiation factor-15) were the top individual proteins that mediated the relationship between comorbidity burden and echocardiographic parameters. In the validation cohort, inflammation was upregulated in HFpEF cases versus controls, and the most prominent inflammation protein cluster identified in PROMIS-HFpEF was also present in HFpEF cases (but not controls) in the validation cohort.
Conclusions
Proteins involved in inflammation form a conserved network in HFpEF across 2 independent cohorts and may mediate the association between comorbidity burden and echocardiographic indicators of worse hemodynamics and right ventricular dysfunction. These findings support the comorbidity-inflammation paradigm in HFpEF.



Circulation: 23 Nov 2020; 142:2029-2044
Sanders-van Wijk S, Tromp J, Beussink-Nelson L, Hage C, ... Lam CSP, Shah SJ
Circulation: 23 Nov 2020; 142:2029-2044 | PMID: 33034202
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Abstract

Prospective Multicenter Study of Myocardial Recovery Using Left Ventricular Assist Devices (RESTAGE-HF [Remission from Stage D Heart Failure]): Medium-Term and Primary End Point Results.

Birks EJ, Drakos SG, Patel SR, Lowes BD, ... Farrar DJ, Rame JE
Background
Left ventricular assist device (LVAD) unloading and hemodynamic support in patients with advanced chronic heart failure can result in significant improvement in cardiac function allowing LVAD removal; however, the rate of this is generally considered to be low. This prospective multicenter nonrandomized study (RESTAGE-HF [Remission from Stage D Heart Failure]) investigated whether a protocol of optimized LVAD mechanical unloading, combined with standardized specific pharmacological therapy to induce reverse remodeling and regular testing of underlying myocardial function, could produce a higher incidence of LVAD explantation.
Methods
Forty patients with chronic advanced heart failure from nonischemic cardiomyopathy receiving the Heartmate II LVAD were enrolled from 6 centers. LVAD speed was optimized with an aggressive pharmacological regimen, and regular echocardiograms were performed at reduced LVAD speed (6000 rpm, no net flow) to test underlying myocardial function. The primary end point was the proportion of patients with sufficient improvement of myocardial function to reach criteria for explantation within 18 months with sustained remission from heart failure (freedom from transplant/ventricular assist device/death) at 12 months.
Results
Before LVAD, age was 35.1±10.8 years, 67.5% were men, heart failure mean duration was 20.8±20.6 months, 95% required inotropic and 20% temporary mechanical support, left ventricular ejection fraction was 14.5±5.3%, end-diastolic diameter was 7.33±0.89 cm, end-systolic diameter was 6.74±0.88 cm, pulmonary artery saturations were 46.7±9.2%, and pulmonary capillary wedge pressure was 26.2±7.6 mm Hg. Four enrolled patients did not undergo the protocol because of medical complications unrelated to the study procedures. Overall, 40% of all enrolled (16/40) patients achieved the primary end point, <0.0001, with 50% (18/36) of patients receiving the protocol being explanted within 18 months (pre-explant left ventricular ejection fraction, 57±8%; end-diastolic diameter, 4.81±0.58 cm; end-systolic diameter, 3.53±0.51 cm; pulmonary capillary wedge pressure, 8.1±3.1 mm Hg; pulmonary artery saturations 63.6±6.8% at 6000 rpm). Overall, 19 patients were explanted (19/36, 52.3% of those receiving the protocol). The 15 ongoing explanted patients are now 2.26±0.97 years after explant. After explantation survival free from LVAD or transplantation was 90% at 1-year and 77% at 2 and 3 years.
Conclusions
In this multicenter prospective study, this strategy of LVAD support combined with a standardized pharmacological and cardiac function monitoring protocol resulted in a high rate of LVAD explantation and was feasible and reproducible with explants occurring in all 6 participating sites. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01774656.



Circulation: 23 Nov 2020; 142:2016-2028
Birks EJ, Drakos SG, Patel SR, Lowes BD, ... Farrar DJ, Rame JE
Circulation: 23 Nov 2020; 142:2016-2028 | PMID: 33100036
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Abstract

Neurocognitive Dysfunction and Smaller Brain Volumes in Adolescents and Adults with a Fontan Circulation.

Verrall CE, Yang JYM, Chen J, Schembri A, ... MacKay MT, Cordina R

Neurocognitive outcomes beyond childhood in people with a Fontan circulation are not well-defined. This study aimed to investigate neurocognitive functioning in adolescents and adults with a Fontan circulation and associations with structural brain injury, brain volumetry and post-natal clinical factors.In a bi-national study, participants with a Fontan circulation without a pre-existing major neurological disability were prospectively recruited from the Australia and New Zealand Fontan Registry. Neurocognitive function was assessed using Cogstate software in 107 Fontan-participants and compared with control groups with transposition of the great arteries (TGA; n=50) and a normal circulation (n=41). Brain MRI with volumetric analysis was performed in the Fontan-participants and compared with healthy control data from the ABIDE I and II and PING data repositories. Clinical data were retrospectively collected.Of the Fontan-participants with neurocognitive assessment, 55% were male and the mean age was 22.6 years (SD 7.8). Fontan-participants performed worse in several areas of neurocognitive function compared with those with TGA and healthy controls (p<0.05). Clinical factors associated with worse neurocognitive outcomes included more inpatient days during childhood, younger age at Fontan and longer time since Fontan procedure (p<0.05). Fontan-adults had more marked neurocognitive dysfunction than Fontan-adolescents in two domains (psychomotor function, p=0.01 and working memory, p=0.02). Structural brain injury was present in the entire Fontan cohort; presence of white matter injury was associated with worse paired associate learning (p<0.001), but neither the presence or severity of infarct, subcortical grey matter injury and microhemorrhage was associated with neurocognitive outcomes. Compared with healthy controls, people with a Fontan circulation had smaller global brain volumes (p<0.001 in all regions) and smaller regional brain volumes in the majority of cerebral cortical regions (p<0.05). Smaller global brain volumes were associated with worse neurocognitive functioning in several domains (p<0.05). A significant positive association was also identified between global brain volumes and resting oxygen saturations (p≤0.04).Neurocognitive impairment is common in adolescents and adults with a Fontan circulation and is associated with smaller grey and white matter brain volume. Understanding modifiable factors that contribute to brain injury to optimize neurocognitive function is paramount.



Circulation: 23 Nov 2020; epub ahead of print
Verrall CE, Yang JYM, Chen J, Schembri A, ... MacKay MT, Cordina R
Circulation: 23 Nov 2020; epub ahead of print | PMID: 33231097
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Abstract

Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis.

Trinder M, Wang Y, Madsen CM, Ponomarev T, ... Boyd JH, Brunham LR

The high-density lipoprotein (HDL) hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors which failed to show significant reductions in cardiovascular events. Plasma levels of HDL-cholesterol (HDL-C) decline drastically during sepsis and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacologic inhibition of CETP would preserve HDL levels and decrease mortality in clinical cohorts and animal models of sepsis.We examined the effect of a gain-of-function variant in(rs1800777, p.Arg468Gln) and a genetic score for decreasedfunction on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5,949), Identification of SNPs Predisposing to Altered Acute Lung Injury Risk (iSPAAR; n=882), Copenhagen General Population Study (n=2,068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St. Paul\'s Intensive Care Unit 2 (n=203), and Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor anacetrapib in adult, female APOE*3-Leiden mice with or with human CETP expression using the cecal-ligation and puncture model of sepsis.A fixed-effect meta-analysis of all 7 cohorts found that thegain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio [95% confidence interval]: 1.44 [1.22-1.70], p<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio [95% confidence interval]: 0.77 [0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio [95% confidence interval]: 0.60 [0.37-0.98] per 1 mmol/L increase HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% vs 35.3%, Log-rank p=0.03), while there was no effect of anacetrapib on the survival of APOE*3-Leiden mice which do not express(50.0% vs 42.9%, Log-rank p=0.87).Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve HDL levels and improve outcomes for individuals with sepsis.



Circulation: 23 Nov 2020; epub ahead of print
Trinder M, Wang Y, Madsen CM, Ponomarev T, ... Boyd JH, Brunham LR
Circulation: 23 Nov 2020; epub ahead of print | PMID: 33228395
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Abstract

Cardiac Pressure Overload Decreases ETV1 Expression in the Left Atrium, Contributing to Atrial Electrical and Structural Remodeling.

Yamaguchi N, Xiao J, Narke D, Shaheen D, ... Chung MK, Park DS

Elevated intracardiac pressure due to heart failure induces electrical and structural remodeling in the left atrium (LA) that begets atrial myopathy and arrhythmias. The underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. The purpose of this study is to characterize the response of the ETV1 signaling axis in the LA during cardiac pressure overload in humans and mouse models and explore the role of ETV1 in atrial electrical and structural remodeling.We performed gene expression profiling in 265 left atrial samples from patients who underwent cardiac surgery. Comparative gene expression profiling was performed between two murine models of cardiac pressure overload, transverse aortic constriction (TAC) banding and Angiotensin II (AngII) infusion, and a genetic model ofcardiomyocyte-selective knockout ().Using the Cleveland Clinic biobank of human LA specimens, we found thatexpression is decreased in patients with reduced ejection fraction. Consistent with its role as an important mediator of the Neuregulin-1 (NRG1) signaling pathway and activator of rapid conduction gene programming, we identified a direct correlation betweenexpression level and , andlevels in human LA samples. In a similar fashion to heart failure patients, we showed that left atrial ETV1 expression is downregulated at the RNA and protein levels in murine pressure overload models. Comparative analysis of LA RNA-seq datasets from TAC and AngII treated mice showed a high Pearson correlation, reflecting a highly ordered process by which the LA undergoes electrical and structural remodeling. Cardiac pressure overload produced a consistent downregulation ofandand upregulation of profibrotic gene programming, which includesand numerous collagen genes.mice displayed atrial conduction disease and arrhythmias. Correspondingly, the LA frommice showed downregulation of rapid conduction genes and upregulation of profibrotic gene programming, whereas analysis of a gain-of-function ETV1 RNA-seq dataset from neonatal rat ventricular myocytes transduced withshowed reciprocal changes.ETV1 is downregulated in the LA during cardiac pressure overload, contributing to both electrical and structural remodeling.



Circulation: 22 Nov 2020; epub ahead of print
Yamaguchi N, Xiao J, Narke D, Shaheen D, ... Chung MK, Park DS
Circulation: 22 Nov 2020; epub ahead of print | PMID: 33225722
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Abstract

Expression Associates with Inflammation in Early Atherosclerosis in Humans and Can be Therapeutically Silenced to Reduce NF-κB Activation and Atherogenesis in Mice.

Karunakaran D, Nguyen MA, Geoffrion M, Vreeken D, ... van Gils JM, Rayner KJ

Chronic activation of the innate immune system drives inflammation and contributes directly to atherosclerosis. Previously, we showed that macrophages in the atherogenic plaque undergo RIPK3-MLKL-dependent programmed necroptosis in response to sterile ligands such as oxidized LDL and damage-associated patterns (DAMPs) and necroptosis is active in advanced atherosclerotic plaques. Upstream of the RIPK3-MLKL necroptotic machinery lies RIPK1, which acts as a master switch that controls whether the cell undergoes NFκB-dependent inflammation, caspase-dependent apoptosis or necroptosis in response to extracellular stimuli. We therefore set out to investigate the role of RIPK1 in the development of atherosclerosis, which is largely driven by NFκB-dependent inflammation at early stages. We hypothesize that, unlike RIPK3 and MLKL, RIPK1 primarily drives NFκB-dependent inflammation in early atherogenic lesions and knocking down RIPK1 will reduce inflammatory cell activation and protect against the progression of atherosclerosis.We examined expression of RIPK1 protein and mRNA in both human and mouse atherosclerotic lesions, and using loss-of-function approaches in vitro in macrophages and endothelial cells to measure inflammatory responses. We administered weekly injections of RIPK1 anti-sense oligonucleotides (ASO) tomice fed a cholesterol-rich (Western) diet for 8 weeks.We find RIPK1 expression is abundant in early-stage atherosclerotic lesions in both humans and mice. Treatment with RIPK1 ASOs led to a reduction in aortic sinus andlesion areas (47.2% or 58.8% decrease relative to control, p<0.01) and plasma inflammatory cytokines (IL-1α, IL-17A, p<0.05) compared to controls.knockdown in macrophages decreased inflammatory genes (NFκB, TNFα, IL-1α) andLPS- and atherogenic diet-induced NF-κB activation. In endothelial cells, knockdown ofprevented NF-κB translocation to the nucleus in response to TNFα, where accordingly there was a reduction in gene expression ofand monocyte attachment.We have identified RIPK1 as a central driver of inflammation in atherosclerosis by its ability to activate the NF-κB pathway and promote inflammatory cytokine release. Given the high levels of RIPK1 expression in human atherosclerotic lesions, our study suggests RIPK1 as a future therapeutic target to reduce residual inflammation in patients at high risk of coronary artery disease.



Circulation: 22 Nov 2020; epub ahead of print
Karunakaran D, Nguyen MA, Geoffrion M, Vreeken D, ... van Gils JM, Rayner KJ
Circulation: 22 Nov 2020; epub ahead of print | PMID: 33222501
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Abstract

Durable Polymer Versus Biodegradable Polymer Drug-Eluting Stents After Percutaneous Coronary Intervention in Patients with Acute Coronary Syndrome: The HOST-REDUCE-POLYTECH-ACS Trial.

Kim HS, Kang J, Hwang D, Han JK, ... Park KW,

Large scale randomized comparison of drug-eluting stents (DES) based on durable polymer (DP) versus biodegradable polymer (BP) technology is currently insufficient in patients with acute coronary syndrome (ACS). The present study sought to prove the non-inferiority of the DP-DES compared with the BP-DES in such patients.The HOST-REDUCE-POLYTECH-ACS trial is an investigator-initiated, randomized, open-label, adjudicator-blinded, multicenter, non-inferiority trial which compared the efficacy and safety of DP-DES and BP-DES in patients with ACS. The primary endpoint was patient oriented composite outcome (POCO, a composite of all-cause death, non-fatal myocardial infarction (MI), and any repeat revascularization) at 12 months. The key secondary endpoint was device oriented composite outcome (DOCO; a composite of cardiac death, target-vessel MI, or target lesion revascularization) at 12 months.A total of 3413 patients were randomized to receive the DP-DES (1713 patients) and BP-DES (1700 patients). At 12 months, POCO occurred in 5.2% in the DP-DES group and 6.4% in the BP-DES group (Absolute risk difference: -1.2%, P<0.001). The key secondary endpoint, DOCO, occurred less frequently in the DP-DES group (DP-DES vs. BP-DES: 2.6% vs. 3.9%, HR 0.67, 95% CI 0.46-0.98, p=0.038), mostly due to a reduction in target lesion revascularization. The rate of spontaneous non-fatal MI and stent thrombosis were extremely low, with no significant difference between the 2 groups (0.6% vs. 0.8%; p=0.513 and 0.1% vs 0.4%; p=0.174, respectively).In ACS patients receiving percutaneous coronary intervention (PCI), DP-DES was non-inferior to BP-DES with regard to POCO at 12 months after index PCI.URL: clinicaltrials.gov Unique identifier: NCT02193971.



Circulation: 17 Nov 2020; epub ahead of print
Kim HS, Kang J, Hwang D, Han JK, ... Park KW,
Circulation: 17 Nov 2020; epub ahead of print | PMID: 33205662
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Abstract

Colchicine in Patients With Acute Coronary Syndrome: The Australian COPS Randomized Clinical Trial.

Tong DC, Quinn S, Nasis A, Hiew C, ... Wilson A, Layland J
Background
Inflammation plays a crucial role in clinical manifestations and complications of acute coronary syndromes (ACS). Colchicine, a commonly used treatment for gout, has recently emerged as a novel therapeutic option in cardiovascular medicine owing to its anti-inflammatory properties. We sought to determine the potential usefulness of colchicine treatment in patients with ACS.
Methods
This was a multicenter, randomized, double-blind, placebo-controlled trial involving 17 hospitals in Australia that provide acute cardiac care service. Eligible participants were adults (18-85 years) who presented with ACS and had evidence of coronary artery disease on coronary angiography managed with either percutaneous coronary intervention or medical therapy. Patients were assigned to receive either colchicine (0.5 mg twice daily for the first month, then 0.5 mg daily for 11 months) or placebo, in addition to standard secondary prevention pharmacotherapy, and were followed up for a minimum of 12 months. The primary outcome was a composite of all-cause mortality, ACS, ischemia-driven (unplanned) urgent revascularization, and noncardioembolic ischemic stroke in a time to event analysis.
Results
A total of 795 patients were recruited between December 2015 and September 2018 (mean age, 59.8±10.3 years; 21% female), with 396 assigned to the colchicine group and 399 to the placebo group. Over the 12-month follow-up, there were 24 events in the colchicine group compared with 38 events in the placebo group (=0.09, log-rank). There was a higher rate of total death (8 versus 1; =0.017, log-rank) and, in particular, noncardiovascular death in the colchicine group (5 versus 0; =0.024, log-rank). The rates of reported adverse effects were not different (colchicine 23.0% versus placebo 24.3%), and they were predominantly gastrointestinal symptoms (colchicine, 23.0% versus placebo, 20.8%).
Conclusions
The addition of colchicine to standard medical therapy did not significantly affect cardiovascular outcomes at 12 months in patients with ACS and was associated with a higher rate of mortality. Registration: URL: https://www.anzctr.org.au; Unique identifier: ACTRN12615000861550.



Circulation: 16 Nov 2020; 142:1890-1900
Tong DC, Quinn S, Nasis A, Hiew C, ... Wilson A, Layland J
Circulation: 16 Nov 2020; 142:1890-1900 | PMID: 32862667
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Abstract

Complex Arrhythmia Syndrome in a Knock-In Mouse Model Carrier of the N98S Mutation.

Tsai WC, Guo S, Olaopa MA, Field LJ, ... Chen PS, Rubart M
Background
Calmodulin mutations are associated with arrhythmia syndromes in humans. Exome sequencing previously identified a de novo mutation inresulting in a p.N98S substitution in a patient with sinus bradycardia and stress-induced bidirectional ventricular ectopy. The objectives of the present study were to determine if mice carrying the N98S mutation knocked intoreplicate the human arrhythmia phenotype and to examine arrhythmia mechanisms.
Methods
Mouse lines heterozygous for the Calm1 allele (Calm1) were generated using CRISPR/Cas9 technology. Adult mutant mice and their wildtype littermates (Calm1) underwent electrocardiographic monitoring. Ventricular de- and repolarization was assessed in isolated hearts using optical voltage mapping. Action potentials and whole-cell currents and [Ca], as well, were measured in single ventricular myocytes using the patch-clamp technique and fluorescence microscopy, respectively. The microelectrode technique was used for in situ membrane voltage monitoring of ventricular conduction fibers.
Results
Two biologically independent knock-in mouse lines heterozygous for the Calm1 allele were generated. Calm1 mice of either sex and line exhibited sinus bradycardia, QT interval prolongation, and catecholaminergic bidirectional ventricular tachycardia. Male mutant mice also showed QRS widening. Pharmacological blockade and activation of β-adrenergic receptors rescued and exacerbated, respectively, the long-QT phenotype of Calm1 mice. Optical and electric assessment of membrane potential in isolated hearts and single left ventricular myocytes, respectively, revealed β-adrenergically induced delay of repolarization. β-Adrenergic stimulation increased peak density, slowed inactivation, and left-shifted the activation curve ofsignificantly more in Calm1 versus Calm1 ventricular myocytes, increasing latein the former. Rapidly paced Calm1 ventricular myocytes showed increased propensity to delayed afterdepolarization-induced triggered activity, whereas in situ His-Purkinje fibers exhibited increased susceptibility for pause-dependent early afterdepolarizations. Epicardial mapping of Calm1 hearts showed that both reentry and focal mechanisms contribute to arrhythmogenesis.
Conclusions
Heterozygosity for themutation is causative of an arrhythmia syndrome characterized by sinus bradycardia, QRS widening, adrenergically mediated QTc interval prolongation, and bidirectional ventricular tachycardia. β-Adrenergically induceddysregulation contributes to the long-QT phenotype. Pause-dependent early afterdepolarizations and tachycardia-induced delayed afterdepolarizations originating in the His-Purkinje network and ventricular myocytes, respectively, constitute potential sources of arrhythmia in Calm1 hearts.



Circulation: 16 Nov 2020; 142:1937-1955
Tsai WC, Guo S, Olaopa MA, Field LJ, ... Chen PS, Rubart M
Circulation: 16 Nov 2020; 142:1937-1955 | PMID: 32929985
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Abstract

Metabolic Architecture of Acute Exercise Response in Middle-Aged Adults in the Community.

Nayor M, Shah RV, Miller PE, Blodgett JB, ... Vasan RS, Lewis GD
Background
Whereas regular exercise is associated with lower risk of cardiovascular disease and mortality, mechanisms of exercise-mediated health benefits remain less clear. We used metabolite profiling before and after acute exercise to delineate the metabolic architecture of exercise response patterns in humans.
Methods
Cardiopulmonary exercise testing and metabolite profiling was performed on Framingham Heart Study participants (age 53±8 years, 63% women) with blood drawn at rest (n=471) and at peak exercise (n=411).
Results
We observed changes in circulating levels for 502 of 588 measured metabolites from rest to peak exercise (exercise duration 11.9±2.1 minutes) at a 5% false discovery rate. Changes included reductions in metabolites implicated in insulin resistance (glutamate, -29%; =1.5×10; dimethylguanidino valeric acid [DMGV], -18%; =5.8×10) and increases in metabolites associated with lipolysis (1-methylnicotinamide, +33%; =6.1×10), nitric oxide bioavailability (arginine/ornithine + citrulline, +29%; =2.8×10), and adipose browning (12,13-dihydroxy-9Z-octadecenoic acid +26%; =7.4×10), among other pathways relevant to cardiometabolic risk. We assayed 177 metabolites in a separate Framingham Heart Study replication sample (n=783, age 54±8 years, 51% women) and observed concordant changes in 164 metabolites (92.6%) at 5% false discovery rate. Exercise-induced metabolite changes were variably related to the amount of exercise performed (peak workload), sex, and body mass index. There was attenuation of favorable excursions in some metabolites in individuals with higher body mass index and greater excursions in select cardioprotective metabolites in women despite less exercise performed. Distinct preexercise metabolite levels were associated with different physiologic dimensions of fitness (eg, ventilatory efficiency, exercise blood pressure, peak Vo). We identified 4 metabolite signatures of exercise response patterns that were then analyzed in a separate cohort (Framingham Offspring Study; n=2045, age 55±10 years, 51% women), 2 of which were associated with overall mortality over median follow-up of 23.1 years (≤0.003 for both).
Conclusions
In a large sample of community-dwelling individuals, acute exercise elicits widespread changes in the circulating metabolome. Metabolic changes identify pathways central to cardiometabolic health, cardiovascular disease, and long-term outcome. These findings provide a detailed map of the metabolic response to acute exercise in humans and identify potential mechanisms responsible for the beneficial cardiometabolic effects of exercise for future study.



Circulation: 16 Nov 2020; 142:1905-1924
Nayor M, Shah RV, Miller PE, Blodgett JB, ... Vasan RS, Lewis GD
Circulation: 16 Nov 2020; 142:1905-1924 | PMID: 32927962
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Abstract

A Unique Population of Regulatory T Cells in Heart Potentiates Cardiac Protection From Myocardial Infarction.

Xia N, Lu Y, Gu M, Li N, ... Yang X, Cheng X
Background
Regulatory T cells (Tregs), traditionally recognized as potent suppressors of immune response, are increasingly attracting attention because of a second major function: residing in parenchymal tissues and maintaining local homeostasis. However, the existence, unique phenotype, and function of so-called tissue Tregs in the heart remain unclear.
Methods
In mouse models of myocardial infarction (MI), myocardial ischemia/reperfusion injury, or cardiac cryoinjury, the dynamic accumulation of Tregs in the injured myocardium was monitored. The bulk RNA sequencing was performed to analyze the transcriptomic characteristics of Tregs from the injured myocardium after MI or ischemia/reperfusion injury. Photoconversion, parabiosis, single-cell T-cell receptor sequencing, and adoptive transfer were applied to determine the source of heart Tregs. The involvement of the interleukin-33/suppression of tumorigenicity 2 axis and Sparc (secreted acidic cysteine-rich glycoprotein), a molecule upregulated in heart Tregs, was further evaluated in functional assays.
Results
We showed that Tregs were highly enriched in the myocardium of MI, ischemia/reperfusion injury, and cryoinjury mice. Transcriptomic data revealed that Tregs isolated from the injured hearts had plenty of differentially expressed transcripts in comparison with their lymphoid counterparts, including heart-draining lymphoid nodes, with a phenotype of promoting infarct repair, indicating a unique characteristic. The heart Tregs were accumulated mainly because of recruitment from the circulating Treg pool, whereas local proliferation also contributed to their expansion. Moreover, a remarkable case of repeatedly detected T-cell receptor of heart Tregs, more than that of spleen Tregs, suggests a model of clonal expansion. Besides, HeliosNrp-1 phenotype proved the mainly thymic origin of heart Tregs, with a small contribution of phenotypic conversion of conventional CD4 T cells, proved by the analysis of T-cell receptor repertoires and conventional CD4 T cells adoptive transfer experiments. The interleukin-33/suppression of tumorigenicity 2 axis was essential for sustaining heart Treg populations. Last, we demonstrated that Sparc, which was highly expressed by heart Tregs, acted as a critical factor to protect the heart against MI by increasing collagen content and boosting maturation in the infarct zone.
Conclusions
We identified and characterized a phenotypically and functionally unique population of heart Tregs that may lay the foundation to harness Tregs for cardioprotection in MI and other cardiac diseases.



Circulation: 16 Nov 2020; 142:1956-1973
Xia N, Lu Y, Gu M, Li N, ... Yang X, Cheng X
Circulation: 16 Nov 2020; 142:1956-1973 | PMID: 32985264
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Abstract

Contemporary Diagnosis and Management of Rheumatic Heart Disease: Implications for Closing the Gap: A Scientific Statement From the American Heart Association.

Kumar RK, Antunes MJ, Beaton A, Mirabel M, ... Sable C,

The global burden of rheumatic heart disease continues to be significant although it is largely limited to poor and marginalized populations. In most endemic regions, affected patients present with heart failure. This statement will seek to examine the current state-of-the-art recommendations and to identify gaps in diagnosis and treatment globally that can inform strategies for reducing disease burden. Echocardiography screening based on World Heart Federation echocardiographic criteria holds promise to identify patients earlier, when prophylaxis is more likely to be effective; however, several important questions need to be answered before this can translate into public policy. Population-based registries effectively enable optimal care and secondary penicillin prophylaxis within available resources. Benzathine penicillin injections remain the cornerstone of secondary prevention. Challenges with penicillin procurement and concern with adverse reactions in patients with advanced disease remain important issues. Heart failure management, prevention, early diagnosis and treatment of endocarditis, oral anticoagulation for atrial fibrillation, and prosthetic valves are vital therapeutic adjuncts. Management of health of women with unoperated and operated rheumatic heart disease before, during, and after pregnancy is a significant challenge that requires a multidisciplinary team effort. Patients with isolated mitral stenosis often benefit from percutaneous balloon mitral valvuloplasty. Timely heart valve surgery can mitigate the progression to heart failure, disability, and death. Valve repair is preferable over replacement for rheumatic mitral regurgitation but is not available to the vast majority of patients in endemic regions. This body of work forms a foundation on which a companion document on advocacy for rheumatic heart disease has been developed. Ultimately, the combination of expanded treatment options, research, and advocacy built on existing knowledge and science provides the best opportunity to address the burden of rheumatic heart disease.



Circulation: 16 Nov 2020; 142:e337-e357
Kumar RK, Antunes MJ, Beaton A, Mirabel M, ... Sable C,
Circulation: 16 Nov 2020; 142:e337-e357 | PMID: 33073615
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Abstract

The American Heart Association\'s Call to Action for Reducing the Global Burden of Rheumatic Heart Disease: A Policy Statement From the American Heart Association.

Beaton A, Kamalembo FB, Dale J, Kado JH, ... Carapetis J,

Rheumatic heart disease (RHD) affects ≈40 million people and claims nearly 300 000 lives each year. The historic passing of a World Health Assembly resolution on RHD in 2018 now mandates a coordinated global response. The American Heart Association is committed to serving as a global champion and leader in RHD care and prevention. Here, we pledge support in 5 key areas: (1) professional healthcare worker education and training, (2) technical support for the implementation of evidence-based strategies for rheumatic fever/RHD prevention, (3) access to essential medications and technologies, (4) research, and (5) advocacy to increase global awareness, resources, and capacity for RHD control. In bolstering the efforts of the American Heart Association to combat RHD, we hope to inspire others to collaborate, communicate, and contribute.



Circulation: 16 Nov 2020; 142:e358-e368
Beaton A, Kamalembo FB, Dale J, Kado JH, ... Carapetis J,
Circulation: 16 Nov 2020; 142:e358-e368 | PMID: 33070654
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Abstract

Racial and Ethnic Differences in Presentation and Outcomes for Patients Hospitalized with COVID-19: Findings from the American Heart Association\'s COVID-19 Cardiovascular Disease Registry.

Rodriguez F, Solomon N, de Lemos JA, Das SR, ... Yancy CW, Wang TY

The COVID-19 pandemic has exposed longstanding racial/ethnic inequities in health risks and outcomes in the U.S.. We sought to identify racial/ethnic differences in presentation and outcomes for patients hospitalized with COVID-19.The American Heart Association COVID-19 Cardiovascular Disease Registry is a retrospective observational registry capturing consecutive patients hospitalized with COVID-19. We present data on the first 7,868 patients by race/ethnicity treated at 88 hospitals across the US between 01/17/2020 and 7/22/2020. The primary outcome was in-hospital mortality; secondary outcomes included major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, heart failure) and COVID-19 cardiorespiratory ordinal severity score (worst to best: death, cardiac arrest, mechanical ventilation with mechanical circulatory support, mechanical ventilation with vasopressors/inotrope support, mechanical ventilation without hemodynamic support, and hospitalization without any of the above). Multivariable logistic regression analyses were performed to assess the relationship between race/ethnicity and each outcome adjusting for differences in sociodemographic, clinical, and presentation features, and accounting for clustering by hospital.Among 7,868 patients hospitalized with COVID-19, 33.0% were Hispanic, 25.5% were non-Hispanic Black, 6.3% were Asian, and 35.2% were non-Hispanic White. Hispanic and Black patients were younger than non-Hispanic White and Asian patients and were more likely to be uninsured. Black patients had the highest prevalence of obesity, hypertension, and diabetes. Black patients also had the highest rates of mechanical ventilation (23.2%) and renal replacement therapy (6.6%) but the lowest rates of remdesivir use (6.1%). Overall mortality was 18.4% with 53% of all deaths occurring in Black and Hispanic patients. The adjusted odds ratios (ORs) for mortality were 0.93 (95% confidence interval [CI] 0.76-1.14) for Black patients, 0.90 (95% CI 0.73-1.11) for Hispanic patients, and 1.31 (95% CI 0.96-1.80) for Asian patients compared with non-Hispanic White patients. The median OR across hospitals was 1.99 (95% CI 1.74-2.48). Results were similar for MACE. Asian patients had the highest COVID-19 cardiorespiratory severity at presentation (adjusted OR 1.48, 95% CI 1.16-1.90).Although in-hospital mortality and MACE did not differ by race/ethnicity after adjustment, Black and Hispanic patients bore a greater burden of mortality and morbidity due to their disproportionate representation among COVID-19 hospitalizations.



Circulation: 16 Nov 2020; epub ahead of print
Rodriguez F, Solomon N, de Lemos JA, Das SR, ... Yancy CW, Wang TY
Circulation: 16 Nov 2020; epub ahead of print | PMID: 33200953
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Abstract

Benefit-Risk Tradeoffs in Assessment of New Drugs and Devices.

Kaul S, Stockbridge N, Butler J

Balancing benefits and risks is a complex task that poses a major challenge, both to the approval of new medicines and devices by regulatory authorities and in therapeutic decision-making in practice. Several analysis methods and visualization tools have been developed to help evaluate and communicate whether the benefit-risk profile is favorable or unfavorable. In this White Paper, we describe approaches to benefit-risk assessment using qualitative approaches such as the Benefit Risk Action Team framework developed by the Pharmaceutical Research and Manufacturers of America, and the Benefit-Risk Framework developed by the United States Food and Drug Administration; and quantitative approaches such as the numbers needed to treat for benefit and harm, the benefit-risk ratio, and Incremental Net Benefit. We give illustrative examples of benefit-risk evaluations using 4 treatment interventions including sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes; a direct antithrombin agent, dabigatran, for reducing stroke and systemic embolism in patients with nonvalvular atrial fibrillation; transcatheter aortic valve replacement in patients with symptomatic severe aortic valve stenosis; and antiplatelet agents vorapaxar and prasugrel for reducing cardiovascular events in patients at high cardiovascular risk. Regular applications of structured benefit-risk assessment, whether qualitative, quantitative, or both, enabled by easy-to-understand graphical presentations that capture uncertainties around the benefit-risk metric, may aid shared decision-making and enhance transparency of those decisions.



Circulation: 16 Nov 2020; 142:1974-1988
Kaul S, Stockbridge N, Butler J
Circulation: 16 Nov 2020; 142:1974-1988 | PMID: 33196311
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Abstract

Risk Factor Control and Cardiovascular Event Risk in People With Type 2 Diabetes in Primary and Secondary Prevention Settings.

Wright AK, Suarez-Ortegon MF, Read SH, Kontopantelis E, ... Wild SH, Rutter MK
Background
To examine the association between the degree of risk factor control and cardiovascular disease (CVD) risk in type 2 diabetes and to assess if the presence of cardio-renal disease modifies these relationships.
Methods
A retrospective cohort study using data from English practices from CPRD GOLD (Clinical Practice Research Datalink) and the SCI-Diabetes dataset (Scottish Care Information-Diabetes), with linkage to hospital and mortality data. We identified 101 749 with type 2 diabetes (T2D) in CPRD matched with 378 938 controls without diabetes and 330 892 with type 2 diabetes in SCI-Diabetes between 2006 and 2015. The main exposure was number of optimized risk factors: nonsmoker, total cholesterol ≤4 mmol/L, triglycerides ≤1.7 mmol/L, glycated haemoglobin (HbA1c) ≤53 mmol/mol (≤7.0%), systolic blood pressure <140mm Hg, or <130 mm Hg if high risk. Cox models were used to assess cardiovascular risk associated with levels of risk factor control.
Results
In CPRD, the mean baseline age in T2D was 63 years and 28% had cardio-renal disease (SCI-Diabetes: 62 years; 35% cardio-renal disease). Over 3 years follow-up (SCI-Diabetes: 6 years), CVD events occurred among 27 900 (27%) CPRD-T2D, 101 362 (31%) SCI-Diabetes-T2D, and 75 520 (19%) CPRD-controls. In CPRD, compared with controls, T2D participants with optimal risk factor control (all risk factors controlled) had a higher risk of CVD events (adjusted hazard ratio, 1.21; 95% confidence interval, 1.12-1.29). In T2D participants from CPRD and SCI-Diabetes, pooled hazard ratios for CVD associated with 5 risk factors being elevated versus optimal risk factor control were 1.09 (95% confidence interval, 1.01-1.17) in people with cardio-renal disease but 1.96 (95% confidence interval, 1.82-2.12) in people without cardio-renal disease. People without cardio-renal disease were younger and more likely to have likely to have suboptimal risk factor control but had fewer prescriptions for risk factor modifying medications than those with cardio-renal disease.
Conclusions
Optimally managed people with T2D have a 21% higher CVD risk when compared with controls. People with T2D without cardio-renal disease would be predicted to benefit greatly from CVD risk factor intervention.



Circulation: 16 Nov 2020; 142:1925-1936
Wright AK, Suarez-Ortegon MF, Read SH, Kontopantelis E, ... Wild SH, Rutter MK
Circulation: 16 Nov 2020; 142:1925-1936 | PMID: 33196309
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