Journal: Circulation

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Abstract

A Notch3-Marked Subpopulation of Vascular Smooth Muscle Cells is the Cell of Origin for Occlusive Pulmonary Vascular Lesions.

Steffes LC, Froistad AA, Andruska A, Boehm M, ... Spiekerkoetter E, Kumar ME

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by profound vascular remodeling in which pulmonary arteries narrow due to medial thickening and occlusion by neointimal lesions, resulting in elevated pulmonary vascular resistance and right heart failure. Therapies targeting the neointima would represent a significant advance in PAH treatment, however our understanding of the cellular events driving neointima formation, and the molecular pathways that control them, remains limited.We comprehensively map the stepwise remodeling of pulmonary arteries in a robust, chronic inflammatory mouse model of pulmonary hypertension. This model demonstrates pathologic features of the human disease, including increased right ventricular pressures, medial thickening, neointimal lesion formation, elastin breakdown, increased anastomosis within the bronchial circulation, and perivascular inflammation. Using genetic lineage tracing, clonal analysis, multiplexedhybridization, immunostaining, deep confocal imaging and staged pharmacologic inhibition we define the cell behaviors underlying each stage of vascular remodeling and identify a pathway required for neointima formation.Neointima arises from smooth muscle cells (SMCs) and not endothelium. Medial SMCs proliferate broadly to thicken the media, after which a small number of SMCs are selected to establish the neointima. These neointimal founder cells subsequently undergoing massive clonal expansion to form occlusive neointimal lesions. The normal pulmonary artery SMC population is heterogeneous and we identify a Notch3-marked minority subset of SMCs as the major neointimal cell of origin. Notch signaling is specifically required for the selection of neointimal founder cells, and Notch inhibition significantly improves pulmonary artery pressure in animals with pulmonary hypertension.This work describes the first nongenetically driven murine model of PH that generates robust and diffuse occlusive neointimal lesions across the pulmonary vascular bed and does so in a stereotyped timeframe. We uncover distinct cellular and molecular mechanisms underlying medial thickening and neointima formation and highlight novel transcriptional, behavioral and pathogenic heterogeneity within pulmonary artery SMCs. In this model, inflammation is sufficient to generate characteristic vascular pathologies and physiologic measures of human PAH. We hope that identifying the molecular cues regulating each stage of vascular remodeling will open new avenues for therapeutic advancements in the treatment of PAH.



Circulation: 13 Aug 2020; epub ahead of print
Steffes LC, Froistad AA, Andruska A, Boehm M, ... Spiekerkoetter E, Kumar ME
Circulation: 13 Aug 2020; epub ahead of print | PMID: 32794408
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Abstract

Pathogenic Autoimmunity in Atherosclerosis Evolves from Initially Protective ApoB-Reactive CD4 T-Regulatory Cells.

Wolf D, Gerhardt T, Winkels H, Anto Michel N, ... Sette A, Ley K

Throughout the inflammatory response that accompanies atherosclerosis, autoreactive CD4 T-helper cells accumulate in the atherosclerotic plaque. Apolipoprotein B-100 (ApoB), the core protein of low-density lipoprotein (LDL), is an autoantigen that drives the generation of pathogenic T-helper type 1 (T1) cells with pro-inflammatory cytokine secretion. Clinical data suggest the existence of ApoB-specific CD4 T cells with an atheroprotective, regulatory T cell (T) phenotype in healthy individuals. Yet, the function of ApoB-reactive T and their relationship with pathogenic T1 cells remain unknown.To interrogate the function of autoreactive CD4+ T cells in atherosclerosis, we used a novel tetramer of MHC-II to track T cells reactive to the mouse self-peptide ApoB (ApoB) on a single cell level.We found that ApoB T cells build an oligoclonal population in lymph nodes of healthy mice that exhibit a T-like transcriptome, although only 21% of all ApoB T cells expressed the T-transcription factor FoxP3 protein as detected by flow cytometry. In single-cell RNAsequencing (scRNAseq), ApoB T cells formed several clusters with mixed T-signatures that suggested overlapping multilineage phenotypes with pro- and anti-inflammatory transcripts of T helper cells type -1, -2, -17, and of follicular-helper T cells. ApoB T cells were increased in mice and humans with atherosclerosis and progressively converted into pathogenic T1-/T17- like cells with pro-inflammatory properties and only a residual T transcriptome. Consistently, plaque T cells that expanded during progression of atherosclerosis showed a mixed T1-/T17 phenotype in scRNAseq. In addition, we observed a loss of FoxP3 in a fraction of ApoB T in lineage tracing of hyperlipidemicmice. In adoptive transfer experiments, converting ApoB T failed to protect from atherosclerosis.Our results demonstrate an unexpected mixed phenotype of ApoB-reactive autoimmune T cells in atherosclerosis and suggest an initially protective autoimmune response against ApoB with a progressive derangement in clinical disease. These findings identify ApoB auto-reactive T as a novel cellular target in atherosclerosis.



Circulation: 23 Jul 2020; epub ahead of print
Wolf D, Gerhardt T, Winkels H, Anto Michel N, ... Sette A, Ley K
Circulation: 23 Jul 2020; epub ahead of print | PMID: 32703007
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Abstract

Fontan-Associated Liver Disease: Screening, Management, and Transplant Considerations.

Emamaullee J, Zaidi AN, Schiano T, Kahn J, ... Bucuvalas J, Fischer R

Surgical innovation and multidisciplinary management have allowed children born with univentricular physiology congenital heart disease to survive into adulthood. An estimated global population of 70 000 patients have undergone the Fontan procedure and are alive today, most of whom are <25 years of age. Several unexpected consequences of the Fontan circulation include Fontan-associated liver disease. Surveillance biopsies have demonstrated that virtually 100% of these patients develop clinically silent fibrosis by adolescence. As they mature, there are increasing reports of combined heart-liver transplantation resulting from advanced liver disease, including bridging fibrosis, cirrhosis, and hepatocellular carcinoma, in this population. In the absence of a transplantation option, these young patients face a poor quality of life and overall survival. Acknowledging that there are no consensus guidelines for diagnosing and monitoring Fontan-associated liver disease or when to consider heart transplantation versus combined heart-liver transplantation in these patients, a multidisciplinary working group reviewed the literature surrounding Fontan-associated liver disease, with a specific focus on considerations for transplantation.



Circulation: 10 Aug 2020; 142:591-604
Emamaullee J, Zaidi AN, Schiano T, Kahn J, ... Bucuvalas J, Fischer R
Circulation: 10 Aug 2020; 142:591-604 | PMID: 32776846
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Abstract

Medical Marijuana, Recreational Cannabis, and Cardiovascular Health: A Scientific Statement From the American Heart Association.

Page RL, Allen LA, Kloner RA, Carriker CR, ... Saucedo JF,

Cannabis, or marijuana, has potential therapeutic and medicinal properties related to multiple compounds, particularly Δ-9-tetrahydrocannabinol and cannabidiol. Over the past 25 years, attitudes toward cannabis have evolved rapidly, with expanding legalization of medical and recreational use at the state level in the United States and recreational use nationally in Canada and Uruguay. As a result, the consumption of cannabis products is increasing considerably, particularly among youth. Our understanding of the safety and efficacy of cannabis has been limited by decades of worldwide illegality and continues to be limited in the United States by the ongoing classification of cannabis as a Schedule 1 controlled substance. These shifts in cannabis use require clinicians to understand conflicting laws, health implications, and therapeutic possibilities. Cannabis may have therapeutic benefits, but few are cardiovascular in nature. Conversely, many of the concerning health implications of cannabis include cardiovascular diseases, although they may be mediated by mechanisms of delivery. This statement critically reviews the use of medicinal and recreational cannabis from a clinical but also a policy and public health perspective by evaluating its safety and efficacy profile, particularly in relationship to cardiovascular health.



Circulation: 04 Aug 2020:CIR0000000000000883; epub ahead of print
Page RL, Allen LA, Kloner RA, Carriker CR, ... Saucedo JF,
Circulation: 04 Aug 2020:CIR0000000000000883; epub ahead of print | PMID: 32752884
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Abstract

Atrial Fibrillation and Dementia.

Bunch TJ

Atrial fibrillation is associated with multiple adverse comorbidities, including the development of dementia in patients with and without a history of stroke. Mechanistic models have been proposed to explain the association of AF and dementia. Alterations of brain perfusion from embolic events, bleeding, and rhythm-related hypoperfusion underlie many of these models. Multiple mediators such as oxidative injury, inflammatory and autoimmune mechanisms, and genetic predisposition also interplay in the disease association. There are potential therapeutic opportunities to reduce dementia risk, including early and effective use of anticoagulation and strategies to improve brain perfusion through rhythm and rate control approaches. Prospective trials are needed to evaluate these therapeutic opportunities that carefully measure cognitive function and dementia incidence.



Circulation: 17 Aug 2020; 142:618-620
Bunch TJ
Circulation: 17 Aug 2020; 142:618-620 | PMID: 32804567
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Abstract

4HNE Impairs Myocardial Bioenergetics in Congenital Heart DiseaseInduced Right Ventricular Failure.

Hwang HV, Sandeep N, Paige SL, Ranjbarvaziri S, ... Bernstein D, Reddy S

In patients with complex congenital heart disease, such as those with tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload stress, leading to RV hypertrophy and eventually RV failure. The role of lipid peroxidation, a potent form of oxidative stress, in mediating RV hypertrophy and failure in congenital heart disease is unknown.Lipid peroxidation and mitochondrial function and structure were assessed in RV myocardium collected from patients with RV hypertrophy with normal RV systolic function (RV FAC 47.3±3.8%) and in patients with RV failure showing decreased RV systolic function (RV FAC 26.6±3.1%). The mechanism of the effect of lipid peroxidation, mediated by 4-hydroxynonenal (4HNE; a byproduct of lipid peroxidation) on mitochondrial function and structure was assessed in HL1 murine cardiomyocytes and human induced pluripotent stem cellderived cardiomyocytes.RV failure was characterized by an increase in 4HNE adduction of metabolic and mitochondrial proteins (16/27 identified proteins), in particular electron transport chain proteins. Sarcomeric (myosin) and cytoskeletal proteins (desmin, tubulin) also underwent 4HNEadduction. RV failure showed lower oxidative phosphorylation [moderate RV hypertrophy 287.6±19.75 vs. RV failure 137.8±11.57 pmol/(sec*ml), p=0.0004], and mitochondrial structural damage. Using a cell model, we show that 4HNE decreases cell number and oxidative phosphorylation (control 388.1±23.54 vs. 4HNE 143.7±11.64 pmol/(sec*ml), p<0.0001). Carvedilol, a known antioxidant did not decrease 4HNE adduction of metabolic and mitochondrial proteins and did not improve oxidative phosphorylation.Metabolic, mitochondrial, sarcomeric and cytoskeletal proteins are susceptible to 4HNE-adduction in patients with RV failure. 4HNE decreases mitochondrial oxygen consumption by inhibiting electron transport chain complexes. Carvedilol did not improve the 4HNE-mediated decrease in oxygen consumption. Strategies to decrease lipid peroxidation could improve mitochondrial energy generation and cardiomyocyte survival and improve RV failure in patients with congenital heart disease.



Circulation: 17 Aug 2020; epub ahead of print
Hwang HV, Sandeep N, Paige SL, Ranjbarvaziri S, ... Bernstein D, Reddy S
Circulation: 17 Aug 2020; epub ahead of print | PMID: 32806952
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Abstract

Venous Thromboembolism Research Priorities: A Scientific Statement From the American Heart Association and the International Society on Thrombosis and Haemostasis.

Cushman M, Barnes GD, Creager MA, Diaz JA, ... Wolberg AS,

Venous thromboembolism is a major cause of morbidity and mortality. The impact of the US Surgeon General\'sin 2008 has been lower than expected given the public health impact of this disease. This scientific statement highlights future research priorities in venous thromboembolism, developed by experts and a crowdsourcing survey across 16 scientific organizations. At the fundamental research level (T0), researchers need to identify pathobiological causative mechanisms for the 50% of patients with unprovoked venous thromboembolism and to better understand mechanisms that differentiate hemostasis from thrombosis. At the human level (T1), new methods for diagnosing, treating, and preventing venous thromboembolism will allow tailoring of diagnostic and therapeutic approaches to individuals. At the patient level (T2), research efforts are required to understand how foundational evidence impacts care of patients (eg, biomarkers). New treatments, such as catheter-based therapies, require further testing to identify which patients are most likely to experience benefit. At the practice level (T3), translating evidence into practice remains challenging. Areas of overuse and underuse will require evidence-based tools to improve care delivery. At the community and population level (T4), public awareness campaigns need thorough impact assessment. Large population-based cohort studies can elucidate the biological and environmental underpinnings of venous thromboembolism and its complications. To achieve these goals, funding agencies and training programs must support a new generation of scientists and clinicians who work in multidisciplinary teams to solve the pressing public health problem of venous thromboembolism.



Circulation: 10 Aug 2020; 142:e85-e94
Cushman M, Barnes GD, Creager MA, Diaz JA, ... Wolberg AS,
Circulation: 10 Aug 2020; 142:e85-e94 | PMID: 32776842
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Abstract

Biomarkers Enhance Discrimination and Prognosis of Type 2 Myocardial Infarction.

Horiuchi Y, Wettersten N, Patel MP, Mueller C, ... Peacock WF, Maisel AS

The observed incidence of type 2 myocardial infarction (T2MI) is expected to increase with the implementation of increasingly sensitive cardiac troponin (cTn) assays. However, it remains to be determined how to diagnose, risk stratify and treat patients with T2MI. We aimed to discriminate and risk-stratify T2MI using biomarkers.Patients presenting to the Emergency Department with chest pain, enrolled in the CHOPIN study, were retrospectively analyzed. Two cardiologists adjudicated type 1 MI (T1MI) and T2MI. The prognostic ability of several biomarkers alone or in combination to discriminate T2MI from T1MI was investigated using receiver operating characteristic (ROC) curve analysis. The biomarkers analyzed were cTnI, copeptin, mid-regional pro-atrial natriuretic peptide (MRproANP), C-terminal pro-endothelin-1 (CT-proET1), mid-regional pro-adrenomedullin (MRproADM) and procalcitonin. Prognostic utility of these biomarkers for all-cause mortality and major adverse cardiovascular event (MACE: a composite of acute MI, unstable angina pectoris, reinfarction, heart failure, and stroke) at 180-day follow-up was also investigated.Among the 2071 patients, T1MI and T2MI were adjudicated in 94 and 176 patients, respectively. Patients with T1MI had higher levels of baseline cTnI, while those with T2MI had higher baseline levels of MR-proANP, CT-proET1, MR-proADM, and procalcitonin. The area under the ROC curve (AUC) for the diagnosis of T2MI was higher for CT-proET1, MRproADM and MR-proANP (0.765, 0.750, and 0.733, respectively) than for cTnI (0.631). Combining all biomarkers resulted in a similar accuracy to a model using clinical variables and cTnI (0.854 versus 0.884, p = 0.294). Addition of biomarkers to the clinical model yielded the highest AUC (0.917). Other biomarkers, but not cTnI, were associated with mortality and MACE at 180-day among all patients, with no interaction between the diagnosis of T1MI or T2MI.Assessment of biomarkers reflecting pathophysiologic processes occurring with T2MI might help differentiate it from T1MI. Additionally, all biomarkers measured, except cTnI, were significant predictors of prognosis, regardless of type of MI.



Circulation: 20 Aug 2020; epub ahead of print
Horiuchi Y, Wettersten N, Patel MP, Mueller C, ... Peacock WF, Maisel AS
Circulation: 20 Aug 2020; epub ahead of print | PMID: 32820656
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Abstract

General versus Local Anesthesia with Conscious Sedation in Transcatheter Aortic Valve Implantation: The Randomized SOLVE-TAVI Trial.

Thiele H, Kurz T, Feistritzer HJ, Stachel G, ... de Waha-Thiele S,

In clinical practice, local anesthesia with conscious sedation (CS) is performed in roughly 50% of patients undergoing transcatheter aortic valve replacement (TAVR). However, no randomized data assessing the safety and efficacy of CS versus general anesthesia (GA) are available.SOLVE-TAVI is a multicenter, open-label, 2x2 factorial, randomized trial of 447 patients with aortic stenosis undergoing transfemoral TAVR comparing CS versus GA. The primary efficacy endpoint was powered for equivalence (equivalence margin 10% with significance level 0.05) and consisted of the composite of all-cause mortality, stroke, myocardial infarction, infection requiring antibiotic treatment, and acute kidney injury at 30 days.The primary composite endpoint occurred in 27.2% of CS and 26.4% of GA patients (rate difference 0.8 [90%CI -6.2 to 7.8]; P=0.015). Event rates for the individual components were as follows: all-cause mortality 3.2% versus 2.3% (rate difference 1.0 [90%CI - 2.9 to 4.8]; P<0.001), stroke 2.4% versus 2.8% (rate difference -0.4 [90%CI -3.8 to 3.8]; P<0.001), myocardial infarction 0.5% versus 0.0% (rate difference 0.5 [90%CI -3.0 to 3.9]; P<0.001), infection requiring antibiotics 21.1% versus 22.0% (rate difference -0.9 [90%CI -7.5 to 5.7]; P=0.011), acute kidney injury 9.0% versus 9.2% (rate difference - 0.2 [90%CI -5.2 to 4.8]; P=0.0005). There was a lower need for inotropes or vasopressors with CS (62.8%) versus GA (97.3%) (rate difference -34.4 [90%CI -41.0 to -27.8]).Among patients with aortic stenosis undergoing transfemoral TAVR, use of CS compared with GA resulted in similar outcomes for the primary efficacy endpoint. These findings suggest that CS can be safely applied for TAVR.URL: https://clinicaltrials.gov Unique Identifier: NCT02737150.



Circulation: 20 Aug 2020; epub ahead of print
Thiele H, Kurz T, Feistritzer HJ, Stachel G, ... de Waha-Thiele S,
Circulation: 20 Aug 2020; epub ahead of print | PMID: 32819145
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Abstract

MDM2-Mediated Ubiquitination of ACE2 Contributes to the Development of Pulmonary Arterial Hypertension.

Shen H, Zhang J, Wang C, Jain PP, ... Yuan JX, Shyy JY

Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II (Ang II), a potent vasoconstrictor, to Ang 1-7 and is also a membrane protein that enables COVID-19 infectivity. AMP-activated protein kinase (AMPK) phosphorylation of ACE2 enhances ACE2 stability. This mode of post-translational modification (PTM) of ACE2 in vascular endothelial cells (ECs) is causative of a pulmonary hypertension (PH)-protective phenotype. The oncoprotein murine double minute 2 (MDM2) is an E3 ligase that ubiquitinates its substrates to cause their degradation. In this study, we investigated whether MDM2 is involved in the PTM of ACE2 via its ubiquitination of ACE2, and whether an AMPK and MDM2 crosstalk regulates the pathogenesis of PH.Bioinformatic analyses were used to explore E3 ligase that ubiquitinates ACE2. Cultured endothelial cells, mouse models, and specimens from patients with idiopathic pulmonary arterial hypertension were used to investigate the crosstalk between AMPK and MDM2 in regulating ACE2 phosphorylation and ubiquitination in the context of PH.Levels of MDM2 were increased and those of ACE2 decreased in lung tissues or pulmonary arterial endothelial cells from patients with idiopathic pulmonary arterial hypertension and rodent models of experimental PH. MDM2 inhibition by JNJ-165 reversed the SU5416/hypoxia-induced PH in C57BL/6 mice. ACE2-S680L mice (dephosphorylation at S680) showed PH susceptibility, and ectopic expression of ACE2-S680L/K788R (deubiquitination at K788) reduced experimental PH. Moreover, ACE2-K788R overexpression in mice with endothelial cell-specific AMPKα2 knockout mitigated PH.Maladapted PTM (phosphorylation and ubiquitination) of ACE2 at Ser-680 and Lys-788 is involved in the pathogenesis of pulmonary arterial hypertension and experimental PH. Thus, a combined intervention of AMPK and MDM2 in the pulmonary endothelium might be therapeutically effective in PH treatment.



Circulation: 27 Jul 2020; epub ahead of print
Shen H, Zhang J, Wang C, Jain PP, ... Yuan JX, Shyy JY
Circulation: 27 Jul 2020; epub ahead of print | PMID: 32755395
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Abstract

A Reservoir of Fibroblasts Promotes Recovery from Limb Ischemia.

Meng S, Lv J, Chanda PK, Owusu I, Chen K, Cooke JP

The angiogenic response to ischemia restores perfusion so as to preserve tissue. A role for mesenchymal-to-endothelial transition in the angiogenic response is controversial. This study is to determine if resident fibroblasts contribute to angiogenesis.We utilized the murine model of hindlimb ischemia, andmatrigel plug assay together with lineage tracing studies and single cell RNA-sequencing (scRNA-seq) to examine the transcriptional and functional changes in fibroblasts in response to ischemia.Lineage tracing using Fsp1-Cre: R26R-EYFP mice revealed the emergence within the ischemic hindlimb of a small subset of YFP CD144 CD11b fibroblasts (E* cells) that expressed endothelial cell (EC) genes. Subcutaneous administration of matrigel in Fsp1-Cre: R26R-EYFP mice generated a plug that became vascularized within 5 days. Isolation of YFP CD11b cells from the plug revealed a small subset of YFP CD144 CD11b E* cells which expressed EC genes. Pharmacological or genetic suppression of innate immune signaling reduced vascularity of the matrigel plug and abrogated the generation of these E* cells. These studies were repeated using human fibroblasts, with FACS analysis revealing that a small percentage of human fibroblasts that were induced to express EC markers in matrigel plug assay. Pharmacological suppression or genetic knockout of inflammatory signaling abolished the generation of E* cells, impaired perfusion recovery and increased tissue injury after femoral artery ligation. To further characterize these E* cells, scRNA-seq studies were performed, and revealed eight discrete clusters of cells expressing characteristic fibroblast genes, of which two clusters (C5 and C8) also expressed some EC genes. Ischemia of the hindlimb induced expansion of clusters C5 and C8. The C8 cells did not express CD144, nor did they form networks in Matrigel, but did generate angiogenic cytokines. The C5 fibroblasts most resembled E* cells in their expression of CD144 and their ability to form EC-like networks in Matrigel.Together, these studies indicate the presence of subsets of tissue fibroblasts which seem poised to contribute to the angiogenic response. The expansion of these subsets with ischemia is dependent upon activation of innate immune signaling, and contributes to recovery of perfusion and preservation of ischemic tissue.



Circulation: 20 Aug 2020; epub ahead of print
Meng S, Lv J, Chanda PK, Owusu I, Chen K, Cooke JP
Circulation: 20 Aug 2020; epub ahead of print | PMID: 32820662
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Abstract

Initial Invasive versus Conservative Management of Stable Ischemic Heart Disease Patients with a History of Heart Failure or Left Ventricular Dysfunction: Insights from the ISCHEMIA Trial.

Lopes RD, Alexander KP, Stevens SR, Reynolds HR, ... Hochman JS, Maron DJ

It is unknown whether an initial invasive strategy in patients with stable ischemic heart disease and at least moderate ischemia improves outcomes in patients with a history of heart failure (HF) or left ventricular dysfunction (LVD) when EF ≥35%, but <45%.Among 5179 participants randomized into the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA), all of whom had LVEF ≥35%, we compared cardiovascular outcomes by treatment strategy in those with a history of HF or LV dysfunction (HF/LVD) at baseline versus those without HF/LVD. Median followup was 3.2 years.There were 398 (7.7%) participants with HF/LVD at baseline of whom 177 had HF/LVEF>45%, 28 had HF/LVEF 35-45% and 193 had LVEF 35-45% but no prior history of HF. HF/LVD was associated with more comorbidities at baseline, particularly prior myocardial infarction (MI), stroke and hypertension. Compared to those without HF/LVD, those with HF/LVD were more likely to experience a primary outcome composite of cardiovascular death, nonfatal MI, or hospitalization for unstable angina, HF, or resuscitated cardiac arrest; four-year cumulative incidence rate (22.7% vs. 13.8%), cardiovascular death or MI (19.7% vs. 12.3%), and all-cause death or HF (15.0% vs. 6.9%). Those with HF/LVD randomized to the invasive versus conservative strategy had a lower rate of the primary outcome (17.2% vs. 29.3%, difference in 4-year event rate -12.1%; 95% CI: -22.6, -1.6%), whereas those without HF/LVD did not (13.0% vs. 14.6%, difference in 4-year event rate -1.6%; 95% CI: -3.8%, 0.7%; p-interaction = 0.055). A similar differential effect was seen for the primary outcome, all-cause mortality, and CV mortality when invasive versus conservative strategy associated outcomes were analyzed with LVEF as a continuous variable for those with and without prior HF.ISCHEMIA trial participants with stable ischemic heart disease and at least moderate ischemia with a history of HF or LVD were at increased risk for the primary outcome. In the small, high-risk subgroup with HF and LVEF 35-45%, an initial invasive approach was associated with a better event-free survival. This result should be considered hypothesis generating.URL: https://clinicaltrials.gov Unique Identifier: NCT01471522.



Circulation: 28 Aug 2020; epub ahead of print
Lopes RD, Alexander KP, Stevens SR, Reynolds HR, ... Hochman JS, Maron DJ
Circulation: 28 Aug 2020; epub ahead of print | PMID: 32862662
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Abstract

Immunothrombotic Dysregulation in COVID-19 Pneumonia is Associated with Respiratory Failure and Coagulopathy.

Nicolai L, Leunig A, Brambs S, Kaiser R, ... Pekayvaz K, Stark K

SARS-CoV-2 infection causes severe pneumonia (COVID-19), but the mechanisms of subsequent respiratory failure and complicating renal and myocardial involvement are poorly understood. In addition, a systemic prothrombotic phenotype has been reported in COVID-19 patients.A total of 62 subjects were included in our study (n=38 patients with RT-PCR confirmed COVID-19 and n=24 non-COVID-19 controls). We performed histopathological assessment of autopsy cases, surface-marker based phenotyping of neutrophils and platelets, and functional assays for platelet, neutrophil functions as well as coagulation tests.We provide evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. We show that in COVID-19 inflammatory microvascular thrombi are present in the lung, kidney, and heart, containing neutrophil extracellular traps associated with platelets and fibrin. COVID-19 patients also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood, which changes with disease severity. Whereas cases of intermediate severity show an exhausted platelet and hyporeactive neutrophil phenotype, severely affected COVID-19 patients are characterized by excessive platelet and neutrophil activation compared to healthy controls and non-COVID-19 pneumonia. Dysregulated immunothrombosis in SARS-CoV-2 pneumonia is linked to both ARDS and systemic hypercoagulability.Taken together, our data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19. Further work is necessary to determine the role of immunothrombosis in COVID-19.



Circulation: 27 Jul 2020; epub ahead of print
Nicolai L, Leunig A, Brambs S, Kaiser R, ... Pekayvaz K, Stark K
Circulation: 27 Jul 2020; epub ahead of print | PMID: 32755393
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Abstract

The Effect of Adding Ticagrelor to Standard Aspirin on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting (POPular CABG): A Randomized, Double-Blind, Placebo-Controlled Trial.

Willemsen LM, Janssen PWA, Peper J, Soliman-Hamad MA, ... Swaans MJ, Ten Berg JM

Approximately 15% of saphenous vein grafts (SVGs) occlude during the first year after coronary artery bypass graft surgery (CABG) despite aspirin use. The POPular CABG trial investigated whether ticagrelor added to standard aspirin improves SVG patency at one year after CABG.In this investigator-initiated, randomized, double-blind, placebo-controlled, multicenter trial, patients with ≥1 SVGs were randomly assigned (1:1) after CABG to ticagrelor or placebo added to standard aspirin (80mg or 100mg). The primary outcome was SVG occlusion at one year, assessed with coronary computed tomography angiography, in all patients that had primary outcome imaging available. A generalized estimating equation model was used to perform the primary analysis per SVG. The secondary outcome was one-year SVG failure, which was a composite of SVG occlusion, SVG revascularization, myocardial infarction in myocardial territory supplied by a SVG or sudden death.Among 499 randomized patients, the mean age was 67.9±8.3 years, 87.1% were male, the indication for CABG was Acute Coronary Syndrome in 31.3%, and 95.2% of procedures used cardiopulmonary bypass. Primary outcome imaging was available in 220 patients in the ticagrelor group and 223 patients in the placebo group. The SVG occlusion rate in the ticagrelor group was 10.5% (51 of 484 SVGs) versus 9.1% in the placebo group (43 of 470 SVGs), OR 1.29 [95% CI: 0.73 -2.30]; =0.38. SVG failure occurred in 35 (14.2%) patients in the ticagrelor group versus 29 (11.6%) patients in the placebo group (OR 1.22, [95% CI: 0.72-2.05]).In this randomized, placebo-controlled trial, the addition of ticagrelor to standard aspirin did not reduce SVG occlusion at one year after CABG.URL: https://clinicaltrials.gov; Unique Identifier: NCT02352402.



Circulation: 30 Aug 2020; epub ahead of print
Willemsen LM, Janssen PWA, Peper J, Soliman-Hamad MA, ... Swaans MJ, Ten Berg JM
Circulation: 30 Aug 2020; epub ahead of print | PMID: 32862716
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Abstract

Challenges and Potential Improvements to Patient Access to Pharmaceuticals: Examples From Cardiology.

Psotka MA, Fiuzat M, Solomon SD, Chauhan C, ... O\'Connor CM, Konstam MA

Patient access to a drug after US regulatory approval is controlled by complex interactions between governmental and third-party payers, pharmacy benefit managers, distributers, manufacturers, health systems, and pharmacies that together mediate the receipt of goods by patients after prescription by clinicians. Recent medication approvals highlight why and how the distribution of clinically beneficial novel therapies is controlled. Although imposed limitations on availability may be rational considering the fiduciary responsibilities of payers and escalating spending on health care and pharmaceuticals, transparency and communication are lacking, and some utilization management may disproportionately affect vulnerable populations. Analysis of the current health insurance landscape suggests mechanisms by which patient access to appropriate medications can be improved and patient and clinician frustration reduced while acknowledging the financial realities of the pharmaceutical marketplace. We propose creation of a shared, standardized, and transparent process for coverage decisions that minimizes administrative barriers and is defensible on the basis of clinical and cost-effectiveness evidence. These reforms would benefit patients and improve the efficiency of the pharmaceutical system.



Circulation: 24 Aug 2020; 142:790-798
Psotka MA, Fiuzat M, Solomon SD, Chauhan C, ... O'Connor CM, Konstam MA
Circulation: 24 Aug 2020; 142:790-798 | PMID: 32833519
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Abstract

Considerations for Reduction of Risk of Perioperative Stroke in Adult Patients Undergoing Cardiac and Thoracic Aortic Operations: A Scientific Statement From the American Heart Association.

Gaudino M, Benesch C, Bakaeen F, DeAnda A, ... Rong LQ,

Perioperative stroke is one of the most severe and feared complications of cardiac surgery. Based on the timing of onset and detection, perioperative stroke can be classified as intraoperative or postoperative. The pathogenesis of perioperative stroke is multifactorial, which makes prediction and prevention challenging. However, information on its incidence, mechanisms, diagnosis, and treatment can be helpful in minimizing the perioperative neurological risk for individual patients. We herein provide suggestions on preoperative, intraoperative, and postoperative strategies aimed at reducing the risk of perioperative stroke and at improving the outcomes of patients who experience a perioperative stroke.



Circulation: 25 Aug 2020:CIR0000000000000885; epub ahead of print
Gaudino M, Benesch C, Bakaeen F, DeAnda A, ... Rong LQ,
Circulation: 25 Aug 2020:CIR0000000000000885; epub ahead of print | PMID: 32842767
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Impact:
Abstract

Comparison Between Ticagrelor and Clopidogrel in Elderly Patients with an Acute Coronary Syndrome: Insights from the SWEDEHEART Registry.

Szummer K, Montez-Rath ME, Alfredsson J, Erlinge D, ... Svensson P, Jernberg T

The comparative efficacy and safety of ticagrelor vs. clopidogrel in older myocardial infarction (MI) patients has received limited study.We performed an observational analysis of all patients ≥80 years (n=14005) who were discharged alive with aspirin combined with either clopidogrel (60.2%) or ticagrelor (39.8%) after a MI between 2010 and 2017 registered in the national registry Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART). Inverse probability treatment weighting was used in Cox regression models to adjust for differences in demographics, in-hospital therapies, and medications. The primary ischemic outcome (death, MI or stroke), and bleeding were obtained from national registries at 1 year. A sensitivity analysis in <80-year-old patients was performed.In patients ≥80 years, the incidence of the primary ischemic outcome (HR 0.97, 95% CI 0.88-1.06) was similar for ticagrelor- and clopidogrel-treated patients. Ticagrelor was associated with a 17% and 48% higher risk of death (1.17 (1.03- 1.32)) and bleeding (1.48 (1.25- 1.76)), but a lower risk of MI (0.80 (0.70- 0.92)) and stroke (0.72 (0.56-0.93)). In <80-year-old patients the incidence of the primary ischemic outcome was 17% (0.83 (0.77-0.89)) lower with ticagrelor. Ticagrelor was associated with 15% (0.85 (0.76-0.96)) lower risk of death, 32% higher risk of bleeding (1.32 (1.18-1.47)), but lower risk of MI (0.82 (0.75-0.91)) and stroke (0.82 (0.69-0.98)).Ticagrelor use among elderly MI patients was associated with higher risk of bleeding and death compared with clopidogrel. A randomized study of ticagrelor vs clopidogrel in the elderly is needed.



Circulation: 31 Aug 2020; epub ahead of print
Szummer K, Montez-Rath ME, Alfredsson J, Erlinge D, ... Svensson P, Jernberg T
Circulation: 31 Aug 2020; epub ahead of print | PMID: 32867508
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Abstract

Lifelong Aspirin for All in the Secondary Prevention of Chronic Coronary Syndrome: Still Sacrosanct or is Reappraisal Warranted?

Jacobsen AP, Raber I, McCarthy CP, Blumenthal RS, ... Wijns W, McEvoy JW

Four decades have passed since the first trial suggesting aspirin\'s efficacy in the secondary prevention of myocardial infarction. Further trials, summarized in the Antithrombotic Trialists\' Collaboration, solidified the historical role of aspirin in secondary prevention. Although the benefit of aspirin in the immediate phase following a myocardial infarction remains incontrovertible, a number of emerging lines of evidence - discussed in this narrative review - now raise some uncertainty as to the primacy of aspirin for the lifelong management of all patients with chronic coronary syndrome (CCS). For example, data challenging the previously unquestioned role of aspirin in CCS have come from recent trials where aspirin was discontinued in specific clinical scenarios; including early discontinuation of the aspirin component of dual-antiplatelet therapy following percutaneous coronary intervention and the withholding of aspirin among CCS patients with atrial fibrillation who require anticoagulation. Added to this, recent primary prevention trials have failed to consistently demonstrate net benefit for aspirin in patients treated to optimal contemporary cardiovascular risk-factor targets, indicating that the efficacy of aspirin for secondary prevention of CCS may similarly have changed with the addition of more modern secondary prevention therapies. Therefore, the totality of recent evidence supports further study of the universal need for lifelong aspirin in the modern secondary prevention of all adults with CCS, particularly in stable older patients who are at highest risk for aspirin-induced bleeding.



Circulation: 03 Sep 2020; epub ahead of print
Jacobsen AP, Raber I, McCarthy CP, Blumenthal RS, ... Wijns W, McEvoy JW
Circulation: 03 Sep 2020; epub ahead of print | PMID: 32886529
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Abstract

Renal and Cardiovascular Effects of SGLT2 Inhibition in Combination with Loop Diuretics in Patients with Type 2 Diabetes and Chronic Heart Failure: The RECEDE-CHF Trial.

Mordi NA, Mordi IR, Singh JS, McCrimmon RJ, Struthers AD, Lang CC

Sodium-Glucose Co-Transporter-2 (SGLT2) inhibitors improve heart failure (HF) associated-outcomes in patients with type 2 diabetes (T2D). In patients with HF, SGLT2 inhibitors will likely be co-prescribed with a loop diuretic, but this combined effect is not well-defined. Our aim was to assess the diuretic and natriuretic effect of empagliflozin in combination with loop diuretics.The RECEDE-CHF trial (NCT03226457) was a randomized, double-blind, placebo-controlled, cross-over trial of patients with T2D and HF with reduced ejection fraction taking regular loop diuretic who were randomized to empagliflozin 25 mg once daily or placebo for 6 weeks with a 2-week washout period. The primary outcome was change in 24-hour urinary volume from baseline at week 6.Twenty-three participants (mean age 69.8 years, 73.9% male, mean furosemide dose of 49.6±31.3mg/day, mean HbA1c 7.9±3.8%) were recruited. Compared to placebo, empagliflozin caused a significant increase in 24-hour urinary volume at both day 3 (mean difference 535 ml, 95% CI 133 to 936, p =0.005) and week 6, (mean difference 545 ml, 95% CI 136 to 954 p = 0.005) after adjustment for treatment order, baseline 24-hour urine volume and percentage change in loop diuretic dose. At 6 weeks empagliflozin did not cause a significant change in 24-hour urinary sodium (mean difference -7.85 mmol/L, 95% CI -2.43 to 6.73, p = 0.57). Empagliflozin caused a non-significant increase in fractional excretion of sodium at day 3 which was absent at week 6 (mean difference day 3: 0.30%, 95% CI -0.03 to 0.63, p=0.09; week 6 0.11%, 95% CI -0.22 to 0.44, p > 0.99) and a significant increase in electrolyte-free water clearance at week 6 (mean difference 312 ml, 95% CI 26 to 598, p=0.026) compared to placebo. Empagliflozin also caused significant reductions in body weight and serum urate at week 6.Empagliflozin caused a significant increase in 24-hour urine volume without an increase in urinary sodium when used in combination with loop diuretic.URL: https://clinicaltrials.gov Unique Identifier: NCT03226457.



Circulation: 28 Aug 2020; epub ahead of print
Mordi NA, Mordi IR, Singh JS, McCrimmon RJ, Struthers AD, Lang CC
Circulation: 28 Aug 2020; epub ahead of print | PMID: 32865004
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Abstract

Dapagliflozin and Cardiac, Kidney and Limb Outcomes in Patients With and Without Peripheral Artery Disease in DECLARE-TIMI 58.

Bonaca MP, Wiviott SD, Zelniker TA, Mosenzon O, ... Raz I, Sabatine MS

Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular complications. The SGLT2 inhibitor (SGLT2i) dapagliflozin reduces the risk for hospitalization for heart failure (HHF) and kidney events in patients with type 2 diabetes mellitus (T2DM). An increased risk of amputation has been observed with canagliflozin in one prior trial. We examined cardiovascular and kidney efficacy and the risk of limb related events in patients with and without peripheral artery disease (PAD) in an exploratory analysis.17,160 patients with T2DM, including 1,025 (6%) with PAD, were randomized. Key efficacy outcomes were MACE (CV Death, MI, stroke), CV Death/HHF, and progression of kidney disease. Amputations, peripheral revascularization and limb ischemic adverse events were site reported and categorized by a blinded reviewer.Patients in the placebo arm with PAD versus those without tended to have higher adjusted risk of MACE (Adj HR 1.23, 95% CI 0.97 - 1.56, p=0.094) and significantly higher adjusted risk of CV Death/HHF (Adj HR 1.60, 95% CI 1.21 - 2.12, p=0.0010) and progression of kidney disease (Adj HR 1.51, 95% CI 1.13 - 2.03, p=0.0058). The relative risk reductions with dapagliflozin for CV Death/HHF (HR 0.86 PAD, HR 0.82 no-PAD, p-interaction 0.79) and progression of kidney disease (HR 0.78 PAD, HR 0.76 no-PAD, p-interaction 0.84) were consistent regardless of PAD. There were 560 patients who had at least one limb ischemic event, 454 patients with at least one peripheral revascularization, and 236 patients with at least one amputation with a total of 407 amputations reported. Overall, there were no significant differences in any limb outcome with dapagliflozin vs. placebo including limb ischemic adverse events (HR 1.07, 95% CI 0.90 - 1.26) and amputation (HR 1.09, 95% CI 0.84 - 1.40), with no significant interactions by a history of PAD vs. not (P interactions 0.30 and 0.093 respectively).Patients with versus without PAD are at higher risk of MACE, CV Death/HHF and kidney outcomes, and have consistent benefits for CV Death/HHF and progression of kidney disease with dapagliflozin. Patients with PAD had higher risk of limb events, with no consistent pattern of incremental risk observed with dapagliflozin.AstraZeneca URL: http://www.clinicaltrials.gov Unique Identifier: NCT01730534.



Circulation: 02 Aug 2020; epub ahead of print
Bonaca MP, Wiviott SD, Zelniker TA, Mosenzon O, ... Raz I, Sabatine MS
Circulation: 02 Aug 2020; epub ahead of print | PMID: 32795086
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Abstract

An Important Role for DNMT3A-Mediated DNA Methylation in Cardiomyocyte Metabolism and Contractility.

Madsen A, Höppner G, Krause J, Hirt MN, ... Eschenhagen T, Stenzig J

DNA methylation acts as a mechanism of gene transcription regulation. It has recently gained attention as a possible therapeutic target in cardiac hypertrophy and heart failure. However, its exact role in cardiomyocytes remains controversial. Thus, we knocked out the mainDNA methyltransferase in cardiomyocytes, DNMT3A, in human induced pluripotent stem cells (hiPSC). Functional consequences of DNA methylation-deficiency under control and stress conditions were then assessed in human engineered heart tissue (EHT) from knockout hiPSC-derived cardiomyocytes.DNMT3A was knocked out in hiPSCs by CRISPR/Cas9 gene editing. Fibrin-based EHTs were generated from knockout (KO) and control hiPSC-derived cardiomyocytes. Development and baseline contractility were analyzed by video-optical recording. EHTs were subjected to different stress protocols, including serum starvation, serum variation, and restrictive feeding. Molecular, histological and ultrastructural analyses were performed afterwards.Knockout of DNMT3A in human cardiomyocytes had three main consequences for cardiomyocyte morphology and function: (1) Gene expression changes of contractile proteins such as higher atrial gene expression and lower MYH7/MYH6 ratio correlated with different contraction kinetics in knockout vs. wild-type. (2) Aberrant activation of the glucose/lipid metabolism regulator PPARγ was associated with accumulation of lipid vacuoles within KO cardiomyocytes. (3) HIF-1 protein instability was associated with impaired glucose metabolism and lower glycolytic enzyme expression, rendering KO EHTs sensitive to metabolic stress such as serum withdrawal and restrictive feeding.The results suggest an important role of DNA methylation in the normal homeostasis of cardiomyocytes and during cardiac stress, which could make it an interesting target for cardiac therapy.



Circulation: 03 Sep 2020; epub ahead of print
Madsen A, Höppner G, Krause J, Hirt MN, ... Eschenhagen T, Stenzig J
Circulation: 03 Sep 2020; epub ahead of print | PMID: 32885664
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Abstract

High-Resolution Transcriptomic Profiling of the Heart During Chronic Stress Reveals Cellular Drivers of Cardiac Fibrosis and Hypertrophy.

McLellan MA, Skelly DA, Dona MSI, Squiers GT, ... Rosenthal NA, Pinto AR

Cardiac fibrosis is a key antecedent to many types of cardiac dysfunction including heart failure. Physiological factors leading to cardiac fibrosis have been recognized for decades. However, the specific cellular and molecular mediators that drive cardiac fibrosis, and the relative impact of disparate cell populations on cardiac fibrosis, remain unclear.We developed a novel cardiac single-cell transcriptomics strategy to characterize the cardiac cellulome-the network of cells that forms the heart. This method was utilized to profile the cardiac cellular ecosystem in response to two weeks of continuous administration of Angiotensin II, a pro-fibrotic stimulus which drives pathological cardiac remodeling.Our analysis provides a comprehensive map of the cardiac cellular landscape uncovering multiple cell populations that contribute to pathological remodeling of the extracellular matrix of the heart. Two phenotypically distinct fibroblast populations-Fibroblast- and Fibroblast--emerged after induction of tissue stress to promote fibrosis in the absence of smooth muscle actin-expressing myofibroblasts, a key pro-fibrotic cell population. Following Angiotensin II treatment, Fibroblast- develops as the most abundant fibroblast subpopulation and the predominant fibrogenic cell type. Mapping intercellular communication networks within the heart, we identified key intercellular trophic relationships and shifts in cellular communication after Angiotensin II treatment, that promote development of a profibrotic cellular microenvironment. Further, the cellular responses to Angiotensin II and the relative abundance of fibrogenic cells were sexually dimorphic.These results offer a valuable resource for exploring the cardiac cellular landscape in health and after chronic cardiovascular stress. These data provide insights into the cellular and molecular mechanisms that promote pathological remodeling of the mammalian heart, highlighting early transcriptional changes which precede chronic cardiac fibrosis.



Circulation: 29 Jul 2020; epub ahead of print
McLellan MA, Skelly DA, Dona MSI, Squiers GT, ... Rosenthal NA, Pinto AR
Circulation: 29 Jul 2020; epub ahead of print | PMID: 32795101
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Abstract

Effect of Dapagliflozin on Outpatient Worsening of Patients with Heart Failure and Reduced Ejection Fraction: A Prespecified Analysis of DAPA-HF.

Docherty KF, Jhund PS, Anand I, Bengtsson O, ... Verma S, McMurray JJV

In the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF), dapagliflozin, added to guideline-recommended therapies, reduced the risk of mortality and HF hospitalization. We examined the frequency and significance of episodes of outpatient heart failure-worsening, requiring augmentation of oral therapy, and the effects of dapagliflozin on these additional events.Patients in New York Heart Association (NYHA) functional class II-IV, with a left ventricular ejection fraction ≤40%, and elevation of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were eligible. The primary outcome was the composite of an episode of worsening heart failure (HF hospitalization or urgent HF visit requiring intravenous [IV] therapy) or cardiovascular (CV) death, whichever occurred first. An additional prespecified exploratory outcome was the primary outcome plus worsening HF symptoms/signs leading to initiation of new, or augmentation of existing, oral treatment.Overall, 36% more patients experienced the expanded, compared with the primary, composite outcome. In the placebo group, 684/2371 (28.8%) patients, and 527/2373 (22.2%) participants in the dapagliflozin group, experienced the expanded outcome (HR 0.73, 0.65-0.82; P<0.0001); each component of the composite was reduced significantly by dapagliflozin. Over the median follow-up of 18.2 months, the number of patients needed to treat (NNT) with dapagliflozin to prevent one experiencing an episode of fatal or non-fatal worsening was 16. Among the 4744 randomized patients, the first episode of worsening was outpatient augmentation of treatment in 407 participants (8.6%), an urgent HF visit with IV therapy in 20 (0.4%), HF hospitalization in 489 (10.3%) and CV death in 295 (6.2%) patients. The adjusted risk of death from any cause (compared with no event) following an outpatient worsening was HR 2.67 (95%CI 2.03-3.52), after an urgent HF visit 3.00 (1.39-6.48) and after a HF hospitalization 6.21 (5.07-7.62).In DAPA-HF, outpatient episodes of HF worsening were common, of prognostic importance and reduced by dapagliflozin.URL: https://clinicaltrials.gov Unique Identifier: NCT03036124.



Circulation: 03 Sep 2020; epub ahead of print
Docherty KF, Jhund PS, Anand I, Bengtsson O, ... Verma S, McMurray JJV
Circulation: 03 Sep 2020; epub ahead of print | PMID: 32883108
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Abstract

Dual Antiplatelet Therapy After Percutaneous Coronary Intervention and Drug-Eluting Stents: A Systematic Review and Network Meta-Analysis.

Khan SU, Singh M, Valavoor S, Khan MU, ... Kalra A, Bhatt DL

The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) remains uncertain. We compared short-term (<6-month) DAPT followed by aspirin or P2Y12 inhibitor monotherapy; mid-term (6-month) DAPT; 12-month DAPT; and extended-term (>12-month) DAPT after PCI with DES.Twenty-four randomized controlled trials were selected using Medline, Embase, Cochrane library, and online databases through September 2019. The co-primary endpoints were myocardial infarction (MI) and major bleeding, which constituted the net clinical benefit. A frequentist network meta-analysis was conducted with random effects model.In 79,073 patients, at a median follow-up of 18 months, extended-term DAPT was associated with a reduced risk of MI compared with 12-month DAPT (absolute risk difference [ARD], -3.8 incident cases per 1000 person-years; relative risk (RR), 0.68 [95% CI, 0.54-0.87]), mid-term DAPT (ARD, -4.6 incident cases per 1000 person-years; RR, 0.61 [0.45-0.83]), and short-term DAPT followed by aspirin monotherapy (ARD, -6.1 incident cases per 1000 personyears; RR, 0.55 [0.37-0.83]), or P2Y12 inhibitor monotherapy (ARD, -3.7 incident cases per 1000 person-years; RR, 0.69 [0.51-0.95]). Conversely, extended-term DAPT was associated with a higher risk of major bleeding compared with all other DAPT groups. Compared with 12-month DAPT, no significant differences in the risks of ischemic endpoints or major bleeding were observed with mid-term or short-term DAPT followed by aspirin monotherapy, except that shortterm DAPT followed by P2Y12 inhibitor monotherapy was associated with a reduced risk of major bleeding. There were no significant differences with respect to mortality between the different DAPT strategies. In acute coronary syndrome (ACS), extended-term compared with 12-month DAPT was associated with a reduced risk of MI without significant increase in the risk of major bleeding.The present network meta-analysis suggests that compared with 12-month DAPT, short-term DAPT followed by P2Y12 inhibitor monotherapy reduces major bleeding after PCI with DES, while extended-term DAPT reduces myocardial infarction at the expense of more bleeding events.



Circulation: 02 Aug 2020; epub ahead of print
Khan SU, Singh M, Valavoor S, Khan MU, ... Kalra A, Bhatt DL
Circulation: 02 Aug 2020; epub ahead of print | PMID: 32795096
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Abstract

Prioritizing Candidates of Post-Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics.

Chan MY, Efthymios M, Tan SH, Pickering JW, ... Pilbrow A, Richards AM

Heart failure (HF) is the most common long-term complication of acute myocardial infarction (MI). Understanding plasma proteins associated with post-MI HF and their gene expression may identify new candidates for biomarker and drug target discovery.We employed aptamer-based affinity-capture plasma proteomics to measure 1305 plasma proteins at one month post-MI in a New Zealand cohort (CDCS) including 181 post-MI patients who were subsequently hospitalized for HF compared with 250 post-MI patients who remained event-free over a median follow-up of 4.9 years. We then correlated plasma proteins with left ventricular ejection fraction measured at 4 months post-MI and identified proteins potentially co-regulated in post-MI HF using Weighted Gene Co-expression Network Analysis (WCGNA). A Singapore cohort (IMMACULATE) of 223 post-MI patients, of which 33 patients were hospitalized for HF (median follow-up 2.0 years), was used for further candidate enrichment of plasma proteins using Fisher meta-analysis, resampling-based statistical testing and machine learning. We then cross-referenced differentially-expressed proteins with their differentially-expressed genes from single-cell transcriptomes of non-myocyte cardiac cells isolated from a murine MI model, and single-cell and single-nuclei transcriptomes of cardiac myocytes from murine HF models and human HF patients.In the CDCS cohort, 212 differentially-expressed plasma proteins were significantly associated with subsequent HF events. Of these, 96 correlated with left ventricular ejection fraction measured at 4 months post-MI. WCGNA prioritised 63 of the 212 proteins that demonstrated significantly higher correlations among patients who developed post-MI HF compared with event-free controls (dataset 1). Cross-cohort meta-analysis of the IMMACULATE cohort identified 36 plasma proteins associated with post-MI HF (dataset 2) while single-cell transcriptomes identified 15 gene-protein candidates (dataset 3). The majority of prioritized proteins were of matricellular origin. The 6 most highly-enriched proteins that were common to all 3 datasets included well-established biomarkers of post-MI HF - N-terminal B-type natriuretic peptide and troponin T - as well as newly-emergent biomarkers - angiopoietin-2, thrombospondin-2, latent transforming growth factor-β binding protein-4 and follistatin-related protein-3.Large-scale human plasma proteomics, cross-referenced to unbiased cardiac cell transcriptomics at single-cell resolution, prioritized protein candidates associated with post-MI HF for further mechanistic and clinical validation.



Circulation: 03 Sep 2020; epub ahead of print
Chan MY, Efthymios M, Tan SH, Pickering JW, ... Pilbrow A, Richards AM
Circulation: 03 Sep 2020; epub ahead of print | PMID: 32885678
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Abstract

Anti-Inflammatory Actions of Soluble Ninjurin-1 Ameliorate Atherosclerosis.

Jeon S, Kim TK, Jeong SJ, Jung IH, ... Park SH, Oh GT

Macrophages produce many inflammation-associated molecules, released by matrix metallo-proteinases (MMPs), such as adhesion molecules as well as cytokines, which play a crucial role in atherosclerosis. In this context, we investigated the relationship between Ninjurin-1 (nerve injury-induced protein [Ninj1]), a novel MMP9 substrate, expression and atherosclerosis progression.Ninj1 expression and atherosclerosis progression were assessed in atherosclerotic aortic tissue and serum samples from coronary artery disease patients and healthy controls as well as athero-prone Apolipoprotein -deficient () and wild-type mice.mice lacking systemic Ninj1 expression () were generated to assess functional effects of Ninj1. Bone marrow (BM) transplantation was also used to generate low-density lipoprotein receptor-deficient () mice that lack Ninj1 specifically in BM-derived cells. Mice were fed a western diet (WD) for 5 to 23 weeks, and atherosclerotic lesions were investigated. The anti-inflammatory role of Ninj1 was verified by treating macrophages and mice with the peptides Ninj1 (ML56) and Ninj1 (PN12), which mimic the soluble form of Ninj1 (sNinj1).Ourresults conclusively showed a correlation between Ninj1 expression in aortic macrophages and the extent of human and mouse atherosclerotic lesions. -deficient macrophages promoted pro-inflammatory gene expression by activating mitogenactivated protein kinase (MAPK) and inhibiting the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Whole-body and BM-specificdeficiencies significantly increased monocyte recruitment and macrophage accumulation in atherosclerotic lesion through elevated macrophage-mediated inflammation. Macrophage Ninj1 was directly cleaved by MMP9 to generate a soluble form that exhibited anti-atherosclerotic effects, as assessedand . Treatment with the sNinj1-mimetic peptides, ML56 and PN12, reduced proinflammatory gene expression in human and mouse classically activated macrophages (CAMs), thereby attenuating monocyte transendothelial migration. Moreover, continuous administration of mPN12 alleviated atherosclerosis by inhibiting the enhanced monocyte recruitment and inflammation characteristics of this disorder in mice, regardless of the presence of Ninj1.Ninj1 is a novel MMP9 substrate in macrophages, and sNinj1 is a secreted athero-protective protein that regulates macrophage inflammation and monocyte recruitment in atherosclerosis. Moreover, sNinj1-mediated anti-inflammatory effects are conserved in human macrophages and likely contribute to human atherosclerosis.



Circulation: 03 Sep 2020; epub ahead of print
Jeon S, Kim TK, Jeong SJ, Jung IH, ... Park SH, Oh GT
Circulation: 03 Sep 2020; epub ahead of print | PMID: 32883094
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Abstract

US Mortality Due to Congenital Heart Disease Across the Lifespan from 1999-2017 Exposes Persistent Racial/Ethnic Disparities.

Lopez KN, Morris SA, Sexson Tejtel SK, Espaillat A, Salemi JL

Congenital heart disease (CHD) accounts for approximately 40% of deaths in United States (US) children with birth defects. Previous US data from 1999-2006 demonstrated an overall decrease in CHD mortality. Our study aimed to assess current trends in US mortality related to CHD from infancy to adulthood over the last 19 years and determine differences by sex and race/ethnicity.We conducted an analysis of death certificates from 1999-2017 to calculate annual CHD mortality by age at death, race/ethnicity, and sex. Population estimates used as denominators in mortality rate calculations for infants were based on National Center for Health Statistics live birth data. Mortality rates in individuals ≥1 year of age utilized US Census Bureau bridged-race estimates as denominators for population estimates. We characterized temporal trends in all-cause mortality, mortality resulting directly due to and related to CHD by age, race/ethnicity, and sex using joinpoint regression.There were 47.7 million deaths with 1 in 814 deaths due to CHD (n=58,599). While all-cause mortality decreased 16.4% across all ages, mortality resulting from CHD declined 39.4% overall. The mean annual decrease in CHD mortality was 2.6%, with the largest decrease for those age >65 years. The age-adjusted mortality rate decreased from 1.37 to 0.83 per 100,000. Males had higher mortality due to CHD than females throughout the study, although both sexes declined at a similar rate (~40% overall), with a 3-4% annual decrease between 1999 and 2009, followed by a slower annual decrease of 1.4% through 2017. Mortality resulting from CHD significantly declined among all races/ethnicities studied, although disparities in mortality persisted for non-Hispanic blacks versus non-Hispanic whites (mean annual decrease 2.3% versus 2.6%, respectively; age-adjusted mortality rate 1.67 to 1.05 versus 1.35 to 0.80 per 100,000, respectively).While overall US mortality due to CHD has decreased over the last 19 years, disparities in mortality persist for males compared to females and for non-Hispanic blacks compared to non-Hispanic whites. Determining factors that contribute to these disparities such as access to quality care, timely diagnosis, and maintenance of insurance will be important moving into the next decade.



Circulation: 02 Aug 2020; epub ahead of print
Lopez KN, Morris SA, Sexson Tejtel SK, Espaillat A, Salemi JL
Circulation: 02 Aug 2020; epub ahead of print | PMID: 32795094
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Abstract

Altered Hemodynamics and End-Organ Damage in Heart Failure: Impact on the Lung and Kidney.

Verbrugge FH, Guazzi M, Testani JM, Borlaug BA

Heart failure is characterized by pathologic hemodynamic derangements, including elevated cardiac filling pressures (\"backward\" failure), which may or may not coexist with reduced cardiac output (\"forward\" failure). Even when normal during unstressed conditions such as rest, hemodynamics classically become abnormal during stressors such as exercise in patients with heart failure. This has important upstream and downstream effects on multiple organ systems, particularly with respect to the lungs and kidneys. Hemodynamic abnormalities in heart failure are affected by processes that extend well beyond the cardiac myocyte, including important roles for pericardial constraint, ventricular interaction, and altered venous capacity. Hemodynamic perturbations have widespread effects across multiple heart failure phenotypes, ranging from reduced to preserved ejection fraction, acute to chronic disease, and cardiogenic shock to preserved perfusion states. In the lung, hemodynamic derangements lead to the development of abnormalities in ventilatory control and efficiency, pulmonary congestion, capillary stress failure, and eventually pulmonary vascular disease. In the kidney, hemodynamic perturbations lead to sodium and water retention and worsening renal function. Improved understanding of the mechanisms by which altered hemodynamics in heart failure affect the lungs and kidneys is needed in order to design novel strategies to improve clinical outcomes.



Circulation: 07 Sep 2020; 142:998-1012
Verbrugge FH, Guazzi M, Testani JM, Borlaug BA
Circulation: 07 Sep 2020; 142:998-1012 | PMID: 32897746
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Abstract

Angiotensin-Neprilysin Inhibition and Renal Outcomes in Heart Failure with Preserved Ejection Fraction.

Mc Causland FR, Lefkowitz MP, Claggett B, Anavekar NS, ... McMurray JJV, Solomon SD

In patients with heart failure, chronic kidney disease (CKD) is common and associated with a higher risk of renal events than in patients without CKD. We assessed the renal effects of angiotensin/neprilysin inhibition in patients with heart failure and preserved ejection fraction (HFpEF) enrolled in PARAGON-HF.In this randomized, double-blind, event-driven trial, we assigned 4,822 patients with HFpEF to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein we present the results of the pre-specified renal composite outcome (time to first occurrence of either: ≥50% reduction in eGFR, end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope.At randomization, eGFR was 63±19 ml/min/1.73m. At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio [HR], 0.50; 95%CI, 0.33 to 0.77; P=0.001). The treatment effect on the composite renal endpoint did not differ according to the baseline eGFR (<60 vs ≥ 60 ml/min/1.73 m (P-interaction=0.92). The decline in eGFR was less for sacubitril/valsartan compared with valsartan (-1.8 [95%CI, -2.0 to -1.6] vs. -2.4 [95%CI, -2.6 to - 2.2] ml/min/1.73m/year).In patients with HFpEF, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, compared with valsartan.URL: https://clinicaltrials.gov/ Unique Identifier: NCT01920711.



Circulation: 16 Aug 2020; epub ahead of print
Mc Causland FR, Lefkowitz MP, Claggett B, Anavekar NS, ... McMurray JJV, Solomon SD
Circulation: 16 Aug 2020; epub ahead of print | PMID: 32845715
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Abstract

CD4 T-Cell Endogenous Cystathionine γ Lyase-Hydrogen Sulfide Attenuates Hypertension by Sulfhydrating Liver Kinase B1 to Promote T Regulatory Cell Differentiation and Proliferation.

Cui C, Fan J, Zeng Q, Cai J, ... Cai J, Geng B

Hydrogen sulfide (HS) has anti-hypertension and anti-inflammatory effects, and its endogenous-generation key enzyme cystathionine γ lyase (CSE) is expressed in CD4 T cells. However, the role of CD4 T-cell endogenous CSE/HS in the development of hypertension is unclear.Peripheral blood lymphocytes were isolated from hypertensive patients or spontaneously hypertensive rats (SHRs), then HS production and expression of its generation enzymes, cystathionine β synthase (CBS) and CSE, were measured to determine the major HS generation system changes in hypertension. Mice with CSE-specific knockout in T cells (CKO, by CD4 mice hybridization) and CD4 null mice were generated for investigating the pathophysiological relevance of the CSE/HS system.In lymphocytes, HS from CSE but not CBS responded to blood pressure (BP) changes, supported by lymphocyte CSE protein changes and negative correlation between HS production with systolic BP (sBP) and diastolic BP (dBP) but positive correlation with serum level of interleukin 10 (IL-10, an anti-inflammatory cytokine). Deletion of CSE in T cells elevated BP (5-8 mmHg) under the physiological condition and exacerbated angiotensin II (AngII)-induced hypertension. In keeping with hypertension, mesenteric artery dilation impaired, association with arterial inflammation, an effect attributed to reduced immunoinhibitory T regulatory cell (Treg) numbers in blood and kidney, thus causing excess CD4 and CD8 T-cell infiltration in perivascular adipose tissues and kidney. CSE knockout CD4-T cell transfer into CD4 null mice, also showed the similar phenotypes confirming the role of endogenous CSE/HS action. Adoptive transfer of Tregs (to CKO mice) reversed hypertension, vascular relaxation impairment and immunocyte infiltration, which confirmed that CKO-induced hypertension was due in part to the reduced Treg numbers. Mechanistically, endogenous CSE/HS promoted Treg differentiation and proliferation by activating AMP-activated protein kinase (AMPK). In part, it depended on activation of its upstream kinase, liver kinase B1 (LKB1), by sulfhydration to facilitate its substrate binding and phosphorylation.The constitutive sulfhydration of LKB1 by CSE-derived HS activates its target kinase, AMPK, and promotes Treg differentiation and proliferation, which attenuates the vascular and renal immune-inflammation, thereby preventing hypertension.



Circulation: 08 Sep 2020; epub ahead of print
Cui C, Fan J, Zeng Q, Cai J, ... Cai J, Geng B
Circulation: 08 Sep 2020; epub ahead of print | PMID: 32900241
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Abstract

Single-Cell RNA-seq Unveils Unique Transcriptomic Signatures of Organ-Specific Endothelial Cells.

Paik DT, Tian L, Williams IM, Rhee S, ... Red-Horse K, Wu JC

Endothelial cells (ECs) display considerable functional heterogeneity depending on the vessel and tissue in which they are located. While these functional differences are presumably imprinted in the transcriptome, the pathways and networks which sustain EC heterogeneity have not been fully delineated.To investigate the transcriptomic basis of EC specificity, we analyzed single-cell RNA-sequencing (scRNA-seq) data from tissue-specific mouse ECs generated by theconsortium. We employed a number of bioinformatics tools to uncover markers and sources of EC heterogeneity from scRNA-seq data.We found a strong correlation between tissue-specific EC transcriptomic measurements generated by either scRNA-seq or bulk RNA-seq, thus validating the approach. Using a graph-based clustering algorithm, we found that certain tissue-specific ECs cluster strongly by tissue (e.g. liver, brain) whereas others (i.e. adipose, heart) have considerable transcriptomic overlap with ECs from other tissues. We identified novel markers of tissue-specific ECs and signaling pathways that may be involved in maintaining their identity. Sex was a considerable source of heterogeneity in the endothelial transcriptome and we discoveredto be a gene that is highly enriched in ECs from male mice. In addition, we found that markers of heart and lung ECs in mice were conserved in human fetal heart and lung ECs. Finally, we identified potential angiocrine interactions between tissue-specific ECs and other cell types by analyzing ligand and receptor expression patterns.In summary, we use scRNA-seq data generated by theconsortium to uncover transcriptional networks that maintain tissue-specific EC identity and to identify novel angiocrine and functional relationships between tissue-specific ECs.



Circulation: 14 Sep 2020; epub ahead of print
Paik DT, Tian L, Williams IM, Rhee S, ... Red-Horse K, Wu JC
Circulation: 14 Sep 2020; epub ahead of print | PMID: 32929989
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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

While regular exercise exposure is associated with lower risk of cardiovascular disease (CVD) 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.Cardiopulmonary exercise testing (CPET) and metabolite profiling was performed on Framingham Heart Study (FHS) participants (age 53±8 years, 63% women) with blood drawn at rest (n=471) and at peak exercise (n=411).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 (FDR). Changes included reductions in metabolites implicated in insulin resistance (glutamate -29%, P=1.5x10, dimethylguanidinovaleric acid -18%, P=5.8x10), and increases in metabolites associated with lipolysis (1-methylnicotinamide, +33%, P=6.1x10), nitric oxide bioavailability (arginine/ornithine + citrulline, +29%, P=2.8x10), and adipose browning (12,13-dihydroxy-9Z-octadecenoic acid +26%, P=7.4x10), among other pathways relevant to cardiometabolic risk. We assayed 177 metabolites in a separate FHS replication sample (n=783, age 54±8 years, 51% women) and observed concordant changes in 164 metabolites (92.6%) at 5% FDR. Exercise-induced metabolite changes were variably related to the amount of exercise performed (peak workload), sex, and body mass index (BMI). There was attenuation of favorable excursions in some metabolites in individuals with higher BMI and greater excursions in select cardioprotective metabolites in women despite less exercise performed. Distinct pre-exercise metabolite levels were associated with different physiologic dimensions of fitness (e.g., ventilatory efficiency, exercise blood pressure, peak VO). We identified four 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), two of which were associated with overall mortality over median follow-up of 23.1 years (P≤0.003 for both).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, CVD, 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: 14 Sep 2020; epub ahead of print
Nayor M, Shah RV, Miller PE, Blodgett JB, ... Vasan RS, Lewis GD
Circulation: 14 Sep 2020; epub ahead of print | PMID: 32927962
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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

Calmodulin mutations are associated with arrhythmia syndromes in humans. Exome sequencing previously identified amutation 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.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 as well as [Ca] were measured in single ventricular myocytes using the patch-clamp technique and fluorescence microscopy, respectively. The microelectrode technique was employed formembrane voltage monitoring of ventricular conduction fibers.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 electrical 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 vs Calm1 ventricular myocytes, increasing latein the former. Rapidly paced Calm1 ventricular myocytes showed increased propensity to delayed afterdepolarization-induced triggered activity, whereasHis-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.Heterozygosity for themutation is causative of an arrhythmia syndrome characterized by sinus bradycardia, QRS widening, adrenergically mediated QT 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: 14 Sep 2020; epub ahead of print
Tsai WC, Guo S, Olaopa MA, Field LJ, ... Chen PS, Rubart M
Circulation: 14 Sep 2020; epub ahead of print | PMID: 32929985
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Abstract

Drug-Induced Arrhythmias: A Scientific Statement From the American Heart Association.

Tisdale JE, Chung MK, Campbell KB, Hammadah M, ... Rajagopalan B,

Many widely used medications may cause or exacerbate a variety of arrhythmias. Numerous antiarrhythmic agents, antimicrobial drugs, psychotropic medications, and methadone, as well as a growing list of drugs from other therapeutic classes (neurological drugs, anticancer agents, and many others), can prolong the QT interval and provoke torsades de pointes. Perhaps less familiar to clinicians is the fact that drugs can also trigger other arrhythmias, including bradyarrhythmias, atrial fibrillation/atrial flutter, atrial tachycardia, atrioventricular nodal reentrant tachycardia, monomorphic ventricular tachycardia, and Brugada syndrome. Some drug-induced arrhythmias (bradyarrhythmias, atrial tachycardia, atrioventricular node reentrant tachycardia) are significant predominantly because of their symptoms; others (monomorphic ventricular tachycardia, Brugada syndrome, torsades de pointes) may result in serious consequences, including sudden cardiac death. Mechanisms of arrhythmias are well known for some medications but, in other instances, remain poorly understood. For some drug-induced arrhythmias, particularly torsades de pointes, risk factors are well defined. Modification of risk factors, when possible, is important for prevention and risk reduction. In patients with nonmodifiable risk factors who require a potentially arrhythmia-inducing drug, enhanced electrocardiographic and other monitoring strategies may be beneficial for early detection and treatment. Management of drug-induced arrhythmias includes discontinuation of the offending medication and following treatment guidelines for the specific arrhythmia. In overdose situations, targeted detoxification strategies may be needed. Awareness of drugs that may cause arrhythmias and knowledge of distinct arrhythmias that may be drug-induced are essential for clinicians. Consideration of the possibility that a patient\'s arrythmia could be drug-induced is important.



Circulation: 14 Sep 2020:CIR0000000000000905; epub ahead of print
Tisdale JE, Chung MK, Campbell KB, Hammadah M, ... Rajagopalan B,
Circulation: 14 Sep 2020:CIR0000000000000905; epub ahead of print | PMID: 32929996
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Abstract

Signalosome-Regulated SRF 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

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 asymmetric 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 asymmetric myocyte growth could provide new therapeutic targets for the prevention or treatment of heart failure.Primary adult rat ventricular myocytes, adeno-associated virus (AAV)-mediated gene delivery in mice, and human tissue samples are used to define a regulatory pathway controlling pathological myocyte hypertrophy. Chromatin Immunoprecipitation Assays with Sequencing (ChIP-seq) and Precision Nuclear Run-On Sequencing (PRO-seq) are used to define a transcriptional mechanism.Here we report that asymmetric cardiac myocyte hypertrophy is modulated by serum response factor (SRF) phosphorylation, constituting an epigenomic switch balancing the growth in width versus length of adult ventricular myocytesand . SRF Ser phosphorylation is bidirectionally regulated by p90 ribosomal S6 kinase type 3 (RSK3) and protein phosphatase 2A (PP2A) at signalosomes organized by the scaffold protein muscle A-kinase anchoring protein β (mAKAPβ), such that increased SRF phosphorylation activates Activator Protein 1 (AP1)-dependent enhancers that direct myocyte growth in width. AAV are used to expressmAKAPβ-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 due to 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.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: 15 Sep 2020; epub ahead of print
Li J, Tan Y, Passariello CL, Martinez EC, ... Rosenfeld MG, Kapiloff MS
Circulation: 15 Sep 2020; epub ahead of print | PMID: 32933333
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Abstract

Ten-Year Differences in Women\'s Awareness Related to Coronary Heart Disease: Results of the 2019 American Heart Association National Survey: A Special Report From the American Heart Association.

Cushman M, Shay CM, Howard VJ, Jiménez MC, ... Mosca LJ,
Background
High awareness that cardiovascular disease is the leading cause of death (LCOD) among women is critical to prevention. This study evaluated longitudinal trends in this awareness among women.
Methods and results
Online surveys of US women (≥25 years of age) were conducted in January 2009 and January 2019. Data were weighted to the US population distribution of sociodemographic characteristics. Multivariable logistic regression was used to evaluate knowledge of the LCOD. In 2009, awareness of heart disease as the LCOD was 65%, decreasing to 44% in 2019. In 2019, awareness was greater with older age and increasing education and lower among non-White women and women with hypertension. The 10-year awareness decline was observed in all races/ethnicities and ages except women ≥65 years of age. The greatest declines were among Hispanic women (odds ratio of awareness comparing 2019 to 2009, 0.14 [95% CI, 0.07-0.28]), non-Hispanic Black women (odds ratio, 0.31 [95% CI, 0.19-0.49]), and 25- to 34-year-olds (odds ratio, 0.19 [95% CI, 0.10-0.34]). In 2019, women were more likely than in 2009 to incorrectly identify breast cancer as the LCOD (odds ratio, 2.59 [95% CI, 1.86-3.67]), an association that was greater in younger women. Awareness of heart attack symptoms also declined.
Conclusions
Awareness that heart disease is the LCOD among women declined from 2009 to 2019, particularly among Hispanic and non-Hispanic Black women and in younger women (in whom primordial/primary prevention may be most effective). An urgent redoubling of efforts by organizations interested in women\'s health is required to reverse these trends.



Circulation: 20 Sep 2020:CIR0000000000000907; epub ahead of print
Cushman M, Shay CM, Howard VJ, Jiménez MC, ... Mosca LJ,
Circulation: 20 Sep 2020:CIR0000000000000907; epub ahead of print | PMID: 32954796
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Abstract

Trends in Recurrent Coronary Heart Disease Following Myocardial Infarction Among US Women and Men Between 2008 and 2017.

Peters SAE, Colantonio LD, Dai Y, Zhao H, ... Muntner P, Woodward M

Rates for recurrent coronary heart disease (CHD) events have declined in the US. However, few studies have assessed whether this decline has been similar among women and men.Data were used from 770,408 US women and 700,477 US men <65 years of age with commercial health insurance through MarketScan and ≥66 years of age with government health insurance through Medicare who had a myocardial infarction (MI) hospitalization between 2008 and 2017. Women and men were followed for recurrent MI, recurrent CHD events (i.e., recurrent MI or coronary revascularization), heart failure hospitalization, and all-cause mortality (Medicare only) in the 365 days post-MI.From 2008 to 2017, age-standardized recurrent MI rates per 1,000 person-years decreased from 89.2 to 72.3 in women and from 94.2 to 81.3 in men (multivariable-adjusted p-interaction by sex<0.001). Recurrent CHD event rates decreased from 166.3 to 133.3 in women and from 198.1 to 176.8 in men (p-interaction<0.001). Heart failure hospitalization rates decreased from 177.4 to 158.1 in women and from 162.9 to 156.1 in men (p-interaction=0.001). All-cause mortality rates decreased from 403.2 to 389.5 in women and from 436.1 to 417.9 in men (p-interaction=0.82). In 2017, the multivariable-adjusted rate ratios (95%CI), comparing women with men were 0.90 (0.86, 0.93) for recurrent MI, 0.80 (0.78, 0.82) for recurrent CHD events, 0.99 (0.96, 1.01) for heart failure hospitalization, and 0.82 (0.80-0.83) for all-cause mortality.Rates of recurrent MI, recurrent CHD events, heart failure hospitalization, and mortality in the first year after an MI declined considerably between 2008 and 2017 in both men and women, with proportionally greater reductions for women than men. However, rates remain very high and rates of recurrent MI, recurrent CHD events and death continue to be higher among men than women.



Circulation: 20 Sep 2020; epub ahead of print
Peters SAE, Colantonio LD, Dai Y, Zhao H, ... Muntner P, Woodward M
Circulation: 20 Sep 2020; epub ahead of print | PMID: 32951451
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Abstract

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

Kern KB, Radsel P, Jentzer JC, Seder DB, ... Hsu CH, Noc M

The benefit of emergent coronary angiography after resuscitation from out-of-hospital cardiac arrest (OHCA) is uncertain for patients without ST-segment elevation (STE). 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 OHCA patients without STE.Adult (>18 years) comatose survivors without STE after resuscitation from OHCA 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 multi-center study. Early angiography was defined as ≤ 120 minutes from arrival at the percutaneous coronary intervention capable facility. The primary endpoint was a composite of efficacy and safety measures, including efficacy parameters of survival to discharge, favorable neurological status at discharge (Cerebral Performance Category ≤ 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 re-arrest, pulmonary edema on chest x-ray, acute renal dysfunction, bleeding requiring transfusion or intervention, hypotension (systolic arterial pressure ≤90 mmHg), and pneumonia. Secondary endpoints included the incidence of culprit vessels with acute occlusion.The study was prematurely terminated before enrolling the target number of patients. A total of 99 patients were enrolled from 2015-2018, including 75 with initially shockable rhythms. Forty-nine patients were randomized to early coronary angiography. The primary endpoint of efficacy and safety was not different between the two groups (55.1% vs 46.0%; p=0.64). Early coronary angiography was not associated with any significant increase in survival (55.1% vs 48.0%; p=0.55 or adverse events (26.5% vs 26.0%; p=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.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.URL: https://www.clinicaltrials.gov. Unique identifier: NCT02387398.



Circulation: 27 Sep 2020; epub ahead of print
Kern KB, Radsel P, Jentzer JC, Seder DB, ... Hsu CH, Noc M
Circulation: 27 Sep 2020; epub ahead of print | PMID: 32985249
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Abstract

P-COSCA (Pediatric Core Outcome Set for Cardiac Arrest) in Children: An Advisory Statement From the International Liaison Committee on Resuscitation.

Topjian AA, Scholefield BR, Pinto NP, Fink EL, ... Hazinski MF, Slomine BS

Studies of pediatric cardiac arrest use inconsistent outcomes, including return of spontaneous circulation and short-term survival, and basic assessments of functional and neurological status. In 2018, the International Liaison Committee on Resuscitation sponsored the COSCA initiative (Core Outcome Set After Cardiac Arrest) to improve consistency in reported outcomes of clinical trials of adult cardiac arrest survivors and supported this P-COSCA initiative (Pediatric COSCA). The P-COSCA Steering Committee generated a list of potential survival, life impact, and economic impact outcomes and assessment time points that were prioritized by a multidisciplinary group of healthcare providers, researchers, and parents/caregivers of children who survived cardiac arrest. Then expert panel discussions achieved consensus on the core outcomes, the methods to measure those core outcomes, and the timing of the measurements. The P-COSCA includes assessment of survival, brain function, cognitive function, physical function, and basic daily life skills. Survival and brain function are assessed at discharge or 30 days (or both if possible) and between 6 and 12 months after arrest. Cognitive function, physical function, and basic daily life skills are assessed between 6 and 12 months after cardiac arrest. Because many children have prearrest comorbidities, the P-COSCA also includes documentation of baseline (ie, prearrest) brain function and calculation of changes after cardiac arrest. Supplementary outcomes of survival, brain function, cognitive function, physical function, and basic daily life skills are assessed at 3 months and beyond 1 year after cardiac arrest if resources are available.



Circulation: 23 Sep 2020:CIR0000000000000911; epub ahead of print
Topjian AA, Scholefield BR, Pinto NP, Fink EL, ... Hazinski MF, Slomine BS
Circulation: 23 Sep 2020:CIR0000000000000911; epub ahead of print | PMID: 32967446
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Abstract

Automated Recognition of Regional Wall Motion Abnormalities Through Deep Neural Network Interpretation of Transthoracic Echocardiography.

Huang MS, Wang CS, Chiang JH, Liu PY, Tsai WC

Automated interpretation of echocardiography by deep neural networks could support clinical reporting and improve efficiency. Whilst prior studies have evaluated spatial relationships using still frame images, our aim was to train and test a deep neural network for video analysis by combining spatial and temporal information, to automate the recognition of left ventricular regional wall motion abnormalities.We collected a series of transthoracic echocardiography examinations performed between July 2017 and April 2018 in two tertiary care hospitals. Regional wall abnormalities were defined by experienced physiologists and confirmed by trained cardiologists. First, we developed a 3-dimensional (3D) convolutional neural network (CNN) model for view selection ensuring stringent image quality control. Second, a U-net model segmented images to annotate the location of each left ventricular wall. Third, a final 3D CNN model evaluated echocardiographic videos from four standard views, before and after segmentation, and calculated a wall motion abnormality confidence level (0-1) for each segment. To evaluate model stability, we performed 5-fold cross-validation and external validation.In a series of 10,638 echocardiograms, our view selection model identified 6,454 (61%) examinations with sufficient image quality in all standard views. In this training set, 2,740 frames were annotated to develop the segmentation model, which achieved a Dice similarity coefficient of 0.756. External validation was performed in 1,756 examinations from an independent hospital. A regional wall motion abnormality was observed in 8.9% and 4.9% in the training and external validation datasets, respectively. The final model recognized regional wall motion abnormalities in the cross-validation and external validation datasets with an area under the receiver operating characteristic curve of 0.912 (95% confidence interval [CI] 0.896 to 0.928) and 0.891 (95% CI 0.834 to 0.948), respectively. In the external validation dataset, the sensitivity was 81.8% (95% CI 73.8 to 88.2%) and specificity was 81.6% (95% CI 80.4 to 82.8%).In echocardiographic examinations of sufficient image quality, it is feasible for deep neural networks to automate the recognition of regional wall motion abnormalities using temporal and spatial information from moving images. Further investigation is required to optimise model performance and evaluate clinical applications.



Circulation: 22 Sep 2020; epub ahead of print
Huang MS, Wang CS, Chiang JH, Liu PY, Tsai WC
Circulation: 22 Sep 2020; epub ahead of print | PMID: 32964749
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Abstract

Glucagon-Like Peptide 1 Receptor Agonists and Heart Failure: The Need for Further Evidence Generation and Practice Guidelines Optimization.

Khan MS, Fonarow GC, McGuire DK, Hernandez AF, ... Kosiborod MN, Butler J

With worsening epidemiological trends for both the incidence and prevalence of type 2 diabetes mellitus (T2DM) and heart failure (HF) worldwide, it is critical to implement optimal prevention and treatment strategies for patients with these comorbidities, either alone or concomitantly. Several guidelines and consensus statements have recommended glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter type 2 inhibitors as add-ons to lifestyle interventions with or without metformin in those at high atherosclerotic cardiovascular disease risk. However, these recommendations are either silent about HF or fail to differentiate between the prevention of HF in those at risk versus the treatment of individuals with manifest HF. Furthermore, these documents do not differentiate among those with different HF phenotypes. This distinction, even though important, may not be critical for sodium-glucose cotransporter type 2 inhibitors in view of the consistent data for benefit for both atherosclerotic cardiovascular disease- and HF-related outcomes that have emerged from the regulatory-mandated cardiovascular outcome trials for all sodium-glucose cotransporter type 2 inhibitors and the recent DAPA-HF trial (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction)demonstrating the benefit of dapagliflozin on HF-related outcomes in patients with HF with reduced ejection fraction with or without T2DM. However, the distinction may be crucial for glucagon-like peptide-1 receptor agonists and other antihyperglycemic agents. Indeed, in several of the new statements, glucagon-like peptide-1 receptor agonists are suggested treatment not only for patients with T2DM and atherosclerotic cardiovascular disease, but also in those with manifest HF, despite a lack of evidence for the latter recommendation. Although glucagon-like peptide-1 receptor agonists may be appropriate to use in patients at risk for HF, mechanistic insights and observations from randomized trials suggest no clear benefit on HF-related outcomes and even uncertainty regarding the safety in those with HF with reduced ejection fraction. Conversely, theoretical rationales suggest that these agents may benefit patients with HF with preserved ejection fraction. Considering that millions of patients with T2DM have HF, these concerns have public health implications that necessitate the thoughtful use of these therapies. Achieving this aim will require dedicated trials with these drugs in both patients who have HF with reduced ejection fraction and HF with preserved ejection fraction with T2DM to assess their efficacy, safety, and risk-benefit profile.



Circulation: 21 Sep 2020; 142:1205-1218
Khan MS, Fonarow GC, McGuire DK, Hernandez AF, ... Kosiborod MN, Butler J
Circulation: 21 Sep 2020; 142:1205-1218 | PMID: 32955939
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Cardiorenal Protection With the Newer Antidiabetic Agents in Patients With Diabetes and Chronic Kidney Disease: A Scientific Statement From the American Heart Association.

Rangaswami J, Bhalla V, de Boer IH, Staruschenko A, ... McCullough PA,

Chronic kidney disease (CKD) with type 2 diabetes (T2D) is a major public health problem, resulting in significant cardiovascular and kidney adverse outcomes worldwide. Despite the widespread use of standard-of-care therapies for CKD with T2D over the past few decades, rates of progression to end-stage kidney disease remain high with no beneficial impact on its accompanying burden of cardiovascular disease. The advent of the newer classes of antihyperglycemic agents, including SGLT2 (sodium glucose cotransporter 2) inhibitors and GLP-1 (glucagon-like peptide-1) receptor agonists, has changed the landscape of therapeutic options for patients with CKD with T2D, with demonstration of significant reductions in cardiovascular adverse events and progression to end-stage kidney disease. Several potential mechanisms exist through which these beneficial effects are achieved in both drug classes, which may be independent of their antihyperglycemic effects. This scientific statement summarizes the current literature on the cardiorenal protective effects with SGLT2 inhibitors and GLP-1 receptor agonists in patients with CKD and T2D. It reviews potential mechanistic pathways that may drive these benefits and summarizes the literature on adverse effects in patients with CKD and T2D at risk for or with established cardiovascular disease. Last, it provides practical guidance on a proposed collaborative care model bridging cardiologists, nephrologists, endocrinologists, and primary care physicians to facilitate the prompt and appropriate integration of these therapeutic classes in the management of patients with T2D and CKD.



Circulation: 27 Sep 2020:CIR0000000000000920; epub ahead of print
Rangaswami J, Bhalla V, de Boer IH, Staruschenko A, ... McCullough PA,
Circulation: 27 Sep 2020:CIR0000000000000920; epub ahead of print | PMID: 32981345
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Long-Term Follow-Up of Patients with Tetralogy of Fallot and Implantable Cardioverter Defibrillator: The DAI-T4F (Implantable Cardioverter Defibrillator-Tetralogy of Fallot) Nationwide Registry.

Waldmann V, Bouzeman A, Duthoit G, Koutbi L, ... Combes N, Marijon E

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, and sudden cardiac death represents an important mode of death in these patients. Data evaluating the implantable cardioverter defibrillator (ICD) in this patient population remain scarce.Nationwide French Registry including all TOF patients with an ICD initiated in 2010 by the French Institute of Health and Medical Research. The primary time to event endpoint was the time from ICD implantation to first appropriate ICD therapy. Secondary outcomes included ICD-related complications, heart transplantation, and death. Clinical events were centrally adjudicated by a blinded committee.A total of 165 patients (mean age 42.2±13.3 years, 70.1% males) were included from 40 centers, including 104 (63.0%) in secondary prevention. During a median (IQR) follow-up of 6.8 (2.5-11.4) years, 78 (47.3%) patients received at least one appropriate ICD therapy. The annual incidence of the primary outcome was 10.5% (7.1% and 12.5% in primary and secondary prevention, respectively, p=0.03). Overall, 71 (43.0%) patients presented with at least one ICD complication, including inappropriate shocks in 42 (25.5%) patients and lead dysfunction in 36 (21.8%) patients. Among 61 (37.0%) primary prevention patients, the annual rate of appropriate ICD therapies was 4.1%, 5.3%, 9.5%, and 13.3% in patients with respectively no, one, two, or ≥ three guideline-recommended risk factors. QRS fragmentation was the only independent predictor of appropriate ICD therapies (HR 3.47, 95% CI 1.19-10.11), and its integration in a model with current criteria increased the 5-year time-dependent area under the curve from 0.68 to 0.81 (p=0.006). Patients with congestive heart failure and/or reduced LVEF had a higher risk of non-arrhythmic death or heart transplantation (HR=11.01, 95% CI: 2.96-40.95).Patients with TOF and an ICD experience high rates of appropriate therapies, including those implanted in primary prevention. The considerable long-term burden of ICD-related complications, however, underlines the need for careful candidate selection. A combination of easy-to-use criteria including QRS fragmentation might improve risk stratification.URL: https://clinicaltrials.gov Unique Identifier: NCT03837574.



Circulation: 30 Sep 2020; epub ahead of print
Waldmann V, Bouzeman A, Duthoit G, Koutbi L, ... Combes N, Marijon E
Circulation: 30 Sep 2020; epub ahead of print | PMID: 32998542
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Abstract

Empagliflozin in Heart Failure: Diuretic and Cardiorenal Effects.

Griffin M, Rao VS, Ivey-Miranda J, Fleming J, ... Inzucchi SE, Testani JM
Background
Sodium-glucose cotransporter-2 inhibitors improve heart failure-related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics such as furosemide induce substantial neurohormonal activation, contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the sodium-glucose cotransporter-2 inhibitors may help circumvent these limitations.
Methods
Twenty patients with type 2 diabetes mellitus and chronic, stable heart failure completed a randomized, placebo-controlled crossover study of empagliflozin 10 mg daily versus placebo. Patients underwent an intensive 6-hour biospecimen collection and cardiorenal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with the above protocol repeated.
Results
Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours (<0.0001). Fractional excretion of sodium increased significantly with empagliflozin monotherapy versus placebo (fractional excretion of sodium, 1.2±0.7% versus 0.7±0.4%; =0.001), and there was a synergistic effect in combination with bumetanide (fractional excretion of sodium, 5.8±2.5% versus 3.9±1.9%; =0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208 mL [interquartile range, -536 to 153 mL] versus -14 mL [interquartile range, -282 to 335 mL]; =0.035) and plasma volume (-138 mL, interquartile range, -379 to 154±453 mL; =0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation because the change in norepinephrine was superior (=0.02) and all other neurohormones were similar (<0.34) during the empagliflozin versus placebo period. Furthermore, there was no evidence of potassium wasting (=0.20) or renal dysfunction (>0.11 for all biomarkers), whereas both serum magnesium (<0.001) and uric acid levels (=0.008) improved.
Conclusions
Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in patients with heart failure and may represent a mechanism contributing to the superior long-term heart failure outcomes observed with these agents. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03027960.



Circulation: 14 Sep 2020; 142:1028-1039
Griffin M, Rao VS, Ivey-Miranda J, Fleming J, ... Inzucchi SE, Testani JM
Circulation: 14 Sep 2020; 142:1028-1039 | PMID: 32410463
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Abstract

Familial Clustering of Aortic Size, Aneurysms, and Dissections in the Community.

Raunsø J, Song RJ, Vasan RS, Bourdillon MT, ... Xanthakis V, Andersson C
Background
Ruptured aortic aneurysm and aortic dissections are potentially preventable disorders associated with high mortality. Screening of individuals at risk may translate into elective surgical interventions and lowered mortality. It is uncertain if the risk of aortic dilation of varying degrees aggregates within families.
Methods
We investigated the risk of having thoracic and abdominal aortic sizes in the highest quartile (measured by computed tomography scans and indexed for body size) if at least 1 parent did so in the Framingham Heart Study cohorts, and estimated the incidence rates and hazard ratios of developing aortic aneurysm or dissection among first-degree relatives of those with aortic aneurysm or dissection, in comparison with age- and sex-matched controls (1:10 for aortic aneurysm and 1:100 for aortic dissection) using the Danish nationwide administrative registries.
Results
In the Framingham Heart Study, offspring (n=235) whose parent(s) had a sex- and age-standardized aortic size in the upper quartile had a multivariable-adjusted ≈3-fold increased odds ratio of belonging to the upper quartile themselves. In Denmark, a total of 68 939 individuals (mean age, 42 years) had a first-degree relative with aortic aneurysm and 7209 persons (mean age, 39 years) had a first-degree relative with aortic dissection. During an average follow-up of 7 years, first-degree relatives of patients with aortic aneurysm and dissection had a hazard ratio of 6.70 (95% CI, 5.96-7.52) for developing aortic aneurysm and a hazard ratio of 9.24 (95% CI, 5.53-15.44) for dissection in comparison with matched controls. These estimates remained unchanged on adjusting for several comorbidities, including prevalent hypertension, bicuspid aortic valve, and the Marfan syndrome. For both aortic aneurysm and dissections, the absolute event rates approached 1 per 1000 person-years for first-degree relatives versus 11 to 13 (aortic aneurysm) and 2 to 3 (aortic dissections) per 100 000 person-years among controls.
Conclusions
Increased aortic size, a precursor of aortic aneurysm and a risk factor for dissection, clusters in families. The incidence rates of aortic aneurysm and dissections approach the incidence rates of other common cardiovascular conditions in first-degree relatives, supporting the use of systematic screening for these conditions.



Circulation: 07 Sep 2020; 142:920-928
Raunsø J, Song RJ, Vasan RS, Bourdillon MT, ... Xanthakis V, Andersson C
Circulation: 07 Sep 2020; 142:920-928 | PMID: 32580567
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Abstract

Postoperative Atrial Fibrillation and Long-Term Risk of Stroke After Isolated Coronary Artery Bypass Graft Surgery.

Benedetto U, Gaudino MF, Dimagli A, Gerry S, ... Taggart DP,
Background
Postoperative atrial fibrillation (pAF) after coronary artery bypass grafting is a common complication. Whether pAF is associated with an increased risk of cerebrovascular accident (CVA) remains uncertain. We investigated the association between pAF and long-term risk of CVA by performing a post hoc analysis of 10-year outcomes of the ART (Arterial Revascularization Trial).
Methods
For the present analysis, among patients enrolled in the ART (n=3102), we excluded those who did not undergo surgery (n=25), had a history of atrial fibrillation (n=45), or had no information on the incidence of pAF (n=9). The final population consisted of 3023 patients, of whom 734 (24.3%) developed pAF with the remaining 2289 maintaining sinus rhythm. Competing risk and Cox regression analyses were used to investigate the association between pAF and the risk of CVA.
Results
At 10 years, the cumulative incidence of CVA was 6.3% (4.6%-8.1%) versus 3.7% (2.9%-4.5%) in patients with pAF and sinus rhythm, respectively. pAF was an independent predictor of CVA at 10 years (hazard ratio, 1.53 [95% CI, 1.06-2.23]; =0.025) even when CVAs that occurred during the index admission were excluded from the analysis (hazard ratio, 1.47 [95% 1.02-2.11]; =0.04).
Conclusions
Patients with pAF after coronary artery bypass grafting are at higher risk of CVA. These findings challenge the notion that pAF is a benign complication.



Circulation: 05 Oct 2020; 142:1320-1329
Benedetto U, Gaudino MF, Dimagli A, Gerry S, ... Taggart DP,
Circulation: 05 Oct 2020; 142:1320-1329 | PMID: 33017213
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Abstract

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, ... Tanck MWT, Bezzina CR
Background
Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.
Methods
We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score.
Results
Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (<5×10) near , , and , and 1 missense variant in (p.Asp85Asn) at the suggestive threshold (<10). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r=0.40; =3.2×10). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (<0.005).
Conclusions
This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.



Circulation: 27 Jul 2020; 142:324-338
Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, ... Tanck MWT, Bezzina CR
Circulation: 27 Jul 2020; 142:324-338 | PMID: 32429735
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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

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.In mouse models of myocardial infarction (MI), myocardial ischemia/reperfusion injury (I/R 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 I/R injury. Photoconversion, parabiosis, single-cell TCR sequencing and adoptive transfer were applied to determine the source of heart Tregs. The involvement of the interleukin (IL)-33/ST2 axis and secreted acidic cysteine rich glycoprotein (Sparc), a molecule upregulated in heart Tregs, was further evaluated in functional assays.We showed that Tregs were highly enriched in the myocardium of MI, I/R injury and cryoinjury mice. Transcriptomic data revealed that Tregs isolated from the injured hearts had plenty of differentially expressed transcripts compared to 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 due to recruitment from circulating Treg pool, while local proliferation also contributed to their expansion. Moreover, a remarkable case of repeatedly detected TCR 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 (Tconvs), proved by the analysis of TCR repertoires and Tconvs adoptive transfer experiments. Notably, the IL-33/ST2 axis was essential for sustaining heart Treg populations. Finally, 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.We identified and characterized a phenotypically and functionally unique population of heart Tregs, which may lay the foundation to harness Tregs for cardioprotection in MI and other cardiac diseases.



Circulation: 27 Sep 2020; epub ahead of print
Xia N, Lu Y, Gu M, Li N, ... Yang X, Cheng X
Circulation: 27 Sep 2020; epub ahead of print | PMID: 32985264
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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

Immune checkpoint inhibitors (ICI) 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.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 two-year period after and the \"control period\" as the two-year prior to 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. Additionally, in an imaging sub-study (n=40), the rate of atherosclerotic plaque progression was compared from before and after starting an ICI. All study measures and outcomes were blindly adjudicated.In the matched cohort study, there was a 3-fold higher risk for cardiovascular events after starting an ICI (HR, 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 two years (adjusted HR, 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%/year pre-to 6.7%/year post). This association between ICI use and increased atherosclerotic plaque progression was attenuated with concomitant use of statins or corticosteroids.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, prior to, during and after treatment, should be considered among patients on an ICI.



Circulation: 01 Oct 2020; epub ahead of print
Drobni ZD, Alvi RM, Taron J, Zafar A, ... Hoffmann U, Neilan TG
Circulation: 01 Oct 2020; epub ahead of print | PMID: 33003973
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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

Smooth muscle cells (SMC) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC dedifferentiation, migration and transdifferentiation into other cell types. Yet, how SMC contribute to pathophysiology of atherosclerosis remains elusive.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 employed pharmacological studies targeting SMC-derived cells bothand .We found that SMC 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, were multipotent and could differentiate into macrophage-like and fibrochondrocyte-like cells, as well as return towards 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 (GWAS) signals for coronary artery disease (CAD) in RA signaling target gene loci and correlation between CAD risk alleles and repressed expression of these genes. Activation of RA signaling by all-trans retinoic acid (ATRA), an anti-cancer drug for acute promyelocytic leukemia, blocked SMC transition to SEM cells, reduced atherosclerotic burden and promoted fibrous cap stability.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: 22 Sep 2020; epub ahead of print
Pan H, Xue C, Auerbach BJ, Fan J, ... Li M, Reilly MP
Circulation: 22 Sep 2020; epub ahead of print | PMID: 32962412
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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,

In patients with type 2 diabetes mellitus (T2DM), sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure (HHF). We assessed the effect of ertugliflozin on HHF and related outcomes.VERTIS CV, a double-blind, placebo-controlled trial, randomized patients with T2DM 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 hazard 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.8246 patients were randomized 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 pre-trial ejection fraction (EF) available, including n=959 with EF≤45%. Ertugliflozin did not significantly reduce first HHF/CV death (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). Prior 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% vs 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 three populations with baseline eGFR<60mL/min/1.73m, albuminuria, and diuretic use (eachinteraction<0.05). Ertugliflozin reduced total events of HHF (RR, 0.70; 95% CI, 0.56, 0.87) and total HHF/CV death (RR, 0.83; 95% CI, 0.72, 0.96).In patients with T2DM with or without baseline HF, ertugliflozin reduced risk for first and total HHF and total HHF/CV death, adding further support for the use of SGLT2 inhibitors in primary and secondary prevention of HHF.URL: https://clinicaltrials.gov Unique Identifier: NCT01986881.



Circulation: 06 Oct 2020; epub ahead of print
Cosentino F, Cannon CP, Cherney DZI, Masiukiewicz U, ... McGuire DK,
Circulation: 06 Oct 2020; epub ahead of print | PMID: 33026243
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Abstract

PCSK9 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

Proprotein convertase subtilisin/kexin 9 (PCSK9), mainly secreted by the liver and released into the blood, elevates plasma low-density lipoprotein (LDL) cholesterol by degrading LDL receptor. Pleiotropic effects of PCSK9 beyond lipid-metabolism have been shown. However, the direct effects of PCSK9 on platelet activation and thrombosis, as well as the underlying mechanisms, still remain unclear.We detected the direct effects of PCSK9 on agonists-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, α granule release, spreading, and clot retraction. These studies were complemented byanalysis of FeCl3-injured mouse mesenteric arteriole thrombosis. We also investigated the underlying mechanisms. Using myocardial infarct (MI) model, we explored the effects of PCSK9 on microvascular obstruction and infarct expansion post-MI.PCSK9 directly enhances agonists-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, P-selection release from α granules, spreading, and clot retraction. In line, PCSK9 enhancesthrombosis in a FeCl3-injured mesenteric arteriole thrombosis mouse model, while PCSK9 inhibitor evolocumab ameliorates its enhancing effects. Mechanism studies revealed that PCSK9 binds to platelet CD36 and thus activates Src kinase and mitogen-activated protein kinase (MAPK)- extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase, increases the generation of reactive oxygen species, as well as activates the p38MAPK/cytosolic phospholipase A2/cyclooxygenase-1/thromboxane A signaling pathways downstream of CD36 to enhance platelet activation. Using CD36 knockout mice, we showed the enhancing effects of PCSK9 on platelet activation are CD36 dependent. Consistently and importantly, aspirin abolishes the enhancing effects of PCSK9 on platelet activation andthrombosis. Finally, we showed that PCSK9 activating platelet CD36 aggravates microvascular obstruction and promotes MI expansion post-MI.PCSK9 in plasma directly enhances platelet activation andthrombosis, as well as MI expansion post-MI, 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: 28 Sep 2020; epub ahead of print
Qi Z, Hu L, Zhang J, Yang W, ... Ding Z, Ge J
Circulation: 28 Sep 2020; epub ahead of print | PMID: 32988222
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Abstract

Comprehensive Ex Vivo Comparison of 5 Clinically Used Conduit Configurations for Valve-Sparing Aortic Root Replacement Using a 3-Dimensional-Printed Heart Simulator.

Paulsen MJ, Imbrie-Moore AM, Baiocchi M, Wang H, ... MacArthur JW, Woo YJ
Background
Many graft configurations are clinically used for valve-sparing aortic root replacement, some specifically focused on recapitulating neosinus geometry. However, the specific impact of such neosinuses on valvular and root biomechanics and the potential influence on long-term durability are unknown.
Methods
Using a custom 3-dimenstional-printed heart simulator with porcine aortic roots (n=5), the anticommissural plication, Stanford modification, straight graft (SG), Uni-Graft, and Valsalva graft configurations were tested in series using an incomplete counterbalanced measures design, with the native root as a control, to mitigate ordering effects. Hemodynamic and videometric data were analyzed using linear models with conduit as the fixed effect of interest and valve as a fixed nuisance effect with post hoc pairwise testing using Tukey\'s correction.
Results
Hemodynamics were clinically similar between grafts and control aortic roots. Regurgitant fraction varied between grafts, with SG and Uni-Graft groups having the lowest regurgitant fractions and anticommissural plication having the highest. Root distensibility was significantly lower in SG versus both control roots and all other grafts aside from the Stanford modification (≤0.01 for each). All grafts except SG had significantly higher cusp opening velocities versus native roots (<0.01 for each). Relative cusp opening forces were similar between SG, Uni-Graft, and control groups, whereas anticommissural plication, Stanford modification, and Valsalva grafts had significantly higher opening forces versus controls (<0.01). Cusp closing velocities were similar between native roots and the SG group, and were significantly lower than observed in the other conduits (≤0.01 for each). Only SG and Uni-Graft groups experienced relative cusp closing forces approaching that of the native root, whereas relative forces were >5-fold higher in the anticommissural plication, Stanford modification, and Valsalva graft groups.
Conclusions
In this ex vivo modeling system, clinically used valve-sparing aortic root replacement conduit configurations have comparable hemodynamics but differ in biomechanical performance, with the straight graft most closely recapitulating native aortic root biomechanics.



Circulation: 05 Oct 2020; 142:1361-1373
Paulsen MJ, Imbrie-Moore AM, Baiocchi M, Wang H, ... MacArthur JW, Woo YJ
Circulation: 05 Oct 2020; 142:1361-1373 | PMID: 33017215
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Abstract

National Variation in Congenital Heart Surgery Outcomes.

Pasquali SK, Thibault D, O\'Brien SM, Jacobs JP, ... Backer CL, Mayer JE
Background
Optimal strategies to improve national congenital heart surgery outcomes and reduce variability across hospitals remain unclear. Many policy and quality improvement efforts have focused primarily on higher-risk patients and mortality alone. Improving our understanding of both morbidity and mortality and current variation across the spectrum of complexity would better inform future efforts.
Methods
Hospitals participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database (2014-2017) were included. Case mix-adjusted operative mortality, major complications, and postoperative length of stay were evaluated using Bayesian models. Hospital variation was quantified by the interdecile ratio (IDR, upper versus lower 10%) and 95% credible intervals (CrIs). Stratified analyses were performed by risk group (Society of Thoracic Surgeons-European Association for Cardiothoracic Surgery [STAT] category) and simulations evaluated the potential impact of reductions in variation.
Results
A total of 102 hospitals (n=84 407) were included, representing ≈85% of US congenital heart programs. STAT category 1 to 3 (lower risk) operations comprised 74% of cases. All outcomes varied significantly across hospitals: adjusted mortality by 3-fold (upper versus lower decile 5.0% versus 1.6%, IDR 3.1 [95% CrI 2.5-3.7]), mean length of stay by 1.8-fold (19.2 versus 10.5 days, IDR 1.8 [95% CrI 1.8-1.9]), and major complications by >3-fold (23.5% versus 7.0%, IDR 3.4 [95% CrI 3.0-3.8]). The degree of variation was similar or greater for low- versus high-risk cases across outcomes, eg, ≈3-fold mortality variation across hospitals for STAT 1 to 3 (IDR 3.0 [95% CrI 2.1-4.2]) and STAT 4 or 5 (IDR 3.1 [95% CrI 2.4-3.9]) cases. High-volume hospitals had less variability across outcomes and risk categories. Simulations suggested potential reductions in deaths (n=282), major complications (n=1539), and length of stay (101 183 days) over the 4-year study period if all hospitals were to perform at the current median or better, with 37% to 60% of the improvement related to the STAT 1 to 3 (lower risk) group across outcomes.
Conclusions
We demonstrate significant hospital variation in morbidity and mortality after congenital heart surgery. Contrary to traditional thinking, a substantial portion of potential improvements that could be realized on a national scale were related to variability among lower-risk cases. These findings suggest modifications to our current approaches to optimize care and outcomes in this population are needed.



Circulation: 05 Oct 2020; 142:1351-1360
Pasquali SK, Thibault D, O'Brien SM, Jacobs JP, ... Backer CL, Mayer JE
Circulation: 05 Oct 2020; 142:1351-1360 | PMID: 33017214
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Abstract

Randomized, Controlled Trial Comparing Mitral Valve Repair With Leaflet Resection Versus Leaflet Preservation on Functional Mitral Stenosis: The CAMRA CardioLink-2 Study.

Chan V, Mazer CD, Ali FM, Quan A, ... Leong-Poi H, Verma S
Background
Equipoise exists between the use of leaflet resection and preservation for surgical repair of mitral regurgitation caused by prolapse. We therefore performed a randomized, controlled trial comparing these 2 techniques, particularly in regard to functional mitral stenosis.
Methods
One hundred four patients with degenerative mitral regurgitation surgically amenable to either leaflet resection or preservation were randomized at 7 specialized cardiac surgical centers. Exclusion criteria included anterior leaflet or commissural prolapse, as well as a mixed cause for mitral valve disease. Using previous data, we determined that a sample size of 88 subjects would provide 90% power to detect a 5-mm Hg difference in mean mitral valve gradient at peak exercise, assuming an SD of 6.7 mm with a 2-sided test with α=5% and 10% patient attrition. The primary end point was the mean mitral gradient at peak exercise 12 months after repair.
Results
Patient age, proportion who were female, and Society of Thoracic Surgeons risk score were 63.9±10.4 years, 19%, and 1.4±2.8% for those who were assigned to leaflet resection (n=54), and 66.3±10.8 years, 16%, and 1.9±2.6% for those who underwent leaflet preservation (n=50). There were no perioperative deaths or conversions to replacement. At 12 months, moderate mitral regurgitation was observed in 3 subjects in the leaflet resection group and 2 in the leaflet preservation group. The mean transmitral gradient at 12 months during peak exercise was 9.1±5.2 mm Hg after leaflet resection and 8.3±3.3 mm Hg after leaflet preservation (=0.43). The participants had similar resting peak (8.3±4.4 mm Hg versus 8.4±2.6 mm Hg; =0.96) and mean resting (3.2±1.9 mm Hg versus 3.1±1.1 mm Hg; =0.67) mitral gradients after leaflet resection and leaflet preservation, respectively. The 6-minute walking distance was 451±147 m for those in the leaflet resection versus 481±95 m for the leaflet preservation group (=0.27).
Conclusions
In this adequately powered randomized trial, repair of mitral prolapse with either leaflet resection or leaflet preservation was associated with similar transmitral gradients at peak exercise at 12 months postoperatively. These data do not support the hypothesis that a strategy of leaflet resection (versus preservation) is associated with a risk of functional mitral stenosis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier NCT02552771.



Circulation: 05 Oct 2020; 142:1342-1350
Chan V, Mazer CD, Ali FM, Quan A, ... Leong-Poi H, Verma S
Circulation: 05 Oct 2020; 142:1342-1350 | PMID: 33017212
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Abstract

Progress Toward Cardiac Xenotransplantation.

Pierson RN, Fishman JA, Lewis GD, D\'Alessandro DA, ... Madsen JC, Azimzadeh AM

Consistent survival of life-supporting pig heart xenograft recipients beyond 90 days was recently reported using genetically modified pigs and a clinically applicable drug treatment regimen. If this remarkable achievement proves reproducible, published benchmarks for clinical translation of cardiac xenografts appear to be within reach. Key mechanistic insights are summarized here that informed recent pig design and therapeutic choices, which together appear likely to enable early clinical translation.



Circulation: 05 Oct 2020; 142:1389-1398
Pierson RN, Fishman JA, Lewis GD, D'Alessandro DA, ... Madsen JC, Azimzadeh AM
Circulation: 05 Oct 2020; 142:1389-1398 | PMID: 33017208
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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

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 (GUG), in patients with masked hypertension.Patients with an office BP of <140/90 mmHg and daytime ambulatory BP of 135-150 mmHg systolic and/or 85-95 mmHg diastolic were randomized 1:1 to the treatment of GUG or placebo 5-10 grams twice daily for 4 weeks. The primary efficacy variable was the change in daytime ambulatory BP.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 mellitus, and smoking, respectively) averaged 129/82 and 135/89 mmHg, respectively. In the intention-to-treat analysis, daytime systolic/diastolic BP was reduced by 5.44 /3.39 and 2.91/1.60 mmHg in the GUG and placebo groups, respectively. The between-group difference in BP reductions was significant for the daytime (2.52/1.79 mmHg, ≤0.025) and 24-h BP (2.33/1.49 mmHg, ≤0.012), but not for the clinic and nighttime BPs (≥0.162). The per-protocol analysis in 229 patients produced similar results. Only one adverse event (sleepiness during the day) was reported and no serious adverse event occurred.BP lowering treatment with Chinese traditional medicine GUG is efficacious for patients with masked hypertension.URL: https://www.clinicaltrials.gov. Unique identifier: NCT02156024.



Circulation: 05 Oct 2020; epub ahead of print
Zhang DY, Cheng YB, Guo QH, Shan XL, ... Li Y, Wang JG
Circulation: 05 Oct 2020; epub ahead of print | 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: 07 Oct 2020:CIR0000000000000914; epub ahead of print
Caceres BA, Streed CG, Corliss HL, Lloyd-Jones DM, ... Ross LM,
Circulation: 07 Oct 2020:CIR0000000000000914; epub ahead of print | PMID: 33028085
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Abstract

Built Environment Approaches to Increase Physical Activity: A Science Advisory From the American Heart Association.

Omura JD, Carlson SA, Brown DR, Hopkins DP, ... Fulton JE,

Engaging in regular physical activity is one of the most important things people can do to improve their cardiovascular health; however, population levels of physical activity remain low in the United States. Effective population-based approaches implemented in communities can help increase physical activity among all Americans. Evidence suggests that built environment interventions offer one such approach. These interventions aim to create or modify community environmental characteristics to make physical activity easier or more accessible for all people in the places where they live. In 2016, the Community Preventive Services Task Force released a recommendation for built environment approaches to increase physical activity. This recommendation is based on a systematic review of 90 studies (search period, 1980-June 2014) conducted using methods outlined by the Guide to Community Preventive Services. The Community Preventive Services Task Force found sufficient evidence of effectiveness to recommend combined built environment strategies. Specifically, these strategies combine interventions to improve pedestrian or bicycle transportation systems with interventions to improve land use and environmental design. Components of transportation systems can include street pattern design and connectivity, pedestrian infrastructure, bicycle infrastructure, and public transit infrastructure and access. Components of land use and environmental design can include mixed land use, increased residential density, proximity to community or neighborhood destinations, and parks and recreational facility access. Implementing this Community Preventive Services Task Force recommendation in communities across the United States can help promote healthy and active living, increase physical activity, and ultimately improve cardiovascular health.



Circulation: 14 Sep 2020; 142:e160-e166
Omura JD, Carlson SA, Brown DR, Hopkins DP, ... Fulton JE,
Circulation: 14 Sep 2020; 142:e160-e166 | PMID: 32787451
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Abstract

Creating Built Environments That Expand Active Transportation and Active Living Across the United States: A Policy Statement From the American Heart Association.

Young DR, Cradock AL, Eyler AA, Fenton M, ... Whitsel LP,

Physical activity is vital for the health and well-being of youth and adults, although the prevalence of physical activity continues to be low. Promoting active transportation or human-powered transportation through policy, systems, and environmental change is one of the leading evidence-based strategies to increase physical activity regardless of age, income, racial/ethnic background, ability, or disability. Initiatives often require coordination across federal, state, and local agencies. To maximize the effectiveness of all types of interventions, it is imperative to establish strong and broad partnerships across professional disciplines, community members, and advocacy groups. Health organizations can play important roles in facilitating these partnerships. This policy statement provides recommendations and resources that can improve transportation systems, enhance land use design, and provide education to support policies and environments to promote active travel. The American Heart Association supports safe, equitable active transportation policies in communities across the country that incorporate consistent implementation evaluation. Ultimately, to promote large increases in active transportation, policies need to be created, enforced, and funded across multiple sectors in a coordinated and equitable fashion. Active transportation policies should operate at 3 levels: the macroscale of land use, the mesoscale of pedestrian and bicycle networks and infrastructure such as Complete Streets policies and Safe Routes to School initiatives, and the microscale of design interventions and placemaking such as building orientation and access, street furnishings, and safety and traffic calming measures. Health professionals and organizations are encouraged to become involved in advocating for active transportation policies at all levels of government.



Circulation: 14 Sep 2020; 142:e167-e183
Young DR, Cradock AL, Eyler AA, Fenton M, ... Whitsel LP,
Circulation: 14 Sep 2020; 142:e167-e183 | PMID: 32787443
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Abstract

Suppression of Endothelial AGO1 Promotes Adipose Tissue Browning and Improves Metabolic Dysfunction.

Tang X, Miao Y, Luo Y, Sriram K, ... Zhong S, Chen ZB
Background
Metabolic disorders such as obesity and diabetes mellitus can cause dysfunction of endothelial cells (ECs) and vascular rarefaction in adipose tissues. However, the modulatory role of ECs in adipose tissue function is not fully understood. Other than vascular endothelial growth factor-vascular endothelial growth factor receptor-mediated angiogenic signaling, little is known about the EC-derived signals in adipose tissue regulation. We previously identified Argonaute 1 (AGO1; a key component of microRNA-induced silencing complex) as a crucial regulator in hypoxia-induced angiogenesis. In this study, we intend to determine the AGO1-mediated EC transcriptome, the functional importance of AGO1-regulated endothelial function in vivo, and the relevance to adipose tissue function and obesity.
Methods
We generated and subjected mice with EC-AGO1 deletion (EC-AGO1-knockout [KO]) and their wild-type littermates to a fast food-mimicking, high-fat high-sucrose diet and profiled the metabolic phenotypes. We used crosslinking immunoprecipitation- and RNA-sequencing to identify the AGO1-mediated mechanisms underlying the observed metabolic phenotype of EC-AGO1-KO. We further leveraged cell cultures and mouse models to validate the functional importance of the identified molecular pathway, for which the translational relevance was explored using human endothelium isolated from healthy donors and donors with obesity/type 2 diabetes mellitus.
Results
We identified an antiobesity phenotype of EC-AGO1-KO, evident by lower body weight and body fat, improved insulin sensitivity, and enhanced energy expenditure. At the organ level, we observed the most significant phenotype in the subcutaneous and brown adipose tissues of KO mice, with greater vascularity and enhanced browning and thermogenesis. Mechanistically, EC-AGO1 suppression results in inhibition of thrombospondin-1 (/TSP1), an antiangiogenic and proinflammatory cytokine that promotes insulin resistance. In EC-AGO1-KO mice, overexpression of TSP1 substantially attenuated the beneficial phenotype. In human endothelium isolated from donors with obesity or type 2 diabetes mellitus, AGO1 and THBS1 are expressed at higher levels than the healthy controls, supporting a pathological role of this pathway.
Conclusions
Our study suggests a novel mechanism by which ECs, through the AGO1-TSP1 pathway, control vascularization and function of adipose tissues, insulin sensitivity, and whole-body metabolic state.



Circulation: 27 Jul 2020; 142:365-379
Tang X, Miao Y, Luo Y, Sriram K, ... Zhong S, Chen ZB
Circulation: 27 Jul 2020; 142:365-379 | PMID: 32393053
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Abstract

Environment-Sensing Aryl Hydrocarbon Receptor Inhibits the Chondrogenic Fate of Modulated Smooth Muscle Cells in Atherosclerotic Lesions.

Kim JB, Zhao Q, Nguyen T, Pjanic M, ... Kundu R, Quertermous T
Background
Smooth muscle cells (SMC) play a critical role in atherosclerosis. The Aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that contributes to vascular development, and has been implicated in coronary artery disease risk. We hypothesized that AHR can affect atherosclerosis by regulating phenotypic modulation of SMC.
Methods
We combined RNA-sequencing, chromatin immunoprecipitation followed by sequencing, assay for transposase-accessible chromatin using sequencing, and in vitro assays in human coronary artery SMCs, with single-cell RNA-sequencing, histology, and RNAscope in an SMC-specific lineage-tracingknockout mouse model of atherosclerosis to better understand the role ofin vascular disease.
Results
Genomic studies coupled with functional assays in cultured human coronary artery SMCs revealed thatmodulates the human coronary artery SMC phenotype and suppresses ossification in these cells. Lineage-tracing and activity-tracing studies in the mouse aortic sinus showed that thepathway is active in modulated SMCs in the atherosclerotic lesion cap. Furthermore, single-cell RNA-sequencing studies of the SMC-specificknockout mice showed a significant increase in the proportion of modulated SMCs expressing chondrocyte markers such asand , which localized to the lesion neointima. These cells, which we term \"chondromyocytes,\" were also identified in the neointima of human coronary arteries. In histological analyses, these changes manifested as larger lesion size, increased lineage-traced SMC participation in the lesion, decreased lineage-traced SMCs in the lesion cap, and increased alkaline phosphatase activity in lesions in theknockout in comparison with wild-type mice. We propose thatis likely protective based on these data and inference from human genetic analyses.
Conclusions
Overall, we conclude thatpromotes the maintenance of lesion cap integrity and diminishes the disease-related SMC-to-chondromyocyte transition in atherosclerotic tissues.



Circulation: 10 Aug 2020; 142:575-590
Kim JB, Zhao Q, Nguyen T, Pjanic M, ... Kundu R, Quertermous T
Circulation: 10 Aug 2020; 142:575-590 | PMID: 32441123
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Abstract

Extracellular Vesicle-Mediated Delivery of Circular RNA SCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models.

Yang L, Han B, Zhang Z, Wang S, ... Wang J, Yao H
Background
Stroke is a leading cause of adult disability that can severely compromise the quality of life of patients, yet no effective medication currently exists to accelerate rehabilitation. A variety of circular RNA (circRNA) molecules are known to function in ischemic brain injury. Lentivirus-based expression systems have been widely used in basic studies of circRNAs, but safety issues with such delivery systems have limited exploration of the potential therapeutic roles for circRNAs.
Methods
Circular RNA SCMH1 (circSCMH1) was screened from the plasma of patients with acute ischemic stroke by using circRNA microarrays. Engineered rabies virus glycoprotein-circSCMH1-extracellular vesicles were generated to selectively deliver circSCMH1 to the brain. Nissl staining was used to examine infarct size. Behavioral tasks were performed to evaluate motor functions in both rodent and nonhuman primate ischemic stroke models. Golgi staining and immunostaining were used to examine neuroplasticity and glial activation. Proteomic assays and RNA-sequencing data combined with transcriptional profiling were used to identify downstream targets of circSCMH1.
Results
CircSCMH1 levels were significantly decreased in the plasma of patients with acute ischemic stroke, offering significant power in predicting stroke outcomes. The decreased levels of circSCMH1 were further confirmed in the plasma and peri-infarct cortex of photothrombotic stroke mice. Beyond demonstrating proof-of-concept for an RNA drug delivery technology, we observed that circSCMH1 treatment improved functional recovery after stroke in both mice and monkeys, and we discovered that circSCMH1 enhanced the neuronal plasticity and inhibited glial activation and peripheral immune cell infiltration. CircSCMH1 binds mechanistically to the transcription factor MeCP2 (methyl-CpG binding protein 2), thereby releasing repression of MeCP2 target gene transcription.
Conclusions
Rabies virus glycoprotein-circSCMH1-extracellular vesicles afford protection by promoting functional recovery in the rodent and the nonhuman primate ischemic stroke models. Our study presents a potentially widely applicable nucleotide drug delivery technology and demonstrates the basic mechanism of how circRNAs can be therapeutically exploited to improve poststroke outcomes.



Circulation: 10 Aug 2020; 142:556-574
Yang L, Han B, Zhang Z, Wang S, ... Wang J, Yao H
Circulation: 10 Aug 2020; 142:556-574 | PMID: 32441115
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Abstract

Phosphoinositide 3-Kinase-Regulated Pericyte Maturation Governs Vascular Remodeling.

Figueiredo AM, Villacampa P, Diéguez-Hurtado R, José Lozano J, ... Carracedo A, Graupera M
Background
Pericytes regulate vessel stabilization and function, and their loss is associated with diseases such as diabetic retinopathy or cancer. Despite their physiological importance, pericyte function and molecular regulation during angiogenesis remain poorly understood.
Methods
To decipher the transcriptomic programs of pericytes during angiogenesis, we crossedmice into RiboTag mice. Pericyte morphological changes were assessed in mural cell-specific R26-mTmG reporter mice, in which low doses of tamoxifen allowed labeling of single-cell pericytes at high resolution. To study the role of phosphoinositide 3-kinase (PI3K) signaling in pericyte biology during angiogenesis, we used genetic mouse models that allow selective inactivation of PI3Kα and PI3Kβ isoforms and their negative regulator phosphate and tensin homolog deleted on chromosome 10 (PTEN) in mural cells.
Results
At the onset of angiogenesis, pericytes exhibit molecular traits of cell proliferation and activated PI3K signaling, whereas during vascular remodeling, pericytes upregulate genes involved in mature pericyte cell function, together with a remarkable decrease in PI3K signaling. Immature pericytes showed stellate shape and high proliferation, and mature pericytes were quiescent and elongated. Unexpectedly, we demonstrate that PI3Kβ, but not PI3Kα, regulates pericyte proliferation and maturation during vessel formation. Genetic PI3Kβ inactivation in pericytes triggered early pericyte maturation. Conversely, unleashing PI3K signaling by means of PTEN deletion delayed pericyte maturation. Pericyte maturation was necessary to undergo vessel remodeling during angiogenesis.
Conclusions
Our results identify new molecular and morphological traits associated with pericyte maturation and uncover PI3Kβ activity as a checkpoint to ensure appropriate vessel formation. In turn, our results may open new therapeutic opportunities to regulate angiogenesis in pathological processes through the manipulation of pericyte PI3Kβ activity.



Circulation: 17 Aug 2020; 142:688-704
Figueiredo AM, Villacampa P, Diéguez-Hurtado R, José Lozano J, ... Carracedo A, Graupera M
Circulation: 17 Aug 2020; 142:688-704 | PMID: 32466671
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Abstract

Early Cardiac Remodeling Promotes Tumor Growth and Metastasis.

Avraham S, Abu-Sharki S, Shofti R, Haas T, ... Shaked Y, Aronheim A
Background
Recent evidence suggests that cancer and cardiovascular diseases are associated. Chemotherapy drugs are known to result in cardiotoxicity, and studies have shown that heart failure and stress correlate with poor cancer prognosis. However, whether cardiac remodeling in the absence of heart failure is sufficient to promote cancer is unknown.
Methods
To investigate the effect of early cardiac remodeling on tumor growth and metastasis colonization, we used transverse aortic constriction (TAC), a model for pressure overload-induced cardiac hypertrophy, and followed it by cancer cell implantation.
Results
TAC-operated mice developed larger primary tumors with a higher proliferation rate and displayed more metastatic lesions compared with controls. Serum derived from TAC-operated mice potentiated cancer cell proliferation in vitro, suggesting the existence of secreted tumor-promoting factors. Using RNA-sequencing data, we identified elevated mRNA levels of periostin in the hearts of TAC-operated mice. Periostin levels were also found to be high in the serum after TAC. Depletion of periostin from the serum abrogated the proliferation of cancer cells; conversely, the addition of periostin enhanced cancer cell proliferation in vitro. This is the first study to show that early cardiac remodeling nurtures tumor growth and metastasis and therefore promotes cancer progression.
Conclusions
Our study highlights the importance of early diagnosis and treatment of cardiac remodeling because it may attenuate cancer progression and improve cancer outcome.



Circulation: 17 Aug 2020; 142:670-683
Avraham S, Abu-Sharki S, Shofti R, Haas T, ... Shaked Y, Aronheim A
Circulation: 17 Aug 2020; 142:670-683 | PMID: 32475164
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Abstract

Loss of Protease-Activated Receptor 4 Prevents Inflammation Resolution and Predisposes the Heart to Cardiac Rupture After Myocardial Infarction.

Kolpakov MA, Guo X, Rafiq K, Vlasenko L, ... Houser SR, Sabri A
Background
Cardiac rupture is a major lethal complication of acute myocardial infarction (MI). Despite significant advances in reperfusion strategies, mortality from cardiac rupture remains high. Studies suggest that cardiac rupture can be accelerated by thrombolytic therapy, but the relevance of this risk factor remains controversial.
Methods
We analyzed protease-activated receptor 4 (Par4) expression in mouse hearts with MI and investigated the effects of Par4 deletion on cardiac remodeling and function after MI by echocardiography, quantitative immunohistochemistry, and flow cytometry.
Results
Par4 mRNA and protein levels were increased in mouse hearts after MI and in isolated cardiomyocytes in response to hypertrophic and inflammatory stimuli. Par4-deficient mice showed less myocyte apoptosis, reduced infarct size, and improved functional recovery after acute MI relative to wild-type (WT). Conversely, Par4 mice showed impaired cardiac function, greater rates of myocardial rupture, and increased mortality after chronic MI relative to WT. Pathological evaluation of hearts from Par4 mice demonstrated a greater infarct expansion, increased cardiac hemorrhage, and delayed neutrophil accumulation, which resulted in impaired post-MI healing compared with WT. Par4 deficiency also attenuated neutrophil apoptosis in vitro and after MI in vivo and impaired inflammation resolution in infarcted myocardium. Transfer of Par4 neutrophils, but not of Par4 platelets, in WT recipient mice delayed inflammation resolution, increased cardiac hemorrhage, and enhanced cardiac dysfunction. In parallel, adoptive transfer of WT neutrophils into Par4 mice restored inflammation resolution, reduced cardiac rupture incidence, and improved cardiac function after MI.
Conclusions
These findings reveal essential roles of Par4 in neutrophil apoptosis and inflammation resolution during myocardial healing and point to Par4 inhibition as a potential therapy that should be limited to the acute phases of ischemic insult and avoided for long-term treatment after MI.



Circulation: 24 Aug 2020; 142:758-775
Kolpakov MA, Guo X, Rafiq K, Vlasenko L, ... Houser SR, Sabri A
Circulation: 24 Aug 2020; 142:758-775 | PMID: 32489148
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Impact:
Abstract

Health Impact and Cost-Effectiveness of Volume, Tiered, and Absolute Sugar Content Sugar-Sweetened Beverage Tax Policies in the United States: A Microsimulation Study.

Lee Y, Mozaffarian D, Sy S, Liu J, ... Gaziano TA, Micha R
Background
Sugar-sweetened beverage taxes are a rapidly growing policy tool and can be based on absolute volume, sugar content tiers, or absolute sugar content. Yet, their comparative health and economic impacts have not been quantified, in particular, tiered or sugar content taxes that provide industry incentives for sugar reduction.
Methods
We estimated incremental changes in diabetes mellitus and cardiovascular disease, quality-adjusted life-years, costs, and cost-effectiveness of 3 sugar-sweetened beverage tax designs in the United States, on the basis of (1) volume ($0.01/oz), (2) tiers (<5 g of added sugar/8 oz: no tax; 5-20 g/8 oz: $0.01/oz; and >20 g/8 oz: $0.02/oz), and (3) absolute sugar content ($0.01 per teaspoon added sugar), each compared with a base case of modest ongoing voluntary industry reformulation. A validated microsimulation model, CVD-PREDICT (Cardiovascular Disease Policy Model for Risk, Events, Detection, Interventions, Costs, and Trends), incorporated national demographic and dietary data from the National Health and Nutrition Examination Survey, policy effects and sugar-sweetened beverage-related diseases from meta-analyses, and industry reformulation and health-related costs from established sources.
Results
Over a lifetime, the volume, tiered, and absolute sugar content taxes would generate $80.4 billion, $142 billion, and $41.7 billion in tax revenue, respectively. From a healthcare perspective, the volume tax would prevent 850 000 cardiovascular disease (95% CI, 836 000-864 000) and 269 000 diabetes mellitus (265 000-274 000) cases, gain 2.44 million quality-adjusted life-years (2.40-2.48), and save $53.2 billion net costs (52.3-54.1). Health gains and savings were approximately doubled for the tiered and absolute sugar content taxes. Results were robust for societal and government perspectives, at 10 years follow-up, and with lower (50%) tax pass-through. Health gains were largest in young adults, blacks and Hispanics, and lower-income Americans.
Conclusions
All sugar-sweetened beverage tax designs would generate substantial health gains and savings. Tiered and absolute sugar content taxes should be considered and evaluated for maximal potential gains.



Circulation: 10 Aug 2020; 142:523-534
Lee Y, Mozaffarian D, Sy S, Liu J, ... Gaziano TA, Micha R
Circulation: 10 Aug 2020; 142:523-534 | PMID: 32564614
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Abstract

Prevalence of Infective Endocarditis in Streptococcal Bloodstream Infections Is Dependent on Streptococcal Species.

Chamat-Hedemand S, Dahl A, Østergaard L, Arpi M, ... Torp-Pedersen C, Bruun NE
Background
Streptococci frequently cause infective endocarditis (IE), yet the prevalence of IE in patients with bloodstream infections (BSIs) caused by different streptococcal species is unknown. We aimed to investigate the prevalence of IE at species level in patients with streptococcal BSIs.
Methods
We investigated all patients with streptococcal BSIs, from 2008 to 2017, in the Capital Region of Denmark. Data were crosslinked with Danish nationwide registries for identification of concomitant hospitalization with IE. In a multivariable logistic regression analysis, we investigated the risk of IE according to streptococcal species adjusted for age, sex, ≥3 positive blood culture bottles, native valve disease, prosthetic valve, previous IE, and cardiac device.
Results
Among 6506 cases with streptococcal BSIs (mean age 68.1 years [SD 16.2], 52.8% men) the IE prevalence was 7.1% (95% CI, 6.5-7.8). The lowest IE prevalence was found with() 1.2% (0.8-1.6) and1.9% (0.9-3.3). An intermediary IE prevalence was found with4.8% (3.0-7.3),5.8% (2.9-10.1), and9.1% (6.6-12.1). The highest IE prevalence was found with19.4% (15.6-23.5),(formerly ) 30.2% (24.3-36.7),34.6% (26.6-43.3),44.2% (34.0-54.8), and47.9% (33.3-62.8). In multivariable analysis usingas reference, all species exceptwere associated with significantly higher IE risk, with the highest risk found withodds ratio (OR) 31.0 (18.8-51.1),OR 31.6 (19.8-50.5),OR 59.1 (32.6-107),OR 80.8 (43.9-149), andOR 81.3 (37.6-176).
Conclusions
The prevalence of IE in streptococcal BSIs is species dependent with , andhaving the highest IE prevalence and the highest associated IE risk after adjusting for IE risk factors.



Circulation: 24 Aug 2020; 142:720-730
Chamat-Hedemand S, Dahl A, Østergaard L, Arpi M, ... Torp-Pedersen C, Bruun NE
Circulation: 24 Aug 2020; 142:720-730 | PMID: 32580572
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Impact:
Abstract

Independent and Opposing Associations of Habitual Exercise and Chronic PM Exposures on Hypertension Incidence.

Guo C, Zeng Y, Chang LY, Yu Z, ... Tam T, Lao XQ
Background
We investigated the joint associations of habitual physical activity (PA) and long-term exposure to fine particulate matter (PM) with the development of hypertension in a longitudinal cohort in Taiwan.
Methods
We selected 140 072 adults (≥18 years of age) without hypertension who joined a standard medical screening program with 360 905 medical examinations between 2001 and 2016. PM exposure was estimated at each participant\'s address using a satellite data-based spatiotemporal model with 1 km resolution. Information on habitual PA and a wide range of covariates was collected using a standard self-administered questionnaire. We used the Cox regression model with time-dependent covariates to examine the joint associations.
Results
The mean age of all observations was 41.7 years, and 48.8% were male. The mean value for systolic and diastolic blood pressure was 112.5 and 68.7mm Hg, respectively. Approximately 34.2% of all observations were inactive (0 metabolic equivalence values-hours), 29.8% had moderate-PA (median [interquartile range]; 3.75 [3.38 to 4.38] metabolic equivalence values-hours), and 36.0% had high-PA (15.7 [10.3 to 24.8] metabolic equivalence values-hours). The mean±SD of PM was 26.1±7.3 μg/m. The prevalence of cardiovascular disease, diabetes mellitus, and cancer was 2.1%, 2.9%, and 1.5%, respectively. After adjusting for a wide range of covariates (including a mutual adjustment for PA or PM), a higher PA level was associated with a lower risk of hypertension (hazard ratio [HR] for the moderate- and high-PA was 0.93 [95% CI, 0.89-0.97] and 0.92 [95% CI, 0.88-0.96], respectively, as compared with the inactive-PA), whereas a higher level of PM was associated with a higher risk of hypertension (HR for the moderate- and high-PM was 1.37 [95% CI, 1.32-1.43] and 1.92 [95% CI, 1.81-2.04], respectively, as compared with the low-PM group]. No significant interaction was observed between PA and PM (HR 1.01 [95% CI, 1.00-1.02]).
Conclusions
A high-PA and low PM exposure were associated with a lower risk of hypertension. The negative association between PA and hypertension remained stable in people exposed to various levels of PM, and the positive association between PM and hypertension was not modified by PA. Our results indicated that PA is a suitable hypertension prevention strategy for people residing in relatively polluted regions.



Circulation: 17 Aug 2020; 142:645-656
Guo C, Zeng Y, Chang LY, Yu Z, ... Tam T, Lao XQ
Circulation: 17 Aug 2020; 142:645-656 | PMID: 32686482
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Impact:
Abstract

Diagnostic Yield of Electroanatomic Voltage Mapping in Guiding Endomyocardial Biopsies.

Casella M, Dello Russo A, Bergonti M, Catto V, ... Basso C, Tondo C

Electroanatomic voltage mapping (EVM) is a promising modality for guiding endomyocardial biopsies (EMB). However, few data support its feasibility and safety. We now report the largest cohort of patients undergoing EVM-guided EMB in order to show its diagnostic yield and to compare it with a cardiac magnetic resonance (CMR) guided approach.One-hundred and sixty-two consecutive patients undergoing EMB at our Institution from 2010 to 2019 were included. EMB was performed in pathological areas identified at EVM and CMR. According to EMB results, CMR and EVM sensitivity and specificity regarding the identification of pathological substrates of myocardium were evaluated.Pre-operative CMR showed late gadolinium enhancement (LGE) in 70% of the patients, while EVM identified areas of low voltages in 61%. Right (73%), left (19%) or both ventricles (8%) underwent sampling. EVM proved to have similar sensitivity to CMR (74% vs. 77%), with specificity being respectively 70% and 47%. In 12 patients with EMB-proven cardiomyopathy, EVM identified pathological areas, which had been undetected at CMR evaluation. Sensitivity of pooled EVM and CMR was as high as 95%. EMB analysis allowed to reach a new diagnosis, different from the suspected clinical diagnosis, in 39% of patients. Complications rate was low, mostly vascular access related, with no patients requiring urgent management.EVM proved to be a promising tool for targeted-EMB due to its sensitivity and specificity for identification of myocardial pathological substrates. EVM demonstrated to have an accuracy similar to CMR. EVM and CMR together conferred EMB a positive predictive value of 89%.



Circulation: 13 Aug 2020; epub ahead of print
Casella M, Dello Russo A, Bergonti M, Catto V, ... Basso C, Tondo C
Circulation: 13 Aug 2020; epub ahead of print | PMID: 32791857
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Abstract

Cangrelor, Tirofiban, and Chewed or Standard Prasugrel Regimens in Patients With ST-Segment-Elevation Myocardial Infarction: Primary Results of the FABOLUS-FASTER Trial.

Gargiulo G, Esposito G, Avvedimento M, Nagler M, ... Windecker S, Valgimigli M
Background
Standard administration of newer oral P2Y inhibitors, including prasugrel or ticagrelor, provides suboptimal early inhibition of platelet aggregation (IPA) in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. We aimed to investigate the effects of cangrelor, tirofiban, and prasugrel, administered as chewed or integral loading dose, on IPA in patients undergoing primary percutaneous coronary intervention.
Methods
The FABOLUS-FASTER trial (Facilitation Through Aggrastat or Cangrelor Bolus and Infusion Over Prasugrel: A Multicenter Randomized Open-Label Trial in Patients with ST-Elevation Myocardial Infarction Referred for Primary Percutaneous Intervention) is an investigator-initiated, multicenter, open-label, randomized study. A total of 122 P2Y-naive patients with ST-segment-elevation myocardial infarction were randomly allocated (1:1:1) to cangrelor (n=40), tirofiban (n=40) (both administered as bolus and 2-hour infusion followed by 60 mg of prasugrel), or 60-mg loading dose of prasugrel (n=42). The latter group underwent an immediate 1:1 subrandomization to chewed (n=21) or integral (n=21) tablets administration. The trial was powered to test 3 hypotheses (noninferiority of cangrelor compared with tirofiban using a noninferiority margin of 9%, superiority of both tirofiban and cangrelor compared with chewed prasugrel, and superiority of chewed prasugrel as compared with integral prasugrel, each with α=0.016 for the primary end point, which was 30-minute IPA at light transmittance aggregometry in response to 20 μmol/L adenosine diphosphate.
Results
At 30 minutes, cangrelor did not satisfy noninferiority compared with tirofiban, which yielded superior IPA over cangrelor (95.0±8.9 versus 34.1±22.5; <0.001). Cangrelor or tirofiban were both superior to chewed prasugrel (IPA, 10.5±11.0; <0.001 for both comparisons), which did not provide higher IPA over integral prasugrel (6.3±11.4; =0.47), despite yielding higher prasugrel active metabolite concentration (ng/mL; 62.3±82.6 versus 17.1±43.5; =0.016).
Conclusions
Cangrelor provided inferior IPA compared with tirofiban; both treatments yielded greater IPA compared with chewed prasugrel, which led to higher active metabolite concentration but not greater IPA compared with integral prasugrel. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02978040; URL: https://www.clinicaltrialsregister.eu; EudraCT 2017-001065-24.



Circulation: 03 Aug 2020; 142:441-454
Gargiulo G, Esposito G, Avvedimento M, Nagler M, ... Windecker S, Valgimigli M
Circulation: 03 Aug 2020; 142:441-454 | PMID: 32795098
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Abstract

Associations Between High-Density Lipoprotein Particles and Ischemic Events by Vascular Domain, Sex, and Ethnicity: A Pooled Cohort Analysis.

Singh K, Chandra A, Sperry T, Joshi PH, ... Ayers CR, Rohatgi A
Background
High-density lipoprotein (HDL) cholesterol concentration (HDL-C) is an established atheroprotective marker, in particular for coronary artery disease; however, HDL particle concentration (HDL-P) may better predict risk. The associations of HDL-C and HDL-P with ischemic stroke and myocardial infarction (MI) among women and Blacks have not been well studied. We hypothesized that HDL-P would consistently be associated with MI and stroke among women and Blacks compared with HDL-C.
Methods
We analyzed individual-level participant data in a pooled cohort of 4 large population studies without baseline atherosclerotic cardiovascular disease: DHS (Dallas Heart Study; n=2535), ARIC (Atherosclerosis Risk in Communities; n=1595), MESA (Multi-Ethnic Study of Atherosclerosis; n=6632), and PREVEND (Prevention of Renal and Vascular Endstage Disease; n=5022). HDL markers were analyzed in adjusted Cox proportional hazard models for MI and ischemic stroke.
Results
In the overall population (n=15 784), HDL-P was inversely associated with the combined outcome of MI and ischemic stroke, adjusted for cardiometabolic risk factors (hazard ratio [HR] for quartile 4 [Q4] versus quartile 1 [Q1], 0.64 [95% CI, 0.52-0.78]), as was HDL-C (HR for Q4 versus Q1, 0.76 [95% CI, 0.61-0.94]). Adjustment for HDL-C did not attenuate the inverse relationship between HDL-P and atherosclerotic cardiovascular disease, whereas adjustment for HDL-P attenuated all associations between HDL-C and events. HDL-P was inversely associated with the individual end points of MI and ischemic stroke in the overall population, including in women. HDL-P was inversely associated with MI among White participants but not among Black participants (HR for Q4 versus Q1 for Whites, 0.49 [95% CI, 0.35-0.69]; for Blacks, 1.22 [95% CI, 0.76-1.98]; =0.001). Similarly, HDL-C was inversely associated with MI among White participants (HR for Q4 versus Q1, 0.53 [95% CI, 0.36-0.78]) but had a weak direct association with MI among Black participants (HR for Q4 versus Q1, 1.75 [95% CI, 1.08-2.83]; <0.0001).
Conclusions
Compared with HDL-C, HDL-P was consistently associated with MI and ischemic stroke in the overall population. Differential associations of both HDL-C and HDL-P for MI by Black ethnicity suggest that atherosclerotic cardiovascular disease risk may differ by vascular domain and ethnicity. Future studies should examine individual outcomes separately.



Circulation: 17 Aug 2020; 142:657-669
Singh K, Chandra A, Sperry T, Joshi PH, ... Ayers CR, Rohatgi A
Circulation: 17 Aug 2020; 142:657-669 | PMID: 32804568
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Abstract

Transcatheter Mitral Valve Replacement After Surgical Repair or Replacement: Comprehensive Mid-Term Evaluation of Valve-in-Valve and Valve-in-Ring Implantation from the VIVID Registry.

Simonato M, Whisenant B, Barbosa Ribeiro H, Webb JG, ... Stone GW, Dvir D

Mitral valve-in-valve (ViV) and valve-in-ring (ViR) are alternatives to surgical reoperation in patients with recurrent mitral valve failure after previous surgical valve repair or replacement. Our aim was to perform a large-scale analysis examining mid-term outcomes after mitral ViV and ViR.Patients undergoing mitral ViV and ViR were enrolled in the Valve-in-Valve International Data Registry. Cases were performed between March 2006 and March 2020. Clinical endpoints are reported according to the Mitral Valve Academic Research Consortium (MVARC) definitions. Significant residual mitral stenosis (MS) was defined as mean gradient ≥10 mmHg and significant residual mitral regurgitation (MR) as ≥ moderate.A total of 1,079 patients (857 ViV, 222 ViR; mean age 73.5 years ± 12.5; 40.8% male) from 90 centers were included. Median STS-PROM score 8.6%; median clinical follow-up 492 days [IQR 76 - 996 days]; median echocardiographic follow-up for patients that survived 1 year 772.5 days [IQR 510 - 1211.75 days]. Four-year Kaplan-Meier survival rate was 62.5% in ViV vs. 49.5% for ViR (p<0.001). Mean gradient across the mitral valve post-procedure was 5.7 ± 2.8 mmHg (≥5mmHg, 61.4% of patients). Significant residual MS occurred in 8.2% of the ViV and 12.0% of the ViR patients (p=0.09). Significant residual MR was more common in ViR patients (16.6% vs. 3.1%; p<0.001) and was associated with lower survival at 4 years (35.1% vs. 61.6%; p=0.02). The rates of MVARC-defined device success were low for both procedures (39.4% total; 32.0% ViR vs. 41.3% ViV; p=0.01), mostly related to having post-procedural mean gradient ≥5mmHg. Correlates for residual MS were smaller true internal diameter, younger age and larger body mass index. The only correlate for residual MR was ViR. Significant residual MS (SHR 4.67; 95% CI 1.74 - 12.56; p=0.002) and significant residual MR (SHR 7.88; 95% CI 2.88 - 21.53; p<0.001) were both independently associated with repeat mitral valve replacement.Significant residual MS and/or MR were not infrequent after mitral ViV and ViR procedures and were both associated with a need for repeat valve replacement. Strategies to improve post-procedural hemodynamics in mitral ViV and ViR should be further explored.



Circulation: 24 Sep 2020; epub ahead of print
Simonato M, Whisenant B, Barbosa Ribeiro H, Webb JG, ... Stone GW, Dvir D
Circulation: 24 Sep 2020; epub ahead of print | PMID: 32975133
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Abstract

Single-Cell RNA-seq Analysis Reveals a Crucial Role for Collagen Triple Helix Repeat Containing 1 (CTHRC1) Cardiac Fibroblasts after Myocardial Infarction.

Ruiz-Villalba A, Romero JP, Hernandez SC, Vilas-Zornoza A, ... Lara-Astiaso D, Prósper F

Cardiac fibroblasts (CF) have a central role in the ventricular remodeling process associated with different types of fibrosis. Recent studies have shown that fibroblasts do not respond homogeneously to heart injury. Due to the limited set offibroblast markers, a proper characterization of fibroblast population heterogeneity in response to cardiac damage is still missing. The purpose of this study was to define the CF heterogeneity during ventricular remodeling and the underlying mechanisms that regulate their function.Collagen1α1-GFP CF were characterized after myocardial infarction (MI) by single-cell and bulk RNA-seq, ATAC-seq and functional assays. Swine and patient samples were studied using bulk RNA-seq.We identified and characterized a unique CF subpopulation that emerges after MI in mice. These activated fibroblasts exhibit a clear pro-fibrotic signature, express high levels of Collagen Triple Helix Repeat Containing 1 () and localize into the scar. Non-canonical TGF-β signaling and different transcription factors including SOX9 are important regulators mediating their response to cardiac injury. Moreover, the absence of CTHRC1 results in pronounced lethality due to ventricular rupture. Finally, a population of CF with a similar transcriptome was identified in a swine model of MI and in heart tissue from patients with MI and dilated cardiomyopathy.We report CF heterogeneity, their dynamics during the course of MI and redefine the CF that respond to cardiac injury and participate in myocardial remodeling. Our study identifiesas a novel regulator of the healing scar process, and as a target for future translational studies.



Circulation: 24 Sep 2020; epub ahead of print
Ruiz-Villalba A, Romero JP, Hernandez SC, Vilas-Zornoza A, ... Lara-Astiaso D, Prósper F
Circulation: 24 Sep 2020; epub ahead of print | PMID: 32972203
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Abstract

The Safety and Efficacy of Aspirin Discontinuation on a Background of a P2Y Inhibitor in Patients After Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis.

O\'Donoghue ML, Murphy SA, Sabatine MS
Background
Dual antiplatelet therapy with aspirin and a P2Y inhibitor has been shown to reduce the risk of major adverse cardiovascular events (MACE) compared with aspirin alone after percutaneous coronary intervention (PCI) or acute coronary syndrome but with increased risk of bleeding. The safety of discontinuing aspirin in favor of P2Y inhibitor monotherapy remains disputed.
Methods
A meta-analysis was conducted from randomized trials (2001-2020) that studied discontinuation of aspirin 1 to 3 months after PCI with continued P2Y inhibitor monotherapy compared with traditional dual antiplatelet therapy. Five trials were included; follow-up duration ranged from 12 to 15 months after PCI. Primary bleeding and MACE outcomes were the prespecified definitions in each trial.
Results
The study population included 32 145 patients: 14 095 (43.8%) with stable coronary artery disease and 18 046 (56.1%) with acute coronary syndrome. In the experimental arm, background use of a P2Y inhibitor included clopidogrel in 2649 (16.5%) and prasugrel or ticagrelor in 13 408 (83.5%) patients. In total, 820 patients experienced a primary bleeding outcome and 937 experienced MACE. Discontinuation of aspirin therapy 1 to 3 months after PCI significantly reduced the risk of major bleeding by 40% compared with dual antiplatelet therapy (1.97% versus 3.13%; hazard ratio [HR], 0.60 [95% CI, 0.45-0.79]), with no increase observed in the risk of MACE (2.73% versus 3.11%; HR, 0.88 [95% CI, 0.77-1.02]), myocardial infarction (1.08% versus 1.27%; HR, 0.85 [95% CI, 0.69-1.06]), or death (1.25% versus 1.47%; HR, 0.85 [95% CI, 0.70-1.03]). Findings were consistent among patients who underwent PCI for an acute coronary syndrome, in whom discontinuation of aspirin after 1 to 3 months reduced bleeding by 50% (1.78% versus 3.58%; HR, 0.50 [95% CI, 0.41-0.61]) and did not appear to increase the risk of MACE (2.51% versus 2.98%; HR, 0.85 [95% CI, 0.70-1.03]).
Conclusions
Discontinuation of aspirin with continued P2Y inhibitor monotherapy reduces risk of bleeding when stopped 1 to 3 months after PCI. An increased risk of MACE was not observed after discontinuation of aspirin, including in patients with acute coronary syndrome.



Circulation: 10 Aug 2020; 142:538-545
O'Donoghue ML, Murphy SA, Sabatine MS
Circulation: 10 Aug 2020; 142:538-545 | PMID: 32551860
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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

Pathogenicvariants are a cause of hypertrophic (HCM) and dilated (DCM) cardiomyopathies, which promote heart failure by incompletely understood mechanisms. Additionally, the precise functional significance for 87% ofvariants remains undetermined partially due to a lack of functional genomics studies. The knowledge of which and howvariants cause HCM and DCM could improve heart failure risk determination, treatment efficacy, and therapeutic discovery, as well as provide new insights into cardiomyopathy pathogenesis.We created a toolkit of human induced pluripotent stem cell (hiPSC) models and functional assays using CRISPR/Cas9 to studyvariant pathogenicity and pathophysiology. Using hiPSC-derived cardiomyocytes (hiPSC-CMs) in cardiac microtissue and single cell assays, we functionally interrogated 51variants, including 30 pathogenic/likely pathogenic variants and 21 variants of unknown significance (VUS). We utilized 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.HCM-associatedvariants caused increased cardiac microtissue contraction, while DCM-associated variants decreased contraction.variant-dependent changes in sarcomere contractile function induced graded regulation of 101 gene transcripts, includingsignaling targets, , and . We distinguished pathogenicvariants from wildtype controls using a sarcomere functional reporter engineered by inserting tdTomato into the endogenouslocus. Based on a combination ofreporter activity and cardiac microtissue contraction, our study provides experimental support for the reclassification of 2 pathogenic/likely pathogenic variants and 2 VUSs.Our study found that HCM-associatedvariants increased cardiac microtissue contraction, while DCM-associated variants cause decreased contraction, both of which paralleled changes in myofilament calcium affinity. Transcriptomic changes, includinglevels, directly correlated with sarcomere function and can be utilized to predictvariant pathogenicity.



Circulation: 06 Oct 2020; epub ahead of print
Pettinato AM, Ladha FA, Mellert DJ, Legere N, ... Chen YS, Hinson JT
Circulation: 06 Oct 2020; epub ahead of print | PMID: 33025817
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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

A systemic pro-inflammatory 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.In 228 HFpEF patients from the multicenter PROMIS-HFpEF study, 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 (PC) analysis to summarize 47 proteins knownto be involved in inflammation. In an inductive approach, we performed unbiased weighted co-expression 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 HF.Comorbidity burden was associated with abnormal cardiac structure/function and with PCs/clusters of inflammation proteins. Systemic inflammation was also associated with increased mitral E velocity, E/e\' ratio, and tricuspid regurgitation (TR) velocity; and worse right ventricular function (tricuspid annular plane systolic excursion [TAPSE] and right ventricular. [RV] free wall strain). Inflammation mediated the association between comorbidity burden and mitral E velocity (proportion mediated 19-35%), E/e\' ratio (18-29%), TR velocity (27-41%), and tricuspid annular plane systolic excursion (13%) (P<0.05 for all) but not RV free wall strain. TNF-R1, UPAR, IGFBP-7 and GDF-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.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 RV dysfunction. These findings support the comorbidity-inflammation paradigm in HFpEF.



Circulation: 08 Oct 2020; epub ahead of print
Sanders-van Wijk S, Tromp J, Beussink-Nelson L, Hage C, ... Lam CSP, Shah SJ
Circulation: 08 Oct 2020; epub ahead of print | PMID: 33034202
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Abstract

Efficacy of Dapagliflozin on Renal Function and Outcomes in Patients with Heart Failure with Reduced Ejection Fraction: Results of DAPA-HF.

Jhund PS, Solomon SD, Docherty KF, Heerspink HJL, ... Sjöstrand M, McMurray JJV

Many patients with heart failure and reduced ejection fraction (HFrEF) have chronic kidney disease (CKD) which complicates pharmacological management and is associated with worse outcomes. We assessed the safety and efficacy of dapagliflozin in patients with HFrEF, according to baseline kidney function, in the Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). We also examined the effect of dapagliflozin on kidney function after randomization. Many patients with heart failure and reduced ejection fraction (HFrEF) have chronic kidney disease (CKD) which complicates pharmacological management and is associated with worse outcomes. We assessed the safety and efficacy of dapagliflozin in patients with HFrEF, according to baseline kidney function, in the Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). We also examined the effect of dapagliflozin on kidney function after randomization.HFrEF patients with or without type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73m were enrolled in DAPA-HF. We calculated the incidence of the primary outcome (CV death or worsening HF) according to eGFR category at baseline (<60 and ≥60 ml/min/1.73m) as well as using eGFR at baseline as a continuous measure. Secondary cardiovascular outcomes and a pre-specified composite renal outcome (≥ 50% sustained decline eGFR, end stage renal disease (ESRD) or renal death) were also examined, along with decline in eGFR over time.Of 4742 with a baseline eGFR, 1926 (41%) had eGFR <60 ml/min/1.73m. The effect of dapagliflozin on the primary and secondary outcomes did not differ by eGFR category or examining eGFR as a continuous measurement. The hazard ratio (95% confidence interval (CI)) for the primary endpoint in patients with CKD was 0.71 (0.59, 0.86) vs. 0.77 (0.64, 0.93) in those with an eGFR ≥60 ml/min/1.73m (interaction p=0.54). The composite renal outcome was not reduced by dapagliflozin (HR=0.71, 95% CI 0.44, 1.16; p=0.17) but the rate of decline in eGFR between day 14 and 720 was less with dapagliflozin, -1.09 (-1.41, -0.78) vs. placebo -2.87 (-3.19, -2.55) ml/min/1.73m per year (p<0.001). This was observed in those with and without type 2 diabetes (p for interaction=0.92)Baseline kidney function did not modify the benefits of dapagliflozin on morbidity and mortality in HFrEF and dapagliflozin slowed the rate of decline in eGFR, including in patients without diabetes.https://clinicaltrials.gov Unique Identifier: NCT03036124.



Circulation: 11 Oct 2020; epub ahead of print
Jhund PS, Solomon SD, Docherty KF, Heerspink HJL, ... Sjöstrand M, McMurray JJV
Circulation: 11 Oct 2020; epub ahead of print | PMID: 33040613
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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

Mutations in the human desmin gene cause myopathies and cardiomyopathies. Aim of this study was to elucidate molecular mechanisms initiated by the heterozygous R406W-desmin mutation in the development of a severe and early-onset cardiac phenotype.We report an adolescent patient, who underwent cardiac transplantation due to 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 andassembly experiments. To prove the genuine deleterious impact 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.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. , 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 histopathological results from the patient are recapitulated in the hearts from R405W-desmin knock-in mice of both genotypes. Moreover, while heterozygous knock-in mice have a normal life span, homozygous animals die at three months of age due to a smooth muscle-related gastrointestinal phenotype.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: 06 Oct 2020; epub ahead of print
Herrmann H, Cabet E, Chevalier NR, Moosmann J, ... Lilienbaum A, Schröder R
Circulation: 06 Oct 2020; epub ahead of print | PMID: 33023321
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Abstract

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

Tamburino C, Bleiziffer S, Thiele H, Scholtz S, ... Hengstenberg C, Capodanno D

There are few randomized trials comparing bioprostheses for transcatheter aortic valve replacement (TAVR), and no trials compared TAVR bioprostheses with supra-annular design. The SCOPE 2 trial was designed to compare the clinical outcomes of the ACURATE neo and CoreValve Evolut valves.SCOPE 2 was a randomized trial performed at 23 centers in 6 countries between April 2017 and April 2019. Patients ≥75 years with an indication for transfemoral TAVR 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 endpoint, powered for non-inferiority of the ACURATE neo valve, was all-cause death or stroke at 1 year. The key secondary endpoint, powered for superiority of the ACURATE neo valve, was new permanent pacemaker implantation at 30 days.Among 796 randomized patients (mean age 83.2±4.3 years; mean STS-PROM score 4.6± 2.9%), clinical follow-up information was available for 778 (98%) patients. Within 1 year, the primary endpoint 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 one-sided 95% confidence limit 6.1%, p=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% confidence interval -12.4 to -2.60, p=0.0027). No significant differences were observed in the components of the primary endpoint. Cardiac death at 30 days (2.8% vs. 0.8%, p=0.03) and 1 year (8.4% vs. 3.9%, p=0.01), and moderate or severe aortic regurgitation at 30 days (10% vs. 3%, p=0.002) were significantly increased in the ACURATE neo group.Transfemoral TAVR with the self-expanding ACURATE neo did not meet non-inferiority compared to the self-expanding CoreValve Evolut in terms of all-cause death or stroke at 1 year, and 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.URL: https://clinicaltrials.gov/ Unique Identifier: NCT03192813.



Circulation: 14 Oct 2020; epub ahead of print
Tamburino C, Bleiziffer S, Thiele H, Scholtz S, ... Hengstenberg C, Capodanno D
Circulation: 14 Oct 2020; epub ahead of print | PMID: 33054367
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Abstract

Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data.

Mahmoodi BK, Tragante V, Kleber ME, Holmes MV, ... Asselbergs FW, Patel RS
Background
Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD.
Methods
We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality.
Results
The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; =28%; -heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity.
Conclusions
Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.



Circulation: 10 Aug 2020; 142:546-555
Mahmoodi BK, Tragante V, Kleber ME, Holmes MV, ... Asselbergs FW, Patel RS
Circulation: 10 Aug 2020; 142:546-555 | PMID: 32654539
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Abstract

Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF.

Jackson AM, Dewan P, Anand IS, Bělohlávek J, ... Jhund PS, McMurray JJV
Background
In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined the efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy after randomization to dapagliflozin or placebo.
Methods
We examined the effects of study treatment in the following subgroups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline. We examined the primary composite end point of cardiovascular death or a worsening heart failure event and its components, all-cause death and symptoms.
Results
Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on <40 mg, 1365 (29.6%) were on 40 mg, and 1204 (26.1%) were taking >40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary end point across each of these subgroups: hazard ratios were 0.57 (95% CI, 0.36-0.92), 0.83 (95% CI, 0.63-1.10), 0.77 (95% CI, 0.60-0.99), and 0.78 (95% CI, 0.63-0.97), respectively ( for interaction=0.61). The hazard ratio in patients taking any diuretic was 0.78 (95% CI, 0.68-0.90). Improvements in symptoms and treatment toleration were consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow-up, and mean diuretic dose did not differ between the dapagliflozin and placebo groups after randomization.
Conclusions
The efficacy and safety of dapagliflozin were consistent across the diuretic subgroups examined in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.



Circulation: 14 Sep 2020; 142:1040-1054
Jackson AM, Dewan P, Anand IS, Bělohlávek J, ... Jhund PS, McMurray JJV
Circulation: 14 Sep 2020; 142:1040-1054 | PMID: 32673497
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Abstract

Impact of Transcatheter Aortic Valve Durability on Life Expectancy in Low-Risk Patients With Severe Aortic Stenosis.

Tam DY, Wijeysundera HC, Naimark D, Gaudino M, ... Cohen DJ, Fremes SE
Background
Recent clinical trial results showed that transcatheter aortic valve replacement (TAVR) is noninferior and may be superior to surgical aortic valve replacement (SAVR) for mortality, stroke, and rehospitalization. However, the impact of transcatheter valve durability remains uncertain.
Methods
Discrete event simulation was used to model hypothetical scenarios of TAVR versus SAVR durability in which TAVR failure times were varied to determine the impact of TAVR valve durability on life expectancy in a cohort of low-risk patients similar to those in recent trials. Discrete event simulation modeling was used to estimate the tradeoff between a less invasive procedure with unknown valve durability (TAVR) and that of a more invasive procedure with known durability (SAVR). Standardized differences were calculated, and a difference >0.10 was considered clinically significant. In the base-case analysis, patients with structural valve deterioration requiring reoperation were assumed to undergo a valve-in-valve TAVR procedure. A sensitivity analysis was conducted to determine the impact of TAVR valve durability on life expectancy in younger age groups (40, 50, and 60 years).
Results
Our cohort consisted of patients with aortic stenosis at low surgical risk with a mean age of 73.4±5.9 years. In the base-case scenario, the standardized difference in life expectancy was <0.10 between TAVR and SAVR until transcatheter valve prosthesis failure time was 70% shorter than that of surgical prostheses. At a transcatheter valve failure time <30% compared with surgical valves, SAVR was the preferred option. In younger patients, life expectancy was reduced when TAVR durability was 30%, 40%, and 50% shorter than that of surgical valves in 40-, 50-, and 60-year-old patients, respectively.
Conclusions
According to our simulation models, the durability of TAVR valves must be 70% shorter than that of surgical valves to result in reduced life expectancy in patients with demographics similar to those of recent trials. However, in younger patients, this threshold for TAVR valve durability was substantially higher. These findings suggest that durability concerns should not influence the initial treatment decision concerning TAVR versus SAVR in older low-risk patients on the basis of current evidence supporting TAVR valve durability. However, in younger low-risk patients, valve durability must be weighed against other patient factors such as life expectancy.



Circulation: 27 Jul 2020; 142:354-364
Tam DY, Wijeysundera HC, Naimark D, Gaudino M, ... Cohen DJ, Fremes SE
Circulation: 27 Jul 2020; 142:354-364 | PMID: 32493077
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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 LV,

The Subcutaneous ICD (S-ICD) is safe and effective for sudden cardiac death prevention. However, patients in previous S-ICD studies had fewer comorbidities, less left ventricular dysfunction and received more inappropriate shocks (IAS) than in typical transvenous (TV)-ICD trials. The UNTOUCHED trial 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.Primary prevention patients with left ventricular ejection fraction (LVEF) ≤ 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 (bpm) and morphology discrimination for rates ≥200 and < 250 bpm. Patients were followed for 18 months. The primary endpoint was the IAS free rate compared to a 91.6% performance goal, derived from the results for the ICD-only patients in the MADIT-RIT study. 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 endpoints.S-ICD implant was attempted in 1116 patients and 1111 patients were included in post-implant follow-up analysis. The cohort had a mean age of 55.8±12.4 years, 25.6% women, 23.4% black race, 53.5% with ischemic heart disease, 87.7% with symptomatic heart failure and a mean LVEF of 26.4±5.8%. Eighteen-month freedom from IAS was 95.9% (Lower confidence limit LCL 94.8%). Predictors of reduced incidence of IAS were implanting the most recent generation of device, using the three-incision technique, no history of atrial fibrillation, and ischemic etiology. The 18-month all cause shock free rate was 90.6% (LCL 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%.This study demonstrates high efficacy and safety with contemporary S-ICD devices and programming despite the relatively high incidence of co-morbidities in comparison to earlier S-ICD trials. The inappropriate shock rate (3.1% at one year) is the lowest reported for the S-ICD and lower than many TV ICD studies using contemporary programming to reduce IAS.URL https://clinicaltrials.gov Unique Identifier NCT02433379.



Circulation: 18 Oct 2020; epub ahead of print
Gold MR, Lambiase PD, El-Chami MF, Knops RE, ... Boersma LV,
Circulation: 18 Oct 2020; epub ahead of print | PMID: 33073614
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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

Whereas cardiovascular disease (CVD) metrics define risk in individuals above age 40 years, 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.We studied 2330 white and Black young adults (mean age 32 years, 45% Black) in the Coronary Artery Risk Development in Young Adults (CARDIA) study to identify metabolite profiles associated with an adverse CVD phenome (myocardial structure/function, fitness, vascular calcification), mechanisms, and outcomes over two 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 (FHS).In CARDIA, metabolite profiles quantified in early adulthood were associated with subclinical CVD development over 20 years, specifying known and novel pathways of CVD (e.g., transcriptional regulation, BDNF, NO, renin-angiotensin). We found two multi-parametric, metabolite-based scores linked independently to vascular and myocardial health, with metabolites included in each score specifying microbial metabolism, hepatic steatosis, oxidative stress, NO modulation, and collagen metabolism. The metabolite-based vascular scores were lower in men, and myocardial scores were lower in Blacks. Over nearly 25 year median follow-up in CARDIA, the metabolite-based vascular score (HR = 0.68 per SD; 95% CI 0.50-0.92, P=0.01) and myocardial score (HR=0.60 per SD; 95% CI 0.45-0.80, P=0.0005) in the third and fourth decade of life were associated with clinical CVD with a synergistic association with outcome (P=0.009). We replicated these findings in 1898 individuals in FHS over 2 decades, with a similar association with outcome (including interaction), reclassification, and discrimination. In FHS, the metabolite scores exhibited an age interaction (P=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.Metabolic signatures of myocardial and vascular health in young adulthood specify known/novel pathways of metabolic dysfunction relevant to CVD, associated with outcome in two independent cohorts. Efforts to include precision measures of metabolic health in risk stratification to interrupt CVD at its earliest stage are warranted.



Circulation: 18 Oct 2020; epub ahead of print
Murthy VL, Reis JP, Pico AR, Kitchen R, ... Clish CB, Shah RV
Circulation: 18 Oct 2020; epub ahead of print | PMID: 33073606
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Abstract

Redox-Resistant SERCA Attenuates Oxidant-Stimulated Mitochondrial Calcium and Apoptosis in Cardiac Myocytes and Pressure Overload-Induced Myocardial Failure in Mice.

Goodman JB, Qin F, Morgan R, Chambers JM, ... Cohen RA, Colucci WS

Sarco(endo)plasmic reticulum calcium ATPase (SERCA) is regulated by oxidative post-translational modifications at cysteine 674 (C674). Since sarcoplasmic reticulum (SR) calcium has been shown to play a critical role in mediating mitochondrial dysfunction in response to reactive oxygen species (ROS), we hypothesized that SERCA oxidation at C674 would modulate the effects of ROS on mitochondrial calcium and mitochondria-dependent apoptosis in cardiac myocytes.Adult rat ventricular myocytes (ARVM) expressing wild-type (WT) SERCA2b or a redox-insensitive mutant in which C674 is replaced by serine (C674S) were exposed to HO (100 M). Free mitochondrial calcium concentration was measured in ARVM using 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 (SKI) were subjected to chronic ascending aortic constriction (AAC).In ARVM expressing WT 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 WT cells, HO caused cytochrome c release and apoptosis, both of which were prevented in C674S-expressing cells. In myocytes from SKI mice, basal SERCA activity and SR calcium content were decreased. To test the effect of C674 oxidation on apoptosis , SKI mice were subjected to chronic AAC. In WT mice, AAC caused myocyte apoptosis, LV dilation and systolic failure - all of which were inhibited in SKI mice.Redox activation of SERCA C674 regulates basal SR calcium content thereby mediating the pathologic ROS-stimulated rise in mitochondrial calcium required for myocyte apoptosis and myocardial failure.



Circulation: 19 Oct 2020; epub ahead of print
Goodman JB, Qin F, Morgan R, Chambers JM, ... Cohen RA, Colucci WS
Circulation: 19 Oct 2020; epub ahead of print | PMID: 33076678
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Abstract

Forty-Year Shifting Distribution of Systolic Blood Pressure With Population Hypertension Treatment and Control.

Lackland DT, Howard VJ, Cushman M, Oparil S, ... McClure LA, Howard G
Background
Hypertension awareness, treatment, and control programs were initiated in the United States during the 1960s and 1970s. Whereas blood pressure (BP) control in the population and subsequent reduced hypertension-related disease risks have improved since the implementation of these interventions, it is unclear whether these BP changes can be generalized to diverse and high-risk populations. This report describes the 4-decade change in BP levels for the population in a high disease risk southeastern region of the United States. The objective is to determine the magnitude of the shift in systolic BP (SBP) among Blacks and Whites from the Southeast between 1960 and 2005 with the assessment of the unique population cohorts.
Methods
A multicohort study design compared BPs from the CHS (Charleston Heart Study) and ECHS (Evans County Heart Study) in 1960 and the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) 4 decades later. The analyses included participants ≥45 years of age from CHS (n=1323), ECHS (n=1842), and REGARDS (n=6294) with the main outcome of SBP distribution.
Results
Among Whites 45 to 54 years of age, the median SBP was 18 mm Hg (95% CI, 16-21 mm Hg) lower in 2005 than 1960. The median shift was a 45 mm Hg (95% CI, 37-51 mm Hg) decline for those ≥75 years of age. The shift was larger for Blacks, with median declines of 38 mm Hg (95% CI, 32-40 mm Hg) at 45 to 54 years of age and 50 mm Hg (95% CI, 33-60 mm Hg) for ages ≥75 years. The 95th percentile of SBP decreased 60 mm Hg for Whites and 70 mm Hg for Blacks.
Conclusions
The results of the current analyses of the unique cohorts in the Southeast confirm the improvements in population SBP levels since 1960. This assessment provides new evidence of improvement in SBP, suggesting that strategies and programs implemented to improve hypertension treatment and control have been extraordinarily successful for both Blacks and Whites residing in a high-risk region of the United States. Severe BP elevations commonly observed in the 1960s have been nearly eliminated, with the current 75th percentile of BP generally less than the 25th percentile of BP in 1960.



Circulation: 19 Oct 2020; 142:1524-1531
Lackland DT, Howard VJ, Cushman M, Oparil S, ... McClure LA, Howard G
Circulation: 19 Oct 2020; 142:1524-1531 | PMID: 33016101
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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, ... Berdal JE, Omland T

Growth differentiation factor 15 (GDF-15) is a strong prognostic marker in sepsis and cardiovascular disease (CVD). The prognostic importance of GDF-15 in COVID-19 is unknown.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 MECH study. Biobank samples were collected at baseline, day 3 and day 9. The primary endpoint 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.Of the 123 patients enrolled, 35 (28%) reached the primary endpoint; these patients were older, more often had diabetes mellitus, had lower oxygen saturations and higher National Early Warning Score 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 p<0.001). Patients reaching the primary endpoint had higher concentrations of GDF-15 (median 4225 [IQR 3197-5972] pg/mL vs 2187 [1344-3620] pg/mL, p<0.001). The C-statistic value was 0.78 (95% confidence interval 0.70-0.86). The association between GDF-15 and outcome persisted after adjusting for age, sex, race, body mass index, estimated glomerular filtration rate and previous myocardial infarction, heart failure or atrial fibrillation (p<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 endpoint (median 1208 [IQR 0-4305] pg/mL versus -86 [IQR -322-491] pg/mL, p<0.001).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 importance of GDF-15 was additional and superior to established cardiovascular and inflammatory biomarkers.



Circulation: 14 Oct 2020; epub ahead of print
Myhre PL, Prebensen C, Strand H, Røysland R, ... Berdal JE, Omland T
Circulation: 14 Oct 2020; epub ahead of print | PMID: 33058695
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Abstract

Innate Immune Nod1/RIP2 Signaling is Essential for Cardiac Hypertrophy, but Requires Mitochondrial Antiviral Signaling Protein (MAVS) for Signal Transductions and Energy Balance.

Lin HB, Naito K, Oh Y, Farber G, ... Harper ME, Liu PP

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-containing protein 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.To elucidate the contribution of Nod1/RIP2 signaling to cardiac hypertrophy, we randomized Nod1, RIP2 or wild-type (WT) mice to transverse aortic constriction (TAC) or sham operations. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice.Nod1 and RIP2 proteins were up-regulated in the heart after TAC, and this was paralleled by increased expression of mitochondrial proteins, including mitochondrial antiviral signaling protein (MAVS). Nod1 and RIP2 mice subjected to TAC exhibited better survival, improved cardiac function and decreased cardiac hypertrophy. Downstream signal transduction pathways that regulate inflammation and fibrosis including NF-κB and MAPK-GATA4/p300, were reduced in both Nod1 and RIP2 mice after TAC compared with WT mice. Co-immunoprecipitation 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 signalling 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.We have identified that innate immune Nod1/RIP2 signaling is a major contributor to cardiac remodeling following 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: 18 Oct 2020; epub ahead of print
Lin HB, Naito K, Oh Y, Farber G, ... Harper ME, Liu PP
Circulation: 18 Oct 2020; epub ahead of print | PMID: 33070627
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Abstract

Single-Cell RNA Sequencing to Dissect the Immunological Network of Autoimmune Myocarditis.

Hua X, Hu G, Hu Q, Chang Y, ... Li M, Song J
Background
Myocarditis can develop into dilated cardiomyopathy, which may require heart transplantation. The immunological network of myocarditis phases remains unknown. This study aimed to investigate the immunological network during the transition from myocarditis to cardiomyopathy and to identify the genes contributing to the inflammatory response to myocarditis.
Methods
Mice were treated with myosin heavy chain-α peptides to generate an experimental autoimmune myocarditis (EAM) model. We performed single-cell RNA sequencing analysis ofcells extracted from mouse hearts during different EAM phases, including normal control, acute inflammatory, subacute inflammatory, and myopathy phases. Human heart tissues were collected from the surgically removed hearts of patients who had undergone heart transplantation.
Results
We identified 26 cell subtypes among 34 665 cells. Macrophages constituted the main immune cell population at all disease phases (>60%), and an inflammation-associated macrophage cluster was identified in which the expression of -regulated genes was upregulated. The neutrophil population was increased after the induction of EAM, and neutrophils then releasedto participate in the EAM process. T cells were observed at the highest percentage at the subacute inflammatory phase. T-helper 17 cells, in which the expression of -regulated genes was upregulated, constituted the main T-cell population detected at the acute inflammatory phase, whereas regulatory T cells were the main T-cell population detected at the subacute inflammatory phase, and γδ T cells releasingwere the main T-cell population observed at the myopathy phase. Moreover, theexpression level correlated with the extent of inflammation. In addition, PX-478 could alleviate the inflammatory responses of the different EAM phases. Last,was expressed at higher levels in patients with acute autoimmune myocarditis than in patients with dilated cardiomyopathy and healthy control subjects.
Conclusions
We present here a comprehensive single-cell landscape of the cardiac immune cells in different EAM phases. In addition, we elucidate the contribution ofto the inflammatory response through the regulation of immune cell activity, particularly of macrophage cluster 2 and T-helper 17 cells. Moreover, aninhibitor alleviated inflammatory cell infiltration of the EAM model and may serve as a potential therapeutic target in the clinic.



Circulation: 27 Jul 2020; 142:384-400
Hua X, Hu G, Hu Q, Chang Y, ... Li M, Song J
Circulation: 27 Jul 2020; 142:384-400 | PMID: 32431172
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