Journal: Circulation

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Abstract

Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction: DEFINE-HF.

Selvaraj S, Fu Z, Jones P, Kwee LC, ... Kosiborod MN, Shah SH
Background: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are foundational therapy in patients with heart failure with reduced ejection fraction (HFrEF), yet underlying mechanisms of benefit are not well defined. We sought to investigate the relationships between SGLT2i treatment, changes in metabolic pathways, and outcomes using targeted metabolomics.
Methods:
Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction (DEFINE-HF) was a placebo-controlled trial of dapagliflozin in HFrEF. We performed targeted mass spectrometry-based profiling of 63 metabolites (45 acylcarnitines [markers of fatty acid oxidation], 15 amino acids, and 3 conventional metabolites) in plasma samples at randomization and 12 weeks. Using mixed models, we identified principal components analysis (PCA)-defined metabolite clusters that changed differentially with treatment, and also examined the relationship between change in metabolite clusters with change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Models were adjusted for relevant clinical covariates, and nominal p<0.05 with FDR-adjusted p-value<0.10 were used to determine statistical significance.
Results:
Among the 234 DEFINE-HF participants with targeted metabolomic data, the mean age was 62.0±11.1 years, 25% were women, 38% were Black, and mean ejection fraction was 27±8%. Dapagliflozin increased ketone-related and short/medium-chain acylcarnitine PCA metabolite clusters compared with placebo (nominal p=0.01, FDR-adjusted p-value=0.08 for both clusters). However, ketosis (Β-hydroxybutyrate levels > 500 μM), was infrequently achieved (3 [2.5%] in dapagliflozin arm vs. 1 [0.9%] in placebo arm), and supraphysiologic levels were not observed. Conversely, increases in long-chain acylcarnitine, long-chain dicarboxylacylcarnitine, and aromatic amino acid metabolite clusters were associated with decreases in KCCQ scores (i.e. worse quality of life) and increases in NT-proBNP levels, without interaction by treatment group. Conclusions: In this study of targeted metabolomics in a placebo-controlled trial of SGLT2i in HFrEF, we observed effects of dapagliflozin on key metabolic pathways, supporting a role for altered ketone and fatty acid biology with SGLT2i in patients with HFrEF. Reassuringly, only physiologic levels of ketosis were observed. Additionally, we identified several metabolic biomarkers associated with adverse HFrEF outcomes.




Circulation: 23 May 2022; epub ahead of print
Selvaraj S, Fu Z, Jones P, Kwee LC, ... Kosiborod MN, Shah SH
Circulation: 23 May 2022; epub ahead of print | PMID: 35603596
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Abstract

Indoleamine 2,3-Dioxygenase 1 Deletion-Mediated Kynurenine Insufficiency in Vascular Smooth Muscle Cells Exacerbates Arterial Calcification.

Ouyang L, Yu C, Xie Z, Su X, ... Ding Y, Zou MH
Background
IDO1 (indoleamine 2,3-dioxygenase 1) is the rate-limiting enzyme for tryptophan metabolism. IDO1 malfunction is involved in the pathogenesis of atherosclerosis. Vascular smooth muscle cells (VSMCs) with an osteogenic phenotype promote calcification and features of plaque instability. However, it remains unclear whether aberrant IDO1-regulated tryptophan metabolism causes VSMCs osteogenic reprogramming and calcification.
Methods
We generated global apoE (apolipoprotein E) and IDO1 double knockout mice, and apoE knockout mice with specific deletion of IDO1 in VSMCs or macrophages. Arterial intimal calcification was evaluated by a Western diet-induced atherosclerotic calcification model.
Results
Global deficiency of IDO1 boosted calcific lesion formation without sex bias in vivo. Conditional IDO1 loss of function in VSMCs rather than macrophages promoted calcific lesion development and the abundance of RUNX2 (runt-related transcription factor 2). In contrast, administration of kynurenine via intraperitoneal injection markedly delayed the progression of intimal calcification in parallel with decreased RUNX2 expression in both Apoe-/- and Apoe-/- Ido1-/- mice. We found that IDO1 deletion restrained RUNX2 from proteasomal degradation, which resulted in enhanced osteogenic reprogramming of VSMCs. Kynurenine administration downregulated RUNX2 in an aryl hydrocarbon receptor-dependent manner. Kynurenine acted as the endogenous ligand of aryl hydrocarbon receptor, controlled resultant interactions between cullin 4B and aryl hydrocarbon receptor to form an E3 ubiquitin ligase that bound with RUNX2, and subsequently promoted ubiquitin-mediated instability of RUNX2 in VSMCs. Serum samples from patients with coronary artery calcification had impaired IDO1 activity and decreased kynurenine catabolites compared with those without calcification.
Conclusions
Kynurenine, an IDO1-mediated tryptophan metabolism main product, promotes RUNX2 ubiquitination and subsequently leads to its proteasomal degradation via an aryl hydrocarbon receptor-dependent nongenomic pathway. Insufficient kynurenine exerts the deleterious role of IDO1 ablation in promoting RUNX2-mediated VSMCs osteogenic reprogramming and calcification in vivo.



Circulation: 18 May 2022:101161CIRCULATIONAHA121057868; epub ahead of print
Ouyang L, Yu C, Xie Z, Su X, ... Ding Y, Zou MH
Circulation: 18 May 2022:101161CIRCULATIONAHA121057868; epub ahead of print | PMID: 35582948
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Abstract

Text Messages to Improve Medication Adherence and Secondary Prevention After Acute Coronary Syndrome: The TEXTMEDS Randomized Clinical Trial.

Chow CK, Klimis H, Thiagalingam A, Redfern J, ... Rodgers A, TEXTMEDS Investigators*
Background
TEXTMEDS (Text Messages to Improve Medication Adherence and Secondary Prevention After Acute Coronary Syndrome) examined the effects of text message-delivered cardiac education and support on medication adherence after an acute coronary syndrome.
Methods
TEXTMEDS was a single-blind, multicenter, randomized controlled trial of patients after acute coronary syndrome. The control group received usual care (secondary prevention as determined by the treating clinician); the intervention group also received multiple motivational and supportive weekly text messages on medications and healthy lifestyle with the opportunity for 2-way communication (text or telephone). The primary end point of self-reported medication adherence was the percentage of patients who were adherent, defined as >80% adherence to each of up to 5 indicated cardioprotective medications, at both 6 and 12 months.
Results
A total of 1424 patients (mean age, 58 years [SD, 11]; 79% male) were randomized from 18 Australian public teaching hospitals. There was no significant difference in the primary end point of self-reported medication adherence between the intervention and control groups (relative risk, 0.93 [95% CI, 0.84-1.03]; P=0.15). There was no difference between intervention and control groups at 12 months in adherence to individual medications (aspirin, 96% vs 96%; β-blocker, 84% vs 84%; angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, 77% vs 80%; statin, 95% vs 95%; second antiplatelet, 84% vs 84% [all P>0.05]), systolic blood pressure (130 vs 129 mm Hg; P=0.26), low-density lipoprotein cholesterol (2.0 vs 1.9 mmol/L; P=0.34), smoking (P=0.59), or exercising regularly (71% vs 68%; P=0.52). There were small differences in lifestyle risk factors in favor of intervention on body mass index <25 kg/m2 (21% vs 18%; P=0.01), eating ≥5 servings per day of vegetables (9% vs 5%; P=0.03), and eating ≥2 servings per day of fruit (44% vs 39%; P=0.01).
Conclusions
A text message-based program had no effect on medical adherence but small effects on lifestyle risk factors.
Registration
URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364448; Unique identifier: ANZCTR ACTRN12613000793718.



Circulation: 10 May 2022; 145:1443-1455
Chow CK, Klimis H, Thiagalingam A, Redfern J, ... Rodgers A, TEXTMEDS Investigators*
Circulation: 10 May 2022; 145:1443-1455 | PMID: 35533220
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Abstract

Strengthening US Food Policies and Programs to Promote Equity in Nutrition Security: A Policy Statement From the American Heart Association.

Thorndike AN, Gardner CD, Kendrick KB, Seligman HK, ... Schwartz MB, American Heart Association Advocacy Coordinating Committee
Nutritionally inadequate dietary intake is a leading contributor to chronic cardiometabolic diseases. Differences in dietary quality contribute to socioeconomic and racial and ethnic health disparities. Food insecurity, a household-level social or economic condition of limited access to sufficient food, is a common cause of inadequate dietary intake. Although US food assistance policies and programs are designed to improve food security, there is growing consensus that they should have a broader focus on nutrition security. In this policy statement, we define nutrition security as an individual or household condition of having equitable and stable availability, access, affordability, and utilization of foods and beverages that promote well-being and prevent and treat disease. Despite existing policies and programs, significant gaps remain for achieving equity in nutrition security across the life span. We provide recommendations for expanding and improving current food assistance policies and programs to achieve nutrition security. These recommendations are guided by several overarching principles: emphasizing nutritional quality, improving reach, ensuring optimal utilization, improving coordination across programs, ensuring stability of access to programs across the life course, and ensuring equity and dignity for access and utilization. We suggest a critical next step will be to develop and implement national measures of nutrition security that can be added to the current US food security measures. Achieving equity in nutrition security will require coordinated and sustained efforts at the federal, state, and local levels. Future advocacy, innovation, and research will be needed to expand existing food assistance policies and programs and to develop and implement new policies and programs that will improve cardiovascular health and reduce disparities in chronic disease.



Circulation: 10 May 2022:101161CIR0000000000001072; epub ahead of print
Thorndike AN, Gardner CD, Kendrick KB, Seligman HK, ... Schwartz MB, American Heart Association Advocacy Coordinating Committee
Circulation: 10 May 2022:101161CIR0000000000001072; epub ahead of print | PMID: 35535604
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Abstract

Rapid Exclusion of Acute Myocardial Injury and Infarction with a Single High Sensitivity Cardiac Troponin T in the Emergency Department: a Multicenter United States Evaluation.

Sandoval Y, Lewis BR, Mehta RA, Ola O, ... Gulati R, Jaffe AS
Background
There are good data to support using a single high-sensitivity cardiac troponin T (hs-cTnT) below the limit of detection (LoD) of 5 ng/L to exclude acute myocardial infarction. Per the United States (US) Food and Drug Administration (FDA), hs-cTnT can only report to the limit of quantitation (LoQ) of 6 ng/L, a threshold for which there is limited data. Our goal was to determine whether a single hs-cTnT below the LoQ of 6 ng/L is a safe strategy to identify patients at low-risk for acute myocardial injury and infarction.
Methods
The efficacy (proportion identified as low-risk based on baseline hs-cTnT<6 ng/L) of identifying low-risk patients was examined in a multicenter (n=22 sites) US cohort study of emergency department patients undergoing at least one hs-cTnT (CV Data Mart Biomarker cohort). We then determined the performance of a single hs-cTnT<6 ng/L (biomarker alone) to exclude acute myocardial injury (subsequent hs-cTnT >99th percentile in those with an initial hs-cTnT<6 ng/L). The clinically intended rule-out strategy combining a nonischemic electrocardiogram with a baseline hs-cTnT<6 ng/L was subsequently tested in an adjudicated cohort in which the diagnostic performance for ruling-out acute myocardial infarction and safety (myocardial infarction or death at 30-days) were evaluated.
Results
A total of 85,610 patients were evaluated in the CV Data Mart Biomarker cohort, amongst which 24,646 (29%) had a baseline hs-cTnT<6 ng/L. Women were more likely than men to have hs-cTnT<6 ng/L (38% vs. 20%, p<0.0001). Among 11,962 patients with baseline hs-cTnT<6 ng/L and serial measurements, only 1.2% developed acute myocardial injury, resulting in a negative predictive value of 98.8% (95% CI 98.6, 99.0) and sensitivity of 99.6% (95% CI 99.5, 99.6). In the adjudicated cohort, a nonischemic electrocardiogram with hs-cTnT<6 ng/L identified 33% of patients (610 of 1849) as low-risk and resulted in a negative predictive value and sensitivity of 100% and a 30-day rate of 0.2% for 30-day myocardial infarction or death.
Conclusions
A single hs-cTnT below the LoQ of 6 ng/L is a safe and rapid method to identify a substantial number of patients at very low risk for acute myocardial injury and infarction.



Circulation: 10 May 2022; epub ahead of print
Sandoval Y, Lewis BR, Mehta RA, Ola O, ... Gulati R, Jaffe AS
Circulation: 10 May 2022; epub ahead of print | PMID: 35535607
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Abstract

Call to Action for Cardiovascular Disease in Women: Epidemiology, Awareness, Access, and Delivery of Equitable Health Care: A Presidential Advisory From the American Heart Association.

Wenger NK, Lloyd-Jones DM, Elkind MSV, Fonarow GC, ... Roger VL, American Heart Association
Addressing the pervasive gaps in knowledge and care delivery to reduce sex-based disparities and achieve equity is fundamental to the American Heart Association\'s commitment to advancing cardiovascular health for all by 2024. This presidential advisory serves as a call to action for the American Heart Association and other stakeholders around the globe to identify and remove barriers to health care access and quality for women. A concise and current summary of existing data across the areas of risk and prevention, access and delivery of equitable care, and awareness and education provides a framework to consider knowledge gaps and research needs critical toward achieving significant progress for the health and well-being of all women.



Circulation: 09 May 2022:101161CIR0000000000001071; epub ahead of print
Wenger NK, Lloyd-Jones DM, Elkind MSV, Fonarow GC, ... Roger VL, American Heart Association
Circulation: 09 May 2022:101161CIR0000000000001071; epub ahead of print | PMID: 35531777
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Abstract

rECHOmmend: An ECG-based Machine-learning Approach for Identifying Patients at High-risk of Undiagnosed Structural Heart Disease Detectable by Echocardiography.

Ulloa-Cerna AE, Jing L, Pfeifer JM, Raghunath S, ... Fornwalt BK, Chen R
Background: Timely diagnosis of structural heart disease improves patient outcomes, yet many remain underdiagnosed. While population screening with echocardiography is impractical, electrocardiogram (ECG)-based prediction models can help target high-risk patients. We developed a novel ECG-based machine learning approach to predict multiple structural heart conditions, hypothesizing that a composite model would yield higher prevalence and positive predictive values (PPVs) to facilitate meaningful recommendations for echocardiography.
Methods:
Using 2,232,130 ECGs linked to electronic health records and echocardiography reports from 484,765 adults between 1984-2021, we trained machine learning models to predict the presence or absence of any of seven echocardiography-confirmed diseases within one year. This composite label included: moderate or severe valvular disease (aortic/mitral stenosis or regurgitation, tricuspid regurgitation), reduced ejection fraction <50%, or interventricular septal thickness >15mm. We tested various combinations of input features (demographics, labs, structured ECG data, ECG traces) and evaluated model performance using 5-fold cross-validation, multi-site validation trained on one site and tested on 10 independent sites, and simulated retrospective deployment trained on pre-2010 data and deployed in 2010.
Results:
Our composite \'rECHOmmend\' model using age, sex and ECG traces had an area under the receiver operating characteristic curve (AUROC) of 0.91 and PPV of 42% at 90% sensitivity, with a composite label prevalence of 17.9%. Individual disease models had AUROCs from 0.86-0.93 and lower PPVs from 1%-31%. AUROCs for models using different input features ranged from 0.80-0.93, increasing with additional features. Multi-site validation showed similar results to cross-validation, with an aggregate AUROC of 0.91 across our independent test set of 10 clinical sites after training on a separate site. Our simulated retrospective deployment showed that for ECGs acquired in patients without pre-existing structural heart disease in the year 2010, 11% were classified as high-risk, of which 41% (4.5% of total patients) developed true echocardiography-confirmed disease within one year. Conclusions: An ECG-based machine learning model using a composite endpoint can identify a high-risk population for having undiagnosed, clinically significant structural heart disease while outperforming single disease models and improving practical utility with higher PPVs. This approach can facilitate targeted screening with echocardiography to improve under-diagnosis of structural heart disease.




Circulation: 09 May 2022; epub ahead of print
Ulloa-Cerna AE, Jing L, Pfeifer JM, Raghunath S, ... Fornwalt BK, Chen R
Circulation: 09 May 2022; epub ahead of print | PMID: 35533093
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Abstract

Efficacy and Safety of Dapagliflozin in Type 2 Diabetes According to Baseline Blood Pressure: Observations From DECLARE-TIMI 58 Trial.

Furtado RHM, Raz I, Goodrich EL, Murphy SA, ... Sabatine MS, Wiviott SD
Background: Dapagliflozin improved heart failure and kidney outcomes in patients with type 2 diabetes mellitus (T2DM) with or at high risk for cardiovascular disease in the DECLARE-TIMI 58 trial. Here, the aim was to analyze efficacy and safety of dapagliflozin stratified according to baseline systolic blood pressure (SBP).
Methods:
The DECLARE-TIMI 58 trial randomized patients with T2DM and either prior atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk factors to dapagliflozin or placebo. Patients were categorized by baseline SBP levels: < 120, 120-129, 130-139, 140-159 and ≥ 160 mmHg (respectively, normal, elevated, stage 1, stage 2 and severe hypertension). Efficacy outcomes of interest were hospitalization for heart failure (HHF) and a renal-specific composite outcome (sustained decrease in estimated glomerular filtration rate by 40%, progression to end-stage renal disease or renal death). Safety outcomes included symptoms of volume depletion, lower extremity amputations and acute kidney injury.
Results:
The trial comprised 17,160 patients; mean age of 64.0 ± 6.8 years ; 37.4% women; median duration of T2DM 11 years; 40.6% with prevalent CVD. Overall, dapagliflozin reduced SBP by 2.4 mmHg (95% CI 1.9-2.9; p < 0.0001) compared with placebo at 48 months. The beneficial effects of dapagliflozin on HHF and renal outcomes were consistent across all baseline SBP categories, with no evidence of modification of treatment effect (p-interactions = 0.28 and 0.52, respectively). Among normotensive patients, the HR´s were 0.66 (95% CI 0.42-1.05) and 0.39 (95% CI 0.19-0.78), respectively for HHF and the renal specific outcome. Events of volume depletion, amputation and acute kidney injury did not differ with dapagliflozin overall or within any baseline SBP group. Conclusions: In patients with T2DM with or at high ASCVD risk, dapagliflozin reduced risk for HHF and renal outcomes regardless of baseline systolic blood pressure, with no difference in adverse events of interest at any level of baseline SBP. These results indicate that dapagliflozin provides important cardiorenal benefit in patients with T2DM at high ASCVD risk, independent of baseline blood pressure.




Circulation: 05 May 2022; epub ahead of print
Furtado RHM, Raz I, Goodrich EL, Murphy SA, ... Sabatine MS, Wiviott SD
Circulation: 05 May 2022; epub ahead of print | PMID: 35510542
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Abstract

First-Line Catheter Ablation of Monomorphic Ventricular Tachycardia in Cardiomyopathy Concurrent with Defibrillator Implantation: The PAUSE-SCD Randomized Trial.

Tung R, Xue Y, Chen M, Jiang C, ... Yao Y, PAUSE-SCD Investigators
Background: Catheter ablation as first-line therapy for ventricular tachycardia (VT) at the time of implantable cardioverter defibrillator (ICD) implantation has not been adopted into clinical guidelines. Also, there is an unmet clinical need to prospectively examine the role of VT ablation in patients with non-ischemic cardiomyopathy (NICM), an increasingly prevalent population referred for advanced therapies globally.
Methods:
We conducted an international, multi-center, randomized controlled trial enrolling 180 patients with cardiomyopathy and monomorphic VT with an indication for implantable cardioverter defibrillator (ICD) implantation to assess the role of early, first-line ablation therapy. A total of 121 patients were randomized (1:1) to ablation + an ICD versus conventional medical therapy + an ICD. Patients who refused ICD (n=47) were followed in a prospective registry after stand-alone ablation treatment. The primary outcome was a composite endpoint of VT recurrence, cardiovascular hospitalization, or death.
Results:
Randomized patients had a mean age of 55 years old (IQR 46-64) and left ventricular ejection fraction of 40 % (IQR 30-49 %); 81 % were male. The underlying heart disease was ischemic cardiomyopathy (ICM) in 35 %, NICM in 30 %, and arrhythmogenic cardiomyopathy (ARVC) in 35 %. Ablation was performed a median of 2 days prior to ICD implantation (IQR 5 days prior to 14 days after). At 31-months, the primary outcome occurred in 49.3 %of the ablation group and 65.5 % in the control group (HR 0.58, 95 % CI, 0.35-0.96; P=0.04). The observed difference was driven by a reduction in VT recurrence in the ablation arm (HR 0.51 [95 %CI, 0.29-0.90 ]; P=0.02). A statistically significant reduction in both ICD shocks (10.0 vs 24.6 %; p=0.03) and anti-tachycardia pacing (16.2 % vs 32.8 %; p=0.04) was observed in patients who underwent ablation compared with control. No differences in cardiovascular hospitalization (32.0 % vs. 33.7 %; HR 0.82 [95 % CI, 0.43-1.56 ]; P=0.55) or mortality (8.9% vs 8.8 %, HR 1.40 [95 %CI, 0.38-5.22 ]; P=0.62]) were observed. Ablation-related complications occurred in 8.3 % of patients. Conclusions: Among patients with cardiomyopathy of varied etiologies, early catheter ablation performed at the time of ICD implantation significantly reduced the composite primary outcome of VT recurrence, cardiovascular hospitalization, or death. These findings were driven by a reduction in ICD therapies.




Circulation: 04 May 2022; epub ahead of print
Tung R, Xue Y, Chen M, Jiang C, ... Yao Y, PAUSE-SCD Investigators
Circulation: 04 May 2022; epub ahead of print | PMID: 35507499
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Abstract

Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity.

Chakraborty R, Ostriker AC, Xie Y, Dave JM, ... Hwa J, Martin KA
Background
Vascular smooth muscle cell (VSMC) phenotypic switching contributes to cardiovascular diseases. Epigenetic regulation is emerging as a key regulatory mechanism, with the methylcytosine dioxygenase TET2 acting as a master regulator of smooth muscle cell phenotype. The histone acetyl-transferases p300 and CREB-binding protein (CBP) are highly homologous and often considered to be interchangeable, and their roles in smooth muscle cell phenotypic regulation are not known.
Methods
We assessed the roles of p300 and CBP in human VSMC with knockdown, in inducible smooth muscle-specific knockout mice (inducible knockout [iKO]; p300iKO or CBPiKO), and in samples of human intimal hyperplasia.
Results
P300, CBP, and histone acetylation were differently regulated in VSMCs undergoing phenotypic switching and in vessel remodeling after vascular injury. Medial p300 expression and activity were repressed by injury, but CBP and histone acetylation were induced in neointima. Knockdown experiments revealed opposing effects of p300 and CBP in the VSMC phenotype: p300 promoted contractile protein expression and inhibited migration, but CBP inhibited contractile genes and enhanced migration. p300iKO mice exhibited severe intimal hyperplasia after arterial injury compared with controls, whereas CBPiKO mice were entirely protected. In normal aorta, p300iKO reduced, but CBPiKO enhanced, contractile protein expression and contractility compared with controls. Mechanistically, we found that these histone acetyl-transferases oppositely regulate histone acetylation, DNA hydroxymethylation, and PolII (RNA polymerase II) binding to promoters of differentiation-specific contractile genes. Our data indicate that p300 and TET2 function together, because p300 was required for TET2-dependent hydroxymethylation of contractile promoters, and TET2 was required for p300-dependent acetylation of these loci. TET2 coimmunoprecipitated with p300, and this interaction was enhanced by rapamycin but repressed by platelet-derived growth factor (PDGF) treatment, with p300 promoting TET2 protein stability. CBP did not associate with TET2, but instead facilitated recruitment of histone deacetylases (HDAC2, HDAC5) to contractile protein promoters. Furthermore, CBP inhibited TET2 mRNA levels. Immunostaining of cardiac allograft vasculopathy samples revealed that p300 expression is repressed but CBP is induced in human intimal hyperplasia.
Conclusions
This work reveals that p300 and CBP serve nonredundant and opposing functions in VSMC phenotypic switching and coordinately regulate chromatin modifications through distinct functional interactions with TET2 or HDACs. Targeting specific histone acetyl-transferases may hold therapeutic promise for cardiovascular diseases.



Circulation: 03 May 2022:101161CIRCULATIONAHA121057599; epub ahead of print
Chakraborty R, Ostriker AC, Xie Y, Dave JM, ... Hwa J, Martin KA
Circulation: 03 May 2022:101161CIRCULATIONAHA121057599; epub ahead of print | PMID: 35502657
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Abstract

Exercise Causes Arrhythmogenic Remodeling of Intracellular Calcium Dynamics in Plakophilin-2-Deficient Hearts.

van Opbergen CJM, Bagwan N, Maurya SR, Kim JC, ... Lundby A, Delmar M
Background: Exercise training, and catecholaminergic stimulation, increase the incidence of arrhythmic events in patients affected with arrhythmogenic right ventricular cardiomyopathy correlated with plakophilin-2 (PKP2) mutations. Separate data show that reduced abundance of PKP2 leads to dysregulation of intracellular Ca2+ (Ca2+i) homeostasis. Here, we study the relation between exercise, catecholaminergic stimulation, Ca2+i homeostasis, and arrhythmogenesis in PKP2-deficient murine hearts.
Methods:
Experiments were performed in myocytes from a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout murine line (PKP2cKO). For training, mice underwent 75 minutes of treadmill running once per day, 5 days each week for 6 weeks. We used multiple approaches including imaging, high-resolution mass spectrometry, electrocardiography, and pharmacological challenges to study the functional properties of cells/hearts in vitro and in vivo.
Results:
In myocytes from PKP2cKO animals, training increased sarcoplasmic reticulum Ca2+ load, increased the frequency and amplitude of spontaneous ryanodine receptor (ryanodine receptor 2)-mediated Ca2+ release events (sparks), and changed the time course of sarcomeric shortening. Phosphoproteomics analysis revealed that training led to hyperphosphorylation of phospholamban in residues 16 and 17, suggesting a catecholaminergic component. Isoproterenol-induced increase in Ca2+i transient amplitude showed a differential response to β-adrenergic blockade that depended on the purported ability of the blockers to reach intracellular receptors. Additional experiments showed significant reduction of isoproterenol-induced Ca2+i sparks and ventricular arrhythmias in PKP2cKO hearts exposed to an experimental blocker of ryanodine receptor 2 channels. Conclusions: Exercise disproportionately affects Ca2+i homeostasis in PKP2-deficient hearts in a manner facilitated by stimulation of intracellular β-adrenergic receptors and hyperphosphorylation of phospholamban. These cellular changes create a proarrhythmogenic state that can be mitigated by ryanodine receptor 2 blockade. Our data unveil an arrhythmogenic mechanism for exercise-induced or catecholaminergic life-threatening arrhythmias in the setting of PKP2 deficit. We suggest that membrane-permeable β-blockers are potentially more efficient for patients with arrhythmogenic right ventricular cardiomyopathy, highlight the potential for ryanodine receptor 2 channel blockers as treatment for the control of heart rhythm in the population at risk, and propose that PKP2-dependent and phospholamban-dependent arrhythmogenic right ventricular cardiomyopathy-related arrhythmias have a common mechanism.




Circulation: 01 May 2022; epub ahead of print
van Opbergen CJM, Bagwan N, Maurya SR, Kim JC, ... Lundby A, Delmar M
Circulation: 01 May 2022; epub ahead of print | PMID: 35491884
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Abstract

Vitamin K2 and D in Patients With Aortic Valve Calcification: A Randomized Double-Blinded Clinical Trial.

Diederichsen ACP, Lindholt JS, Möller S, Øvrehus KA, ... Mickley H, Sanchez Dahl JS
Background: Menaquinone-7 (MK-7), also known as vitamin K2, is a cofactor for the carboxylation of proteins involved in the inhibition of arterial calcification and has been suggested to reduce the progression rate of aortic valve calcification (AVC) in patients with aortic stenosis.
Methods:
In a randomized, double-blind, multicenter trial, men from the community with an AVC score >300 arbitrary units (AU) on cardiac noncontrast computer tomography were randomized to daily treatment with tablet 720 μg MK-7 plus 25 μg vitamin D or matching placebo for 24 months. The primary outcome was the change in AVC score. Selected secondary outcomes included change in aortic valve area and peak aortic jet velocity on echocardiography, heart valve surgery, change in aortic and coronary artery calcification, and change in dp-ucMGP (dephosphorylated-undercarboxylated matrix Gla-protein). Safety outcomes included all-cause death and cardiovascular events.
Results:
From February 1, 2018, to March 21, 2019, 365 men were randomized. Mean age was 71.0 (±4.4) years. The mean (95% CI) increase in AVC score was 275 AU (95% CI, 225-326 AU) and 292 AU (95% CI, 246-338 AU) in the intervention and placebo groups, respectively. The mean difference on AVC progression was 17 AU (95% CI, -86 to 53 AU; P=0.64). The mean change in aortic valve area was 0.02 cm2 (95% CI, -0.09 to 0.12 cm2; P=0.78) and in peak aortic jet velocity was 0.04 m/s (95% CI, -0.11 to 0.02 m/s; P=0.21). The progression in aortic and coronary artery calcification score was not significantly different between patients treated with MK-7 plus vitamin D and patients receiving placebo. There was no difference in the rate of heart valve surgery (1 versus 2 patients; P=0.99), all-cause death (1 versus 4 patients; P=0.37), or cardiovascular events (10 versus 10 patients; P=0.99). Compared with patients in the placebo arm, a significant reduction in dp-ucMGP was observed with MK-7 plus vitamin D (-212 pmol/L versus 45 pmol/L; P<0.001). Conclusions: In elderly men with an AVC score >300 AU, 2 years MK-7 plus vitamin D supplementation did not influence AVC progression.




Circulation: 25 Apr 2022; epub ahead of print
Diederichsen ACP, Lindholt JS, Möller S, Øvrehus KA, ... Mickley H, Sanchez Dahl JS
Circulation: 25 Apr 2022; epub ahead of print | PMID: 35465686
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Abstract

Hourly Air Pollutants and Acute Coronary Syndrome Onset In 1.29 Million Patients.

Chen R, Jiang Y, Hu J, Chen H, ... Huo Y, Kan H
Background: Short-term exposure to ambient air pollution has been linked with daily hospitalization and mortality of acute coronary syndrome (ACS); however, the associations of sub-daily (hourly) levels of criteria air pollutants with the onset of ACS and its subtypes have rarely been evaluated.
Methods:
We conducted a time-stratified case-crossover study among 1,292,880 ACS patients from 2,239 hospitals in 318 Chinese cities between January 1, 2015, and September 30, 2020. Hourly concentrations of fine particulate matter (PM2.5), coarse particulate matter (PM2.5-10), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO), and ozone (O3) were collected. Hourly onset data of ACS and its subtypes, including ST-segment-elevation myocardial infarction, non-ST-segment-elevation myocardial infarction, and unstable angina, were also obtained. Conditional logistic regressions combined with polynomial distributed lag models were applied.
Results:
Acute exposures to PM2.5, NO2, SO2, and CO were each associated with the onset of ACS and its subtype. These associations were strongest in the concurrent hour of exposure and were attenuated thereafter, with the weakest effects observed after 15-29 hours. There were no apparent thresholds in the concentration-response curves. An interquartile range increase in concentrations of PM2.5 (36.0 μg/m3), NO2 (29.0 μg/m3), SO2 (9.0 μg/m3), and CO (0.6 mg/m3) over the 0-24 hours preceding onset was significantly associated with 1.32%, 3.89%, 0.67%, and 1.55% higher risks of ACS onset, respectively. For a given pollutant, the associations were comparable in magnitude across different subtypes of ACS. Generally, NO2 showed the strongest associations with all three subtypes, followed by PM2.5, CO, and SO2. Greater magnitude of associations was observed among patients older than 65, without a history of smoking or chronic cardiorespiratory diseases, and in the cold season. Null associations of exposure to either PM2.5-10 or O3 with ACS onset were observed. Conclusions: The results suggest that transient exposure to the air pollutants of PM2.5, NO2, SO2, CO, but not PM2.5-10 or O3, may trigger the onset of ACS, even at concentrations below the World Health Organization air-quality guidelines.




Circulation: 22 Apr 2022; epub ahead of print
Chen R, Jiang Y, Hu J, Chen H, ... Huo Y, Kan H
Circulation: 22 Apr 2022; epub ahead of print | PMID: 35450432
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Impact:
Abstract

Initial Decline (\"dip\") in Estimated Glomerular Filtration Rate Following Initiation of Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction: Insights from DAPA-HF.

Adamson C, Docherty KF, Heerspink HJL, de Boer RA, ... Jhund PS, McMurray JJV
Background: In a post hoc analysis, the frequency of occurrence of an early decline (\"dip\") in estimated glomerular filtration rate (eGFR) after initiation of dapagliflozin, and its association with outcomes, was evaluated in patients with heart failure and reduced ejection fraction (HFrEF) randomized in the Dapagliflozin and Prevention of Adverse outcomes in Heart Failure trial.
Methods:
HFrEF patients with or without type 2 diabetes and an eGFR ≥30 mL/min/1.73m2 were randomized to placebo or dapagliflozin 10mg daily. The primary outcome was the composite of worsening heart failure or cardiovascular death. The extent of the dip in eGFR between baseline and 2 weeks, patient characteristics associated with a >10% decline, and cardiovascular outcomes and eGFR slopes in participants experiencing this decline were investigated. Time-to-event outcomes were assessed in Cox regression from 14 days; eGFR slopes were assessed using repeated measure mixed effect models.
Results:
The mean change in eGFR between day 0 and 14 was -1.1 ml/min/1.73m2 (95% CI -1.5,-0.7) with placebo and -4.2 ml/min/1.73m2 (-4.6,-3.9) with dapagliflozin, giving a between treatment difference of 3.1 (2.6, 3.7) ml/min/1.73m2. The proportions of patients randomized to dapagliflozin experiencing a >10%, >20% and >30% decline in eGFR were: 38.2%, 12.6%, and 3.4%, respectively; for placebo they were 21.0%, 6.4% and 1.3%, respectively. The odds ratio for a >10% early decline in eGFR with dapagliflozin, compared with placebo, was 2.36 (95%CI 2.07-2.69), P<0.001. Baseline characteristics associated with a >10% decline in eGFR on dapagliflozin were older age, lower eGFR, higher ejection fraction, and type 2 diabetes. The hazard ratio for the primary outcome in patients in the placebo group experiencing a >10% decline in eGFR, compared with ≤10% decline in eGFR was 1.45 (95% CI 1.19-1.78). The corresponding hazard ratio in the dapagliflozin group was 0.73 (95% CI 0.59-0.91), P-interaction <0.001. A >10% initial decline in eGFR was not associated with greater long-term decline in eGFR or more adverse events. Conclusions: The average dip in eGFR after starting dapagliflozin was small and associated with better clinical outcomes, compared with a similar decline on placebo in patients with HFrEF. Large declines in eGFR were uncommon with dapagliflozin.




Circulation: 20 Apr 2022; epub ahead of print
Adamson C, Docherty KF, Heerspink HJL, de Boer RA, ... Jhund PS, McMurray JJV
Circulation: 20 Apr 2022; epub ahead of print | PMID: 35442064
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Impact:
Abstract

Coronary Artery and Cardiac Disease in Patients With Type 2 Myocardial Infarction: A Prospective Cohort Study.

Bularga A, Hung J, Daghem M, Stewart S, ... Mills NL, Chapman AR
Background
Type 2 myocardial infarction is caused by myocardial oxygen supply-demand imbalance, and its diagnosis is increasingly common with the advent of high-sensitivity cardiac troponin assays. Although this diagnosis is associated with poor outcomes, widespread uncertainty and confusion remain among clinicians as to how to investigate and manage this heterogeneous group of patients with type 2 myocardial infarction.
Methods
In a prospective cohort study, 8064 consecutive patients with increased cardiac troponin concentrations were screened to identify patients with type 2 myocardial infarction. We excluded patients with frailty or renal or hepatic failure. All study participants underwent coronary (invasive or computed tomography angiography) and cardiac (magnetic resonance or echocardiography) imaging, and the underlying causes of infarction were independently adjudicated. The primary outcome was the prevalence of coronary artery disease.
Results
In 100 patients with a provisional diagnosis of type 2 myocardial infarction (median age, 65 years [interquartile range, 55-74 years]; 43% women), coronary and cardiac imaging reclassified the diagnosis in 7 patients: type 1 or 4b myocardial infarction in 5 and acute myocardial injury in 2 patients. In those with type 2 myocardial infarction, median cardiac troponin I concentrations were 195 ng/L (interquartile range, 62-760 ng/L) at presentation and 1165 ng/L (interquartile range, 277-3782 ng/L) on repeat testing. The prevalence of coronary artery disease was 68% (63 of 93), which was obstructive in 30% (28 of 93). Infarct-pattern late gadolinium enhancement or regional wall motion abnormalities were observed in 42% (39 of 93), and left ventricular systolic dysfunction was seen in 34% (32 of 93). Only 10 patients had both normal coronary and normal cardiac imaging. Coronary artery disease and left ventricular systolic dysfunction were previously unrecognized in 60% (38 of 63) and 84% (27 of 32), respectively, with only 33% (21 of 63) and 19% (6 of 32) on evidence-based treatments.
Conclusions
Systematic coronary and cardiac imaging of patients with type 2 myocardial infarction identified coronary artery disease in two-thirds and left ventricular systolic dysfunction in one-third of patients. Unrecognized and untreated coronary or cardiac disease is seen in most patients with type 2 myocardial infarction, presenting opportunities for initiation of evidence-based treatments with major potential to improve clinical outcomes.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier: NCT03338504.



Circulation: 19 Apr 2022; 145:1188-1200
Bularga A, Hung J, Daghem M, Stewart S, ... Mills NL, Chapman AR
Circulation: 19 Apr 2022; 145:1188-1200 | PMID: 35341327
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Impact:
Abstract

Percutaneous Transvalvular Microaxial Flow Pump Support in Cardiology.

Lüsebrink E, Kellnar A, Krieg K, Binzenhöfer L, ... Schäfer A, Orban M
The Impella device (Impella, Abiomed, Danvers, MA) is a percutaneous transvalvular microaxial flow pump that is currently used for (1) cardiogenic shock, (2) left ventricular unloading (combination of venoarterial extracorporeal membrane oxygenation and Impella concept), (3) high-risk percutaneous coronary interventions, (4) ablation of ventricular tachycardia, and (5) treatment of right ventricular failure. Impella-assisted forward blood flow increased mean arterial pressure and cardiac output, peripheral tissue perfusion, and coronary blood flow in observational studies and some randomized trials. However, because of the need for large-bore femoral access (14 F for the commonly used Impella CP device) and anticoagulation, the incidences of bleeding and ischemic complications are as much as 44% and 18%, respectively. Hemolysis is reported in as many as 32% of patients and stroke in as many as 13%. Despite the rapidly growing use of the Impella device, there are still insufficient data on its effect on outcome and complications on the basis of large, adequately powered randomized controlled trials. The only 2 small and also underpowered randomized controlled trials in cardiogenic shock comparing Impella versus intra-aortic balloon pump did not show improved mortality. Several larger randomized controlled trials are currently recruiting patients or are in preparation in cardiogenic shock (DanGer Shock [Danish-German Cardiogenic Shock Trial; NCT01633502]), left ventricular unloading (DTU-STEMI [Door-To-Unload in ST-Segment-Elevation Myocardial Infarction; NCT03947619], UNLOAD ECMO [Left Ventricular Unloading to Improve Outcome in Cardiogenic Shock Patients on VA-ECMO], and REVERSE [A Prospective Randomised Trial of Early LV Venting Using Impella CP for Recovery in Patients With Cardiogenic Shock Managed With VA ECMO; NCT03431467]) and high-risk percutaneous coronary intervention (PROTECT IV [Impella-Supported PCI in High-Risk Patients With Complex Coronary Artery Disease and Reduced Left Ventricular Function; NCT04763200]).



Circulation: 19 Apr 2022; 145:1254-1284
Lüsebrink E, Kellnar A, Krieg K, Binzenhöfer L, ... Schäfer A, Orban M
Circulation: 19 Apr 2022; 145:1254-1284 | PMID: 35436135
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Impact:
Abstract

Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy.

Riaz M, Park J, Sewanan LR, Ren Y, ... Campbell SG, Qyang Y
Background
Familial hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. HCM manifestations include left ventricular hypertrophy and heart failure, arrythmias, and sudden cardiac death. How dysregulated sarcomeric force production is sensed and leads to pathological remodeling remains poorly understood in HCM, thereby inhibiting the efficient development of new therapeutics.
Methods
Our discovery was based on insights from a severe phenotype of an individual with HCM and a second genetic alteration in a sarcomeric mechanosensing protein. We derived cardiomyocytes from patient-specific induced pluripotent stem cells and developed robust engineered heart tissues by seeding induced pluripotent stem cell-derived cardiomyocytes into a laser-cut scaffold possessing native cardiac fiber alignment to study human cardiac mechanobiology at both the cellular and tissue levels. Coupled with computational modeling for muscle contraction and rescue of disease phenotype by gene editing and pharmacological interventions, we have identified a new mechanotransduction pathway in HCM, shown to be essential in modulating the phenotypic expression of HCM in 5 families bearing distinct sarcomeric mutations.
Results
Enhanced actomyosin crossbridge formation caused by sarcomeric mutations in cardiac myosin heavy chain (MYH7) led to increased force generation, which, when coupled with slower twitch relaxation, destabilized the MLP (muscle LIM protein) stretch-sensing complex at the Z-disc. Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy. We demonstrate that the common muscle LIM protein-W4R variant is an important modifier, exacerbating the phenotypic expression of HCM, but alone may not be a disease-causing mutation. By mitigating enhanced actomyosin crossbridge formation through either genetic or pharmacological means, we alleviated stress at the Z-disc, preventing the development of hypertrophy associated with sarcomeric mutations.
Conclusions
Our studies have uncovered a novel biomechanical mechanism through which dysregulated sarcomeric force production is sensed and leads to pathological signaling, remodeling, and hypertrophic responses. Together, these establish the foundation for developing innovative mechanism-based treatments for HCM that stabilize the Z-disc MLP-mechanosensory complex.



Circulation: 19 Apr 2022; 145:1238-1253
Riaz M, Park J, Sewanan LR, Ren Y, ... Campbell SG, Qyang Y
Circulation: 19 Apr 2022; 145:1238-1253 | PMID: 35384713
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Impact:
Abstract

Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization.

Henry A, Gordillo-Marañón M, Finan C, Schmidt AF, ... Lumbers RT, HERMES and SCALLOP Consortia
Background
Heart failure (HF) is a highly prevalent disorder for which disease mechanisms are incompletely understood. The discovery of disease-associated proteins with causal genetic evidence provides an opportunity to identify new therapeutic targets.
Methods
We investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity-based proteomic assays. First, we estimated the associations of 90 cardiovascular proteins with incident heart failure by means of a fixed-effect meta-analysis of 4 population-based studies, composed of a total of 3019 participants with 732 HF events. The causal effects of HF-associated proteins were then investigated by Mendelian randomization, using cis-protein quantitative loci genetic instruments identified from genomewide association studies in more than 30 000 individuals. To improve the precision of causal estimates, we implemented an Mendelian randomization model that accounted for linkage disequilibrium between instruments and tested the robustness of causal estimates through a multiverse sensitivity analysis that included up to 120 combinations of instrument selection parameters and Mendelian randomization models per protein. The druggability of candidate proteins was surveyed, and mechanism of action and potential on-target side effects were explored with cross-trait Mendelian randomization analysis.
Results
Forty-four of ninety proteins were positively associated with risk of incident HF (P<6.0×10-4). Among these, 8 proteins had evidence of a causal association with HF that was robust to multiverse sensitivity analysis: higher CSF-1 (macrophage colony-stimulating factor 1), Gal-3 (galectin-3) and KIM-1 (kidney injury molecule 1) were positively associated with risk of HF, whereas higher ADM (adrenomedullin), CHI3L1 (chitinase-3-like protein 1), CTSL1 (cathepsin L1), FGF-23 (fibroblast growth factor 23), and MMP-12 (matrix metalloproteinase-12) were protective. Therapeutics targeting ADM and Gal-3 are currently under evaluation in clinical trials, and all the remaining proteins were considered druggable, except KIM-1.
Conclusions
We identified 44 circulating proteins that were associated with incident HF, of which 8 showed evidence of a causal relationship and 7 were druggable, including adrenomedullin, which represents a particularly promising drug target. Our approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases.



Circulation: 19 Apr 2022; 145:1205-1217
Henry A, Gordillo-Marañón M, Finan C, Schmidt AF, ... Lumbers RT, HERMES and SCALLOP Consortia
Circulation: 19 Apr 2022; 145:1205-1217 | PMID: 35300523
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Impact:
Abstract

Progressive Reduction in Right Ventricular Contractile Function Due to Altered Actin Expression in an Aging Mouse Model of Arrhythmogenic Cardiomyopathy.

Camors EM, Roth AH, Alef JR, Sullivan RD, ... Purevjav E, Towbin JA
Background
Arrhythmogenic cardiomyopathy (ACM) is an inherited genetic disorder of desmosomal dysfunction, and plakophilin-2 (PKP2) has been reported to be the most common disease-causing gene when mutation-positive. In the early \"concealed\" phase, the ACM heart is at high risk of sudden cardiac death before cardiac remodeling occurs due to mistargeted ion channels and altered Ca2+ handling. However, the results of pathogenic PKP2 variants on myocyte contraction in ACM pathogenesis remain unknown.
Methods
We studied the outcomes of a human truncating variant of PKP2 on myocyte contraction using a novel knock-in mouse model with insertion of thymidine in exon 5 of Pkp2, which mimics a familial case of ACM (PKP2-L404fsX5). We used serial echocardiography, electrocardiography, blood pressure measurements, histology, cardiomyocyte contraction, intracellular calcium measurements, and gene and protein expression studies.
Results
Serial echocardiography of Pkp2 heterozygous (Pkp2-Het) mice revealed progressive failure of the right ventricle (RV) in animals older than three months of age. By contrast, left ventricular (LV) function remained normal. Electrocardiograms of six-month-old anesthetized Pkp2-Het mice showed normal baseline heart rates and QRS complexes. Cardiac responses to β-adrenergic agonist isoproterenol (2 mg.kg-1) plus caffeine (120 mg.kg-1) were also normal. However, adrenergic stimulation enhanced the susceptibility of Pkp2-Het hearts to tachyarrhythmia and sudden cardiac death. Histologic staining showed no significant fibrosis or adipocyte infiltration in the RVs and LVs of six- and twelve-month-old Pkp2-Het hearts. Contractility assessment of isolated myocytes demonstrated progressively reduced Pkp2-Het RV cardiomyocyte function consistent with RV failure measured by echocardiography. However, aging Pkp2-Het and control RV myocytes loaded with intracellular Ca2+ indicator Fura-2 showed comparable Ca2+ transients. Western blotting of Pkp2-RV homogenates revealed a 40% decrease in actin, while actin immunoprecipitation followed by a 2, 4-dinitrophenylhydrazine staining showed doubled oxidation level. This correlated with a 39% increase in troponin-I phosphorylation. In contrast, Pkp2-Het LV myocytes had normal contraction, actin expression and oxidation, and troponin-I phosphorylation. Finally, Western blotting of cardiac biopsies revealed actin expression was 40% decreased in RVs of end-stage ACM patients.
Conclusions
During the early \"concealed\" phase of ACM, reduced actin expression drives loss of RV myocyte contraction, contributing to progressive RV dysfunction.



Circulation: 19 Apr 2022; epub ahead of print
Camors EM, Roth AH, Alef JR, Sullivan RD, ... Purevjav E, Towbin JA
Circulation: 19 Apr 2022; epub ahead of print | PMID: 35437032
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Impact:
Abstract

Temporal Trends in the Remaining Lifetime Risk of Cardiovascular Disease Among Middle-Aged Adults Across 6 Decades: The Framingham Study.

Vasan RS, Enserro DM, Xanthakis V, Beiser AS, Seshadri S
Background: The remaining lifetime risk (RLR) is the probability of developing an outcome over the remainder of one\'s lifespan at any given age. The RLR for atherosclerotic cardiovascular disease (ASCVD) in three 20-year periods were assessed using data from a single community-based cohort study of predominantly White participants
Methods:
Longitudinal data from the Framingham study in 3 epochs (epoch 1, 1960-1979; epoch 2, 1980-1999; epoch 3, 2000-2018) were evaluated. The RLR of a first ASCVD event (myocardial infarction, coronary heart disease death, or stroke) from 45 years of age (adjusting for competing risk of death) in the 3 epochs were compared overall, and according to the following strata: sex, body mass index, blood pressure and cholesterol categories, diabetes, smoking, and Framingham risk score groups.
Results:
There were 317 849 person-years of observations during the 3 epochs (56% women; 94% White) and 4855 deaths occurred. Life expectancy rose by 10.1 years (men) to 11.9 years (women) across the 3 epochs. There were 1085 ASCVD events over the course of 91 330 person-years in epoch 1, 1330 ASCVD events over the course of 107 450 person years in epoch 2, and 775 ASCVD events over the course of 119 069 person-years in epoch 3. The mean age at onset of first ASCVD event was greater in the third epoch by 8.1 years (men) to 10.3 years (women) compared with the first epoch. The RLR of ASCVD from 45 years of age declined from 43.7% in epoch 1 to 28.1% in epoch 3 (P<0.0001), a finding that was consistent in both sexes (RLR [epoch 1 versus epoch 3], 36.3% versus 26.5% [women]; 52.5% versus 30.1% [men]; P<0.001 for both). The lower RLR of ASCVD in the last 2 epochs was observed consistently across body mass index, blood pressure, cholesterol, diabetes, smoking, and Framingham risk score strata (P<0.001 for all). The RLR of coronary heart disease events and stroke declined in both sexes (P<0.001). Conclusions: Over the past 6 decades, mean life expectancy increased and the RLR of ASCVD decreased in the community based, predominantly White Framingham study. The residual burden of ASCVD underscores the importance of continued and effective primary prevention efforts with better screening for risk factors and their effective treatment.




Circulation: 18 Apr 2022; epub ahead of print
Vasan RS, Enserro DM, Xanthakis V, Beiser AS, Seshadri S
Circulation: 18 Apr 2022; epub ahead of print | PMID: 35430874
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Impact:
Abstract

Cardiac Resident Macrophage-derived Legumain Improves Cardiac Repair via Promoting Clearance and Degradation of Apoptotic Cardiomyocytes after Myocardial Infarction.

Jia D, Chen S, Bai P, Luo C, ... Sun A, Ge J
Background: Cardiac resident macrophages are self-maintaining that originate from embryonic hematopoiesis. After myocardial infarction (MI), cardiac resident macrophages are responsible for the efficient clearance and degradation of apoptotic cardiomyocytes (efferocytosis). This process is required for inflammation resolution and tissue repair; however, the underlying molecular mechanisms remain unknown. Therefore, we aimed to identify the mechanisms of the continued clearance and degradation of phagolysosomal cargo by cardiac resident macrophages during MI.
Methods:
Multiple transgenic mice such us Lgmn-/-, Lgmn F/F; LysMCre, LgmnF/F; Cx3cr1CreER, LgmnF/F; LyveCre, and cardiac macrophage Lgmn overexpression by adenovirus gene transfer were used to determine the functional significance of Lgmn in MI. Immune cell filtration and inflammation were examined by flow cytometry and quantitative real-time polymerase chain reaction (qPCR). Moreover, Lgmn expression was analyzed by immunohistochemistry and qPCR in the cardiac tissues of patients with ischemic cardiomyopathy and healthy controls.
Results:
We identified legumain (Lgmn) as a gene specifically expressed by cardiac resident macrophages. Lgmn deficiency resulted in a considerable exacerbation in cardiac function, accompanied with the accumulation of apoptotic cardiomyocytes and a reduced index of in vivo efferocytosis in the border area. It also led to decreased cytosolic calcium due to defective intracellular calcium mobilization. Furthermore, the formation of LC3-II-dependent phagosome around secondary-encountered apoptotic cardiomyocytes was disabled. In addition, Lgmn deficiency increased infiltration of MHC-IIhigh CCR2+ macrophages and the enhanced recruitment of MHC-IIlow CCR2+ monocytes with downregulation of anti-inflammatory mediators, IL-10 and TGF-β; and upregulation proinflammatory mediators, IL-1β, TNF-α, IL-6, and IFN-γ. Conclusions: Our results directly link efferocytosis to wound healing in the heart and identify Lgmn as a significant link between acute inflammation resolution and organ function.




Circulation: 18 Apr 2022; epub ahead of print
Jia D, Chen S, Bai P, Luo C, ... Sun A, Ge J
Circulation: 18 Apr 2022; epub ahead of print | PMID: 35430895
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Impact:
Abstract

Deep Lipidomics in Human Plasma - Cardiometabolic Disease Risk and Effect of Dietary Fat Modulation.

Eichelmann F, Sellem L, Wittenbecher C, Jäger S, ... Lovegrove JA, Schulze MB
Background: In blood and tissues, dietary and endogenously generated fatty acids (FAs) occur in free form or as part of complex lipid molecules that collectively represent the lipidome of the respective tissue. We assessed associations of plasma lipids derived from high-resolution lipidomics with incident cardiometabolic diseases and subsequently tested if the identified risk-associated lipids were sensitive to dietary fat modification.
Methods:
The European Prospective Investigation into Cancer and Nutrition (EPIC) Potsdam cohort study comprises 27,548 participants recruited within an age-range of 35-65 years from the general population around Potsdam, Germany. We generated two disease-specific case-cohorts based on a fixed random subsample (n=1,262) and all respective cohort-wide identified incident primary cardiovascular disease (CVD, composite of fatal and non-fatal myocardial infarction and stroke) (n=551) and type 2 diabetes (T2D) (n=775) cases. We estimated the associations of baseline plasma concentrations of 282 class-specific FA abundances (calculated from 940 distinct molecular species across 15 lipid classes) with the outcomes in multivariable-adjusted Cox models. We tested the effect of an isoenergetic dietary fat modification on risk-associated lipids in The Dietary Intervention and VAScular function randomized controlled trial (DIVAS) (n=113). Participants consumed either a diet rich in saturated FAs (control), monounsaturated FAs, or a mixture of monounsaturated and n-6 polyunsaturated FAs for 16 weeks.
Results:
69 lipids associated (false discovery rate (FDR) <0.05) with at least one outcome (both=8, only CVD=49, only T2D=12). In brief, several monoacylglycerols and FA16:0 and FA18:0 in diacylglycerols were associated with both outcomes, cholesteryl esters, free fatty acids, and sphingolipids were largely CVD-specific, and several (glycero)phospholipids T2D-specific. In addition, nineteen risk-associated lipids were affected (FDR<0.05) by the diets rich in unsaturated dietary FAs compared to the saturated fat diet (17 in a direction consistent with a potential beneficial effect on long-term cardiometabolic risk). For example, the monounsaturated FA-rich diet decreased DG(FA16:0) by 0.4 (95%-CI:0.5,0.3) SD-units and increased TG(FA22:1) by 0.5 (95%-CI:0.4,0.7) SD-units. Conclusions: We identified several lipids associated with cardiometabolic disease risk. A subset was beneficially altered by a dietary fat intervention, which supports substitution of dietary saturated FAs with unsaturated FAs as a potential tool for primary disease prevention.




Circulation: 15 Apr 2022; epub ahead of print
Eichelmann F, Sellem L, Wittenbecher C, Jäger S, ... Lovegrove JA, Schulze MB
Circulation: 15 Apr 2022; epub ahead of print | PMID: 35422138
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Impact:
Abstract

Novel CaMKII-δ Inhibitor Hesperadin Exerts Dual Functions to Ameliorate Cardiac Ischemia/Reperfusion Injury and Inhibit Tumor Growth.

Zhang J, Liang R, Wang K, Zhang W, ... Lei X, Zhang Y
Background
Cardiac ischemia/reperfusion (I/R) injury has emerged as an important therapeutic target for ischemic heart disease, the leading cause of morbidity and mortality worldwide. At present, there is no effective therapy for reducing cardiac I/R injury. CaMKII (Ca2+/calmodulin-dependent kinase II) plays a pivotal role in the pathogenesis of severe heart conditions, including I/R injury. Pharmacological inhibition of CaMKII is an important strategy in the protection against myocardial damage and cardiac diseases. To date, there is no drug targeting CaMKII for the clinical therapy of heart disease. Furthermore, at present, there is no selective inhibitor of CaMKII-δ, the major CaMKII isoform in the heart.
Methods
A small-molecule kinase inhibitor library and a high-throughput screening system for the kinase activity assay of CaMKII-δ9 (the most abundant CaMKII-δ splice variant in human heart) were used to screen for CaMKII-δ inhibitors. Using cultured neonatal rat ventricular myocytes, human embryonic stem cell-derived cardiomyocytes, and in vivo mouse models, in conjunction with myocardial injury induced by I/R (or hypoxia/reoxygenation) and CaMKII-δ9 overexpression, we sought to investigate the protection of hesperadin against cardiomyocyte death and cardiac diseases. BALB/c nude mice with xenografted tumors of human cancer cells were used to evaluate the in vivo antitumor effect of hesperadin.
Results
Based on the small-molecule kinase inhibitor library and screening system, we found that hesperadin, an Aurora B kinase inhibitor with antitumor activity in vitro, directly bound to CaMKII-δ and specifically blocked its activation in an ATP-competitive manner. Hesperadin functionally ameliorated both I/R- and overexpressed CaMKII-δ9-induced cardiomyocyte death, myocardial damage, and heart failure in both rodents and human embryonic stem cell-derived cardiomyocytes. In addition, in an in vivo BALB/c nude mouse model with xenografted tumors of human cancer cells, hesperadin delayed tumor growth without inducing cardiomyocyte death or cardiac injury.
Conclusions
Here, we identified hesperadin as a specific small-molecule inhibitor of CaMKII-δ with dual functions of cardioprotective and antitumor effects. These findings not only suggest that hesperadin is a promising leading compound for clinical therapy of cardiac I/R injury and heart failure, but also provide a strategy for the joint therapy of cancer and cardiovascular disease caused by anticancer treatment.



Circulation: 12 Apr 2022; 145:1154-1168
Zhang J, Liang R, Wang K, Zhang W, ... Lei X, Zhang Y
Circulation: 12 Apr 2022; 145:1154-1168 | PMID: 35317609
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Impact:
Abstract

Prevalence, Characteristics, and Outcomes of COVID-19-Associated Acute Myocarditis.

Ammirati E, Lupi L, Palazzini M, Hendren NS, ... de Lemos JA, Metra M
Background
Acute myocarditis (AM) is thought to be a rare cardiovascular complication of COVID-19, although minimal data are available beyond case reports. We aim to report the prevalence, baseline characteristics, in-hospital management, and outcomes for patients with COVID-19-associated AM on the basis of a retrospective cohort from 23 hospitals in the United States and Europe.
Methods
A total of 112 patients with suspected AM from 56 963 hospitalized patients with COVID-19 were evaluated between February 1, 2020, and April 30, 2021. Inclusion criteria were hospitalization for COVID-19 and a diagnosis of AM on the basis of endomyocardial biopsy or increased troponin level plus typical signs of AM on cardiac magnetic resonance imaging. We identified 97 patients with possible AM, and among them, 54 patients with definite/probable AM supported by endomyocardial biopsy in 17 (31.5%) patients or magnetic resonance imaging in 50 (92.6%). We analyzed patient characteristics, treatments, and outcomes among all COVID-19-associated AM.
Results
AM prevalence among hospitalized patients with COVID-19 was 2.4 per 1000 hospitalizations considering definite/probable and 4.1 per 1000 considering also possible AM. The median age of definite/probable cases was 38 years, and 38.9% were female. On admission, chest pain and dyspnea were the most frequent symptoms (55.5% and 53.7%, respectively). Thirty-one cases (57.4%) occurred in the absence of COVID-19-associated pneumonia. Twenty-one (38.9%) had a fulminant presentation requiring inotropic support or temporary mechanical circulatory support. The composite of in-hospital mortality or temporary mechanical circulatory support occurred in 20.4%. At 120 days, estimated mortality was 6.6%, 15.1% in patients with associated pneumonia versus 0% in patients without pneumonia (P=0.044). During hospitalization, left ventricular ejection fraction, assessed by echocardiography, improved from a median of 40% on admission to 55% at discharge (n=47; P<0.0001) similarly in patients with or without pneumonia. Corticosteroids were frequently administered (55.5%).
Conclusions
AM occurrence is estimated between 2.4 and 4.1 out of 1000 patients hospitalized for COVID-19. The majority of AM occurs in the absence of pneumonia and is often complicated by hemodynamic instability. AM is a rare complication in patients hospitalized for COVID-19, with an outcome that differs on the basis of the presence of concomitant pneumonia.



Circulation: 12 Apr 2022; 145:1123-1139
Ammirati E, Lupi L, Palazzini M, Hendren NS, ... de Lemos JA, Metra M
Circulation: 12 Apr 2022; 145:1123-1139 | PMID: 35404682
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Impact:
Abstract

MicroRNA-210 Controls Mitochondrial Metabolism and Protects Heart Function in Myocardial Infarction.

Song R, Dasgupta C, Mulder C, Zhang L
Background
Ischemic heart disease remains a leading cause of death worldwide. In this study, we test the hypothesis that microRNA-210 protects the heart from myocardial ischemia-reperfusion (IR) injury by controlling mitochondrial bioenergetics and reactive oxygen species (ROS) flux.
Methods
Myocardial infarction in an acute setting of IR was examined through comparing loss- versus gain-of-function experiments in microRNA-210-deficient and wild-type mice. Cardiac function was evaluated by echocardiography. Myocardial mitochondria bioenergetics was examined using a Seahorse XF24 Analyzer.
Results
MicroRNA-210 deficiency significantly exaggerated cardiac dysfunction up to 6 weeks after myocardial IR in male, but not female, mice. Intravenous injection of microRNA-210 mimic blocked the effect and recovered the increased myocardial IR injury and cardiac dysfunction. Analysis of mitochondrial metabolism revealed that microRNA-210 inhibited mitochondrial oxygen consumption, increased glycolytic activity, and reduced mitochondrial ROS flux in the heart during IR injury. Inhibition of mitochondrial ROS with MitoQ consistently reversed the effect of microRNA-210 deficiency. Mechanistically, we showed that mitochondrial glycerol-3-phosphate dehydrogenase is a novel target of microRNA-210 in the heart, and loss-of-function and gain-of-function experiments revealed that glycerol-3-phosphate dehydrogenase played a key role in the microRNA-210-mediated effect on mitochondrial metabolism and ROS flux in the setting of heart IR injury. Knockdown of glycerol-3-phosphate dehydrogenase negated microRNA-210 deficiency-induced increases in mitochondrial ROS production and myocardial infarction and improved left ventricular fractional shortening and ejection fraction after the IR treatment.
Conclusions
MicroRNA-210 targeting glycerol-3-phosphate dehydrogenase controls mitochondrial bioenergetics and ROS flux and improves cardiac function in a murine model of myocardial infarction in the setting of IR injury. The findings suggest new insights into the mechanisms and therapeutic targets for treatment of ischemic heart disease.



Circulation: 12 Apr 2022; 145:1140-1153
Song R, Dasgupta C, Mulder C, Zhang L
Circulation: 12 Apr 2022; 145:1140-1153 | PMID: 35296158
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Impact:
Abstract

Rewiring of 3D Chromatin Topology Orchestrates Transcriptional Reprogramming and the Development of Human Dilated Cardiomyopathy.

Feng Y, Cai L, Hong W, Zhang C, ... Huang W, Jiang L
Background: Transcriptional reconfiguration is central to heart failure, the common cause of which is dilated cardiomyopathy (DCM). However, the impact of three-dimensional (3D) chromatin topology on transcriptional dysregulation and pathogenesis in human DCM remains elusive.
Methods:
We generated a compendium of 3D-epigenome and transcriptome maps from 101 biobanked human DCM and non-failing heart tissues through HiChIP (H3K27ac), in situ Hi-C, ChIP-seq, ATAC-seq and RNA-seq profiling. We employed human iPSC-derived cardiomyocytes (hiPSC-CMs) and mouse models to further interrogate the key transcription factor implicated in 3D chromatin organization and transcriptional regulation in DCM pathogenesis.
Results:
We discovered that the active regulatory elements (H3K27ac peaks) and their connectome (H3K27ac loops) were extensively reprogrammed in DCM hearts and contributed to transcriptional dysregulation implicated for DCM development. For example, we identified that non-transcribing NPPA-AS1 promoter functions as an enhancer and physically interacts with the NPPA and NPPB promoters, leading to the co-transcription of NPPA and NPPB in DCM hearts. We uncovered that DCM-enriched H3K27ac loops largely resided in conserved high-order chromatin architectures (Compartments, Topologically Associating Domains) and unexpectedly their anchors had equivalent chromatin accessibility. Intriguingly, we discovered that the DCM-enriched H3K27ac loop anchors exhibited a strong enrichment for Heart and Neural Crest Derivatives Expressed 1 (HAND1), a key transcription factor involved in early cardiogenesis. In line with this, its protein expression was upregulated in human DCM and mouse failing hearts. To further validate whether HAND1 is a causal driver for the reprogramming of enhancer/promoter connectome in DCM hearts, we performed comprehensive 3D epigenome mappings in hiPSC-CMs. We found that forced overexpression of HAND1 in hiPSC-CM induced a distinct gain of enhancer/promoter connectivity and, correspondingly, increased the expression of their connected genes implicated in DCM etiology, thus recapitulating the transcriptional signature in human DCM hearts. Moreover, electrophysiology analysis demonstrated that forced overexpression of HAND1 in hiPSC-CM induced abnormal calcium handling. Furthermore, cardiomyocyte-specific overexpression of Hand1 in the mouse hearts resulted in a dilated cardiac remodeling with impaired contractility/Ca2+ handling in cardiomyocytes, increased ratio of heart weight/body weight and compromised cardiac function, which were ascribed to recapitulation of transcriptional reprogramming in DCM. Conclusions: This study provided novel chromatin topology insights into DCM pathogenesis and illustrated a model whereby a single transcription factor (HAND1) reprograms the genome-wide enhancer/promoter connectome to drive DCM pathogenesis.




Circulation: 11 Apr 2022; epub ahead of print
Feng Y, Cai L, Hong W, Zhang C, ... Huang W, Jiang L
Circulation: 11 Apr 2022; epub ahead of print | PMID: 35400201
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Impact:
Abstract

Computational Analysis of Routine Biopsies Improves Diagnosis and Prediction of Cardiac Allograft Vasculopathy.

Peyster EG, Janowczyk A, Swamidoss A, Kethireddy S, Feldman MD, Margulies KB
Background: Cardiac allograft vasculopathy (CAV) is a leading cause of morbidity and mortality for heart transplant recipients. While clinical risk factors for CAV have been established, no personalized prognostic test exists to confidently identify patients at high vs. low risk of developing aggressive CAV. The aim of this investigation was to leverage computational methods for analyzing digital pathology images from routine endomyocardial biopsies (EMB) to develop a precision medicine tool for predicting CAV years before overt clinical presentation.
Methods:
Clinical data from 1-year post-transplant was collected on 302 transplant recipients from the University of Pennsylvania, including 53 \'early CAV\' patients and 249 \'no-CAV\' controls. This data was used to generate a \'clinical model\' (ClinCAV-Pr) for predicting future CAV development. From this cohort, n=183 archived EMBs were collected for CD31 and modified trichrome staining and then digitally scanned. These included 1-year post-transplant EMBs from 50 \'early CAV\' patients and 82 no-CAV patients, as well as 51 EMBs from \'disease control\' patients obtained at the time of definitive coronary angiography confirming CAV. Using biologically-inspired, hand-crafted features extracted from digitized EMBs, quantitative histologic models for differentiating no-CAV from disease controls (HistoCAV-Dx), and for predicting future CAV from 1-year post-transplant EMBs were developed (HistoCAV-Pr). The performance of histologic and clinical models for predicting future CAV (i.e. HistoCAV-Pr and ClinCAV-Pr, respectively) were compared in a held-out validation set, before being combined to assess the added predictive value of an integrated predictive model (iCAV-Pr).
Results:
ClinCAV-Pr achieved modest performance on the independent test set, with area under the receiver operating curve (AUROC) of 0.70. The HistoCAV-Dx model for diagnosing CAV achieved excellent discrimination, with an AUROC of 0.91, while HistoCAV-Pr model for predicting CAV achieved good performance with an AUROC of 0.80. The integrated iCAV-Pr model achieved excellent predictive performance, with an AUROC of 0.93 on the held-out test set. Conclusions: Prediction of future CAV development is greatly improved by incorporation of computationally extracted histologic features. These results suggest morphologic details contained within regularly obtained biopsy tissue have the potential to enhance precision and personalization of treatment plans for post-heart transplant patients.




Circulation: 11 Apr 2022; epub ahead of print
Peyster EG, Janowczyk A, Swamidoss A, Kethireddy S, Feldman MD, Margulies KB
Circulation: 11 Apr 2022; epub ahead of print | PMID: 35405081
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Impact:
Abstract

SARS-CoV-2 Infection and Associated Cardiovascular Manifestations and Complications in Children and Young Adults: A Scientific Statement From the American Heart Association.

Jone PN, John A, Oster ME, Allen K, ... American Heart Association Leadership Committee and Congenital Cardiac Defects Committee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Hypertension, and Council on Peripheral Vascular Disease
Coronavirus disease 2019 (COVID-19) resulted in a global pandemic and has overwhelmed health care systems worldwide. In this scientific statement, we describe the epidemiology, pathophysiology, clinical presentations, treatment, and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and multisystem inflammatory syndrome in children and young adults with a focus on cardiovascular manifestations and complications. We review current knowledge about the health consequences of this illness in children and young adults with congenital and acquired heart disease, the public health burden and health disparities of this infection in these populations, and vaccine-associated myocarditis.



Circulation: 11 Apr 2022:101161CIR0000000000001064; epub ahead of print
Jone PN, John A, Oster ME, Allen K, ... American Heart Association Leadership Committee and Congenital Cardiac Defects Committee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Hypertension, and Council on Peripheral Vascular Disease
Circulation: 11 Apr 2022:101161CIR0000000000001064; epub ahead of print | PMID: 35400169
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Impact:
Abstract

Sodium-glucose Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People with Type 2 diabetes: A Meta-analysis of Individual Participant Data from Randomized Controlled Trials.

Neuen BL, Oshima M, Agarwal R, Arnott C, ... Zinman B, Heerspink HJL
Background: Hyperkalemia increases risk of cardiac arrhythmias and death and limits the use of renin-angiotensin-aldosterone system (RAAS) inhibitors and mineralocorticoid receptor antagonists (MRAs), which improve clinical outcomes in people with chronic kidney disease (CKD) and/or systolic heart failure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiorenal events in people with type 2 diabetes at high cardiovascular risk or with CKD. However, their effect on hyperkalemia has not been systematically evaluated.
Methods:
A meta-analysis was conducted using individual participant data from randomized, double-blind, placebo-controlled clinical outcome trials with SGLT2 inhibitors in people with type 2 diabetes at high cardiovascular risk and/or with CKD, in which serum potassium levels were routinely measured. The primary outcome was time to serious hyperkalemia, defined as central laboratory determine serum potassium ≥6.0 mmol/L, with other outcomes including investigator-reported hyperkalemia events and hypokalemia (serum potassium ≤3.5 mmol/L). Cox regression analyses were performed to estimate treatment effects from each trial with hazards ratios (HR) and corresponding 95% CI pooled using random effects models to obtain summary treatment effects, overall and across key subgroups.
Results:
Results from six trials were included comprising 49,875 participants assessing four SGLT2 inhibitors. 1,754 participants developed serious hyperkalemia and an additional 1,119 investigator-reported hyperkalemia events were recorded. SGLT2 inhibitors reduced the risk of serious hyperkalemia (HR 0.84, 95% CI 0.76-0.93), an effect consistent across studies (P-heterogeneity=0.71). The incidence of investigator-reported hyperkalemia was also lower with SGLT2 inhibitors (HR 0.80, 95% CI 0.68-0.93; P-heterogeneity=0.21). Reductions in serious hyperkalemia were observed across a range of subgroups including baseline kidney function, history of heart failure, RAAS inhibitor, diuretic and MRA use. SGLT2 inhibitors did not increase the risk of hypokalemia (HR 1.04, 95% CI 0.94-1.15; P-heterogeneity=0.42). Conclusions: SGLT2 inhibitors reduce the risk of serious hyperkalemia in people with type 2 diabetes at high cardiovascular risk and/or with CKD, without increasing the risk of hypokalemia.




Circulation: 08 Apr 2022; epub ahead of print
Neuen BL, Oshima M, Agarwal R, Arnott C, ... Zinman B, Heerspink HJL
Circulation: 08 Apr 2022; epub ahead of print | PMID: 35394821
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Impact:
Abstract

Association of Bleeding Severity with Mortality in Extended Thromboprophylaxis of Medically Ill Patients in the MAGELLAN and MARINER Trials.

Spyropoulos AC, Raskob GE, Cohen AT, Ageno W, ... Sugarmann C, Barnathan ES
Background: Extended thromboprophylaxis has not been widely implemented in acutely ill medical patients due to bleeding concerns. The MAGELLAN and MARINER trials evaluated whether rivaroxaban compared with enoxaparin or placebo could prevent venous thromboembolism (VTE) without increased bleeding. We hypothesized that patients with major bleeding (MB) but not those with non-major clinically relevant bleeding (NMCRB), would be at an increased risk of all-cause mortality (ACM).
Methods:
We evaluated all bleeding events in patients taking at least one dose of study drug and their association with ACM in 4 mutually exclusive groups: (1) no bleeding, or first event was (2) NMCRB, (3) MB, or (4) trivial bleeding. Using a Cox proportional hazards model adjusted for differences in baseline characteristics associated with ACM, we assessed the risk of ACM after such events.
Results:
Compared to patients with no bleeding, the risk of ACM for patients with NMCRB was not increased in MARINER (HR 0.43, p=0.235) but was increased in MAGELLAN (HR 1.74 p=0.021). MB was associated with a higher incidence of ACM in both studies, while trivial bleeding was not associated with ACM in either study. Conclusions: Patients with MB had an increased risk of ACM, while NMCRB was not consistently associated with an increased risk of death. These results inform the risk-benefit calculus of extended thromboprophylaxis in medically ill patients.




Circulation: 07 Apr 2022; epub ahead of print
Spyropoulos AC, Raskob GE, Cohen AT, Ageno W, ... Sugarmann C, Barnathan ES
Circulation: 07 Apr 2022; epub ahead of print | PMID: 35389229
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Impact:
Abstract

Monogenic and Polygenic Contributions to QTc Prolongation in the Population.

Nauffal V, Morrill VN, Jurgens SJ, Choi SH, ... Ellinor PT, Lubitz SA
Background: Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variation to the QT interval in the population.
Methods:
We performed a genome wide association study (GWAS) of the QTc in 84,630 United Kingdom Biobank (UKB) participants and created a polygenic risk score (PRS). Among 26,976 participants with whole genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed.
Results:
Fifty-four independent loci were identified by GWAS in the UKB. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS comprising 1,110,494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/decile of PRS = 1.4 ms, 95% CI 1.3 -1.5; p-value=1.1×10-196). Carriers of putative pathogenic rare variants had longer QTc than non-carriers (ΔQTc=10.9 ms [7.4-14.4]). 23.7% of individuals with QTc>480 ms carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). Conclusions: QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.




Circulation: 07 Apr 2022; epub ahead of print
Nauffal V, Morrill VN, Jurgens SJ, Choi SH, ... Ellinor PT, Lubitz SA
Circulation: 07 Apr 2022; epub ahead of print | PMID: 35389749
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Impact:
Abstract

Skeletal Muscle Disorders: A Non-cardiac Source of Cardiac Troponin T.

du Fay de Lavallaz J, Prepoudis A, Wendebourg MJ, Kesenheimer E, ... Mueller C, BASEL XII Investigators
Background: Cardiac troponin T (cTnT) and cTnI are considered cardiac-specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a non-cardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMD).
Methods:
We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in four hospitals in two countries. After cardiac work-up, patients were adjudicated into three predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed using high-sensitivity cTnT (hs-cTnT-Elecsys) and three hs-cTnI assays (hs-cTnI-Architect, hs-cTnI-Access, hs-cTnI-Vista), and compared to controls without SMD presenting with adjudicated non-cardiac chest pain to the emergency department (n=3508, mean age 55y, 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared to biopsies obtained in controls without SMD.
Results:
Among 211 patients (mean age 57y, 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) mild and 59 (28%) severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no versus mild versus severe cardiac disease for all assays (all p<0.001). hs-cTnT-Elecsys concentrations were significantly higher in patients with SMD versus controls (median 16ng/L (IQR 7-32.5) versus 5ng/L (IQR 3-9), p<0.001) while hs-cTnI concentrations were mostly similar (hs-cTnI-Architect 2.5ng/L (IQR 1.2-6.2) versus 2.9ng/L (IQR 1.8-5.0), hs-cTnI-Access 3.3ng/L (IQR 2.4-6.1) versus 2.7ng/L (IQR 1.6-5.0) and hs-cTnI-Vista 7.4ng/L (IQR 5.2-13.4) versus 7.5ng/L (IQR 6-10)). hs-cTnT-Elecsys concentrations were above the upper-limit of normal (ULN) in 55% of patients with SMD vs 13% of controls (p<0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from non-inflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2, encoding cTnT (but none for TNNI3, encoding cTnI); versus controls (n=16, pWald <0.001), the expression correlated with pathological disease activity (R=0.59, pt-statistic <0.001) and circulating hs-cTnT concentrations (R=0.26, pt-statistic =0.031). Conclusions: In patients with active chronic SMD, elevations in cTnT concentrations are common and not due to cardiac disease in the majority. This was not observed for cTnI, and may in part be explained by re-expression of cTnT in skeletal muscle.




Circulation: 07 Apr 2022; epub ahead of print
du Fay de Lavallaz J, Prepoudis A, Wendebourg MJ, Kesenheimer E, ... Mueller C, BASEL XII Investigators
Circulation: 07 Apr 2022; epub ahead of print | PMID: 35389756
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Impact:
Abstract

Genetic Landscape of the ACE2 Coronavirus Receptor.

Yang Z, MacDonald-Dunlop E, Chen J, Zhai R, ... Shen X, GenOMICC Consortium and the IMI-DIRECT Consortium
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, enters human cells using the angiotensin-converting enzyme 2 (ACE2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart, respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biologic systems. However, the genetic basis of the ACE2 protein levels is not well understood.
Methods:
We conduct so far the largest genome-wide association meta-analysis of plasma ACE2 levels in over 28,000 individuals of the SCALLOP Consortium. We summarize the cross-sectional epidemiologic correlates of circulating ACE2. Using the summary-statistics-based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 disease severity using Mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data.
Results:
We identified ten loci, including eight novel, capturing 30% of the protein\'s heritability. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis-pQTL-based Mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio (OR), 1.63; 95% CI, 1.10 to 2.42; P = 0.01), hospitalization (OR, 1.52; 95% CI, 1.05 to 2.21; P = 0.03), and infection (OR, 1.60; 95% CI, 1.08 to 2.37; P = 0.02). Tissue- and cell-type-specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells. Conclusions: Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.




Circulation: 07 Apr 2022; epub ahead of print
Yang Z, MacDonald-Dunlop E, Chen J, Zhai R, ... Shen X, GenOMICC Consortium and the IMI-DIRECT Consortium
Circulation: 07 Apr 2022; epub ahead of print | PMID: 35387486
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Impact:
Abstract

A Randomized Trial of Chocolate Touch Compared with Lutonix Drug-Coated Balloon in Femoropopliteal Lesions (The CHOCOLATE TOUCH Study).

Shishehbor MH, Zeller T, Werner M, Brodmann M, ... Wali AU, Lansky AJ
Background
First-generation drug-coated balloons (DCBs) have significantly reduced the rate of restenosis compared with balloon angioplasty alone; however, high rates of bailout stenting and dissections persist. The Chocolate Touch DCB is a nitinol constrained balloon designed to reduce acute vessel trauma and inhibit neointima formation and restenosis.
Methods
Patients with claudication or ischemic rest pain (Rutherford class 2-4) and superficial femoral or popliteal disease (≥70% stenosis) were randomized 1:1 to Chocolate Touch or Lutonix DCB at 34 sites in the United States, Europe, and New Zealand. The primary efficacy endpoint was DCB success defined as primary patency at 12 months (peak systolic velocity ratio <2.4 by duplex ultrasound without clinically driven target lesion revascularization in the absence of clinically driven bailout stenting). The primary safety endpoint was freedom from major adverse events at 12 months, a composite of target limb-related death, major amputation, or re-intervention. Both primary endpoints were tested for non-inferiority, and if met, sequential superiority testing for efficacy followed by safety was prespecified. An independent clinical event committee, angiographic and duplex ultrasound core laboratories blinded to treatment allocation reviewed all endpoints.
Results
A total of 313 patients were randomized to Chocolate Touch (n=152) versus Lutonix DCB (n=161). Follow-up at 1 year was available in 94% of patients. Mean age was 69.4±9.5 years, the average lesion length was 78.1±46.9 mm, and 46.2% had moderate-to-severe calcification. The primary efficacy rates of DCB success at 12 months was 78.8% (108/137) with Chocolate Touch and 67.7% (88/130) with Lutonix DCB (difference 11. %; 95% confidence interval [CI] 0.6-21.7), meeting non-inferiority (Pnon-inferiority<0.0001) and sequential superiority (Psuperiority=0.04). The primary safety event rate was 88.9% (128/144) with Chocolate Touch and 84.6% (126/149) with Lutonix DCB (Pnon-inferiority<0.001, Psuperiority=0.27).
Conclusions
In this prospective, multicenter, randomized trial, the second-generation Chocolate Touch DCB met both non-inferiority endpoints for efficacy and safety and was more effective than Lutonix DCB at 12 months for the treatment of femoropopliteal disease.



Circulation: 04 Apr 2022; epub ahead of print
Shishehbor MH, Zeller T, Werner M, Brodmann M, ... Wali AU, Lansky AJ
Circulation: 04 Apr 2022; epub ahead of print | PMID: 35377157
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Impact:
Abstract

Edoxaban versus Dual Antiplatelet Therapy for Leaflet Thrombosis and Cerebral Thromboembolism after TAVR: The ADAPT-TAVR Randomized Clinical Trial.

Park DW, Ahn JM, Kang DY, Kim KW, ... Lee JH, Park SJ
Background: It is unknown whether direct oral anticoagulant edoxaban can reduce leaflet thrombosis and the accompanying cerebral thromboembolic risk after transcatheter aortic-valve replacement (TAVR). Also, the causal relationship of subclinical leaflet thrombosis with cerebral thromboembolism and neurological or neurocognitive dysfunction remains unclear.
Methods:
We conducted a multicenter, open-label randomized trial comparing edoxaban with dual antiplatelet therapy (DAPT; aspirin plus clopidogrel) in patients who had undergone successful TAVR and did not have an indication for anticoagulation. The primary end point was an incidence of leaflet thrombosis on four-dimensional computed tomography (CT) at 6-month. Key secondary end points were the number and volume of new cerebral lesions on brain magnetic resonance imaging (MRI) and the serial changes of neurological and neurocognitive function between 6-month and immediate post-TAVR.
Results:
A total of 229 patients were included in the final intention-to-treat population. There was a trend toward a lower incidence of leaflet thrombosis in the edoxaban group than in the DAPT group (9.8% vs. 18.4%; absolute difference, -8.5%; 95% confidence interval [CI], -17.8% to 0.8%; P=0.076). The percentage of patients with new cerebral lesions on brain MRI (edoxaban vs. DAPT; 25.0% vs. 20.2%; difference, 4.8%; 95% CI, -6.4% to 16.0%) and median total new lesion number and volume were not different between two groups. Also, the percentages of patients with worsening of neurological and neurocognitive function were not different among the groups. The incidence of any or major bleeding events were not different between two groups. We found no significant association of the presence or extent of leaflet thrombosis with new cerebral lesions and a change of neurological or neurocognitive function. Conclusions: In patients without an indication for long-term anticoagulation after successful TAVR, the incidence of leaflet thrombosis was numerically lower with edoxaban than with DAPT, but this was not statistically significant. The effect on new cerebral thromboembolism and neurological or neurocognitive function were also not different between two groups. Because the study was underpowered, the results should be considered hypothesis-generating, highlighting the need for further research.




Circulation: 04 Apr 2022; epub ahead of print
Park DW, Ahn JM, Kang DY, Kim KW, ... Lee JH, Park SJ
Circulation: 04 Apr 2022; epub ahead of print | PMID: 35373583
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Impact:
Abstract

Effects of Empagliflozin on Symptoms, Physical Limitations and Quality of Life in Patients Hospitalized for Acute Heart Failure - Results From the EMPULSE Trial.

Kosiborod MN, Angermann CE, Collins SP, Teerlink JR, ... Salsali A, Voors AA
Background: Patients hospitalized for acute heart failure (AHF) experience poor health status, including high burden of symptoms and physical limitations, and poor quality of life. Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve health status in chronic HF, but their impact on these outcomes in AHF are not well characterized. We investigated the effects of the SGLT2 inhibitor empagliflozin on symptoms, physical limitations and quality of life, using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the EMPULSE trial.
Methods:
Patients hospitalized for AHF were randomized to empagliflozin 10 mg daily or placebo for 90 days. The KCCQ was assessed at randomization and 15, 30 and 90 days. The effects of empagliflozin on the primary endpoint of clinical benefit (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in KCCQ Total Symptom Score (TSS) change from baseline to 90 days) were examined post hoc across the tertiles of baseline KCCQ-TSS. In pre-specified analyses, changes (randomization to Day 90) in KCCQ domains, including TSS, Physical Limitations (PLS), quality of life (QoL), clinical summary (CSS) and overall summary (OSS) scores were evaluated using a repeated measures model.
Results:
In total, 530 patients were randomized (265 each arm). Baseline KCCQ-TSS was low overall (mean, SD; 40.8, 24.0 points). Empagliflozin-treated patients experienced greater clinical benefit across the range of KCCQ-TSS, with no treatment effect heterogeneity (win ratio [95% CIs] from lowest to highest tertile: 1.49 [1.01, 2.20], 1.37 [0.94, 1.99], and 1.48 [1.00, 2.20], respectively; P for interaction=0.94). Beneficial effects of empagliflozin on health status were observed as early as 15 days and persisted through 90 days, at which point empagliflozin-treated patients experienced a greater improvement in KCCQ TSS, PLS, QoL, CSS and OSS (placebo-adjusted mean differences (95% CI): 4.45 (0.32, 8.59), P=0.03; 4.80 (0.00, 9.61), P=0.05; 4.66 (0.32, 9.01), P=0.04; 4.85 (0.77, 8.92), P=0.02; and 4.40 points (0.33, 8.48), P=0.03, respectively). Conclusions: Initiation of empagliflozin in patients hospitalized for AHF produced clinical benefit regardless of the degree of symptomatic impairment at baseline; and improved symptoms, physical limitations and quality of life, with benefits seen as early as 15 days and maintained through 90 days.




Circulation: 04 Apr 2022; epub ahead of print
Kosiborod MN, Angermann CE, Collins SP, Teerlink JR, ... Salsali A, Voors AA
Circulation: 04 Apr 2022; epub ahead of print | PMID: 35377706
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Impact:
Abstract

Does Timing of Ventricular Tachycardia Ablation Affect Prognosis in Patients With an Implantable Cardioverter Defibrillator? Results From the Multicenter Randomized PARTITA Trial.

Della Bella P, Baratto F, Vergara P, Bertocchi P, ... Peretto G, Radinovic A
Background: Optimal timing for catheter ablation of ventricular tachycardia is an important unresolved issue. There are no randomized trials evaluating the benefit of ablation after the first implantable cardioverter defibrillator (ICD) shock.
Methods:
We conducted a 2-phase, prospective, multicenter, randomized clinical trial. Patients with ischemic or nonischemic dilated cardiomyopathy and primary or secondary prevention indication for ICD were enrolled in an initial observational phase until first appropriate shock (phase A). After reconsenting, patients were randomly assigned 1:1 in phase B to immediate ablation (within 2 months from shock delivery) or continuation of standard therapy. The primary end point was a composite of death from any cause or hospitalization for worsening heart failure. Amiodarone intake was not allowed except for documented atrial tachyarrhythmias. On July 23, 2021, phase B of the trial was interrupted as a result of the first interim analysis on the basis of the Bayesian adaptive design.
Results:
Of the 517 patients enrolled in phase A, 154 (30%) had ventricular tachycardia, 56 (11%) received an appropriate shock over a median follow-up of 2.4 years (interquartile range, 1.4-4.4), and 47 of 56 (84%) agreed to participate in phase B. After 24.2 (8.5-24.4) months, the primary end point occurred in 1 of 23 (4%) patients in the ablation group and 10 of 24 (42%) patients in the control group (hazard ratio, 0.11 [95% CI, 0.01-0.85]; P=0.034). The results met the prespecified termination criterion of >99% Bayesian posterior probability of superiority of treatment over standard therapy. No deaths were observed in the ablation group versus 8 deaths (33%) in the control group (P=0.004); there was 1 worsening heart failure hospitalization in the ablation group (4%) versus 4 in the control group (17%; P=0.159). ICD shocks were less frequent in the ablation group (9%) than in the control group (42%; P=0.039). Conclusions: Ventricular tachycardia ablation after first appropriate shock was associated with a reduced risk of the combined death or worsening heart failure hospitalization end point, lower mortality, and fewer ICD shocks. These findings provide support for considering ventricular tachycardia ablation after the first ICD shock.




Circulation: 03 Apr 2022; epub ahead of print
Della Bella P, Baratto F, Vergara P, Bertocchi P, ... Peretto G, Radinovic A
Circulation: 03 Apr 2022; epub ahead of print | PMID: 35369700
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Impact:
Abstract

Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.

Bergmark BA, Marston NA, Bramson CR, Curto M, ... Sabatine MS, Wiviott SD
Background: Genetic loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis.
Methods:
Adults with non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). The primary end point was placebo-adjusted percentage change from baseline in non-HDL-C at 24 weeks. Secondary end points included placebo-adjusted percentage changes from baseline in triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and ANGPTL3.
Results:
Two hundred eighty-six subjects were randomized: 44 to placebo and 242 to vupanorsen. The median age was 64 (interquartile range, 58-69) years, 44% were female, the median non-HDL-C was 132.4 (interquartile range, 118.0-154.1) mg/dL, and the median triglycerides were 216.2 (interquartile range, 181.4-270.4) mg/dL. Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL-C ranging from 22.0% in the 60 mg every 2 weeks arm to 27.7% in the 80 mg every 2 weeks arm (all P<0.001 for all doses). There were dose-dependent reductions in triglycerides that ranged from 41.3% to 56.8% (all P<0.001). The effects on LDL-C and ApoB were more modest (7.9%-16.0% and 6.0%-15.1%, respectively) and without a clear dose-response relationship\' and only the higher reductions achieved statistical significance. ANGPTL3 levels were decreased in a dose-dependent manner by 69.9% to 95.2% (all P<0.001). There were no confirmed instances of significant decline in renal function or platelet count with vupanorsen. Injection site reactions and >3x elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively), and there was a dose-dependent increase in hepatic fat fraction (up to 76%). Conclusions: Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non-HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic f at fraction.




Circulation: 03 Apr 2022; epub ahead of print
Bergmark BA, Marston NA, Bramson CR, Curto M, ... Sabatine MS, Wiviott SD
Circulation: 03 Apr 2022; epub ahead of print | PMID: 35369705
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Impact:
Abstract

Quality of Life After Fractional Flow Reserve-Guided PCI Compared with Coronary Bypass Surgery.

Fearon WF, Zimmermann FM, Ding VY, Zelis JM, ... Hlatky MA, FAME 3 Investigators
Background: Previous studies have shown quality of life improves after coronary revascularization, more so after coronary artery bypass grafting (CABG) than after percutaneous coronary intervention (PCI). This study aimed to evaluate the impact of fractional flow reserve (FFR) guidance and current generation, zotarolimus drug-eluting stents (DES) on quality of life after PCI compared with CABG.
Methods:
The Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) 3 trial is a multicenter, international trial including 1500 patients with three-vessel coronary artery disease (CAD) who were randomly assigned to either CABG or FFR-guided PCI. Quality of life was measured using the European Quality of Life-5 Dimensions (EQ-5D) questionnaire at baseline, 1 and 12 months. The Canadian Cardiovascular Class (CCS) angina grade and working status were assessed at the same time points and at 6 months. The primary objective was to compare EQ-5D summary index at 12 months. Secondary endpoints included angina grade and work status.
Results:
The EQ-5D summary index at 12 months did not differ between the PCI and CABG groups (difference=0.001, 95% confidence interval (CI) -0.016 to 0.017, p=0.946). The trajectory of EQ-5D over the 12 months differed (p<0.001) between PCI and CABG: at 1 month, EQ-5D was 0.063 (95% CI 0.047 to 0.079) higher in the PCI group. A similar trajectory was found for the EQ visual analogue scale. The proportion of patients with CCS 2 or greater angina at 12 months was 6.2% vs 3.1% (OR=2.5, 95% CI 0.96 to 6.8), respectively in the PCI group compared with the CABG group. A greater percentage of younger patients (<65 years-old) were working at 12 months in the PCI group compared with the CABG group (68% vs 57%, OR=3.9, 95% CI 1.7 to 8.8). Conclusions: In the FAME 3 trial, quality of life after FFR-guided PCI with current generation DES compared with CABG was similar at one year. The rate of significant angina was low in both groups and not significantly different. The trajectory of improvement in quality of life was significantly better after PCI, as was working status in those less than 65 years old.




Circulation: 02 Apr 2022; epub ahead of print
Fearon WF, Zimmermann FM, Ding VY, Zelis JM, ... Hlatky MA, FAME 3 Investigators
Circulation: 02 Apr 2022; epub ahead of print | PMID: 35369704
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Impact:
Abstract

Associations of Dietary Cholesterol, Serum Cholesterol, and Egg Consumption With Overall and Cause-Specific Mortality, and Systematic Review and Updated Meta-Analysis.

Zhao B, Gan L, Graubard BI, Männistö S, Albanes D, Huang J
Background: Despite substantial attention underscoring the importance of exogenous dietary and endogenous serum cholesterol to human health, thorough evaluation of the associations is lacking. Our study objective was to examine overall and cause-specific mortality in relation to dietary and serum cholesterol, as well as egg consumption, and conduct an updated meta-regression analysis of cohort studies.
Methods:
We conducted a prospective analysis of 27,078 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Multivariable-controlled cause-specific Cox proportional hazards regression models calculated hazard ratios (HR) and 31-year absolute mortality risk differences (ARD). A systematic review and meta-analysis of cohort studies was also performed (PROSPERO: CRD42021272756).
Results:
Based on 482,316 person-years of follow-up, we identified 22,035 deaths, including 9,110 deaths from cardiovascular disease (CVD). Greater dietary cholesterol and egg consumption were associated with increased risk of overall and CVD mortality. HRs for each additional 300 mg cholesterol intake per day were 1.10 and 1.13 for overall and CVD mortality (respectively), and for each additional 50 g egg consumed daily HRs were 1.06 and 1.09, respectively, for overall and CVD mortality (all P-values<0.0001). After multivariable adjustment, higher serum total cholesterol concentrations were associated with increased risk of CVD mortality (HRs per 1-SD increment: 1.14; P-value<0.0001). The observed associations were generally similar across cohort subgroups. The updated meta-analysis of cohort studies based on 49 risk estimates, 3,601,401 participants, and 255,479 events) showed consumption of one additional 50 g egg daily was associated with significantly increased CVD risk: pooled RR=1.04 (95% CI: 1.00, 1.08); I2=80.1%). In the subgroup analysis of geographical regions (P-value-for-interaction=0.02), an increase of 50 g egg consumed daily was associated with a higher risk of CVD among US cohorts (pooled-RR=1.08, 95% CI: 1.02, 1.14), appeared related to a higher CVD risk in European cohorts with a borderline significance (pooled-RR=1.05), but was not associated with CVD risk in Asian cohorts. Conclusions: In this prospective cohort study and updated meta-analysis, greater dietary cholesterol and egg consumption were associated with increased risk of overall and CVD mortality. Our findings support restricted consumption of dietary cholesterol as a means to improve long-term health and longevity.




Circulation: 01 Apr 2022; epub ahead of print
Zhao B, Gan L, Graubard BI, Männistö S, Albanes D, Huang J
Circulation: 01 Apr 2022; epub ahead of print | PMID: 35360933
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Impact:
Abstract

2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, ... Vest AR, Yancy CW
Aim
The \"2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure\" replaces the \"2013 ACCF/AHA Guideline for the Management of Heart Failure\" and the \"2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure.\" The 2022 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose, and manage patients with heart failure.
Methods
A comprehensive literature search was conducted from May 2020 to December 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from MEDLINE (PubMed), EMBASE, the Cochrane Collaboration, the Agency for Healthcare Research and Quality, and other relevant databases. Additional relevant clinical trials and research studies, published through September 2021, were also considered. This guideline was harmonized with other American Heart Association/American College of Cardiology guidelines published through December 2021. Structure: Heart failure remains a leading cause of morbidity and mortality globally. The 2022 heart failure guideline provides recommendations based on contemporary evidence for the treatment of these patients. The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients\' interests. Many recommendations from the earlier heart failure guidelines have been updated with new evidence, and new recommendations have been created when supported by published data. Value statements are provided for certain treatments with high-quality published economic analyses.



Circulation: 01 Apr 2022:101161CIR0000000000001063; epub ahead of print
Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, ... Vest AR, Yancy CW
Circulation: 01 Apr 2022:101161CIR0000000000001063; epub ahead of print | PMID: 35363499
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Impact:
Abstract

2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, ... Vest AR, Yancy CW
Aim
The \"2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure\" replaces the \"2013 ACCF/AHA Guideline for the Management of Heart Failure\" and the \"2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure.\" The 2022 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose, and manage patients with heart failure.
Methods
A comprehensive literature search was conducted from May 2020 to December 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from MEDLINE (PubMed), EMBASE, the Cochrane Collaboration, the Agency for Healthcare Research and Quality, and other relevant databases. Additional relevant clinical trials and research studies, published through September 2021, were also considered. This guideline was harmonized with other American Heart Association/American College of Cardiology guidelines published through December 2021. Structure: Heart failure remains a leading cause of morbidity and mortality globally. The 2022 heart failure guideline provides recommendations based on contemporary evidence for the treatment of these patients. The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients\' interests. Many recommendations from the earlier heart failure guidelines have been updated with new evidence, and new recommendations have been created when supported by published data. Value statements are provided for certain treatments with high-quality published economic analyses.



Circulation: 01 Apr 2022:101161CIR0000000000001062; epub ahead of print
Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, ... Vest AR, Yancy CW
Circulation: 01 Apr 2022:101161CIR0000000000001062; epub ahead of print | PMID: 35363500
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Impact:
Abstract

Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure.

Borlaug BA, Blair J, Bergmann MW, Bugger H, ... Shah SJ, REDUCE LAP-HF-II investigators
Background: In the REDUCE LAP-HF II trial, implantation of an atrial shunt device did not provide, overall, clinical benefit for patients with heart failure and preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). However, pre-specified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial (RA) volume, and sex. Shunt implantation reduces left atrial (LA) pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). Based upon these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance (PVR) during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit.
Methods:
REDUCE LAP-HF II enrolled 626 patients with HF, EF ≥40%, exercise pulmonary capillary wedge pressure ≥25 mmHg, and resting PVR <3.5 WU who were randomized 1:1 to atrial shunt device or sham control. The primary outcome, a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status, was analyzed using the win ratio. Latent PVD was defined as PVR ≥1.74 WU (highest tertile) at peak exercise, measured prior to randomization.
Results:
Compared to patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated LA pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio 0.60, [95% CI 0.42, 0.86]; p=0.005) and signal of clinical benefit in patients without PVD (win ratio 1.31 [95% CI 1.02, 1.68]; p=0.038). Patients with larger RA volumes and men had worse outcomes with the device, and both groups were more likely to have pacemakers, HFmrEF, and increased LA volume. For patients without latent PVD or pacemaker (n=313, 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio 1.51 [95% CI 1.14, 2.00]; p=0.004). Conclusions: In patients with HFpEF/HFmrEF, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.




Circulation: 31 Mar 2022; epub ahead of print
Borlaug BA, Blair J, Bergmann MW, Bugger H, ... Shah SJ, REDUCE LAP-HF-II investigators
Circulation: 31 Mar 2022; epub ahead of print | PMID: 35354306
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Impact:
Abstract

Takotsubo Syndrome: Pathophysiology, Emerging Concepts, and Clinical Implications.

Singh T, Khan H, Gamble DT, Scally C, Newby DE, Dawson D
Takotsubo syndrome is a condition characterized by acute transient left ventricular systolic dysfunction, which at presentation can be challenging to distinguish from acute myocardial infarction. Although previously thought to be a benign, self-limiting condition, recent studies have confirmed that patients with takotsubo syndrome have persistent subtle ongoing cardiac dysfunction, and many continue to have limiting symptoms despite restoration of left ventricular ejection fraction. Moreover, these patients have a substantial burden of morbidity and mortality, as well, with high rates of subsequent major adverse cardiovascular events that approach those of patients with acute coronary syndrome. The mechanisms behind this condition remain elusive. Despite substantial research, the medical community continues to have an incomplete understanding of its underlying pathogenesis and pathophysiology. Catecholamine-induced myocardial injury is the most established and well-known theory, but this does not explain all the clinical features and presentations of the condition, and numerous other pathways and abnormalities are emerging. Because of the poor understanding of its underlying pathophysiology, there is a lack of evidence-based interventions to treat the acute episode, to avoid recurrences, and to prevent major adverse cardiovascular events. This highlights the need for further research to gain a better understanding of the underlying pathophysiology to inform appropriate randomized controlled trials of interventions targeting the causative pathways. Only then can evidence-based management strategies be established to improve clinical outcomes of this potentially lethal condition.



Circulation: 29 Mar 2022; 145:1002-1019
Singh T, Khan H, Gamble DT, Scally C, Newby DE, Dawson D
Circulation: 29 Mar 2022; 145:1002-1019 | PMID: 35344411
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Impact:
Abstract

Randomized Ablation-Based Rhythm-Control Versus Rate-Control Trial in Patients with Heart Failure and Atrial Fibrillation: Results from the RAFT-AF trial.

Parkash R, Wells GA, Rouleau J, Talajic M, ... Sapp JL, Tang ASL
Background: Atrial fibrillation (AF) and heart failure (HF) frequently coexist and can be challenging to treat. Pharmacologic based rhythm-control of AF has not proven to be superior to rate-control. Ablation-based rhythm-control was compared to rate-control to evaluate if clinical outcomes in patients with HF and AF could be improved.
Methods:
This was a multicenter, open-label trial with blinded outcome evaluation using a central adjudication committee. Patients with high burden paroxysmal (>4 episodes in six months) or persistent (duration < three years) AF, New York Heart Association class II-III HF, and elevated NT-proBNP were randomized to ablation-based rhythm-control or rate-control. The primary outcome was a composite of all-cause mortality and all HF events, with a minimum follow up of two years. Secondary outcomes included left ventricular ejection fraction (LVEF), six-minute walk test and NT-proBNP. Quality of life was measured using the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and the AF Effect on quality of life (AFEQT). The primary analysis was time-to-event using Cox proportional hazards modeling. The trial was stopped early due to a determination of apparent futility by the Data Safety Monitoring Committee.
Results:
From December 1, 2011, to January 20, 2018, 411 patients were randomized to ablation-based rhythm-control (n=214) or rate-control (n=197). The primary outcome occurred in 50 (23.4%) patients in the ablation-based rhythm-control group and 64 (32.5%) patients in the rate-control group (hazard ratio 0.71 95% CI (0.49, 1.03), p=0.066). LVEF increased in the ablation-based group (10.1±1.2% vs 3.8±1.2%, p=0.017); six-minute walk distance improved (44.9±9.1 meters 27.5±9.7 meters, p=0.025) and NT-proBNP demonstrated a decrease (mean change -77.1% vs -39.2%, p<0.0001). MLHFQ demonstrated greater improvement in the ablation-based rhythm-control group (LSMD of -5.4, 95%CI (-10.5, -0.3), p=0.0036), as did the AFEQT score (LSMD of 6.2, 95%CI (1.7, 10.7), p=0.0005). Serious adverse events were observed in 50% of patients in both treatment groups. Conclusions: In patients with high burden AF and HF, there was no statistical difference in all-cause mortality or HF events with ablation-based rhythm-control versus rate-control, however, there was a non-significant trend for improved outcomes with ablation-based rhythm control over rate-control.




Circulation: 22 Mar 2022; epub ahead of print
Parkash R, Wells GA, Rouleau J, Talajic M, ... Sapp JL, Tang ASL
Circulation: 22 Mar 2022; epub ahead of print | PMID: 35313733
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Impact:
Abstract

Understanding the Importance of the Lay Responder Experience in Out-of-Hospital Cardiac Arrest: A Scientific Statement From the American Heart Association.

Dainty KN, Colquitt B, Bhanji F, Hunt EA, ... Swor RA, Panchal A
Bystander cardiopulmonary resuscitation (CPR) is critical to increasing survival from out-of-hospital cardiac arrest. However, the percentage of cases in which an individual receives bystander CPR is actually low, at only 35% to 40% globally. Preparing lay responders to recognize the signs of sudden cardiac arrest, call 9-1-1, and perform CPR in public and private locations is crucial to increasing survival from this public health problem. The objective of this scientific statement is to summarize the most recent published evidence about the lay responder experience of training, responding, and dealing with the residual impact of witnessing an out-of-hospital cardiac arrest. The scientific statement focuses on the experience-based literature of actual responders, which includes barriers to responding, experiences of doing CPR, use of an automated external defibrillator, the impact of dispatcher-assisted CPR, and the potential for postevent psychological sequelae. The large body of qualitative and observational studies identifies several gaps in crucial knowledge that, if targeted, could increase the likelihood that those who are trained in CPR will act. We suggest using the experience of actual responders to inform more contextualized training, including the implications of performing CPR on a family member, dispelling myths about harm, training and litigation, and recognition of the potential for psychologic sequelae after the event.



Circulation: 21 Mar 2022:CIR0000000000001054; epub ahead of print
Dainty KN, Colquitt B, Bhanji F, Hunt EA, ... Swor RA, Panchal A
Circulation: 21 Mar 2022:CIR0000000000001054; epub ahead of print | PMID: 35306832
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Impact:
Abstract

Cost-effectiveness of a Household Salt Substitution Intervention: Findings From 20,995 Participants of the Salt Substitute and Stroke Study (SSaSS).

Li KC, Huang L, Tian M, Di Tanna GL, ... Lung T, Si L
Background:: The Salt Substitute and Stroke Study (SSaSS) ─ a five-year cluster randomized controlled trial, demonstrated that replacing regular salt with a reduced-sodium added-potassium salt substitute reduced the risks of stroke, major adverse cardiovascular events and premature death among individuals with prior stroke or uncontrolled high blood pressure living in rural China. This study assessed the cost-effectiveness profile of the intervention.
Methods:
A within-trial economic evaluation of SSaSS was conducted from the perspective of the healthcare system and consumers. The primary health outcome assessed was stroke and we also quantified effects on quality-adjusted life years (QALYs). Healthcare costs were identified from participant health insurance records and the literature. All costs (Chinese Yuan - CNY ¥) and QALYs were discounted at 5% per annum. Incremental costs, stroke events averted, and QALYs gained were estimated using bivariate multilevel models.
Results:
Mean follow-up of the 20,995 participants was 4.7 years. Over this period, replacing regular salt with salt substitute reduced the risk of stroke by 14% (rate ratio 0.86, 95% confidence interval 0.77 to 0.96; p=0.006) and the salt substitute group had on average 0.054 more QALYs per person. The average costs (CNY ¥1,538 for the intervention group and CNY ¥1,649 for the control group) were lower in the salt substitute group (CNY ¥110 less). The intervention was dominant (better outcomes at lower cost) for prevention of stroke as well as for QALYs gained. Sensitivity analyses showed that these conclusions were robust, except when the price of salt substitute was increased to the median and highest market prices identified in China. The salt substitute intervention had a 95.0% probability of being cost-saving, and a greater than 99.9% probability of being cost-effective. Conclusions: Replacing regular salt with salt substitute was a cost-saving intervention for the prevention of stroke and improvement of quality of life amongst the SSaSS participants.




Circulation: 21 Mar 2022; epub ahead of print
Li KC, Huang L, Tian M, Di Tanna GL, ... Lung T, Si L
Circulation: 21 Mar 2022; epub ahead of print | PMID: 35311346
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Impact:
Abstract

Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document From the Hypertension Academic Research Consortium.

Kandzari DE, Mahfoud F, Weber MA, Townsend R, ... Cutlip DE, Spitzer E
The clinical implications of hypertension in addition to a high prevalence of both uncontrolled blood pressure and medication nonadherence promote interest in developing device-based approaches to hypertension treatment. The expansion of device-based therapies and ongoing clinical trials underscores the need for consistency in trial design, conduct, and definitions of clinical study elements to permit trial comparability and data poolability. Standardizing methods of blood pressure assessment, effectiveness measures beyond blood pressure alone, and safety outcomes are paramount. The Hypertension Academic Research Consortium (HARC) document represents an integration of evolving evidence and consensus opinion among leading experts in cardiovascular medicine and hypertension research with regulatory perspectives on clinical trial design and methodology. The HARC document integrates the collective information among device-based therapies for hypertension to better address existing challenges and identify unmet needs for technologies proposed to treat the world\'s leading cause of death and disability. Consistent with the Academic Research Consortium charter, this document proposes pragmatic consensus clinical design principles and outcomes definitions for studies aimed at evaluating device-based hypertension therapies.



Circulation: 14 Mar 2022; 145:847-863
Kandzari DE, Mahfoud F, Weber MA, Townsend R, ... Cutlip DE, Spitzer E
Circulation: 14 Mar 2022; 145:847-863 | PMID: 35286164
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Impact:
Abstract

Age and Racial/Ethnic Disparities in Pediatric Out-of-Hospital Cardiac Arrest.

Shekhar AC, Campbell T, Mann NC, Blumen IJ, Madhok M
Out-of-hospital cardiac arrest (OHCA) in the pediatric population is a significant public health concern. Estimates of mortality suggest ≈7000 pediatric cardiac arrests occur annually in the United States.1 The existence of racial disparities in adult OHCA has been well established2; however, there is limited research examining whether similar disparities might also be present in the pediatric population. Age-related disparities in pediatric OHCA have also been previously identified.3 For cardiac arrests in both adult and pediatric patients, early cardiopulmonary resuscitation (CPR) is crucial to prevent permanent injury and promote a desirable outcome; in the out-of-hospital setting, this often involves CPR being initiated by nonmedical bystanders.1,3 Emergency medical services (EMS) are often the first professional responders to OHCA, and data from the EMS perspective might be the only means of determining whether disparities-defined as significant differences in care and/or outcomes-are present in pediatric OHCA.



Circulation: 13 Mar 2022; epub ahead of print
Shekhar AC, Campbell T, Mann NC, Blumen IJ, Madhok M
Circulation: 13 Mar 2022; epub ahead of print | PMID: 35285238
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Impact:
Abstract

Comprehensive Quality of Life Outcomes with Invasive versus Conservative Management of Chronic Coronary Disease in ISCHEMIA.

Mark DB, Spertus JA, Bigelow R, Anderson S, ... Hochman JS, ISCHEMIA Research Group
Background: The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) compared an initial invasive treatment strategy (INV) with an initial conservative strategy (CON) in 5,179 participants with chronic coronary disease (CCD) and moderate or severe ischemia. The ISCHEMIA research program included a comprehensive quality of life (QOL) substudy.
Methods:
In 1,819 participants (907 INV, 912 CON), we collected a battery of disease-specific and generic QOL instruments by structured interviews at baseline; at 3, 12, 24, and 36 months post-randomization; and at study close-out. Assessments included angina-related QOL (19-item Seattle Angina Questionnaire [SAQ-19]), generic health status (EQ-5D), depressive symptoms (Patient Health Questionnaire-8), and, for North American patients, cardiac functional status (Duke Activity Status Index [DASI]).
Results:
Median age was 67 years, 19.2% were female, and 15.9% were non-white. The estimated mean difference for the SAQ-19 Summary score favored INV (1.4 points, 95% confidence interval [CI] 0.2, 2.5 over all follow-up). No differences were observed in patients with rare/absent baseline angina (SAQ Angina Frequency [AF] score >80). Among patients with more frequent angina at baseline (SAQ AF score ≤80, 744 patients, 41%), those randomized to INV had a mean 3.7-point higher SAQ-19 Summary score than CON (95% CI 1.6, 5.8) with consistent effects across SAQ subscales: Physical Limitations 3.2 points (95% CI 0.2, 6.1), Angina Frequency 3.2 points (95% CI 1.2, 5.1), Quality of Life/Health Perceptions 5.3 points (95% CI 2.8, 7.8). For the DASI, no difference was estimated overall by treatment, but in patients with baseline SAQ AF scores ≤80, DASI scores were higher for INV (3.2 points, 95% CI 0.6, 5.7), whereas patients with rare/absent baseline angina showed no treatment-related differences. Moderate to severe depression was infrequent at randomization (11.5% to 12.8%) and was unaffected by treatment assignment. Conclusions: In the ISCHEMIA comprehensive QOL substudy, patients with more frequent baseline angina reported greater improvements in the symptom, physical functioning, and psychological well-being dimensions of QOL when treated with an invasive strategy, whereas patients who had rare/absent angina at baseline reported no consistent treatment-related QOL differences.




Circulation: 08 Mar 2022; epub ahead of print
Mark DB, Spertus JA, Bigelow R, Anderson S, ... Hochman JS, ISCHEMIA Research Group
Circulation: 08 Mar 2022; epub ahead of print | PMID: 35259918
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Impact:
Abstract

Amulet or Watchman Device for Percutaneous Left Atrial Appendage Closure: Primary Results of the SWISS-APERO Randomized Clinical Trial.

Galea R, De Marco F, Meneveau N, Aminian A, ... Räber L, Valgimigli M
Background
No study has so far compared Amulet with the new Watchman FLX in terms of residual left atrial appendage (LAA) patency or clinical outcomes in patients undergoing percutaneous LAA closure.
Methods
In the investigator-initiated SWISS APERO trial (Comparison of Amulet Versus Watchman/FLX Device in Patients Undergoing Left Atrial Appendage Closure), patients undergoing LAA closure were randomly assigned (1:1) open label to receive Amulet or Watchman 2.5 or FLX (Watchman) across 8 European centers. The primary end point was the composite of justified crossover to a nonrandomized device during LAA closure procedure or residual LAA patency detected by cardiac computed tomography angiography (CCTA) at 45 days. The secondary end points included procedural complications, device-related thrombus, peridevice leak at transesophageal echocardiography, and clinical outcomes at 45 days.
Results
Between June 2018 and May 2021, 221 patients were randomly assigned to Amulet (111 [50.2%]) or Watchman (110 [49.8%]), of whom 25 (22.7%) patients included before October 2019 received Watchman 2.5, and 85 (77.3%) patients received Watchman FLX. The primary end point was assessable in 205 (92.8%) patients and occurred in 71 (67.6%) patients receiving Amulet and 70 (70.0%) patients receiving Watchman, respectively (risk ratio, 0.97 [95% CI, 0.80-1.16]; P=0.713). A single justified crossover occurred in a patient with Amulet who fulfilled LAA patency criteria at 45-day CCTA. Major procedure-related complications occurred more frequently in the Amulet group (9.0% versus 2.7%; P=0.047) because of more frequent bleeding (7.2% versus 1.8%). At 45 days, the peridevice leak rate at transesophageal echocardiography was higher with Watchman than with Amulet (27.5% versus 13.7%, P=0.020), albeit none was major (ie, >5 mm), whereas device-related thrombus was detected in 1 (0.9%) patient with Amulet and 3 (3.0%) patients with Watchman at CCTA and in 2 (2.1%) and 5 (5.5%) patients at transesophageal echocardiography, respectively. Clinical outcomes at 45 days did not differ between the groups.
Conclusions
Amulet was not associated with a lower rate of the composite of crossover or residual LAA patency compared with Watchman at 45-day CCTA. Amulet, however, was associated with lower peridevice leak rates at transesophageal echocardiography, higher procedural complications, and similar clinical outcomes at 45 days compared with Watchman. The clinical relevance of CCTA-detected LAA patency requires further investigation.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier: NCT03399851.



Circulation: 07 Mar 2022; 145:724-738
Galea R, De Marco F, Meneveau N, Aminian A, ... Räber L, Valgimigli M
Circulation: 07 Mar 2022; 145:724-738 | PMID: 34747186
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Impact:
Abstract

DREAM-ICD-II Study.

Steinberg C, Dognin N, Sodhi A, Champagne C, ... Philippon F, Chakrabarti S
Background
Regulatory authorities of most industrialized countries recommend 6 months of private driving restriction after implantation of a secondary prevention implantable cardioverter-defibrillator (ICD). These driving restrictions result in significant inconvenience and social implications. This study aimed to assess the incidence rate of appropriate device therapies in contemporary recipients of a secondary prevention ICD.
Methods
This retrospective study at 3 Canadian tertiary care centers enrolled consecutive patients with new secondary prevention ICD implants between 2016 and 2020.
Results
For a median of 760 days (324, 1190 days), 721 patients were followed up. The risk of recurrent ventricular arrhythmia was highest during the first 3 months after device insertion (34.4%) and decreased over time (10.6% between 3 and 6 months, 11.7% between 6 and 12 months). The corresponding incidence rate per 100 patient-days was 0.48 (95% CI, 0.35-0.64) at 90 days, 0.28 (95% CI, 0.17-0.45) at 180 days, and 0.21 (95% CI, 0.13-0.33) between 181 and 365 days after ICD insertion (P<0.001). The cumulative incidence of arrhythmic syncope resulting in sudden cardiac incapacitation was 1.8% within the first 90 days and subsequently dropped to 0.4% between 91 and 180 days (P<0.001) after ICD insertion.
Conclusions
The incidence rate of appropriate therapies resulting in sudden cardiac incapacitation in contemporary recipients of a secondary prevention ICD is much lower than previously reported and declines significantly after the first 3 months. Lowering driving restrictions to 3 months after the index cardiac event seems safe, and revision of existing guidelines should be considered in countries still adhering to a 6-month period. Existing restrictions for private driving after implantation of a secondary prevention ICD should be reconsidered.



Circulation: 07 Mar 2022; 145:742-753
Steinberg C, Dognin N, Sodhi A, Champagne C, ... Philippon F, Chakrabarti S
Circulation: 07 Mar 2022; 145:742-753 | PMID: 34913361
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Impact:
Abstract

Periodic Repolarization Dynamics Identifies ICD Responders in Nonischemic Cardiomyopathy: A DANISH Substudy.

Boas R, Sappler N, von Stülpnagel L, Klemm M, ... Bauer A, Rizas KD
Background
Identification of patients with nonischemic cardiomyopathy who may benefit from prophylactic implantation of a cardioverter-defibrillator. We hypothesized that periodic repolarization dynamics (PRD), a marker of repolarization instability associated with sympathetic activity, could be used to identify patients who will benefit from prophylactic implantable cardioverter defibrillator (ICD) implantation.
Methods
We performed a post hoc analysis of DANISH (Danish ICD Study in Patients With Dilated Cardiomyopathy), in which patients with nonischemic cardiomyopathy, left ventricular ejection fraction (LVEF) ≤35%, and elevated NT-proBNP (N-terminal probrain natriuretic peptides) were randomized to ICD implantation or control group. Patients were included in the PRD substudy if they had a 24-hour Holter monitor recording at baseline with technically acceptable ECG signals during the night hours (00:00-06:00). PRD was assessed using wavelet analysis according to previously validated methods. The primary end point was all-cause mortality. Cox regression models were adjusted for age, sex, NT-proBNP, estimated glomerular filtration rate, LVEF, atrial fibrillation, ventricular pacing, diabetes, cardiac resynchronization therapy, and mean heart rate. We proposed PRD ≥10 deg2 as an exploratory cut-off value for ICD implantation.
Results
A total of 748 of the 1116 patients in DANISH qualified for the PRD substudy. During a mean follow-up period of 5.1±2.0 years, 82 of 385 patients died in the ICD group and 85 of 363 patients died in the control group (P=0.40). In Cox regression analysis, PRD was independently associated with mortality (hazard ratio [HR], 1.28 [95% CI, 1.09-1.50] per SD increase; P=0.003). PRD was significantly associated with mortality in the control group (HR, 1.51 [95% CI, 1.25-1.81]; P<0.001) but not in the ICD group (HR, 1.04 [95% CI, 0.83-1.54]; P=0.71). There was a significant interaction between PRD and the effect of ICD implantation on mortality (P=0.008), with patients with higher PRD having greater benefit in terms of mortality reduction. ICD implantation was associated with an absolute mortality reduction of 17.5% in the 280 patients with PRD ≥10 deg2 (HR, 0.54 [95% CI, 0.34-0.84]; P=0.006; number needed to treat=6), but not in the 468 patients with PRD <10 deg2 (HR, 1.17 [95% CI, 0.77-1.78]; P=0.46; P for interaction=0.01).
Conclusions
Increased PRD identified patients with nonischemic cardiomyopathy in whom prophylactic ICD implantation led to significant mortality reduction.



Circulation: 07 Mar 2022; 145:754-764
Boas R, Sappler N, von Stülpnagel L, Klemm M, ... Bauer A, Rizas KD
Circulation: 07 Mar 2022; 145:754-764 | PMID: 34889650
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Impact:
Abstract

CCL17 Aggravates Myocardial Injury by Suppressing Recruitment of Regulatory T Cells.

Feng G, Bajpai G, Ma P, Koenig A, ... Kreisel D, Lavine KJ
Background
Recent studies have established that CCR2 (C-C chemokine receptor type 2) marks proinflammatory subsets of monocytes, macrophages, and dendritic cells that contribute to adverse left ventricle (LV) remodeling and heart failure progression. Elucidation of the effector mechanisms that mediate adverse effects of CCR2+ monocytes, macrophages, and dendritic cells will yield important insights into therapeutic strategies to suppress myocardial inflammation.
Methods
We used mouse models of reperfused myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation to investigate CCL17 (C-C chemokine ligand 17). We used Ccl17 knockout mice, flow cytometry, RNA sequencing, biochemical assays, cell trafficking studies, and in vivo cell depletion to identify the cell types that generate CCL17, define signaling pathways that controlled its expression, delineate the functional importance of CCL17 in adverse LV remodeling and heart failure progression, and determine the mechanistic basis by which CCL17 exerts its effects.
Results
We demonstrated that CCL17 is expressed in CCR2+ macrophages and cluster of differentiation 11b+ conventional dendritic cells after myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation. We clarified the transcriptional signature of CCL17+ macrophages and dendritic cells and identified granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling as a key regulator of CCL17 expression through cooperative activation of STAT5 (signal transducer and activator of transcription 5) and canonical NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling. Ccl17 deletion resulted in reduced LV remodeling, decreased myocardial fibrosis and cardiomyocyte hypertrophy, and improved LV systolic function after myocardial infarction and angiotensin II and phenylephrine infusion. We observed increased abundance of regulatory T cells (Tregs) in the myocardium of injured Ccl17 knockout mice. CCL17 inhibited Treg recruitment through biased activation of CCR4. CCL17 activated Gq signaling and CCL22 (C-C chemokine ligand 22) activated both Gq and ARRB (β-arrestin) signaling downstream of CCR4. CCL17 competitively inhibited CCL22 stimulated ARRB signaling and Treg migration. We provide evidence that Tregs mediated the protective effects of Ccl17 deletion on myocardial inflammation and adverse LV remodeling.
Conclusions
These findings identify CCL17 as a proinflammatory mediator of CCR2+ macrophages and dendritic cells and suggest that inhibition of CCL17 may serve as an effective strategy to promote Treg recruitment and suppress myocardial inflammation.



Circulation: 07 Mar 2022; 145:765-782
Feng G, Bajpai G, Ma P, Koenig A, ... Kreisel D, Lavine KJ
Circulation: 07 Mar 2022; 145:765-782 | PMID: 35113652
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Impact:
Abstract

Beyond Ten-Year Risk: A Cost-Effectiveness Analysis of Statins for the Primary Prevention of Cardiovascular Disease.

Kohli-Lynch CN, Lewsey J, Boyd KA, French DD, ... Preiss D, Briggs AH
Background: Cholesterol guidelines typically prioritize primary prevention statin therapy based on 10-year risk of cardiovascular disease. The advent of generic pricing may justify expansion of statin eligibility. Moreover, 10-year risk may not be the optimal approach for statin prioritization. We estimated the cost-effectiveness of expanding preventive statin eligibility and evaluated novel approaches to prioritization from a Scottish health sector perspective.
Methods:
A computer simulation model predicted long-term health and cost outcomes in Scottish adults aged ≥40 years. Epidemiologic analysis was completed using the Scottish Heart Health Extended Cohort, Scottish Morbidity Records, and National Records of Scotland. A simulation cohort was constructed with data from the Scottish Health Survey 2011 and contemporary population estimates. Treatment and cost inputs were derived from published literature and health service cost data. The main outcome measure was the lifetime incremental cost-effectiveness ratio (ICER), evaluated as cost (GBP 2020) per quality-adjusted life year (QALY) gained. Three approaches to statin prioritization were analyzed: 10-year risk scoring using the ASSIGN score, age-stratified (Age-Strat) risk thresholds to increase treatment rates in younger individuals, and absolute risk reduction (ARR)-guided therapy to increase treatment rates in individuals with elevated cholesterol levels. For each approach, two policies were considered: one which treats the same number of individuals as an ASSIGN score ≥20% (ASSIGN 20, Age-Strat 20, ARR 20) and one which treats the same number as an ASSIGN score ≥10% (ASSIGN 10, Age-Strat 10, ARR 10).
Results:
Compared to ASSIGN 20, reducing the risk threshold for statin initiation to 10% expanded eligibility from 804,000 (32% of CVD-free adults aged ≥40 years) to 1,445,500 individuals (58%). This policy would be cost-effective (ICER: £12,300/QALY, 95% CI: £7,690/QALY-£26,500/QALY). Incremental to ASSIGN 20, ARR 20 produced around 8,800 QALYs and was cost-effective (£7,050/QALY, 95% CI: £4,560/QALY-£10,700/QALY). Incremental to ASSIGN 10, ARR 10 produced around 7,950 QALYs and was cost-effective (£11,700/QALY, 95% CI: £9,250/QALY-£16,900/QALY). Both age-stratified risk threshold strategies were dominated (i.e., more expensive and less effective than alternative treatment strategies). Conclusions: Generic pricing has rendered preventive statin therapy cost-effective for many adults. Absolute risk reduction-guided therapy is more effective than 10-year risk scoring and is cost-effective.




Circulation: 06 Mar 2022; epub ahead of print
Kohli-Lynch CN, Lewsey J, Boyd KA, French DD, ... Preiss D, Briggs AH
Circulation: 06 Mar 2022; epub ahead of print | PMID: 35249370
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Impact:
Abstract

Cardio-Oncology Drug Interactions: A Scientific Statement From the American Heart Association.

Beavers CJ, Rodgers JE, Bagnola AJ, Beckie TM, ... Dent S, American Heart Association Clinical Pharmacology Committee and Cardio-Oncology Committee of the Council on Clinical Cardiology and Council on Genomic and Precision Medicine; and the Council on Peripheral Vascular Disease
In the cardio-oncology population, drug interactions are of particular importance given the complex pharmacological profile, narrow therapeutic index, and inherent risk of therapies used to manage cardiovascular disease and cancer. Drug interactions may be beneficial or detrimental to the desired therapeutic effect. Clinicians in both cardiology and oncology should be cognizant of these potential drug-drug interactions that may reduce the efficacy or safety of either cardiovascular or cancer therapies. These risks can be mitigated through increased recognition of potential drug-drug interaction, use of alternative medications when possible, and careful monitoring. This scientific statement provides clinicians with an overview of pharmacodynamic and pharmacokinetic drug-drug interactions in patients with cancer exposed to common cardiovascular and cancer medications.



Circulation: 06 Mar 2022:CIR0000000000001056; epub ahead of print
Beavers CJ, Rodgers JE, Bagnola AJ, Beckie TM, ... Dent S, American Heart Association Clinical Pharmacology Committee and Cardio-Oncology Committee of the Council on Clinical Cardiology and Council on Genomic and Precision Medicine; and the Council on Peripheral Vascular Disease
Circulation: 06 Mar 2022:CIR0000000000001056; epub ahead of print | PMID: 35249373
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Impact:
Abstract

Heteroplasmy of Wild Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.

Lechuga-Vieco AV, Latorre-Pellicer A, Calvo E, Torroja C, ... Ruíz-Cabello J, Enríquez JA
Background: In most eukaryotic cells, the mitochondrial DNA (mtDNA) is uniparentally transmitted and present in multiple copies derived from the clonal expansion of maternally inherited mtDNA. All copies are therefore near-identical, or homoplasmic. The presence of more than one mtDNA variant in the same cytoplasm can arise naturally or result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent non-pathological mtDNAs heteroplasmy (DNPH). We hypothesized that DNPH is maladaptive and usually prevented by the cell.
Methods:
We engineered and characterized DNPH mice throughout their lifespan using transcriptomic, metabolomic, biochemical, physiological and phenotyping techniques. We focused on in vivo imaging techniques for non-invasive assessment of cardiac and pulmonary energy metabolism.
Results:
We show that DNPH impairs mitochondrial function, with profound consequences in critical tissues that cannot resolve heteroplasmy, particularly cardiac and skeletal muscle. Progressive metabolic stress in these tissues leads to severe pathology in adulthood, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. Symptom severity is strongly modulated by the nuclear context. Conclusions: Medical interventions that may generate DNPH should address potential incompatibilities between donor and recipient mtDNA.




Circulation: 02 Mar 2022; epub ahead of print
Lechuga-Vieco AV, Latorre-Pellicer A, Calvo E, Torroja C, ... Ruíz-Cabello J, Enríquez JA
Circulation: 02 Mar 2022; epub ahead of print | PMID: 35236094
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Impact:
Abstract

DYRK1B-STAT3 Drives Cardiac Hypertrophy and Heart Failure by Impairing Mitochondrial Bioenergetics.

Zhuang L, Jia K, Chen C, Li Z, ... Chen K, Yan X
Background: Heart failure is a global public health issue that is associated with increasing morbidity and mortality. Previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure; however, the underlying mechanisms remain unclear. Since kinases have been reported to modulate mitochondrial function, we investigated the effects of dual-specificity tyrosine-regulated kinase 1B (DYRK1B) on mitochondrial bioenergetics, cardiac hypertrophy, and heart failure.
Methods:
We engineered DYRK1B transgenic and knock out mice and used transverse aortic constriction (TAC) to produce an in vivo model of cardiac hypertrophy. The effects of DYRK1B and its downstream mediators were subsequently elucidated using RNA-seq analysis and mitochondrial functional analysis.
Results:
We found that DYRK1B expression was clearly upregulated in failing human myocardium as well as in hypertrophic murine hearts. Cardiac-specific DYRK1B overexpression resulted in cardiac dysfunction accompanied by a decline in the left ventricular ejection fraction, fraction shortening, and increased cardiac fibrosis. In striking contrast to DYRK1B overexpression, the deletion of DYRK1B mitigated TAC-induced cardiac hypertrophy and heart failure. Mechanistically, DYRK1B was positively associated with impaired mitochondrial bioenergetics by directly binding with STAT3 to increase its phosphorylation and nuclear accumulation, ultimately contributing toward the downregulation of PGC-1α. Furthermore, the inhibition of DYRK1B or STAT3 activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bioenergetics. Conclusions: Taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1B in mitochondrial bioenergetics and the progression of cardiac hypertrophy and heart failure. Consequently, these findings may provide new therapeutic options for patients with heart failure.




Circulation: 01 Mar 2022; epub ahead of print
Zhuang L, Jia K, Chen C, Li Z, ... Chen K, Yan X
Circulation: 01 Mar 2022; epub ahead of print | PMID: 35235343
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Impact:
Abstract

Screening for Atrial Fibrillation in Older Adults at Primary Care Visits: the VITAL-AF Randomized Controlled Trial.

Lubitz SA, Atlas SJ, Ashburner JM, Trisini Lipsanopoulos AT, ... McManus DD, Singer DE
Background: Undiagnosed atrial fibrillation (AF) may cause preventable strokes. Guidelines differ regarding AF screening recommendations. We tested whether point-of-care screening with a handheld single lead electrocardiogram (ECG) at primary care practice visits increases diagnoses of AF.
Methods:
We randomized 16 primary care clinics 1:1 to AF screening using a handheld single-lead ECG (AliveCor KardiaMobile) during vital sign assessments, or usual care. Patients included were aged ≥65 years. Screening results were provided to primary care clinicians at the encounter. All confirmatory diagnostic testing and treatment decisions were made by the primary care clinician. New AF diagnoses over one-year follow-up were ascertained electronically and manually adjudicated. Proportions and incidence rates were calculated. Effect heterogeneity was assessed.
Results:
Of 30,715 patients without prevalent AF (n=15,393 screening [91% screened], n=15,322 control), 1.72% of individuals in the screening group had new AF diagnosed at one year versus 1.59% in the control group (risk difference [RD] 0.13%, 95% confidence interval [CI] -0.16-0.42, P=0.38). In prespecified subgroup analyses, new AF diagnoses in the screening and control groups were greater among those aged ≥85 years (5.56% versus 3.76%, respectively, RD 1.80%, 95% CI 0.18-3.30). The difference in newly diagnosed AF between the screening period and the prior year was marginally greater in the screening versus control group (0.32% versus -0.12%, RD 0.43%, 95% CI -0.01-0.84). The proportion of individuals with newly diagnosed AF who were initiated on oral anticoagulants was not different in the screening (n=194, 73.5%) and control (n=172, 70.8%) arms (RD 2.7%, 95% CI -5.5-10.4). Conclusions: Screening for AF using a single-lead ECG at primary care visits did not affect new AF diagnoses among all individuals aged 65 years or older compared to usual care.




Circulation: 01 Mar 2022; epub ahead of print
Lubitz SA, Atlas SJ, Ashburner JM, Trisini Lipsanopoulos AT, ... McManus DD, Singer DE
Circulation: 01 Mar 2022; epub ahead of print | PMID: 35232217
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Impact:
Abstract

Nationwide Analysis of Persistent Type II Endoleak and Late Outcomes of Endovascular Abdominal Aortic Aneurysm Repair in Japan: a Propensity-matched Analysis.

Seike Y, Matsuda H, Shimizu H, Ishimaru S, ... Komori K, Japanese Committee for Stentgraft Management (JACSM)
Background: We reviewed the results of endovascular aneurysm repair (EVAR) in patients from the Japanese Committee for Stentgraft Management (JACSM) registry, to determine the significance of persistent type II endoleak (p-T2EL) and the risk of late adverse events including aneurysm sac enlargement.
Methods:
The prospectively captured medical records of 17,099 patients aged <75 years who underwent EVAR for abdominal aortic aneurysm (AAA) from 2006 to 2015 were reviewed. Patients were divided into two groups (with or without p-T2EL) and compared to examine the correlation between p-T2EL and the occurrence of aneurysm sac enlargement after EVAR.
Results:
Of the patients, 4,957 (29.0%) had and 12,142 (71.0%) had no p-T2EL, respectively. Mean age was significantly higher (p <0.001) and males were fewer (p <0.001) in the p-T2EL group. Among comorbidities, hypertension (p = 0.019) and chronic kidney disease (CKD) (p = 0.040) were more prevalent and respiratory disorders were less prevalent (p <0.001) in the p-T2EL group. From each group, 4957 patients were matched according to propensity score (PS) to adjust for differences in patient characteristics. The cumulative incidence rates of AAA-related mortality (p-T2EL: 52/4,957 [1.0%] vs non-T2EL: 21/12,142 [0.2%]), rupture, (p-T2EL: 38/4,957 [0.8%] vs non-T2EL: 13/12,142 [0.1%]) sac enlargement (≥5 mm) (p-T2EL: 1,359/4,957 [27.4%] vs non-T2EL: 332/12,142 [2.7%]), and reintervention (p-T2EL: 739/4,957 [14.9%] vs non-T2EL: 91/12,142 [0.7%]) were significantly higher in the p-T2EL than in the non-pT2EL group (p <0.001). PS matching yielded higher estimated incremental risk, including AAA-related mortality, rupture, sac enlargement (≥5 mm), and reintervention for p-T2EL (p <0.001). Cox regression analysis revealed older age (p = 0.010), proximal neck diameter (p = 0.003), and CKD (p <0.001) as independent positive predictors and male sex as an independent negative predictor (p = 0.015) of sac enlargement. Conclusions: The JACSM registry data show a correlation between p-T2EL and late adverse events, including aneurysm sac enlargement, reintervention, rupture, and AAA-related mortality after EVAR. Other than p-T2EL, older age, female sex, CKD, and dilated proximal neck were associated with sac enlargement.




Circulation: 24 Feb 2022; epub ahead of print
Seike Y, Matsuda H, Shimizu H, Ishimaru S, ... Komori K, Japanese Committee for Stentgraft Management (JACSM)
Circulation: 24 Feb 2022; epub ahead of print | PMID: 35209732
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Impact:
Abstract

Cytokine Hemoadsorption During Cardiac Surgery versus Standard Surgical Care for Infective Endocarditis (REMOVE): Results from a Multicenter, Randomized, Controlled Trial.

Diab M, Lehmann T, Bothe W, Akhyari P, ... Doenst T, REMOVE Trial Investigators
Background: Cardiac surgery often represents the only treatment option in patients with infective endocarditis (IE). However, IE surgery may lead to a sudden release of inflammatory mediators, which is associated with the severity of postoperative organ dysfunction. We investigated the impact of hemoadsorption during IE surgery on postoperative organ dysfunction.
Methods:
This multi-center, randomized, non-blinded, controlled trial assigned patients undergoing cardiac surgery for IE to hemoadsorption [integration of CytoSorb® to cardiopulmonary bypass (CPB)] or control. The Primary outcome (ΔSOFA) was defined as the difference between the mean total postoperative sequential organ failure assessment score (SOFA), calculated maximally to the 9th postoperative day, and the basal SOFA score. The analysis was by modified intention-to-treat. A predefined inter-group comparison was done using a linear mixed model for ΔSOFA including surgeon and baseline SOFA as fixed effect covariates and with the surgical center as random effect. The SOFA score assesses dysfunction in six organ systems, each scored from zero to four. Higher scores indicate worsening dysfunction. Secondary outcomes were 30-day mortality, durations of mechanical ventilation, vasopressor and renal replacement therapy. Cytokines were measured in the first 50 patients.
Results:
Between January 17, 2018 and January 31, 2020, A total of 288 patients were randomly assigned to hemoadsorption (n=142) or control (n=146). Four patients in the hemoadsorption and two in the control group were excluded as they did not undergo surgery. The primary outcome ΔSOFA did not differ between the hemoadsorption and the control group (1.79 ± 3.75 and 1.93 ± 3.53, respectively, 95% CI: -1.30 to 0.83, p=0.6766). Mortality at 30 days (21% hemoadsorption vs 22% control, p=0.782), the durations of mechanical ventilation, vasopressor and renal replacement therapy did not differ between groups. Levels of IL-1β and IL-18 at the end of CPB were significantly lower in the hemoadsorption than in the control group. Conclusions: This randomized trial failed to demonstrate a reduction in postoperative organ dysfunction through intraoperative hemoadsorption in patients undergoing cardiac surgery for IE. Although hemoadsorption reduced plasma cytokines at the end of CPB, there was no difference in any of the clinically relevant outcome points.




Circulation: 24 Feb 2022; epub ahead of print
Diab M, Lehmann T, Bothe W, Akhyari P, ... Doenst T, REMOVE Trial Investigators
Circulation: 24 Feb 2022; epub ahead of print | PMID: 35213213
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Impact:
Abstract

Insulin Prevents Hypercholesterolemia by Suppressing 12a-Hydroxylated Bile Acid Production.

Semova I, Levenson AE, Krawczyk J, Bullock K, ... Clish CB, Biddinger SB
Background: The risk of cardiovascular disease in type 1 diabetes remains extremely high, despite marked advances in blood glucose control and even the widespread use of cholesterol synthesis inhibitors. Thus, a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type 1 diabetes, could reveal better treatment strategies.
Methods:
To define the mechanisms by which insulin controls plasma cholesterol levels, we knocked down the insulin receptor, FoxO1, and the key bile acid synthesis enzyme, CYP8B1. We measured bile acid composition, cholesterol absorption, and plasma cholesterol. In parallel, we measured markers of cholesterol absorption and synthesis in humans with type 1 diabetes treated with ezetimibe and statins in a double-blind crossover study.
Results:
Mice with hepatic deletion of the insulin receptor showed marked increases in 12α-hydroxylated bile acids (12HBAs), cholesterol absorption, and plasma cholesterol. This phenotype was entirely reversed by hepatic deletion of FoxO1. FoxO1 is inhibited by insulin, and required for the production of 12HBAs, which promote intestinal cholesterol absorption and suppress hepatic cholesterol synthesis. Knockdown of Cyp8b1 normalized 12HBA levels and completely prevented hypercholesterolemia in mice with hepatic deletion of the insulin receptor (n=5-30) as well as mouse models of type 1 diabetes (n=5-22). In parallel, the cholesterol absorption inhibitor, ezetimibe, normalized cholesterol absorption and LDL-cholesterol in patients with type 1 diabetes as well as, or better than, the cholesterol synthesis inhibitor, simvastatin (n=20). Conclusions: Insulin, by inhibiting FoxO1 in the liver, reduces 12HBAs, cholesterol absorption, and plasma cholesterol levels. Thus, type 1 diabetes leads to a unique set of derangements in cholesterol metabolism, with increased absorption rather than synthesis. These derangements are reversed by ezetimibe, but not statins, which are currently the first line of lipid-lowering treatment in type 1 diabetes. Taken together, these data suggest that a personalized approach to lipid lowering in type 1 diabetes may be more effective and highlight the need for further studies specifically in this group of patients.




Circulation: 22 Feb 2022; epub ahead of print
Semova I, Levenson AE, Krawczyk J, Bullock K, ... Clish CB, Biddinger SB
Circulation: 22 Feb 2022; epub ahead of print | PMID: 35193378
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Impact:
Abstract

Efpeglenatide and Clinical Outcomes With and Without Concomitant Sodium-Glucose Cotransporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial.

Lam CSP, Ramasundarahettige C, Branch KRH, Sattar N, ... Baek S, Gerstein HC
Background
Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists reduce cardiovascular events among patients with type 2 diabetes. However, no cardiovascular outcome trial has evaluated the long-term effects of their combined use. The AMPLITUDE-O trial (Effect of Efpeglenatide on Cardiovascular Outcomes) reported that once-weekly injections of the glucagon-like peptide-1 receptor agonists efpeglenatide (versus placebo) reduced major adverse cardiovascular events (MACEs); MACEs, coronary revascularization, or unstable angina hospitalization (expanded MACEs); a renal composite outcome; and MACEs or death in people with type 2 diabetes and cardiovascular or renal disease. The trial uniquely stratified randomization by baseline or anticipated use of SGLT2 inhibitors and included the highest prevalence at baseline (N=618, 15.2%) of SGLT2 inhibitor use among glucagon-like peptide-1 receptor agonist cardiovascular outcome trials to date. Its results were analyzed to estimate the combined effect of SGLT2 inhibitors and efpeglenatide on clinical outcomes.
Methods
Cardiovascular and renal outcomes were analyzed with Cox proportional hazards models adjusted for region, SGLT2 inhibitor randomization strata, and the SGLT2 inhibitor-by-treatment interaction. Continuous variables were analyzed with a mixed-effects models for repeated measures that also included an interaction term.
Results
The effect (hazard ratio [95% CI]) of efpeglenatide versus placebo in the absence and presence of baseline SGLT2 inhibitors on MACEs (0.74 [0.58-0.94] and 0.70 [0.37-1.30], respectively), expanded MACEs (0.77 [0.62-0.96] and 0.87 [0.51-1.48]), renal composite (0.70 [0.59-0.83] and 0.52 [0.33-0.83]), and MACEs or death (0.74 [0.59-0.93] and 0.65 [0.36-1.19]) did not differ by baseline SGLT2 inhibitor use (P for all interactions >0.2). The reduction of blood pressure, body weight, low-density lipoprotein cholesterol, and urinary albumin-to-creatinine ratio by efpeglenatide also appeared to be independent of concurrent SGLT2 inhibitor use (all interaction P≥0.08). Last, adverse events did not differ by baseline SGLT2 inhibitor use.
Conclusions
The efficacy and safety of efpeglenatide appear to be independent of concurrent SGLT2 inhibitor use. These data support combined SGLT2 inhibitor and glucagon-like peptide-1 receptor agonist therapy in type 2 diabetes. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03496298.



Circulation: 21 Feb 2022; 145:565-574
Lam CSP, Ramasundarahettige C, Branch KRH, Sattar N, ... Baek S, Gerstein HC
Circulation: 21 Feb 2022; 145:565-574 | PMID: 34775781
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This program is still in alpha version.