Journal: J Am Coll Cardiol

Sorted by: date / impact
Abstract

Modulation of Cardiac Arrhythmogenesis by Epicardial Adipose Tissue: JACC State-of-the-Art Review.

Ernault AC, Meijborg VMF, Coronel R
Obesity is a significant risk factor for arrhythmic cardiovascular death. Interactions between epicardial adipose tissue (EAT) and myocytes are thought to play a key role in the development of arrhythmias. In this review, the authors investigate the influence of EAT on arrhythmogenesis. First, they summarize electrocardiographic evidence showing the association between increased EAT volume and atrial and ventricular conduction delay. Second, they detail the structural cross talk between EAT and the heart and its arrhythmogenicity. Adipose tissue infiltration within the myocardium constitutes an anatomical obstacle to cardiac excitation. It causes activation delay and increases the risk of arrhythmias. Intercellular electrical coupling between cardiomyocytes and EAT can further slow conduction and increase the risk of block, favoring re-entry and arrhythmias. Finally, EAT secretes multiple substances that influence cardiomyocyte electrophysiology either by modulating ion currents and electrical coupling or by stimulating fibrosis. Thus, structural and paracrine cross talk between EAT and cardiomyocytes facilitates arrhythmias.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 25 Oct 2021; 78:1730-1745
Ernault AC, Meijborg VMF, Coronel R
J Am Coll Cardiol: 25 Oct 2021; 78:1730-1745 | PMID: 34674819
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Abstract

Burnout and Well-Being Among Cardiology Fellowship Program Directors.

Cullen MW, Damp JB, Soukoulis V, Keating FK, ... Theriot P, Weissman G
Objectives
The third annual Cardiovascular Diseases (CV) Fellowship Program Directors (PDs) Survey sought to understand burnout and well-being among CV fellowship PDs.
Background
Physician burnout is a common phenomenon. Data on burnout among cardiologists, specifically CV PDs, remain limited.
Methods
The survey contained 8 questions examining satisfaction, stress, and burnout among CV fellowship PDs. Burnout was defined based on the self-reported presence of ≥1 symptom of burnout, constant feelings of burnout, or complete burnout.
Results
Survey response rate was 57%. Most respondents were men (78%) and 54% represented university-based programs. Eighty percent reported satisfaction with their current job as PD, and 96% identified interactions with fellows as a driver of their satisfaction. Forty-five percent reported feeling a great deal of stress from their job. Stress was higher among women PDs, early-career PDs, and PDs of larger and university-based programs. Twenty-one percent reported some symptoms of burnout, and only 36% reported enjoyment without stress or burnout. Rates of enjoyment without stress or burnout were higher among men and late-career PDs, PDs of smaller programs, and PDs of community-based programs. Seventeen percent of PDs reported a high likelihood of resigning in the next year, of which the most common reason was the tasks of PDs were becoming overwhelming.
Conclusions
Most CV fellowship PDs are satisfied with their position, but stress and burnout remain common. Women PDs, early-career PDs, and PDs of larger, university-based programs demonstrate more adverse markers of well-being. Opportunities exist to support CV fellowship PDs in their critical role.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 25 Oct 2021; 78:1717-1726
Cullen MW, Damp JB, Soukoulis V, Keating FK, ... Theriot P, Weissman G
J Am Coll Cardiol: 25 Oct 2021; 78:1717-1726 | PMID: 34674817
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Abstract

Improving Longitudinal Outcomes, Efficiency, and Equity in the Care of Patients With Congenital Heart Disease.

Anderson BR, Dragan K, Crook S, Woo JL, ... Billings J, New York State Congenital Heart Surgery Collaborative for Longitudinal Outcomes and Utilization of Resources (CHS-COLOUR)
Background
Longitudinal follow-up, resource utilization, and health disparities are top congenital heart research and care priorities. Medicaid claims include longitudinal data on inpatient, outpatient, emergency, pharmacy, rehabilitation, home health utilization, and social determinants of health-including mother-infant pairs.
Objectives
The New York Congenital Heart Surgeons Collaborative for Longitudinal Outcomes and Utilization of Resources linked robust clinical details from locally held state and national registries from 10 of 11 New York congenital heart centers to Medicaid claims, building a novel, statewide mechanism for longitudinal assessment of outcomes, expenditures, and health inequities.
Methods
The authors included all children <18 years of age undergoing cardiac surgery in The Society of Thoracic Surgeons Congenital Heart Surgery Database or the New York State Pediatric Congenital Cardiac Surgery Registry from 10 of 11 New York centers, 2006 to 2019. Data were linked via iterative, ranked deterministic matching on direct identifiers. Match rates were calculated and compared. Proportions of the linked cohort trackable over 3, 5, and 10 years were described.
Results
Of 14,097 registry cases, 59% (n = 8,322) reported Medicaid use. Of these, 7,414 were linked to New York claims, at an 89% match rate. Of matched cases, the authors tracked 79%, 74%, and 65% of children over 3, 5, and 10 years when requiring near-continuous Medicaid enrollment. Allowing more lenient enrollment criteria, the authors tracked 86%, 82%, and 76%, respectively. Mortality over this time was 7.7%, 8.4%, and 10.0%, respectively. Manual validation revealed ∼100% true matches.
Conclusions
This establishes a novel statewide data resource for assessment of longitudinal outcome, health expenditure, and disparities for children with congenital heart disease.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 25 Oct 2021; 78:1703-1713
Anderson BR, Dragan K, Crook S, Woo JL, ... Billings J, New York State Congenital Heart Surgery Collaborative for Longitudinal Outcomes and Utilization of Resources (CHS-COLOUR)
J Am Coll Cardiol: 25 Oct 2021; 78:1703-1713 | PMID: 34674815
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Abstract

Association of Genetic Variants With Outcomes in Patients With Nonischemic Dilated Cardiomyopathy.

Escobar-Lopez L, Ochoa JP, Mirelis JG, Espinosa MÁ, ... Domínguez F, Garcia-Pavia P
Background
The clinical relevance of genetic variants in nonischemic dilated cardiomyopathy (DCM) is unsettled.
Objectives
The study sought to assess the prognostic impact of disease-causing genetic variants in DCM.
Methods
Baseline and longitudinal clinical data from 1,005 genotyped DCM probands were retrospectively collected at 20 centers. A total of 372 (37%) patients had pathogenic or likely pathogenic variants (genotype positive) and 633 (63%) were genotype negative. The primary endpoint was a composite of major adverse cardiovascular events. Secondary endpoints were end-stage heart failure (ESHF), malignant ventricular arrhythmia (MVA), and left ventricular reverse remodeling (LVRR).
Results
After a median follow-up of 4.04 years (interquartile range: 1.70-7.50 years), the primary endpoint had occurred in 118 (31.7%) patients in the genotype-positive group and in 125 (19.8%) patients in the genotype-negative group (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.17-1.94; P = 0.001). ESHF occurred in 60 (16.1%) genotype-positive patients and in 55 (8.7%) genotype-negative patients (HR: 1.67; 95% CI: 1.16-2.41; P = 0.006). MVA occurred in 73 (19.6%) genotype-positive patients and in 77 (12.2%) genotype-negative patients (HR: 1.50; 95% CI: 1.09-2.07; P = 0.013). LVRR occurred in 39.6% in the genotype-positive group and in 46.2% in the genotype-negative group (P = 0.047). Among individuals with baseline left ventricular ejection fraction ≤35%, genotype-positive patients exhibited more major adverse cardiovascular events, ESHF, and MVA than their genotype-negative peers (all P < 0.02). LVRR and clinical outcomes varied depending on the underlying affected gene.
Conclusions
In this study, DCM patients with pathogenic or likely pathogenic variants had worse prognosis than genotype-negative individuals. Clinical course differed depending on the underlying affected gene.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 25 Oct 2021; 78:1682-1699
Escobar-Lopez L, Ochoa JP, Mirelis JG, Espinosa MÁ, ... Domínguez F, Garcia-Pavia P
J Am Coll Cardiol: 25 Oct 2021; 78:1682-1699 | PMID: 34674813
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Abstract

Contributions of Systolic and Diastolic Blood Pressures to Cardiovascular Outcomes in the ALLHAT Study.

Itoga NK, Tawfik DS, Montez-Rath ME, Chang TI
Background
SBP and DBP have important associations with cardiovascular events, but are seldom considered simultaneously.
Objectives
This study sought to simultaneously analyze systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements on the associated risk of a primary composite outcome of all-cause mortality, myocardial infarction (MI), congestive heart failure (CHF), or stroke.
Methods
This study analyzed ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) data, which randomized adults to chlorthalidone, amlodipine, or lisinopril. The authors evaluated the simultaneous association of repeated SBP and DBP measurements on the primary composite outcome, and each outcome using proportional hazards regression. The authors report hazard ratios using a \"heat map\" to represent high and low risk according to SBP and DBP combinations.
Results
During a median follow-up of 4.4 years (interquartile range: 3.6-5.4 years), 33,357 participants experienced 2,636 MIs, 866 CHF events, 936 strokes, and 3,700 deaths; 8,138 patients (24.4%) had at least 1 event. For the composite outcome, all-cause mortality, MI, and CHF, a U-shaped association was observed with SBP and DBP, but the SBP and DBP associated with the lowest hazards differed for each outcome. For example, SBP/DBP of 140-155/70-80 mm Hg was associated with the lowest HR for all-cause mortality, compared with 110-120/85-90 mm Hg for MI and 125-135/70-75 mm Hg for CHF. In contrast, the association of SBP and stroke was linear.
Conclusions
The risk pattern of SBP and DBP differs by clinical outcomes, and the SBP and DBP associated with the lowest risk. Our results suggest individualization of blood pressure targets may depend in part on the cardiovascular event for which the patient is most at risk.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 25 Oct 2021; 78:1671-1678
Itoga NK, Tawfik DS, Montez-Rath ME, Chang TI
J Am Coll Cardiol: 25 Oct 2021; 78:1671-1678 | PMID: 34674811
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Abstract

Stress Cardiac Magnetic Resonance Myocardial Perfusion Imaging: JACC Review Topic of the Week.

Patel AR, Salerno M, Kwong RY, Singh A, Heydari B, Kramer CM
Stress cardiovascular magnetic resonance imaging (CMR) is a cost-effective, noninvasive test that accurately assesses myocardial ischemia, myocardial viability, and cardiac function without the need for ionizing radiation. There is a large body of literature, including randomized controlled trials, validating its diagnostic performance, risk stratification capabilities, and ability to guide appropriate use of coronary intervention. Specifically, stress CMR has shown higher diagnostic sensitivity than single-photon emission computed tomography imaging in detecting angiographically significant coronary artery disease. Stress CMR is particularly valuable for the evaluation of patients with moderate to high pretest probability of having stable ischemic heart disease and for patients known to have challenging imaging characteristics, including women, individuals with prior revascularization, and those with left ventricular dysfunction. This paper reviews the basics principles of stress CMR, the data supporting its clinical use, the added-value of myocardial blood flow quantification, and the assessment of myocardial function and viability routinely obtained during a stress CMR study.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 18 Oct 2021; 78:1655-1668
Patel AR, Salerno M, Kwong RY, Singh A, Heydari B, Kramer CM
J Am Coll Cardiol: 18 Oct 2021; 78:1655-1668 | PMID: 34649703
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Abstract

Proteomics-Enabled Deep Learning Machine Algorithms Can Enhance Prediction of Mortality.

Unterhuber M, Kresoja KP, Rommel KP, Besler C, ... Thiele H, Lurz P
Background
Individualized risk prediction represents a prerequisite for providing personalized medicine.
Objectives
This study compared proteomics-enabled machine-learning (ML) algorithms with classical and clinical risk prediction methods for all-cause mortality in cohorts of patients with cardiovascular risk factors in the LIFE-Heart Study, followed by validation in the PLIC (Progressione della Lesione Intimale Carotidea) study.
Methods
Using the OLINK-Cardiovascular-II panel, 92 proteins were measured in a cohort of 1,998 individuals from the LIFE-Heart Study (derivation) and 772 subjects from the PLIC cohort (external validation). We constructed protein-based mortality prediction models using eXtreme Gradient Boosting (XGBoost) and a neural network, comparing the prediction performance with classical clinical risk scores (Systemic Coronary Risk Evaluation, Framingham), logistic and Cox regression models.
Results
All-cause mortality occurred in 156 (8%) patients in the internal validation and 68 (9%) patients in the external validation cohort, within a median follow-up of 10 and 11 years, respectively. On internal and external validation, the Framingham Risk Score achieved areas under the curve (AUCs) of 0.64 (95% CI: 0.59-0.68) and 0.65 (95% CI: 0.58-0.74), logistic regression AUCs of 0.65 (95% CI: 0.57-0.73) and 0.67 (95% CI: 0.59-0.74), Cox regression AUCs of 0.55 (95% CI: 0.51-0.59) and 0.65 (95% CI: 0.57-0.73), the XGBoost classifier AUCs of 0.83 (95% CI: 0.79-0.87) and 0.91 (95% CI: 0.86-0.95), the XGBoost survival estimator AUCs of 0.83 (95% CI: 0.79-0.87) and 0.93 (95% CI: 0.88-0.97), and the neural network AUCs of 0.87 (95% CI: 0.83-0.91) and 0.94 (95% CI: 0.90-0.98), respectively (modern vs classical ML: P < 0.001).
Conclusions
ML-driven multiprotein risk models outperform classical regression models and clinical scores for prediction of all-cause mortality in patients at increased cardiovascular risk.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 18 Oct 2021; 78:1621-1631
Unterhuber M, Kresoja KP, Rommel KP, Besler C, ... Thiele H, Lurz P
J Am Coll Cardiol: 18 Oct 2021; 78:1621-1631 | PMID: 34649700
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Abstract

Distinct Features of Probands With Early Repolarization and Brugada Syndromes Carrying SCN5A Pathogenic Variants.

Zhang ZH, Barajas-Martínez H, Xia H, Li B, ... Antzelevitch C, Hu D
Background
Two major forms of inherited J-wave syndrome (JWS) are recognized: early repolarization syndrome (ERS) and Brugada syndrome (BrS).
Objectives
This study sought to assess the distinct features between patients with ERS and BrS carrying pathogenic variants in SCN5A.
Methods
Clinical evaluation and next-generation sequencing were performed in 262 probands with BrS and 104 with ERS. Nav1.5 and Kv4.3 channels were studied with the use of patch-clamp techniques. A computational model was used to investigate the protein structure.
Results
The SCN5A+ yield in ERS was significantly lower than in BrS (9.62% vs 22.90%; P = 0.004). Patients diagnosed with ERS displayed shorter QRS and QTc than patients with BrS. More than 2 pathogenic SCN5A variants were found in 5 probands. These patients displayed longer PR intervals and QRS duration and experienced more major arrhythmia events (MAE) compared with those carrying only a single pathogenic variant. SCN5A-L1412F, detected in a fever-induced ERS patient, led to total loss of function, destabilized the Nav1.5 structure, and showed a dominant-negative effect, which was accentuated during a febrile state. ERS-related SCN5A-G452C did not alter the inward sodium current (INa) when SCN5A was expressed alone, but when coexpressed with KCND3 it reduced peak INa by 44.52% and increased the transient outward potassium current (Ito) by 106.81%.
Conclusions
These findings point to SCN5A as a major susceptibility gene in ERS as much as it is in BrS, whereas the lower SCN5A+ ratio in ERS indicates the difference in underlying electrophysiology. These findings also identify the first case of fever-induced ERS and demonstrate a critical role of Ito in JWS and a higher risk for MAE in JWS probands carrying multiple pathogenic variants in SCN5A.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 18 Oct 2021; 78:1603-1617
Zhang ZH, Barajas-Martínez H, Xia H, Li B, ... Antzelevitch C, Hu D
J Am Coll Cardiol: 18 Oct 2021; 78:1603-1617 | PMID: 34649698
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Abstract

Prevalence and Prognostic Implications of Diabetes With Cardiomyopathy in Community-Dwelling Adults.

Segar MW, Khan MS, Patel KV, Butler J, ... McGuire DK, Pandey A
Background
Diabetes is associated with abnormalities in cardiac remodeling and high risk of heart failure (HF).
Objectives
The purpose of this study was to evaluate the prevalence and prognostic implications of diabetes with cardiomyopathy (DbCM) among community-dwelling individuals.
Methods
Adults without prevalent cardiovascular disease or HF were pooled from 3 cohort studies (ARIC [Atherosclerosis Risk In Communities], CHS [Cardiovascular Health Study], CRIC [Chronic Renal Insufficiency Cohort]). Among participants with diabetes, DbCM was defined using different definitions: 1) least restrictive: ≥1 echocardiographic abnormality (left atrial enlargement, left ventricle hypertrophy, diastolic dysfunction); 2) intermediate restrictive: ≥2 echocardiographic abnormalities; and 3) most restrictive: elevated N-terminal pro-B-type natriuretic peptide levels (>125 in normal/overweight or >100 pg/mL in obese) plus ≥2 echocardiographic abnormalities. Adjusted Fine-Gray models were used to evaluate the risk of HF.
Results
Among individuals with diabetes (2,900 of 10,208 included), the prevalence of DbCM ranged from 67.0% to 11.7% in the least and most restrictive criteria, respectively. Higher fasting glucose, body mass index, and age as well as worse kidney function were associated with higher risk of DbCM. The 5-year incidence of HF among participants with DbCM ranged from 8.4%-12.8% in the least and most restrictive definitions, respectively. Compared with euglycemia, DbCM was significantly associated with higher risk of incident HF with the highest risk observed for the most restrictive definition of DbCM (HR: 2.55 [95% CI: 1.69-3.86]; least restrictive criteria HR: 1.99 [95% CI: 1.50-2.65]). A similar pattern of results was observed across cohort studies, across sex and race subgroups, and among participants without hypertension or obesity.
Conclusions
Regardless of the criteria used to define cardiomyopathy, DbCM identifies a high-risk subgroup for developing HF.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 18 Oct 2021; 78:1587-1598
Segar MW, Khan MS, Patel KV, Butler J, ... McGuire DK, Pandey A
J Am Coll Cardiol: 18 Oct 2021; 78:1587-1598 | PMID: 34649696
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Abstract

Modeling the Recommended Age for Initiating Coronary Artery Calcium Testing Among At-Risk Young Adults.

Dzaye O, Razavi AC, Dardari ZA, Shaw LJ, ... Mortensen MB, Blaha MJ
Background
There are currently no recommendations guiding when best to perform coronary artery calcium (CAC) scanning among young adults to identify those susceptible for developing premature atherosclerosis.
Objectives
The purpose of this study was to determine the ideal age at which a first CAC scan has the highest utility according to atherosclerotic cardiovascular disease (ASCVD) risk factor profile.
Methods
We included 22,346 CAC Consortium participants aged 30-50 years who underwent noncontrast computed tomography. Sex-specific equations were derived from multivariable logistic modeling to estimate the expected probability of CAC >0 according to age and the presence of ASCVD risk factors.
Results
Participants were on average 43.5 years of age, 25% were women, and 34% had CAC >0, in whom the median CAC score was 20. Compared with individuals without risk factors, those with diabetes developed CAC 6.4 years earlier on average, whereas smoking, hypertension, dyslipidemia, and a family history of coronary heart disease were individually associated with developing CAC 3.3-4.3 years earlier. Using a testing yield of 25% for detecting CAC >0, the optimal age for a potential first scan would be at 36.8 years (95% CI: 35.5-38.4 years) in men and 50.3 years (95% CI: 48.7-52.1 years) in women with diabetes, and 42.3 years (95% CI: 41.0-43.9 years) in men and 57.6 years (95% CI: 56.0-59.5 years) in women without risk factors.
Conclusions
Our derived risk equations among health-seeking young adults enriched in ASCVD risk factors inform the expected prevalence of CAC >0 and can be used to determine an appropriate age to initiate clinical CAC testing to identify individuals most susceptible for early/premature atherosclerosis.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 18 Oct 2021; 78:1573-1583
Dzaye O, Razavi AC, Dardari ZA, Shaw LJ, ... Mortensen MB, Blaha MJ
J Am Coll Cardiol: 18 Oct 2021; 78:1573-1583 | PMID: 34649694
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Abstract

Bridging Antiplatelet Therapy After Percutaneous Coronary Intervention: JACC Review Topic of the Week.

Sullivan AE, Nanna MG, Wang TY, Bhatt DL, ... Rao SV, Ohman EM
Patients undergoing early surgery after coronary stent implantation are at increased risk for mortality from ischemic and hemorrhagic complications. The optimal antiplatelet strategy in patients who cannot discontinue dual antiplatelet therapy (DAPT) before surgery is unclear. Current guidelines, based on surgical and clinical characteristics, provide risk stratification for bridging therapy with intravenous antiplatelet agents, but management is guided primarily by expert opinion. This review summarizes perioperative risk factors to consider before discontinuing DAPT and reviews the data for intravenous bridging therapies. Published reports have included bridging options such as small molecule glycoprotein IIb/IIIa inhibitors (eptifibatide or tirofiban) and cangrelor, an intravenous P2Y12 inhibitor. However, optimal management of these complex patients remains unclear in the absence of randomized controlled data, without which an argument can be made both for and against the use of perioperative intravenous bridging therapy after discontinuing oral P2Y12 inhibitors. Multidisciplinary risk assessment remains a critical component of perioperative care.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 11 Oct 2021; 78:1550-1563
Sullivan AE, Nanna MG, Wang TY, Bhatt DL, ... Rao SV, Ohman EM
J Am Coll Cardiol: 11 Oct 2021; 78:1550-1563 | PMID: 34620413
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Abstract

Microvascular Resistance Reserve for Assessment of Coronary Microvascular Function: JACC Technology Corner.

De Bruyne B, Pijls NHJ, Gallinoro E, Candreva A, ... Collet C, Fearon WF
The need for a quantitative and operator-independent assessment of coronary microvascular function is increasingly recognized. We propose the theoretical framework of microvascular resistance reserve (MRR) as an index specific for the microvasculature, independent of autoregulation and myocardial mass, and based on operator-independent measurements of absolute values of coronary flow and pressure. In its general form, MRR equals coronary flow reserve (CFR) divided by fractional flow reserve (FFR) corrected for driving pressures. In 30 arteries, pressure, temperature, and flow velocity measurements were obtained simultaneously at baseline (BL), during infusion of saline at 10 mL/min (rest) and 20 mL/min (hyperemia). A strong correlation was found between continuous thermodilution-derived MRR and Doppler MRR (r = 0.88; 95% confidence interval: 0.72-0.93; P < 0.001). MRR was independent from the epicardial resistance, the lower the FFR value, the greater the difference between MRR and CFR. Therefore, MRR is proposed as a specific, quantitative, and operator-independent metric to quantify coronary microvascular dysfunction.

Copyright © 2021. Published by Elsevier Inc.

J Am Coll Cardiol: 11 Oct 2021; 78:1541-1549
De Bruyne B, Pijls NHJ, Gallinoro E, Candreva A, ... Collet C, Fearon WF
J Am Coll Cardiol: 11 Oct 2021; 78:1541-1549 | PMID: 34620412
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Abstract

Comparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT.

Gaba P, Bhatt DL, Giugliano RP, Steg PG, ... Budoff MJ, Gibson CM
Background
REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE.
Objectives
The purpose of this study was to determine the effects of IPE on investigator-reported events.
Methods
Potential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. Investigator-reported events were compared with adjudicated events for concordance.
Results
There was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. Based on investigator-reported events in 8,179 randomized patients, IPE significantly reduced the rate of the primary endpoint (19.1% vs 24.6%; HR: 0.74 [95% CI: 0.67-0.81]; P < 0.0001) and the key secondary endpoint (10.5% vs 13.6%; HR: 0.75 [95% CI: 0.66-0.85]; P < 0.0001). Among adjudicated events, IPE similarly reduced the rate of the primary and key secondary endpoints.
Conclusions
IPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361).

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 11 Oct 2021; 78:1525-1537
Gaba P, Bhatt DL, Giugliano RP, Steg PG, ... Budoff MJ, Gibson CM
J Am Coll Cardiol: 11 Oct 2021; 78:1525-1537 | PMID: 34620410
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Abstract

Biventricular Myocardial Fibrosis and Sudden Death in Patients With Brugada Syndrome.

Miles C, Asimaki A, Ster IC, Papadakis M, ... Sheppard MN, Behr ER
Background
Electrophysiological, imaging, and pathological studies have reported the presence of subtle structural abnormalities in hearts from patients with Brugada syndrome (BrS). However, data concerning disease involvement outside of the right ventricular outflow tract are limited.
Objectives
This study sought to characterize the presence and distribution of ventricular myocardial fibrosis in a cohort of decedents experiencing sudden cardiac death caused by BrS.
Methods
The authors evaluated 28 whole hearts from consecutive sudden cardiac death cases attributed to BrS and 29 hearts from a comparator group comprised of noncardiac deaths (control subjects). Cardiac tissue from 6 regions across the right and left ventricle were stained with Picrosirius red for collagen and tissue composition was determined using image analysis software. Postmortem genetic testing was performed in cases with DNA retained for analysis.
Results
Of 28 BrS decedents (75% men; median age of death 25 years), death occurred in sleep or at rest in 24 of 28 (86%). The highest proportion of collagen was observed in the epicardial right ventricular outflow tract of the BrS group (23.7%; 95% CI: 20.8%-26.9%). Ventricular myocardium from BrS decedents demonstrated a higher proportion of collagen compared with control subjects (ratio 1.45; 95% CI: 1.22-1.71; P < 0.001), with no significant interactions with respect to sampling location or tissue layer. There was insufficient evidence to support differences in collagen proportion in SCN5A-positive cases (n = 5) when compared with control subjects (ratio 1.23; 95% CI: 0.75-1.43; P = 0.27).
Conclusions
Brugada syndrome is associated with increased collagen content throughout right and left ventricular myocardium, irrespective of sampling location or myocardial layer.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 11 Oct 2021; 78:1511-1521
Miles C, Asimaki A, Ster IC, Papadakis M, ... Sheppard MN, Behr ER
J Am Coll Cardiol: 11 Oct 2021; 78:1511-1521 | PMID: 34620408
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Abstract

Baseline Low-Density Lipoprotein Cholesterol and Clinical Outcomes of Combining Ezetimibe With Statin Therapy in IMPROVE-IT.

Oyama K, Giugliano RP, Blazing MA, Park JG, ... Cannon CP, Braunwald E
Background
The 2018 U.S. cholesterol management guideline recommends additional lipid-lowering therapy with ezetimibe for secondary prevention in very high-risk patients with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL despite maximally tolerated statin.
Objectives
The purpose of this study was to evaluate the relationship between baseline LDL-C above and below 70 mg/dL and the benefit of adding ezetimibe to statin in patients post-acute coronary syndrome (ACS).
Methods
IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a double-blind, placebo-controlled, randomized trial of ezetimibe/simvastatin vs placebo/simvastatin in post-ACS patients followed for 6 years (median). A total of 17,999 patients were stratified by LDL-C at qualifying event into 3 groups (50-<70, 70-<100, and 100-125 mg/dL). The primary endpoint was a composite of cardiovascular death, major coronary events, or stroke.
Results
Absolute differences in median LDL-C achieved at 4 months between treatment arms were similar (17-20 mg/dL). The effect of ezetimibe/simvastatin vs placebo/simvastatin on primary endpoint was consistent regardless of baseline LDL-C of 50-<70 mg/dL (HR: 0.92 [95% CI: 0.80-1.05]), 70-<100 mg/dL (HR: 0.93 [95% CI: 0.87-1.01]), or 100-125 mg/dL (HR: 0.94 [95% CI: 0.86-1.03]; P interaction = 0.95). Normalized relative risk reductions per 1-mmol/L difference in achieved LDL-C at 4 months between treatment arms were 21% in patients with baseline LDL-C of 50-<70 mg/dL, 16% in those with 70-<100 mg/dL, and 13% in those with 100-125 mg/dL (P interaction = 0.91). No significant treatment interactions by baseline LDL-C were present for safety endpoints.
Conclusions
Adding ezetimibe to statin consistently reduced the risk for cardiovascular events in post-ACS patients irrespective of baseline LDL-C values, supporting the use of intensive lipid-lowering therapy with ezetimibe even in patients with baseline LDL-C <70 mg/dL. (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878).

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 11 Oct 2021; 78:1499-1507
Oyama K, Giugliano RP, Blazing MA, Park JG, ... Cannon CP, Braunwald E
J Am Coll Cardiol: 11 Oct 2021; 78:1499-1507 | PMID: 34620406
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Impact:
Abstract

On-Treatment Blood Pressure and Cardiovascular Outcomes in Adults With Hypertension and Left Ventricular Hypertrophy.

Lee HH, Lee H, Cho SMJ, Kim DW, Park S, Kim HC
Background
Benefits of intensive blood pressure lowering on health outcomes have been demonstrated in high-risk patients. However, little is known about such benefits in patients with left ventricular hypertrophy (LVH).
Objectives
This study sought to investigate the association of on-treatment blood pressure with cardiovascular disease (CVD) risk in adults with hypertension and LVH.
Methods
From a nationwide health examination database, this study identified 95,545 participants aged 40-79 years who were taking antihypertensive medication and had LVH on baseline electrocardiography. Using Cox models, HRs and 95% CIs for CVD events were calculated according to systolic blood pressure (SBP) or diastolic blood pressure (DBP).
Results
Over a median follow-up of 11.5 years, 12,035 new CVD events occurred. An SBP of <130 mm Hg and DBP of <80 mm Hg were associated with the lowest risk for CVD events in cubic spline models. When the group with SBP of 120-129 mm Hg was the reference, multivariable-adjusted HRs were 1.31 (95% CI: 1.24-1.38) in the ≥140 mm Hg group, 1.08 (95% CI: 1.02-1.15) in the 130-139 mm Hg group, and 1.03 (95% CI: 0.93-1.15) in the <120 mm Hg group. Likewise, when the group with DBP of 70-79 mm Hg was the reference, multivariable-adjusted HRs were 1.30 (95% CI: 1.24-1.37) in the ≥90 mm Hg group, 1.06 (95% CI: 1.01-1.12) in the 80-89 mm Hg group, and 1.08 (95% CI: 0.96 to 1.20) in the <70 mm Hg group.
Conclusions
In adults with hypertension and LVH, the risk for CVD events was the lowest at SBP <130 mm Hg and DBP <80 mm Hg. Further randomized trials are warranted to establish optimal blood pressure-lowering strategies for these patients.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 11 Oct 2021; 78:1485-1495
Lee HH, Lee H, Cho SMJ, Kim DW, Park S, Kim HC
J Am Coll Cardiol: 11 Oct 2021; 78:1485-1495 | PMID: 34620404
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Abstract

Assessing Microvascular Dysfunction in Angina With Unobstructed Coronary Arteries: JACC Review Topic of the Week.

Jansen TPJ, Konst RE, Elias-Smale SE, van den Oord SC, ... van Royen N, Damman P
Coronary microvascular dysfunction is a highly prevalent condition of both structural and functional coronary disorders in patients with angina and nonobstructive coronary artery disease (ANOCA). Current diagnostic modalities to assess microvascular function are related to prognosis, but these modalities have several technical shortcomings and lack the opportunity to determine true coronary blood flow and microvascular resistance. Intracoronary continuous thermodilution assessment of absolute coronary flow (Q) and microvascular resistance (R) was recently shown to be safe and feasible in ANOCA. Further exploration and implementation could lead to a better understanding and treatment of patients with ANOCA. This review discuss the coronary pathophysiology of microvascular dysfunction, provides an overview of noninvasive and invasive diagnostics, and focuses on the novel continuous thermodilution method. Finally, how these measurements of absolute Q and R could be integrated and how this would affect future clinical care are discussed.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 04 Oct 2021; 78:1471-1479
Jansen TPJ, Konst RE, Elias-Smale SE, van den Oord SC, ... van Royen N, Damman P
J Am Coll Cardiol: 04 Oct 2021; 78:1471-1479 | PMID: 34593129
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Impact:
Abstract

Exercise-Induced Cardiovascular Adaptations and Approach to Exercise and Cardiovascular Disease: JACC State-of-the-Art Review.

Martinez MW, Kim JH, Shah AB, Phelan D, ... Chung EH, Levine BD
The role of the sports cardiologist has evolved into an essential component of the medical care of athletes. In addition to the improvement in health outcomes caused by reductions in cardiovascular risk, exercise results in adaptations in cardiovascular structure and function, termed exercise-induced cardiac remodeling. As diagnostic modalities have evolved over the last century, we have learned much about the healthy athletic adaptation that occurs with exercise. Sports cardiologists care for those with known or previously unknown cardiovascular conditions, distinguish findings on testing as physiological adaptation or pathological changes, and provide evidence-based and \"best judgment\" assessment of the risks of sports participation. We review the effects of exercise on the heart, the approach to common clinical scenarios in sports cardiology, and the importance of a patient/athlete-centered, shared decision-making approach in the care provided to athletes.

Copyright © 2021. Published by Elsevier Inc.

J Am Coll Cardiol: 04 Oct 2021; 78:1453-1470
Martinez MW, Kim JH, Shah AB, Phelan D, ... Chung EH, Levine BD
J Am Coll Cardiol: 04 Oct 2021; 78:1453-1470 | PMID: 34593128
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Impact:
Abstract

Hepatic Sensing Loop Regulates PCSK9 Secretion in Response to Inhibitory Antibodies.

Oleaga C, Shapiro MD, Hay J, Mueller PA, ... Pamir N, Fazio S
Background
Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9i) lower LDL-C by up to 60% and increase plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels by 10-fold.
Objectives
The authors studied the reasons behind the robust increase in plasma PCSK9 levels by testing the hypothesis that mechanisms beyond clearance via the low-density lipoprotein receptor (LDLR) contribute to the regulation of cholesterol homeostasis.
Methods
In clinical cohorts, animal models, and cell-based studies, we measured kinetic changes in PCSK9 production and clearance in response to PCSK9i.
Results
In a patient cohort receiving PCSK9i therapy, plasma PCSK9 levels rose 11-fold during the first 3 months and then plateaued for 15 months. In a cohort of healthy volunteers, a single injection of PCSK9i increased plasma PCSK9 levels within 12 hours; the rise continued for 9 days until it plateaued at 10-fold above baseline. We recapitulated the rapid rise in PCSK9 levels in a mouse model, but only in the presence of LDLR. In vivo turnover and in vitro pulse-chase studies identified 2 mechanisms contributing to the rapid increase in plasma PCSK9 levels in response to PCSK9i: 1) the expected delayed clearance of the antibody-bound PCSK9; and 2) the unexpected post-translational increase in PCSK9 secretion.
Conclusions
PCSK9 re-entry to the liver via LDLR triggers a sensing loop regulating PCSK9 secretion. PCSK9i therapy enhances the secretion of PCSK9, an effect that contributes to the increased plasma PCSK9 levels in treated subjects.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 04 Oct 2021; 78:1437-1449
Oleaga C, Shapiro MD, Hay J, Mueller PA, ... Pamir N, Fazio S
J Am Coll Cardiol: 04 Oct 2021; 78:1437-1449 | PMID: 34593126
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Abstract

Association of Circulating Ketone Bodies With Functional Outcomes After ST-Segment Elevation Myocardial Infarction.

de Koning MLY, Westenbrink BD, Assa S, Garcia E, ... Lipsic E, van der Harst P
Background
Circulating ketone bodies (KBs) are increased in patients with heart failure (HF), corresponding with increased cardiac KB metabolism and HF severity. However, the role of circulating KBs in ischemia/reperfusion remains unknown.
Objectives
This study sought to investigate longitudinal changes of KBs and their associations with functional outcomes in patients presenting with ST-segment elevation myocardial infarction (STEMI).
Methods
KBs were measured in 369 participants from a randomized trial on early metformin therapy after STEMI. Nonfasting plasma concentrations of KBs (β-hydroxybutyrate, acetoacetate, and acetone) were measured by nuclear magnetic resonance spectroscopy at presentation, at 24 hours, and after 4 months. Myocardial infarct size and left ventricular ejection fraction (LVEF) were determined by cardiac magnetic resonance imaging at 4 months. Associations of circulating KBs with infarct size and LVEF were determined using multivariable linear regression analyses.
Results
Circulating KBs were high at presentation with STEMI (median total KBs: 520 μmol/L; interquartile range [IQR]: 315-997 μmol/L). At 24 hours after reperfusion, KBs were still high compared with levels at 4-month follow-up (206 μmol/L [IQR: 174-246] vs 166 μmol/L [IQR: 143-201], respectively; P < 0.001). Increased KB concentrations at 24 hours were independently associated with larger myocardial infarct size (total KBs, per 100 μmol/L: β = 1.56; 95% confidence interval: 0.29-2.83; P = 0.016) and lower LVEF (β = -1.78; 95% CI: (-3.17 to -0.39; P = 0.012).
Conclusions
Circulating KBs are increased in patients presenting with STEMI. Higher KBs at 24 hours are associated with functional outcomes after STEMI, which suggests a potential role for ketone metabolism in response to myocardial ischemia. (Metabolic Modulation With Metformin to Reduce Heart Failure After Acute Myocardial Infarction: Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III): a Randomized Controlled Trial; NCT01217307).

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 04 Oct 2021; 78:1421-1432
de Koning MLY, Westenbrink BD, Assa S, Garcia E, ... Lipsic E, van der Harst P
J Am Coll Cardiol: 04 Oct 2021; 78:1421-1432 | PMID: 34593124
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Impact:
Abstract

Troponin-Guided Coronary Computed Tomographic Angiography After Exclusion of Myocardial Infarction.

Lee KK, Bularga A, O\'Brien R, Ferry AV, ... Gray AJ, Mills NL
Background
Patients with suspected acute coronary syndrome in whom myocardial infarction has been excluded are at risk of future adverse cardiac events.
Objectives
This study evaluated the usefulness of high-sensitivity cardiac troponin I (hs-cTnI) to select patients for further investigation after myocardial infarction has been excluded.
Methods
This is a prospective cohort study of patients presenting to the emergency department with suspected acute coronary syndrome and hs-cTnI concentrations below the sex-specific 99th percentile. Patients were recruited in a 2:1 fashion, stratified by peak hs-cTnI concentration above and below the risk stratification threshold of 5 ng/L. All patients underwent coronary computed tomography angiography (CCTA) after hospital discharge.
Results
Overall, 250 patients were recruited (61.4 ± 12.2 years 31% women) in whom 62.4% (156 of 250 patients) had coronary artery disease (CAD). Patients with intermediate hs-cTnI concentrations (between 5 ng/L and the sex-specific 99th percentile) were more likely to have CAD than those with hs-cTnI concentrations <5 ng/L (71.9% [120 of 167 patients] vs 43.4% [36 of 83 patients]; odds ratio: 3.33; 95% CI: 1.92-5.78). Conversely, there was no association between anginal symptoms and CAD (63.2% [67 of 106 patients] vs 61.8% [89 of 144 patients]; odds ratio: 0.92; 95% CI: 0.48-1.76). Most patients with CAD did not have a previous diagnosis (53.2%; 83 of 156 patients) and were not on antiplatelet and statin therapies (63.5%; 99 of 156 patients) before they underwent CCTA.
Conclusions
In patients who had myocardial infarction excluded, CAD was 3× more likely in those with intermediate hs-cTnI concentrations compared with low hs-cTnI concentrations. In such patients, CCTA could help to identify those with occult CAD and to target preventative treatments, thereby improving clinical outcomes.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 04 Oct 2021; 78:1407-1417
Lee KK, Bularga A, O'Brien R, Ferry AV, ... Gray AJ, Mills NL
J Am Coll Cardiol: 04 Oct 2021; 78:1407-1417 | PMID: 34593122
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Impact:
Abstract

Three- Versus Two-Drug Therapy for Patients With Newly Diagnosed Pulmonary Arterial Hypertension.

Chin KM, Sitbon O, Doelberg M, Feldman J, ... Simonneau G, Galiè N
Background
In pulmonary arterial hypertension (PAH), there are no data comparing initial triple oral therapy with initial double oral therapy.
Objectives
TRITON (The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension; NCT02558231), a multicenter, double-blind, randomized phase 3b study, evaluated initial triple (macitentan, tadalafil, and selexipag) versus initial double (macitentan, tadalafil, and placebo) oral therapy in newly diagnosed, treatment-naive patients with PAH.
Methods
Efficacy was assessed until the last patient randomized completed week 26 (end of main observation period). The primary endpoint was change in pulmonary vascular resistance (PVR) at week 26.
Results
Patients were assigned to initial triple (n = 123) or initial double therapy (n = 124). At week 26, both treatment strategies reduced PVR compared with baseline (by 54% and 52%), with no significant difference between groups (ratio of geometric means: 0.96; 95% confidence interval: 0.86-1.07; P = 0.42). Six-minute walk distance and N-terminal pro-brain natriuretic peptide improved by week 26, with no difference between groups. Risk for disease progression (to end of main observation period) was reduced with initial triple versus initial double therapy (hazard ratio: 0.59; 95% confidence interval: 0.32-1.09). Most common adverse events with initial triple therapy included headache, diarrhea, and nausea. By the end of the main observation period, 2 patients in the initial triple and 9 in the initial double therapy groups had died.
Conclusions
In patients with newly diagnosed PAH, both treatment strategies markedly reduced PVR by week 26, with no significant difference between groups (primary endpoint not met). Exploratory analyses suggested a possible signal for improved long-term outcomes with initial triple versus initial double oral therapy.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 04 Oct 2021; 78:1393-1403
Chin KM, Sitbon O, Doelberg M, Feldman J, ... Simonneau G, Galiè N
J Am Coll Cardiol: 04 Oct 2021; 78:1393-1403 | PMID: 34593120
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Impact:
Abstract

Surveillance Imaging Following Acute Type A Aortic Dissection.

An KR, de Mestral C, Tam DY, Qiu F, ... Wijeysundera HC, Chung JC
Background
Survivors of acute type A aortic dissection (ATAAD) repair remain at risk for long-term complications. Guidelines recommend postoperative imaging surveillance, but adherence is uncertain.
Objectives
The aim of this study was to define the real-world frequency of postoperative imaging and characterize long-term outcomes of ATAAD.
Methods
Population-based administrative health databases for Ontario, Canada, were linked to identify patients who underwent ATAAD repair and survived at least 90 days. Guideline-directed imaging surveillance (GDIS) was defined as undergoing a computed tomographic or magnetic resonance imaging scan at 6 and 12 months postoperatively and then annually thereafter. Multivariable time-to-event analysis explored the associations between GDIS and all-cause mortality and reintervention.
Results
A total of 888 patients who survived urgent ATAAD repair between April 1, 2005, and March 31, 2018, were included. Median follow-up after ATAAD repair was 5.2 years (interquartile range: 2.4-7.9 years). A total of 14% patients received GDIS throughout follow-up. At 6 years, 3.9% of patients had received GDIS. The mortality rate was 4% at 1 year, 14% at 5 years, and 29% at 10 years. Incidence of aortic reintervention was 3% at 1 year, 9% at 5 years, and 17% at 10 years; the majority of these were urgent (68%), and they carried a 9% 30-day mortality rate. Greater adherence to GDIS was associated with mortality (hazard ratio: 1.08; 95% confidence interval: 1.05-1.11) and reintervention (hazard ratio: 1.04; 95% confidence interval: 1.01-1.07).
Conclusions
Adherence to GDIS following ATAAD repair is poor, while long-term mortality and reinterventions remain substantial. Further research is needed to determine if guidelines should be modified.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 04 Oct 2021; epub ahead of print
An KR, de Mestral C, Tam DY, Qiu F, ... Wijeysundera HC, Chung JC
J Am Coll Cardiol: 04 Oct 2021; epub ahead of print | PMID: 34696957
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Impact:
Abstract

Intracranial Hemorrhage During Dual Antiplatelet Therapy: JACC Review Topic of the Week.

Ha ACT, Bhatt DL, Rutka JT, Johnston SC, Mazer CD, Verma S
Dual antiplatelet therapy (DAPT) with acetylsalicylic acid and a P2Y12 inhibitor is an established therapy for a broad spectrum of patients with cardiovascular disease. The ischemic benefit of DAPT is partially offset by its increased bleeding risk, with intracranial hemorrhage (ICH) being the most serious complication. Although uncommon (0.2%-0.3% annually), its cumulative burden can be substantial given the number of patients afflicted by cardiovascular disease worldwide. Patients with a history of stroke or transient ischemic attack harbor a particularly high risk for ICH when treated with DAPT. Prediction rules may assist clinicians when weighing the risk/benefit ratio of prescribing DAPT for patients with stroke/transient ischemic attack in the nonacute, ambulatory setting. Currently, there are no reversal agents that can rapidly and effectively reverse the effect of P2Y12 inhibitors in routine practice, although a reversal agent for ticagrelor is under clinical investigation.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Sep 2021; 78:1372-1384
Ha ACT, Bhatt DL, Rutka JT, Johnston SC, Mazer CD, Verma S
J Am Coll Cardiol: 27 Sep 2021; 78:1372-1384 | PMID: 34556323
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Impact:
Abstract

Coronary Microvascular Dysfunction Across the Spectrum of Cardiovascular Diseases: JACC State-of-the-Art Review.

Del Buono MG, Montone RA, Camilli M, Carbone S, ... Niccoli G, Crea F
Coronary microvascular dysfunction (CMD) encompasses several pathogenetic mechanisms involving coronary microcirculation and plays a major role in determining myocardial ischemia in patients with angina without obstructive coronary artery disease, as well as in several other conditions, including obstructive coronary artery disease, nonischemic cardiomyopathies, takotsubo syndrome, and heart failure, especially the phenotype associated with preserved ejection fraction. Unfortunately, despite the identified pathophysiological and prognostic role of CMD in several conditions, to date, there is no specific treatment for CMD. Due to the emerging role of CMD as common denominator in different clinical phenotypes, additional research in this area is warranted to provide personalized treatments in this \"garden variety\" of patients. The purpose of this review is to describe the pathophysiological mechanisms of CMD and its mechanistic and prognostic role across different cardiovascular diseases. We will also discuss diagnostic modalities and the potential therapeutic strategies resulting from recent clinical studies.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Sep 2021; 78:1352-1371
Del Buono MG, Montone RA, Camilli M, Carbone S, ... Niccoli G, Crea F
J Am Coll Cardiol: 27 Sep 2021; 78:1352-1371 | PMID: 34556322
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Abstract

Empagliflozin Improves Cardiovascular and Renal Outcomes in Heart Failure Irrespective of Systolic Blood Pressure.

Böhm M, Anker SD, Butler J, Filippatos G, ... Packer M, EMPEROR-Reduced Trial Committees and Investigators
Background
Empagliflozin reduces the risk of cardiovascular death or heart failure (HF) hospitalization in patients with reduced ejection fraction. Its interplay with systolic blood pressure (SBP) is not known.
Objectives
The goal of this study was to evaluate the interplay of SBP and the effects of empagliflozin in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).
Methods
Study patients (N = 3,730) were randomly assigned to groups according to SBP at baseline (<110 mm Hg, n = 928; 110-130 mm Hg, n = 1,755; >130 mm Hg, n = 1,047). This study explored the influence of SBP on the effects of empagliflozin on cardiovascular death or HF hospitalization (primary outcome), as well as on total HF hospitalizations, rate of decline in estimated glomerular filtration rate, renal outcomes, and empagliflozin\'s effects and significance on SBP.
Results
Over a median of 16 months considering only patients receiving placebo, baseline SBP and the risk of cardiovascular death or hospitalization for HF (P trend = 0.0015) were inversely related. Corrected for placebo, a slight early increase was observed in SBP at <110 mm Hg, no change at 110-130 mm Hg, and a slight reduction at >130 mm Hg. These between-group differences were of borderline significance (P for interaction trend = 0.05-0.10) after 4 and 12 weeks but were not significant later. SBP at baseline did not influence the effect of empagliflozin to reduce the risk of HF events or renal endpoints. When treated with empagliflozin, patients with SBP <110 mm Hg did not have an increased rate of symptomatic hypotension.
Conclusions
Empagliflozin was effective and safe, with no meaningful interaction between SBP and the effects of empagliflozin in the EMPEROR-Reduced trial. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Sep 2021; 78:1337-1348
Böhm M, Anker SD, Butler J, Filippatos G, ... Packer M, EMPEROR-Reduced Trial Committees and Investigators
J Am Coll Cardiol: 27 Sep 2021; 78:1337-1348 | PMID: 34556320
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Impact:
Abstract

Prognostic Importance of NT-proBNP and Effect of Empagliflozin in the EMPEROR-Reduced Trial.

Januzzi JL, Zannad F, Anker SD, Butler J, ... Packer M, EMPEROR-Reduced Trial Committees and Investigators
Background
The relationship between the benefits of empagliflozin in heart failure with reduced ejection fraction (HFrEF) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) has not been reported.
Objectives
The authors sought to evaluate the relationship between NT-proBNP and empagliflozin effects in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).
Methods
Patients with HFrEF were randomly assigned to placebo or empagliflozin 10 mg daily. NT-proBNP was measured at baseline, 4 weeks, 12 weeks, 52 weeks, and 100 weeks. Patients were divided into quartiles of baseline NT-proBNP.
Results
Incidence rates for each study outcome were 4- to 6-fold higher among those in the highest versus lowest NT-proBNP quartiles (≥3,480 vs <1,115 pg/mL). Study participants with higher NT-proBNP had 2- to 3-fold total hospitalizations higher than the lowest NT-proBNP quartile. Empagliflozin reduced risk for major cardiorenal events without heterogeneity across NT-proBNP quartiles (primary endpoint Pinteraction = 0.94; renal composite endpoint Pinteraction = 0.71). Empagliflozin treatment significantly reduced NT-proBNP at all timepoints examined; by 52 weeks, the adjusted mean difference from placebo was 13% (P < 0.001). An NT-proBNP in the lowest quartile (<1,115 pg/mL) 12 weeks after randomization was associated with lower risk for subsequent cardiovascular death or heart failure hospitalization regardless of baseline concentration. Treatment with empagliflozin resulted in 27% higher adjusted odds of an NT-proBNP concentration of <1,115 pg/mL by 12 weeks compared with placebo (P = 0.01).
Conclusions
In EMPEROR-Reduced, higher baseline NT-proBNP concentrations were associated with greater risk for adverse heart failure or renal outcomes, but empagliflozin reduced risk regardless of baseline NT-proBNP concentration. The NT-proBNP concentration after treatment with empagliflozin better informs subsequent prognosis than pretreatment concentrations. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Sep 2021; 78:1321-1332
Januzzi JL, Zannad F, Anker SD, Butler J, ... Packer M, EMPEROR-Reduced Trial Committees and Investigators
J Am Coll Cardiol: 27 Sep 2021; 78:1321-1332 | PMID: 34556318
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Impact:
Abstract

Management and Outcomes of Cardiogenic Shock in Cardiac ICUs With Versus Without Shock Teams.

Papolos AI, Kenigsberg BB, Berg DD, Alviar CL, ... Barnett CF, Critical Care Cardiology Trials Network Investigators
Background
Single-center studies suggest that implementation of multidisciplinary cardiogenic shock (CS) teams is associated with improved CS survival.
Objectives
The aim was to characterize practice patterns and outcomes in the management of CS across multiple centers with versus without shock teams.
Methods
The Critical Care Cardiology Trials Network is a multicenter network of cardiac intensive care units (CICUs) in North America. All consecutive medical admissions to each CICU (n = 24) were captured during annual 2-month collection periods (2017-2019; n = 6,872). Shock management and CICU mortality among centers with versus without shock teams were compared using inverse probability weighting.
Results
Ten of the 24 centers had shock teams. Among 1,242 CS admissions, 44% were at shock team centers. The groups were well-balanced with respect to demographics, shock etiology, Sequential Organ Failure Assessment score, biochemical markers of end organ dysfunction, and invasive hemodynamics. Centers with shock teams used more pulmonary artery catheters (60% vs 49%; adjusted odds ratio [OR]: 1.86; 95% CI: 1.47-2.35; P < 0.001), less overall mechanical circulatory support (MCS) (35% vs 43%; adjusted OR: 0.74; 95% CI: 0.59-0.95; P = 0.016), and more advanced types of MCS (53% vs 43% of all MCS; adjusted OR: 1.73; 95% CI: 1.19-2.51; P = 0.005) rather than intra-aortic balloon pumps. The presence of a shock team was independently associated with lower CICU mortality (23% vs 29%; adjusted OR: 0.72; 95% CI: 0.55-0.94; P = 0.016).
Conclusions
In this multicenter observational study, centers with shock teams were more likely to obtain invasive hemodynamics, use advanced types of MCS, and have lower risk-adjusted mortality. A standardized multidisciplinary shock team approach may improve outcomes in CS.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Sep 2021; 78:1309-1317
Papolos AI, Kenigsberg BB, Berg DD, Alviar CL, ... Barnett CF, Critical Care Cardiology Trials Network Investigators
J Am Coll Cardiol: 27 Sep 2021; 78:1309-1317 | PMID: 34556316
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Impact:
Abstract

Percutaneous Myocardial Revascularization in Late-Presenting Patients With STEMI.

Bouisset F, Gerbaud E, Bataille V, Coste P, ... Ferrières J, FAST-MI Investigators
Background
The optimal management of patients with ST-segment elevation myocardial infarction (STEMI) presenting late->12 hours following symptom onset-is still under debate.
Objectives
The purpose of this study was to describe characteristics, temporal trends, and impact of revascularization in a large population of latecomer STEMI patients.
Methods
The authors analyzed the data of 3 nationwide observational studies from the FAST-MI (French Registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction) program, conducted over a 1-month period in 2005, 2010, and 2015. Patients presenting between 12 and 48 hours after symptom onset were classified as latecomers.
Results
A total of 6,273 STEMI patients were included in the 3 cohorts, 1,169 (18.6%) of whom were latecomers. After exclusion of patients treated with fibrinolysis and patients deceased within 2 days after admission, 1,077 patients were analyzed, of whom 729 (67.7%) were revascularized within 48 hours after hospital admission. At 30-day follow-up, all-cause death rate was significantly lower among revascularized latecomers (2.1% vs 7.2%; P < 0.001). After a median follow-up of 58 months, the rate of all-cause death was 30.4 (95% CI: 25.7-35.9) per 1,000 patient-years in the revascularized latecomers group vs 78.7 (95% CI: 67.2-92.3) per 1,000 patient-years in the nonrevascularized latecomers group (P < 0.001). In multivariate analysis, revascularization of latecomer STEMI patients was independently associated with a significant reduction of mortality occurrence during follow-up (HR: 0.65 [95% CI: 0.50-0.84]; P = 0.001).
Conclusions
Coronary revascularization of latecomer STEMI patients is associated with better short and long-term clinical outcomes.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Sep 2021; 78:1291-1305
Bouisset F, Gerbaud E, Bataille V, Coste P, ... Ferrières J, FAST-MI Investigators
J Am Coll Cardiol: 27 Sep 2021; 78:1291-1305 | PMID: 34556314
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Abstract

Optical Coherence Tomography of Coronary Plaque Progression and Destabilization: JACC Focus Seminar Part 3/3.

Adriaenssens T, Allard-Ratick MP, Thondapu V, Sugiyama T, ... Kakuta T, Jang IK
The development of optical coherence tomography (OCT) has revolutionized our understanding of coronary artery disease. In vivo OCT research has paralleled with advances in computational fluid dynamics, providing additional insights in the various hemodynamic factors influencing plaque growth and stability. Recent OCT studies introduced a new concept of plaque healing in relation to clinical presentation. In addition to known mechanisms of acute coronary syndromes such as plaque rupture and plaque erosion, a new classification of calcified plaque was recently reported. This review will focus on important new insights that OCT has provided in recent years into coronary plaque development, progression, and destabilization, with a focus on the role of local hemodynamics and endothelial shear stress, the layered plaque (signature of previous subclinical plaque destabilization and healing), and the calcified culprit plaque.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Sep 2021; 78:1275-1287
Adriaenssens T, Allard-Ratick MP, Thondapu V, Sugiyama T, ... Kakuta T, Jang IK
J Am Coll Cardiol: 20 Sep 2021; 78:1275-1287 | PMID: 34531029
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Abstract

Optical Coherence Tomography of Plaque Erosion: JACC Focus Seminar Part 2/3.

Kolte D, Yonetsu T, Ye JC, Libby P, Fuster V, Jang IK
Plaque erosion, a distinct histopathological and clinical entity, accounts for over 30% of acute coronary syndromes (ACS). Optical coherence tomography allows in vivo diagnosis of plaque erosion. Local flow perturbation with activation of Toll-like receptor 2 and CD8+ T cells and subsequent desquamation of endothelium and neutrophil extracellular trap formation contribute to mechanisms of plaque erosion. Compared with ACS patients with plaque rupture, those with plaque erosion are younger, have fewer traditional cardiovascular risk factors, have lower plaque burden, and are more likely to present with non-ST-segment elevation ACS. Early evidence suggests that in patients with ACS caused by plaque erosion, antithrombotic therapy without stenting may be a safe and effective option. Future randomized trials are needed to validate these findings. Clinical studies to develop noninvasive point-of-care biomarkers that distinguish plaque rupture from erosion, and to test novel therapies that target molecular pathways involved in plaque erosion are needed.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Sep 2021; 78:1266-1274
Kolte D, Yonetsu T, Ye JC, Libby P, Fuster V, Jang IK
J Am Coll Cardiol: 20 Sep 2021; 78:1266-1274 | PMID: 34531028
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Abstract

Optical Coherence Tomography of Plaque Vulnerability and Rupture: JACC Focus Seminar Part 1/3.

Aguirre AD, Arbab-Zadeh A, Soeda T, Fuster V, Jang IK
Plaque rupture is the most common cause of acute coronary syndromes and sudden cardiac death. Characteristics and pathobiology of vulnerable plaques prone to plaque rupture have been studied extensively over 2 decades in humans using optical coherence tomography (OCT), an intravascular imaging technique with micron scale resolution. OCT studies have identified key features of plaque vulnerability and described the in vivo characteristics and spatial distribution of thin cap fibroatheromas as major precursors to plaque rupture. In addition, OCT data supports the evolving understanding of coronary heart disease as a panvascular process associated with inflammation. In the setting of high atherosclerotic burden, plaque ruptures often occur at multiple sites in the coronary arteries, and plaque progression and healing are dynamic processes modulated by systemic risk factors. This review details major investigations with intravascular OCT into the biology and clinical implications of plaque vulnerability and plaque rupture.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Sep 2021; 78:1257-1265
Aguirre AD, Arbab-Zadeh A, Soeda T, Fuster V, Jang IK
J Am Coll Cardiol: 20 Sep 2021; 78:1257-1265 | PMID: 34531027
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Abstract

Hospitalizations and Outcomes of T1MI Observed Before and After the Introduction of MI Subtype Codes.

McCarthy CP, Kolte D, Kennedy KF, Pandey A, ... Januzzi JL, Wasfy JH
Background
International Classification of Disease (ICD)-10 coding of type 1 myocardial infarction (MI) is used for reimbursement, value-based programs, and clinical research.
Objectives
This study sought to determine whether the introduction of ICD-10 codes for type 2 and types 3-5 MI was associated with changes in hospitalizations for ICD-10 codes now attributed to type 1 MI.
Methods
Using the Nationwide Readmissions Database, we identified patients with ICD-10 codes now attributed to type 1 MI between January 2016 and December 2018. Patients were stratified according to the timing of their event in relation to the introduction of the type 2 and types 3-5 MI codes on October 1, 2017.
Results
There were 2,680,323 hospitalizations for ICD-10 codes now attributed to type 1 MI; after adjustment for seasonality, there was a 13.7% decline in hospitalizations after the introduction of the new subtype codes. Patients with ICD-10 codes now attributed to type 1 MI after the coding change were less likely to be female, had lower prevalence of several cardiovascular and noncardiovascular comorbidities, and had higher rates of coronary angiography and revascularization. After introduction of the new codes, there was a positive deflection in the slope of risk-adjusted in-hospital mortality (0.007%; P <0.001) and a negative deflection in risk-adjusted 30-day readmission (-0.002%; P = 0.05) for patients with ICD-10 codes now attributed to type 1 MI.
Conclusions
The introduction of ICD-10 codes for type 2 and types 3-5 MI was associated with a decrease in hospitalizations for ICD-10 codes now attributed to type 1 MI and changes in the observed characteristics and treatment patterns of these patients.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Sep 2021; 78:1242-1253
McCarthy CP, Kolte D, Kennedy KF, Pandey A, ... Januzzi JL, Wasfy JH
J Am Coll Cardiol: 20 Sep 2021; 78:1242-1253 | PMID: 34531025
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Impact:
Abstract

External Validation of the SYNTAX Score II 2020.

Hara H, Shiomi H, van Klaveren D, Kent DM, ... Kimura T, Serruys PW
Background
The SYNTAX score II 2020 (SSII-2020) was derived from cross correlation and externally validated in randomized trials to predict death and major adverse cardiac and cerebrovascular events (MACE) following percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with 3-vessel disease (3VD) and/or left main coronary artery disease (LMCAD).
Objectives
The authors aimed to investigate the SSII-2020\'s value in identifying the safest modality of revascularization in a non-randomized setting.
Methods
Five-year mortality and MACE were assessed in 7,362 patients with 3VD and/or LMCAD enrolled in a Japanese PCI/CABG registry. The discriminative abilities of the SSII-2020 were assessed using Harrell\'s C statistic. Agreement between observed and predicted event rates following PCI or CABG and treatment benefit (absolute risk difference [ARD]) for these outcomes were assessed by calibration plots.
Results
The SSII-2020 for 5-year mortality well predicted the prognosis after PCI and CABG (C-index = 0.72, intercept = -0.11, slope = 0.92). When patients were grouped according to the predicted 5-year mortality ARD, <4.5% (equipoise of PCI and CABG) and ≥4.5% (CABG better), the observed mortality rates after PCI and CABG were not significantly different in patients with lower predicted ARD (observed ARD: 2.1% [95% CI: -0.4% to 4.4%]), and the significant difference in survival in favor of CABG was observed in patients with higher predicted ARD (observed ARD: 9.7% [95% CI: 6.1%-13.3%]). For MACE, the SSII-2020 could not recommend a specific treatment with sufficient accuracy.
Conclusions
The SSII-2020 for predicting 5-year death has the potential to support decision making on revascularization in patients with 3VD and/or LMCAD.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Sep 2021; 78:1227-1238
Hara H, Shiomi H, van Klaveren D, Kent DM, ... Kimura T, Serruys PW
J Am Coll Cardiol: 20 Sep 2021; 78:1227-1238 | PMID: 34531023
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Impact:
Abstract

Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment.

Howard JP, Wood FA, Finegold JA, Nowbar AN, ... Shun-Shin MJ, Francis DP
Background
Most people who begin statins abandon them, most commonly because of side effects.
Objectives
The purpose of this study was to assess daily symptom scores on statin, placebo, and no treatment in participants who had abandoned statins.
Methods
Participants received 12 1-month medication bottles, 4 containing atorvastatin 20 mg, 4 placebo, and 4 empty. We measured daily symptom intensity for each using an app (scale 1-100). We also measured the \"nocebo\" ratio: the ratio of symptoms induced by taking statin that was also induced by taking placebo.
Results
A total of 60 participants were randomized and 49 completed the 12-month protocol. Mean symptom score was 8.0 (95% CI: 4.7-11.3) in no-tablet months. It was higher in statin months (16.3; 95% CI: 13.0-19.6; P < 0.001), but also in placebo months (15.4; 95% CI: 12.1-18.7; P < 0.001), with no difference between the 2 (P = 0.388). The corresponding nocebo ratio was 0.90. In the individual-patient daily data, neither symptom intensity on starting (OR: 1.02; 95% CI: 0.98-1.06; P = 0.28) nor extent of symptom relief on stopping (OR: 1.01; 95% CI: 0.98-1.05; P = 0.48) distinguished between statin and placebo. Stopping was no more frequent for statin than placebo (P = 0.173), and subsequent symptom relief was similar between statin and placebo. At 6 months after the trial, 30 of 60 (50%) participants were back taking statins.
Conclusions
The majority of symptoms caused by statin tablets were nocebo. Clinicians should not interpret symptom intensity or timing of symptom onset or offset (on starting or stopping statin tablets) as indicating pharmacological causation, because the pattern is identical for placebo. (Self-Assessment Method for Statin Side-effects Or Nocebo [SAMSON]; NCT02668016).

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Sep 2021; 78:1210-1222
Howard JP, Wood FA, Finegold JA, Nowbar AN, ... Shun-Shin MJ, Francis DP
J Am Coll Cardiol: 20 Sep 2021; 78:1210-1222 | PMID: 34531021
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Abstract

Healthy Sleep Patterns and Risk of Incident Arrhythmias.

Li X, Zhou T, Ma H, Huang T, ... Manson JE, Qi L
Background
Emerging evidence has linked sleep behaviors with the risk of cardiac arrhythmias. The various sleep behaviors are typically correlated; however, most of the previous studies only focused on the individual sleep behavior, without considering the overall sleep patterns.
Objectives
The purpose of this study was to prospectively investigate the associations between a healthy sleep pattern with the risks of cardiac arrhythmias.
Methods
A total of 403,187 participants from UK Biobank were included. A healthy sleep pattern was defined by chronotype, sleep duration, insomnia, snoring, and daytime sleepiness. Weighted genetic risk score for atrial fibrillation was calculated.
Results
The healthy sleep pattern was significantly associated with lower risks of atrial fibrillation/flutter (AF) (HR comparing extreme categories: 0.71; 95% CI: 0.64-0.80) and bradyarrhythmia (HR: 0.65; 95% CI: 0.54-0.77), but not ventricular arrhythmias, after adjustment for demographic, lifestyle, and genetic risk factors. Compared with individuals with a healthy sleep score of 0-1 (poor sleep group), those with a healthy sleep score of 5 had a 29% and 35% lower risk of developing AF and bradyarrhythmia, respectively. Additionally, the genetic predisposition to AF significantly modified the association of the healthy sleep pattern with the risk of AF (P interaction = 0.017). The inverse association of the healthy sleep pattern with the risk of AF was stronger among those with a lower genetic risk of AF.
Conclusions
Our results indicate that a healthy sleep pattern is associated with lower risks of AF and bradyarrhythmia, independent of traditional risk factors, and the association with AF is modified by genetic susceptibility.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Sep 2021; 78:1197-1207
Li X, Zhou T, Ma H, Huang T, ... Manson JE, Qi L
J Am Coll Cardiol: 20 Sep 2021; 78:1197-1207 | PMID: 34531019
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Impact:
Abstract

Exercise Intolerance in Older Adults With Heart Failure With Preserved Ejection Fraction: JACC State-of-the-Art Review.

Pandey A, Shah SJ, Butler J, Kellogg DL, ... Pipinos II, Kitzman D
Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the rationale for a transdisciplinary, \"gero-centric\" approach to advance our understanding of EI in HFpEF and identify promising new therapeutic targets. We also provide a framework for prioritizing future research, including developing a uniform, comprehensive approach to phenotypic characterization of HFpEF, elucidating key geroscience targets for treatment, and conducting proof-of-concept trials to modify these targets.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 13 Sep 2021; 78:1166-1187
Pandey A, Shah SJ, Butler J, Kellogg DL, ... Pipinos II, Kitzman D
J Am Coll Cardiol: 13 Sep 2021; 78:1166-1187 | PMID: 34503685
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Impact:
Abstract

Medial Arterial Calcification: JACC State-of-the-Art Review.

Lanzer P, Hannan FM, Lanzer JD, Janzen J, ... Virmani R, St Hilaire C
Medial arterial calcification (MAC) is a chronic systemic vascular disorder distinct from atherosclerosis that is frequently but not always associated with diabetes mellitus, chronic kidney disease, and aging. MAC is also a part of more complex phenotypes in numerous less common diseases. The hallmarks of MAC include disseminated and progressive precipitation of calcium phosphate within the medial layer, a prolonged and clinically silent course, and compromise of hemodynamics associated with chronic limb-threatening ischemia. MAC increases the risk of complications during vascular interventions and mitigates their outcomes. With the exception of rare monogenetic defects affecting adenosine triphosphate metabolism, MAC pathogenesis remains unknown, and causal therapy is not available. Implementation of genetics and omics-based approaches in research recognizing the critical importance of calcium phosphate thermodynamics holds promise to unravel MAC molecular pathogenesis and to provide guidance for therapy. The current state of knowledge concerning MAC is reviewed, and future perspectives are outlined.

Copyright © 2021 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 13 Sep 2021; 78:1145-1165
Lanzer P, Hannan FM, Lanzer JD, Janzen J, ... Virmani R, St Hilaire C
J Am Coll Cardiol: 13 Sep 2021; 78:1145-1165 | PMID: 34503684
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Abstract

Innate Lymphoid Cells Promote Recovery of Ventricular Function After Myocardial Infarction.

Yu X, Newland SA, Zhao TX, Lu Y, ... Cheriyan J, Mallat Z
Background
Innate lymphoid cells type 2 (ILC2s) play critical homeostatic functions in peripheral tissues. ILC2s reside in perivascular niches and limit atherosclerosis development.
Objectives
ILC2s also reside in the pericardium but their role in postischemic injury is unknown.
Methods
We examined the role of ILC2 in a mouse model of myocardial infarction (MI), and compared mice with or without genetic deletion of ILC2. We determined infarct size using histology and heart function using echocardiography. We assessed cardiac ILC2 using flow cytometry and RNA sequencing. Based on these data, we devised a therapeutic strategy to activate ILC2 in mice with acute MI, using exogenous interleukin (IL)-2. We also assessed the ability of low-dose IL-2 to activate ILC2 in a double-blind randomized clinical trial of patients with acute coronary syndromes (ACS).
Results
We found that ILC2 levels were increased in pericardial adipose tissue after experimental MI, and genetic ablation of ILC2 impeded the recovery of heart function. RNA sequencing revealed distinct transcript signatures in ILC2, and pointed to IL-2 axis as a major upstream regulator. Treatment of T-cell-deficient mice with IL-2 (to activate ILC2) significantly improved the recovery of heart function post-MI. Administration of low-dose IL-2 to patients with ACS led to activation of circulating ILC2, with significant increase in circulating IL-5, a prototypic ILC2-derived cytokine.
Conclusions
ILC2s promote cardiac healing and improve the recovery of heart function after MI in mice. Activation of ILC2 using low-dose IL-2 could be a novel therapeutic strategy to promote a reparative response after MI.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 13 Sep 2021; 78:1127-1142
Yu X, Newland SA, Zhao TX, Lu Y, ... Cheriyan J, Mallat Z
J Am Coll Cardiol: 13 Sep 2021; 78:1127-1142 | PMID: 34503682
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Impact:
Abstract

Technology-Assisted Self-Selection of Candidates for Nonprescription Statin Therapy.

Nissen SE, Hutchinson HG, Wang TY, Ballantyne CM, ... Wolski K, Ridker PM
Background
Although statins reduce cardiovascular morbidity and mortality, only about one-half of eligible patients receive treatment. Safe and appropriate consumer access to statins could have a significant positive public health impact.
Objectives
This study compares the concordance between a participant and clinician assessment of eligibility for statin therapy using a technology-assisted approach.
Methods
A total of 500 participants, 83 with limited literacy, completed an at-home Web-based application to assess appropriateness for treatment with rosuvastatin 5 mg. The Web application is designed to assess eligibility for a moderate-intensity statin based on current guidelines and deny access to individuals with contraindications to rosuvastatin. Subsequently, participants visited a research site where clinicians, blinded to the information the participant entered, performed an independent Web application assessment. The Web application is programmed for 1 of 3 rosuvastatin treatment outcomes: \"OK to use,\" \"not right for you,\" or \"ask a doctor.\" The primary endpoint was the percent of participants whose self-selected eligibility for nonprescription rosuvastatin was concordant with clinician assessment.
Results
For the primary endpoint, participant selection for statin therapy was concordant with clinician selection in 481 (96.2%) of 500 participants (95% confidence interval: 94.1%-97.7%), of whom 23 (4.6%) were deemed appropriate and 458 (91.6%) were deemed inappropriate for treatment. Discordance was due to incorrect self-selection (\"OK to use\") in 3 cases, incorrect rejection (\"not right for you\") in 14 cases and an incorrect \"ask a doctor\" outcome in 2 cases.
Conclusions
The use of a technology-assisted approach to consumer self-selection for statin therapy resulted in participant self-selection that showed substantial agreement with clinician selection.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 13 Sep 2021; 78:1114-1123
Nissen SE, Hutchinson HG, Wang TY, Ballantyne CM, ... Wolski K, Ridker PM
J Am Coll Cardiol: 13 Sep 2021; 78:1114-1123 | PMID: 34503680
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Impact:
Abstract

Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy.

de Marvao A, McGurk KA, Zheng SL, Thanaj M, ... Ware JS, O\'Regan DP
Background
Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.
Objectives
The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults.
Methods
This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status.
Results
The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001).
Conclusions
In this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 13 Sep 2021; 78:1097-1110
de Marvao A, McGurk KA, Zheng SL, Thanaj M, ... Ware JS, O'Regan DP
J Am Coll Cardiol: 13 Sep 2021; 78:1097-1110 | PMID: 34503678
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Impact:
Abstract

High-Sensitivity C-Reactive Protein Modifies the Cardiovascular Risk of Lipoprotein(a): Multi-Ethnic Study of Atherosclerosis.

Zhang W, Speiser JL, Ye F, Tsai MY, ... Herrington DM, Shapiro MD
Background
Little is known about the relationship between lipoprotein (a) [Lp(a)] and high-sensitivity C-reactive protein (hsCRP) and their joint association with atherosclerotic cardiovascular disease (ASCVD).
Objectives
The purpose of this study was to assess whether Lp(a)-associated ASCVD risk is modified by hsCRP in the context of primary prevention.
Methods
The current study included 4,679 participants from the MESA (Multi-Ethnic Study of Atherosclerosis) Apolipoprotein ancillary data set. Cox proportional hazards models and Kaplan-Meier curves were used to assess the association among Lp(a), hsCRP, and time to cardiovascular disease (CVD) events.
Results
During a mean follow-up of 13.6 years, 684 CVD events occurred. A significant interaction was observed between Lp(a) and hsCRP (P = 0.04). With hsCRP <2 mg/L, no significant CVD risk was observed at any level of Lp(a) from <50 mg/dL to >100 mg/dL. However, with hsCRP ≥2 mg/L, a significant CVD risk was observed with Lp(a) of 50-99.9 mg/dL (HR: 1.36; 95% CI: 1.02-1.81) and Lp(a) ≥100 mg/dL (HR: 2.09; 95% CI: 1.40-3.13). Isolated elevations of either Lp(a) or hsCRP were not associated with increased CVD risk. In contrast, the combination of elevated Lp(a) (≥50 mg/dL) and hsCRP (≥2 mg/L) was independently associated with significant CVD risk (HR: 1.62; 95% CI: 1.25-2.10) and all-cause mortality (HR: 1.39; 95% CI: 1.12-1.72).
Conclusions
Lp(a)-associated ASCVD risk is observed only with concomitant elevation of hsCRP. Individuals with concomitant presence of elevated Lp(a) and systemic inflammation have greater ASCVD risk and all-cause mortality, and thus may merit closer surveillance and more aggressive ASCVD risk management.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 13 Sep 2021; 78:1083-1094
Zhang W, Speiser JL, Ye F, Tsai MY, ... Herrington DM, Shapiro MD
J Am Coll Cardiol: 13 Sep 2021; 78:1083-1094 | PMID: 34503676
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Abstract

Myocardial Viability Assessment Before Surgical Revascularization in Ischemic Cardiomyopathy: JACC Review Topic of the Week.

Panza JA, Chrzanowski L, Bonow RO
Ischemic cardiomyopathy results from the combination of scar with fibrosis replacement and areas of dysfunctional but viable myocardium that may improve contractile function with revascularization. Observational studies reported that only patients with substantial amounts of myocardial viability had better outcomes following surgical revascularization. Accordingly, dedicated noninvasive techniques have evolved to quantify viable myocardium with the objective of selecting patients for this form of therapeutic intervention. However, prospective trials have not confirmed the interaction between myocardial viability and the treatment effect of revascularization. Furthermore, recent observations indicate that recovery of left ventricular function is not the principal mechanism by which surgical revascularization improves prognosis. In this paper, the authors describe a more contemporary application of viability testing that is founded on the alternative concept that the main goal of surgical revascularization is to prevent further damage by protecting the residual viable myocardium from subsequent acute coronary events.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 06 Sep 2021; 78:1068-1077
Panza JA, Chrzanowski L, Bonow RO
J Am Coll Cardiol: 06 Sep 2021; 78:1068-1077 | PMID: 34474740
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Impact:
Abstract

Chronic Fatigue Syndrome and Cardiovascular Disease: JACC State-of-the-Art Review.

Natelson BH, Brunjes DL, Mancini D
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a medically unexplained illness characterized by severe fatigue limiting normal daily activities for at least 6 months accompanied by problems with unrefreshing sleep, exacerbation of symptoms following physical or mental efforts (postexertional malaise [PEM]), and either cognitive reports or physiological evidence of orthostatic intolerance in the form of either orthostatic tachycardia and/or hypocapnia. Although rarely considered to have cardiac dysfunction, ME/CFS patients frequently have reduced stroke volume with a significant inverse relation between cardiac output and PEM severity. Magnetic resonance imaging of ME/CFS patients compared with normal control subjects found significantly reduced stroke, end-systolic, and end-diastolic volumes together with reduced end-diastolic wall mass. Another cardiovascular abnormality is reduced nocturnal blood pressure assessed by 24-hour monitoring. Autonomic dysfunction is also frequently observed with postural orthostatic tachycardia and/or hypocapnia. Two consecutive cardiopulmonary stress tests may provide metabolic data substantiating PEM.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 06 Sep 2021; 78:1056-1067
Natelson BH, Brunjes DL, Mancini D
J Am Coll Cardiol: 06 Sep 2021; 78:1056-1067 | PMID: 34474739
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Impact:
Abstract

Compression-Only Versus Rescue-Breathing Cardiopulmonary Resuscitation After Pediatric Out-of-Hospital Cardiac Arrest.

Naim MY, Griffis HM, Berg RA, Bradley RN, ... Vetter V, Rossano JW
Background
There are conflicting data regarding the benefit of compression-only bystander cardiopulmonary resuscitation (CO-CPR) compared with CPR with rescue breathing (RB-CPR) after pediatric out-of-hospital cardiac arrest (OHCA).
Objectives
This study sought to test the hypothesis that RB-CPR is associated with improved neurologically favorable survival compared with CO-CPR following pediatric OHCA, and to characterize age-stratified outcomes with CPR type compared with no bystander CPR (NO-CPR).
Methods
Analysis of the CARES registry (Cardiac Arrest Registry to Enhance Survival) for nontraumatic pediatric OHCAs (patients aged ≤18 years) from 2013-2019 was performed. Age groups included infants (<1 year), children (1 to 11 years), and adolescents (≥12 years). The primary outcome was neurologically favorable survival at hospital discharge.
Results
Of 13,060 pediatric OHCAs, 46.5% received bystander CPR. CO-CPR was the most common bystander CPR type. In the overall cohort, neurologically favorable survival was associated with RB-CPR (adjusted OR: 2.16; 95% CI: 1.78-2.62) and CO-CPR (adjusted OR: 1.61; 95% CI: 1.34-1.94) compared with NO-CPR. RB-CPR was associated with a higher odds of neurologically favorable survival compared with CO-CPR (adjusted OR: 1.36; 95% CI: 1.10-1.68). In age-stratified analysis, RB-CPR was associated with better neurologically favorable survival versus NO-CPR in all age groups. CO-CPR was associated with better neurologically favorable survival compared with NO-CPR in children and adolescents, but not in infants.
Conclusions
CO-CPR was the most common type of bystander CPR in pediatric OHCA. RB-CPR was associated with better outcomes compared with CO-CPR. These results support present guidelines for RB-CPR as the preferred CPR modality for pediatric OHCA.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 06 Sep 2021; 78:1042-1052
Naim MY, Griffis HM, Berg RA, Bradley RN, ... Vetter V, Rossano JW
J Am Coll Cardiol: 06 Sep 2021; 78:1042-1052 | PMID: 34474737
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Abstract

Effect of Heart Rate on the Outcome of Renal Denervation in Patients With Uncontrolled Hypertension.

Böhm M, Tsioufis K, Kandzari DE, Kario K, ... Fahy M, Mahfoud F
Background
Sham-controlled trials demonstrated safety and efficacy of renal denervation (RDN) to lower blood pressure (BP). Association of baseline heart rate with BP reduction after RDN is incompletely understood.
Objectives
The purpose of this analysis was to evaluate the impact of baseline heart rate on BP reduction without antihypertensive medications in the SPYRAL HTN-OFF MED (Global Clinical Study of Renal Denervation With the Symplicity Spyral Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications) Pivotal trial.
Methods
Patients removed from any antihypertensive medications were enrolled with office systolic blood pressure (SBP) ≥150 and <180 mm Hg and randomized 1:1 to RDN or sham control. Patients were separated according to baseline office heart rate <70 or ≥70 beats/min. BP changes from baseline to 3 months between treatment arms were adjusted for baseline SBP using analysis of covariance.
Results
Scatter plots of 3-month changes in 24-hour and office SBP illustrate a wide range of changes in SBP for different baseline heart rates. Treatment difference at 3 months between RDN and sham control with baseline office heart rate ≥70 beats/min for 24-hour SBP was -6.2 mm Hg (95% CI: -9.0 to -3.5 mm Hg) (P < 0.001) and for baseline office heart rate <70 beats/min it was -0.1 mm Hg (-3.8 to 3.6 mm Hg) (P = 0.97) with an interaction P value of 0.008. Results were similar for changes in office, daytime, and nighttime SBP at 3 months, with a greater reduction in SBP with baseline office heart rate ≥70 beats/min.
Conclusions
Reduction in mean office, 24-hour, daytime, and nighttime SBP for RDN at 3 months was greater with baseline office heart rate ≥70 than <70 beats/min, suggesting an association between baseline heart rate and BP reduction after RDN. (SPYRAL PIVOTAL-SPYRAL HTN-OFF MED Study; NCT02439749).

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 06 Sep 2021; 78:1028-1038
Böhm M, Tsioufis K, Kandzari DE, Kario K, ... Fahy M, Mahfoud F
J Am Coll Cardiol: 06 Sep 2021; 78:1028-1038 | PMID: 34474735
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Abstract

Risk of Cardiovascular Hospital Admission After Exposure to Fine Particulate Pollution.

Zhang Y, Ma R, Ban J, Lu F, ... Li T, Shi X
Background
Heavy fine particulate matter with an aerodynamic diameter ≤2.5 μm (PM2.5) pollution events continue to occur frequently in developing countries.
Objectives
The authors conducted a case-crossover study aimed at exploring the association between heavy PM2.5 pollution events and hospital admission for cardiovascular diseases.
Methods
Hospital admissions for cardiovascular diseases were observed by Beijing Municipal Commission of Health and Family Planning Information Center from 2013 to 2017. Air pollution data were collected from the Beijing Municipal Environmental Monitoring Center. Distinct definitions were used to identify heavy and extremely heavy fine particulate pollution events. A conditional logistic regression model was used. The hospital admission burdens for cardiovascular disease were also estimated.
Results
A total of 2,202,244 hospital admissions for cardiovascular diseases and 222 days of extremely heavy PM2.5 pollution events (PM2.5 concentration ≥150 μg/m3) were observed. The ORs associated with extremely heavy PM2.5 pollution events lasting for 3 days or more for total cardiovascular disease, angina, myocardial infarction, ischemic stroke, and heart failure were 1.085 (95% CI: 1.077-1.093), 1.112 (95% CI: 1.095-1.130), 1.068 (95% CI: 1.037-1.100), 1.071 (95% CI: 1.053-1.090), and 1.060 (95% CI: 1.021-1.101), respectively. The numbers and days of cardiovascular disease hospital admission annually related to extremely heavy PM2.5 pollution events lasting for 1 day or more were 3,311 (95% CI: 2,969-3,655) and 37,020 (95% CI: 33,196-40,866), respectively.
Conclusions
Heavy and extremely heavy PM2.5 pollution events resulted in substantial increased hospital admission risk for cardiovascular disease. With higher PM2.5 concentration and longer duration of heavy PM2.5 pollution events, a greater risk of cardiovascular hospital admission was observed.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 06 Sep 2021; 78:1015-1024
Zhang Y, Ma R, Ban J, Lu F, ... Li T, Shi X
J Am Coll Cardiol: 06 Sep 2021; 78:1015-1024 | PMID: 34474733
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Abstract

Device Therapy in Chronic Heart Failure: JACC State-of-the-Art Review.

Fudim M, Abraham WT, von Bardeleben RS, Lindenfeld J, ... Anker SD, Butler J
The regulatory landscape for device-based heart failure (HF) therapies has seen a major shift in the last 7 years. In 2013, the U.S. Food and Drug Administration released guidance for early feasibility and first-in-human studies, thereby encouraging device innovation, and in 2016 the U.S. Congress authorized the Breakthrough Devices Program to expedite access for Americans to innovative devices indicated for diagnosis and treatment of serious illnesses, such as HF. Since December 2016, there has been an increase in the number of HF devices for which manufacturers are seeking approval through the breakthrough designation pathway. This has led to a rapid uptake in the development and evaluation of device-based HF therapies. This article reviews the current and future landscape of device therapies for chronic HF and associated comorbidities and the regulatory environment that is driving current and future innovation.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 30 Aug 2021; 78:931-956
Fudim M, Abraham WT, von Bardeleben RS, Lindenfeld J, ... Anker SD, Butler J
J Am Coll Cardiol: 30 Aug 2021; 78:931-956 | PMID: 34446165
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Abstract

Cryoballoon Ablation as Initial Treatment for Atrial Fibrillation: JACC State-of-the-Art Review.

Andrade JG, Wazni OM, Kuniss M, Hawkins NM, ... Wells GA, Turgeon RD
Atrial fibrillation (AF), the most common sustained arrhythmia observed in clinical practice, is a chronic and progressive disorder characterized by exacerbations and remissions. Guidelines recommend antiarrhythmic drugs as the initial therapy for the maintenance of sinus rhythm; however, antiarrhythmic drugs have modest efficacy to maintain sinus rhythm and can be associated with significant adverse effects. An initial treatment strategy of cryoballoon catheter ablation in patients with treatment-naïve AF has been shown to significantly improve arrhythmia outcomes (freedom from any, or symptomatic atrial tachyarrhythmia), produce clinically meaningful improvements in patient-reported outcomes (symptoms and quality of life), and significantly reduce subsequent health care resource use (hospitalization), and it does not increase the risk of serious or any adverse events compared with initial antiarrhythmic drug therapy. These findings are relevant to inform patients, providers, and health care systems regarding the initial choice of rhythm-control therapy in patients with treatment-naïve AF.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 30 Aug 2021; 78:914-930
Andrade JG, Wazni OM, Kuniss M, Hawkins NM, ... Wells GA, Turgeon RD
J Am Coll Cardiol: 30 Aug 2021; 78:914-930 | PMID: 34446164
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Abstract

Gender Differences in the Pursuit of Cardiac Electrophysiology Training in North America.

Abdulsalam N, Gillis AM, Rzeszut AK, Yong CM, ... Killic S, O\'Leary EL
Background
Despite the increase in the number of female physicians across most specialties within cardiology, <10% of clinical cardiac electrophysiology (EP) fellows are women.
Objectives
This study sought to determine the factors that influence fellows-in-training (FITs) to pursue EP as a career choice and whether this differs by gender.
Methods
The authors conducted an online multiple-choice survey through the American College of Cardiology to assess the decision factors that influence FITs in the United States and Canada to pursue cardiovascular subspecialties.
Results
A total of 933 (30.5%) FITs completed the survey; 129 anticipated specializing in EP, 259 in interventional cardiology (IC), and 545 in a different field or were unsure. A total of 1 in 7 (14%) FITs indicated an interest in EP. Of this group, more men chose EP than women (84% vs 16%; P < 0.001). The most important factor that influenced FITs to pursue EP was a strong interest in the field. Women were more likely to be influenced by having a female role model (P = 0.001) compared with men. After excluding FITs interested in IC, women who deselected EP were more likely than men to be influenced by greater interest in another field (P = 0.004), radiation concerns (P = 0.001), lack of female role models (P = 0.001), a perceived \"old boys\' club\" culture (P = 0.001) and discrimination/harassment concerns (P = 0.001).
Conclusions
Women are more likely than men to be negatively influenced by many factors when it comes to pursuing EP as a career choice. Addressing those factors will help decrease the gender disparity in the field.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 30 Aug 2021; 78:898-909
Abdulsalam N, Gillis AM, Rzeszut AK, Yong CM, ... Killic S, O'Leary EL
J Am Coll Cardiol: 30 Aug 2021; 78:898-909 | PMID: 34446162
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Abstract

Contemporary Left Ventricular Assist Device Outcomes in an Aging Population: An STS INTERMACS Analysis.

Emerson D, Chikwe J, Catarino P, Hassanein M, ... Moriguchi J, Kirklin JK
Background
Survival, functional outcomes, and quality of life after left ventricular assist device (LVAD) are ill-defined in elderly patients, and with new-generation devices.
Objectives
This study sought to evaluate survival, functional outcomes, and quality of life after LVAD in contemporary practice.
Methods
Adults receiving durable LVADs between January 1, 2010, and March 1, 2020, were identified from the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) database. The primary outcome was adjusted survival; secondary outcomes included quality of life rated using a visual analogue scale (where 0 represents \"worst health\" and 100 \"best health\"); 6-minute walk distance; stroke; device malfunction; and rehospitalization, stratified by patient age. Median follow-up was 15 months (IQR: 6-32 months).
Results
The cohort comprised 68.9% (n = 16,808) patients aged <65 years, 26.3% (n = 6,418) patients aged 65-75 years, and 4.8% (n = 1,182) patients aged >75 years, who were predominantly male (n = 19,119, 78%) and on destination therapy (n = 12,425, 51%). Competing outcomes analysis demonstrated mortality (70% CIs) of 34% (33%-34%), 54% (54%-55%), and 66% (64%-68%) for patients aged <65, 65-75, and >75 years, respectively, which improved during the study in patients aged >75 years. Newer-generation devices were associated with reduced late mortality (HR: 0.35; 95% CI: 0.25-0.49). Stroke, device malfunction or thrombosis, and rehospitalizations decreased with increasing age (all P < 0.01). Median 6-minute walk distance increased from 0 feet (IQR: 0-665 feet) to 1,065 feet (IQR: 642-1,313 feet) (P < 0.001), and quality of life improved from 40 (IQR: 15-60) to 75 (IQR: 60-90) (P < 0.001) after LVAD in all age groups.
Conclusions
In elderly patients, LVADs are associated with increased functional capacity, similar improvements in quality of life, and fewer complications compared with younger patients.

Copyright © 2021. Published by Elsevier Inc.

J Am Coll Cardiol: 30 Aug 2021; 78:883-894
Emerson D, Chikwe J, Catarino P, Hassanein M, ... Moriguchi J, Kirklin JK
J Am Coll Cardiol: 30 Aug 2021; 78:883-894 | PMID: 34446160
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Abstract

Pregnancy-Related Aortic Complications in Women With Marfan Syndrome.

Narula N, Devereux RB, Malonga GP, Hriljac I, Roman MJ
Background
The risk of pregnancy-associated vascular complications in Marfan syndrome (MFS) is uncertain because of ascertainment bias, prepartum lack of knowledge of diagnosis, and insufficient peripartum imaging data. Furthermore, U.S. and European guidelines differ in pregnancy recommendations in MFS.
Objectives
This study describes a single-center experience of 169 MFS women to address these gaps.
Methods
Clinical, imaging, and pregnancy history were compared in never vs ever-pregnant MFS women, and pregnancy-associated vascular complications were described.
Results
A total of 74 ever-pregnant women had 112 live births. Elective aortic root replacement occurred at a younger age in never-pregnant women (33 years vs 42 years; P = 0.0026). Although aortic dissection prevalence did not differ between never-pregnant vs ever-pregnant women (23% vs 31%; P = 0.25), it tended to occur at an earlier age in the former group (38 years vs 45 years; P = 0.07). Of observed \"sanctioned\" pregnancies with prepartum diameters ≤4.5 cm, mean pregnancy-related aortic diameters remained stable. In total, 5 dissections were associated with pregnancy: 2 type A in women unaware of their diagnosis; and 2 type B and 1 isolated coronary artery dissection in women aware of their diagnosis. Dissection rates were 5-fold higher in the pregnancy vs nonpregnancy period.
Conclusions
Pregnancy-related type A dissection only occurred in patients unaware of their diagnosis. Type B dissection remains an unpredictable complication. Although there were baseline differences between the never- and ever-pregnant groups, no difference in dissection risk was observed outside the peripartum period. Those with prepartum aortic diameters between 4.0 and 4.5 cm demonstrated stable aortic dimensions throughout pregnancy. These findings provide a rationale to update existing U.S. guidelines for the management of pregnancy in MFS.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 30 Aug 2021; 78:870-879
Narula N, Devereux RB, Malonga GP, Hriljac I, Roman MJ
J Am Coll Cardiol: 30 Aug 2021; 78:870-879 | PMID: 34446158
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Impact:
Abstract

Colchicine in Patients With Chronic Coronary Disease in Relation to Prior Acute Coronary Syndrome.

Opstal TSJ, Fiolet ATL, van Broekhoven A, Mosterd A, ... Cornel JH, LoDoCo2 Trial Investigators
Background
Colchicine reduces risk of cardiovascular events in patients post-myocardial infarction and in patients with chronic coronary disease. It remains unclear whether this effect is related to the time of onset of treatment following an acute coronary syndrome (ACS).
Objectives
This study investigates risk for major adverse cardiovascular events in relation to history and timing of prior ACS, to determine whether the benefits of colchicine are consistent independent of prior ACS status.
Methods
The LoDoCo2 (Low-Dose Colchicine 2) trial randomly allocated patients with chronic coronary disease to colchicine 0.5 mg once daily or placebo. The rate of the composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization was compared between patients with no prior, recent (6-24 months), remote (2-7 years), or very remote (>7 years) ACS; interaction between ACS status and colchicine treatment effect was assessed.
Results
In 5,522 randomized patients, risk of the primary endpoint was independent of prior ACS status. Colchicine consistently reduced the primary endpoint in patients with no prior ACS (incidence: 2.8 vs 3.4 events per 100 person-years; hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.52-1.27), recent ACS (incidence: 2.4 vs 3.3 events per 100 person-years; HR: 0.75; 95% CI: 0.51-1.10), remote ACS (incidence: 1.8 vs 3.2 events per 100 person-years, HR: 0.55; 95% CI: 0.37-0.82), and very remote ACS (incidence: 3.0 vs 4.3 events per 100 person-years, HR: 0.70; 95% CI: 0.51-0.96) (P for interaction = 0.59).
Conclusions
The benefits of colchicine are consistent irrespective of history and timing of prior ACS. (The LoDoCo2 Trial: Low Dose Colchicine for secondary prevention of cardiovascular disease [LoDoCo2] ACTRN12614000093684).

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 30 Aug 2021; 78:859-866
Opstal TSJ, Fiolet ATL, van Broekhoven A, Mosterd A, ... Cornel JH, LoDoCo2 Trial Investigators
J Am Coll Cardiol: 30 Aug 2021; 78:859-866 | PMID: 34446156
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Abstract

De-Escalation of Dual Antiplatelet Therapy in Patients With Acute Coronary Syndromes.

Shoji S, Kuno T, Fujisaki T, Takagi H, ... Latib A, Kohsaka S
Background
Balancing the effects of dual antiplatelet therapy (DAPT) in the era of potent P2Y12 inhibitors has become a cornerstone of acute coronary syndrome (ACS) management. Recent randomized controlled trials (RCTs) have investigated DAPT de-escalation to decrease the risk of bleeding outcomes.
Objectives
The aim of this study was to compare the efficacy and safety outcomes of various DAPT strategies in patients with ACS, including de-escalation from a potent P2Y12 inhibitor to clopidogrel or low-dose prasugrel.
Methods
MEDLINE and EMBASE were searched through January 2021 for RCTs investigating the efficacy and safety of DAPT in patients with ACS, and a network meta-analysis was conducted. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, and stroke. The primary bleeding outcome was trial-defined major or minor bleeding.
Results
Our search identified 15 eligible RCTs, including 55,798 patients with ACS. De-escalation therapy was associated with reduced risk of primary bleeding outcomes (HR: 0.48 [95% CI: 0.30-0.77] vs clopidogrel; HR: 0.32 [95% CI: 0.20-0.52] vs ticagrelor; HR: 0.36 [95% CI: 0.24-0.55] vs standard-dose prasugrel; and HR: 0.40 [95% CI: 0.22-0.75] vs low-dose prasugrel) without negatively affecting primary efficacy outcomes. There were no significant differences in ischemic or bleeding outcomes between de-escalation to clopidogrel or low-dose prasugrel.
Conclusions
Compared with other established uses of DAPT, de-escalation was the most effective strategy for ACS treatment, resulting in fewer bleeding events without increasing ischemic events.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 23 Aug 2021; 78:763-777
Shoji S, Kuno T, Fujisaki T, Takagi H, ... Latib A, Kohsaka S
J Am Coll Cardiol: 23 Aug 2021; 78:763-777 | PMID: 34275697
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Impact:
Abstract

Global Chronic Total Occlusion Crossing Algorithm: JACC State-of-the-Art Review.

Wu EB, Brilakis ES, Mashayekhi K, Tsuchikane E, ... Yeh RW, Zhang Q
The authors developed a global chronic total occlusion crossing algorithm following 10 steps: 1) dual angiography; 2) careful angiographic review focusing on proximal cap morphology, occlusion segment, distal vessel quality, and collateral circulation; 3) approaching proximal cap ambiguity using intravascular ultrasound, retrograde, and move-the-cap techniques; 4) approaching poor distal vessel quality using the retrograde approach and bifurcation at the distal cap by use of a dual-lumen catheter and intravascular ultrasound; 5) feasibility of retrograde crossing through grafts and septal and epicardial collateral vessels; 6) antegrade wiring strategies; 7) retrograde approach; 8) changing strategy when failing to achieve progress; 9) considering performing an investment procedure if crossing attempts fail; and 10) stopping when reaching high radiation or contrast dose or in case of long procedural time, occurrence of a serious complication, operator and patient fatigue, or lack of expertise or equipment. This algorithm can improve outcomes and expand discussion, research, and collaboration.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 23 Aug 2021; 78:840-853
Wu EB, Brilakis ES, Mashayekhi K, Tsuchikane E, ... Yeh RW, Zhang Q
J Am Coll Cardiol: 23 Aug 2021; 78:840-853 | PMID: 34412818
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Impact:
Abstract

Primary and Secondary Outcome Reporting in Randomized Trials: JACC State-of-the-Art Review.

Pocock SJ, Rossello X, Owen R, Collier TJ, Stone GW, Rockhold FW
Consensus as to best practices for the selection, reporting, and interpretation of primary and secondary outcomes of randomized controlled trials is lacking. We reviewed the strategies adopted in publications of randomized controlled trials (RCTs) for the analysis, presentation, and interpretation of efficacy outcomes from a survey of all cardiovascular RCTs published in the New England Journal of Medicine, Lancet, and the Journal of the American Medical Association during 2019. We focus on the choice of primary outcomes, the variety of approaches to selecting secondary outcomes, the options sometimes used to control type I error, and the common practice to not correct for multiple testing in reporting secondary outcomes. We comment on current practice across journals in the reporting of P values and also how conclusions in trial reports frequently adhere to an undue reliance on P < 0.05 as a basis for positive claims of treatment efficacy. We conclude with recommendations for how future RCT reports could best select, report, and interpret their findings on primary and secondary outcomes.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 23 Aug 2021; 78:827-839
Pocock SJ, Rossello X, Owen R, Collier TJ, Stone GW, Rockhold FW
J Am Coll Cardiol: 23 Aug 2021; 78:827-839 | PMID: 34412817
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Impact:
Abstract

The Characteristics and Outcomes of Native Aortic Valve Thrombosis: A Systematic Review.

Alajaji W, Hornick JM, Malek E, Klein AL
Background
There is a lack of knowledge in the current medical literature about native aortic valve thrombosis.
Objectives
The aim of this systematic review was to summarize the characteristics, presentations, underlying etiologies, and outcomes of native aortic valve thrombosis and to present a meta-analysis of the best available data.
Methods
The authors performed a literature search, identified published cases of patients with native aortic valve thrombosis, and pooled the data in this meta-analysis. The statistical analysis included calculations of the prevalence of the various presentations, underlying etiologies, aortic cusp involvement, as well as choices of diagnostic testing. They calculated the sensitivities of the various diagnostic testing as well as in-hospital mortality event rates and the univariate ORs of the risk factors for poor outcomes.
Results
The search strategy and screening process yielded 74 cases of native aortic valve thrombosis, which are included in this meta-analysis. The data revealed that the most common presentation was myocardial infarction in 36%, and the most common underlying etiology was hypercoagulable state in 30%. In-hospital clinical deterioration after presentation including recurrent embolism occurred in ∼38%, and in-hospital mortality rate was ∼20%.
Conclusions
Native aortic valve thrombosis is clinically relevant, especially in patients presenting with embolic events. Awareness about native aortic valve or root thrombosis as well as its underlying etiologies, diagnostic work-up, and management is essential, because this condition can be associated with poor outcomes.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 23 Aug 2021; 78:811-824
Alajaji W, Hornick JM, Malek E, Klein AL
J Am Coll Cardiol: 23 Aug 2021; 78:811-824 | PMID: 34412815
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Impact:
Abstract

Dissemination of Transcatheter Aortic Valve Replacement in the United States.

Valle JA, Li Z, Kosinski AS, Nelson AJ, ... Waldo SW, Carroll JD
Background
Societal guidelines and payor coverage decisions for transcatheter aortic valve replacement (TAVR) attempt to strike a balance between providing access and maintaining quality. The extent to which dissemination of TAVR has achieved these ideals remains unknown.
Objectives
This study sought to define patterns of TAVR dissemination in the United States and their influence on outcomes.
Methods
Using data from the TVT (Transcatheter Valvular Therapy) registry, this study identified TAVR sites from 2011 to 2018 and calculated drive-times from existing to new sites. In a contemporary cohort, this study compared site and patient characteristics by annual case volume and density of sites per million Medicare beneficiaries. Using hierarchical regression and Cox methods, this study determined the association between case volumes, site density, and changes in volume and density with patient risk profiles and outcomes.
Results
TAVR sites participating in the TVT registry increased from 198 to 556 from 2011 to 2018. Median drive-time from existing to new sites decreased from 403 minutes (interquartile range: 211-587 minutes) to 26 minutes (interquartile range: 17-48 minutes). In a contemporary cohort, higher site density was associated with lower procedural risk as well as with an increased hazard of 30-day risk-adjusted mortality (P = 0.017). Similarly, longitudinal increases in site density over time were associated with a higher hazard of 30-day (P = 0.011) and 1-year (P = 0.013) mortality.
Conclusions
TAVR has expanded significantly over time, but with regional clustering of sites. Although procedural risk is lower at higher density sites, these sites demonstrate an increased hazard of mortality. These findings suggest that the expansion of TAVR services in the United States may have had unintended consequences on procedural quality.

Copyright © 2021 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 23 Aug 2021; 78:794-806
Valle JA, Li Z, Kosinski AS, Nelson AJ, ... Waldo SW, Carroll JD
J Am Coll Cardiol: 23 Aug 2021; 78:794-806 | PMID: 34412813
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Impact:
Abstract

A Biomarker Model to Distinguish Types of Myocardial Infarction and Injury.

Neumann JT, Weimann J, Sörensen NA, Hartikainen TS, ... Zeller T, Westermann D
Background
Discrimination among patients with type 1 myocardial infarction (T1MI), type 2 myocardial infarction (T2MI), and myocardial injury is difficult.
Objectives
The aim of this study was to investigate the discriminative value of a 29-biomarker panel in an emergency department setting.
Methods
Patients presenting with suspected myocardial infarction (MI) were recruited. The final diagnosis in all patients was adjudicated on the basis of the fourth universal definition of MI. A panel of 29 biomarkers was measured, and multivariable logistic regression analysis was used to evaluate the associations of these biomarkers with the diagnosis of MI or myocardial injury. Biomarkers were chosen using backward selection. The model was internally validated using bootstrapping.
Results
Overall, 748 patients were recruited (median age 64 years), of whom 138 had MI (107 T1MI and 31 T2MI) and 221 had myocardial injury. In the multivariable model, 4 biomarkers (apolipoprotein A-II, N-terminal prohormone of brain natriuretic peptide, copeptin, and high-sensitivity cardiac troponin I) remained significant discriminators between T1MI and T2MI. Internal validation of the model showed an area under the curve of 0.82. For discrimination between MI and myocardial injury, 6 biomarkers (adiponectin, N-terminal prohormone of brain natriuretic peptide, pulmonary and activation-regulated chemokine, transthyretin, copeptin, and high-sensitivity troponin I) were selected. Internal validation showed an area under the curve of 0.84.
Conclusions
Among 29 biomarkers, 7 were identified to be the most relevant discriminators between subtypes of MI or myocardial injury. Regression models based on these biomarkers allowed good discrimination. (Biomarkers in Acute Cardiac Care [BACC]; NCT02355457).

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 23 Aug 2021; 78:781-790
Neumann JT, Weimann J, Sörensen NA, Hartikainen TS, ... Zeller T, Westermann D
J Am Coll Cardiol: 23 Aug 2021; 78:781-790 | PMID: 34412811
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Impact:
Abstract

Increasing Participation of Women in Cardiovascular Trials: JACC Council Perspectives.

Cho L, Vest AR, O\'Donoghue ML, Ogunniyi MO, ... Mehran R, Cardiovascular Disease in Women Committee Leadership Council
Although some progress has been made in the last 3 decades to increase the number of women in clinical cardiology trials, review of recent cardiovascular literature demonstrates that women and underrepresented minority women are still underrepresented in most clinical cardiology trials. This is especially notable in trials of patients with coronary artery disease, heart failure with reduced ejection fraction, and arrhythmia studies, especially those involving devices and procedures. Despite the call from National Institutes of Health, Food and Drug Administration, Institute of Medicine, and various professional societies, the gap remains. This paper seeks to identify the barriers for low enrollment and retention from patient, clinician, research team, study design, and system perspectives, and offers recommendations to improve recruitment and retention in the current era.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Aug 2021; 78:737-751
Cho L, Vest AR, O'Donoghue ML, Ogunniyi MO, ... Mehran R, Cardiovascular Disease in Women Committee Leadership Council
J Am Coll Cardiol: 16 Aug 2021; 78:737-751 | PMID: 34384555
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Impact:
Abstract

Coronary Computed Tomographic Angiography for Complete Assessment of Coronary Artery Disease: JACC State-of-the-Art Review.

Serruys PW, Hara H, Garg S, Kawashima H, ... Andreini D, Onuma Y
Coronary computed tomography angiography (CTA) has shown great technological improvements over the last 2 decades. High accuracy of CTA in detecting significant coronary stenosis has promoted CTA as a substitute for conventional invasive coronary angiography in patients with suspected coronary artery disease. In patients with coronary stenosis, CTA-derived physiological assessment is surrogate for intracoronary pressure and velocity wires, and renders possible decision-making about revascularization solely based on computed tomography. Computed tomography coronary anatomy with functionality assessment could potentially become a first line in diagnosis. Noninvasive imaging assessment of plaque burden and morphology is becoming a valuable substitute for intravascular imaging. Recently, wall shear stress and perivascular inflammation have been introduced. These assessments could support risk management for both primary and secondary cardiovascular prevention. Anatomy, functionality, and plaque composition by CTA tend to replace invasive assessment. Complete CTA assessment could provide a 1-stop-shop for diagnosis, risk management, and decision-making on treatment.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Aug 2021; 78:713-736
Serruys PW, Hara H, Garg S, Kawashima H, ... Andreini D, Onuma Y
J Am Coll Cardiol: 16 Aug 2021; 78:713-736 | PMID: 34384554
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Abstract

Association of Variants Near the Bradykinin Receptor B Gene With Angioedema in Patients Taking ACE Inhibitors.

Ghouse J, Ahlberg G, Andreasen L, Banasik K, ... Bundgaard H, Olesen MS
Background
Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensin-converting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients.
Objectives
The aim of this study was to identify genetic factors associated with ACE inhibitor-associated angioedema.
Methods
A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors ≤180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model.
Results
The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor-treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor-treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 × 10-8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 × 10-9). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 × 10-3). We found that carriers of the risk allele had significantly lower systolic (-0.46 mm Hg per T allele; 95% CI: -0.83 to -0.10; P = 0.013) and diastolic (-0.26 mm Hg per T allele; 95% CI: -0.46 to -0.05; P = 0.013) blood pressure.
Conclusions
In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B2 gene were associated with increased risk for ACE inhibitor-related angioedema.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Aug 2021; 78:696-709
Ghouse J, Ahlberg G, Andreasen L, Banasik K, ... Bundgaard H, Olesen MS
J Am Coll Cardiol: 16 Aug 2021; 78:696-709 | PMID: 34384552
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Abstract

Association of Preterm Birth With Myocardial Fibrosis and Diastolic Dysfunction in Young Adulthood.

Lewandowski AJ, Raman B, Bertagnolli M, Mohamed A, ... Neubauer S, Leeson P
Background
Preterm birth affects about 10% of live births worldwide and is associated with cardiac alterations. Animal models of preterm birth suggest that left ventricular functional impairment may be due to an up-regulation of myocardial fibrosis.
Objectives
The aim of this study was to determine whether diffuse left ventricular fibrosis is evident in young adults born preterm.
Methods
One hundred one normotensive young adults born preterm (n = 47, mean gestational age 32.8 ± 3.2 weeks) and term (n = 54) were included from YACHT (Young Adult Cardiovascular Health sTudy). Left ventricular structure and function were quantified by cardiovascular magnetic resonance and echocardiography. Intravenous administration of a gadolinium-based contrast agent during cardiovascular magnetic resonance was used to quantify focal myocardial fibrosis on the basis of late gadolinium enhancement and, in combination with T1 mapping, to quantify diffuse myocardial fibrosis on the basis of assessment of myocardial extracellular volume fraction.
Results
Adults born preterm had smaller left ventricular end-diastolic and stroke volumes, with greater left ventricular mass and wall thickness (P < 0.001). In addition, longitudinal peak systolic strain and diastolic strain rate by both cardiovascular magnetic resonance and echocardiography, and E/A ratio measured by echocardiography, were lower in preterm-born compared to term-born adults (P < 0.05). Extracellular volume fraction was greater in preterm-born compared with term-born adults (27.81% ± 1.69% vs 25.48% ± 1.41%; P < 0.001) and was a significant mediator in the relationship between gestational age and both longitudinal peak diastolic strain rate and E/A ratio.
Conclusions
Preterm-born young adults have greater extracellular volume fraction in the left ventricle that is inversely related with gestational age and may underlie their diastolic functional impairments.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Aug 2021; 78:683-692
Lewandowski AJ, Raman B, Bertagnolli M, Mohamed A, ... Neubauer S, Leeson P
J Am Coll Cardiol: 16 Aug 2021; 78:683-692 | PMID: 34384550
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Abstract

Lignan Intake and Risk of Coronary Heart Disease.

Hu Y, Li Y, Sampson L, Wang M, ... Rimm E, Sun Q
Background
Evidence regarding lignan consumption in relation to coronary heart disease (CHD) risk remains limited and mixed.
Objectives
The aim of this study was to prospectively examine associations between lignan intake and CHD risk in U.S. men and women.
Methods
We prospectively followed 214,108 men and women in 3 cohorts who did not have cardiovascular disease or cancer at baseline. Diet was repeatedly assessed using a validated food frequency questionnaire every 2-4 years since baseline.
Results
During 5,517,225 person-years of follow-up, we documented 10,244 CHD cases, including 6,283 nonfatal myocardial infarction and 3,961 fatal CHD cases. In multivariable-adjusted analyses, comparing extreme quintiles, the pooled hazard ratios of CHD were 0.85 (95% CI: 0.79-0.92) for total lignans, 0.76 (95% CI: 0.71-0.82) for matairesinol, 0.87 (95% CI: 0.81-0.93) for secoisolariciresinol, 0.89 (95% CI: 0.83-0.95) for pinoresinol, and 0.89 (95% CI: 0.83-0.95) for lariciresinol (all P values for trend ≤0.003). Nonlinear relationships were found for total lignan, matairesinol, and secoisolariciresinol: the risk reduction plateaued at intakes above approximately 300 μg/d, 10 μg/d, and 100 μg/d, respectively (P < 0.01 for all nonlinearity). The inverse associations for total lignan intake appeared to be more apparent among participants with higher total fiber intake (P = 0.04 for interaction). In addition, lignan intake was more strongly associated with plasma concentrations of enterolactone when fiber intake was higher.
Conclusions
Increased long-term intake of lignans was associated with a significantly lower risk of total CHD in both men and women. Possible synergistic effects may exist between lignan and fiber intake in relation to CHD risk reduction, possibly through enhancing the production of enterolignans.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Aug 2021; 78:666-678
Hu Y, Li Y, Sampson L, Wang M, ... Rimm E, Sun Q
J Am Coll Cardiol: 16 Aug 2021; 78:666-678 | PMID: 34384548
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Abstract

Clinical Risk Prediction in Patients With Left Ventricular Myocardial Noncompaction.

Casas G, Limeres J, Oristrell G, Gutierrez-Garcia L, ... Ferreira-González I, Rodríguez-Palomares JF
Background
Left ventricular noncompaction (LVNC) is a heterogeneous entity with uncertain prognosis.
Objectives
This study sought to develop and validate a prediction model of major adverse cardiovascular events (MACE) and to identify LVNC cases without events during long-term follow-up.
Methods
This is a retrospective longitudinal multicenter cohort study of consecutive patients fulfilling LVNC criteria by echocardiography or cardiovascular magnetic resonance. MACE were defined as heart failure (HF), ventricular arrhythmias (VAs), systemic embolisms, or all-cause mortality.
Results
A total of 585 patients were included (45 ± 20 years of age, 57% male). LV ejection fraction (LVEF) was 48% ± 17%, and 18% presented late gadolinium enhancement (LGE). After a median follow-up of 5.1 years, MACE occurred in 223 (38%) patients: HF in 110 (19%), VAs in 87 (15%), systemic embolisms in 18 (3%), and 34 (6%) died. LVEF was the main variable independently associated with MACE (P < 0.05). LGE was associated with HF and VAs in patients with LVEF >35% (P < 0.05). A prediction model of MACE was developed using Cox regression, composed by age, sex, electrocardiography, cardiovascular risk factors, LVEF, and family aggregation. C-index was 0.72 (95% confidence interval: 0.67-0.75) in the derivation cohort and 0.72 (95% confidence interval: 0.71-0.73) in an external validation cohort. Patients with no electrocardiogram abnormalities, LVEF ≥50%, no LGE, and negative family screening presented no MACE at follow-up.
Conclusions
LVNC is associated with an increased risk of heart failure and ventricular arrhythmias. LVEF is the variable most strongly associated with MACE; however, LGE confers additional risk in patients without severe systolic dysfunction. A risk prediction model is developed and validated to guide management.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Aug 2021; 78:643-662
Casas G, Limeres J, Oristrell G, Gutierrez-Garcia L, ... Ferreira-González I, Rodríguez-Palomares JF
J Am Coll Cardiol: 16 Aug 2021; 78:643-662 | PMID: 34384546
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Abstract

Return-to-Play for Athletes With Long QT Syndrome or Genetic Heart Diseases Predisposing to Sudden Death.

Tobert KE, Bos JM, Garmany R, Ackerman MJ
Background
Within the last 5 years, cardiac society guidelines have begun to acknowledge shared decision making (SDM) for the athlete with sudden cardiac death-predisposing genetic heart diseases (GHDs), such as long QT syndrome (LQTS), and the possibility for that athlete\'s return to play. Previously, international guidelines embraced a de facto disqualification for all such athletes including athletes with solely a positive genetic test in Europe.
Objectives
This study sought to examine the prevalence and outcomes of athletes with sudden cardiac death-predisposing GHDs, particularly LQTS, after their return to play.
Methods
A retrospective review of the electronic medical record was performed on all athletes with GHD, with a primary analysis for those with LQTS, who were evaluated, risk stratified, and treated in Mayo Clinic\'s Windland Smith Rice Genetic Heart Rhythm Clinic by a single genetic cardiologist between July 1, 2000, and July 31, 2020.
Results
There were 672 athletes with GHD overall including 494 athletes with LQTS (231 female athletes [46.8%]; mean age at diagnosis 14.8 ± 10.5 years; mean follow-up 4.2 ± 4.8 years) who were given return-to-play approval. Overall, 79 of 494 athletes with LQTS (16.0%) were symptomatic before diagnosis, and 58 (11.7%) had an implantable cardioverter-defibrillator. In 2,056 combined years of follow-up, there was no GHD-sports associated mortality. Instead, 29 patients (5.9%) had ≥1 nonlethal, LQTS-associated breakthrough cardiac event. Of those, 15 (3.0%) were athletes at the time of the breakthrough cardiac event, with 3 (0.6%) experiencing a sports-related breakthrough cardiac event, and 12 (2.4%) a non-sports-related event. Overall, the event rate was 1.16 nonlethal events per 100 athlete-years of follow-up.
Conclusions
This 20-year single center experience challenges the status quo of disqualification for all athletes with LQTS and provides additional observational evidence, albeit from a single center, in support of the more contemporary SDM approaches to this complex issue.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Aug 2021; 78:594-604
Tobert KE, Bos JM, Garmany R, Ackerman MJ
J Am Coll Cardiol: 09 Aug 2021; 78:594-604 | PMID: 34330632
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Abstract

Factor XI Inhibition to Uncouple Thrombosis From Hemostasis: JACC Review Topic of the Week.

Hsu C, Hutt E, Bloomfield DM, Gailani D, Weitz JI
Hemostasis and thrombosis are believed to be so intricately linked that any strategies that reduce thrombosis will have an inevitable impact on hemostasis. Consequently, bleeding is viewed as an unavoidable side effect of anticoagulant therapy. Emerging evidence suggests that factor XI is important for thrombosis but has a minor role in hemostasis. This information raises the possibility that anticoagulants that target factor XI will be safer than currently available agents. The authors provide a visual representation of the coagulation pathways that distinguishes between the steps involved in thrombosis and hemostasis to explain why factor XI inhibitors may serve as hemostasis-sparing anticoagulants. A safer class of anticoagulants would provide opportunities for treatment of a wider range of patients, including those at high risk for bleeding. Ongoing clinical studies will determine the extent to which factor XI inhibitors attenuate thrombosis without disruption of hemostasis.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Aug 2021; 78:625-631
Hsu C, Hutt E, Bloomfield DM, Gailani D, Weitz JI
J Am Coll Cardiol: 09 Aug 2021; 78:625-631 | PMID: 34353538
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Abstract

Sleep Disordered Breathing and Cardiovascular Disease: JACC State-of-the-Art Review.

Cowie MR, Linz D, Redline S, Somers VK, Simonds AK
Sleep disordered breathing causes repetitive episodes of nocturnal hypoxemia, sympathetic nervous activation, and cortical arousal, often associated with excessive daytime sleepiness. Sleep disordered breathing is common in people with, or at risk of, cardiovascular (CV) disease including those who are obese or have hypertension, coronary disease, heart failure, or atrial fibrillation. Current therapy of obstructive sleep apnea includes weight loss (if obese), exercise, and positive airway pressure (PAP) therapy. This improves daytime sleepiness. Obstructive sleep apnea is associated with increased CV risk, but treatment with PAP in randomized trials has not been shown to improve CV outcome. Central sleep apnea (CSA) is not usually associated with daytime sleepiness in heart failure or atrial fibrillation and is a marker of increased CV risk, but PAP has been shown to be harmful in 1 randomized trial. The benefits of better phenotyping, targeting of higher-risk patients, and a more personalized approach to therapy are being explored in ongoing trials.

Copyright © 2021. Published by Elsevier Inc.

J Am Coll Cardiol: 09 Aug 2021; 78:608-624
Cowie MR, Linz D, Redline S, Somers VK, Simonds AK
J Am Coll Cardiol: 09 Aug 2021; 78:608-624 | PMID: 34353537
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Abstract

Multicenter Study of Endocarditis After Transcatheter Pulmonary Valve Replacement.

McElhinney DB, Zhang Y, Aboulhosn JA, Morray BH, ... Schubert S, Ewert P
Background
Endocarditis has emerged as one of the most impactful adverse events after transcatheter pulmonary valve replacement (TPVR), but there is limited information about risk factors for and outcomes of this complication.
Objectives
The purpose of this study was to evaluate risk factors for and outcomes of endocarditis in a large multicenter cohort.
Methods
The authors established an international registry focused on characterizing endocarditis after TPVR, including the incidence, risk factors, characteristics, and outcomes.
Results
Investigators submitted data for 2,476 patients who underwent TPVR between July 2005 and March 2020 and were followed for 8,475 patient-years. In total, 182 patients were diagnosed with endocarditis a median of 2.7 years after TPVR, for a cumulative incidence of 9.5% (95% CI: 7.9%-11.1%) at 5 years and 16.9% (95% CI: 14.2%-19.8%) at 8 years (accounting for competing risks: death, heart transplant, and explant) and an annualized incidence of 2.2 per 100 patient-years. Staphylococcus aureus and Viridans group Streptococcus species together accounted for 56% of cases. Multivariable analysis confirmed that younger age, a previous history of endocarditis, and a higher residual gradient were risk factors for endocarditis, but transcatheter pulmonary valve type was not. Overall, right ventricular outflow tract (RVOT) reintervention was less often to treat endocarditis than for other reasons, but valve explant was more often caused by endocarditis. Endocarditis was severe in 44% of patients, and 12 patients (6.6%) died, nearly all of whom were infected with Staphylococcus aureus.
Conclusions
The incidence of endocarditis in this multicenter registry was constant over time and consistent with prior smaller studies. The findings of this study, along with ongoing efforts to understand and mitigate risk, will be critical to improve the lifetime management of patients with heart disease involving the RVOT. Although endocarditis can be a serious adverse outcome, TPVR remains an important tool in the management of RVOT dysfunction.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Aug 2021; 78:575-589
McElhinney DB, Zhang Y, Aboulhosn JA, Morray BH, ... Schubert S, Ewert P
J Am Coll Cardiol: 09 Aug 2021; 78:575-589 | PMID: 34353535
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Abstract

Determinants and Outcomes of Asymptomatic Intracranial Atherosclerotic Stenosis.

Gutierrez J, Khasiyev F, Liu M, DeRosa JT, ... Sacco RL, Elkind MSV
Background
Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide and confers a high risk of stroke recurrence, despite aggressive management of risk factors.
Objectives
This study identified the role of risk factors and risk of vascular events in subjects with asymptomatic ICAS for improved risk stratification.
Methods
Stroke-free participants in the NOMAS (Northern Manhattan Study) trial, prospectively followed since 1993, underwent a brain magnetic resonance angiogram from 2003 to 2008. The study rated stenosis in 11 brain arteries as: 0: no stenosis; 1: <50% or luminal irregularities; 2: 50%-69%; and 3: ≥70% stenosis or flow gap. The study ascertained vascular events during the post-magnetic resonance imaging (MRI) period. Proportional odds regression quantified the association of pre-MRI exposures, and proportional hazard adjusted models were built to identify the risk of events in the post-MRI period.
Results
The included sample included 1,211 participants from NOMAS (mean age: 71 ± 9 years; 59% women; 65% Hispanic; 45% had any stenosis). Older age (OR: 1.02 per year; 95% CI: 1.01 to 1.04), hypertension duration (OR: 1.01 per year; 95% CI: 1.00 to 1.02), higher number of glucose-lowering drugs (OR: 1.64 per each medication; 95% CI: 1.24 to 2.15), and high-density lipoprotein (OR: 0.96 per mg/dL; 95% CI: 0.92 to 0.99) were associated with ICAS. The highest event risk was noted among participants with ICAS ≥70% (5.5% annual risk of vascular events; HR: 2.1; 95% CI:1.4 to 3.2; compared with those with no ICAS).
Conclusions
ICAS is an imaging marker of established atherosclerotic disease in stroke-free subjects, and incidental diagnosis of ICAS should trigger a thorough assessment of vascular health.

Copyright © 2021 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 09 Aug 2021; 78:562-571
Gutierrez J, Khasiyev F, Liu M, DeRosa JT, ... Sacco RL, Elkind MSV
J Am Coll Cardiol: 09 Aug 2021; 78:562-571 | PMID: 34353533
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Abstract

Markers of Myocardial Damage Predict Mortality in Patients With Aortic Stenosis.

Kwak S, Everett RJ, Treibel TA, Yang S, ... Dweck MR, Lee SP
Background
Cardiovascular magnetic resonance (CMR) is increasingly used for risk stratification in aortic stenosis (AS). However, the relative prognostic power of CMR markers and their respective thresholds remains undefined.
Objectives
Using machine learning, the study aimed to identify prognostically important CMR markers in AS and their thresholds of mortality.
Methods
Patients with severe AS undergoing AVR (n = 440, derivation; n = 359, validation cohort) were prospectively enrolled across 13 international sites (median 3.8 years\' follow-up). CMR was performed shortly before surgical or transcatheter AVR. A random survival forest model was built using 29 variables (13 CMR) with post-AVR death as the outcome.
Results
There were 52 deaths in the derivation cohort and 51 deaths in the validation cohort. The 4 most predictive CMR markers were extracellular volume fraction, late gadolinium enhancement, indexed left ventricular end-diastolic volume (LVEDVi), and right ventricular ejection fraction. Across the whole cohort and in asymptomatic patients, risk-adjusted predicted mortality increased strongly once extracellular volume fraction exceeded 27%, while late gadolinium enhancement >2% showed persistent high risk. Increased mortality was also observed with both large (LVEDVi >80 mL/m2) and small (LVEDVi ≤55 mL/m2) ventricles, and with high (>80%) and low (≤50%) right ventricular ejection fraction. The predictability was improved when these 4 markers were added to clinical factors (3-year C-index: 0.778 vs 0.739). The prognostic thresholds and risk stratification by CMR variables were reproduced in the validation cohort.
Conclusions
Machine learning identified myocardial fibrosis and biventricular remodeling markers as the top predictors of survival in AS and highlighted their nonlinear association with mortality. These markers may have potential in optimizing the decision of AVR.

Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Aug 2021; 78:545-558
Kwak S, Everett RJ, Treibel TA, Yang S, ... Dweck MR, Lee SP
J Am Coll Cardiol: 09 Aug 2021; 78:545-558 | PMID: 34353531
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Abstract

Cardiovascular and Kidney Outcomes Across the Glycemic Spectrum: Insights From the UK Biobank.

Honigberg MC, Zekavat SM, Pirruccello JP, Natarajan P, Vaduganathan M
Background
Treatment guidelines for prediabetes primarily focus on glycemic control and lifestyle management. Few evidence-based cardiovascular and kidney risk-reduction strategies are available in this population.
Objectives
This study sought to characterize cardiovascular and kidney outcomes across the glycemic spectrum.
Methods
Among participants in the UK Biobank without prevalent type 1 diabetes, cardiovascular disease, or kidney disease, Cox models tested the association of glycemic exposures (type 2 diabetes [T2D], prediabetes, normoglycemia) with outcomes (atherosclerotic cardiovascular disease [ASCVD], chronic kidney disease [CKD], and heart failure), adjusting for demographic, lifestyle, and cardiometabolic risk factors.
Results
Among 336,709 individuals (mean age: 56.3 years, 55.4% female), 46,911 (13.9%) had prediabetes and 12,717 (3.8%) had T2D. Over median follow-up of 11.1 years, 6,476 (13.8%) individuals with prediabetes developed ≥1 incident outcome, of whom only 802 (12.4%) developed T2D prior to an incident diagnosis. Prediabetes and T2D were independently associated with ASCVD (prediabetes: adjusted HR [aHR]: 1.11; 95% CI: 1.08-1.15; P < 0.001; T2D: aHR: 1.44; 95% CI: 1.37-1.51; P < 0.001), CKD (prediabetes: aHR: 1.08; 95% CI: 1.02-1.14; P < 0.001; T2D: aHR: 1.57; 95% CI: 1.46-1.69; P < 0.001), and heart failure (prediabetes: aHR: 1.07; 95% CI: 1.01-1.14; P = 0.03; T2D: aHR: 1.25; 95% CI: 1.14-1.37; P < 0.001). Compared with hemoglobin A1c (HbA1c) <5.0%, covariate-adjusted risks increased significantly for ASCVD above HbA1c of 5.4%, CKD above HbA1c of 6.2%, and heart failure above HbA1c of 7.0%.
Conclusions
Prediabetes and T2D were associated with ASCVD, CKD, and heart failure, but a substantial gradient of risk was observed across HbA1c levels below the threshold for diabetes. These findings highlight the need to design risk-reduction strategies across the glycemic spectrum.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 02 Aug 2021; 78:453-464
Honigberg MC, Zekavat SM, Pirruccello JP, Natarajan P, Vaduganathan M
J Am Coll Cardiol: 02 Aug 2021; 78:453-464 | PMID: 34015477
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Abstract

Management of Obesity in Cardiovascular Practice: JACC Focus Seminar.

Després JP, Carpentier AC, Tchernof A, Neeland IJ, Poirier P
Obesity contributes to reduced life expectancy because of its link with type 2 diabetes and cardiovascular disease. Yet, targeting this poorly diagnosed, ill-defined, and underaddressed modifiable risk factor remains a challenge. In this review, we emphasize that the tendency among health care professionals to amalgam all forms of obesity altogether as a single entity may contribute to such difficulties and discrepancies. Obesity is a heterogeneous condition both in terms of causes and health consequences. Attention should be given to 2 prevalent subgroups of individuals: 1) patients who are overweight or moderately obese with excess visceral adipose tissue; and 2) patients with severe obesity, the latter group having distinct additional health issues related to their large body fat mass. The challenge of tackling high-cardiovascular-risk forms of obesity through a combination of personalized clinical approaches and population-based solutions is compounded by the current obesogenic environment and economy.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 02 Aug 2021; 78:513-531
Després JP, Carpentier AC, Tchernof A, Neeland IJ, Poirier P
J Am Coll Cardiol: 02 Aug 2021; 78:513-531 | PMID: 34325840
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Abstract

Genetics of Type 2 Diabetes: Opportunities for Precision Medicine: JACC Focus Seminar.

Kim DS, Gloyn AL, Knowles JW
Type 2 diabetes (T2D) is highly prevalent and is a strong contributor for cardiovascular disease. However, there is significant heterogeneity in disease pathogenesis and the risk of complications. Enormous progress has been made in our ability to catalog genetic variation associated with T2D risk and variation in disease-relevant quantitative traits. These discoveries hold the potential to shed light on tractable targets and pathways for safe and effective therapeutic development, but the promise of precision medicine has been slow to be realized. Recent studies have identified subgroups of individuals with differential risk for intermediate phenotypes (eg, lipid levels, fasting insulin, body mass index) that contribute to T2D risk, helping to account for the observed clinical heterogeneity. These \"partitioned genetic risk scores\" not only have the potential to identify patients at greatest risk of cardiovascular disease and rapid disease progression, but also could aid patient stratification bridging the gap toward precision medicine for T2D.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 02 Aug 2021; 78:496-512
Kim DS, Gloyn AL, Knowles JW
J Am Coll Cardiol: 02 Aug 2021; 78:496-512 | PMID: 34325839
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Abstract

Molecular Aspects of Lifestyle and Environmental Effects in Patients With Diabetes: JACC Focus Seminar.

Nayor M, Shah SH, Murthy V, Shah RV
Diabetes is characterized as an integrated condition of dysregulated metabolism across multiple tissues, with well-established consequences on the cardiovascular system. Recent advances in precision phenotyping in biofluids and tissues in large human observational and interventional studies have afforded a unique opportunity to translate seminal findings in models and cellular systems to patients at risk for diabetes and its complications. Specifically, techniques to assay metabolites, proteins, and transcripts, alongside more recent assessment of the gut microbiome, underscore the complexity of diabetes in patients, suggesting avenues for precision phenotyping of risk, response to intervention, and potentially novel therapies. In addition, the influence of external factors and inputs (eg, activity, diet, medical therapies) on each domain of molecular characterization has gained prominence toward better understanding their role in prevention. Here, the authors provide a broad overview of the role of several of these molecular domains in human translational investigation in diabetes.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 02 Aug 2021; 78:481-495
Nayor M, Shah SH, Murthy V, Shah RV
J Am Coll Cardiol: 02 Aug 2021; 78:481-495 | PMID: 34325838
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Abstract

Pulmonary-to-Systemic Arterial Shunt to Treat Children With Severe Pulmonary Hypertension.

Grady RM, Canter MW, Wan F, Shmalts AA, ... Bonnet D, International Registry Potts Shunt
Background
The placement of a pulmonary-to-systemic arterial shunt in children with severe pulmonary hypertension (PH) has been demonstrated, in relatively small studies, to be an effective palliation for their disease.
Objectives
The aim of this study was to expand upon these earlier findings using an international registry for children with PH who have undergone a shunt procedure.
Methods
Retrospective data were obtained from 110 children with PH who underwent a shunt procedure collected from 13 institutions in Europe and the United States.
Results
Seventeen children died in-hospital postprocedure (15%). Of the 93 children successfully discharged home, 18 subsequently died or underwent lung transplantation (20%); the mean follow-up was 3.1 years (range: 25 days to 17 years). The overall 1- and 5-year freedom from death or transplant rates were 77% and 58%, respectively, and 92% and 68% for those discharged home, respectively. Children discharged home had significantly improved World Health Organization functional class (P < 0.001), 6-minute walk distances (P = 0.047) and lower brain natriuretic peptide levels (P < 0.001). Postprocedure, 59% of children were weaned completely from their prostacyclin infusion (P < 0.001). Preprocedural risk factors for dying in-hospital postprocedure included intensive care unit admission (hazard ratio [HR]: 3.2; P = 0.02), mechanical ventilation (HR: 8.3; P < 0.001) and extracorporeal membrane oxygenation (HR: 10.7; P < 0.001).
Conclusions
A pulmonary-to-systemic arterial shunt can provide a child with severe PH significant clinical improvement that is both durable and potentially free from continuous prostacyclin infusion. Five-year survival is comparable to children undergoing lung transplantation for PH. Children with severely decompensated disease requiring aggressive intensive care are not good candidates for the shunt procedure.

Copyright © 2021 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 02 Aug 2021; 78:468-477
Grady RM, Canter MW, Wan F, Shmalts AA, ... Bonnet D, International Registry Potts Shunt
J Am Coll Cardiol: 02 Aug 2021; 78:468-477 | PMID: 34325836
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Abstract

Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease.

Schachtl-Riess JF, Kheirkhah A, Grüneis R, Di Maio S, ... Coassin S, GCKD Investigators
Background
Lipoprotein(a) (Lp(a)) concentrations are a major independent risk factor for coronary artery disease (CAD) and are mainly determined by variation in LPA. Up to 70% of the LPA coding sequence is located in the hypervariable kringle IV type 2 (KIV-2) region. It is hardly accessible by conventional technologies, but may contain functional variants.
Objectives
This study sought to investigate the new, very frequent splicing variant KIV-2 4733G>A on Lp(a) and CAD.
Methods
We genotyped 4733G>A in the GCKD (German Chronic Kidney Disease) study (n = 4,673) by allele-specific polymerase chain reaction, performed minigene assays, identified proxy single nucleotide polymorphisms and used them to characterize its effect on CAD by survival analysis in UK Biobank (n = 440,234). Frequencies in ethnic groups were assessed in the 1000 Genomes Project.
Results
The 4733G>A variant (38.2% carrier frequency) was found in most isoform sizes. It reduces allelic expression without abolishing protein production, lowers Lp(a) by 13.6 mg/dL (95% CI: 12.5-14.7; P < 0.0001) and is the strongest variance-explaining factor after the smaller isoform. Splicing of minigenes was modified. Compound heterozygosity (4.6% of the population) for 4733G>A and 4925G>A, another KIV-2 splicing mutation, reduces Lp(a) by 31.8 mg/dL and most importantly narrows the interquartile range by 9-fold (from 42.1 to 4.6 mg/dL) when compared to the wild type. In UK Biobank 4733G>A alone and compound heterozygosity with 4925G>A reduced HR for CAD by 9% (95% CI: 7%-11%) and 12% (95% CI: 7%-16%) (both P < 0.001). Frequencies in ethnicities differ notably.
Conclusions
Functional variants in the previously inaccessible LPA KIV-2 region cooperate in determining Lp(a) variance and CAD risk. Even a moderate but lifelong genetic Lp(a) reduction translates to a noticeable CAD risk reduction.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 02 Aug 2021; 78:437-449
Schachtl-Riess JF, Kheirkhah A, Grüneis R, Di Maio S, ... Coassin S, GCKD Investigators
J Am Coll Cardiol: 02 Aug 2021; 78:437-449 | PMID: 34325833
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Abstract

Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol.

Schwartz GG, Szarek M, Bittner VA, Diaz R, ... Gabriel Steg P, ODYSSEY Outcomes Committees and Investigators
Background
Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk.
Objectives
In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels.
Methods
ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was <70 mg/dL (median 69.4 mg/dL; interquartile range: 64.3-74.0 mg/dL); in 14,573 patients (77.0%), both determinations were ≥70 mg/dL (median 94.0 mg/dL; interquartile range: 83.2-111.0 mg/dL).
Results
In the lower LDL-C subgroup, MACE rates were 4.2 and 3.1 per 100 patient-years among placebo-treated patients with baseline lipoprotein(a) greater than or less than or equal to the median (13.7 mg/dL). Corresponding adjusted treatment hazard ratios were 0.68 (95% confidence interval [CI]: 0.52-0.90) and 1.11 (95% CI: 0.83-1.49), with treatment-lipoprotein(a) interaction on MACE (Pinteraction = 0.017). In the higher LDL-C subgroup, MACE rates were 4.7 and 3.8 per 100 patient-years among placebo-treated patients with lipoprotein(a) >13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43.
Conclusions
In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 02 Aug 2021; 78:421-433
Schwartz GG, Szarek M, Bittner VA, Diaz R, ... Gabriel Steg P, ODYSSEY Outcomes Committees and Investigators
J Am Coll Cardiol: 02 Aug 2021; 78:421-433 | PMID: 34325831
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This program is still in alpha version.