Journal: J Am Coll Cardiol

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Abstract

Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function.

Rosoff DB, Bell AS, Jung J, Wagner J, Mavromatis LA, Lohoff FW
Background
Lipid-lowering therapy with statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition are effective strategies in reducing cardiovascular disease risk; however, concerns remain about potential long-term adverse neurocognitive effects.
Objectives
This genetics-based study aimed to evaluate the relationships of long-term PCSK9 inhibition and statin use on neurocognitive outcomes.
Methods
We extracted single-nucleotide polymorphisms in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and PCSK9 from predominantly European ancestry-based genome-wide association studies summary-level statistics of low-density lipoprotein cholesterol and performed drug-target Mendelian randomization, proxying the potential neurocognitive impact of drug-based PCSK9 and HMGCR inhibition using a range of outcomes to capture the complex facets of cognition and dementia.
Results
Using data from a combined sample of ∼740,000 participants, we observed a neutral cognitive profile related to genetic PCSK9 inhibition, with no significant effects on cognitive performance, memory performance, or cortical surface area. Conversely, we observed several adverse associations for HMGCR inhibition with lowered cognitive performance (beta: -0.082; 95% CI: -0.16 to -0.0080; P = 0.03), reaction time (beta = 0.00064; 95% CI: 0.00030-0.00098; P = 0.0002), and cortical surface area (beta = -0.18; 95% CI: -0.35 to -0.014; P = 0.03). Neither PCSK9 nor HMGCR inhibition impacted biomarkers of Alzheimer\'s disease progression or Lewy body dementia risk. Consistency of findings across Mendelian randomization methods accommodating different assumptions about genetic pleiotropy strengthens causal inference.
Conclusions
Using a wide range of cognitive function and dementia endpoints, we failed to find genetic evidence of an adverse PCSK9-related impact, suggesting a neutral cognitive profile. In contrast, we observed adverse neurocognitive effects related to HMGCR inhibition, which may well be outweighed by the cardiovascular benefits of statin use, but nonetheless may warrant pharmacovigilance.

Published by Elsevier Inc.

J Am Coll Cardiol: 16 Aug 2022; 80:653-662
Rosoff DB, Bell AS, Jung J, Wagner J, Mavromatis LA, Lohoff FW
J Am Coll Cardiol: 16 Aug 2022; 80:653-662 | PMID: 35953131
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Abstract

Prevalence and Prognostic Implications of Discordant Grading and Flow-Gradient Patterns in Moderate Aortic Stenosis.

Stassen J, Ewe SH, Singh GK, Butcher SC, ... Marsan NA, Bax JJ
Background
The prognostic implications of discordant grading in severe aortic stenosis (AS) are well known. However, the prevalence of different flow-gradient patterns and their prognostic implications in moderate AS are unknown.
Objectives
The purpose of this study was to investigate the occurrence and prognostic implications of different flow-gradient patterns in patients with moderate AS.
Methods
Patients with moderate AS (aortic valve area >1.0 and ≤1.5 cm2) were identified and divided in 4 groups based on transvalvular mean gradient (MG), stroke volume index (SVi), and left ventricular ejection fraction (LVEF): concordant moderate AS (MG ≥20 mm Hg) and discordant moderate AS including 3 subgroups: normal-flow, low-gradient moderate AS (MG <20 mm Hg, SVi ≥35 mL/m2, and LVEF ≥50%); \"paradoxical\" low-flow, low-gradient moderate AS (MG <20 mm Hg, SVi <35 mL/m2, and LVEF ≥50%) and \"classical\" low-flow, low-gradient moderate AS (MG <20 mm Hg and LVEF <50%). The primary endpoint was all-cause mortality.
Results
Of 1,974 patients (age 73 ± 10 years, 51% men) with moderate AS, 788 (40%) had discordant grading, and these patients showed significantly higher mortality rates than patients with concordant moderate AS (P < 0.001). On multivariable analysis, \"paradoxical\" low-flow, low-gradient (HR: 1.458; 95% CI: 1.072-1.983; P = 0.014) and \"classical\" low-flow, low-gradient (HR: 1.710; 95% CI: 1.270-2.303; P < 0.001) patterns but not the normal-flow, low-gradient moderate AS pattern were independently associated with all-cause mortality.
Conclusions
Discordant grading is frequently (40%) observed in patients with moderate AS. Low-flow, low-gradient patterns account for an important proportion of the discordant cases and are associated with increased mortality. These findings underline the need for better phenotyping patients with discordant moderate AS.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Aug 2022; 80:666-676
Stassen J, Ewe SH, Singh GK, Butcher SC, ... Marsan NA, Bax JJ
J Am Coll Cardiol: 16 Aug 2022; 80:666-676 | PMID: 35953133
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Abstract

Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease.

Hemnes AR, Leopold JA, Radeva MK, Beck GJ, ... Horn EM, PVDOMICS Study Group
Background
PVDOMICS (Pulmonary Vascular Disease Phenomics) is a precision medicine initiative to characterize pulmonary vascular disease (PVD) using deep phenotyping. PVDOMICS tests the hypothesis that integration of clinical metrics with omic measures will enhance understanding of PVD and facilitate an updated PVD classification.
Objectives
The purpose of this study was to describe clinical characteristics and transplant-free survival in the PVDOMICS cohort.
Methods
Subjects with World Symposium Pulmonary Hypertension (WSPH) group 1-5 PH, disease comparators with similar underlying diseases and mild or no PH and healthy control subjects enrolled in a cross-sectional study. PH groups, comparators were compared using standard statistical tests including log-rank tests for comparing time to transplant or death.
Results
A total of 1,193 subjects were included. Multiple WSPH groups were identified in 38.9% of PH subjects. Nocturnal desaturation was more frequently observed in groups 1, 3, and 4 PH vs comparators. A total of 50.2% of group 1 PH subjects had ground glass opacities on chest computed tomography. Diffusing capacity for carbon monoxide was significantly lower in groups 1-3 PH than their respective comparators. Right atrial volume index was higher in WSPH groups 1-4 than comparators. A total of 110 participants had a mean pulmonary artery pressure of 21-24 mm Hg. Transplant-free survival was poorest in group 3 PH.
Conclusions
PVDOMICS enrolled subjects across the spectrum of PVD, including mild and mixed etiology PH. Novel findings include low diffusing capacity for carbon monoxide and enlarged right atrial volume index as shared features of groups 1-3 and 1-4 PH, respectively; unexpected, frequent presence of ground glass opacities on computed tomography; and sleep alterations in group 1 PH, and poorest survival in group 3 PH. PVDOMICS will facilitate a new understanding of PVD and refine the current PVD classification. (Pulmonary Vascular Disease Phenomics Program PVDOMICS [PVDOMICS]; NCT02980887).

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Aug 2022; 80:697-718
Hemnes AR, Leopold JA, Radeva MK, Beck GJ, ... Horn EM, PVDOMICS Study Group
J Am Coll Cardiol: 16 Aug 2022; 80:697-718 | PMID: 35953136
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Abstract

Management of Patients With Severe Mitral Annular Calcification: JACC State-of-the-Art Review.

Chehab O, Roberts-Thomson R, Bivona A, Gill H, ... Prendergast B, Rajani R
Mitral annular calcification (MAC) is a common and challenging pathologic condition, especially in the context of an aging society. Surgical mitral valve intervention in patients with MAC is difficult, with varying approaches to the calcified annular anatomy, and the advent of transcatheter valve interventions has provided additional treatment options. Advanced imaging provides the foundation for heart team discussions and management decisions concerning individual patients. This review focuses on the prognosis of, preoperative planning for, and management strategies for patients with MAC.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Aug 2022; 80:722-738
Chehab O, Roberts-Thomson R, Bivona A, Gill H, ... Prendergast B, Rajani R
J Am Coll Cardiol: 16 Aug 2022; 80:722-738 | PMID: 35953138
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Abstract

Mitral Valve Dysfunction in Patients With Annular Calcification: JACC Review Topic of the Week.

Churchill TW, Yucel E, Deferm S, Levine RA, Hung J, Bertrand PB
Mitral annular calcification (MAC) is a common clinical finding and is associated with adverse clinical outcomes, but the clinical impact of MAC-related mitral valve (MV) dysfunction remains underappreciated. Patients with MAC frequently have stenotic, regurgitant, or mixed valvular disease, and this valvular dysfunction is increasingly recognized to be independently associated with worse prognosis. MAC-related MV dysfunction is a distinct pathophysiologic entity, and importantly much of the diagnostic and therapeutic paradigm from published rheumatic MV disease research cannot be applied in this context, leaving important gaps in our knowledge. This review summarizes the current epidemiology, pathophysiology, diagnosis, and classification of MAC-related MV dysfunction and proposes both an integrative definition and an overarching approach to this important and increasingly recognized clinical condition.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Aug 2022; 80:739-751
Churchill TW, Yucel E, Deferm S, Levine RA, Hung J, Bertrand PB
J Am Coll Cardiol: 16 Aug 2022; 80:739-751 | PMID: 35953139
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Abstract

Cardiovascular Disease Projections in the United States Based on the 2020 Census Estimates.

Mohebi R, Chen C, Ibrahim NE, McCarthy CP, ... Wasfy JH, Januzzi JL
Background
Understanding trends in cardiovascular (CV) risk factors and CV disease according to age, sex, race, and ethnicity is important for policy planning and public health interventions.
Objectives
The goal of this study was to project the number of people with CV risk factors and disease and further explore sex, race, and ethnical disparities.
Methods
The prevalence of CV risk factors (diabetes mellitus, hypertension, dyslipidemia, and obesity) and CV disease (ischemic heart disease, heart failure, myocardial infarction, and stroke) according to age, sex, race, and ethnicity was estimated by using logistic regression models based on 2013-2018 National Health and Nutrition Examination Survey data and further combining them with 2020 U.S. Census projection counts for years 2025-2060.
Results
By the year 2060, compared with the year 2025, the number of people with diabetes mellitus will increase by 39.3% (39.2 million [M] to 54.6M), hypertension by 27.2% (127.8M to 162.5M), dyslipidemia by 27.5% (98.6M to 125.7M), and obesity by 18.3% (106.3M to 125.7M). Concurrently, projected prevalence will similarly increase compared with 2025 for ischemic heart disease by 31.1% (21.9M to 28.7M), heart failure by 33.0% (9.7M to 12.9M), myocardial infarction by 30.1% (12.3M to 16.0M), and stroke by 34.3% (10.8M to 14.5M). Among White individuals, the prevalence of CV risk factors and disease is projected to decrease, whereas significant increases are projected in racial and ethnic minorities.
Conclusions
Large future increases in CV risk factors and CV disease prevalence are projected, disproportionately affecting racial and ethnic minorities. Future health policies and public health efforts should take these results into account to provide quality, affordable, and accessible health care.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Aug 2022; 80:565-578
Mohebi R, Chen C, Ibrahim NE, McCarthy CP, ... Wasfy JH, Januzzi JL
J Am Coll Cardiol: 09 Aug 2022; 80:565-578 | PMID: 35926929
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Abstract

Sustained-Release Ivabradine Hemisulfate in Patients With Systolic Heart Failure.

Ye F, Wang X, Wu S, Ma S, ... Wang J, FIRST Investigators
Background
Ivabradine has potent actions in reducing heart rate and improving clinical outcomes of chronic heart failure with reduced ejection fraction (HFrEF). At present, only the short-acting formulation of ivabradine is available that needs to be administered twice daily.
Objectives
This study sought to evaluate the role of ivabradine hemisulfate sustained release (SR), a novel long-acting formulation of ivabradine dosed once daily, in stable patients with HFrEF.
Methods
Patients with stabilized HFrEF in New York Heart Association functional class II-IV were enrolled and randomized to receive placebo or ivabradine SR in addition to standard medications. The primary endpoint was the change of left ventricular (LV) end-systolic volume index from baseline to week 32.
Results
We randomly assigned 181 patients to placebo and 179 patients to ivabradine SR. After 32 weeks, a significant improvement of LV end-systolic volume index from baseline was observed in both arms with a greater effect in the ivabradine SR arm. Ivabradine SR therapy also exhibited superiority in improving LV end-diastolic volume index, LV ejection fraction, resting heart rate, the Kansas City Cardiomyopathy Questionnaire score, and hospital admission for heart failure worsening and cardiovascular disease in comparison to placebo. Overall adverse events showed no difference between the treatment arms. There were fewer occurrences of worsening heart failure in the ivabradine SR arm.
Conclusions
The present study demonstrates that ivabradine SR once daily in addition to optimum standard therapy improved heart function in patients with HFrEF. (Clinical Trial of Systolic Heart Failure Treatment of IvabRadine Hemisulfate Sustained-release Tablets [FIRST]; NCT02188082).

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Aug 2022; 80:584-594
Ye F, Wang X, Wu S, Ma S, ... Wang J, FIRST Investigators
J Am Coll Cardiol: 09 Aug 2022; 80:584-594 | PMID: 35926931
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Abstract

Cardiorespiratory Fitness and Mortality Risk Across the Spectra of Age, Race, and Sex.

Kokkinos P, Faselis C, Samuel IBH, Pittaras A, ... Zhang J, Myers J
Background
Cardiorespiratory fitness (CRF) is inversely associated with all-cause mortality. However, the association of CRF and mortality risk for different races, women, and elderly individuals has not been fully assessed.
Objectives
The aim of this study was to evaluate the association of CRF and mortality risk across the spectra of age, race, and sex.
Methods
A total of 750,302 U.S. veterans aged 30 to 95 years (mean age 61.3 ± 9.8 years) were studied, including septuagenarians (n = 110,637), octogenarians (n = 26,989), African Americans (n = 142,798), Hispanics (n = 35,197), Native Americans (n = 16,050), and women (n = 45,232). Age- and sex-specific CRF categories (quintiles and 98th percentile) were established objectively on the basis of peak METs achieved during a standardized exercise treadmill test. Multivariable Cox models were used to estimate HRs and 95% CIs for mortality across the CRF categories.
Results
During follow-up (median 10.2 years, 7,803,861 person-years of observation), 174,807 subjects died, averaging 22.4 events per 1,000 person-years. The adjusted association of CRF and mortality risk was inverse and graded across the age spectrum, sex, and race. The lowest mortality risk was observed at approximately 14.0 METs for men (HR: 0.24; 95% CI: 0.23-0.25) and women (HR: 0.23; 95% CI: 0.17-0.29), with no evidence of an increase in risk with extremely high CRF. The risk for least fit individuals (20th percentile) was 4-fold higher (HR: 4.09; 95% CI: 3.90-4.20) compared with extremely fit individuals.
Conclusions
The association of CRF and mortality risk across the age spectrum (including septuagenarians and octogenarians), men, women, and all races was inverse, independent, and graded. No increased risk was observed with extreme fitness. Being unfit carried a greater risk than any of the cardiac risk factors examined.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Aug 2022; 80:598-609
Kokkinos P, Faselis C, Samuel IBH, Pittaras A, ... Zhang J, Myers J
J Am Coll Cardiol: 09 Aug 2022; 80:598-609 | PMID: 35926933
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Abstract

Deep Learning Electrocardiographic Analysis for Detection of Left-Sided Valvular Heart Disease.

Elias P, Poterucha TJ, Rajaram V, Moller LM, ... Leon MB, Perotte AJ
Background
Valvular heart disease is an important contributor to cardiovascular morbidity and mortality and remains underdiagnosed. Deep learning analysis of electrocardiography (ECG) may be useful in detecting aortic stenosis (AS), aortic regurgitation (AR), and mitral regurgitation (MR).
Objectives
This study aimed to develop ECG deep learning algorithms to identify moderate or severe AS, AR, and MR alone and in combination.
Methods
A total of 77,163 patients undergoing ECG within 1 year before echocardiography from 2005-2021 were identified and split into train (n = 43,165), validation (n = 12,950), and test sets (n = 21,048; 7.8% with any of AS, AR, or MR). Model performance was assessed using area under the receiver-operating characteristic (AU-ROC) and precision-recall curves. Outside validation was conducted on an independent data set. Test accuracy was modeled using different disease prevalence levels to simulate screening efficacy using the deep learning model.
Results
The deep learning algorithm model accuracy was as follows: AS (AU-ROC: 0.88), AR (AU-ROC: 0.77), MR (AU-ROC: 0.83), and any of AS, AR, or MR (AU-ROC: 0.84; sensitivity 78%, specificity 73%) with similar accuracy in external validation. In screening program modeling, test characteristics were dependent on underlying prevalence and selected sensitivity levels. At a prevalence of 7.8%, the positive and negative predictive values were 20% and 97.6%, respectively.
Conclusions
Deep learning analysis of the ECG can accurately detect AS, AR, and MR in this multicenter cohort and may serve as the basis for the development of a valvular heart disease screening program.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Aug 2022; 80:613-626
Elias P, Poterucha TJ, Rajaram V, Moller LM, ... Leon MB, Perotte AJ
J Am Coll Cardiol: 09 Aug 2022; 80:613-626 | PMID: 35926935
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Abstract

Impact of the COVID-19 Pandemic on Cardiovascular Health in 2020: JACC State-of-the-Art Review.

Roth GA, Vaduganathan M, Mensah GA
The impact of COVID-19 on the burden of cardiovascular diseases (CVD) during the early pandemic remains unclear. COVID-19 has become one of the leading causes of global mortality, with a disproportionate impact on persons with CVD. Studies of health facility admissions for CVD found significant decreases during the pandemic. Studies of hospital mortality for CVD were more variable. Studies of population-level CVD mortality differed across countries, with most showing decreases, although some revealed increases in deaths. In some countries where large increases in CVD deaths were reported in vital registration systems, misclassification of COVID-19 as CVD may have occurred. Taken together, studies suggest heterogeneous effects of the COVID-19 pandemic on CVD without large increases in CVD mortality in 2020 for a number of countries. Clinical and population science research is needed to examine the ways in which the pandemic has affected CVD burden.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Aug 2022; 80:631-640
Roth GA, Vaduganathan M, Mensah GA
J Am Coll Cardiol: 09 Aug 2022; 80:631-640 | PMID: 35926937
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Abstract

Harmonization of the American College of Cardiology/American Heart Association and European Society of Cardiology/European Society of Hypertension Blood Pressure/Hypertension Guidelines: Comparisons, Reflections, and Recommendations.

Whelton PK, Carey RM, Mancia G, Kreutz R, Bundy JD, Williams B
The 2017 American College of Cardiology/American Heart Association and 2018 European Society of Cardiology/European Society of Hypertension clinical practice guidelines for management of high blood pressure/hypertension are influential documents. Both guidelines are comprehensive, were developed using rigorous processes, and underwent extensive peer review. The most notable difference between the 2 guidelines is the blood pressure cut points recommended for the diagnosis of hypertension. There are also differences in the timing and intensity of treatment, with the American College of Cardiology/American Heart Association guideline recommending a somewhat more intensive approach. Overall, there is substantial concordance in the recommendations provided by the 2 guideline-writing committees, with greater congruity between them than their predecessors. Additional harmonization of future guidelines would help to underscore the commonality of their core recommendations and could serve to catalyze changes in practice that would lead to improved prevention, awareness, treatment, and control of hypertension, worldwide.

Copyright © 2022 American Heart Association, Inc. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 04 Aug 2022; epub ahead of print
Whelton PK, Carey RM, Mancia G, Kreutz R, Bundy JD, Williams B
J Am Coll Cardiol: 04 Aug 2022; epub ahead of print | PMID: 35965201
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Abstract

Impact of Peridevice Leak on 5-Year Outcomes After Left Atrial Appendage Closure.

Dukkipati SR, Holmes DR, Doshi SK, Kar S, ... Allocco DJ, Reddy VY
Background
In the U.S. Food and Drug Administration (FDA) clinical trials of left atrial appendage (LAA) closure, a postimplantation peridevice leak (PDL) of ≤5 mm (PDL≤5) was accepted as sufficient LAA \"closure.\" However, the clinical consequences of these PDLs on subsequent thromboembolism are poorly characterized.
Objectives
We sought to assess the impact of PDL≤5 on clinical outcomes after implantation of the Watchman device.
Methods
Using combined data from the FDA studies PROTECT-AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation), PREVAIL (Evaluation of the Watchman Left Atrial Appendage Closure Device in Patients With Atrial Fibrillation vs Long Term Warfarin Therapy), and CAP2 (Continued Access to PREVAIL), we assessed patients with successful device implantation for PDL by means of protocol-mandated transesophageal echocardiograms (TEEs) at 45 days and 1 year. Five-year outcomes were assessed as a function of the absence or presence of PDL≤5.
Results
The cohort included 1,054 patients: mean age 74 ± 8.3 years, 65% male, and CHA2DS2-VASc 4.1 ± 1.4. TEE imaging at 45 days revealed 634 patients (60.2%) without and 404 (38.3%) with PDL≤5, and 1-year TEE revealed 704 patients (71.6%) without and 272 (27.7%) with PDL≤5. The presence of PDL≤5 at 1 year, but not at 45 days, was associated with an increased 5-year risk of ischemic stroke or systemic embolism (adjusted HR: 1.94; 95% CI: 1.15-3.29; P = 0.014), largely driven by an increase in nondisabling stroke (HR: 1.97; 95% CI: 1.03-3.78; P = 0.04), while disabling or fatal stroke rates were similar (HR: 0.69; 95% CI: 0.19-2.46; P = 0.56). PDL≤5 was not associated with an increased risk of cardiovascular or unexplained death (HR: 1.20; P = 0.45) or all-cause death (HR: 0.87; P = 0.42).
Conclusions
PDL≤5 at 1 year after percutaneous LAA closure with the Watchman device are associated with increased thromboembolism, driven by increased nondisabling stroke, but similar mortality. (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation [PROTECT-AF; NCT00129545]; Evaluation of the Watchman Left Atrial Appendage Closure Device in Patients With Atrial Fibrillation vs Long Term Warfarin Therapy [PREVAIL; NCT01182441]; Continued Access to PREVAIL [CAP2; NCT01760291]).

Copyright © 2022. Published by Elsevier Inc.

J Am Coll Cardiol: 02 Aug 2022; 80:469-483
Dukkipati SR, Holmes DR, Doshi SK, Kar S, ... Allocco DJ, Reddy VY
J Am Coll Cardiol: 02 Aug 2022; 80:469-483 | PMID: 35902169
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Abstract

Spatially Distinct Genetic Determinants of Aortic Dimensions Influence Risks of Aneurysm and Stenosis.

Nekoui M, Pirruccello JP, Di Achille P, Choi SH, ... Lindsay ME, Ellinor PT
Background
The left ventricular outflow tract (LVOT) and ascending aorta are spatially complex, with distinct pathologies and embryologic origins. Prior work examined the genetics of thoracic aortic diameter in a single plane.
Objectives
We sought to elucidate the genetic basis for the diameter of the LVOT, aortic root, and ascending aorta.
Methods
Using deep learning, we analyzed 2.3 million cardiac magnetic resonance images from 43,317 UK Biobank participants. We computed the diameters of the LVOT, the aortic root, and at 6 locations of ascending aorta. For each diameter, we conducted a genome-wide association study and generated a polygenic score. Finally, we investigated associations between these scores and disease incidence.
Results
A total of 79 loci were significantly associated with at least 1 diameter. Of these, 35 were novel, and most were associated with 1 or 2 diameters. A polygenic score of aortic diameter approximately 13 mm from the sinotubular junction most strongly predicted thoracic aortic aneurysm (n = 427,016; mean HR: 1.42 per SD; 95% CI: 1.34-1.50; P = 6.67 × 10-21). A polygenic score predicting a smaller aortic root was predictive of aortic stenosis (n = 426,502; mean HR: 1.08 per SD; 95% CI: 1.03-1.12; P = 5 × 10-6).
Conclusions
We detected distinct genetic loci underpinning the diameters of the LVOT, aortic root, and at several segments of ascending aorta. We spatially defined a region of aorta whose genetics may be most relevant to predicting thoracic aortic aneurysm. We further described a genetic signature that may predispose to aortic stenosis. Understanding genetic contributions to proximal aortic diameter may enable identification of individuals at risk for aortic disease and facilitate prioritization of therapeutic targets.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 02 Aug 2022; 80:486-497
Nekoui M, Pirruccello JP, Di Achille P, Choi SH, ... Lindsay ME, Ellinor PT
J Am Coll Cardiol: 02 Aug 2022; 80:486-497 | PMID: 35902171
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Abstract

Effects of Cyproheptadine on Mitral Valve Remodeling and Regurgitation After Myocardial Infarction.

Marsit O, Clavel MA, Paquin A, Deschênes V, ... Pibarot P, Beaudoin J
Background
Ischemic mitral regurgitation (MR) is primarily caused by left ventricle deformation, but leaflet thickening with fibrotic changes are also observed in the valve. Increased levels of 5-hydroxytryptamine (5-HT; ie, serotonin) are described after myocardial infarction (MI); 5-HT can induce valve fibrosis through the 5-HT type 2B receptor (5-HT2BR).
Objectives
This study aims to test the hypothesis that post-MI treatment with cyproheptadine (5-HT2BR antagonist) can prevent ischemic MR by reducing the effect of serotonin on mitral biology.
Methods
Thirty-six sheep were divided into 2 groups: inferior MI and inferior MI treated with cyproheptadine (0.5 mg/kg/d). Animals were followed for 90 days. Blood 5-HT, infarct size, left ventricular volume and function, MR fraction and mitral leaflet size were assessed. In a complementary in vitro study, valvular interstitial cells were exposed to pre-MI and post-MI serum collected from the experimental animals.
Results
Increased 5-HT levels were observed after MI in nontreated animals, but not in the group treated with cyproheptadine. Infarct size was similar in both groups (11 ± 3 g vs 9 ± 5 g; P = 0.414). At 90 days, MR fraction was 16% ± 7% in the MI group vs 2% ± 6% in the cyproheptadine group (P = 0.0001). The increase in leaflet size following MI was larger in the cyproheptadine group (+40% ± 9% vs +22% ± 12%; P = 0.001). Mitral interstitial cells overexpressed extracellular matrix genes when treated with post-MI serum, but not when exposed to post-MI serum collected from treated animals.
Conclusions
Cyproheptadine given after inferior MI reduces post-MI 5-HT levels, prevents valvular fibrotic remodeling, is associated with larger increase in mitral valve size and less MR.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 02 Aug 2022; 80:500-510
Marsit O, Clavel MA, Paquin A, Deschênes V, ... Pibarot P, Beaudoin J
J Am Coll Cardiol: 02 Aug 2022; 80:500-510 | PMID: 35902173
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Abstract

Nurse-Provided Lung and Inferior Vena Cava Assessment in Patients With Heart Failure.

Zisis G, Yang Y, Huynh Q, Whitmore K, ... Carrington MJ, Marwick TH
Background
Residual congestion detected using handheld ultrasound may be associated with increased risk of readmission and death after hospitalization for acute decompensated heart failure (ADHF). However, effective application necessitates routine use by nonexperts delivering clinical care.
Objectives
The objective of this study was to determine the ability of heart failure (HF) nurses to deliver a predischarge lung and inferior vena cava (IVC) assessment (LUICA) to predict 90-day outcomes.
Methods
In this multisite, prospective, observational study, HF nurses scanned 240 patients with ADHF (median age: 77 years; 56% men) using a 9-zone LUICA protocol. Obtained images were reviewed by independent nurses who were blinded to clinical characteristics and outcomes. Based on a B-line cut-off of 10, patients were dichotomized as congested (n = 115) or not congested (n = 125).
Results
Congested patients were more likely to have previous cardiac operations, long-standing HF (>6 months), and renal impairment. At 90 days, HF readmission or mortality occurred in 42 congested patients (37%) compared with 18 noncongested patients (14%). Pulmonary congestion increased at 30-day (OR: 3.86; 95% CI: 1.65-8.99; P < 0.01) and 90-day (OR: 3.42; 95% CI: 1.82-6.4; P < 0.01) HF readmission or mortality risk and 90-day mortality (OR: 5.18; 95% CI: 1.44-18.69; P < 0.01). Pulmonary congestion increased the 90-day odds of HF readmission and/or death by 3.3- to 4.2-fold (P < 0.01), independent of demographics, HF characteristics, comorbidities, and event risk score. Over 90 days, days alive out of hospital were fewer (78.3 ± 21.4 days vs 85.5 ± 12.4 days; P < 0.01) in congested patients.
Conclusions
LUICA can be a powerful tool for detection of predischarge residual congestion. HF nurses can obtain images and provide diagnostic reports that are predictive of ADHF outcomes.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 02 Aug 2022; 80:513-523
Zisis G, Yang Y, Huynh Q, Whitmore K, ... Carrington MJ, Marwick TH
J Am Coll Cardiol: 02 Aug 2022; 80:513-523 | PMID: 35902175
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Abstract

Bioprosthetic Aortic Valve Hemodynamics: Definitions, Outcomes, and Evidence Gaps: JACC State-of-the-Art Review.

Herrmann HC, Pibarot P, Wu C, Hahn RT, ... Leon MB, Heart Valve Collaboratory
A virtual workshop was organized by the Heart Valve Collaboratory to identify areas of expert consensus, areas of disagreement, and evidence gaps related to bioprosthetic aortic valve hemodynamics. Impaired functional performance of bioprosthetic aortic valve replacement is associated with adverse patient outcomes; however, this assessment is complicated by the lack of standardization for labelling, definitions, and measurement techniques, both after surgical and transcatheter valve replacement. Echocardiography remains the standard assessment methodology because of its ease of performance, widespread availability, ability to do serial measurements over time, and correlation with outcomes. Management of a high gradient after replacement requires integration of the patient\'s clinical status, physical examination, and multimodality imaging in addition to shared patient decisions regarding treatment options. Future priorities that are underway include efforts to standardize prosthesis sizing and labelling for both surgical and transcatheter valves as well as trials to characterize the consequences of adverse hemodynamics.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 02 Aug 2022; 80:527-544
Herrmann HC, Pibarot P, Wu C, Hahn RT, ... Leon MB, Heart Valve Collaboratory
J Am Coll Cardiol: 02 Aug 2022; 80:527-544 | PMID: 35902177
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Abstract

Standardized Definitions for Bioprosthetic Valve Dysfunction Following Aortic or Mitral Valve Replacement: JACC State-of-the-Art Review.

Pibarot P, Herrmann HC, Wu C, Hahn RT, ... Leon MB, Heart Valve Collaboratory
Bioprosthetic valve dysfunction (BVD) and bioprosthetic valve failure (BVF) may be caused by structural or nonstructural valve dysfunction. Both surgical and transcatheter bioprosthetic valves have limited durability because of structural valve deterioration. The main objective of this summary of experts participating in a virtual workshop was to propose standardized definitions for nonstructural and structural BVD and BVF following aortic or mitral biological valve replacement with the goal of facilitating research reporting and implementation of these terms in clinical practice. Definitions of structural BVF, based on valve reintervention or death, underestimate the true incidence of BVF. However, definitions solely based on the presence of high transprosthetic gradient at a given echocardiogram during follow-up overestimate the incidence of structural BVD and BVF. Definitions of aortic or mitral structural BVD must therefore include the confirmation by imaging of permanent structural changes to the leaflets alongside evidence of deterioration in valve hemodynamic function at echocardiography follow-up.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 02 Aug 2022; 80:545-561
Pibarot P, Herrmann HC, Wu C, Hahn RT, ... Leon MB, Heart Valve Collaboratory
J Am Coll Cardiol: 02 Aug 2022; 80:545-561 | PMID: 35902178
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Abstract

Presenting Pattern of Atrial Fibrillation and Outcomes of Early Rhythm Control Therapy.

Goette A, Borof K, Breithardt G, Camm AJ, ... Kirchhof P, EAST-AFNET 4 Investigators
Background
Whether atrial fibrillation (AF) pattern or timing of AF therapy modifies the effectiveness of early rhythm control (ERC) is not known.
Objectives
This study sought to compare clinical characteristics and outcomes in patients presenting with different AF patterns on ERC vs usual care.
Methods
The effects of ERC were compared in first-diagnosed AF (FDAF), paroxysmal AF (paroxAF), and persistent AF (persAF) in this prespecified analysis of the EAST-AFNET 4 (Early treatment of atrial fibrillation for stroke prevention) trial. Associations between AF pattern and primary outcomes (first primary outcome: cardiovascular death, stroke, and hospitalization for heart failure and acute coronary syndrome; second primary outcome: nights spent in hospital per year) were compared over a mean follow-up of 5.1 years. Changes in health-related quality of life were assessed by the EQ-5D.
Results
FDAF patients (n = 1,048, enrolled 7 days after diagnosing AF) were slightly older (71 years of age, 48.0% female) than patients with paroxAF (n = 994, 70 years of age, 50.0% female) and persAF (n = 743, 70 years of age, 38.0% female). ERC reduced the primary outcome in all 3 AF patterns. Hospitalizations for acute coronary syndrome were highest in FDAF (incidence rate ratio [IRR]: 1.50; 95% CI: 0.83-2.69; P for interaction = 0.032) compared with paroxAF (IRR: 0.64; 95% CI: 0.32-1.25) and persAF (IRR: 0.50; 95% CI: 0.25-1.00). FDAF patients spent more nights in hospital (IRR: 1.38; 95% CI: 1.12-1.70; P for interaction = 0.004) than paroxAF (IRR: 0.84; 95% CI: 0.67-1.03), and persAF (IRR: 1.02; 95% CI: 0.80-1.30) patients. ERC improved health-related quality of life (EQ-5D score) in patients with paroxAF and persAF but not in patients with FDAF (P = 0.019).
Conclusions
ERC reduces the first primary composite outcome in all AF patterns. Patients with FDAF are at high risk for hospitalization and acute coronary syndrome, particularly on ERC. (Early treatment of atrial fibrillation for stroke prevention trial; ISRCTN04708680; Early Treatment of Atrial Fibrillation for Stroke Prevention Trial [EAST]; NCT01288352; Early treatment of Atrial fibrillation for Stroke prevention Trial [EAST]; EudraCT2010-021258-20).

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 26 Jul 2022; 80:283-295
Goette A, Borof K, Breithardt G, Camm AJ, ... Kirchhof P, EAST-AFNET 4 Investigators
J Am Coll Cardiol: 26 Jul 2022; 80:283-295 | PMID: 35863844
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Abstract

Phenotypic Heterogeneity of Fulminant COVID-19--Related Myocarditis in Adults.

Barhoum P, Pineton de Chambrun M, Dorgham K, Kerneis M, ... Gorochov G, Hékimian G
Background
Adults who have been infected with SARS-CoV-2 can develop a multisystem inflammatory syndrome (MIS-A), including fulminant myocarditis. Yet, several patients fail to meet MIS-A criteria, suggesting the existence of distinct phenotypes in fulminant COVID-19-related myocarditis.
Objectives
This study sought to compare the characteristics and clinical outcome between patients with fulminant COVID-19-related myocarditis fulfilling MIS-A criteria (MIS-A+) or not (MIS-A-).
Methods
A monocentric retrospective analysis of consecutive fulminant COVID-19-related myocarditis in a 26-bed intensive care unit (ICU).
Results
Between March 2020 and June 2021, 38 patients required ICU admission (male 66%; mean age 32 ± 15 years) for suspected fulminant COVID-19-related myocarditis. In-ICU treatment for organ failure included dobutamine 79%, norepinephrine 60%, mechanical ventilation 50%, venoarterial extracorporeal membrane oxygenation 42%, and renal replacement therapy 29%. In-hospital mortality was 13%. Twenty-five patients (66%) met the MIS-A criteria. MIS-A- patients compared with MIS-A+ patients were characterized by a shorter delay between COVID-19 symptoms onset and myocarditis, a lower left ventricular ejection fraction, and a higher rate of in-ICU organ failure, and were more likely to require mechanical circulatory support with venoarterial extracorporeal membrane oxygenation (92% vs 16%; P < 0.0001). In-hospital mortality was higher in MIS-A- patients (31% vs 4%). MIS-A+ had higher circulating levels of interleukin (IL)-22, IL-17, and tumor necrosis factor-α (TNF-α), whereas MIS-A- had higher interferon-α2 (IFN-α2) and IL-8 levels. RNA polymerase III autoantibodies were present in 7 of 13 MIS-A- patients (54%) but in none of the MIS-A+ patients.
Conclusion
MIS-A+ and MIS-A- fulminant COVID-19-related myocarditis patients have 2 distinct phenotypes with different clinical presentations, prognosis, and immunological profiles. Differentiating these 2 phenotypes is relevant for patients\' management and further understanding of their pathophysiology.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 26 Jul 2022; 80:299-312
Barhoum P, Pineton de Chambrun M, Dorgham K, Kerneis M, ... Gorochov G, Hékimian G
J Am Coll Cardiol: 26 Jul 2022; 80:299-312 | PMID: 35863846
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Abstract

Association of Blood Viscosity With Mortality Among Patients Hospitalized With COVID-19.

Choi D, Waksman O, Shaik A, Mar P, ... Goonewardena SN, Rosenson RS
Background
Coronavirus disease-2019 (COVID-19) is characterized by a dysfunctional immune response and abnormal blood rheology that contribute to endothelial dysfunction and thrombotic complications. Whole blood viscosity (WBV) is a clinically validated measure of blood rheology and an established predictor of cardiovascular risk. We hypothesize that increased WBV is associated with mortality among patients hospitalized with COVID-19.
Objectives
This study sought to determine the association between estimated BV (eBV) and mortality among hospitalized COVID-19 patients.
Methods
The study population included 5,621 hospitalized COVID-19 patients at the Mount Sinai Health System from February 27, 2020, to November 27, 2021. eBV was calculated using the Walburn-Schneck model. Multivariate Cox proportional hazards models were used to evaluate the association between eBV and mortality. Considered covariates included age, sex, race, cardiovascular and metabolic comorbidities, in-house pharmacotherapy, and baseline inflammatory biomarkers.
Results
Estimated high-shear BV (eHSBV) and estimated low-shear BV were associated with increased in-hospital mortality. One-centipoise increases in eHSBV and estimated low-shear BV were associated with a 36.0% and 7.0% increase in death, respectively (P < 0.001). Compared with participants in the lowest quartile of eHSBV, those in the highest quartile of eHSBV had higher mortality (adjusted HR: 1.53; 95% CI: 1.27-1.84). The association was consistent among multiple subgroups, notably among patients without any comorbidities (adjusted HR: 1.69; 95% CI: 1.28-2.22).
Conclusions
Among hospitalized COVID-19 patients, increased eBV is significantly associated with higher mortality. This suggests that eBV can prognosticate patient outcomes in earlier stages of COVID-19, and that future therapeutics aimed at reducing WBV should be evaluated.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 26 Jul 2022; 80:316-328
Choi D, Waksman O, Shaik A, Mar P, ... Goonewardena SN, Rosenson RS
J Am Coll Cardiol: 26 Jul 2022; 80:316-328 | PMID: 35863848
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Abstract

Criteria for Referral of Patients With Advanced Heart Failure for Specialized Palliative Care.

Chang YK, Allen LA, McClung JA, Denvir MA, ... Collins A, Hui D
Background
Patients with advanced heart failure have substantial supportive care needs. Specialist palliative care can be beneficial, but it is unclear who is most appropriate for referral and when patients should be referred.
Objectives
We conducted a Delphi study of international experts to identify consensus referral criteria for specialist palliative care for patients with advanced heart failure.
Methods
Clinicians from 5 continents with expertise in the integration of cardiology and palliative care were asked to rate 34 disease-based, 24 needs-based, and 9 time-based criteria over 3 rounds. Consensus was defined a priori as ≥70% agreement. A criterion was coded as major if the experts endorsed that meeting that criterion alone was adequate to justify a referral.
Results
The response rate was 44 of 46 (96%), 41 of 46 (89%), and 43 of 46 (93%) in the first, second, and third rounds, respectively. Panelists reached consensus on 25 major criteria for specialist palliative care referral. The 25 major criteria were categorized under 6 topics, including \"advanced/refractory heart failure, comorbidities, and complications\" (eg, cardiac cachexia, cardiorenal syndrome) (n = 8), \"advanced heart failure therapies\" (eg, chronic inotropes, precardiac transplant) (n = 4), \"hospital utilization\" (eg, emergency room visits, hospitalization) (n = 2), \"prognostic estimate\" (n = 1), \"symptom burden/distress\" (eg, severe physical/emotional/spiritual distress) (n = 6), and \"decision making/social support\" (eg, goals-of-care discussions) (n = 4). The majority (68%) of major criteria had ≥90% agreement.
Conclusions
International experts reached consensus on a large number of criteria for referral to specialist palliative care. With further validation, these criteria may be useful for standardizing palliative care access in the inpatient and/or outpatient settings.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 26 Jul 2022; 80:332-344
Chang YK, Allen LA, McClung JA, Denvir MA, ... Collins A, Hui D
J Am Coll Cardiol: 26 Jul 2022; 80:332-344 | PMID: 35863850
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Abstract

Coronary In-Stent Restenosis: JACC State-of-the-Art Review.

Giustino G, Colombo A, Camaj A, Yasumura K, ... Kini A, Sharma SK
The introduction and subsequent iterations of drug-eluting stent technologies have substantially improved the efficacy and safety of percutaneous coronary interventions. However, the incidence of in-stent restenosis (ISR) and the resultant need for repeated revascularization still occur at a rate of 1%-2% per year. Given that millions of drug-eluting stents are implanted each year around the globe, ISR can be considered as a pathologic entity of public health significance. The mechanisms of ISR are multifactorial. Since the first description of the angiographic patterns of ISR, the advent of intracoronary imaging has further elucidated the mechanisms and patterns of ISR. The armamentarium and treatment strategies of ISR have also evolved over time. Currently, an individualized approach using intracoronary imaging to characterize the underlying substrate of ISR is recommended. In this paper, we comprehensively reviewed the incidence, mechanisms, and imaging characterization of ISR and propose a contemporary treatment algorithm.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 26 Jul 2022; 80:348-372
Giustino G, Colombo A, Camaj A, Yasumura K, ... Kini A, Sharma SK
J Am Coll Cardiol: 26 Jul 2022; 80:348-372 | PMID: 35863852
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Abstract

New Cardiovascular Risk Assessment Techniques for Primary Prevention: JACC Review Topic of the Week.

Verma KP, Inouye M, Meikle PJ, Nicholls SJ, Carrington MJ, Marwick TH
Risk factor-based models fail to accurately estimate risk in select populations, in particular younger individuals. A sizable number of people are also classified as being at intermediate risk, for whom the optimal preventive strategy could be more precise. Several personalized risk prediction tools, including coronary artery calcium scoring, polygenic risk scores, and metabolic risk scores may be able to improve risk assessment, pending supportive outcome data from clinical trials. Other tools may well emerge in the near future. A multidimensional approach to risk prediction holds the promise of precise risk prediction. This could allow for targeted prevention minimizing unnecessary costs and risks while maximizing benefits. High-risk individuals could also be identified early in life, creating opportunities to arrest the development of nascent coronary atherosclerosis and prevent future clinical events.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 26 Jul 2022; 80:373-387
Verma KP, Inouye M, Meikle PJ, Nicholls SJ, Carrington MJ, Marwick TH
J Am Coll Cardiol: 26 Jul 2022; 80:373-387 | PMID: 35863853
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This program is still in alpha version.