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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