Circulation最新文献

The science of cardiac rehabilitation and the secondary prevention of cardiovascular disease has progressed substantially since the most recent American Heart Association and American Association of Cardiovascular and Pulmonary Rehabilitation update on the core components of cardiac rehabilitation and secondary prevention programs was published in 2007. In addition, the advent of new care models, including virtual and remote delivery of cardiac rehabilitation services, has expanded the ways that cardiac rehabilitation programs can reach patients. In this scientific statement, we update the scientific basis of the core components of patient assessment, nutritional counseling, weight management and body composition, cardiovascular disease and risk factor management, psychosocial management, aerobic exercise training, strength training, and physical activity counseling. In addition, in recognition that high-quality cardiac rehabilitation programs regularly monitor their processes and outcomes and engage in an ongoing process of quality improvement, we introduce a new core component of program quality. High-quality program performance will be essential to improve widely documented low enrollment and adherence rates and reduce health disparities in cardiac rehabilitation access.

Background: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2. Variant classification is difficult, often because of lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes.

Methods: We quantified cell-surface trafficking of 18 796 variants in KCNH2 using a multiplexed assay of variant effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping. We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1458 patients with KCNH2 missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian long QT syndrome penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events.

Results: Variant MAVE trafficking scores and automated patch clamping peak tail currents were highly correlated (Spearman rank-order ρ=0.69; n=433). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian long QT syndrome penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and adjusted QT interval (QTc); however, MAVE data became nonsignificant when peak tail current and penetrance estimates were also available. The area under the receiver operator characteristic curve for 20-year event outcomes based on patient-specific sex and QTc (area under the curve, 0.80 [0.76-0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (area under the curve, 0.86 [0.83-0.89]) or attainable automated patch clamping peak tail current data (area under the curve, 0.84 [0.81-0.88]).

Conclusions: High-throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale, whereas long QT syndrome penetrance estimates and automated patch clamping peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants.

Background: Short-coupled ventricular fibrillation (SCVF) is increasingly being recognized as a distinct primary electrical disorder and cause of otherwise unexplained cardiac arrest. However, the pathophysiology of SCVF remains largely elusive. Despite extensive genetic screening, there is no convincing evidence of a robust monogenic disease gene, thus raising the speculations for alternative pathogeneses. The role of autoimmune mechanisms in SCVF has not been investigated so far. The objective of this study was to screen for circulating autoantibodies in patients with SCVF and assess their role in arrhythmogenesis.

Methods: This is a prospective, single-center, case-control study enrolling cardiac arrest survivors diagnosed with SCVF or idiopathic ventricular fibrillation (IVF) between 2019 and 2023 at the Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval Inherited Arrhythmia Clinic in Canada. Plasma samples were screened for autoantibodies targeting cardiac ion channels using peptide microarray technology. Identified target autoantibodies were then purified from pooled plasma samples for subsequent cellular electrophysiological studies.

Results: Fourteen patients with SCVF (n=4 [29%] female patients; median age, 45 years [36, 58]; n=14 [100%] non-Hispanic White) and 19 patients with idiopathic ventricular fibrillation (n=8 [42%] female patients; median age, 49 years [38, 57]; n=19 [100%] non-Hispanic White) were enrolled in the study and compared with 38 (n=20 [53%] female subjects; median age, 45 years [29, 66]; n=36 [95%] non-Hispanic White) sex-, age- and ethnicity-matched healthy controls. During the study period, 11 (79%) SCVF probands experienced ventricular fibrillation recurrence after a median of 4.3 months (interquartile range, 0.3-20.7). Autoantibodies targeting cardiac TREK-1 (TWIK [tandem of pore-domains in a weakly inward rectifying potassium channel]-related potassium channel 1 were identified in 7 (50%) patients with SCVF (P=0.049). Patch clamp experiments demonstrated channel-activating properties of anti-TREK-1 autoantibodies that are antagonized by quinidine in both HEK293 cells and human induced pluripotent stem cell-derived cardiomyocytes.

Conclusions: Patients with SCVF harbor circulating autoantibodies against the cardiac TREK-1 channel. Anti-TREK-1 autoantibodies not only present the first reported biomarker for SCVF, but our functional studies also suggest a direct implication in the arrhythmogenesis of SCVF.

Background: Higher circulating concentrations of NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) are associated with left ventricular remodeling and with incident heart failure. The associations of these cardiac biomarkers with changes in cardiac structure and function over time are uncharacterized.

Methods: Among 2006 participants in the ARIC prospective cohort study (Atherosclerosis Risk in Communities) who were free of overt cardiovascular disease and underwent echocardiography at study visits 5 (2011- 2013) and 7 (2018-2019), we assessed the associations of NT-proBNP, hs-cTnT, and hs-cTnI concentrations at visit 5 with changes in left ventricular structure and function between visits 5 and 7 (≈7-year change) using multivariable linear regression with the biomarkers modeled as restricted cubic splines. Models were adjusted for age, sex, race, body mass index, smoking, diabetes, hypertension, and renal function at visit 5; blood pressure and heart rate at both visits; and the baseline value of the echocardiographic parameter of interest.

Results: Mean±SD age was 74±4 years at visit 5; 61% were women; and 23% were Black adults. Median (25th-75th percentile) concentrations at visit 5 of NT-proBNP, hs-cTnT, and hs-cTnI were 87 ng/L (50-157 ng/L), 9 ng/L (6-12 ng/L), and 2.6 ng/L (1.9-3.9 ng/L). In adjusted models, elevated baseline concentrations of NT-proBNP and hs-cTnI were significantly associated with 7-year decline in left ventricular systolic function (ejection fraction, longitudinal and circumferential strain) and worsening diastolic indices. In contrast, elevated baseline concentrations of hs-cTnT were not significantly associated with 7-year changes in cardiac structure, systolic function, or diastolic function (all P>0.05).

Conclusions: Higher concentrations of NT-proBNP and hs-cTnI, but not hs-cTnT, were associated with greater declines in left ventricular function over ≈7 years in late life independently of traditional cardiovascular risk factors.AQ.

Background: BMP9 (bone morphogenetic protein 9) is a member of the TGF-β (transforming growth factor β) family of cytokines with pleiotropic effects on glucose metabolism, fibrosis, and lymphatic development. However, the role of BMP9 in myocardial infarction (MI) remains elusive.

Methods: The expressional profiles of BMP9 in cardiac tissues and plasma samples of subjects with MI were determined by immunoassay or immunoblot. The role of BMP9 in MI was determined by evaluating the impact of BMP9 deficiency and replenishment with adeno-associated virus-mediated BMP9 expression or recombinant human BMP9 protein in mice.

Results: We show that circulating BMP9 and its cardiac levels are markedly increased in humans and mice with MI and are negatively associated with cardiac function. It is important to note that BMP9 deficiency exacerbates left ventricular dysfunction, increases infarct size, and augments cardiac fibrosis in mice with MI. In contrast, replenishment of BMP9 significantly attenuates these adverse effects. We further demonstrate that BMP9 improves lymphatic drainage function, thereby leading to a decrease of cardiac edema. In addition, BMP9 increases the expression of mitochondrial DECR1 (2,4-dienoyl-CoA reductase 1), a rate-limiting enzyme involved in β-oxidation, which, in turn, promotes cardiac mitochondrial bioenergetics and mitigates MI-induced cardiomyocyte injury. Moreover, DECR1 deficiency exacerbates MI-induced cardiac damage in mice, whereas this adverse effect is restored by the treatment of adeno-associated virus-mediated DECR1. Consistently, DECR1 deletion abrogates the beneficial effect of BMP9 against MI-induced cardiomyopathy and cardiac damage in mice.

Conclusions: These results suggest that BMP9 protects against MI by fine-tuning the multiorgan cross-talk among the liver, lymph, and the heart.