Daily Cardiology Research Analysis

Long-standing hypertension (HTN) affects multiple organs and leads to pathologic arterial remodeling, which is driven by smooth muscle cell (SMC) plasticity. To identify relevant genes regulating SMC function in HTN, we considered Genome Wide Association Studies (GWAS) of blood pressure, focusing on genes encoding epigenetic enzymes, which control SMC fate in cardiovascular disease. Using statistical fine mapping of the KDM6 Jumonji domain-containing protein D3 (JMJD3) locus, we found that rs62059712 is the most likely casual variant, with each major T allele copy associated with a 0.47 mmHg increase in systolic blood pressure. We show that the T allele decreased JMJD3 transcription in SMCs via decreased SP1 binding to the JMJD3 promoter. Using our unique SMC-specific Jmjd3-deficient murine model (Jmjd3fl/flMyh11CreERT), we show that loss of Jmjd3 in SMCs results in HTN due to decreased endothelin receptor B (EDNRB) expression and increased endothelin receptor A (EDNRA) expression. Importantly, the EDNRA antagonist BQ-123 reversed HTN after Jmjd3 deletion in vivo. Additionally, single-cell RNA-Seq (scRNA-Seq) of human arteries revealed a strong correlation between JMJD3 and EDNRB in SMCs. Further, JMJD3 is required for SMC-specific gene expression, and loss of JMJD3 in SMCs increased HTN-induced arterial remodeling. Our findings link a HTN-associated human DNA variant with regulation of SMC plasticity, revealing targets that may be used in personalized management of HTN.

BACKGROUND: Identifying structural heart diseases (SHDs) early can change the course of the disease, but their diagnosis requires cardiac imaging, which is limited in accessibility. OBJECTIVES: The purpose of this study was to leverage images of 12-lead electrocardiograms (ECGs) for automated detection and prediction of multiple SHDs using an ensemble deep learning approach. METHODS: We developed a series of convolutional neural network models for detecting a range of individual SHDs from images of ECGs with SHDs defined by transthoracic echocardiograms performed within 30 days of the ECG at the Yale New Haven Hospital (YNHH). SHDs were defined as left ventricular ejection fraction <40%, moderate-to-severe left-sided valvular disease (aortic/mitral stenosis or regurgitation), or severe left ventricular hypertrophy (interventricular septal diameter at end-diastole >1.5 cm and diastolic dysfunction). We developed an ensemble XGBoost model, PRESENT-SHD (Practical scREening using ENsemble machine learning sTrategy for SHD detection), as a composite screen across all SHDs. We validated PRESENT-SHD at 4 U.S. hospitals and the prospective, population-based ELSA-Brasil (Brazilian Longitudinal Study of Adult Health) cohort, with concurrent protocolized ECGs and transthoracic echocardiograms. We also used PRESENT-SHD for risk stratification of new-onset SHD or heart failure (HF) in clinical cohorts and the population-based UK Bi

BACKGROUND: Guideline-directed medical therapy (GDMT) with multiple risk factor goals is recommended for patients with chronic coronary disease (CCD), yet achieving all GDMT goals is uncommon. The relative importance of these goals and timing of their attainment on cardiovascular events is uncertain. OBJECTIVES: This study aims to describe the relationship between achieving specific GDMT goals, when they are achieved, and clinical outcomes. METHODS: This was an observational study of participants with CCD in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. The primary outcome was cardiovascular (CV) death or myocardial infarction (MI). GDMT goals were systolic blood pressure (SBP) <130 mm Hg, low-density lipoprotein cholesterol <70 mg/dL, not smoking, and antiplatelet therapy. Frequency of GDMT goals met at baseline and during follow-up is described. Bayesian joint modeling for longitudinal goal status and time-to-event analyses characterized the relative importance of specific GDMT goal attainment and timing with CV death/MI. RESULTS: All 5,179 ISCHEMIA participants were included. Among 4,914 participants with complete data on all 4 GDMT goals at baseline, 386 (9%), 2,073 (42%), 1,843 (38%), and 612 (12%) met 0-1, 2, 3, and 4 GDMT goals, respectively. The 4-year cumulative event rate for CV death/MI was highest for participants who attained no GDMT goals (24.5%; 95% credible interval [CrI]: 13.5%-42.2%) and lowest for those who attained all goals at baseline and remained at goal during follow-up (8.7%; 95% CrI: 6.7%-10.9%). SBP goal attainment was associated with a significant absolute event reduction in CV death/MI (-5.1%; 95% CrI: -11.3% to -1.0%), followed by antiplatelet therapy (-11.2%; 95% CrI: -29.1% to 0.8%), achieving low-density lipoprotein cholesterol <70 mg/dL (-2.0%; 95% CrI: -6.0% to 2.4%), and not smoking (-1.7%; 95% CrI: -9.3% to 4.2%). Ten millimeters of mercury lower SBP during follow-up was associated with 10% relative risk reduction of CV death/MI (RR [relative risk] = 0.90; 95% CrI: 0.82-0.98), after adjusting for other GDMT goals and baseline characteristics. CONCLUSIONS: Among participants with CCD, early attainment and maintenance of GDMT goals, especially SBP, were associated with fewer cardiovascular events. Compared with no GDMT goals at target, having all 4 GDMT goals at target at baseline was associated with an absolute 16% fewer CV deaths and MIs. (ISCHEMIA [International Study of Comparative Health Effectiveness With Medical and Invasive Approaches]; NCT01471522).