Post-mortem genetic testing in sudden cardiac death and genetic screening of relatives at risk: lessons learned from a Czech pilot multidisciplinary study.

Sudden cardiac death (SCD) might have an inherited cardiac condition background. Genetic testing supports post-mortem diagnosis and screening of relatives at risk. Our aim is to determine the feasibility of a Czech national collaboration group and to establish the clinical importance of molecular autopsy and family screening. From 2016 to 2021, we have evaluated 100 unrelated SCD cases (71.0% males, age: 33.3 (12.8) years). Genetic testing was performed by next-generation sequencing utilizing a panel of 100 genes related to inherited cardiac/aortic conditions and/or whole exome sequencing. According to autopsy, cases were divided into cardiomyopathies, sudden arrhythmic death syndrome, sudden unexplained death syndrome, and sudden aortic death. We identified pathogenic/likely pathogenic variants following ACMG/AMP recommendations in 22/100 (22.0%) of cases. Since poor DNA quality, we have performed indirect DNA testing in affected relatives or in healthy parents reaching a diagnostic genetic yield of 11/24 (45.8%) and 1/10 (10.0%), respectively. Cardiological and genetic screening disclose 83/301 (27.6%) relatives at risk of SCD. Genetic testing in affected relatives as starting material leads to a high diagnostic yield offering a valuable alternative when suitable material is not available. This is the first multidisciplinary/multicenter molecular autopsy study in the Czech Republic which supports the establishment of this type of diagnostic tests. A central coordinator and proper communication among centers are crucial for the success of a collaboration at a national level.

Cardiac resynchronization therapy guided by cardiac magnetic resonance imaging: A prospective, single-centre randomized study (CMR-CRT).

BACKGROUND: Cardiac resynchronization therapy (CRT) improves symptoms of heart failure (HF), morbidity and mortality in selected population. The aim of the study was to investigate the impact of cardiac magnetic resonance (CMR)-guided left ventricular (LV) lead placement on clinical outcomes and LV reverse remodelling in CRT recipients. METHODS: Patients with CRT indication were randomized for CMR-guided (CMR group) or electrophysiologically guided (EP group) LV lead placement between 2011 and 2014. The target site in the CMR group was defined as the most delayed, scar-free, in the EP group as the site with the longest interval between the QRS onset and local electrogram. The primary endpoint was a combination of cardiovascular death or HF hospitalization. Secondary endpoints were New York Heart Association (NYHA) Class improvement ≥1, LV endsystolic diameter reduction >10%, B-type natriuretic peptide reduction by ≥30%. RESULTS: A total of 99 patients (47 in the CMR and 52 in the EP group) were enrolled. During a median follow-up of 47 months, primary composite endpoint occurred in 5 patients in the CMR group and 14 patients in the EP group (HR = 0.46; 95% CI: 0.16-1.32). Patients with left bundle branch block and NYHA Class >2 had better clinical outcome in the CMR group (HR = 0.09; 95% CI: 0.01-0.75). CONCLUSIONS: The use of CMR did not result in significant reduction of combined endpoint of cardiovascular death or HF hospitalization in the total study population. Significant clinical benefit from CMR-guided procedure was observed in a subgroup of optimum CRT candidates with advanced HF.

Glucose Homeostasis, Pancreatic Endocrine Function, and Outcomes in Advanced Heart Failure.

BACKGROUND: The mechanisms and relevance of impaired glucose homeostasis in advanced heart failure (HF) are poorly understood. The study goals were to examine glucose regulation, pancreatic endocrine function, and metabolic factors related to prognosis in patients with nondiabetic advanced HF. METHODS AND RESULTS: In total, 140 advanced HF patients without known diabetes mellitus and 21 sex-, age-, and body mass index-matched controls underwent body composition assessment, oral glucose tolerance testing, and measurement of glucose-regulating hormones to model pancreatic ß-cell secretory response. Compared with controls, HF patients had similar fasting glucose and insulin levels but higher levels after oral glucose tolerance testing. Insulin secretion was not impaired, but with increasing HF severity, there was a reduction in glucose, insulin, and insulin/glucagon ratio-a signature of starvation. The insulin/C-peptide ratio was decreased in HF, indicating enhanced insulin clearance, and this was correlated with lower cardiac output, hepatic insufficiency, right ventricular dysfunction, and body wasting. After a median of 449 days, 41% of patients experienced an adverse event (death, urgent transplant, or assist device). Increased glucagon and, paradoxically, low fasting plasma glucose displayed the strongest relations to outcome (P=0.01). Patients in the lowest quartile of fasting plasma glucose (3.8-5.1 mmol·L-1, 68-101 mg·dL-1) had 3-times higher event risk than in the top quartile (6.0-7.9 mmol·L-1, 108-142 mg·dL-1; relative risk: 3.05 [95% confidence interval, 1.46-6.77]; P=0.002). CONCLUSIONS: Low fasting plasma glucose and increased glucagon are robust metabolic predictors of adverse events in advanced HF. Pancreatic insulin secretion is preserved in advanced HF, but levels decrease with increasing HF severity due to enhanced insulin clearance that is coupled with right heart failure and cardiac cachexia.