Clinical care of family members of patients with dilated cardiomyopathy.

Genetic family screening following the detection of a pathogenic or likely pathogenic variant in a proband with dilated cardiomyopathy (DCM) remains one of the main applications of genetic testing. While cardiac screening is recommended for all first-degree relatives, the a priori risk among family members varies. Consequently, screening regimens should be tailored according to both genetic and clinical information at the individual and familial level.

Titin-related familial dilated cardiomyopathy: factors associated with disease onset.

Background And Aims: Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv.

Methods: An international multicentre retrospective observational study was performed in families with TTNtv-related DCM.

Genetic and Phenotypic Characterization of Nexilin (NEXN)-Related Cardiomyopathy: Results From a Multicentric Study.

Background: Nexilin (NEXN)-related cardiomyopathies (CMPs) are largely unexplored.

Objectives: This study investigated the causative role of NEXN in CMPs, examining its phenotypic expression and prognostic profile.

Methods: Twelve referral centers collected phenotypic/genotypic data of patients with NEXN variants.

Basic principles of genetics and genetic counselling.

Genetic counselling and testing is a fast growing field in modern medicine. Genetic analysis can aid in the diagnosis, treatment, management and prevention of (genetic) diseases in patients. This review provides an overview of the fundamental principles of genetics from a clinical perspective, focusing on the practical application and interpretation of genetic testing.

Integrated role of cardiac magnetic resonance and genetics in predicting left ventricular reverse remodelling in dilated and non-dilated cardiomyopathy.

Aims: Left ventricular reverse remodelling (LVRR) is a prognostic marker in patients with dilated (DCM) and non-dilated left ventricular cardiomyopathy (NDLVC). The utility of combining late gadolinium enhancement (LGE) and genetic testing in predicting LVRR in DCM/NDLVC remains a knowledge gap. This study aimed to assess an integrated approach including LGE data and genetics to predict LVRR in DCM/NDLVC patients.

Diastolic dysfunction as predictive parameter for the development of post-TIPS cardiac decompensation.

Background/aim Of The Study: Heart failure (HF) as a consequence of Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement is associated with high mortality. Currently, no parameters can predict heart failure post-TIPS. This study evaluates the value of clinical, biochemical, and echocardiographic parameters, including speckle tracking echocardiography (STE) and hemodynamic forces (HDF), to predict development of post-TIPS HF.

Echocardiographic and biomarker characteristics in diabetes, coronary artery disease or both: insights from HOMAGE trial.

Background: Coronary artery disease (CAD) and diabetes mellitus (DM) can induce changes in myocardial structure and function, thereby increasing the risk of heart failure (HF). We aimed to identify the alterations in echocardiographic variables and circulating biomarkers associated with DM, CAD, or both and to assess the effect of spironolactone on them.

Methods: The "Heart OMics in AGEing" (HOMAGE) trial evaluated the effect of spironolactone on circulating markers of fibrosis over 9 months of follow-up in people at risk for HF.

Cardiomyocyte SORBS2 expression increases in heart failure and regulates integrin interactions and extracellular matrix composition.

Aims: In this study, we aimed to uncover genes associated with stressed cardiomyocytes by combining single-cell transcriptomic data sets from failing cardiac tissue from both humans and mice.

Methods And Results: Our bioinformatic analysis identified SORBS2 as conserved NPPA-correlated gene. Using mouse models and cardiac tissue from human heart failure patients, we demonstrated that SORBS2 expression is consistently increased during pathological remodelling, correlates to disease severity, and is regulated by GATA4.

Arrhythmic Risk Stratification of Carriers of Filamin C Truncating Variants.

Importance: Filamin C truncating variants (FLNCtv) are a rare cause of cardiomyopathy with heterogeneous phenotypic presentations. Despite a high incidence of life-threatening ventricular arrhythmias and sudden cardiac death (SCD), reliable risk predictors to stratify carriers of FLNCtv are lacking.

Objective: To determine factors predictive of SCD/major ventricular arrhythmias (MVA) in carriers of FLNCtv.

Reproductive options and genetic testing for patients with an inherited cardiac disease.

In the past decade, genetic testing for cardiac disease has become part of routine clinical care. A genetic diagnosis provides the possibility to clarify risk for relatives. For family planning, a genetic diagnosis provides reproductive options, including prenatal diagnosis and preimplantation genetic testing, that can prevent an affected parent from having a child with the genetic predisposition.

Heart rate reactivity, recovery, and endurance of the incremental shuttle walk test in patients prone to heart failure.

Aims: Few randomized trials assessed the changes over time in the chronotropic heart rate (HR) reactivity (CHR), HR recovery (HRR) and exercise endurance (EE) in response to the incremental shuttle walk test (ISWT). We addressed this issue by analysing the open HOMAGE (Heart OMics in Aging) trial.

Methods: In HOMAGE, 527 patients prone to heart failure were randomized to usual treatment with or without spironolactone (25-50 mg/day).

Papillary Muscle Delayed Hyperenhancement: Prevalence and Clinical Implications in a Large Population With Dilated Cardiomyopathy.

Background: Papillary muscle-delayed hyperenhancement (papHE) at cardiac magnetic resonance indicates fibrotic or infiltrative processes. Contrary to myocardial HE, the prevalence and prognostic implications of papHE in patients with nonischemic dilated cardiomyopathy are unclear.

Objectives: The purpose of this study was to determine the prevalence of papHE and describe its association with adverse clinical outcomes.

Proteomic profiles of left atrial volume and its influence on response to spironolactone: Findings from the HOMAGE trial and STANISLAS cohort.

Aims: High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables.

Methods And Results: In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m).

Clinical Guideline for Preimplantation Genetic Testing in Inherited Cardiac Diseases.

Background: Preimplantation genetic testing (PGT) is a reproductive technology that selects embryos without (familial) genetic variants. PGT has been applied in inherited cardiac disease and is included in the latest American Heart Association/American College of Cardiology guidelines. However, guidelines selecting eligible couples who will have the strongest risk reduction most from PGT are lacking.

Immunomodulation of Myocardial Fibrosis.

Immunotherapy is a potential cornerstone in the treatment of myocardial fibrosis. During a myocardial insult or heart failure, danger signals stimulate innate immune cells to produce chemokines and profibrotic cytokines, which initiate self-escalating inflammatory processes by attracting and stimulating adaptive immune cells. Stimulation of fibroblasts by inflammatory processes and the need to replace damaged cardiomyocytes fosters reshaping of the cardiac fibroblast landscape.