368 Serial vs. single cardiovascular screening of adolescent athletes

The primary objective of preparticipation cardiovascular evaluation (PPCE) in young athletes is to detect asymptomatic individuals with cardiovascular disease (CVD) at risk of sudden cardiac death (SCD). The study population included a consecutive series of competitive athletes age 12–18 years who underwent PPCE, which according to Italian law is mandatory and based on yearly evaluations, at the Center for Sports Medicine of Treviso (Veneto region of Italy), from 2009 to 2019. The screening protocol included personal and family history questionnaire, physical examination, resting 12-lead ECG, and limited stress testing for evaluation of exertional ventricular arrhythmias. 2,3 This latter test was performed using a bicycle with constant-load increases (i.e. 2 W/kg in female participants and 3 W/kg in male participants) for 3 min for at least 85% or more of maximal heart rate was achieved, plus 3 min of postexercise monitoring. 3 Athletes with a positive medical history and abnormal physical examination, ECG, or stress test underwent further investigations. The diagnostic yield of the initial screening session was compared with that of repeat PPCEs. Athletes with a definitive diagnosis of CVD at risk of SCD were considered ineligible for competitive sports, although they received a tailored programme for leisure physical activity and were enrolled in a yearly follow-up programme. Outcome data of screened athletes, either eligible or ineligible to play competitive sports, were obtained from office visits, hospital records, or interrogation of the Registry of Juvenile SCD of the Veneto region. The study population included 15 127 consecutive athletes (64% male, 96% White) who underwent a total of 53 396 annual PPCEs (mean 3.7 per athlete) over the 11-year study period. The median age at first screening was 13 years [interquartile range (IQR): 12–14]. Sixty-three athletes (65% male) were diagnosed with a CVD at risk of SCD such as congenital heart disease (n = 17), ion channel disease (n = 11), inherited cardiomyopathy (n = 13), isolated nonischaemic left ventricular scar (NLVS) with ventricular arrhythmias (n = 18), or other (n = 4); 266 athletes had cardiac conditions not associated with SCD. Seventeen of the 63 athletes (27%) with atrisk CVD had a positive family history, symptoms, or abnormal physical examination, 38 (60%) had ECG abnormalities, and 32 (51%) developed arrhythmias on limited exercise testing. CVDs more frequently identified on repeat evaluation included inherited cardiomyopathies [7/11 (64%)], NLVS with ventricular arrhythmias [15/18 (83%)], and long QT syndrome [7/11 (64%)]. During a mean follow-up of 6.7 ± 3.5 years, 1 athlete with a negative PPCE experienced an episode of aborted SCD attributable to ventricular fibrillation that remained unexplained after a comprehensive diagnostic workup (event rate, 0.98/100 000 athletes per year). These results show that annual cardiovascular screening of adolescent athletes increased by three times the diagnostic yield of CVD at risk of SCD compared with a once-only (initial) evaluation. Inherited cardiomyopathies and isolated NLVS with ventricular arrhythmias were the CVDs more frequently identified on repeat evaluation.

Understanding the Molecular Basis of Cardiomyopathy

Inherited cardiomyopathies are a major cause of mortality and morbidity worldwide and can be caused by mutations in a wide range of proteins located in different cellular compartments. The present review is based on Dr. Ju Chen's 2021 Robert M. Berne Distinguished Lectureship of the American Physiological Society Cardiovascular section, in which he provided an overview of the current knowledge on the cardiomyopathy-associated proteins that have been studied in his laboratory. The review provides a general summary of the proteins in different compartments of cardiomyocytes associated with cardiomyopathies with specific focus on the proteins that have been studied in Dr. Chen's laboratory.

Cardiomyocyte Dysfunction in Inherited Cardiomyopathies

Inherited cardiomyopathies form a heterogenous group of disorders that affect the structure and function of the heart. Defects in the genes encoding sarcomeric proteins are associated with various perturbations that induce contractile dysfunction and promote disease development. In this review we aimed to outline the functional consequences of the major inherited cardiomyopathies in terms of myocardial contraction and kinetics, and to highlight the structural and functional alterations in some sarcomeric variants that have been demonstrated to be involved in the pathogenesis of the inherited cardiomyopathies. A particular focus was made on mutation-induced alterations in cardiomyocyte mechanics. Since no disease-specific treatments for familial cardiomyopathies exist, several novel agents have been developed to modulate sarcomere contractility. Understanding the molecular basis of the disease opens new avenues for the development of new therapies. Furthermore, the earlier the awareness of the genetic defect, the better the clinical prognostication would be for patients and the better the prevention of development of the disease.

Uncovering Inherited Cardiomyopathy With Human Induced Pluripotent Stem Cells

In the past decades, researchers discovered the contribution of genetic defects to the pathogenesis of primary cardiomyopathy and tried to explain the pathogenesis of these diseases by establishing a variety of disease models. Although human heart tissues and primary cardiomyocytes have advantages in modeling human heart diseases, they are difficult to obtain and culture in vitro. Defects developed in genetically modified animal models are notably different from human diseases at the molecular level. The advent of human induced pluripotent stem cells (hiPSCs) provides an unprecedented opportunity to further investigate the pathogenic mechanisms of inherited cardiomyopathies in vitro using patient-specific hiPSC-derived cardiomyocytes. In this review, we will make a summary of recent advances in in vitro inherited cardiomyopathy modeling using hiPSCs.

The Z-Disk Final Common Pathway in Cardiomyopathies

The sarcomeres represent the essential contractile units of the cardiac myocyte and are bordered by two Z-lines (disks) that are made by various proteins. The cardiac Z-disk is recognized as one of the nodal points in cardiomyocyte structural organization, mechano-sensation and signal transduction. Rapid progress in molecular and cellular biology has significantly improved the knowledge about pathogenic mechanisms and signaling pathways involved in the development of inherited cardiomyopathies. Genetic insult resulting in expression of mutated proteins that maintain the structure of the heart can perturb cardiac function. The primary mutation in the cardiac contractile apparatus or other subcellular complexes can lead to cardiac pathology on a tissue level, resulting in organ and organism level pathophysiology. The “final common pathway” hypothesis interpreting the genetic basis and molecular mechanisms involved in the development of cardiomyopathies suggests that mutations in cardiac genes encoding proteins with similar structure, function, or location and operating in the same pathway, are responsible for a particular phenotype of cardiomyopathy with unique morpho-histological remodeling of the heart. This chapter will describe genetic abnormalities of cardiac Z-disk and related “final common pathways” that are triggered by a Z-disk genetic insult leading to heart muscle diseases. In addition, animal models carrying mutations in Z-disk proteins will be described.