Ventricular arrhythmia and sudden cardiac death in hypertrophic cardiomyopathy: From bench to bedside

Abstract

Patients with hypertrophic cardiomyopathy (HCM) mostly experience minimal symptoms throughout their lifetime, and some individuals have an increased risk of ventricular arrhythmias and sudden cardiac death (SCD). How to identify patients with a higher risk of ventricular arrythmias and SCD is the priority in HCM research. The American College of Cardiology/American Heart Association (ACC/AHA) and the European Society of Cardiology (ESC) both recommend the use of risk algorithms to identify patients at high risk of ventricular arrhythmias, to be selected for implantation of implantable cardioverters/defibrillators (ICDs) for primary prevention of SCD, although major discrepancies exist. The present SCD risk scoring systems cannot accurately identify early-stage HCM patients with modest structural remodeling and mild disease manifestations. Unfortunately, SCD events could occur in young asymptomatic HCM patients and even as initial symptoms, prompting the determination of new risk factors for SCD. This review summarizes the studies based on patients' surgical specimens, transgenic animals, and patient-derived induced pluripotent stem cells (hiPSCs) to explore the possible molecular mechanism of ventricular arrhythmia and SCD. Ion channel remodeling, Ca2+ homeostasis abnormalities, and increased myofilament Ca2+ sensitivity may contribute to changes in action potential duration (APD), reentry circuit formation, and trigger activities, such as early aferdepolarization (EAD) or delayed afterdepolarization (DAD), leading to ventricular arrhythmia in HCM. Besides the ICD implantation, novel drugs represented by the late sodium current channel inhibitor and myosin inhibitor also shed light on the prevention of HCM-related arrhythmias. The ideal prevention strategy of SCD in early-stage HCM patients needs to be combined with gene screening, hiPSC-CM testing, machine learning, and advanced ECG studies, thus achieving individualized SCD prevention.

Phosphate toxicity and SERCA2a dysfunction in sudden cardiac arrest

“…12 Patients with hypertrophic cardiomyopathy (HCM) have increased risk of sudden cardiac death and arrhythmias, and further investigations of novel risk factors are needed. 62 A recent case study reported a patient with HCM presenting with secondary hypoparathyroidism, which the authors associated with the effects of hyperphosphatemia and elevated levels of calcium phosphate product and FGF23. 63 Further clinical and epidemiological investigations of dysregulated serum Pi as a novel risk factor associated with HCM are warranted, including population studies of dietary phosphate exposure, animal models, and in vitro and in vivo experiments that illuminate the effects of myocardial Pi in arrhythmia and sudden cardiac arrest.…”

“…Patients with hypertrophic cardiomyopathy (HCM) have increased risk of sudden cardiac death and arrhythmias, and further investigations of novel risk factors are needed 62 . A recent case study reported a patient with HCM presenting with secondary hypoparathyroidism, which the authors associated with the effects of hyperphosphatemia and elevated levels of calcium phosphate product and FGF23 63 .…”

Cardiac Resynchronization Therapy and Hypertrophic Cardiomyopathy: A Comprehensive Review

“…Atrial fibrillation often occurs in up to one quarter of patients with HCM and has a significant hemodynamical impact on these patients. Ventricular tachyarrhythmias comprise premature ventricular beats, non-sustained and sustained ventricular tachycardia and are responsible for a mortality rate of 0.5-1% per year [26].…”

Magnetic Resonance Left Ventricle Mass-Index/Fibrosis: Long-Term Predictors for Ventricular Arrhythmia in Hypertrophic Cardiomyopathy—A Retrospective Registry

“…The percentage of SCD is higher among younger patients with HCM and decreases with aging. Current guidelines endorse an implantable cardioverter defibrillator (ICD) for secondary prevention and for primary prevention of SCD in high-risk individuals with HCM [ 12 ].…”

“…HCM patients report a higher incidence of arrhythmias, including atrial fibrillation, ventricular premature beats (VPB), non-sustained ventricular tachycardia (NSVT), sustained ventricular tachycardia (SVT), ventricular fibrillation (VF), heart failure and SCD compared to the general population of a similar age [ 12 , 22 ]. Multiple studies showed a significant correlation between NSVT and the risk of SCD in patients with HCM.…”