Abstract
Life-threatening ventricular arrhythmias are the main clinical burden in patients with hypertrophic cardiomyopathy (HCM), and frequently occur in young patients with mild structural disease. While massive hypertrophy, fibrosis and microvascular ischemia are the main mechanisms underlying sustained reentry-based ventricular arrhythmias in advanced HCM, cardiomyocyte-based functional arrhythmogenic mechanisms are likely prevalent at earlier stages of the disease. In this review, we will describe studies conducted in human surgical samples from HCM patients, transgenic animal models and human cultured cell lines derived from induced pluripotent stem cells. Current pieces of evidence concur to attribute the increased risk of ventricular arrhythmias in early HCM to different cellular mechanisms. The increase of late sodium current and L-type calcium current is an early observation in HCM, which follows post-translation channel modifications and increases the occurrence of early and delayed afterdepolarizations. Increased myofilament Ca2+ sensitivity, commonly observed in HCM, may promote afterdepolarizations and reentry arrhythmias with direct mechanisms. Decrease of K+-currents due to transcriptional regulation occurs in the advanced disease and contributes to reducing the repolarization-reserve and increasing the early afterdepolarizations (EADs). The presented evidence supports the idea that patients with early-stage HCM should be considered and managed as subjects with an acquired channelopathy rather than with a structural cardiac disease.
Highlights
Human Surgical SamplesAmong the different platforms that have been used to investigate the cellular pathways involved in the pathomechanisms of cardiac diseases, human cardiomyocytes isolated from fresh surgical samples are the most informative [39]
Life-threatening ventricular arrhythmias are the main clinical burden in patients with hypertrophic cardiomyopathy (HCM), and frequently occur in young patients with mild structural disease
In this paper we reviewed two main classes of mechanisms underpinning the arrhythmogenicity of HCM myocardium (Figure 3)
Summary
Among the different platforms that have been used to investigate the cellular pathways involved in the pathomechanisms of cardiac diseases, human cardiomyocytes isolated from fresh surgical samples are the most informative [39]. Our group has access to surgical myectomies from HCM patients, used to isolate fresh viable cardiac cells, suitable for patch clamp recordings. These cells are compared to cardiac cells obtained from samples of non-failing/non-hypertrophic surgical patients [26,40]. The prolongation of AP kinetics we observed in human samples was confirmed by Barajas-Martinez et al in patch-clamped HCM cardiac cells from a patient with HOCM: APD was significantly longer in HCM cardiomyocytes compared to a typical control myocardial cell and the increased INaL appeared to play a leading role in the impairment of AP kinetics [27]. We observed that the alterations of AP shape and duration, combined with the abnormalities of Ca2+ transient kinetics and diastolic [Ca2+], are responsible for an increased likelihood of early and delayed afterdepolarizations (EADs and DADs, respectively) in HCM cardiomyocytes when compared with controls [26,40,41]
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