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Therapy for the CPVT
Conflict of interest
Acknowledgment This work was supported by Health Science Research grant from the Ministry of Health, Labour and Welfare of Japan for Clinical Research on Measures for Intractable Diseases (2016-032).
Introduction Bradyarrhythmia is a serious electrical disorder of the heart with the potential to be life threating. The condition is caused by an electrical dissociation in the cardiac conduction system (CCS) comprising the sinus bradycardia, the sinoatrial (SA) exit block and the atrioventricular block (AVB). It often manifests as abnormally suppressed cardiac output in affected individuals, requiring permanent pacemaker implantation in order to compensate for decreased heart rate. The CCS is equipped with a sophisticated histological structure and specialized cellular function in order to maintain proper impulse generation and propagation. The mechanical burden and scars resulting from structural heart disease are a major cause of bradyarrhythmia. Accumulation of connective tissue such as collagen is almost always associated with progression of heart failure, as it promotes dissociation between electrically coupled cardiomyocytes [1]. Collagen deposition is associated with aging and underlying structural heart disease, reflected by the increased incidence and prevalence of bradyarrhythmia associated with these factors [1,2]. In the absence of underlying structural disease or aging, bradyarrhythmia may occur primarily due to genetic defects. In this review, we aim to describe the current understanding of inherited bradyarrhythmia with a focus on diverse genetic backgrounds and molecular physiology (Fig. 1 and Table 1).
Modulation mechanisms of heart rate and genetic exacerbation factors: physiological regulation of sinus rhythm In the CCS, the sinoatrial node (SAN) is the primary pacemaker component and functions as a resource for automaticity; that is, spontaneous depolarization with regular intervals. Histologically, the SAN is intramurally embedded at the junction of the right atrium and the superior vena cava and lies along the crista terminalis [3]. The SAN displays heterogeneous cellular morphology, tegaserod Supplier configuration, and electrophysiological characteristics [4]. The SAN’s major pacemaker site is situated at its center, however; this site may shift peripherally depending on various interventional factors such as electrolyte concentrations, autonomic nervous stimuli, and temperature [3]. The underlying mechanisms of this pacemaker shift remain undetermined, however; the pacemaker tends to shift to the site where electrical activity is least suppressed by extrinsic factors [3]. The molecular mechanisms underlying myocyte firing in the central SAN are characterized by the SAN’s unique gene expression profile, with minimal expression of KCNJ2 (inwardly rectifying K channel, Kir2.1) and SCN5A (cardiac Na channel, Nav1.5) and higher expression of HCN4 (the pacemaker channel). The absence of KCNJ2 expression allows the resting membrane potential depolarized to enable spontaneous depolarization, while the absence of SCN5A expression can prevent rapid upstroke of action potential. Abundant expression of the HCN4 pacemaker channel promotes spontaneous, slow depolarization in response to phase 4 hyperpolarization. The peripheral SAN, on the other hand, partially shares the gene expression profile and electrophysiological characteristics of the atrial myocytes [3]. The major role of excitation in the peripheral SAN is the rapid transmission of the sinus impulse to surrounding atrial myocytes. An abundant expression of SCN5A causes fast upstroke of action potential in phase 0 and this gives rise to rapid electrical conduction in the peripheral SAN. Thus, loss-of-function mutations in SCN5A could result in SA exit block, an electrical conduction blockade between the central SAN and surrounding atrial myocytes [5]. The mechanism of cyclic activation in voltage-gated ion channels involves the action of the pacemaker current on the cell membrane and is known as a membrane clock. Recently, a growing body of evidence has implicated the involvement of additional complementary mechanisms in this process, in particular, the rhythmic spontaneous release of Ca2+ by the sarcoplasmic reticulum (SR), which is referred to as a calcium clock. The calcium clock functions collaboratively with the membrane clock to form a unified, automatic system, known as a coupled-clock pacemaker system [6]. Genetic defects in the genes involved in membrane and calcium clocks can potentially cause SA disorders.