The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by bidirectional or polymorphic ventricular arrhythmias under conditions of increased sympathetic activity in young patients with structurally normal hearts. Patients with CPVT are at high risk of developing life-threatening ventricular arrhythmias when untreated. A wide variety of arrhythmic event rates on conventional therapy, with β-blockers as the cornerstone, has been reported. Here, we systematically review all available studies describing the efficacy of β-blocker therapy for prevention of arrhythmic events in CPVT. Because of heterogeneity between the studies, a random-effects meta-analysis model was used to assess the efficacy of β-blocker therapy in preventing any arrhythmic event [syncope, aborted cardiac arrest (ACA), and sudden cardiac death (SCD)], near-fatal arrhythmic events (ACA and SCD), and fatal arrhythmic events. Eleven studies including 403 patients, of whom 354 (88%) had a β-blocker prescribed, were identified. Mean follow-up ranged from 20 months to 8 years. Estimated 8-year arrhythmic, near-fatal, and fatal event rates were 37.2% [95% confidence interval (CI): 16.6-57.7], 15.3% (95% CI: 7.4-23.3), and 6.4% (95% CI: 3.2-9.6), respectively. In addition, we review the recent developments in alternate chronic treatment options for CPVT patients, including calcium channel blockers, flecainide, left cardiac sympathetic denervation, and implantable cardioverter defibrillators. A new treatment strategy is proposed, including a stepwise addition of the alternate treatment options to β-blockers in patients who do not respond sufficiently to this first-line therapy. Finally, future developments in chronic treatment options and acute treatment options of ventricular arrhythmias are discussed.

Therapeutic approach for patients with catecholaminergic polymorphic ventricular tachycardia: state of the art and future developments

Background— Catecholaminergic polymorphic ventricular tachycardia is an uncommon, potentially lethal, ion channelopathy. Standard therapies have high failure rates and little is known about treatment in children. Newer options such as flecainide and left cardiac sympathetic denervation are not well validated. We sought to define treatment outcomes in children with catecholaminergic polymorphic ventricular tachycardia.

Methods and Results— This is a Pediatric and Congenital Electrophysiology Society multicenter, retrospective cohort study of catecholaminergic polymorphic ventricular tachycardia patients diagnosed before 19 years of age. The cohort included 226 patients, including 170 probands and 56 relatives. Symptomatic presentation was reported in 176 (78%). Symptom onset occurred at 10.8 (interquartile range, 6.8–13.2) years with a delay to diagnosis of 0.5 (0–2.6) years. Syncope ( P <0.001), cardiac arrest ( P <0.001), and treatment failure ( P =0.008) occurred more often in probands. β-Blockers were prescribed in 205 of 211 patients (97%) on medication, and 25% experienced at least 1 treatment failure event. Implantable cardioverter defibrillators were placed in 121 (54%) and was associated with electrical storm in 22 (18%). Flecainide was used in 24% and left cardiac sympathetic denervation in 8%. Six deaths (3%) occurred during a cumulative follow-up of 788 patient-years.

Conclusions— This study demonstrates a malignant phenotype and lengthy delay to diagnosis in catecholaminergic polymorphic ventricular tachycardia. Probands were typically severely affected. β-Blockers were almost universally initiated; however, treatment failure, noncompliance and subtherapeutic dosing were often reported. Implantable cardioverter defibrillators were common despite numerous device-related complications. Treatment failure was rare in the quarter of patients on flecainide. Left cardiac sympathetic denervation was not uncommon although the indication was variable.

https://www.ahajournals.org/doi/pdf/10.1161/CIRCEP.114.002217

Catecholaminergic polymorphic ventricular tachycardia in children: analysis of therapeutic strategies and outcomes from an international multicenter registry.

Over the last decade, mouse models have become a popular instrument for studying cardiac arrhythmias. This review assesses in which respects a mouse heart is a miniature human heart, a suitable model for studying mechanisms of cardiac arrhythmias in humans and in which respects human and murine hearts differ. Section I considers the issue of scaling of mammalian cardiac (electro) physiology to body mass. Then, we summarize differences between mice and humans in cardiac activation (section II) and the currents underlying the action potential in the murine working myocardium (section III). Changes in cardiac electrophysiology in mouse models of heart disease are briefly outlined in section IV, while section V discusses technical considerations pertaining to recording cardiac electrical activity in mice. Finally, section VI offers general considerations on the influence of cardiac size on the mechanisms of tachy-arrhythmias.

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Cardiac electrophysiology in mice: a matter of size.

Early afterdepolarizations (EADs) are secondary voltage depolarizations during the repolarizing phase of the action potential, which can cause lethal cardiac arrhythmias. The occurrence of EADs requires a reduction in outward current and/or an increase in inward current, a condition called reduced repolarization reserve. However, this generalized condition is not sufficient for EAD genesis and does not explain the voltage oscillations manifesting as EADs. Here, we summarize recent progress that uses dynamical theory to build on and advance our understanding of EADs beyond the concept of repolarization reserve, towards the goal of developing a holistic and integrative view of EADs and their role in arrhythmogenesis. We first introduce concepts from nonlinear dynamics that are relevant to EADs, namely, Hopf bifurcation leading to oscillations and basin of attraction of an equilibrium or oscillatory state. We then present a theory of phase-2 EADs in nonlinear dynamics, which includes the formation of quasi-equilibrium states at the plateau voltage, their stabilities, and the bifurcations leading to and terminating the oscillations. This theory shows that the L-type calcium channel plays a unique role in causing the nonlinear dynamical behaviours necessary for EADs. We also summarize different mechanisms of phase-3 EADs. Based on the dynamical theory, we discuss the roles of each of the major ionic currents in the genesis of EADs, and potential therapeutic targets.

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Early afterdepolarizations in cardiac myocytes: beyond reduced repolarization reserve

The cardiac Na+/Ca2+ exchanger (NCX) generates an inward electrical current during SR-Ca2+ release, thus possibly promoting afterdepolarizations of the action potential (AP). We used transgenic mice 12.5 weeks or younger with cardiomyocyte-directed overexpression of NCX (NCX-Tg) to study the proarrhythmic potential and mechanisms of enhanced NCX activity. NCX-Tg exhibited normal echocardiographic left ventricular function and heart/body weight ratio, while the QT interval was prolonged in surface ECG recordings. Langendorff-perfused NCX-Tg, but not wild-type (WT) hearts, developed ventricular tachycardia. APs and ionic currents were measured in isolated cardiomyocytes. Cell capacitance was unaltered between groups. APs were prolonged in NCX-Tg versus WT myocytes along with voltage-activated K+ currents (Kv) not being reduced but even increased in amplitude. During abrupt changes in pacing cycle length, early afterdepolarizations (EADs) were frequently recorded in NCX-Tg but not in WT myocytes. Next to EADs, delayed afterdepolarizations (DAD) triggering spontaneous APs (sAPs) occurred in NCX-Tg but not in WT myocytes. To test whether sAPs were associated with spontaneous Ca2+ release (sCR), Ca2+ transients were recorded. Despite the absence of sAPs in WT, sCR was observed in myocytes of both genotypes suggesting a facilitated translation of sCR into DADs in NCX-Tg. Moreover, sCR was more frequent in NCX-Tg as compared to WT. Myocardial protein levels of Ca2+-handling proteins were not different between groups except the ryanodine receptor (RyR), which was increased in NCX-Tg versus WT. We conclude that NCX overexpression is proarrhythmic in a non-failing environment even in the absence of reduced KV. The underlying mechanisms are: (1) occurrence of EADs due to delayed repolarization; (2) facilitated translation from sCR into DADs; (3) proneness to sCR possibly caused by altered Ca2+ handling and/or increased RyR expression.

/pdf/proarrhythmia-in-a-non-failing-murine-model-of-cardiac-2r29uommv1.pdf

Proarrhythmia in a non-failing murine model of cardiac-specific Na+/Ca 2+ exchanger overexpression: whole heart and cellular mechanisms.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease that can cause sudden cardiac death due to ventricular fibrillation (VF). While pharmacological therapy with beta-blockers and/or Ca(2)(+) antagonists is often unreliable, a recent study has demonstrated that flecainide can effectively suppress arrhythmia in a murine model of CPVT as well as clinically in two human subjects suffering from CPVT. We here present the case of an 11-year-old boy suffering from CPVT-1 as well as a review of the current relevant literature. After resuscitation due to VF at age 9, an automated implantable cardioverter-defibrillator (ICD) was implanted in 2007. Under beta-blocker therapy, repeated shocks were delivered due to either fast ventricular tachycardia (VT) or VF. This persisted under additional therapy with verapamil. Implantable cardioverter-defibrillator routine interrogations showed frequent non-sustained VT with an average of 8.8 per day. Additionally, the patient suffered from impaired physical performance due to decreased chronotropic competence. In July 2009, flecainide was added to the beta-blocker/verapamil regimen, resulting in a plasma level of 0.20 mg/L. No ICD shock or sustained VT occurred until December 2010. Genetic testing revealed an RyR2 receptor mutation. The case demonstrates the challenge of diagnosis and management of CPVT. It furthermore supports recent experimental evidence that the class 1 antiarrhythmic drug flecainide can suppress CPVT. The presented case supports a novel strategy in treating CPVT with the class I antiarrhythmic agent flecainide.

/pdf/successful-treatment-of-catecholaminergic-polymorphic-41k1sfi82c.pdf

Successful treatment of catecholaminergic polymorphic ventricular tachycardia with flecainide: a case report and review of the current literature.

Cardiac calcium (Ca2+) handling subsumes the mechanisms maintaining the myocardial Ca2+ homeostasis that contribute essentially to cardiac performance. This review addresses the interaction of transplasmalemmal and transsarcoplasmic Ca2+ flux, its potential modifications due to β-adrenergic stimulation and its implications on cardiac action potential.

Adam Muszynski

Papers

Proarrhythmia in a non-failing murine model of cardiac-specific Na+/Ca 2+ exchanger overexpression: whole heart and cellular mechanisms.

Successful treatment of catecholaminergic polymorphic ventricular tachycardia with flecainide: a case report and review of the current literature.

The physiology of cardiac calcium handling.