There has been a significant progress in our understanding of the molecular mechanisms by which calcium (Ca ²⁺ ) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca ²⁺ -handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca ²⁺ in normal cardiac function—in particular, excitation–contraction coupling and normal electric rhythms. The functional involvement of Ca ²⁺ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused by mutations in Ca ²⁺ -handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca ²⁺ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes.

Advances in human genetics are improving the understanding of a variety of inherited cardiovascular diseases, including cardiomyopathies, arrhythmic disorders, vascular disorders, and lipid disorders such as familial hypercholesterolemia. However, not all cardiovascular practitioners are fully aware of the utility and potential pitfalls of incorporating genetic test results into the care of patients and their families. This statement summarizes current best practices with respect to genetic testing and its implications for the management of inherited cardiovascular diseases.

Background—: Excitation-contraction coupling in striated muscle requires proper communication of plasmalemmal voltage-activated Ca ²⁺ channels and Ca ²⁺ release channels on sarcoplasmic reticulum within junctional membrane complexes. Although previous studies revealed a loss of junctional membrane complexes and embryonic lethality in germ-line junctophilin-2 (JPH2) knockout mice, it has remained unclear whether JPH2 plays an essential role in junctional membrane complex formation and the Ca ²⁺ -induced Ca ²⁺ release process in the heart. Our recent work demonstrated loss-of-function mutations in JPH2 in patients with hypertrophic cardiomyopathy. Methods and Results—: To elucidate the role of JPH2 in the heart, we developed a novel approach to conditionally reduce JPH2 protein levels using RNA interference. Cardiac-specific JPH2 knockdown resulted in impaired cardiac contractility, which caused heart failure and increased mortality. JPH2 deficiency resulted in loss of excitation-contraction coupling gain, precipitated by a reduction in the number of junctional membrane complexes and increased variability in the plasmalemma–sarcoplasmic reticulum distance. Conclusions—: Loss of JPH2 had profound effects on Ca ²⁺ release channel inactivation, suggesting a novel functional role for JPH2 in regulating intracellular Ca ²⁺ release channels in cardiac myocytes. Thus, our novel approach of cardiac-specific short hairpin RNA–mediated knockdown of junctophilin-2 has uncovered a critical role for junctophilin in intracellular Ca ²⁺ release in the heart.