Exercise May Be Deadly for Arrhythmia Patients

A new study in mice has provided a potential explanation for why the heartbeat of humans lacking the protein cardiac calsequestrin (CASQ2) is irregular and potentially fatal only during exercise and not at other times.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening disease characterized by an irregular heartbeat during exercise. CPVT can be caused by mutations in the gene encoding CASQ2, a Ca2+ binding protein found in the Ca2+ storage facility of the muscle cells of the heart. Paradoxically, although CASQ2 is thought to have a crucial role in regulating contraction of the heart, individuals lacking both copies of CASQ2 and whose hearts contract relatively normally have been identified.

To help explain this paradox, researchers from Vanderbilt University (Nashville, TN, USA) and other universities generated CASQ2-deficient mice. Similar to humans lacking CASQ2, the CASQ2-deficient mice showed normal heart contraction under basal conditions, but both exercise and exposure to catecholamines--chemicals such as epinephrine made by the body during exercise and stress--induced an irregular heartbeat. The authors found that the lack of CASQ2 was compensated for in several ways, including a substantial increase in the volume of the Ca2+ storage facility in the muscle cells of the heart, which resulted in a regular heartbeat under normal conditions. However, when exposed to catecholamines, a lack of CASQ2 caused Ca2+ to spontaneously leak from its storage facility and trigger an inappropriate heartbeat. The study was published in the September 2006 issue of the Journal of Clinical Investigation.

Calsequestrin is the principal calcium-binding protein present in the sarcoplasmic reticulum (SR) of cardiac and skeletal muscle. It is a highly acidic protein that is able to bind over 40 calcium ions and acts as an internal calcium store in muscle. CASQ2 is thought to be the key SR Ca2+ storage protein, essential for SR Ca2+ release in the mammalian heart.



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