The long QT syndrome (LQTS) is associated with risk for polymorphic ventricular tachycardia, syncope, and sudden death. Molecular genetic approaches have shown that these syndromes are explained by mutations in cardiac ion channel genes, the commonest known mutations being classified as LQT1, LQT2, and LQT3. The degree of QT prolongation is an independent risk factor for cardiac events. The QT interval is exquisitely sensitive to changes in autonomic nervous system activity. The genotype is further linked to the nature of the trigger for cardiovascular events. Events in patients with LQT1 occur during exertion, particularly during swimming. Excitement and auditory stimuli typically trigger events in LQT2 patients. Most events in LQT3 occur at rest. This interaction between genotype, QT, autonomic status and environment is unclear. We propose the overall hypothesis that patients with LQTS have low sympathetic activation at rest and have potentiated autonomic responses to physical, mental, cold, and chemical stress, and that the autonomic, hemodynamic and/or QT responses to stress in LQTS are differentially affected by genotypes characterizing LQT1, LQT2, and LQT3. We will test the following specific hypotheses: 1. Patients with the LQTS have low levels of sympathetic activation at rest as evidenced by slow heart rates and decreased sympathetic nerve traffic to muscle blood vessels. 2. LQTS individuals have potentiated autonomic and/or QT responses to arousal stimuli such as mental stress and loud noise. 3. Abnormalities in cardiac ion channels causing LQTS are associated with abnormalities in arterial baroreflex regulation of heart rate and sympathetic traffic. 4. LQTS individuals (especially LQT1, who have an increased risk for cardiac events during swimming) have abnormal responses to chemoreflex activation, particularly during apnea, and abnormalities in the diving reflex response. Important and novel strengths of the proposal include an integrated translational approach to understanding autonomic mechanisms that may contribute to sudden death in patients with LQTS. We believe that these studies will provide important and clinically relevant insights into the interaction between the genetics of ion channel dysfunction and associated neural control phenotypes.
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