Neural Circulatory Control in the Long QT Syndrome

Project: Research project

Project Details


DESCRIPTION (provided by applicant): 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.
Effective start/end date4/1/023/31/08


  • Medicine(all)