Congenital long QT syndrome (LQTS) comprises a distinct group of cardiac channelopathies characterized by delayed repolarization of the myocardium, QT prolongation, and increased risk for syncope, seizures, and sudden cardiac death in the setting of a structurally normal heart and otherwise healthy individual
Genotype-Phenotype Relationships in Long QT Syndrome
Congenital long QT syndrome (LQTS) comprises a distinct group of cardiac channelopathies characterized by delayed repolarization of the myocardium, QT prolongation, and increased risk for syncope, seizures, and sudden cardiac death in the setting of a structurally normal heart and otherwise healthy individual (Figure 1).(11,12) This repolarization abnormality almost always is without consequence, however rarely, when caught off guard by triggers such as exertion, swimming, emotion, or auditory stimuli the heart can spiral electrically out of control into a potentially life threatening and sometimes lethal dysrhythmia.(11) Though in most incidences the heart’s rhythm spontaneously returns to normal following an episode of syncope, 5% of untreated and unsuspecting LQTS individuals succumb to a fatal arrhythmia as their sentinel event.
LQTS is a genetically heterogeneous disorder most often inherited in an autosomal dominate mode. To date, hundred of mutations have been identified with approximately 75% of clinically robust LQTS due to mutations in 5 genes: KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6) encoding for critical cardiac ion-channel subunits that are responsible for the orchestration of the cardiac action potential (Figure 2).(13)
Since diagnosing his first patient with LQTS and carving out a postdoctoral fellowship in molecular genetics to identify that patient’s LQTS-causing mutation (Pediatric Research 1998), Dr. Ackerman’s laboratory has investigated the genetic basis for over 600 unrelated patients and over 1500 family members referred for LQTS research-based genetic testing. Given that the 3 most common LQTS-susceptibility genes had been discovered already by Dr. Mark Keating, Dr. Ackerman initially conducted genotype-phenotype association studies involving these known genes. This work established swimming as a relatively LQT1-specific trigger (Mayo Clinic Proceedings 1999 and Circulation 2004) and the postpartum period as a relatively LQT2-specific temporal period for women with LQTS (Heart Rhythm 2004).
New Gene Discovery in the Pathogenesis of Long QT Syndrome
The comprehensive and systematic investigation of 541 unrelated patients through all of the known LQTS-susceptibility genes (Heart Rhythm 2005 and JACC 2006) as well as the meticulous search for genetic variation among nearly 1000 healthy volunteers from across 4 different ethnicities (Mayo Clinic Proceedings 2004 and Heart Rhythm 2005) has facilitated the translation of this research based genetic test to a clinical diagnostic test called FAMILION available through PGxHealth since May 2004. Moreover, this effort has also yielded a large cohort of patients (~ N = 100) with strong clinical evidence for LQTS but a negative genetic test providing an enriched cohort for novel gene discovery. Indeed, two new LQTS-susceptibility genes: CAV3 (Circulation 2006, Figure 3) and SCN4B (Circulation 2007 re-submitted), have emerged from this cohort. Both genes encoded sodium channel interacting proteins (ChIPs) that when mutated, functionally perturb the pore-forming alpha subunit and accentuate the late sodium current. Our LQTS disease-gene discovery program is now focused on genes that encode cardiac ChIPs as novel candidate genes.
Catecholamine provocation testing in the evaluation of congenital long QT syndrome
Determining the influence of various stimuli (such as auditory arousal from sleep and activation of dive reflex) on muscle sympathetic nerve activity and cardiac repolarization are the principle pursuits with respect to these human LQTS studies. Through this patient-oriented research, the applicant has developed the Mayo Epinephrine QT Stress Test (Mayo Clinic Proceedings 2002) and demonstrated that paradoxical lengthening of the absolute QT interval during low-dose epinephrine infusion has 75% positive predictive value and 96% negative predictive value with respect to type 1 LQTS (Circulation 2006, Figure 4). This clinical diagnostic test is now used in heart rhythm centers throughout the world in an effort to unmask patients with concealed LQT1. With respect to catecholamine provocation studies, the applicant is again exploring the use of dobutamine and his patented T Wave Lability Index (Ackerman MJ, Nemec J, Shen, WK. Non-alternating Beat-to-Beat Fluctuations in T Wave Morphology: Patent No. 6,821,256. Mayo Foundation for Medical Education and Research - Rochester, MN. Issued November 23, 2004. as a means of risk stratification in LQTS (Mayo Clinic Proceedings 2003).
Sleep and neural circulatory control in long QT syndrome
Over 200 of the applicant’s LQTS genotype positive patients have participated as research subjects in our Clinical Research Unit (CRU)-based studies investigating Neural Circulatory Control in LQTS (HL/NS70302). Overnight sleep studies identified dysregulated sleep architecture and abnormal cardiac repolarization in women with type 2 LQTS (Circulation 2002) while microneurography studies revealed profoundly attenuated muscle sympathetic nerve activity in all patients with LQTS irrespective of the mutated gene (Circulation 2003).
Genotype-Phenotype Relationships in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is another heritable arrhythmia syndrome that classically manifests with exertion induced syncope or sudden death and closely mimics that of LQTS.(14) CPVT is associated with a completely normal resting ECG and is electrocardiographically suspected following either exercise or catecholamine stress testing that demonstrates significant ventricular ectopy. Like that of LQTS, CPVT is generally associated with a structurally normal heart. Perturbations pursuant to mutations in the RyR2¬-encoded cardiac ryanodine receptor represent the most common genetic subtype of CPVT (Figure 5). Approximately 65% of CPVT is due to RyR2 mutations and is regarded as type 1 CPVT (CPVT1). The lethality of CPVT is illustrated by the presence of a positive family history of juvenile (< 40 years) SCD for more than a third of CPVT individuals and in as many as 60% of families hosting RyR2 mutations.(14,15)