Genotype-Phenotype Relationships in Long QT Syndrome: Role of Mental Stress, Adrenergic Activity and a Common KCNH2 Polymorphism

6 ABSTRACT Long QT syndrome is a congenital or acquired arrhythmic disorder which manifests as a prolonged QT-interval on the electrocardiogram and as a tendency to develop ventricular arrhythmias which can lead to sudden death. Arrhythmias occur during intense exercise and/or emotional stress. The two most common subtypes of LQTS are LQT1, caused by mutations in the KCNQ1 gene and LQT2, caused by mutations in the KCNH2 gene. LQT1 and LQT2 patients exhibit arrhythmias in different types of situations: in LQT1 the trigger is usually vigorous exercise whereas in LQT2 arrhythmia results by the patient being startled from rest. It is not clear why trigger factors and clinical outcome differ from each other in the different LQTS subtypes. It is possible that stress hormones such as catecholamines may show different effects depending on the exact nature of the genetic defect, or sensitivity to catecholamines varies from subject to subject. Furthermore, it is possible that subtle genetic variants of putative modifier genes, including those coding for ion channels and hormone receptors, play a role as determinants of individual sensitivity to life-threatening arrhythmias. The present study was designed to identify some of these risk modifiers. Therefore, in vivo studies using systems to induce mental and physical stress as well as in vitro studies on genetic polymorphism of candidate genes were designed. During mental stress validated by hemodynamic and cathecolaminergic responses, the mean QT-interval shortened to a similar extent in controls (-29 ms), LQT1 patients (-34 ms) and LQT2 patients (-30 ms). During exercise, the corresponding QT-adaptation was more pronounced in healthy controls (-47 ms) than in LQT1 (-38 ms) or LQT2 patients (-38 ms). Thus, LQT1 and LQT2 patients could not be differentiated from one another on the basis of QT-adaptation to mental stress. During rapid right atrial pacing at progressively shorter diastolic intervals, LQT1 and LQT2 could be differentiated because LQT1 patients had different action potential restitution kinetics during epinephrine infusion. Furthermore, the monophasic action potential shape measured from the right atrium was different in LQT1 and LQT2. In LQT1, the monophasic action potential shape was less triangular at baseline than in LQT2, during epinephrine infusion, it became more triangular. Action potential triangulation is considered to predispose to ventricular arrhythmia. Therefore, these findings may explain, at least in part, the propensity of LQT1 patients to develop ventricular arrhythmia during intense sympathetic activation. In vitro electrophysiological as well as clinical studies were performed to find out whether the most common KCNH2 polymorphism in Finland, K897T, influences channel function or phenotype. Maximal current of the K897 channel was larger in transiently transfected mammalian cells then the T897 channel due to increased channel expression. In a maximal exercise test in 39 patients carrying an identical KCNQ1 mutation and showing a prolonged QT-interval, QT-intervals were longer in patients carrying the T897 allele than in those homozygous for the K897 allele. It remains to be seen whether this polymorphism is a clinically significant risk factor for symptomaticity in larger LQTS populations. To study the role of 1-adrenergic receptor variations as LQTS modifier genes clinical data and DNA samples from 168 LQT1 patients were analyzed. A common -adrenergic receptor polymorphism (R389G) was found to alter QT-interval and that compound homozygosity for two -adrenergic receptor polymorphisms (R389G and S49G) increased risk of arrhythmia in LQT1 patients. Patients with the R389 genotype have shorter QT-intervals at rest and during exercise than patients with the R389G and G389 genotypes.