Pharmacological and Biological Risk Factors for Cardiac Arrhythmias

Abstract

Sudden death is among the most common causes of death in developed countries. Sudden death from cardiac causes accounts for approximately 50% of all deaths from cardiovascular diseases and 20% of all deaths. The majority of sudden cardiac deaths are caused by acute ventricular arrhythmia. An important potential cause of ventricular arrhythmia is prolongation of ventricular repolarization. Prolongation of ventricular repolarization may result in early after depolarizations, which in turn may induce re- entry and thereby provoke Torsade de Pointes and fatal ventricular arrhythmia. This thesis focused on the effect of certain drugs and endocrine factors on QTc prolongation and sudden cardiac death. Chapter 1 gives an overview of QTc prolongation and sudden cardiac death and its main risk factors, etiology and possibilities for prevention. In chapter 2.1 we studied whether listed putative QTc prolonging psychotropic drugs indeed prolong the QTc interval under everyday circumstances, and evaluated whether this is a class effect or an individual drug effect. We were able to confirm the importance of antidepressants (in particular amitriptyline, imipramine, maprotiline and nortripty- line) and antipsychotics (in particular lithium, olanzapine and thioridazine) as potential contributors to QTc prolongation. Especially starting of tricyclic antidepressant drugs is associated with a significant intra-individual increase in the QTc interval (approximately 10 milliseconds) in comparison to the change in non-users. The tricyclic antidepressants appear to prolong the QTc interval as a class effect. Since common variation in the NOS1AP gene has been associated with QTc interval variation and NOS1 is presumed to influence intracellular calcium, we aimed to study in chapter 2.2 whether NOS1AP single nucleotide polymorphisms modify the QTc prolonging effect of calcium channel blockers. We demonstrated that the minor alleles of both NOS1AP SNPs significantly potentiate the QTc prolonging effect of verapamil. Because QTc prolongation is associated with an increased risk of sudden cardiac death, this gene-drug interaction may be of clinical importance. Virtually all QTc prolonging drugs act by blocking the hERG (human ether a go-go related gene) encoded potassium channels, whereas not all QTc prolonging drugs are associated with an increased risk of serious cardiac arrhythmias. To investigate whether binding capacity to hERG-encoded potassium channels can actually predict hard clinical endpoints, we studied in chapter 3.1 whether non-cardiovascular drugs, which are known to block the hERG-encoded potassium channels, are associated with an increased risk of sudden cardiac death and whether the ratio between therapeutic Summary 211 212\tChapter 8 plasma concentrations and the concentration which inhibits 50% of the potassium channels is an indicator of the risk of sudden cardiac death. We confirmed that cur- rent use of non-cardiovascular hERG-encoded potassium channels inhibiting drugs in the general population is associated with an increased risk of sudden cardiac death. In addition, we demonstrated that drugs with a high hERG-encoded potassium channels inhibiting capacity had a higher risk of sudden cardiac death than patients using drugs with a low potassium channels inhibiting capacity. In chapter 3.2 we evaluated the association between use of domperidone, which is also known to block the hERG- encoded potassium channels, and serious non-fatal ventricular arrhythmias and sudden cardiac death in the general population. We confirmed that current use of domperidone and mainly high doses are associated with an increased risk of sudden cardiac death. We could not demonstrate an effect of domperidone on non-fatal ventricular arrhythmias due to absence of exposed cases. Since sudden cardiac death is frequently reported in epilepsy and the indications of anticonvulsant drug prescriptions now include chronic pain syndromes, we studied whether use of anticonvulsants is associated with an increased risk of sudden cardiac death. In chapter 3.3 we found that use of anticonvulsive drugs is associated with an increased risk of sudden cardiac death in the general population, even in persons who use anticonvulsive drugs for other indications than epilepsy. The risk of sudden cardiac death seems to be higher among users of carbamazepine and other anticonvulsants with sodium channel blocking properties. Since the literature on the effect of excess thyroid hormone on ventricular repolarization is controversial, we aimed to examine whether free T4 and TSH are associated with QTc prolongation. In chapter 4.1 we showed that high levels of free T4 are associated with QTc prolongation in men, which can be explained by an increased activity of cardiac Na+/ K+ ATPase in thyroid hormone excess, leading to increased intracellular K+ with subsequent membrane hyperpolarization and an increase in QTc duration. Although a QTc interval prolongation of 10 milliseconds in one individual usually remains without clinical consequences, an average shift of 10 milliseconds in a Gaussian distribution on a population level will inevitably push more individuals into the upper percentiles of the QTc interval with its increased risk of Torsade de Pointes and sudden cardiac death. In chapter 4.2 we investigated whether use of antithyroid drugs (as a direct cause or as an indicator of poorly controlled hyperthyroidism) is associated with an increased risk of sudden cardiac death. We demonstrated in two independent studies that use of antithyroid drugs seems to be associated with a threefold increased risk of sudden cardiac death. Although this might be due to antithyroid drug use itself, it could be more readily explained by underlying hyperthyroidism, since increased free T4 levels are associated with QTc prolongation and treated patients who developed sudden cardiac Summary 213 death still had low TSH levels shortly before death. This suggests that hyperthyroidism may be a risk factor for sudden cardiac death. It is assumed that testosterone is an important regulator of gender-related differences in ventricular repolarization. Therefore, we studied in chapter 5.1 whether serum levels of testosterone are associated with QTc, QT and RR interval variation. We demonstrated in two population-based studies that serum testosterone is associated with a decreased QTc interval and increased RR interval, however, not with a difference in the QT interval. The decreased QTc interval in men with higher levels is probably due to the association of serum testosterone with prolongation of the RR interval. Diabetes mellitus is a common disease in the elderly which adversely affects cardiac repolarization. Since hyperglycemia itself is a risk factor for cardiovascular disease, we studied whether non-diabetic persons with impaired fasting serum glucose and hyper- insulinemia have QTc/QT-interval prolongation and RR-interval shortening, and whether these were associated with an increased risk of sudden cardiac death. In chapter 5.2 we showed that impaired fasting glucose and hyperinsulinemia are associated with a significantly increased QTc-interval and shortening of the RR interval. We demonstrated in the same population that both prolongation of the QTc/ QT as well as shortening of the RR interval are associated with an increased risk of sudden cardiac death. In chapter 6 we discussed the main findings of the studies presented in this thesis and the methodological considerations of these studies. In addition, we presented potential clinical implications and suggestions for future research. In addition, we presented recently discovered genes involved in atrial fibrillation and the PR interval during studies. In chapter 7.1 we have replicated variants on chromosome 4 associated with atrial fibrillation. The SNPs rs2200733 and rs10033464 are strongly associated with AF in four independent cohorts of European descent. The primary aim of genome-wide association (GWA) studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors and the degree of clinical dis- ease. In chapter 7.2 we conducted meta-analyses of genome-wide association studies for atrial fibrillation in collaboration with the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium and identified the new locus ZFHX3 for atrial fibrillation. The electrocardiographic PR interval reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. In chapter 7.3 we conducted meta-analyses of GWA studies for the PR interval in 7 community- based studies and identified 9 loci. Five of these 9 loci were also associated with atrial fibrillation