KCNJ11 polymorphisms and sudden cardiac death in patients with acute myocardial infarction

Abstract

Purpose. – Patients with an acute myocardial infarction (AMI) are of high risk to develop ischemia-induced ventricular arrhythmias, leading to sudden cardiac death (SCD) in about one third of all AMI patients. The individual susceptibility to ischemia-induced arrhythmias may be modified by polymorphisms in genes encoding ion channels. The cardiac ATP-dependent potassium channel (K_ATP) current is generated by ion channels encoded by the KCNJ11 gene and the SUR2a gene. Opening of the K_ATP channel during ischemia results in action potential shortening in various studies and may therefore influence the outcome of AMI patients.

Methods. – Using a three-primer strategy, we sequenced the complete coding and adjacent 5′ and 3′ sequences of the intronless KCNJ11 gene (1.3 kb) prospectively in two groups. Patients of group 1 (n = 84) survived three or more transmyocardial infarctions without developing any ventricular arrhythmias. Patients of group 2 died suddenly from their first myocardial infarction (n = 86), most of them witnessed SCDs.

Results. – We identified a total of six known polymorphisms (K23E, A190A, L267V, L270V, I337V, and K281K) and two new polymorphisms (L267L, 3′UTR +62 G/A). The allele, genotype, and haplotype frequencies did not differ between the two groups. All polymorphisms were found to be in Hardy–Weinberg equilibrium. In addition, we identified two novel missense mutations in a highly conserved region of the gene in two patients of group 2 (P266T and R371H) with yet unknown functional consequences.

Conclusion. – In this study of AMI patients, SCD was not related to polymorphisms in the KCNJ11 gene.

Introduction

An acute myocardial infarction (AMI) is the leading cause of death in the western world [1]. More than a third of all patients with an AMI are dying suddenly, that means within 1 h after onset of symptoms without any previous condition that would seem fatal [2]. This rate of sudden cardiac death (SCD) victims in case of an AMI was constant over the past three decades [2], [3], [4], [5]. In most cases, ischemia-induced ventricular tachycardia that rapidly progresses to ventricular fibrillation and circulatory collapse cause the terminal event [6]. Unfortunately, in many patients SCD is the decedent’s first symptom of a coronary heart disease (CHD) or AMI [7], [8], [9]. This and the unawareness of clinical signs of an AMI prevent the administration of modern myocardial infarction (MI) therapy to nearly one third of all AMI patients [10].

The individual susceptibility to develop ischemia-induced ventricular arrhythmias may be influenced by various factors like age, gender, left ventricular function, area of ischemic myocardium, collateral blood supply, electrolyte levels as well as race, and genetic background [11], [12], [13], [14]. In order to determine possible genetic factors we studied the KCNJ11 gene, encoding for the pore-forming subunit of the ATP-dependent potassium channel (K_ATP) [15]. The cardiac K_ATP channel consists of the heterodimer of the KCNJ11 encoded polypeptide and the sulfonylurea receptor (SUR2a) and plays a crucial role in coupling metabolic energy to the membrane potential of cells [16], [17]. It opens in ventricular myocardium predominantly during ventricular ischemia [18], [19], [20]. Although K_ATP channels have been proposed to play a role in most types of myocardial damage associated with ischemia/reperfusion [21], the potential benefits of K_ATP channel modulators against the biochemical and electrical disturbances observed during acute ischemia is unclear. In the setting of an acute ischemia and concomitant low glucose concentration, additional opening of K_ATP channels results in action potential shortening [22], [23], which may facilitate re-entry tachycardias and is therefore pro-arrhythmic [24]. Furthermore, it was shown that some polymorphisms and mutations of the KCNJ11 gene, which is also expressed in pancreatic islets, are associated with type II diabetes mellitus and persistent hyperinsulinemic hypoglycemia of infancy [25], [26], [27]. These findings lead to the hypothesis that KCNJ11 mutations or polymorphisms may be functionally relevant also in the heart and may modify the susceptibility to ischemia-induced arrhythmias.

We therefore examined a group of patients who died suddenly from their presumably first profound myocardial ischemia (n = 86). In all these patients a CHD was diagnosed before their death, but none of them had ever developed an AMI before they died suddenly. A second group of age and sex matched AMI patients were identified from 2816 MI patients of the Regensburg MI family study [28]. These patients (n = 84) survived three or more transmyocardial infarctions without developing any ventricular arrhythmias during hospitalization or during follow-up, demonstrating a remarkable stable heart rhythm and high ischemia tolerance.