Long QT Vulnerability in Sudden Infant Death Syndrome

Sudden infant death syndrome (SIDS) is currently defined as the unexpected death of an infant prior to their first birthday, and the death remains unexplained following a post-mortem and death site investigation. It is a diagnosis of exclusion and does not have a clear-cut pathophysiology. It is the third leading cause of infant mortality in the United States, and it has devastating psychological consequences for the victim’s families. There are a large number of potential pathophysiological mechanisms that contribute to SIDS, and some cases likely involve a number of factors. SIDS is currently explained through the framework of the “triple threat hypothesis”, which argues that the death is likely caused by the combination of a vulnerable infant, a critical development period, and the presence of an external stressor. Unfortunately, the underlying causes to infant vulnerability remain largely unknown. Although the consensus is that SIDS is a multifactorial, most cases of infant vulnerability are probably linked to abnormalities in respiratory or cardiac function. This proposal focuses on investigating possible cardiac mechanisms that contribute to SIDS. The coordinated electrical excitation of the heart is necessary for it to efficiently pump blood throughout the body. Electrical impulses normally originate in the sinoatrial node and then propagate through the atria, atrioventricular node, and into the ventricles. The electrical activity of the heart can be measured non-invasively using a 12-lead electrocardiogram (ECG). The first event is the “P wave” and it corresponds to the depolarization of the atria. Atrial depolarization helps to push blood into the ventricle. The next three waves “Q, R, and S” represent the progressive wave of depolarization through the ventricles. The final wave of the cardiac cycle “T” corresponds to ventricular repolarization. Ventricular depolarization activates the ventricles to contract and pump blood into the large arteries, whereas ventricular repolarization allows the ventricles to relax and fill up with blood. Arrhythmias are electrical disturbances that disrupt the normal initiation or propagation of the cardiac impulse, and they are a leading cause of death in people between the age of 20 and 65 years. In 1976, Peter Schwartz suggested that at least some cases of SIDS vulnerability might be caused by a predisposition to cardiac arrhythmias, and he proposed the “QT hypothesis”. The QT interval measured on the ECG reflects the time it takes the ventricles to depolarize and repolarize. Drug induced QT prolongation, acquired QT prolongation secondary to other disease states, or genetic conditions that predispose patients to long QT syndrome (LQS) increase the risk for life-threatening ventricular arrhythmias. Schwartz suggested some cases of SIDS cases were caused by LQTS. Congenital LQTS is primarily linked to mutations in genes that encode cardiac ion channels. Ion channels are macromolecular protein complexes that transverse the myocardial cell membrane, and they are responsible for the initiation and propagation of the electrical wave through the heart. About 75% of congenital LQTS is caused by mutations in one of three different ion channels genes, which makes genetic testing for the disease relatively straightforward. However, a significant percentage of healthy subjects (3-8%) harbor rare but likely benign mutations in one of these three genes. Therefore, it is difficult to discriminate disease-causing mutations from “genetic noise”. The lack of biological or functional validation of mutations identified in LQTS-susceptibility genes remains a severe limitation of genetic test interpretation. The purpose of this proposal is to determine what fraction of SIDS victims harbor pathophysiological mutations in LQTS susceptibility genes. To do this, we plan on functionally validating genetic variants identified from a cohort of 292 SIDS cases. Completion of this proposal will provide mechanistic insight into the LQTS vulnerability in SIDS.