Mechanism underlying impaired cardiac pacemaking rhythm during ischemia: A simulation study

In this study, we tested the hypothesis that the neural control of circulation in humans undergoes continuous but in part predictable changes throughout the day and night. Dynamic 24-hour recordings were obtained in two groups of ambulant subjects. In 18 hospitalized patients free to move, direct high-fidelity arterial pressures and electrocardiograms were recorded, and in an additional 28 nonhospitalized subjects, only electrocardiograms were obtained. Spectral analysis of systolic arterial pressure and of RR interval variabilities provided quantitative markers of sympathetic and vagal control of the sinus node and of sympathetic modulation of vasomotor tone. With this approach, the low-frequency (approximately 0.1 Hz) component of RR interval and systolic arterial pressure variabilities is considered a marker primarily of sympathetic activity, whereas the high-frequency (approximately 0.25 Hz) component of RR interval variability, related to respiration, seems to be a marker primarily of vagal activity. We observed a pronounced and consistent reduction in the markers of sympathetic activity and an increase in those of vagal activity during the night. In the invasive studies, while the subjects were still lying in bed after waking up, the markers of sympathetic activity rose rapidly and concomitantly with a simultaneous vagal withdrawal. Noninvasive studies confirmed the early morning rise of the markers of sympathetic activity and the circadian pattern of sympathovagal balance. These data indicate that the ominously increased rate of cardiovascular events in the morning hours may reflect the sudden rise of sympathetic activity and the reduction of vagal tone.

In the United States, sudden cardiac death accounts for an estimated 300,000 to 350,000 cases each year, with 80,000 presenting as the first manifestation of a preexisting, sometimes unrecognized, coronary artery disease. Acute myocardial infarction (AMI)-induced ventricular fibrillation frequently occurs without warning, often leading to death within minutes in patients who do not receive prompt medical attention. Identification of patients at risk for AMI-induced lethal ventricular arrhythmias remains an unmet medical need. Recent studies suggest that a genetic predisposition may significantly contribute to the vulnerability of the ischemic myocardium to ventricular tachycardia/ventricular fibrillation. Numerous experimental models have been developed for the purpose of advancing our understanding of the mechanisms responsible for the development of cardiac arrhythmias in the setting of ischemia and with the aim of identifying antiarrhythmic therapies that could be of clinical benefit. While our understanding of the mechanisms underlying AMI-induced ventricular arrhythmias is coming into better focus, the risk stratification of patients with AMI remains a major challenge. This review briefly discusses our current state of knowledge regarding the mechanisms of ischemic ventricular arrhythmias and their temporal distribution as revealed by available experimental models, how these correlate with the clinical syndromes, as well as prospective prophylactic therapies for the prevention and treatment of ischemia-induced life-threatening arrhythmias.