Triggers of Ventricular Arrhythmias (TOVA) Study

BACKGROUND:

The classic studies of daily activity prior to myocardial infarction onset conducted by Master in the 1960s failed to show a consistent relationship between any particular activity and disease onset. However, they were conducted at a time when less was known of the pathophysiology of myocardial infarction, when there was less understanding of the effect of daily activities on physiologic processes likely to lead to myocardial infarction onset, and when epidemiologic methods were less well developed than at present. Certain activities now of considerable interest, such as wake time, time of assuming the upright posture, eating and taking of medications, were not examined and those that were examined such as walking and heavy exertion, were evaluated without reference to control exposure. In addition, modern enzymatic methods of confirmation of the diagnosis of acute myocardial infarction were not utilized. Despite these deficiencies, the studies of Master provide the foundation for the hypothesis that the onset of myocardial infarction is almost always a random event.

Observations of morning increase in the incidence of myocardial infarction, sudden cardiac death, and myocardial ischemia demonstrate that the timing of these events is not wholly random. The most extensive data on the time of onset of the pain of myocardial infarction were published in 1976 by the World Health Organization in the report of the Myocardial Infarction Community Registers from 19 European centers. Data from over 8,900 patients clearly demonstrated a peak incidence of onset of pain from 8 to 11 a.m. Data from the Multicenter Investigation of the Limitation of Infarct Size (MILIS) Study revealed a significant circadian variation with an increased incidence of myocardial infarction in the period from 6 a.m to noon. The morning increase was detected despite the fact that data concerning the time of awakening and prior medication usage were lacking in this patient population. This finding has been confirmed by Willich in a study of over 1,700 patients with infarct onset determined by creatine kinase timing. The patients showed a four-fold increased morning onset of myocardial infarction relative to occurrence at night. When the relationship of infarction onset to time of awakening is clarified, and possible precipitants evaluated, increased information about triggering processes will be available. Such information will assist in the design of preventive therapy which can be evaluated in randomized trials.

The Determinants Study began in 1989, shortly after widespread acceptance of the circadian variation in Ml occurrence. The study was initiated to utilize state-of-the art epidemiologic techniques to determine the role of daily activities in the triggering of Ml. The investigators created a new epidemiologic technique (the case-crossover method), developed and tested a 24-page interview form, established a large study group of hospitals with trained interviewers, instituted quality control measures, and enrolled over 2,000 subjects.

The Triggers of Ventricular Arrhythmias (TOVA) Study began in FY 1999 under the same grant number as the Modifiers and Determinants Studies. The TOVA study investigates factors associated with triggering of discharge of implantable cardioverter-defibrillators (ICDs).