Although some of the clinical findings and ECG abnormalities may be transient over time, all were analyzed with consideration for the time from date of first detection. It seemed preferable to model these factors as time-dependent indicators rather than taking the last measurements before the man’s death and the last measurements at the end of follow-up for those alive. Our model provides a novel approach to understanding changes over time of risk for SUCD. Risk factors had both short- and long-term significance, as well as independent effects, in the multivariate model. High short-term risks were shown for excess alcohol consumption and newly developed LBBB. Long-term risks for obesity, and short- and long-term risks for hypertension, ST changes and T changes were thus demonstrated.
The average age at SUCD in the MFUS cohort was 65.5 years, five years younger than the average age of death of the 2660 decedents in the cohort as a whole. Many of the men with SUCD died at a relatively young age, in their 40s and 50s, which is consistent with reports from the Framingham Heart Study (9
Short- and long-term analyses of men and women with sudden cardiac death from the Framingham Heart Study were presented by Cupples et al (14
), but their results were presented at years 8 and 28 of the study. It is not possible to determine the number of men without prior IHD who were in each category of that report. Two reports of time-dependent risk of sudden death were found, but these dealt with patients with prior IHD (15
). It appears that the MFUS analysis of time dependence after detection of risk factors for SUCD in men without prior IHD is unique.
A high resting heart rate was significant, with an RR of 1.92 for SUCD in univariate analysis, but dropped in multivariate analysis for unknown reasons. A high resting heart rate may reflect a high sympathetic tone compared with those individuals with lower heart rates (17
) and may predict cardiovascular or hypertensive disease and sudden death (18
); however, the risk for SUCD was not identified.
Overweight and obesity were themselves fairly common, and both demonstrated a long-term risk for SUCD. Moderate and severe obesity has been linked to sudden death (19
), as well as to late potentials on signal-averaged ECGs, which predict a risk of ventricular arrhythmias, or sudden death (20
). Lesser degrees of obesity pose an uncertain risk. Diabetes is said to be a risk for sudden death, but those data arise from cases with autonomic neuropathy (21
), which was not present in MFUS participants. Diabetes was infrequent in the MFUS, appeared later in life, and although it was a significant risk for SUCD on univariate analysis, it was not a significant risk factor in the multivariate analysis.
Hypertension was highly prevalent and had a high attributable risk as a consequence. After age adjustment, the risk for SUCD was high, and the risk increased with time since detection. Systolic hypertension, diastolic hypertension and hypertension defined on the basis of both blood pressures were all considered for this analysis, and all yielded approximately the same RR. Only the combined systolic and diastolic blood pressure elevation definition is presented in the current paper. Hypertension has been identified as a risk for cardiovascular and cerebrovascular morbidity and mortality in young and old patients alike (22
). Pulse pressure elevation occurred at a lower mean age than the average age at SUCD, was frequent, had a high attributable risk and was significant in the long term in single-variable, age-adjusted analysis. Only hypertension remained significant in the multivariate model.
Excess alcohol consumption remained a significant factor over the short term in the multivariate analysis. This short-term increased risk may be partly due to the method of identifying those with excess consumption because, in many cases, this information was provided by either family members or by physicians before the man’s imminent death, or via clinical information as part of autopsy reports. Light to moderate alcohol consumption may be protective (26
), whereas heavy or excess alcohol consumption is a risk factor for cardiovascular disease (29
). The relationship between alcohol dose and risk of cardiovascular death has been reported to be nonlinear or J-shaped. Alcohol in excess increases blood pressure (31
) and is likely arrhythmogenic (32
Many studies have shown stroke and peripheral vascular disease to be markers of arteriosclerotic vascular disease and, therefore, they appear as predictors of coronary disease (33
). Both stroke and peripheral vascular disease were high short-term risks, but not long-term risks, for SUCD. Because of the high short-term risk for SUCD, it is reasonable to suppose that men with either stroke or peripheral vascular disease did not live long enough to present a long-term risk for SUCD.
Atrial fibrillation was relatively uncommon in this cohort of men without prior IHD, and occurred well beyond the average age of men with SUCD. Therefore, it had a low attributable risk and was not a significant risk factor. Ventricular premature beats were common but were not significantly associated with SUCD. This finding is supported by the Framingham Heart Study in men with SUCD (35
) and by Rose et al (37
). This finding is in contrast to prior reports from the MFUS conducted in younger men, relating ECG data to all deaths due to cardiovascular disease (38
). Although ventricular premature beats and ventricular arrhythmias may be risk factors for sudden death, they remain unsolved therapeutic problems. Antiarrhythmic treatment can be hazardous (40
), and although newer treatment with angiotensin-converting enzyme inhibitors (41
), beta-blocking agents (42
) or lipid-lowering agents such as statins may be of benefit, these treatments have not been tested to prevent SUCD in a disease-free population, such as the population described herein. First-degree atrioventricular block and RBBB were both uncommon in the MFUS and were not independently associated with SUCD.
New-onset LBBB is a very important high short-term risk for SUCD. In days, or even up to five years after its appearance, it carried a high relative risk 7.47 for SUCD. The prevalence of LBBB was low, occurring in only seven individuals with subsequent SUCD. Despite a low attributable risk, it must be considered to be a marker for underlying coronary disease and a warning that SUCD may ensue. MFUS has presented data on the short-term risk of LBBB and SUCD (39
), and although new-onset LBBB was noted to be a harbinger of late cardiovascular disease, hypertension or sudden death, SUCD was not examined separately in the Framingham Heart Study (9
). In another report (14
), intraventricular block was a risk factor for SUCD, but the number of LBBB cases was small.
LVH was moderately common but was not significant, probably because of the concomitant effect of hypertension. LVH was a significant short- and long-term risk in the study by Cupples et al (14
), but they included ST changes in the definition of LVH.
New ST changes conveyed high risks for SUCD, and T wave changes were only less so in the short term, but both remained significant over longer terms. These factors probably reflect underlying IHD, and this idea is supported by more recent studies employing newer diagnostic techniques (43
). In a subsequent study of autopsy cases from MFUS, it will be possible to consider the specificity of ST and T wave changes related to the extent and area of the ischemic damage. For now, it must be said that the development of these ST and T wave changes should be considered relevant to the risk of SUCD, both in the short and long term, even if the man is asymptomatic.
Smoking is a known risk factor for IHD but was not significantly associated with SUCD in the present study. One explanation lies with our operational definition of smoking in this analysis as ever smoked versus never smoked. Many study members smoked at the end of World War II, when they were younger, but the vast majority had stopped smoking by 40 years of age. By the time of our analysis, the label of smoking may not have correctly reflected a man’s current smoking status. In that case, ex-smokers would have dominated the analysis. It is well accepted that the effect of smoking on later cardiovascular disease is nullified when the individual stops smoking (44
The high risk of the occupation of pilot cannot be explained, and may be attributed to personality type or the stress of flying, but we have no data to support any explanation in this regard. The assessment of the effect of family history was not significant and may be related to the timing of the acquisition of that information in 1974. At that time, the average age of these men was 56; many had already died, which may have made the family history data inconclusive.
The MFUS can be criticized because it includes only men. Women in the Framingham Heart Study (14
) had similar risk factors for SUCD compared with men, but women had a peak incidence 20 years older than men, and hemoglobin and glucose levels were of greater importance in women. Precise information concerning alcohol consumption is always difficult to obtain, even in personal interviews, but our method of collection of the data on these men’s alcohol consumption is similar to methods of other studies (26
). Temporal changes in the treatment of primary risk factors may have confounded our data collected over a long time interval. However, Elveback et al (5
) found that over 20 years, there was little change in the incidence of SUCD in either men or women. Our report does not include cholesterol or other newer biochemical markers, but the latter are unproven in long-term epidemiological trials (47
). Cholesterol levels have not been found to be important risk factors for SUCD, especially in older men and women (16
). The MFUS has the strength of a systematic, prospective collection of clinical and ECG data spanning 56 years in originally healthy young men. We present time-related risk factors that can be determined by any medical practitioner and we provide a time base to assess each relative risk for SUCD.