Pantel S. Vokonas

Symptoms of anxiety and risk of coronary heart disease. The Normative Aging Study.

BACKGROUND Several studies have suggested an increased risk of fatal coronary heart disease (CHD) among patients with panic disorder, phobic anxiety, and other anxiety disorders. We prospectively examined this association in the Normative Aging Study. METHODS AND RESULTS An anxiety symptoms scale was constructed out of five items from the Cornell Medical Index, which was administered to the cohort at baseline. During 32 years of follow-up, we observed 402 cases of incident coronary heart disease (137 cases of nonfatal myocardial infarction, 134 cases of angina pectoris, and 131 cases of fatal CHD: made up of 26 cases of sudden cardiac death and 105 cases of nonsudden death). A nested case-control design (involving 1869 control subjects who remained free of diagnosed CHD) was used to assess the association between anxiety and risk of CHD. Compared with men reporting no symptoms of anxiety, men reporting two or more anxiety symptoms had elevated risks of fatal CHD (age-adjusted odds ratio [OR] = 3.20, 95% confidence interval [CI]: 1.27 to 8.09), and sudden death (age-adjusted OR = 5.73, 95% CI: 1.26 to 26.1). The multivariate OR after adjusting for a range of potential confounding variables was 1.94 (95% CI: 0.70-5.41) for fatal CHD and 4.46 (95% CI: 0.92-21.6) for sudden death. No excess risks were found for nonfatal myocardial infarction or angina. CONCLUSIONS These data suggest an association between anxiety and fatal coronary heart disease, in particular, sudden cardiac death.

Rapid DNA methylation changes after exposure to traffic particles.

RATIONALE Exposure to particulate air pollution has been related to increased hospitalization and death, particularly from cardiovascular disease. Lower blood DNA methylation content is found in processes related to cardiovascular outcomes, such as oxidative stress, aging, and atherosclerosis. OBJECTIVES We evaluated whether particulate pollution modifies DNA methylation in heavily methylated sequences with high representation throughout the human genome. METHODS We measured DNA methylation of long interspersed nucleotide element (LINE)-1 and Alu repetitive elements by quantitative polymerase chain reaction-pyrosequencing of 1,097 blood samples from 718 elderly participants in the Boston area Normative Aging Study. We used covariate-adjusted mixed models to account for within-subject correlation in repeated measures. We estimated the effects on DNA methylation of ambient particulate pollutants (black carbon, particulate matter with aerodynamic diameter < or = 2.5 microm [PM2.5], or sulfate) in multiple time windows (4 h to 7 d) before the examination. We estimated standardized regression coefficients (beta) expressing the fraction of a standard deviation change in DNA methylation associated with a standard deviation increase in exposure. MEASUREMENTS AND MAIN RESULTS Repetitive element DNA methylation varied in association with time-related variables, such as day of the week and season. LINE-1 methylation decreased after recent exposure to higher black carbon (beta = -0.11; 95% confidence interval [CI], -0.18 to -0.04; P = 0.002) and PM2.5 (beta = -0.13; 95% CI, -0.19 to -0.06; P < 0.001 for the 7-d moving average). In two-pollutant models, only black carbon, a tracer of traffic particles, was significantly associated with LINE-1 methylation (beta = -0.09; 95% CI, -0.17 to -0.01; P = 0.03). No association was found with Alu methylation (P > 0.12). CONCLUSIONS We found decreased repeated-element methylation after exposure to traffic particles. Whether decreased methylation mediates exposure-related health effects remains to be determined.

The anginal syndrome associated with normal coronary arteriograms: Report of a six year experience

Abstract Although the occurrence of normal coronary arteriograms in patients with anginal pain is now recognized as a clinical entity, a large-scale study of such patients has not been reported. Accordingly, the historic aspects, laboratory findings and subsequent clinical course of 200 subjects (101 men and 99 women) with this syndrome were analyzed. Their average age was 47 years. No specific feature in the history could be discerned which separated these patients from those with angina due to coronary heart disease. The frequency of noncardiac sources of chest pain was similar in all patients. The electrocardiogram demonstrated abnormalities in the ST-T waves in slightly over 50 per cent of the patients, and the postexercise electrocardiogram was abnormal in another 20 per cent. Objective evidence for myocardial ischemia (myocardial lactate production) was three times more frequent in women than in men. The frequency of carbohydrate and/or lipid abnormalities was approximately half that in patients with coronary heart disease and did not correlate with the presence of myocardial ischemia. Long-term follow-up of these patients indicated that over half showed gradual improvement without specific therapy, whereas only 8 per cent had an increase in chest pain. Six patients died (four of unknown cause) in an average follow-up period of three years. Mortality, however, as determined by the life table method, was no greater than in a sex-age matched cohort derived from actuarial data. Although the etiology of this syndrome has not yet been demonstrated, its prognosis both in terms of persistence of pain and mortality appears to be benign.

Is Worrying Bad for Your Heart?: A Prospective Study of Worry and Coronary Heart Disease in the Normative Aging Study

BACKGROUND Worry is an important component of anxiety, which recent work suggests is related to increased incidence of coronary heart disease (CHD). Chronic worry has also been associated with decreased heart rate variability. We hypothesized that high levels of worry may increase CHD risk. METHOD AND RESULTS We examined prospectively the relationship of worry with CHD incidence in the Normative Aging Study, an ongoing cohort of older men. In 1975, 1759 men free of diagnosed CHD completed a Worries Scale, indicating the extent to which they worried about each of five worry domains: social conditions, health, financial, self-definition, and aging. During 20 years of follow-up, 323 cases of incident CHD occurred: 113 cases of nonfatal myocardial infarction (MI); 86 cases of fatal CHD; and 124 cases of angina pectoris. Worry about social conditions was the domain most strongly associated with incident CHD. Compared with men reporting the lowest levels of social conditions worry, men reporting the highest levels had multivariate adjusted relative risks of 2.41 (95% CI, 1.40 to 4.13) for nonfatal MI and 1.48 (95% CI, 0.99 to 2.20) for total CHD (nonfatal MI and fatal CHD). A dose-response relation was found between level of worry and both nonfatal MI (P for trend, .002) and total CHD (P for trend, .04). CONCLUSIONS These results suggest that high levels of worry in specific domains may increase the risk of CHD in older men.

A Prospective Study of Anger and Coronary Heart Disease The Normative Aging Study

BACKGROUND Recent laboratory and epidemiological studies have suggested that high levels of anger may increase the risk of coronary heart disease (CHD). METHODS AND RESULTS We examined prospectively the relationship of anger to CHD incidence in the Veterans Administration Normative Aging Study, an ongoing cohort of older (mean age, 61 years) community-dwelling men. A total of 1305 men who were free of diagnosed CHD completed the revised Minnesota Multiphasic Personality Inventory (MMPI-2) in 1986. Subjects were categorized according to their responses to the MMPI-2 Anger Content Scale, which measures the degree to which individuals have problems controlling their anger. During an average of 7 years of follow-up, 110 cases of incident CHD occurred, including 30 cases of nonfatal myocardial infarction hostility. (MI), 20 cases of fatal CHD, and 60 cases of angina pectoris. Compared with men reporting the lowest levels of anger, the multivariate-adjusted relative risks among men reporting the highest levels of anger were 3.15 (95% confidence interval) [CI]: 0.94 to 10.5) for total CHD (nonfatal MI plus fatal CHD) and 2.66 (95% CI: 1.26 to 5.61) for combined incident coronary events including angina pectoris. A dose-response relation was found between level of anger and overall CHD risk (P for trend, .008). CONCLUSIONS These data suggest that high levels of expressed anger may be a risk factor for CHD among older men.

Is the glass half empty or half full? A prospective study of optimism and coronary heart disease in the normative aging study.

Objective A sense of optimism, which derives from the ways individuals explain causes of daily events, has been shown to protect health, whereas pessimism has been linked to poor physical health. We examined prospectively the relationship of an optimistic or pessimistic explanatory style with coronary heart disease incidence in the Veterans Affairs Normative Aging Study, an ongoing cohort of older men. Methods and Results In 1986, 1306 men completed the revised Minnesota Multiphasic Personality Inventory, from which we derived the bipolar revised Optimism-Pessimism Scale. During an average of 10 years of follow-up, 162 cases of incident coronary heart disease occurred: 71 cases of incident nonfatal myocardial infarction, 31 cases of fatal coronary heart disease, and 60 cases of angina pectoris. Compared with men with high levels of pessimism, those reporting high levels of optimism had multivariate-adjusted relative risks of 0.44 (95% confidence interval = 0.26–0.74) for combined nonfatal myocardial infarction and coronary heart disease death and 0.45 (95% confidence interval = 0.29–0.68) for combined angina pectoris, nonfatal myocardial infarction, and coronary heart disease death. A dose-response relation was found between levels of optimism and each outcome (p value for trend, .002 and .0004, respectively). Conclusions These results suggest that an optimistic explanatory style may protect against risk of coronary heart disease in older men.

Decreased heart rate variability in men with phobic anxiety (data from the normative aging study)

Prospective cohort studies suggest that phobic anxiety is a strong risk factor for fatal coronary artery disease, in particular, sudden cardiac death. It has also been established that reduced heart rate (HR) variability can identify patients at high risk for subsequent sudden cardiac death. We therefore hypothesized that persons with symptoms of phobic anxiety may exhibit reduced HR variability. We tested our hypothesis in 581 men, aged 47 to 86 years, enrolled in the Normative Aging Study who were free of coronary artery disease and diabetes. Symptoms of anxiety were assessed using the Crown-Crisp index, an instrument that has been demonstrated in previous prospective studies to strongly predict risk of sudden cardiac death. HR variability was measured under standardized conditions, with paced deep breathing (6 breaths/1 min). Two measures of HR variability were used: the SD of HR and the maximal minus minimal HR over 1 minute. Men reporting higher levels of phobic anxiety had a higher resting HR (p = 0.025 for linear trend). After adjusting for age, mean HR, and body mass index in analyses of covariance, men reporting higher levels of phobic anxiety had lower HR variability, whether measured by the SD of HR (p = 0.03 for linear trend). These data suggest that phobic anxiety is associated with altered cardiac autonomic control, and hence increased risk of sudden cardiac death.

Effects of air pollution on heart rate variability: the VA normative aging study

Reduced heart rate variability (HRV), a marker of poor cardiac autonomic function, has been associated with air pollution, especially fine particulate matter [< 2.5 μm in aerodynamic diameter (PM2.5)]. We examined the relationship between HRV [standard deviation of normal-to-normal intervals (SDNN), power in high frequency (HF) and low frequency (LF), and LF:HF ratio] and ambient air pollutants in 497 men from the Normative Aging Study in greater Boston, Massachusetts, seen between November 2000 and October 2003. We examined 4-hr, 24-hr, and 48-hr moving averages of air pollution (PM2.5, particle number concentration, black carbon, ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide). Controlling for potential confounders, HF decreased 20.8% [95% confidence interval (CI), 4.6–34.2%] and LF:HF ratio increased 18.6% (95% CI, 4.1–35.2%) per SD (8 μg/m3) increase in 48-hr PM2.5. LF was reduced by 11.5% (95% CI, 0.4–21.3%) per SD (13 ppb) increment in 4-hr O3. The associations between HRV and PM2.5 and O3 were stronger in people with ischemic heart disease (IHD) and hypertension. The associations observed between SDNN and LF and PM2.5 were stronger in people with diabetes. People using calcium-channel blockers and beta-blockers had lower associations between O3 and PM2.5 with LF. No effect modification by other cardiac medications was found. Exposures to PM2.5 and O3 are associated with decreased HRV, and history of IHD, hypertension, and diabetes may confer susceptibility to autonomic dysfunction by air pollution.

Ischemic heart disease and stroke in relation to blood DNA methylation

Background: Epigenetic features such as DNA hypomethylation have been associated with conditions related to cardiovascular risk. We evaluated whether lower blood DNA methylation in heavily methylated repetitive sequences predicts the risk of ischemic heart disease and stroke. Methods: We quantified blood DNA methylation of Long Interspersed Nucleotide Element-1 (LINE-1) repetitive elements through PCR-pyrosequencing in 712 elderly individuals from the Boston-area Normative Aging Study. We estimated risk-factor adjusted relative risks (RRs) for ischemic heart disease and stroke at baseline (242 prevalent cases), and during follow-up (44 new cases; median follow-up, 63 months), as well as subsequent mortality from ischemic heart disease (86 deaths; median follow-up, 75 months). Results: Blood LINE-1 hypomethylation was associated with baseline ischemic heart disease (RR = 2.1 [95% confidence interval = 1.2-4.0] for lowest vs. highest methylation quartile) and for stroke (2.5 [0.9-7.5]). Among participants free of baseline disease, individuals with methylation below the median also had higher risk of developing ischemic heart disease (4.0 [1.8-8.9]) or stroke (5.7 [0.8-39.5]). In the entire cohort, persons with methylation below the median had higher mortality from ischemic heart disease (3.3 [1.3-8.4]) and stroke (2.8 [0.6-14.3]). Total mortality was also increased (2.0 [1.2-3.3]). These results were confirmed in additional regression models using LINE-1 methylation as a continuous variable. Conclusions: Subjects with prevalent IHD and stroke exhibited lower LINE-1 methylation. In longitudinal analyses, persons with lower LINE-1 methylation were at higher risk for incident ischemic heart disease and stroke, and for total mortality.

Clinical studyThe anginal syndrome associated with normal coronary arteriograms: Report of a six year experience☆

Abstract Although the occurrence of normal coronary arteriograms in patients with anginal pain is now recognized as a clinical entity, a large-scale study of such patients has not been reported. Accordingly, the historic aspects, laboratory findings and subsequent clinical course of 200 subjects (101 men and 99 women) with this syndrome were analyzed. Their average age was 47 years. No specific feature in the history could be discerned which separated these patients from those with angina due to coronary heart disease. The frequency of noncardiac sources of chest pain was similar in all patients. The electrocardiogram demonstrated abnormalities in the ST-T waves in slightly over 50 per cent of the patients, and the postexercise electrocardiogram was abnormal in another 20 per cent. Objective evidence for myocardial ischemia (myocardial lactate production) was three times more frequent in women than in men. The frequency of carbohydrate and/or lipid abnormalities was approximately half that in patients with coronary heart disease and did not correlate with the presence of myocardial ischemia. Long-term follow-up of these patients indicated that over half showed gradual improvement without specific therapy, whereas only 8 per cent had an increase in chest pain. Six patients died (four of unknown cause) in an average follow-up period of three years. Mortality, however, as determined by the life table method, was no greater than in a sex-age matched cohort derived from actuarial data. Although the etiology of this syndrome has not yet been demonstrated, its prognosis both in terms of persistence of pain and mortality appears to be benign.