Willem J. Kop

Inflammation and coagulation factors in persons >65 years of age with symptoms of depression but without evidence of myocardial ischemia ∗

Depression is associated with increased cardiovascular disease, but the underlying mechanisms are not well understood. This study examines associations of depressive symptoms with inflammation and coagulation factors in persons aged > 65 years. Blood samples were obtained from 4,268 subjects free of cardiovascular disease (age 72.4 +/- 5.5 years, 2,623 women). Inflammation markers were C-reactive protein (CRP), white blood cell (WBC) count, total platelet count, and albumin; coagulation factors included factors VIIc and VIIIc and fibrinogen. Depression was assessed with the Center for Epidemiologic Studies Depression scale, and states of energy depletion with a validated exhaustion index. Statistical adjustments were made for risk factors (age, sex, race, systolic blood pressure, smoking status, diabetes mellitus) and physical measures of frailty (isometric handgrip, timed 15-feet walk test, activity level). Depression was associated with elevated CRP (3.31 +/- 0.10 vs 3.51 +/- 0.21 mg/L), WBC (6.14 +/- 0.03 vs 6.43 +/- 0.11 10(6)/L), fibrinogen (319 +/- 1 vs 326 +/- 3 mg/dl), and factor VIIc (124.6 +/- 0.6% vs 127.2 +/- 1.3%; all p <0.05). Exhaustion also was related to elevated inflammation and coagulation markers (p < 0.05). Exhausted men had markedly elevated CRP levels (6.82 +/- 2.10 mg/L) versus nonexhausted men (3.05 +/- 0.16: p = 0.007). After adjustment for control variables, exhaustion remained associated with albumin (p = 0.033), fibrinogen (p = 0.017), CRP (p = 0.066), and WBC (p = 0.060), whereas associations of depressive symptoms with biochemistry measures lost statistical significance. Thus, depression and exhaustion are associated with low-grade inflammation and elevated coagulation factors in persons aged > 65 years.

Vital exhaustion predicts new cardiac events after successful coronary angioplasty.

&NA; Excessive tiredness is one of the most prevalent premonitory symptoms of myocardial infarction and sudden cardiac death. This state is labelled as vital exhaustion and consists of three components: fatigue, increased irritability, and demoralization. Vital exhaustion has been found to be an independent risk‐indicator of myocardial infarction in one prospective study and several case‐control studies. It is as yet unclear whether the association between vital exhaustion and future myocardial infarction can be explained by confounding of (subclinical) coronary artery disease. Therefore, the present study investigates the predictive value of vital exhaustion for the occurrence of new cardiac events after percutaneous transluminal coronary angioplasty (PTCA), while explicitly controlling for the severity of coronary artery disease. Patients with a successful PTCA were followed during 1.5 years. A new cardiac event was defined as present if one of the following end points occurred: cardiac death, myocardial infarction, coronary bypass surgery, repeat‐PTCA, increase of coronary atherosclerosis, or new anginal complaints with documented ischemia. Vital exhaustion was assessed using the Maastricht Questionnaire two weeks after hospital discharge. Participants of the present study were 127 patients (mean age 55.6 +/‐ 9.1; 105 men, 22 women). Fifteen (35%) of the 43 exhausted patients experienced a new cardiac event, whereas 14 (17%) of the 84 not exhausted patients had a new cardiac event (OR = 2.7; CI = 1.1–6.3; p = .02). Multiple logistic regression analysis revealed that vital exhaustion continued to be of predictive value when other significant risk factors for new cardiac events were controlled for (i.e., severity of coronary artery disease and hypercholesterolemia).(ABSTRACT TRUNCATED AT 250 WORDS)

Triggers of myocardial ischemia during daily life in patients with coronary artery disease : Physical and mental activities, anger and smoking

OBJECTIVES This study assessed the potency of physical and mental activities and emotions (anger and anxiety) and smoking and other substance use as proximate triggers of ischemia in patients with coronary artery disease during daily life. BACKGROUND Myocardial ischemia occurs during a wide variety of activities in patients with coronary artery disease, but frequency and relative potency of physical and mental activities, smoking and use of caffeine and alcohol as triggers of ischemia during daily life have not been established. METHODS Patients (n = 63) with coronary artery disease and evidence of out-of-hospital ischemia kept a validated structured diary of physical and mental activities and psychologic states while undergoing ambulatory electrocardiographic monitoring for 24 to 48 h. RESULTS Ischemia occurred most frequently during moderately intense physical and mental activities. Patients spent the largest proportion of time engaged in low intensity physical and mental activities (p < 0.05), but the likelihood of ischemia was greatest during intense physical (p < 0.0001) and stressful mental activities (p < 0.03). The percentage of time in ischemia was elevated and approximately equivalent for high intensity physical and high intensity mental activities (5%) compared with 0.2% when patients were engaged in low intensity activities. Strenuous physical activity (e.g., effortful walking, p < 0.05) and the experience of intense anger were potent ischemic triggers, and heart rates at onset of ischemia increased with the intensity of physical and mental activity and with anger. Among smokers, ischemia was more than five times as likely when patients smoked than when they did not (during 24% vs. 5% of diary entries, p < 0.0001). Coffee and alcohol consumption were also related to ischemia (p < 0.05), but this association disappeared after controlling for concurrent cigarette smoking. CONCLUSIONS Triggers of ischemia in patients with coronary artery disease during daily life include not only strenuous exercise, but also activities involving low levels of exertion, such as anger and smoking. Mental activities appear to be as potent as physical activities in triggering daily life ischemia. Coffee and alcohol consumption are related to ischemia only by virtue of their associations with smoking.

MENTAL STRESS AS A TRIGGER OF MYOCARDIAL ISCHEMIA AND INFARCTION

Recent research on the effects of behavioral activities on myocardial ischemia in coronary artery disease patients has provided a pathophysiologic model for understanding the mechanisms by which mental stress can trigger clinical cardiovascular events. This article reviews epidemiologic research implicating psychosocial stress as an acute trigger of myocardial infarction in patients with pre-existing coronary artery disease, and evidence for the pathophysiologic effects of acute mental stress in individuals with pre-existing coronary artery disease. Via its actions on the central and autonomic nervous systems, stress can produce a cascade of physiologic responses in vulnerable individuals that may lead to myocardial ischemia, ventricular fibrillation, plaque rupture, or coronary thrombosis. Also reviewed are field and laboratory studies that suggest important causal links between mental stress and myocardial ischemia, and evidence suggesting clinical significance for vulnerability to mental stress-induced ischemia.

The course of functional decline in older people with persistently elevated depressive symptoms: longitudinal findings from the Cardiovascular Health Study.

Objectives: To examine the relationship between persistently high depressive symptoms and long‐term changes in functional disability in elderly persons.

Frontal electrocortical and cardiovascular reactivity during happiness and anger.

The present study investigated electrocortical and cardiovascular reactivity during positive and negative emotion, and examined the relation of asymmetric frontal lobe activation to cardiovascular responses. Participants were 30 healthy, right-handed university students (mean age, 23.9; 60% female; 76% Caucasian). Electroencephalographic (EEG), blood pressure (BP), and heart rate (HR) responses were assessed while subjects engaged in laboratory tasks (personally-relevant recall tasks and film clips) designed to elicit happiness or anger. Happiness-inducing tasks evoked more prominent left than right frontal EEG activation, and greater left frontal EEG activation than anger-inducing tasks. However, anger-inducing tasks were, on average, associated with comparable left and right frontal EEG activation. Irrespective of emotional valence, cardiovascular activation was more pronounced during personally-relevant recall tasks than during the viewing of film clips. During anger recall, both greater left frontal EEG response (r=-0.46, P<0.02) and greater right frontal EEG response (r=-0.45, P<0.02) were correlated significantly with increased HR reactivity during the task. In addition, a right lateralized frontal EEG response during anger-inducing tasks was associated with greater concomitant systolic BP (P<0.03) and diastolic BP (P<0.008) reactivity. Exploratory analyses also indicated that men who displayed a left lateralized frontal EEG response during happiness-inducing tasks showed the greatest concomitant systolic BP and HR reactivity (Ps<0.03). These findings suggest that asymmetric frontal EEG responses to emotional arousal may elicit different patterns of cardiovascular reactivity in healthy adults.

Prognostic value of mental stress testing in coronary artery disease

This study assesses the prognostic value of mental stress-induced ischemic left ventricular wall motion abnormalities and hemodynamic responses in patients with stable coronary artery disease (CAD). Seventy-nine patients (76 men and 3 women) with prior positive exercise test results were exposed to mental arithmetic and a simulated public speech stress in 2 prior studies. Ischemic wall motion abnormalities were monitored using echocardiography or radionuclide ventriculography (RNV). During mental stress testing, new or worsened ischemic wall motion abnormalities to mental stress and exercise were ascertained, as were peak changes in blood pressure and heart rate to mental stress. The occurrence of subsequent cardiac events (including cardiac death, nonfatal myocardial infarction, or revascularization procedures) was ascertained. New cardiac events were observed in 28 of 79 patients (35%) after a median follow-up duration of 3.5 years (range 2.7 to 7.3). Survival analysis indicated that 20 of 45 patients with mental stress ischemia (44%) experienced new cardiac events more frequently than those without mental stress ischemia (8 of 34; 23%; p = 0.048). Type of cardiac event did not differ between mental stress-positive and stress-negative patients. After controlling for baseline blood pressure and study group status (echocardiography vs RNV), there was a significantly higher relative risk of subsequent events for patients with high versus low peak stress-induced diastolic blood pressure responses (RR = 2.4, confidence interval 1.1 to 5.2; p = 0.03). These results demonstrate that ischemic and hemodynamic measures obtained from mental stress testing may be useful in assessing prognosis in CAD patients with prior positive exercise test results.

The integration of cardiovascular behavioral medicine and psychoneuroimmunology: New developments based on converging research fields ☆

The immune system plays a role in the progression of coronary artery diseases and its clinical manifestations as acute coronary syndromes. It is well established that psychological factors can act as risk factors for acute coronary syndromes. This review describes psychoneuroimmunological pathways involved in coronary disease progression and documents that the stage of coronary disease is a major determinant of pathophysiological mechanisms accounting for the association between psychological risk factors, immune system parameters, and acute coronary syndromes. Chronic psychological risk factors (e.g., hostility and low socioeconomic status) are important at early disease stages, episodic factors (e.g., depression and exhaustion) are involved in the transition from stable to unstable atherosclerotic plaques, and acute psychological triggers (e.g., mental stress and anger) can promote myocardial ischemia and plaque rupture. The psychoneuroimmunological pathways are described for each of these three types of psychological risk factors for acute coronary syndromes.

Changes in Heart Rate and Heart Rate Variability Before Ambulatory Ischemic Events

Abstract OBJECTIVES The aim of this study was to determine the time course of autonomic nervous system activity preceding ambulatory ischemic events. BACKGROUND Vagal withdrawal can produce myocardial ischemia and may be involved in the genesis of ambulatory ischemic events. We analyzed trajectories of heart rate variability (HRV) 1 h before and after ischemic events, and we examined the role of exercise and mental stress in preischemic autonomic changes. METHODS Male patients with stable coronary artery disease (n = 19; 62.1 ± 9.3 years) underwent 48-h ambulatory electrocardiographic monitoring. Frequency domain HRV measures were assessed for 60 min before and after each of 68 ischemic events and during nonischemic heart rate-matched control periods. RESULTS High-frequency HRV decreased from −60, −20 to −10 min before ischemic events (4.8 ± 1.3; 4.6 ± 1.3; 4.4 ± 1.2 ln [ms2], respectively; p = 0.04) and further from −4, −2 min, until ischemia (4.4 ± 1.3; 4.1 ± 1.3; 3.7 ± 1.2 ln [ms2]; p’s CONCLUSIONS Autonomic changes consistent with vagal withdrawal can act as a precipitating factor for daily life ischemia, particularly in episodes triggered by mental activities.

Effects of mental stress on flow-mediated brachial arterial dilation and influence of behavioral factors and hypercholesterolemia in subjects without cardiovascular disease.

Mental and emotional arousal are known to trigger coronary events. The relation between hypercholesterolemia, behavioral factors, and mental stress-induced alterations in endothelial function are not well defined. Flow-mediated brachial arterial vasodilation has been established as a measure of arterial endothelial function. High-resolution ultrasound was used to measure mental stress-mediated, flow-mediated, and the combination of mental stress- and flow-mediated brachial artery dilation in 38 subjects, 20 of whom had total cholesterol levels > or =200 mg/dl. Mental stress was provoked by anger recall and mental arithmetic and trait hostility were assessed using the Cook-Medley scale. Under mental stress, participants with hypercholesterolemia showed less vasodilation than participants without hypercholesterolemia, even after adjustment for age and the magnitude of blood pressure response to mental stress. Mental stress attenuated flow-mediated brachial arterial vasodilation. There was an inverse relation between hostile affect and percent change in brachial artery diameter after mental stress combined with hyperemia (r = -0.57, p <0.001). Thus, hypercholesterolemia is associated with impaired vasodilation in response to mental stress. Mental stress inhibits flow-mediated vasodilation in normal subjects and those with hypercholesterolemia. The magnitude of this inhibition is associated with hostility.