Researchers-again-pinpoint why stress kills
As Valentine’s Day approaches, one prevailing argument for marriage may well be that studies show married people are less depressed than their single counterparts. Behind this string of scientific reasoning for matrimony is a proven fact: the prevalence of depression in patients with coronary artery disease (e.g., myocardial infarction and heart failure) is approximately five times that of the general population.
Major depression is a significant predictor of mortality after myocardial infarction. Its predictive ability on subsequent cardiovascular events, for example, myocardial infarction, arrhythmias, ischemia, or sudden cardiac death, is comparable to that of left ventricular dysfunction, previous myocardial infarction, and smoking. Even more alarming is the finding that depression is a significant risk factor for coronary artery disease in patients without a history of heart disease. In other words, the risk for a heart attack or other cardiac disease for depressed but otherwise healthy patients is similar to the risk for patients with established cardiovascular disease.
Gender does play a role. Psychological depression is a common mood disorder affecting 2–3% of males and 5–9% of females. Depression is the leading cause of disability worldwide (quantified by years lived with a disease) and is exceeded only by coronary artery disease as the leading cause of disability in the United States. So, in addition to all the social and medical costs of depression, the disorder is considered a risk factor for coronary artery disease.
Why? Past studies to establish the link between cardiac disease and depression have focused on hypothalamic-pituitary-adrenal axis dysfunction associated with increased sympathetic activation, an imbalance in parasympathetic and sympathetic inputs to the heart (i.e., increased sympathetic tone and/or decreased parasympathetic tone), manifest as reduced heart rate variability, and altered serotonin activity affecting platelet function.
Scientists have noted an important interaction between stress and ventricular arrhythmias, or loss of rhythm to the heart. This relationship has been supported by animal studies and in observation of some human patients with postmyocardial infarction, where the presence of depression in combination with premature ventricular complexes greatly increases the likelihood of a recurrent heart attack.
A New Study
However, none of these suppositions are well established. A team of University of Iowa researchers set out to ascertain whether an increased susceptibility to life-threatening cardiac arrhythmias in depressed patients influences the risk of morbidity and mortality in coronary artery disease. The findings of their research are reported in “Increased Susceptibility to Ventricular Arrhythmias in a Rodent Model of Experimental Depression,” authored by Angela J. Grippo, Claudia M. Santos, Ralph F. Johnson, Terry G. Beltz, James B. Martins, Robert B. Felder, and Alan Kim Johnson, all from the University of Iowa, Iowa City, IA. Their findings appeared in the February 2004 edition of the American Journal of Physiology–Heart and Circulatory Physiology. The journal is one of 14 peer-reviewed scientific journals published each month by the American Physiological Society (www.aps.org).
Because stressful life events are known to be predisposing factors for depression as well as predictors of the severity of depression, the researchers used a stress-induced rodent model of depression to examine the influence of this disorder on ventricular arrhythmias. Chronic mild stress (CMS) is a rodent model of depression that was developed to mimic particular defining features of mood disorders, such as anhedonia (the reduced responsiveness to pleasurable stimuli) and reduced activity level. Behavioral changes are induced via a combination of seemingly mild annoyances or stressors (e.g., strobe light, white noise, damp bedding, and paired housing) presented in an unpredictable manner.
A control group and a CMS group of rats were established. To generate stress, the CMS group was exposed to the following mild stressors each week, in random order: 1) continuous overnight illumination and 40 degree cage tilt along the vertical axis; 2) paired housing; 3) soiled cage; 4) exposure to an empty water bottle immediately after a period of acute water deprivation; 5) stroboscopic illumination; and 6) white noise. The CMS procedure was carried out for a total of four weeks. Control animals were left undisturbed in their home cages with the exception of routine handling (i.e., regular cage cleaning and measuring of body weight), which was matched to that of the CMS group.
This CMS model provided an opportunity to examine a potential link between experimental anhedonia (absence of pleasure from the performance of acts that would ordinarily be pleasurable) and the susceptibility to ventricular arrhythmias in rats. This entailed the employment of aconitine, in rats exposed to CMS. Aconitine is arrhythmogenic in cardiac myocytes due to enhanced sodium influx into myocardial cells on both depolarization and repolarization and as a result of an increase in active Na+ current during depolarization. The utility of aconitine for the study of electrocardiographic activity is well documented. This drug has been used experimentally in anesthetized rats to investigate the vulnerability to ventricular arrhythmias as well as the efficacy of antiarrhythmic drugs.
The researchers found the following:
- Sucrose intake was significantly reduced in rats exposed to four weeks of CMS. The reduced sucrose intake and sucrose preference in the CMS group is a specific indication of decreased responsiveness to a pleasurable stimulus.
- Anhedonic rats displayed elevated heart rate and reduced heart rate variability. These alterations in CMS rats are similar to changes found in human depressed patients as well as results from our laboratory, which describe cardiovascular and behavioral effects associated with CMS in conscious rats.
- Rats that displayed anhedonia in the current study also showed a reduced threshold for specific ventricular arrhythmias after the fourth week of CMS exposure.
The current study was undertaken to determine whether rats with CMS-induced anhedonia (i.e., experimental depression) were more susceptible than control rats to experimentally induced cardiac arrhythmias. Both behavioral and cardiovascular changes were observed in rats exposed to CMS. This stress appears to produce a reduced threshold for ventricular arrhythmias that may signal an increased risk of detrimental cardiovascular outcomes (e.g., myocardial infarction, heart failure, and sudden cardiac death).
The researchers believe that further research should focus on determining the central nervous system mechanisms that are driving the changes in sympathetic tone and susceptibility to cardiac arrhythmias in the CMS model. The use of controlled experimental methods may shed light on the mechanisms that underlie the increased risk for coronary artery disease in individuals with mood disorders, and may aid in the development of beneficial treatments for these patients.
Source: February 2004 edition of the American Journal of Physiology–Heart and Circulatory Physiology.
The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.
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