How Does Stress Increase Your Risk for Stroke and Heart Attack?

Scientists have shown that anger, anxiety, and depression not only affect the functioning of the heart, but also increase the risk for heart disease.

Stroke and heart attacks are the end products of progressive damage to blood vessels supplying the heart and brain, a process called atherosclerosis. Atherosclerosis progresses when there are high levels of chemicals in the body called pro-inflammatory cytokines.

It is thought that persisting stress increases the risk for atherosclerosis and cardiovascular disease by evoking negative emotions that, in turn, raise the levels of pro-inflammatory chemicals in the body.

Researchers have now investigated the underlying neural circuitry of this process, and report their findings in the current issue of Biological Psychiatry.

“Drawing upon the observation that many of the same brain areas involved in emotion are also involved in sensing and regulating levels of inflammation in the body, we hypothesized that brain activity linked to negative emotions – specifically efforts to regulate negative emotions – would relate to physical signs of risk for heart disease,” explained Dr. Peter Gianaros, Associate Professor at the University of Pittsburgh and first author on the study.

To conduct the study, Gianaros and his colleagues recruited 157 healthy adult volunteers who were asked to regulate their emotional reactions to unpleasant pictures while their brain activity was measured with functional imaging. The researchers also scanned their arteries for signs of atherosclerosis to assess heart disease risk and measured levels of inflammation in the bloodstream, a major physiological risk factor for atherosclerosis and premature death by heart disease.

They found that individuals who show greater brain activation when regulating their negative emotions also exhibit elevated blood levels of interleukin-6, one of the body’s pro-inflammatory cytokines, and increased thickness of the carotid artery wall, a marker of atherosclerosis.

The inflammation levels accounted for the link between signs of atherosclerosis and brain activity patterns seen during emotion regulation. Importantly, the findings were significant even after controlling for a number of different factors, like age, gender, smoking, and other conventional heart disease risk factors.

“These new findings agree with the popular belief that emotions are connected to heart health,” said Gianaros. “We think that the mechanistic basis for this connection may lie in the functioning of brain regions important for regulating both emotion and inflammation.”

These findings may have implications for brain-based prevention and intervention efforts to improve heart health and protect against heart disease.”

“It is remarkable to see the links develop between negative emotional states, brain circuits, inflammation, and markers of poor physical health,” said Dr. John Krystal, Editor of Biological Psychiatry. “As we identify the key mechanisms linking brain and body, we may be able to also break the cycle through which stress and depression impair physical health.”

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Testing method promising for spinal cord injuries, multiple sclerosis

A medical test previously developed to measure a toxin found in tobacco smokers has been adapted to measure the same toxin in people suffering from spinal cord injuries and multiple sclerosis, offering a potential tool to reduce symptoms.

The toxin, called acrolein, is produced in the body after nerve cells are injured, triggering a cascade of biochemical events thought to worsen the injury’s severity. Acrolein (pronounced a-KRO-le-an) also may play an important role in multiple sclerosis and other conditions.

Because drugs already exist to reduce the concentration of acrolein in the body, being able to detect and measure it non-invasively represents a potential treatment advance, said Riyi Shi (pronounced Ree Shee), a professor of neuroscience and biomedical engineering in Purdue University’s Department of Basic Medical Sciences, School of Veterinary Medicine, Center for Paralysis Research and Weldon School of Biomedical Engineering.

"If the acrolein level is high it needs to be reduced, and we already have effective acrolein removers to do so," Shi said. "Reducing or removing acrolein may lessen the severity of symptoms in people who have nerve damage, but there has not been a practical way to monitor acrolein levels in nervous system trauma and diseases."

The toxin is present in tobacco smoke and air pollutants. A method had been developed previously to detect and measure acrolein in the urine of smokers, but it has not been used in people suffering from conditions in which the body produces acrolein internally.

"Based on this method, it was revealed that acrolein is significantly elevated in smokers and decreases following the cessation of cigarette smoke," Shi said. "However, such a method has not been widely used for conditions in which acrolein is elevated due to central nervous system damage or disease."

The researchers tested the method in laboratory animals.

"We wanted to see if higher levels of acrolein corresponds to greater severity of spinal cord injury, and the answer is yes," said Shi, who is working with Bruce Cooper, director of the Metabolite Profiling Facility in the Bindley Bioscience Center of Purdue’s Discovery Park. "This means reducing acrolein may help to control symptoms."

New findings are detailed in a research paper that recently appeared online in the Journal of Neurotrauma. The paper, which also will appear in an upcoming print edition of the journal, was authored by doctoral students Lingxing Zheng, Jonghyuck Park, Michael Walls and Melissa Tully; Amber Jannasch, laboratory manager of the Metabolite Profiling Facility; and Cooper and Shi.

The method does not detect acrolein directly but determines the presence of a byproduct, or metabolite, of acrolein in the urine. The metabolite is a chemical compound called N-acetyl-S-3-Hydroxypropylcysteine, or 3-HPMA.

"Acrolein is very volatile, so it doesn’t remain stable long enough to monitor, but one molecule of acrolein will make one molecule of 3-HPMA, which is very stable in urine," Shi said.

Laboratory rats were injected with different doses of acrolein, and findings showed that the detection technique is able to accurately measure these differences in acrolein concentration in the urine. The technique might one day be performed routinely in a doctor’s office.

"The non-invasive nature of measuring 3-HPMA concentrations in urine allows for long-term monitoring of acrolein in the same animal and ultimately in human clinical studies," Shi said.

Two drugs have been shown to be effective in reducing acrolein levels in the body: hydralazine and phenelzine, which have been approved by the U.S. Food and Drug Administration for hypertension and depression, respectively.

The testing method could be used in conjunction with other measures to test patients for the progress of spinal cord disease.

"Nervous system trauma and diseases are like many other illnesses: A disease-associated marker can be critical for making a diagnosis, a therapeutic selection and a treatment evaluation," Shi said. "Therefore, determination of acrolein levels gives you more assurance that you have an intense biochemical imbalance and biochemical damage and that you should use an acrolein scavenger as a treatment. We used different levels of hydralazine to see if it causes a dose-dependent reduction of 3-HPMA and found that, in fact, it did. This shows that this method is capable of monitoring the decrease of acrolein through treatment with acrolein-removing medications."

Acrolein damages mitochondria, which provide energy for cells, and in multiple sclerosis compromises the myelin sheath surrounding a nerve cell’s axon, preventing nerves from properly conducting electrical impulses. The toxin has a possible role in other diseases, including Alzheimer’s disease, cancer and atherosclerosis.

"Due to widespread involvement of acrolein in the body, the benefits of this study have the potential to significantly enhance human health," Shi said. "For example, there is evidence that heightened levels of acrolein could diminish an individual’s ability to recover fully from stroke and cancer."

In laboratory animals, hydralazine has been shown to delay onset of multiple sclerosis for several days, which could mean several years in humans. Tests with animals also suggests the drug could help to reduce the most severe symptoms once the disease has progressed.

Acrolein has been found to be elevated by about 60 percent in the spinal cord tissues of mice with a disease similar to multiple sclerosis. The toxin causes harm by reacting with the proteins and lipids that make up cells, including neurons.