Summary: Mouse study shows how depression and chronic stress may affect cholesterol-lowering drugs and heart disease risk.
Source: American Heart Association
Results from a new mouse model may help understand how depression and prolonged and severe stress increase cardiovascular disease risk, according to preliminary research presented at the American Heart Association’s Vascular Discovery: From Genes to Medicine Scientific Sessions 2022.
“Previous research has shown that depressive disorders and anxiety resulting from prolonged and severe stress have been linked to an increased rate of cardiovascular disease. The risk of developing cardiovascular disease increases in proportion to the severity of depression said lead study author Özlem Tufanli Kireccibasi, Ph.D., a postdoctoral researcher in the lab of Edward A. Fisher, MD, Ph.D., MPH, FAHA, in the Cardiovascular Research Center at the NYU Grossman School of Medicine in New York City.
“If both major depressive disorder and cardiovascular disease are present, the prognosis for both conditions is worse.”
The researchers say their study is the first to use a mouse model of chronic stress and depression to investigate whether and how chronic stress may affect cholesterol-lowering drugs.
Researchers examined mice without a low-density lipoprotein receptor (LDLr), which is needed to remove LDL (bad) cholesterol from the body. These mice, like humans born without the receptor, are prone to developing fatty deposits called plaque in their arteries and are subject to premature and aggressive cardiovascular disease.
Unstable plaque (which is prone to rupture) can break down, creating blood clots that block blood flow, leading to a heart attack or stroke. To mimic the development of fatty plaque in humans, the mice were fed a cholesterol-rich diet for 24 weeks.
Half of the mice were exposed to social stress by sharing their living space with other larger, aggressive mice for ten days. After each stress episode, the mice were evaluated for social avoidance and depression-like or anxiety-like behavior.
The mice that showed the behavior were classified as susceptible (depressed) and the others were classified as resilient (effective coping). The other half of the mice (controls) were not exposed to social stress.
Both the susceptible (depressed) mice and the control mice were treated for 3 weeks with an LDL-lowering drug to mimic cholesterol treatment in humans. Previous studies have shown that when LDLr-deficient mice are treated with lipid-lowering drugs, arterial plaque becomes less inflammatory and more stable.
After treatment, the mice were tested for changes in the number of inflammatory cells in their plaque, the number of inflammatory white blood cells (monocytes) circulating in the blood, and the number of bone marrow cells, which are precursors to the immune cells that are abundant. on plaque.
The resilient mice were similarly evaluated, but analyzes for this group of mice are ongoing.
The analyzes showed that, compared with mice not exposed to stress (the control group), the sensitive (depressed) mice from the group exposed to social stress:
- 50% higher rise of immune cells in plaque in their arteries;
- double the number of circulating monocytes, which are precursors of inflammatory cells;
- 80% increase in the number of immune cell precursors in bone marrow;
- less collagen in plaque in the arteries, which is an indicator of instability; and
- a similar reduction in lipid levels compared to the response of the control group to LDL-lowering medication.
“The main finding is that repeated stress and the physiological and behavioral effects of hostile interactions (social defeat) appear to prevent the full beneficial changes in plaques that should be caused by lipid-lowering drugs,” Tufanli Kireccibasi said.
The researchers also analyzed whether differences in the bone marrow of the depressed mice may underlie the differences in plaque size and characteristics.
To test this, another group of LDLr-deficient mice received bone marrow transplanted from either the susceptible (depressed) mice or the control group.
After the bone marrow transplant, the mice were fed the cholesterol-rich diet for 24 weeks.
Compared to mice that received bone marrow from the control group (no stress), the mice that received bone marrow from the susceptible group had:
- 16% greater increase in immune cell precursors in bone marrow;
- 50% greater increase in inflammatory monocytes in the blood; and
- no change in plaque size, but in plaque composition, with 23% more inflammation in the plaques.
“Summarizing all our results, we suggest that in situations where there is chronic stress, the adverse effects of high cholesterol may be enhanced and the benefits of low cholesterol reduced.
“This suggests that chronic stress mediates reprogramming at the genetic level, called epigenetic changes, in monocyte bone marrow precursors so that when the cells invade plaques, they are already more inflammatory,” Tufanli Kireccibasi said.
This mouse model may provide a way to investigate and improve the treatment of depression and long-term stress and in turn improve cardiovascular outcomes.
“These findings may indicate that a greater focus on mental health is needed to fight cardiovascular disease, especially for people with depression or chronic stress. In the coming decades, new therapies for atherosclerosis should focus on altering immune responses, inhibiting inflammation and promoting pathways of plaque resolution.
“These therapies have great potential for people with cardiovascular disease, and probably especially those with depression,” Tufanli Kireccibasi said.
The researchers are currently collecting samples from mice that had been subjected to the same repeated stress, but appeared to be resilient to it.
“We will conduct the same analyzes as this study to determine whether stress exposure or susceptibility to it causes changes in plaque that lead to reduction or deterioration of plaque,” said Tufanli Kireccibasi.
Co-authors are Bianca Scolaro, Ph.D.; Ada Weinstock, Ph.D.; Angelica Torres Berrio, Ph.D.; Eric Parise, Ph.D.; Flurin Cathomas, MD; Kenny Chan, Ph.D.; Eric J. Nestler, MD, Ph.D.; Scott J. Russo, Ph.D.; and Edward A. Fisher, MD, Ph.D., MPH, FAHA. The authors’ disclosures are listed in the abstract.
About this research news on mental health and heart disease
Writer: press office
Source: American Heart Association
Contact: Press Office – American Heart Association
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Original research: The findings will be presented at the American Heart Association’s Vascular Discovery: From Genes to Medicine Scientific Sessions 2022