Resume: A mouse study reveals how depression and chronic stress can impact cholesterol-lowering drugs and influence heart disease risk.
Source: American Heart Association
Results from a new mouse model may help understand how depression and prolonged, severe stress increase the risk of cardiovascular disease, according to preliminary research presented in the American Heart Association’s Vascular Discovery: From Genes to Medicine Scientific Sessions 2022.
“Previous research has shown that major depressive disorders and anxiety due to prolonged and severe stress have been associated with an increased rate of cardiovascular disease. The risk of developing cardiovascular disease increases in proportion to the severity of depression,” said study senior author Özlem Tufanli Kireccibasi, Ph.D., a postdoctoral fellow in the lab of Edward A. Fisher, MD, Ph.D. , MPH, FAHA, at the NYU Grossman School of Medicine Cardiovascular Research Center in New York City.
“When both major depressive disorder and cardiovascular disease are present, the prognosis is worse for both conditions.”
The researchers say theirs is the first study to use a mouse model of chronic stress and depression to investigate whether and how chronic stress can affect cholesterol-lowering drugs.
The researchers examined mice that lacked a low-density lipoprotein receptor (LDLr), which is required to remove LDL (bad) cholesterol from the body. These mice, like people born without the receptor, are prone to developing fatty buildups called plaque in their arteries and are subject to early and aggressive cardiovascular disease.
Unstable plaque (with a tendency to rupture) can rupture and cause blood clots to form that block blood flow, which can lead to a heart attack or stroke. To mimic the development of fatty plaque in people, the mice were fed a high-cholesterol diet for 24 weeks.
Half of the mice were exposed to social stress by sharing their living space with larger, more aggressive mice for short periods of time over 10 days. After each stress episode, the mice were assessed for social avoidance behaviors and for depression or anxiety.
The mice that displayed the behaviors were classified as susceptible (depressed) and the others were classified as resistant (effective coping). The other half of the mice (controls) were not exposed to social stress.
Both susceptible (depressed) mice and control mice were treated with an LDL-lowering drug for 3 weeks, to mimic cholesterol treatment in humans. Previous studies have found that when LDLr-deficient mice are treated with lipid-lowering drugs, arterial plaque becomes less inflammatory and more stable.
After treatment, changes in the number of inflammatory cells in the mice’s plaque, the number of inflammatory white blood cells (monocytes) circulating in the blood, and the number of bone marrow cells, which are precursors of monocytes, were analyzed. abundant immune cells. on plate.
Resistant mice were similarly tested, however, testing for this group of mice is ongoing.
The analyzes found that, compared to the mice not exposed to stress (the control group), the susceptible (depressed) mice in the group exposed to social stress had:
- 50% increase in immune cells within the plaque in your arteries;
- double the number of circulating monocytes, which are precursors of inflammatory cells;
- 80% increase in the number of immune cell precursors in the bone marrow;
- less collagen within the plaque in the arteries, which is an indicator of instability; Y
- a similar reduction in lipid levels compared to the response of control groups 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 induced by lipid-lowering drugs,” said Tufanli Kireccibasi.
The researchers also looked at whether differences in the bone marrow of the depressed mice might underlie differences in plaque size and characteristics.
To test this, another group of LDLr-deficient mice received a bone marrow transplant from susceptible (depressed) mice or from the control group.
After bone marrow transplantation, the mice were fed a high-cholesterol diet for 24 weeks.
Compared to mice receiving bone marrow from the control group (no stress), mice receiving bone marrow from the susceptible group had:
- 16% increase in immune cell precursors in the bone marrow;
- 50% greater increase in inflammatory monocytes in the blood; Y
- there was no change in plaque size, but there was a change in plaque composition, with 23% more inflammation within plaques.
“Taking all of our results together, we suggest that in situations where there is chronic stress, the adverse effects of high cholesterol may be increased and the benefits of low cholesterol may be decreased.
“This suggests that chronic stress mediates reprogramming at the genetic level, called epigenetic changes, in monocyte precursors in the bone marrow, so that when the cells enter the plaques they are already more inflammatory,” said Tufanli Kireccibasi.
This mouse model may provide a way to investigate and improve the treatment of depression and prolonged stress, and in turn improve cardiovascular outcomes.
“These findings may indicate that more attention to mental health is needed to combat cardiovascular disease, particularly 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 plaque resolution pathways.
“These therapies have great potential to benefit people with cardiovascular disease, and probably particularly people with depression,” said Tufanli Kireccibasi.
The researchers are currently collecting samples from mice that were exposed to the same repeated stress but seemed to resist it.
“We will perform the same analyzes as this study to determine if it is stress exposure or susceptibility to stress that causes changes in plaque that lead to decreased or worsened plaque,” said Tufanli Kireccibasi.
Coauthors are Bianca Scolaro, Ph.D.; Ada Weinstock, Ph.D.; Angelica Torres Berrio, Ph.D.; Eric Parise, PhD; Flurin Cathomas, MD; Kenny Chan, PhD; Eric J. Nestler, MD, Ph.D.; Scott J. Russo, Ph.D.; and Edward A. Fisher, MD, Ph.D., MPH, FAHA. Authors’ declarations are listed in the abstract.
About this mental health and heart disease research news
original research: The findings will be presented at the American Heart Association’s Vascular Discovery: From Genes to Medicine Scientific Sessions 2022.