Chronic intermittent mental stress promotes atherosclerotic plaque vulnerability, myocardial infarction and sudden death in mice
Introduction
Atherosclerosis is a progressive inflammatory disease of the large and medium-sized arteries, characterized by the formation of plaques in the vessel wall. During the development of the disease, the stability of the atherosclerotic plaque plays a major role. Features of plaque instability include a large necrotic core, a high infiltration of inflammatory macrophages and a thin fibrous cap, composed of few smooth muscle cells (SMCs) and collagen fibers. When a plaque develops such an unstable phenotype, it may easily rupture, leading to thrombosis and subsequent myocardial infarction, stroke or even sudden death [16], [17], [34]. Despite the significant therapeutic advances in cardiology over the past decades, atherosclerotic plaque rupture remains a leading cause of acute cardiovascular death. Therefore, investigating risk factors of atherosclerosis is very important because it may lead to new therapeutic targets or prevention methods.
Recent evidence suggests that mental stress is an important trigger for atherosclerosis and its complications [29], [31]. For instance, grieving over the death of a loved-one, the recession of the stock market but also major sporting events, can increase the risk of an acute myocardial infarction [6], [15], [21]. Moreover, marital stress and job insecurity can have a negative influence on coronary health [5], [26].
The aim of this study was to determine the impact of chronic intermittent mental stress on atherosclerotic plaque stability and cardiovascular mortality. To this end, apolipoprotein E deficient mice (ApoE−/−) with a heterozygous mutation in the fibrillin-1 gene (Fbn1C1039G+/−) were used. Recently, we reported that this unique mouse model shows an accelerated plaque progression, spontaneous plaque ruptures, myocardial infarction and sudden death [32], [33]. Therefore, it is an adequate model to study the effects of mental stress on plaque vulnerability and the occurrence of myocardial infarctions.
Section snippets
Mice
Female ApoE−/−Fbn1C1039G+/− mice were fed a Western-type diet (WD; TD88137, Harlan Teklad) starting at an age of 6 weeks. The animals were housed in a temperature-controlled room with a 12-h light/dark cycle and had free access to water and food. Cases of sudden death were documented. At the end of the experiment (25 weeks WD), plasma samples were obtained from the retro-orbital plexus of anesthetized mice (sodium pentobarbital 75 mg/kg, i.p.). Subsequently, the mice were sacrificed with sodium
Plasma corticosterone and aldosterone, body weight and total plasma cholesterol
Both plasma corticosterone and aldosterone levels were significantly higher (2–3 times) in mice subjected to chronic intermittent mental stress as compared to controls (Table 1).
Control and stress ApoE−/−Fbn1C1039G+/− mice were weighed at the beginning and end of each 5-day stress period. Control mice did not show significant fluctuations, but stressed mice revealed weight loss after each mental stress period of 5 days. At the start of the following stress period (i.e. after 2 recovery days),
Discussion
Mental stress is considered a strong risk factor for cardiovascular disease [3], [12], [23] and our data provide direct evidence that it is associated with plaque vulnerability, myocardial infarction and death.
Mental stress can exert its effects by activating two main pathways. The first pathway is the sympathetic nervous system (SNS), which results in an increased heart rate, blood pressure, myocardial oxygen consumption and thrombogenicity [2], [12]. Moreover, the release of noradrenaline
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Acknowledgments
The authors like to thank Rita Van den Bossche, Hermine Fret, Anne-Elise Van Hoydonck, Frieda Franck, Sanne Lauryssen, Tinne Koninckx and Inge Bats for technical support. This study was funded by the University of Antwerp (BOF) and the Fund for Scientific Research (FWO)-Flanders (G.0126.11). Lynn Roth is a fellow of the FWO-Flanders.
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