Early-life inflammation pathways trigger a cascade leading to development of atherosclerotic plaque through the "butterfly effect" - An hypothesis.

Atherosclerosis is a common disease whose complications, such as myocardial infarction, are a leading cause of mortality worldwide. Therefore, ideas which try to explain the circumstances of atherosclerotic plaque initiation and progression are warranted. We hypothesize that low-grade inflammation in early life (especially an imbalance between pro- and anti-inflammatory macrophages) triggers a "butterfly effect" within the arterial wall by initiating a sequence of processes that finally leads to atherosclerotic plaque development and progression. Therefore, pharmacological and non-pharmacological interventions aimed to prevent atherosclerosis development should be applied not only in the adult population over 40 years old (according to current American and European guidelines) but should start in early life.

Aldosterone and mineralocorticoid receptors in regulation of the cardiovascular system and pathological remodelling of the heart and arteries.

In the review we discuss the role of mineralocorticoid receptors (MRs) in regulation and pathological remodelling of the cardiovascular system and the therapeutic potential of pharmacological targeting of MRs in cardiovascular diseases. MRs are expressed in organs involved in cardiovascular homeostasis: brain, heart, kidneys and vessels. The excessive activation of MRs has deleterious effects on the cardiovascular system through sympatho-excitation, elevated salt appetite, and renal retention of salt with consequent positive sodium balance, fibrosis and remodelling of the heart and arteries, and with propensity for atrial and ventricular arrhythmias. Hence, it provides basis for a common pathophysiological milieu of hypertension and heart failure. Furthermore, MR-mediated changes in the cardiovascular system are potentiated by renin-angiotensin system and activation of angiotensin type 1 receptors. Due to low selectivity, MRs bind both aldosterone and GCs - cortisol in humans and corticosterone in laboratory rodents. The binding of GCs to MRs is determined by availability of tissue specific 11ß-hydroxysteroid dehydrogenase of type 1 (11ß-HSD1) or type 2 (11ß-HSD2). 11ß-HSD1 metabolizes GCs to either active or inactive metabolites depending on the presence of special cofactors, whereas 11ß-HSD2 transforms GCs only into inactive metabolites allowing for selective stimulation of MRs by aldosterone. 11ß-HSD2 is expressed in the vascular wall, renal epithelium and some groups of cardiovascular neurons in the brain. In contrast, cardiac expression of 11ß-HSD2 is low, thus, both aldosterone and GCs interact with cardiac MRs. The importance of MRs in the cardiovascular pathology is reflected in clinical guidelines that recommend use of MR blockers, spironolactone and eplerenone, in the treatment of heart failure, myocardial infarction and hypertension. Furthermore, new MR blockers and selective inhibitors of 11ß-HSD1 have been developed and are currently tested in clinical trials.

Angiotensin converting enzyme inhibition reduces cardiovascular responses to acute stress in myocardially infarcted and chronically stressed rats.

Previous studies showed that chronically stressed and myocardially infarcted rats respond with exaggerated cardiovascular responses to acute stress. The present experiments were designed to elucidate whether this effect can be abolished by treatment with the angiotensin converting enzyme (ACE) inhibitor captopril. Sprague Dawley rats were subjected either to sham surgery (Groups 1 and 2) or to myocardial infarction (Groups 3 and 4). The rats of Groups 2 and 4 were also exposed to mild chronic stressing. Four weeks after the operation, mean arterial blood pressure (MABP) and heart rate (HR) were measured under resting conditions and after application of acute stress. The cardiovascular responses to the acute stress were determined again 24 h after administration of captopril orally. Captopril significantly reduced resting MABP in each group. Before administration of captopril, the maximum increases in MABP evoked by the acute stressor in all (infarcted and sham-operated) chronically stressed rats and also in the infarcted nonchronically stressed rats were significantly greater than in the sham-operated rats not exposed to chronic stressing. These differences were abolished by captopril. The results suggest that ACE may improve tolerance of acute stress in heart failure and during chronic stressing.

The effect of blockade of the central V1 vasopressin receptors on anhedonia in chronically stressed infarcted and non-infarcted rats.

Chronic mild stress (CMS) and myocardial infarction (MI) induce anhedonia, which is one of the symptoms of depression. The purpose of this study was to determine the role of the central V1 vasopressin receptors (V1R) in post-CMS and post-MI anhedonia. To this end, we investigated the effect of blockage the central V1R [28days of intracerebroventricular (ICV) infusion of V1 receptors antagonist (V1RANT)] on CMS-induced and the post-infarct anhedonia. The experiments were conducted on conscious MI or sham-operated (SO) rats that were either exposed to CMS for 20days or remained at rest. The sucrose/water intake ratio (S/W) was measured to determine hedonic behavior. Seven days after MI, the S/W was reduced. This effect was no longer present 37days after the infarction and was also absent in the SO rats. Exposure to CMS reduced the S/W in SO rats also. In the CMS-exposed MI rats, the S/W was similar to that in the CMS-exposed SO rats. ICV administration of V1RANT abolished reductions in the S/W in the CMS-exposed MI rats, however, it did not influence S/W in the SO rats exposed to CMS and in the MI and SO rats not exposed to CMS. We conclude that: (1) myocardial infarction and chronic stressing cause anhedonia, (2) myocardial infarction-induced anhedonia appears to be transient, (3) myocardial infarction does not potentiate CMS-induced anhedonia, and (4) CMS-induced anhedonia critically depends on the stimulation of the central V1 receptors.