Atherosclerosis is a chronic inflammatory disease, in which the immune system has a prominent role in its development and progression. Inflammation-induced endothelial dysfunction results in an increased permeability to lipoproteins and their subendothelial accumulation, leukocyte recruitment, and platelets activation. Recruited monocytes differentiate into macrophages which develop pro- or anti-inflammatory properties according to their microenvironment. Atheroma progression or healing is determined by the balance between these functional phenotypes. Macrophages and smooth muscle cells secrete inflammatory cytokines including interleukins IL-1β, IL-12, and IL-6. Within the arterial wall, low-density lipoprotein cholesterol undergoes an oxidation. Additionally, triglyceride-rich lipoproteins and remnant lipoproteins exert pro-inflammatory effects. Macrophages catabolize the oxidized lipoproteins and coalesce into a lipid-rich necrotic core, encapsulated by a collagen fibrous cap, leading to the formation of fibro-atheroma. In the conditions of chronic inflammation, macrophages exert a catabolic effect on the fibrous cap, resulting in a thin-cap fibro-atheroma which makes the plaque vulnerable. However, their morphology may change over time, shifting from high-risk lesions to more stable calcified plaques. In addition to conventional cardiovascular risk factors, an exposure to acute and chronic psychological stress may increase the risk of cardiovascular disease through inflammation mediated by an increased sympathetic output which results in the release of inflammatory cytokines. Inflammation is also the link between ageing and cardiovascular disease through increased clones of leukocytes in peripheral blood. Anti-inflammatory interventions specifically blocking the cytokine pathways reduce the risk of myocardial infarction and stroke, although they increase the risk of infections.

Many patients with chest pain undergoing coronary angiography do not show significant obstructive coronary lesions. A substantial proportion of these patients have abnormalities in the function and structure of coronary microcirculation due to endothelial and smooth muscle cell dysfunction. The coronary microcirculation has a fundamental role in the regulation of coronary blood flow in response to cardiac oxygen requirements. Impairment of this mechanism, defined as coronary microvascular dysfunction (CMD), carries an increased risk of adverse cardiovascular clinical outcomes. Coronary endothelial dysfunction accounts for approximately two-thirds of clinical conditions presenting with symptoms and signs of myocardial ischemia without obstructive coronary disease, termed “ischemia with non-obstructive coronary artery disease” (INOCA) and for a small proportion of “myocardial infarction with non-obstructive coronary artery disease” (MINOCA). More frequently, the clinical presentation of INOCA is microvascular angina due to CMD, while some patients present vasospastic angina due to epicardial spasm, and mixed epicardial and microvascular forms. CMD may be associated with focal and diffuse epicardial coronary atherosclerosis, which may reinforce each other. Both INOCA and MINOCA are more common in females. Clinical classification of CMD includes the association with conditions in which atherosclerosis has limited relevance, with non-obstructive atherosclerosis, and with obstructive atherosclerosis. Several studies already exist which support the evidence that CMD is part of systemic microvascular disease involving multiple organs, such as brain and kidney. Moreover, CMD is strongly associated with the development of heart failure with preserved ejection fraction (HFpEF), diabetes, hypertensive heart disease, and also chronic inflammatory and autoimmune diseases. Since coronary microcirculation is not visible on invasive angiography or computed tomographic coronary angiography (CTCA), the diagnosis of CMD is usually based on functional assessment of microcirculation, which can be performed by both invasive and non-invasive methods, including the assessment of delayed flow of contrast during angiography, measurement of coronary flow reserve (CFR) and index of microvascular resistance (IMR), evaluation of angina induced by intracoronary acetylcholine infusion, and assessment of myocardial perfusion by positron emission tomography (PET) and magnetic resonance (CMR).

Epidemiological studies have shown that a substantial proportion of acute coronary events occur in individuals who lack the traditional high-risk cardiovascular (CV) profile. Mental stress is an emerging risk and prognostic factor for coronary artery disease and stroke, independently of conventional risk factors. It is associated with an increased rate of CV events. Acute mental stress may develop as a result of anger, fear, or job strain, as well as consequence of earthquakes or hurricanes. Chronic stress may develop as a result of long-term or repetitive stress exposure, such as job-related stress, low socioeconomic status, financial problems, depression, and type A and type D personality. While the response to acute mental stress may result in acute coronary events, the relationship of chronic stress with increased risk of coronary artery disease (CAD) is mainly due to acceleration of atherosclerosis. Emotionally stressful stimuli are processed by a network of cortical and subcortical brain regions, including the prefrontal cortex, insula, amygdala, hypothalamus, and hippocampus. This system is involved in the interpretation of relevance of environmental stimuli, according to individual’s memory, past experience, and current context. The brain transduces the cognitive process of emotional stimuli into hemodynamic, neuroendocrine, and immune changes, called fight or flight response, through the autonomic nervous system and the hypothalamic–pituitary–adrenal axis. These changes may induce transient myocardial ischemia, defined as mental stress-induced myocardial ischemia (MSIMI) in patients with and without significant coronary obstruction. The clinical consequences may be angina, myocardial infarction, arrhythmias, and left ventricular dysfunction. Although MSIMI is associated with a substantial increase in CV mortality, it is usually underestimated because it arises without pain in most cases. MSIMI occurs at lower levels of cardiac work than exercise-induced ischemia, suggesting that the impairment of myocardial blood flow is mainly due to paradoxical coronary vasoconstriction and microvascular dysfunction.

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Endothelial dysfunction is one of the earliest manifestations of atherosclerosis, contributing to its development and progression. Mental stress induces endothelial dysfunction through increased activity of the sympathetic nervous system, release of corticotropin-releasing hormone from the hypothalamus, inhibition of nitric oxide (NO) synthesis by cortisol, and increased levels of pro-inflammatory cytokines. Mental-stress-induced increased output of the sympathetic nervous system and concomitant withdrawal of the parasympathetic inflammatory reflex results in systemic inflammation and activation of a neural–hematopoietic–arterial axis. This includes the brainstem and subcortical regions network, bone marrow activation, release of leukocytes into the circulation and their migration to the arterial wall and atherosclerotic plaques. Low-grade, sterile inflammation is involved in all steps of atherogenesis, from coronary plaque formation to destabilisation and rupture. Increased sympathetic tone may cause arterial smooth-muscle-cell proliferation, resulting in vascular hypertrophy, thus contributing to the development of hypertension. Emotional events also cause instability of cardiac repolarisation due to brain lateralised imbalance of cardiac autonomic nervous stimulation, which may lead to asymmetric repolarisation and arrhythmia. Acute emotional stress can also provoke severe catecholamine release, leading to direct myocyte injury due to calcium overload, known as myocytolysis, coronary microvascular vasoconstriction, and an increase in left ventricular afterload. These changes can trigger a heart failure syndrome mimicking acute myocardial infarction, characterised by transient left ventricular dysfunction and apical ballooning, known as stress (Takotsubo) cardiomyopathy. Women are more prone than men to develop mental-stress-induced myocardial ischemia (MSIMI), probably reflecting gender differences in brain activation patterns during mental stress. Although guidelines on CV prevention recognise psychosocial factors as risk modifiers to improve risk prediction and decision making, the evidence that their assessment and treatment will prevent CAD needs further evaluation.

The definition of normal values of two-dimensional speckle-tracking echocardiography derived left ventricular (LV) deformation parameters, is of critical importance for the routine application of this modality in children. The objectives of this study were to perform a meta-analysis of normal ranges for longitudinal, circumferential and radial strain/strain rate values and to identify confounders that may contribute to differences in reported measures. A systematic search was conducted. Studies describing normal healthy subjects and observational studies that used control groups as a comparison were included. Data were combined using a random-effect model. Effects of demographic, clinical and equipment variables were assessed through meta-regression. The search identified 1,192 subjects form 28 articles. Longitudinal strain (LS) normal mean values varied from -12.9 to -26.5 (mean, -20.5; 95% CI, -20.0 to -21.0). Normal mean values of circumferential strain (CS) varied from -10.5 to -27.0 (mean, -22.06; 95% CI, -21.5 to -22.5). Radial strain (RS) normal mean values varied from 24.9 to 62.1 (mean, 45.4; 95% CI, 43.0 to 47.8). Meta-regression showed LV end diastolic diameter as a significant determinant of variation for LS. Longitudinal systolic strain rate (LSRs) was significantly determined by the age and RS by the type of vendor used. Variations among different normal ranges were dependent on the vendor used, LV end-diastolic diameter and age. Vendor-independent software for analyzing myocardial deformation in children, using images from different vendors would be the ideal solution for strain measurements or else using the same system for patient’s follow up.