Recent findings have deeply changed the current view of coronary heart disease, going beyond the simplistic model of atherosclerosis as a passive process involving cholesterol build-up in the subintimal space of the arteries until their final occlusion and/or thrombosis and instead focusing on the key roles of inflammation and the immune system in plaque formation and destabilization. Chronic inflammation is a typical hallmark of cardiac disease, worsening outcomes irrespective of serum cholesterol levels. Low-grade chronic inflammation correlates with higher incidence of several non-cardiac diseases, including depression, and chronic depression is now listed among the most important cardiovascular risk factors for poor prognosis among patients with myocardial infarction. In this review, we include recent evidence describing the immune and endocrine properties of the heart and their critical roles in acute ischaemic damage and in post-infarct myocardial remodeling. The importance of the central and autonomic regulation of cardiac functions, namely, the neuro-cardiac axis, is extensively explained, highlighting the roles of acute and chronic stress, circadian rhythms, emotions and the social environment in triggering acute cardiac events and worsening heart function and metabolism in chronic cardiovascular diseases. We have also included specific sections related to stress-induced myocardial ischaemia measurements and stress cardiomyopathy. The complex network of reciprocal interconnections between the heart and the main biological systems we have presented in this paper provides a new vision of cardiovascular science based on psychoneuroendocrineimmunology. Until a few years ago, atherosclerosis was considered a “lipid storage disease,” and it was expected that aggressive pharmacological treatment of hypercholesterolemia couldvirtually eliminate coronary artery pathologies. However, despite an intensive campaign against classical risk factors, cardiovascular disease remains the first cause of death worldwide, with an increasing prevalence in developing countries.The notion that coronary artery disease can be considered an inflammatory disturbance emerged in the late 1990s . InflammNew insight into atherosclerosis as a complex multifactorial condition highlights the importance of an excessive inflammatory response in the pathogenesis of the fibro-proliferative reaction in the subintimal arterial space and subsequent thrombus formation following various forms of injurious stimuli, leading to an acute coronary event , 4.Common cardiovascular risk factors, such as a high saturated fat diet, smoking, hypertension, hyperglycaemia or insulin resistance, tend to produce chronic inflammation that leads to endothelial activation through impaired nitric oxide (NO) production and loss of vasodilatory and antithrombotic properties of the coronary endothelium , 4.One of the main interests in current cardiovascular research is the identification of inflammatory markers and cellular molecular pathways underlying atherosclerotic diseases in order to develop strategies for prevention and therapy.Although Rudolf Virchow had already recognized the inflammatory nature of atherosclerotic plaques in the nineteenth century , coronarIn a large clinical trial it was observed that serum high-sensitivity C-reactive protein (hs-CRP), the principle marker of underlying systemic inflammation, was a significant predictor of cardiovascular risk, even in a subgroup of women with low LDL cholesterol .Epidemiological studies  and prosA higher CRP level also seems to correlate with a recurrent risk of myocardial infarction, incidence of sudden death  and periBased on this clinical evidence, The Working Group for Disease Control and Prevention and the American Heart Association suggested the introduction of hs-CRP measurement as a screening practice in all patients for the routine assessment of cardiovascular risk in order to identify asymptomatic patients without any known cardiovascular disease who may be at higher risk than that estimated by traditional risk factors for acute cardiac events .Specifically, assessment of CRP may be helpful in those patients at intermediate risk  over 10 years) to guide further clinical evaluations and start a therapeutic programme.All stages of the atherosclerotic process might be viewed as an inflammatory response to vascular injury  Figure . PatholoInitial atherosclerotic lesions begin with the differentiation of monocytes into macrophages that engulf cholesterol-rich oxidized low density lipoproteins (LDL-ox) to become foam cells that organize into fatty streaks. The perpetuation of pro-inflammatory and oxidizing atherosclerotic stimuli results in the recruitment of further macrophages, mast cells, and activated T and B cells that increase vascular lesions.The fibrous atherosclerotic plaque cap maintains its stability due to interstitial collagen. Cytokines and inflammatory immune cells interfere with the integrity of the collagen matrix, impairing the synthesis of new collagen fibers and stimulating the reabsorption of existing ones through the production and activation of specific enzymes ; this process makes the cap weaker and prone to rupture. The broken cup exposes the atheronecrotic core to coagulation factors and platelets circulating into the arterial blood and induces arterial thrombosis, thus leading to an acute cardiovascular event .A growing body of evidence defines atherosclerosis as a complex and systemic pathology in which hyperlipidaemia is a significant factor; the persistence of inflammation is required for plaque evolution and destabilization and plays a decisive role in the pathogenesis and worsening of coronary artery disease.In the past two decades, research into the genetic basis of coronary heart disease has intensified, although clear evidence regarding the heritability of complex diseases such as coronary artery disease (CAD) is missing . SurprisAccording to the most recent research, the heart can respond to acute tissue injury through complex inflammatory and reparative cascades, acting as an “immune organ” .Several types of immune cells, such as macrophages, dendritic cells, mast cells (MCs) and a small number of B and T lymphocytes, reside in the heart. Irrespective of the origin of cell injury, acute tissue damage promotes an inflammatory response, mainly characterized by the involvement of innate immune cells, followed by a reparative/remodeling phase, with a prevalence of adaptive immune cells and angiogenic/fibrotic events .Histological patterns that characterize acute myocardial infarction include coagulative necrosis as the main process, regulated necrosis (necroptosis), and/or secondary apoptosis.Following myocardial infarction Figure , cellulaIn human hearts, TLR2 and TLR4 are the most representative subtypes and, together with NOD1 and the NLRP3 subtype, have been demonstrated to activate inflammasomes in the heart  and playEndogenous DAMPs can also activate the complement system, as observed with increased C3 fragments in infarcted myocardial tissue, promoting leukocyte translocation in injured myocardium.Immune activation by DAMPs can arise also from mitochondrial DNA released by the mitochondria of damaged cardiac cells due to haemodynamic stress, inducing cardiomyocyte apoptosis. Additionally, ischemic damage leads to mitochondrial dysfunction, accompanied by the generation of a large amount of reactive oxygen species (ROS). Exorbitant production of ROS impairs myocardial function and activates leukocyte migration, reducing the number of vital cardiomyocytes and promoting extracellular matrix degradation .Nuclear factor kB (NF-kB), a highly conserved DNA transcription factor, drives the production of cytokines, interferons, and chemokines in the myocardial infarction zone when activated via the TLR and NOD pathways, complement system, and ROS products .In a vicious circle, interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-α), the main pro-inflammatory cytokines released in the injured myocardium, mediate the synthesis of more chemotactic factors that enhance leukocyte recruitment into the infarct area and play important roles in inflammasome assembly and IL-1β and interleukin 18 (IL-18) maturation .Mast (or mastoid) cells (MCs) are innate immune cells located in mucosal and epithelial tissues throughout the body (including the brain and heart).MCs, accumulating in the arterial adventitial space in response to mechanical or hypoxic stress, play a critical role in the fibrous cap erosion of atherosclerotic plaques and in coronary vasospasms induced by vasoactive and inflammatory mediators . CoronarIn the first 24 h after an acute ischaemic cardiac event, endogenous DAMPs induce the release of histamine, TNF-α, IL-6, prostaglandins, leukotrienes, tryptase, chymase and renin from MCs, leading to an acute immune response (sterile inflammation). Preformed MC mediators and DAMPs from necrotic cardiomyocytes induce neutrophil recruitment, tissue digestion through protease secretion and the phagocytosis of necrotic cells and induction of apoptosis in live cardiomyocytes, thus amplifying the inflammatory response  and chemokines released by tissue- and monocyte-derived macrophages, as well as histamine released by mast cells, can stimulate the cardiac endothelium to express adhesion molecules, favoring further neutrophil transmigration into damaged cardiac tissue. IL-6 is another inflammatory mediator released by neutrophils, monocytes, and cardiomyocytes themselves and enhances leucocyte cytotoxic activity and recruitment. Notably, neutrophils play a decisive role in ischaemia/reperfusion injury through the production of proteases that significantly impair cardiac function .Hi and Ly6CLow, that were recruited sequentially via CCR2 and CX3CR1, respectively. In the early phase, Ly6CHi monocytes removed necrotic tissue exhibiting phagocytic, proteolytic, and inflammatory properties. Ly6CLow monocytes indeed promote tissue healing via myofibroblast maturation, the deposition of collagen fibers, and vascular angiogenesis through increased endothelial growth factor (VEGF) expression. Monocyte recruitment in the human heart depends on innate B cells, which drive monocyte expansion in a CCL7-dependent fashion once they are recruited into ischaemic cardiac tissue.The immune response to acute myocardial infarction includes an inflammatory phase at days 1–4 and a healing phase from days 4 to 15. In a seminal study,  identifi++CD16−, and pro-healing monocytes express CD14+CD16++ , which are T lymphocytes expressing CD4 T-regs. These subsets are involved in the pathophysiology of several chronic diseases, including heart-related diseases. In animal models, following acute myocardial infarction, an imbalance in the Th1/Th2 subpopulation toward Th1 has been observed . Th1-Th1T cells are also implicated in the aging heart in the absence of cardiac events. In a recent study , Ramos eB lymphocytes, both tissue-resident and circulating cells, play a fundamental role in heart homeostasis. The B2 subset has been classified as pro-atherogenic, whereas the B1 subset has an athero-protective role and drives LDL-ox removal through binding with IgM antibodies .Following an ischaemic cardiac event, myocardial proteins released in the bloodstream activate dendritic cells (DC) and other antigen presenting cells (APCs) that interact with memory B cells, leading to clonal expansion and the synthesis of auto-antibodies, which can initiate the apoptosis of live cardiomyocytes. Naïve B cells can perpetuate cell damage through the release of inflammatory cytokines and chemokines that recruit monocytes, as well as T lymphocytes through MHC and T cell receptor interaction .This new knowledge regarding the immunity of acute cardiovascular disease has oriented experimental therapeutic applications toward the blockage of inflammatory mediators such as TNF-α or IL-1, yielding inconclusive outcomes. Promising strategies for patients with severe heart failure and ventricular dysfunction are targeted to the selective removal or neutralization of circulating antibodies against adrenergic receptor beta-1 (anti-β1 AR), which exerts cardiotoxic effects .The presence of immune cells in an infarcted area is essential for the initiation of repair processes in injured cardiac tissue. In the first hours after ischaemic damage, the activation of resident immune cells and recruitment of leukocytes from the circulation aims to remove dead cells, molecular fragments and debris, and release cytokines and growth factors to build highly vascularized granulation tissue to maintain the integrity of the myocardial wall. The subsequent reparative phase characterizes the days and weeks after myocardial infarction, with the formation of fibrotic scars and new vessels in the injured area.Temporal and spatial regulation of post-infarction inflammatory responses is crucial. Patients of different ages with diverse comorbidities  and genetic characteristics may have different remodeling responses, irrespective of the size of the myocardial necrosis. Exorbitant early inflammatory signals may enhance extracellular matrix lysis, leading to cardiac rupture. Prolonged inflammation or defects in the regulatory feedback of inflammatory mediators may reduce collagen deposition and provoke dilatation of the cardiac chambers. Poor control of the inflammatory reaction may extend the immune infiltrate beyond the non-infarcted myocardium, increasing matrix protein deposition and worsening fibrosis and diastolic function .Despite improvements in clinical management and the survival rate in recent years, 12% of patients die within 6 months after acute myocardial infarction, and inflammation takes a central role in atherosclerotic plaque destabilization. Identifying a high-risk pattern of circulating inflammatory cells may have prognostic value for secondary prevention in ischaemic patients. According to Meeuwsen's recent review, elevated numbers of neutrophils appear to be consistently related to adverse outcomes in CAD and post-AMI patients and, despite the limited existing data, adds significant prognostic value in addition to common prediction calculators such as GRACE and the TIMI score .In the middle of the last century, granules similar to those found in endocrine cells were detected for the first time in the cardiac atria, and their ability to lower blood pressure through potent diuretic and natriuretic effects was proven at the end of the 1970s. Only in the early eighties , 47 wereMore recently, the discovery of other endocrine molecules (collectively named cardiokines) released by cardiomyocytes, fibroblasts, vascular endothelial cardiac cells and immune cells was a significant advance in research investigating the endocrine properties of the heart .Any haemodynamic condition determining atrial distention  increases ANP release into the bloodstream. Chemical stimuli such as endothelin, platelet-activating factor, corticotropin-releasing hormone (CRH), and glucagon-like peptide can also trigger the synthesis of ANP.Brain natriuretic peptide (BNP), originally described in the pig brain, is highly expressed in the ventricular myocardium and responds to ventricular wall distension due to volume or pressure overload.C-type natriuretic peptide (CNP) is diffused throughout the central nervous system, as well as in the vascular endothelium. This peptide exerts a weak endocrine natriuretic effect and acts as a paracrine factor for the control of vascular tone .Natriuretic peptides, through increased urinary sodium excretion and vasodilation, can maintain extracellular fluid homeostasis and control blood pressure boosters. In addition to this traditional function, the ability of atrial peptides to stimulate lipolysis and lipid β-oxidation and increase energy usage through ATP synthesis in cardiomyocytes was recently demonstrated.Indeed, natriuretic peptides promote the transformation of classical white adipocytes into beige/brown adipocytes , in this way increasing heat production (thermogenesis) via crosstalk with the sympathetic nervous system .Brown adipose tissue (or “brown fat”) is abundant in newborns and tends to diminish in adulthood. It is detected around great vessels (the aorta and common carotid artery), the brachiocephalic artery, paracardial mediastinal fat, the epicardial coronary artery and veins, the internal mammary artery, and the intercostal artery and veins, as well as in the intrascapular area. In contrast to most representative “white fat,” brown adipose tissue is not specialized in storing energy as fat but instead tends to “burn” lipids, producing heat through alternative catabolic pathways .Indeed, the heart is an organ with high metabolic activity and high energy demands due to its unremitting work; under adverse climatic conditions , maintenance of a normal internal body temperature is crucial for heart functions. Prolonged cold exposure is associated with impaired cardiac performance related to the volume-overload hypertrophy of ventricles. Under these conditions, there is an increase in circulating natriuretic peptides with a parallel enhancement in fatty acid mobilization and catabolism, higher mitochondrial metabolic activation in the cardiac skeletal muscles, and increased heat production to maintain an optimal body temperature .In an experimental context, the controlled infusion of ANP, BNP, and CNP leads to cardiovascular effects, inducing vasodilatation and lowering blood pressure. The administration of ANP, BNP, or CNP may also limit post-infarction ventricular remodeling. In decompensated heart failure, ANP and BNP infusion reduces both pulmonary capillary wedge pressure and systemic vascular resistance, thus enhancing stroke volume .Natriuretic peptides exert beneficial effects on vascular resistance and fluid balance through inhibition of the renin-angiotensin-aldosterone (RAAS) axis, known to be deeply involved in cardiac remodeling in hypertensive and post-ischaemic patients. Local renin-angiotensin production in different tissues, including the heart, vasculature and brain, was recently recognized . Stress,Therapeutic strategies targeting atrial peptide modulation and RAAS downregulation may include lifestyle modifications  and drugs.Classical drugs recommended for the management of heart failure include angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II-receptor blockers (ARBs), β-blockers, digoxin, diuretics, and aldosterone antagonists. Sacubitril/valsartan  is the first-in-class angiotensin receptor neprilysin inhibitor (ARNI) approved by the FDA in 2015 and is recommended by the latest European and American heart failure treatment guidelines  for patiThe natural history of CHD can be influenced by mental stress. First observations of negative emotions and coronary thrombosis were provided in 1910 by Obraztsov and Strazhesko, who included for the first time emotional triggers in the pathogenesis of acute myocardial infarction .Stressful life events, such as natural calamities, financial crises, terroristic attacks and wars, are known to be life-threatening acute triggers for cardiac events, as are positive emotionally charged events (sport matches and Christmas and New Year's holidays), thus worsening the prognosis in vulnerable individuals .Chronic stressors such as negative psychosocial factors represent modifiable risk factors that could be linked to adverse cardiac prognosis and the mortality rate worldwide. The international INTERHEART case control study proved that psychosocial factors were significantly related to acute myocardial infarction, with an odds ratio (OD) of 2.67 .Social inequalities and behavioral factors as determinants of CV morbidity and mortality were also investigated by M. Marmot and colleagues  in a cohFurther meta-analyses of prospective observational studies found that certain psychosocial factors, such as social isolation and loneliness, were associated with a 50% increased risk of CVD; work-related stress showed similar results, with a 40% risk of new CV events .Experimental data confirmed that adverse early life events, including social deprivation and discrimination during childhood and adolescence, predispose an individual toward the development of CVD in adulthood through diverse epigenetic signatures of key regulatory genes involved in the stress response, immune function, inflammation and metabolism .However, the lack of statistical power in recent metanalyses does not allow identification of the type of occupational psychosocial factors that can be considered independent risk factors for major cardiac events .As emerged by large observational studies, people with severe mental diseases  have an increased risk of developing CHD compared with controls, with pooled hazard ratio of 1.54, according to recent meta-analytic results , showingIn 2014, the American Heart Association pointed out the close relationship between high depressive symptoms and poor prognosis after acute myocardial infarction; in a published scientific statement, depression was elevated as an “independent primary risk factor in patients with acute coronary syndrome” , 66. In Racial disparities have been considered in many prospective studies, recognizing race-dependent risk factors for blacks, but not whites, in developing cardiac disease. In the REGARDS study, black individuals with depressive symptoms presented a greater risk of CHD diagnosis or revascularization at follow-up . In the Anxiety is commonly diagnosed together with depressive disorder. Therefore, it is not surprising that there are few studies focusing only on anxiety disturbance and the incidence of cardiovascular disease. In a 2010 meta-analysis by Roest and colleagues, a high anxiety score was a recognized risk factor linked to coronaropathy, although the analysis was not adjusted for depression, a common comorbid disease . In a coThe link between posttraumatic stress disorder (PTSD) and incident fatal and non-fatal CVD events is well established. Diagnosis of PTSD was found to be an established risk factor for acute coronary events in the general population in multiple prospective cohort studies  and in sPositive thoughts and emotions, as well as social cohesion, enhance resilience and influence health trajectories in cardiovascular diseases. In the Health and Retirement Study, optimism appeared to protect against incident heart failure after a cardiac event .Ethnic differences in positive behavioral responses emerged in the Eastern Collaborative Group prospective study, in which the Japanese attitude called “Spirit of Wa,” integrating a sense of community, collaboration and hierarchical social organization, was a protective factor against further cardiac events in Japanese men undergoing coronary angiogram for CAD . AssessmIn western countries, evidence has shown similar results. Adults in the United States without cardiovascular disease who perceived higher neighbourhood social cohesion presented a reduced likelihood of incident myocardial infarction over 4 years .Stress in mammals is responsible for complex psycho-neuro-immuno-endocrine responses that primarily involves both the hypothalamic–pituitary–adrenal (HPA) axis and the autonomic nervous system (ANS), first described by the two founders of stress science, Walter Bradford Cannon and Hans Selye, in the 1930s , 82.Highly conserved in all vertebrates, including humans, the ANS and HPA systems represent the neuronal and hormonal limbs of the stress response, respectively, and provide both short- and long-term changes in behavior, cardiovascular functions, endocrine and metabolic signals, as well as in host defense and immune responses, enabling the individual classically “to fight or flee” and initiate different coping strategies against stressors of different origins, from physical injuries to psychosocial tasks, in order to successfully adaptation . The HPA axis, starting from the hypothalamic paraventricular nucleus, secretes corticotropin-releasing factor (CRF) that regulates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland. Cortisol is the main active hormone released from the adrenal gland in response to ACTH in humans, exerting negative feedback control on hypothalamic CRF and pituitary ACTH secretion .As observed in clinical studies with adults and adolescents, altered HPA axis function may have negative effects on the cardiovascular system, leading to atherosclerotic plaque formation, high blood pressure, insulin resistance, dyslipidaemia, and central adiposity. Biomolecular studies confirm that these stigmata correlate with elevated inflammatory markers and endothelial activation with a hypercoagulable state and increased risk of thrombotic events .A growing body of evidence has demonstrated a close relationship between high levels of cortisol and increased risk of ischaemic heart disease and cardiovascular mortality , 86.Chronic psychological stress is associated with the pathogenesis of atherosclerosis, and serum cortisol might be a reference marker for this disease. Huo et al., showed that serum cortisol levels were higher in the patients with atherosclerosis than in healthy controls, and high plasma cortisol concentrations negatively correlated with circulating immuno-regulatory IL-10, promoting plaque destabilization . ChronicResults from the Whitehall II study showed that male workers with metabolic syndrome at lower job positions had higher levels of norepinephrine, cortisol and serum IL-6 and manifested a higher heart rate at rest and lower heart rate variability .As a systemic disease, obesity itself contributes to the risk for CVD through elevations in basal levels of cortisol, inflammatory cytokines and hormones such as leptin and insulin. In an exiguous group of obese college-aged males, Caslin and colleagues showed that an acute mental stress task elicited a vigorous stress reaction, with an increase in heart rate and catecholamine release (epinephrine and norepinephrine), increased immune response with inflammatory cytokine synthesis  and hormonal changes with a significant reduction in leptin concentrations, without a significant increase in serum cortisol at an early post-task observation time point .Life has evolved on earth under the influence of the alternation of the day-night cycle. Humans, such as other primates, synchronize on this rhythm the variable (circadian) production of hormones, neurotransmitters, and cytokines, as well as brain area activation and the main functions of fundamental organs, such as the pancreas, liver, adrenal glands, bowel, lungs and heart .Sleep is the most important circadian synchronizer in human organisms, and sleep deprivation, due to lifestyle habits or related to organic conditions such as obstructive apnoea, insomnia or neurologic and psychiatric diseases, affects modern societies worldwide. Although most pathophysiological mechanisms are still poorly understood, the biological effects of alterations in the quantity and quality of nocturnal sleep have been deeply studied. Epidemiological observations have demonstrated that short sleep duration is related to increased incidence of hypertension, coronary artery disease, arrhythmias, obesity and diabetes .Recent reports have documented the relationship between sleep duration and sleep quality  with incThe mechanisms underlying the detrimental effects of sleep disorders on cardiovascular disease are limited. In animal models, sleep deprivation alters cardiovascular parameters and increases sympathetic activity and neuroendocrine responses to experimental stressors, as well as induces inflammatory, and pro-oxidant patterns in many tissues , including the heart and vascular endothelium . In humaOne single sleepless night can affect the cardiovascular autonomic response toward sympathetic predominance and induce systemic inflammation through increased IFN-γ secretion in young internists after one night of on-call duty . Recent The autonomic nervous system (ANS) maintains homeostatic equilibrium in response to normal physiological stimuli such as environmental changes  or to pathological conditions such as physical diseases and mental stress. The link between stress and CVD occurrence is mediated by autonomic dysregulation through central and peripheral neurophysiologic mechanisms involved in the onset of arrhythmic and acute coronary events, as well as worsening heart failure.The neuro-cardiac axis is a complex series of reflex control networks containing afferent, efferent, and local circuit neurons that coordinate, in an interdependent fashion, cardiac electrical and mechanical properties  by mediaThe central cardiac control network involves cortical centers, mainly the insular cortex (IC), anterior cingulate cortex (ACC), amygdala (A), hypothalamic nuclei, medulla, and spinal cord. The medulla, located in the lower segment of the brainstem, contains sympathetic and parasympathetic nuclei that directly regulate autonomic nerve efferences to the heart and blood vessels. The nucleus tractus solitarius (NTS) of the medulla receives afferences both from peripheral baroreceptors and chemoreceptors and from the hypothalamus and other cortical regions, directly modulating the activity of vagal and sympathetic innervations. From the medulla, the sympathetic fibers come down the spinal cord, where they immediately make synapses with preganglionic fibers. The sympathetic preganglionic efferent fibers arise in the intermediolateral column (IML) of the spinal cord, receive excitatory glutamatergic inputs in rostral ventrolateral medulla (RVLM) and make synapses in several extracardiac neuronal ganglia . Sympathetic postganglionic efferent fibers finally form synapses in the heart and vasculature.The parasympathetic nerves, primarily located in the nucleus ambiguus (NAmb) and in the dorsal motor nucleus of the vagus (DMN), exit the medulla as long preganglionic efferent fibers forming the vagus nerve or cranial nerve X and finally synapse with postganglionic fibers within the heart or vascular tissue. Vagal and adrenergic postganglionic fibers, together with local circuit neurons, represent the intrinsic cardiac nervous (ICN) system, a complex network organized in clusters of cardiac plexuses that influence the cardiac conductile tissue to affect the heart rate, myocardial contractions and atrioventricular conduction velocity .It is well known that acute injury occurring in the central nervous system  is linked to transient or permanent myocardial and/or arrhythmic damage. Ischaemic damage to the insular cortex, in particular right-sided lesions, is associated with arrhythmic alterations , inverted T wave, sudden cardiac death, altered diurnal blood pressure, and myocardial injury, as well as elevated plasma levels of brain natriuretic peptide, catecholamines, and sympathetic neuropeptide Y (NPY) . NPY is Stress exposure, through its deleterious impact on the autonomic cardiac system, leads to an imbalance in autonomic regulation , resulting in a dramatic shift toward enhanced sympathetic firing and/or withdrawal of vagal tone and higher risks of hypo- and hyperkinetic arrhythmias, platelet aggregation, and vascular thrombosis. It has been experimentally observed that sympathetic stimulation triggers cardiac arrhythmias, reducing both atrial and ventricular arrhythmic thresholds, and induces ECG changes in the repolarization phase . In patiThe stellate ganglia also play an important role in the generation of ventricular and atrial arrhythmias. During experimental sympathetic discharge, stellate ganglia activation induces T wave changes. Removal of the caudal portions of both stellate ganglia suppresses ventricular arrhythmia formation in humans .Esler and co-workers have demonstrated a close relationship between stress exposure and essential hypertension. In an experimental setting, patients affected by panic disorder without an acute panic attack showed multiple “salvoes” of sympathetic nerve firing during normal cardiac activity; researchers found an identical pattern in hypertensive patients, identifying sympathetic firing as a “signature” of chronic stress exposure . The co-In patients suffering from heart failure, autonomic dysregulation correlates with higher plasma NE concentrations and might predict negative outcomes .Heart rate variability (HRV) represents a non-invasive marker of life-threatening arrhythmias and vascular endothelial damage, as well as an indirect marker of chronic stress and emotional arousal. HRV indicates a dynamic variation in the time interval between heartbeats, used as an index of sympathetic activity that affects the variability of the cardiac rate, in general, reduced HRV indicates excessive sympathetic activity and depressed vagal tone. Psycho-social stress tasks may result in chronic sympathetic activation, thus influencing HRV. It has been observed in different cardiac and non-cardiac diseases that reduced HRV negatively affects health outcomes. In the presence of adverse psychosocial factors, there is an autonomic system imbalance with reduced HRV and increased carotid stiffness in post-menopausal women . AccordiExperimental distress is found to be linked not only to autonomic nervous system imbalance but also to enhanced inflammatory activity by myocardial macrophages, resulting in cardiac dysfunction and cardiomyocyte death. In 2000, Tracey and colleagues discovered “the inflammatory reflex,” a characteristic of vagal activity in counteracting sympathetic hyperactivation; these researchers demonstrated that vagus nerve stimulation was able to immediately suppress cytokine synthesis in an animal model of sepsis. Immunofluorescence assays and biomolecular findings have shown that vagal efferent innervation mediates acetylcholine (ACh) release both in the reticulo-endothelial system and in the heart, where the neurotransmitter binds the nicotinic receptor (nAChr) expressed on resident cardiac macrophages, blocking the release of the main pro-inflammatory cytokines  . Non-invMental Stress-Induced Myocardial Ischaemia (MSIMI) is a corollary of different validated techniques used to assess the effects of stress on cardiac function .In contrast to exercise and pharmacologic stress-induced ischaemia, MSIMI is a provocative test that provides psychological rather than physical stimuli, leading to reversible myocardial ischaemic damage. Different mental stressors  are used to recreate behavioral challenges experienced in everyday life .Many different instrumental resources have been tested: ECG recording, echocardiography, ventriculography, myocardial scintigraphy, positron-emission tomography, and coronary angiography .The following heterogenic haemodynamic features associated with MSIMI result in myocardial transient ischaemia: increased resistance of vascular walls, coronary vasospasm, reduced endothelial function, elevated heart rate and/or blood pressure, anomalies in the electrical repolarization phase, ventricular kinetics and myocardial perfusion. Moreover, mental stress-induced activation of the stress-response system increases catecholamine release, leading to cardiac electrical instability . SubjectConversely, the presence of depressive symptoms in young post-myocardial infarction patients was associated with a higher tendency to manifest ischaemic features with mental stress rather than with exercise or a pharmacological stress test .As confirmed in recent metanalyses, a positive MSIMI test represented a negative prognostic factor for adverse outcomes in CAD patients, irrespective of the coronary grade of stenosis. .As shown in recent epidemiological data, the diagnosis of myocardial infarction with normal coronary arteries (MINCA) has increased, constituting 5–25% of total myocardial infarction diagnoses. Approximately 30% of total MINCA is represented by Takotsubo stress cardiomyopathy (TTC), an acute systolic and diastolic dysfunction of the left ventricle that occurs in patients without a history of CAD, although a small fraction of patients may have asymptomatic CAD subsequently discovered with angiography. TTC predominantly affects elderly women  and is often preceded by an acute emotional trigger , albeit physical triggers  or sine causa TTC may also occur. The etiology of TTC is unknown; however, physiological mechanisms underlying the neuro-cardiac axis may provide a fundamental link between acute stress and TTC onset. It has been hypothesized that TTC patients experience excessive catecholamine and NPY release, with subsequent coronary vasospasm, leading to a pathological reduction in myocardial blood flow and alterations to parietal kinetics. Despite previous theorizations that defined TTC as a transient benign disease, data from the International Takotsubo Registry revealed high rates of complications, such as cardiogenic shock and death, during hospitalization, similar to incidence rates of negative outcomes in acute coronary syndrome. Ten years follow-up analysis among TTC patients showed an annual 5.6% incidence of death from any cause and a 9.9% incidence of major adverse cardiac and cerebrovascular events. Moreover, the analysis showed that young patients affected by physically triggered TTC who were comorbid with acute neurological or psychiatric diseases presented a higher risk of complications and death than elderly patients with emotional triggers .The current view of coronary heart disease has deeply changed see ; atherosRecent findings have fundamentally altered the classical vision of the heart as a “mechanical blood pump” that beats through an internal pacemaker. Indeed, cardiac tissue contains resident immune cells and is able to synthesize and release cytokines and hormones after acute myocardial infarction in the ischaemic area, influencing the healing phase both in terms of acute ischaemic damage and in post-infarct myocardial remodeling.Low-grade chronic inflammation (LGCI) is characterized by the persistence of an altered immune response with a shift toward a pro-inflammatory state, characterized by increased plasma levels of Th1/Th 17 cytokines such as interleukins IL-6, IL-1β, IL-17, and TNF-α. The increasing concentrations of these mediators result in the progressive impairment of organ functions and higher incidence of inflammation-related diseases. The pivotal role of chronic inflammation in several chronic diseases, such as asthma, cancer, diabetes, autoimmunity and psychiatric diseases including depression, is now recognized.In recent years, chronic depression has ranked among the most important cardiovascular risk factors for poor prognosis in patients with myocardial infarction.Current understanding of the central and autonomic regulation of cardiac functions, namely, the neuro-cardiac axis, provides a physiological explanation that links psycho-emotional stressors and social adversities to acute cardiac events, including myocardial infarction, myocardial ischaemia, cardiac wall motion abnormalities, and sudden death. Psychological distress can precipitate heart function through a dysregulated neuroendocrine and autonomic response, as demonstrated by increased serum cortisol and catecholamines, reduced HRV and increased inflammatory cascades. Sympathetic hyperactivation can influence cytokine production via the transcription of NFkB-mediated genes involved in pro-inflammatory immune response, thus enhancing vascular endothelial activation and thrombosis.The complex network that links the heart, brain and the main biological systems provides a new vision of cardiovascular science based on psychoneuroendocrineimmunology , a scienMF, AB and FB have equally contributed to the writing of the manuscript. MB, MR, and MGR made intellectual contribution to the work. All authors approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Angioplasty is a fundamental treatment for atherosclerotic disease in the cardiac, cerebrovascular, and peripheral vascular beds. However, the optimal duration of balloon inflation has not been identified. Our study will investigate whether prolonged angioplasty balloon inflation of at least 1 min duration, when compared with brief inflation, affects residual stenosis after arterial angioplasty.In compliance with PRISMA, two independent reviewers will conduct a systematic review of EMBASE, MEDLINE, CENTRAL, trial registries, grey literature, and ancestry and citation search. Data abstraction, quantitative, and quantitative meta-analysis will be performed according to pre-specified criteria. The primary outcome is residual stenosis immediately after initial angioplasty; however, secondary outcomes will include multiple short and long term pre-specific clinical and radiographic outcomes. Risk of bias, subgroup analyses, and sensitivity analyses are planned.Despite the ubiquitous use of angioplasty in atherosclerotic disease and multiple trials investigating the ideal balloon inflation duration, there are no systematic reviews evaluating prolonged angioplasty balloon inflation. Currently synthesized evidence is insufficient to confidently direct clinical decision-making, and the current variation in operator preference of balloon angioplasty duration suggests ongoing clinical equipoise. Given the known availability of current primary evidence, our study intends to synthesize the evidence and guide future clinical decision making and investigation.CRD42018092702PROSPERO The online version of this article (10.1186/s13643-019-0955-2) contains supplementary material, which is available to authorized users. Atherosclerotic vascular disease is a chronic disease that causes blockages of arteries throughout the body. Conditions resulting from atherosclerotic disease are the most common cause of death in North America. The location of the vascular blockage dictates the disease; blockages in coronary arteries may lead to heart attacks, blockages in cerebral arteries may lead to strokes, and blockages in peripheral arteries may lead to gangrene. The prevalence of atherosclerotic peripheral vascular disease in the North American general population over 50 years of age is estimated at 17.4% .Various techniques have been proposed to minimize restenosis following angioplasty; however, many have not been thoroughly evaluated in randomized trials. One such technique is prolonged angioplasty balloon inflation time, which is theorized to reduce post-interventional dissection and induce smooth muscle dysfunction, thereby reducing vasospasm and resulting stenosis. While animal studies have not revealed short-term mechanical advantage for prolonged balloon inflation , smooth Conversely, in addition to being a therapeutic treatment for atherosclerotic disease, balloon angioplasty is known to cause vascular damage to previously healthy arteries in animal models after an inflation time of 60 s –7. TheseWhen angioplasty was first introduced in the last twentieth century, early randomized trials revealed immediate benefit of prolonged balloon inflation, although the sustainability of the patency benefit is conflicting –10. HoweThe objective of this systematic review is to evaluate the risks and benefits of prolonged angioplasty balloon inflation duration in the diverse patients with atherosclerotic disease.Specifically, our primary objective will be to determine if in patients receiving elective arterial angioplasty for stenotic or occlusive atherosclerotic disease, does prolonged balloon inflation of greater than 1 min duration, when compared with brief balloon inflation 1 min or less, improve residual stenosis in the immediate post-procedure angiogram.Is the effect of prolonged balloon inflation modulated by the location of atherosclerotic disease: coronary, cerebrovascular, and peripheral?Does prolonged balloon inflation, when compared with brief balloon inflation, affect immediate adverse radiographic events such as major vascular dissection?Does prolonged balloon inflation, when compared with brief balloon inflation, affect immediate clinically apparent adverse events secondary to vessel territory ischemia, such as heart attack or stroke?Does prolonged balloon inflation, when compared with brief balloon inflation, affect long term radiographic vessel patency?Does prolonged balloon inflation, when compared with brief balloon inflation, affect long term resolution of clinical ischemic symptoms?Secondary questions that will be addressed by this review will include:We will include randomized controlled trial (RCT), including cluster RCT, non-randomized controlled trials, cluster trials, interrupted time series studies, controlled before-after studies (CBA), and prospective or retrospective cohort studies. Case series, nested case-control, cross-sectional studies, and case reports will be excluded.We will include studies examining human adults (age 18 or older) who received angioplasty for atherosclerotic stenotic or obstructive vascular disease. Subgroup analysis examining clinical symptoms will exclude all trials that do not reference ischemia-based symptoms and only report radiographic results. Of note, when multiple arterial lesions are intervened upon within the same patient, each lesion will be counted as a separate “participant.”We will examine studies investigating elective arterial angioplasty. The angioplasty must be the primary purpose of the intervention and not be performed concurrently with a hybrid open vascular procedure on an in-line flow artery. The intervention may be performed on any arterial structure, including coronary, extracranial, intracerebral, or extremity arteries. The balloons may be drug-coated or lined with cutting ribs. However, we will exclude studies which employed adjunctive endovascular procedures prior to measurement of the outcome of interest, including but not limited to stent placement, orbital atherectomy, laser atherectomy, rotational atherectomy, or directional atherectomy. We will exclude venous angioplasty, arteriovenous fistula angioplasty, and studies examining emergency settings. We will only include studies examining de novo stenosis and therefore exclude studies examining angioplasty of restenosis, as the histopathology and outcomes related to restenosis are vastly different than de novo atherosclerosis .The intervention of interest is at least one single prolonged angioplasty balloon inflation greater than 1 min duration, and the control will be brief balloon inflation, with no single balloon inflation duration greater than 1 min.The primary outcome of interest is residual stenosis immediately following angioplasty, as determined by post-inflation angiogram. The definition threshold for residual stenosis must be defined and is generally between 20 and 50% stenosis.Secondary endpoints are categorized into immediate and long-term outcomes. Immediately, we will collect reported information on radiographic adverse events; this excludes residual stenosis and will be defined as a vascular anatomic abnormality that did not exist prior to balloon inflation. This includes arterial dissection, vessel perforation, and acute occlusion where there was a degree of patency prior to intervention. In addition to radiographic adverse events, we will collect newly developed clinically significant adverse events noted during the day of intervention, which broadly encompasses ischemic symptoms secondary to the territory of vascular intervention, for instance, a myocardial infarction following coronary artery angioplasty, stroke following cerebral vessel angioplasty, or acute limb ischemia following peripheral arterial angioplasty.Long-term secondary endpoints will also be differentiated into radiographic or clinical outcomes. We will collect data from any study reporting radiographic vessel patency by any validated modality, when performed on the day following the initial intervention: interventional angiogram, CT-angiogram, MRI-angiogram, and duplex ultrasound will be considered. Clinically, symptoms indicating long term resolution of ischemia will include angina pectoralis, cerebral hypoperfusion syndromes, claudication, or critical limb ischemia.Studies will be selected for inclusion if they report immediate post-angioplasty angiographic results, performed on the same day as the procedure. Long-term endpoint data will also be collected, as described above, if available.There are no restrictions regarding the setting of the study.We will include English and French studies, with a list of potentially relevant translated titles in other languages included in an Additional file A literature search strategy using medical subject headings and text words has been developed. We will search MEDLINE (OVID interface), EMBASE (OVID interface), and the Cochrane Central Register of Controlled Trials (Wiley interface).To ensure capture of all relevant trials, all selected studies will also undergo ancestry search, in addition to citation search using SCOPUS. OpenGrey will be interrogated for unpublished relevant literature.Both qualitative and quantitative studies will be collected. All searches will be limited by date of publication (January 1977–February 2018). The initial year of 1977 has been chosen as the first in-human use of angioplasty was performed that year. No language limit will be placed on the search; however, only English or French studies will be included in the analysis, with titles of potentially relevant studies in alternate languages included in the Additional file Literature search results will be aggregated in EndNote, including where duplicate articles will be removed. The results will then be uploaded to the Distiller SR software, which will facilitate collaboration among all reviewers.The two screening authors will independently screen titles and abstracts resulting from the combined search of all selected databases. The full text of an article will be obtained for any articles that appear to meet eligibility criteria, at which point the full text will be screened and confirmation of article inclusion will be made. Any reasons for exclusion following full text screening will be explicitly documented and listed in an Additional file Once both reviewers have created a complete list of eligible articles, the lists will be compared. Discrepancies in article selection will be addressed with discussion with a third-party author experienced in systematic review conduct. No authors will be blinded to journal titles, study authors, or study location of origin.A standardized form created in Distiller SR will be used as the data collection method. Both reviewers will have a separate form for each article, which will be compared for consistency after data collection has completed. Any discrepancy will be addressed with discussion with a third-party author experienced in systematic review conduct. Study authors will not be contacted to resolve unclear or inadequate reporting of data.Generic article data collected will include year of publication, trial design methodology, trial size (both in number of patients and number of lesions), duration of follow-up, financial support sources and involvement, and publication status.Patient-specific data will include average age, gender, symptom status, and the anatomic location of arterial lesions .Intervention-specific data will include the trial protocol for angioplasty balloon inflation duration, the total number of repeated inflations, target balloon inflation pressure, use of adjunctive endovascular therapy following angioplasty, and the total number of lesions intervened upon in each intervention arm. We will also document the type of angioplasty device used; specifically, we will record any use of drug-eluting balloons, cutting rib balloons, and perfusion catheters.Outcome-specific data will include the blinding status of outcome adjudication, the definition of restenosis, definition of acute or chronic radiologic or symptomatic adverse events, and any long-term vessel patency or symptom status outcomes.The primary outcome will be the number of lesions who do not suffer from residual stenosis immediately following angioplasty balloon inflation, with a threshold as defined specifically by the individual trials but not exceeding the limits of 20–50% residual stenosis. We will record whether the treating physician or a blinded adjudicator determined the end-point.i.Vessel dissectionVessel perforationDistal embolizationComposite endpoint, which may include dissection, perforation, or severe residual stenosisDefined as a vascular anatomic abnormality that did not exist prior to balloon inflation. We will record whether the treating physician or a blinded adjudicator determined the end-point. These will be recorded as dichotomous outcomes.Radiographici.Clinical or biochemical diagnostic confirmationMyocardial infarction or angina pectoralisClinical diagnosis, with or without radiographic confirmationStroke or transient ischemic attackClinical diagnosis, with or without radiographic confirmationAcute limb ischemiaDefined as newly developed ischemic symptoms, temporally related to intervention, and anatomically related to ischemia of the end-organ perfused by the artery receiving angioplasty. These will be recorded as dichotomous outcomes.ClinicalImmediate outcomesi.Interventional angiogramCT angiogramMR angiogramDuplex ultrasoundDefined as any record of radiographic vessel patency by any validated modality, when performed on the day following the initial intervention. The length of follow-up will be noted, and multiple records kept if follow-up images were obtained at multiple time point following the intervention. We will record whether the treating physician or a blinded adjudicator determined the end-point. These will be recorded as dichotomous outcomes.Radiographici.Angina pectoralisCerebral hypoperfusion syndromeClaudicationCritical limb ischemia.Defined as the recurrence or development of chronic ischemic symptoms related to the end-organ perfused by the vessel intervened upon by angioplasty. These will be recorded as dichotomous outcomes.ClinicalLong-term outcomesTo assess individual studies for potential risk of bias, we will collect information guided by the Cochrane Collaboration tool for assessing risk of bias. In summary, this includes sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting. For each category, each study will be determined to be at either low or high risk. Alternately, if the report includes insufficient information to determine the level of risk, the category will be labeled as unclear. Determination of the level of bias will be made by the two reviewers independently and compared following complete assessment of all studies. Any discrepancy will be addressed with discussion with a third-party author experienced in systematic review conduct. The resulting risk of bias for each study, in each category, will be graphically represented by RevMan software.Following data collection, if the studies are homogenous in terms of design, subjects, interventions, and outcomes, we will conduct a meta-analysis with random effects model. All outcomes that may undergo meta-analysis will be dichotomous in nature. Measurement effects will be determined by using risk ratio with 95% confidence intervals. As mentioned, the proposed unit of analysis will be arterial lesions; one subject may lend multiple units of analyses if they have multiple lesions undergoing angioplasty. Clustering of data for purposes of meta-analyses will not be considered due to variable reporting patterns, resulting in statistical limitations. However, for cluster randomized trials, we will account for the interclass correlation coefficient to appropriately modify results, as guided by the Cochrane Handbook for Systematic Reviews of Interventions.Due to the anticipated heterogeneous nature of clinical symptomatic status presentation and reporting, in particular given the broad anatomic inclusion of this study, clinical symptom outcomes will not be assessed using quantitative meta-analysis.In cases of unclear or inadequate data reporting, the authors will not be contacted for further data, and the data will be absent from meta-analysis. For trials that did not report on an intention-to-treat basis, or otherwise are at unique risk for missing or high risk of bias, sensitivity analysis will be used to assess the effect of inclusion of these trials. Trials will not be excluded due to the number of participants, however, will be assessed with sensitivity analysis if the size of trials raises heterogeneity concerns.I2 statistic, with a threshold of 40–60% possibly representing heterogeneity and greater than 60% likely representing heterogeneity. In cases of likely heterogeneity, we will attempt to identify the source of heterogeneity through the use of pre-defined subgroup or post hoc sensitivity analysis.To assess for study heterogeneity, we will first subjectively assess variability in patient and study baseline factors, intervention type, and outcome assessments. Statistical heterogeneity will be tested using the All quantitative data syntheses will be performed on RevMan software as guided by the Cochrane Handbook for Systematic Reviews of Interventions. If acceptable levels of homogeneity are observed, cumulative effect estimates will be calculated with the Mantel-Haenszel method using fixed effects model. Alternately, a qualitative synthesis will be performed.Anatomic location of arterial intervention Number of balloon inflations (single inflation versus repeated inflations)Era of study (prior to year 2000 and following year 2000)Angioplasty device Planned subgroup analyses include:All reported outcomes will be synthesized and reported in a qualitative manner. Furthermore, clinical outcomes will only be synthesized in a qualitative manner, as the expected heterogeneity in clinical situations and reporting will preclude quantitative analysis.In addition to individual study assessment of risk of bias, all studies will be evaluated for indications of meta-bias. We will search for preceding published or registered protocols prior to study publication and evaluate for selective outcome reporting. Potential for reporting bias will be assessed by a funnel plot.The quality of all outcomes will be judged subjectively as a consensus among study authors, using the standardized Grading of Recommendations Assessment, Development and Evaluation methodology.This study intends to focus on a procedural technique for a systemic disease and encompasses a broad scope of specialties and anatomic regions. This breadth is intentional and intended to account for the relatively low anticipated body of evidence on this topic. However, the breadth of the study also introduces limitations during the conduct and interpretation of this review. While a meta-regression to determine the relative impact of angioplasty inflation duration on restenosis could theoretically demonstrate an ideal inflation duration, this will not be feasible due to the anticipated breadth of disease and reporting variability. Therefore, the primary conclusion of this study will determine whether balloon inflation of greater than 60 s is favorable; the specific ideal duration will not be determined in the context of these limitations. Furthermore, case-specific characteristics that are known to affect angioplasty success, such as other systemic diseases and lesion characteristics, will not be feasible to introduce into the analysis. Therefore, this study relies on the integrity of study allocation procedures to ensure the treatment arms are comparable. Despite these limitations, the potential results of this study remain insightful and necessary in light of the ubiquity of angioplasty and variations in practice. Adherence to the PRISMA-P guidelines . (DOCX 24 kb)Additional file 2:PRISMA-P 2015 Checklist. (DOCX 33 kb)


Cardiovascular disease (CVD) is the world's top mortality cause, accounting for 1 in 3 deaths and 1 in 5 dollars of the American healthcare system. Patients deserve more effective, affordable, equitable care—and now—yet we in the clinical and research community struggle to accelerate the rate of reliable and replicable results to keep pace with this growing global epidemic. Computational advances in statistics and machine learning are increasingly bridging the informatics and physiological pipeline uniting precision medicine and population health, getting us thankfully closer to adequately addressing patient needs.Through improved computational models, we could attain a better understanding of the physiologic , clinical , and population  factors that help produce the complex phenomenon of CVD. Computational advances must simplify the CVD problem, so we can act, reassess, and act again on the problem through incremental research gains in a growing snowball fashion. Clinically, patients need such methodological improvements; financially, their medical costs are nonsustainable; and most important, ethically, our patients deserve faster, better, cheaper results from medical science. Health systems internationally are responding to (or forced to react to) these societal changes—patients are rightfully demanding better treatments, clinicians are expecting better data to guide their decisions, payers are requiring higher value care, and regulatory and funding bodies are mandating greater transparent and impact research. Yet where to begin, or go from here in CVD, is nearly as obtuse as the complexity of the above challenges we face as there are no widely accepted evidence-based standards in these computational advances, nor how to optimally apply them to reverse the CVD epidemic.This special issue therefore aims at accelerating the dissemination of promising CVD computational advances. We received 15 submissions worldwide, and after performing rigorous and careful peer review, 6 of them were selected for this special issue. These resultant published studies provided novel computational, statistical, and machine learning approaches or clinical application to improve modelling for blood flow dynamics, solid mechanics, breath wave dynamics, and electrical cardiac rhythm for such patient populations as those affected by aortic aneurysm and dissection, atrial fibrillation, congestive heart failure, and arrhythmias.One flow dynamic study conducted by J. Febina et al. created a 3D non-Newtonian mathematical model of pulsatile cardiac blood flow using CT data to map thoracic aortic aneurysm for computational fluid dynamics (CFD) to thus demonstrate wall shear stress (WSS) as a predictor for impending rupture, risk stratified throughout the cardiac cycle and stress conditions. This model notably included the vortex formation pattern and flow reversal (as in WSS) and therefore provided evidence for WSS nonoverly predicted through non-Newtonian pulsatile flow  but overpredicted when the natural flow pattern of laminar-turbulent-laminar is added to the non-Newtonian pattern. Newtonian fluid dynamics on the other hand were deployed in a different study performed by I. Avrahami and colleagues to assess carotid blood flow and wall dynamics in multiple bifurcation scenarios  using fluid-structure interaction (FSI) numerical simulations. This was done to aid in the clinical decision about suture-based carotid endarterectomy versus patch-based angioplasty. The analysis suggested primary suture was superior to patch angioplasty by higher stress and high oscillatory shear index (OSI) along with lower time-averaged wall shear stress (TAWSS), with the high flexibility patch outperforming the lower flexibility patch. Image improvement was the focus of a third flow dynamic study conducted by Huang and co-workers. In this, an image time-domain integration modelled on blood flow periodicity was proposed to streamline improvements in image and noise suppression for digital subtraction angiography (DSA). In this model, postcontrast cardiac cycle images were synthesized for independent application or as a postprocessing noise suppression technique. This approach demonstrated good real-time performance and efficiency for enhancement and noise suppression in aortic dissection. Flow dynamics were included with solid mechanics in another paper by N. Kiefer et al., in which a global optimization algorithm was proposed and deployed in 17 critically ill atrial fibrillation (AF) patients to approximate diastolic stiffness (to aid in the diagnosis of left ventricular diastolic dysfunction (LVDD)) through a mathematical solution for the ill-posed nonlinear inverse problem of parameter estimation rooted in the physiological model of diastolic filling. This study provides the first known quantification of LV diastolic function using routine clinical data from critically ill patients with AF.Breath wave dynamics were assessed in the study of T.-C. Fu et al. using an autoregressive (AR) mathematical model created to analyze breath-by-breath exercise test data to better analyze cardiopulmonary exercise testing (CPET) exercised-induced periodic breathing (PB) to prognosticate congestive heart failure (CHF). Hilbert–Huang transform (HHT) was utilized to decompose the AR model's breath-by-breath values into intrinsic mode functions (IMFs), mathematically representative of individual breath's physiologic oscillation in various frequencies. This model demonstrated predictive performance for CHF prognosis based on the third and fourth IMF components among 61 CHF patients, evidencing the biologic basis as a physiologic reserve indicated by ventilation and the above HHT approach to modelling CHF.Finally, electrical cardiac rhythm was studied in another paper of S. M. Anwar et al. on dynamic and morphological electrocardiogram (ECG) features which were utilized in a novel approach for arrhythmia classification using discrete wavelet transform  for heart beats and Teager energy operator for nonlinear dynamic RR intervals. These features were then run through a threefold cross-validation neural network algorithm, which was then compared with the MIT-BIH databases for arrhythmia  and supraventricular arrhythmia . Accuracy for class- and subject-orientated schemes was improved to 99.75% and 99.84% using this unique approach. Machine learning methods, such as neural network applied in this paper, and other popular algorithms including support vector machine, k-nearest neighbor, decision tree, and random forest, are gaining attention in their applications for -omics research and precision medicine to augment translational clinical research, notably by providing the unique advantages of handling high-dimensional data more efficiently than traditional statistical strategies.To the researchers who submitted these accepted manuscripts and those which were not, we are grateful for their shared commitment to improved scientific understanding and thus clinical care. We hope that, in some small way, the cardiovascular computational advances they contain may not only improve the patient care to which they apply but also accelerate the CVD research to which their methodologies can be more broadly adapted. Our patients and populations deserve better care. And so we offer this special issue as a humble step forward, believing in the promise of such computational advances to help speed up the journey for conquering CVD together as a global human family.


Qualitative interview data about everyday remembering within the context of older adults ages 62-83,  and younger adults ages 18-24  lives were collected and analyzed using constructivist grounded theory methods. This study sought to compare the processes used by these individuals in their pursuit of everyday memory-demanding goals and their conceptualization of these methods. Older adults typically reported importance beliefs that guided memory-supportive behaviors for things like social engagements or medical appointments, whereas younger adults reported important information as being primarily school-related. There were major differences in the execution and conceptualization for remembering critical information. Younger adults engaged in a form of socially-distributed cognition, wherein they relied on and outsourced remembering to technology and other people via apps. Interestingly, younger adults relied on others to remind them about coursework, extra-curricular activities, and social obligations via social communication platforms (e.g. GroupMe), text messages, and shared calendar alerts. Very few of the younger adults sampled were responsible for reminding others, but relied on the social altruism of their peers who were responsible for disseminating mass reminders. Conversely, technological outsourcing was not as prevalent in the older adults interviewed and only a few shared that they received similar reminders via text or email. Of the few cases that did outsource, a small subset did, however, engage in these processes within small groups or pairs, wherein a friend or significant other reminded them about social gatherings or names but in a much smaller proportion, comparatively.


Being “fit” does not only improve the sense of well-being, but also has beneficial effects on general health: in fact physical exercise is by all means a low-cost, high-efficacy method for preventing or treating several conditions, ranging from purely physical (diabetes and obesity) to psychological (depression and anxiety), highly influencing male reproduction. If male sexual and reproductive health could be positively affected by a proper physical activity, inadequate bouts of strength – both excessive intensity and duration of exercise training – are more likely to have detrimental effects. In addition, the illicit use of prohibited drugs (i.e. doping) has reached pandemic proportions, and their actions, unfortunately very often underestimated by both amateur and professional athletes, are known to disrupt at different levels and throughout various mechanisms the male hypothalamic-pituitary-gonadal axis, resulting in hypogonadism and infertility.It is universally accepted that lifestyle interventions are the first step towards a good overall, reproductive and sexual health. Cessation of unhealthy habits, such as tobacco, alcohol and drug use, poor nutrition and sedentary behavior, is suggested in order to preserve/improve fertility in humans. However, the possible risks of physical exercise  Lifestyle interventions have been proven to be effective as the first step towards a good general health , 2 and ePhysical exercise and sports have been observed to have the potential for affecting human’s reproduction , in both positive and negative ways. In males, sexual and spermatogenetic functions might be maintained or improved by adequate physical activity, whereas impairments in sexuality and/or in fertility have been observed , 7, 8 foThis review aims to address how physical exercise, sports and doping might either improve or impair reproductive capacity/fertility in males.The physiology of male reproduction is the result of fine tuning between several hormones involved in sexual function and spermatogenesis. For such purpose, the hypothalamus, pituitary and testes act together; therefore, it’s common practice to describe them as a single entity, namely the hypothalamic-pituitary-gonadal (HPG) axis. After puberty, pulsatile release of gonadotropin-releasing hormone (GnRH) from hypothalamic GnRH-secreting neurons stimulates production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from secretory cells of the anterior pituitary; in males, FSH and LH act on the testes, stimulating spermatogenesis and testosterone production respectively. Secretion of GnRH is regulated by negative feedback mechanisms involving inhibin B, and both direct and indirect action from testosterone. Energy balance  dynamicaTestosterone is a widely-known determinant of muscle volume, strength, function and adaptation to exercise-related stress in humans , whether young or older –14; howeDespite lacking evidence in regards to exact mechanisms involved, acute maximal and sub-maximal physical exercise may lead to a rapid increase in serum testosterone concentration, likely resulting in better adaptation and performance in both muscle activity and functional capacity during physical exercise . PhysicaAs previously stated, acute exercise often leads to a transient increase in testosterone levels; on the contrary, a marked decrease in testosterone levels has been suggested in athletes undergoing chronic exercise. Incorrectly executed exercise or poorly developed training programs elicit negative endocrine responses and physiological consequences . The chrTo the present date, several authors have reported the effects of short-term and long-term intensive training: significantly decreased concentrations of total and free testosterone, as well as reduced FSH and LH secretion/pulsatility, and increased SHBG levels have been reported following high-intensity exercise , 32. MorWhether testosterone suppression is the result of a physiological adaptation to stress or an undesirable side effect of excessive training is a matter still open to debate. The best treatment for exercise-induced hypogonadism is to reduce exercise load; however, constant monitoring of androgen status is suggested in all athletes undergoing strenuous training in order to promptly address any issues related to testosterone deficiency.Hormones, including testosterone, act on muscle strength, adaptation to exercise and recovery : therefoGiven its properties, testosterone is in the WADA list of prohibited substances, and therefore athletes in need of treatment should obtain a Therapeutic Use Exemption (TUE) according to the WADA criteria by the respective NADO. To prevent misuse, both clinicians and athletes should respect the official therapeutic indications and authorized formulations/doses . This prReduced global physical exercise (i.e. sedentary behavior) is considered a risk factor for several chronic diseases and conditions, including sexual dysfunction in males , 39; thePremature ejaculation (PE) is the most common male sexual dysfunction, with an estimated prevalence ranging from 8 to 30% up to 22–38% in all age groups . The patPhysically active subjects are more likely to have better sexual health, and are therefore more likely to have sexual activity ; howeverDifferent kinds of physical activity characterized by a different exercise load, might have different effects on sperm parameters . The posEvidence would once again seem to suggest that moderate, healthy exercise is the key for a better overall health, whereas excessive loads of endurance training are more likely to induce worse outcomes, also in terms of fertility .Besides volume and intensity, several factors might affect male fertility in athletes. Physical exercise is often suggested as a means for weight loss: in regards to male fertility, this has proven useful in improving sperm parameters . HoweverDespite a solid body of evidence proving that excessive physical exercise might negatively affect male fertility, there is little knowledge concerning the potential mechanisms involved in the decrease of sperm quality. Exercise-induced hypogonadism is likely to occur in a minority of athletes; therefore, several hypotheses have been postulated in order to correctly address this issue. Any increase in scrotal temperature is likely to impair spermatogenesis by induction of germ cell death: mechanisms include autophagy, DNA damage and apoptosis . EverydaSome kinds of sports have been closely associated with male HPG morpho-functional alterations ultimately resulting in worse sexual function and/or reduced fertility. Brain and spinal cord injuries, as well as local trauma, are often cited as the most prevalent sports-related morpho-functional alterations possibly leading to erectile dysfunction and male infertility.Traumatic brain injuries, as observed in football players  and in kPudendal nerve compression due to cycling is another complex, interesting phenomenon often resulting in urogenital complications . Either Increased abdominal pressure supposedly aggravates the development of varicocele in males. Rigano et al. reported significantly increased prevalence of higher grades of varicocele among athletes compared to non-athletes, with more severe forms affecting those training more than 6 h per week . PhysicaSports-related spinal cord injuries (SCIs) are uncommon outcomes of physical activity, although their rate is remarkably higher in some kinds of sports, such as rugby, diving and horseback riding . The incLast, but not least, the issue of pelvic trauma deserves attention: in fact, more than half of testicular injuries occur during physical activity, most often as a result of blunt force trauma. In the most severe circumstances the resulting testicular damage might lead to primary hypogonadism; furthermore, the creation of anti-sperm autoantibodies might also affect male fertility . TesticuThe “doping epidemics” has crossed the boundaries of elite sports, and now appeals to a wide audience of subjects – from medal-winning athletes aiming to excel in competitions, to amateurs aiming to improve their looks without effort, “appearance and performance-enhancing drugs” (APEDs) use is widespread and seemingly increasing in recent years , 101. ThIt is widely accepted that administration of exogenous testosterone and/or of other androgenic anabolic steroids (AAS) exerts a suppressive effect on the HPG axis . Sexual Up to 2% of cases of male infertility can be explained by AAS abuse, whereas the vast majority of behavior-related infertility in female athletes is the result of excessive exercise . UnsurprAAS suppress intra-testicular testosterone production by inhibition of the HPG axis : therefoA question largely left unanswered is whether administration of AAS during puberty is likely to impair spermatogenesis: reports from over-tall boys treated with high doses of testosterone seem to suggest that recovery time is not different from non-treated subjects , but eviDespite being significantly less common than AAS, several substances have been used in different sports in order to enhance performance; however, negative effects of these drugs have been reported concerning sexual and reproductive function. Beta-blockers, often used in order to reduce anxiety and tremors in precision sports, are likely to worsen erectile function ; furtherPhysical exercise and sports may exert both beneficial and deleterious effects on male sexual and reproductive health, depending on the imposed demands of exercise mode itself. Physical exercise is usually a valid tool in prevention of non-communicable diseases, such as heart disease and obesity, and is therefore generally suggested to all patients as a first-line therapy for a variety of conditions. However, while adequate physical exercise is key to a healthy lifestyle, excessive intensity or volume of training often lead to negative, undesired effects, such as infertility and sexual dysfunction. Furthermore, physical injuries resulting from sports, such as head trauma or spinal cord injuries, might have negative effects on general health, as well as sexual function. In order to identify whether reduced loads of exercise should be suggested in order to reduce the burden on male sexual and reproductive functions, assessment by a trained specialist is recommended for all athletes, whether professional or amateurs. Nevertheless, one must be aware that, especially in the case of professional athletes, it may be unrealistic to modify their training loads. Moreover, doping has a negative impact on male reproductive function, not only on semen quality but having an effect on the endocrine regulatory axis as well as the testes and accessory ducts, and sexual performance as evidenced in both human and animal model studies. This effect has been observed to revert in approximately 1 year upon cessation of substance abuse, except in extreme cases. Some studies assessing the impact of AAS abuse reflect that athletes may later on regret taking them. Therefore, it seems logical that clear and ample information to athletes about possible risks of exercise and AAS abuse is a must.


In most cancers, myeloid cells represent the major component of the immune microenvironment. Deciphering the impact of these cells on tumor growth and in response to various anti-tumor therapies is a key issue. Many studies have elucidated the role of tumor-associated monocytes and tumor-associated macrophages (TAM) in tumor development, angiogenesis, and therapeutic failure. In contrast, tumor dendritic cells (DC) are associated with tumor antigen uptake and T-cell priming. Myeloid subpopulations display differences in ontogeny, state of differentiation and distribution within the neoplastic tissue, making them difficult to study. The development of high-dimensional genomic and cytometric analyses has unveiled the large functional diversity of myeloid cells. Important fundamental insights on the biology of myeloid cells have also been provided by a boom in functional fluorescent imaging techniques, in particular for TAM. These approaches allow the tracking of cell behavior in native physiological environments, incorporating spatio-temporal dimensions in the study of their functional activity. Nevertheless, tracking myeloid cells within the TME remains a challenging process as many markers overlap between monocytes, macrophages, DC, and neutrophils. Therefore, perfect discrimination between myeloid subsets remains impossible to date. Herein we review the specific functions of myeloid cells in tumor development unveiled by image-based tracking, the limits of fluorescent reporters commonly used to accurately track specific myeloid cells, and novel combinations of myeloid-associated fluorescent reporters that better discriminate the relative contributions of these cells to tumor biology according to their origin and tissue localization. In contrast, intra-vital imaging at cellular-scale resolution offers the ability to study cell migration and interactions in living tissue in real-time. It is tempting to consider “truth” what is visible to the eye, and thus direct visualization of cell interactions tends to provide more confidence in the interpretation of a biological process. A main hurdle of this approach rests on the accurate tracking of these cells since the number of available markers are more limited than for flow cytometry and many markers overlap between monocytes, macrophages, DC and even neutrophils, potentially leading to misinterpretations. Moreover, one must keep in mind that imaging experiments usually focus on specific cell subsets, avoiding the potential contribution of the “unseen.” Herein, we review how fluorescent imaging, and more specifically in situ live imaging, has contributed to the characterization of TAM and tumor-DC. We discuss limitations of the most common models used for the discrimination and tracking of these different subsets, and we present some perspectives derived from the combination of different fluorescent reporter mouse strains used to unveil microanatomical niches of myeloid subsets in tumors.Myeloid cells form a vast and heterogeneous group of cells that play a major role in shaping the tumor microenvironment (TME). Tumor associated macrophages (TAM) represent the most abundant myeloid subset across multiple cancer types, and they generally correlate with poor outcomes. Dendritic cells (DC) in tumors represent a less abundant subset, and contradictory results surround their association with tumor prognosis. DC are classified into subpopulations exhibiting different specificity for priming T-cells , 2. Macrin situ has generated fundamental insights in cellular functions and is termed “functional imaging.” Here, we mention studies based on monocyte and TAM imaging to highlight how this approach has contributed to our knowledge of their function within tumors.Microscopy studies represent a necessary approach to truly comprehend the relationship between cells in their physiological environment . Beyond In vitro imaging is an important complementary approach to study the molecular pathways involved in this model. Beyond paracrine loops, the combination of in vitro and in vivo imaging has provided evidence that physical contacts between macrophages and tumor cells correlate with invadopodium formation through the induction of RhoA activity on tumor cells  . EvidencSo far, very little information on the role of tissue-resident macrophages in solid tumors is available from imaging studies. The reporter model used in our recent study has been an interesting option for simultaneous tracking of macrophages of different origins in lung tumors . MoD-TAMSo far, modulating the CCL2/CCR2 axis appears useful in identifying the monocytic origin of TAM. Nevertheless, while the accumulation of tissue resident macrophages has been shown to be CCR2-independent in lung tumors , this suin vivo lung imaging  production is never restricted to a specific subset. Moreover, it is not recommended to associate reporter expression with endogenous protein expression. Therefore, a careful phenotypic characterization of each model using flow cytometry is required to adequately define the imaged cell populations.Many transgenic mice (listed below) have been developed with various fluorescent reporters to attempt to discriminate specific myeloid populations.− mApple+ macrophages would depend more on CSF1 for their homeostasis (The development of a Csf1r-EGFP transgene (MacGreen) has confirmed that this receptor is expressed in monocytes, tissue-resident macrophages and some populations of DC, such as the Langerhans cells; yet is also present in trophoblasts and granulocytes , 40. Theeostasis , 46. TheCx3cr1EGFP reporter mouse  typically provide very bright fluorescent signal and are available in different colors  imaging, for example, allows imaging of lipid deposits showing that a MacApple+ subset is enriched in the adipose tissue of the PyMT tumors (Altogether, these transgenic models have demonstrated utility in providing new insights on the dynamics of different myeloid populations . Furtherribution . TAM micentified . EGFP+ cT tumors  and favoT tumors . WhetherT tumors , 62. TraT tumors . Label-fin vivo fluorescent antibody labeling, dextran uptake, endogenous fluorescent reporters, and label-free optical imaging processes, is likely to yield a full appreciation of the phenotypic and functional diversity of TAM and DC. Fate mapping models to label embryonically derived macrophages might additionally identify tumor myeloid cell origin and will certainly be the goal of imaging studies in the near future. Despite some complexity that can dampen the accurate identification of myeloid subsets in the TME, previous studies have been extraordinarily rewarding in our understanding of tumor-associated myeloid cell biology.The delineation of myeloid heterogenity relies on our ability to multiply the number of simultaneously imaged parameters. Although high-dimensional analysis by flow/mass cytometry and single cell transcriptomics is now accessible, accomplishing this characterization with spatiotemporal resolution using optical imaging remains challenging. Because of the strong overlap of commonly used fluorescent reporters between several myeloid subsets, mouse models must be carefully chosen based on the population of interest. The development of spectral unmixing  may offeThe datasets generated for this study are available on request to the corresponding author.Mouse experimentation were approved by the French animal experimentation and ethics committee and validated by “Service Protection et Santé Animales, Environnement” with the number A-75-2065.ML performed the experiments. All authors wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.