Fioranelli M. Front Immunol. 2018 Sep 6;9:2031.
Fioranelli M. et al., conducted a study which reviewed 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 explanation on the importance of the central and autonomic regulation of cardiac functions, namely, the neuro-cardiac axis was done. 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 were highlighted. Specific sections related to stress-induced myocardial ischaemia measurements and stress cardiomyopathy was also included.
New Vision of Coronary Heart Disease
- Serum high sensitivity C-reactive protein (hs-CRP) was the principle marker of underlying systemic inflammation and a significant predictor of cardiovascular risk, also in a subgroup of women with low LDL cholesterol
- A key role for inflammation in atherosclerotic disease highlighted an increased risk of cardiovascular events in patients with high levels of CRP irrespective of cardiovascular risk assessment and lipid profiles
- A higher CRP level is also associated with a recurrent risk of myocardial infarction, incidence of sudden death and peripheral arterial disease in patients with acute coronary syndrome
The Inflammatory Cascade in Ischaemic Myocardial Injury
- TLR2 (toll-like receptors) and TLR4 are the most representative subtypes in human hearts
- NOD1 and the NLRP3 subtype play critical roles in cardiac remodelling following myocardial infarction and ischaemia/reperfusion damage and have been demonstrated to activate inflammasomes in the heart
- Endogenous DAMPs activated the complement system with increased C3 fragments in infarcted myocardial tissue showed development of leukocyte translocation in injured myocardium
- Nuclear factor kB (NF-kB), a highly conserved DNA transcription factor, drives the production of cytokines, interferons, and chemokines in the myocardial infarction zone initiated via the TLR and NOD pathways, complement system, and ROS products
- Interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-a), the main pro-inflammatory cytokines released in the injured myocardium, mediated the synthesis of more chemotactic
factors that enhance leukocyte recruitment into the infarct area and played important roles in inflammasome assembly and IL-1b and interleukin 18 (IL-18) maturation
Mast Cells and Cardiac Events
- Mast cells play a critical role in the fibrous cap erosion of atherosclerotic plaques and in coronary vasospasms induced by vasoactive and inflammatory mediators in response to mechanical or hypoxic stress
Neutrophils in Ischaemic Injury
- Neutrophils were the most prevalent and efficacious leukocytes of innate immunity in preventing pathogens dissemination
- Neutrophil recruitment in the myocardium can be activated by both cardiac ischaemic injury and pressure overload
- Neutrophils showed a decisive role in ischaemia/reperfusion injury through the production of proteases that significantly impair cardiac function
Monocytes, Tissue Macrophages, and Myocardial Infarction
- Ly6CHi monocytes removed necrotic tissue showed 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 enrollment in the human heart depends on innate B cells, which drive monocyte expansion in a CCL7-dependent fashion into ischaemic cardiac tissue
- MHC-II Hi and MHC-II Low macrophages phagocytize apoptotic cells were more efficient than non-embryonic macrophages and developed angiogenesis and render neonatal cardiomyocytes more responsive to proliferative stimuli through minimal inflammation
T and B Cells and Cardiac Events
- T cells in elderly subjects showed cardiac inflammation and functional impairment, even in the absence of organ damage or ongoing infection
- B lymphocytes, both tissue-resident and circulating cells, had a fundamental role in heart homeostasis
- B1 subset had an athero-protective role and drives LDL-ox removal through binding with IgM antibodies and B2 subset has been classified as pro-atherogenic.
The Heart as an Endocrine Gland
- Granules similar to those found in endocrine cells in the cardiac atria has an ability to lower blood pressure through potent diuretic and natriuretic effects and are classified into three main subtypes:
- Atrial natriuretic peptide (ANP)
- Brain natriuretic peptide (BNP)
- Type C natriuretic peptide (CNP)
- ANP release is increased into the bloodstream due to any haemodynamic condition determining atrial distention (i.e., volume expansion with saline solution, water immersion, postural changes, a high quantity of ingested salt, fluid overload due to diastolic cardiac impairment)
- Brain natriuretic peptide (BNP) responds to ventricular wall distension due to volume or pressure overload and was highly expressed in the ventricular myocardium. C-type natriuretic peptide (CNP) exerts a weak endocrine natriuretic effect and acts as a paracrine factor for the control of vascular tone and was diffused throughout the central nervous system and vascular endothelium
- Natriuretic peptides maintained extracellular fluid homeostasis and controlled blood pressure boosters through increased urinary sodium excretion and vasodilation
Psychosocial Factors
Key determinants of CV morbidity and mortality are social inequalities and behavioral factors.
Other combined variables associated with increased risk of CVD mortality were:
- High-strain work (low control and high demands) and low social support
- Presence of financial difficulties in lower employment grades was a risk factor for weight gain and metabolic alterations, especially in female workers
- Social isolation and loneliness, were associated with a 50% increased risk of CVD; work-related stress showed a 40% risk of new CV events
- Adverse early life events, including social deprivation and discrimination during childhood and adolescence
Emotions and Cardiovascular Disease
- The presence of depressive symptoms are positively correlated with the risk of incident stroke.
- A high anxiety score is a recognized risk factor linked to coronaropathy
- Anxiety is commonly diagnosed together with depressive disorder. Diagnosis of post-traumatic stress disorder (PTSD) was found to be an established risk factor for acute coronary events in the general population
- Positive thoughts, emotions and social cohesion increased resilience affect health trajectories in cardiovascular diseases
Stress and Neuroendocrine Patterns in CVD
- Stress had a complex psycho-neuroimmuno- endocrine responses that primarily involves both the hypothalamic–pituitary–adrenal (HPA) axis and the autonomic nervous system (ANS)
- ANS and HPA showed both short and long-term changes in behaviour, cardiovascular functions, endocrine and metabolic signals
- Altered HPA axis function showed negative effects on the cardiovascular system leading to atherosclerotic plaque formation, high blood pressure, insulin resistance, dyslipidaemia, and central adiposity
- 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
- Obesity had a risk for CVD through elevations in basal levels of cortisol, inflammatory cytokines and hormones such as leptin and insulin
Circadian Rhythms and Cardiovascular Health
- Sleep is the most important circadian synchronizer in human organisms, lifestyle habits
- Sleep is related to organic conditions such as obstructive apnoea, insomnia or neurologic and psychiatric diseases caused sleep deprivation
- Short sleep duration is associated to increased incidence of hypertension, coronary artery disease, arrhythmias, obesity and diabetes
- One single sleepless night influenced the cardiovascular autonomic response toward sympathetic predominance and induced systemic inflammation through increased IFN-g secretion
- Lower sleep efficiency among women aged 40–60 exhibited an increase in circulating IL-6 and von Willebrand factor (pro-thrombotic factor)
Stress-Induced Myocardial Ischaemia
- Mental Stress-Induced Myocardial Ischaemia (MSIMI) is a provocative test that provides psychological rather than physical stimuli, leading to reversible myocardial ischaemic damage.
- The following heterogenic haemodynamic features result in myocardial transient ischaemia associated with MSIMI:
- 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.
Myocardial Infarction with Normal Coronary Arteries (MINCA): Takotsubo Stress Cardiomyopathy
- Takotsubo stress cardiomyopathy (TTC) is an acute systolic and diastolic dysfunction of the left ventricle that occurs in patients without a history of CAD constitutes approximately 30% of total MINCA (myocardial infarction with normal coronary arteries)
- TTC patients showed excessive catecholamine and NPY release with subsequent coronary vasospasm, leading to a pathological reduction in myocardial blood flow and alterations to parietal kinetics
- Young patients affected by physically triggered TTC with acute neurological or psychiatric diseases showed a higher risk of complications and death than elderly patients with emotional triggers
Thus, it was concluded that the psychoneuroendocrineimmunology paradigm could make a fundamental contribution to treat major cardiovascular diseases.
NOD: Nucleotide binding and oligomerization domain, NLRP3: nucleotide-binding domain and leucine-rich repeat containing (NLR) family member pyrin domain-containing protein 3
