Cerebral derailment after myocardial infarct: mechanisms and effects of the signaling from the ischemic heart to brain

Abstract

Myocardial infarction (MI) is the leading cause of death among ischemic heart diseases and is associated with several long-term cardiovascular complications, such as angina, re-infarction, arrhythmias, and heart failure. However, MI is frequently accompanied by non-cardiovascular multiple comorbidities, including brain disorders such as stroke, anxiety, depression, and cognitive impairment. Accumulating experimental and clinical evidence suggests a causal relationship between MI and stroke, but the precise underlying mechanisms have not yet been elucidated. Indeed, the risk of stroke remains a current challenge in patients with MI, in spite of the improvement of medical treatment among this patient population has reduced the risk of stroke. In this review, the effects of the signaling from the ischemic heart to the brain, such as neuroinflammation, neuronal apoptosis, and neurogenesis, and the possible actors mediating these effects, such as systemic inflammation, immunoresponse, extracellular vesicles, and microRNAs, are discussed.

Keywords: EVs; Myocardial infarct; Neuroinflammation; Stroke; miRNAs.

Fig. 1

Mechanisms and cerebral effects of heart–brain interaction after MI. Brain alterations after MI may be caused by several mechanisms, including systemic inflammation, activation of the renin–angiotensin–aldosterone system (RAAS), circulating cardiac-derived DAMPs, EVs, and miRNAs, and reduced cardiac output

Fig. 2

Potential pathways of cytokines, miRNAs, and EV passage across the BBB. Cytokines and miRNAs could cross BBB through EV-mediated transcellular routes, such as macropinocytosis, adsorptive mediated transcytosis, and clathrin-mediated transcytosis. In addition to transcellular routes, the breakdown of tight junction by DAMPs or inflammatory mediator may increase the permeability of cytokines and EVs at the paracellular route

Fig. 3

The possible role of miRNAs released from the heart after MI in mediating cerebral effects. An overview of the molecular mechanisms and cerebral effects of the miRNAs whose expression are increased in the peripheral blood of patients with MI and for which it has been reported an involvement in cerebral physiological and pathological conditions

Fig. 4

Summary of mechanisms for neuroinflammation after MI. Circulating pro-inflammatory cytokines, DAMPs, and angiotensin II (Ang II) released from the ischemic heart reach the brain through the blood. Here, they can compromise integrity and enhance permeability of BBB, reducing the expression of junctional proteins such as ZO-1, occludin, and claudin-5. Ang-II and pro-inflammatory cytokines induce the activation of astrocytes and stimulate resting microglia to assume the pro-inflammatory M1 phenotype, which is induced also by the excessive release of ATP from activated astrocytes. In turn, M1 microglia and activated astrocytes produce large amounts of cytokines and ROS, which perpetuate neuroinflammation and lead to enhanced neuronal apoptosis and decreased neurogenesis. Furthermore, they produce an imbalance between excitatory and inhibitory neurotransmission, potentiating excitatory (glutamatergic and adrenergic) currents and inhibiting GABAergic currents