Understanding the heart-brain axis response in COVID-19 patients: A suggestive perspective for therapeutic development

Abstract

In-depth characterization of heart-brain communication in critically ill patients with severe acute respiratory failure is attracting significant interest in the COronaVIrus Disease 19 (COVID-19) pandemic era during intensive care unit (ICU) stay and after ICU or hospital discharge. Emerging research has provided new insights into pathogenic role of the deregulation of the heart-brain axis (HBA), a bidirectional flow of information, in leading to severe multiorgan disease syndrome (MODS) in patients with confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Noteworthy, HBA dysfunction may worsen the outcome of the COVID-19 patients. In this review, we discuss the critical role HBA plays in both promoting and limiting MODS in COVID-19. We also highlight the role of HBA as new target for novel therapeutic strategies in COVID-19 in order to open new translational frontiers of care. This is a translational perspective from the Italian Society of Cardiovascular Researches.

Sex-related susceptibility in coronavirus disease 2019 (COVID-19): Proposed mechanisms

“…SARS-CoV-2 triggers a dysfunction in endothelial cells, causing apoptosis ( Varga et al, 2020 ). This conception is supported by the fact that microvascular endothelial cells express ACE2 and, therefore, are susceptible to SARS-CoV-2 entry ( Lionetti et al, 2021 ). The vascular and neuronal circulation of SARS-CoV-2 is thought to induce heart-brain axis (HBA) dysfunction ( Lionetti et al, 2021 ).…”

“…ACE2 is also expressed in neurons ( Yashavantha Rao and Jayabaskaran, 2020 ). SARS-CoV-2 could enter the central nervous system (CNS) and cause neurological diseases by impairing the crosstalk between neuronal and vascular components of the CNS ( Desforges et al, 2014 ; Lionetti et al, 2021 ). SARS-CoV-2 triggers a dysfunction in endothelial cells, causing apoptosis ( Varga et al, 2020 ).…”

Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

“…ROS are involved in several biological processes such as cellular growth, immune response, embryogenesis, spermatozoa capacitation, and transcription factor activation [ 44 , 65 ]. Furthermore, ROS regulate vascular functions (e.g., vasodilatation, vasoconstriction, angiogenesis, migration, and apoptosis) [ 41 , 44 , 45 , 46 ]. Thus, there is a finely regulated balance between ROS production and ROS degradation [ 46 ].…”

“…TRPM2 was also found to mediate H 2 O 2 -induced cell death in brain microvascular endothelium [ 228 ]. In addition to providing the building blocks for the BBB [ 293 ], brain microvascular endothelial cells are emerging as crucial regulators of neuronal activity and cerebral blood flow under both physiological and pathological conditions [ 24 , 25 , 41 ]. Iadecola’s group first showed that amyloid β 1-40 (Aβ 1-40 ), whose extracellular accumulation on brain microvessels is now regarded as the primary trigger of the pathogenic pathways leading to neuronal damage and dementia [ 294 ], may induce endothelial dysfunction by promoting TRPM2-mediated cytosolic Ca 2+ overload [ 38 ].…”

“…Distinct spatiotemporal endothelial Ca 2+ signals tightly regulate different functions such as nitric oxide (NO) release [ 10 , 11 , 12 ] and endothelium-dependent hyperpolarization (EDH) [ 13 ], vascular permeability [ 14 , 15 ] and repair [ 16 , 17 ], platelet aggregation and blood coagulation [ 18 , 19 ], leukocyte/lymphocyte infiltration [ 20 , 21 , 22 , 23 ], neurovascular coupling [ 24 , 25 ], wound healing [ 16 , 17 ], angiogenesis [ 5 , 26 ], and vasculogenesis [ 27 ]. An aberrant, i.e., resulting either from intracellular Ca 2+ overload or by the dismantling of a specific oscillatory Ca 2+ pattern, or insufficient elevation in [Ca 2+ ] i may lead to endothelial dysfunction and therefore severely compromise cardiovascular homeostasis, as reported in atherosclerosis [ 28 ], hypertension [ 29 , 30 ], pulmonary artery hypertension (PAH) [ 31 ], type 2 diabetes [ 8 , 32 , 33 ], aging [ 34 ], inflammatory disorders [ 21 , 22 , 35 , 36 , 37 ], Alzheimer’s disease, and cerebrovascular dysfunction [ 34 , 38 , 39 , 40 , 41 ]. Therefore, the endothelial [Ca 2+ ] i must be tightly regulated by a sophisticated network of membrane receptors, ion channels, pumps, transporters, and cytosolic Ca 2+ buffers to prevent the onset of inappropriate Ca 2+ signals that could hamper the cardiovascular system [ 1 , 2 , 8 , ...…”