Impact of Myocardial Infarction on Cerebral Homeostasis: Exploring the Protective Role of Estrogen

Abstract

Myocardial infarction (MI), commonly known as a heart attack, results from the rupture of atherosclerotic plaques in coronary arteries, which triggers a series of pathological events including cardiomyocyte death, thrombus formation, and systemic inflammation. These pathological events lead to significant structural and functional changes in the heart, potentially precipitating heart failure. The ramifications of MI extend beyond cardiac dysfunction and impact cerebral health. Accordingly, this review examines the cerebral implications of MI, focusing on how systemic inflammation and reduced cardiac output post-MI affect cerebral blood flow (CBF) and brain function. MI-induced changes in cardiac output can lead to cerebral hypoperfusion, while neuroinflammation and increased blood-brain barrier (BBB) permeability contribute to cognitive decline and neuronal damage, with potential links to Alzheimer's disease (AD). Furthermore, the review explores the role of estrogen in modulating cardiovascular and cerebral health, particularly in post-menopausal women who exhibit distinct cardiovascular risk profiles. Estrogen protects the heart by regulating local renin-angiotensin-aldosterone systems (RAAS) and has significant impacts on brain function. Declining estrogen levels during menopause exacerbate neuroinflammation and cognitive deficits, highlighting the importance of estrogen in maintaining cerebrovascular function. Experimental studies on estrogen replacement therapies, including 17β-estradiol and selective estrogen receptor modulators (SERMs), show potential in mitigating these detrimental effects, enhancing neurogenesis, and improving cognitive outcomes. Estrogen therapy is crucial in preventing cognitive decline and reducing amyloid plaque formation in Alzheimer's models. This review underscores the potential benefits of estrogen therapy in promoting brain recovery post-MI and improving functional outcomes.

Keywords: 17β-estradiol; AD; MI; blood-brain barrier; cerebral hypoperfusion; cognitive decline; heart failure; inflammation; menopause.

Figure 1.

Pathophysiological Pathways Linking Myocardial Infarction to Cognitive Decline. This diagram illustrates the mechanisms by which cardiovascular dysfunction contributes to cognitive impairment. Reduced cardiac function, indicated by decreased EF and CO, triggers systemic inflammation which causes release of cytokines and the activation of perivascular macrophages through angiotensin II signaling. This cascade disrupts CBF, promoting the production of ROS, Aβ aggregation, and tissue injury which exacerbates neuroinflammation. Neuroinflammation activates microglia and astrocytes, further leading to the release of pro-inflammatory cytokines. These processes compromise the integrity of the BBB, facilitating the progression of cognitive impairment. This figure was created with BioRender.com. EF, ejection fraction; CO, cardiac output; CBF, cerebral blood flow; ROS, reactive oxygen species; Aβ, amyloid beta; BBB, blood-brain barrier; +, increase; -, decrease.

Figure 2.

The Role of Estrogen in Cardiac and Brain Cellular Mechanisms: Impacts on Health and Disease. This illustration highlights the effects of E2 on cardiac and brain cells via ER-mediated pathways. In cardiac cells, estrogen enhances vasodilation through NO signaling, reduces fibrosis by upregulating VEGF and Lyve-1, and lowers LDL levels via ApoB-100 regulation. Conversely, it inhibits detrimental effects, such as superoxide and TNF-α production, while modulating Ca2+ accumulation in mitochondria. In brain cells, E2 promotes neuroprotection by increasing hippocampal neurogenesis (via BDNF) and synaptic plasticity (PSD95) while supporting vasodilation (PGI2). It mitigates neuroinflammatory responses by inactivating microglia (Cx3CR1), suppressing pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and enhancing Aβ degradation through NEP regulation. Additionally, estrogen inhibits apoptotic pathways by decreasing cytochrome c release and caspase activation. These pathways demonstrate estrogen’s role in reducing oxidative stress, balancing mitochondrial function, and influencing gene expression to protect against cardiovascular and neurodegenerative diseases. This figure was created with BioRender.com. E2, estrogen; ER, estrogen receptor; NO, nitric oxide; VEGF, vascular endothelial growth factor; Lyve-1, Lymphatic vessel endothelial hyaluronan receptor 1; LDL, low-density lipoprotein; ApoB, Apolipoprotein B; TNF-α, tumor necrosis factor alpha; BDNF, brain-derived neurotrophic factor; PSD95, postsynaptic density 95; PGI2, prostaglandin I2; Cx3CR1, CX3C chemokine receptor 1; IL-1β, interleukin 1beta; IL-6, interleukin 6; Aβ, amyloid beta; NEP, neprilysin; , increase; , decrease. +, upregulation; -, downregulation.