Sex Differences in Therapies against Myocardial Ischemia-Reperfusion Injury: From Basic Science to Clinical Perspectives

Abstract

Mortality from myocardial infarction (MI) has declined over recent decades, which could be attributed in large part to improved treatment methods. Early reperfusion is the cornerstone of current MI treatment. However, reoxygenation via restored blood flow induces further damage to the myocardium, leading to ischemia-reperfusion injury (IRI). While experimental studies overwhelmingly demonstrate that females experience greater functional recovery from MI and decreased severity in the underlying pathophysiological mechanisms, the outcomes of MI with subsequent reperfusion therapy, which is the clinical correlate of myocardial IRI, are generally poorer for women compared with men. Distressingly, women are also reported to benefit less from current guideline-based therapies compared with men. These seemingly contradicting outcomes between experimental and clinical studies show a need for further investigation of sex-based differences in disease pathophysiology, treatment response, and a sex-specific approach in the development of novel therapeutic methods against myocardial IRI. In this literature review, we summarize the current knowledge on sex differences in the underlying pathophysiological mechanisms of myocardial IRI, including the roles of sex hormones and sex chromosomes. Furthermore, we address sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics of current drugs prescribed to limit myocardial IRI. Lastly, we highlight ongoing clinical trials assessing novel pharmacological treatments against myocardial IRI and sex differences that may underlie the efficacy of these new therapeutic approaches.

Edgeworthia gardneri (Wall.) Meisn. Ethanolic Extract Attenuates Endothelial Activation and Alleviates Cardiac Ischemia-Reperfusion Injury

“…It is noteworthy that sex differences play essential roles in determining the pharmacokinetics and pharmacodynamics of drugs. Previous studies have demonstrated that many cardiovascular drugs display sex-biased responses [ 52 ], and emerging evidence from clinical trials indicates that the efficacy of various new drugs targeting cardiac I/R injury is associated with potential sex differences [ 53 ]. This study showed that EG extract protects against cardiac I/R injury in male rats, but its pharmacological action on female animals is still unclear.…”

Functions of RNA-Binding Proteins in Cardiovascular Disease

“…MI due to atherosclerotic or thrombotic occlusion of coronary arteries leads to ischemia in the myocardium. While rapid reperfusion is the cornerstone of current MI treatment, restoring blood flow leads to further damage to the myocardium by causing ischemia-reperfusion injury (IRI) [4]. An IRI is characterized by oxidative stress, cell death, inflammation, and fibrosis.…”

“…MI due to atherosclerotic or thrombotic occlusion of coronary arteries leads to ischemia in the myocardium and cardiomyocyte death. Rapid reperfusion is the cornerstone of current MI treatment, but restoring blood flow leads to further damage to the myocardium by causing ischemia-reperfusion injury (IRI) [4]. Cardiac fibrosis is excessive extracellular matrix production and contributes to numerous cardiac disorders by impairing myocardial compliance, contractility, and electrical conductance [5].…”

Effect of long-term inorganic nitrate administration on myocardial ischemia-reperfusion injury in ovariectomized rats

“…Time-dependent effects of nitrate in OVX rats have been reported previously; for example, glucose-lowering and anti-osteoporotic effects of nitrate have been observed only after 6 months of intervention ( Yousefzadeh et al, 2022b ; Yousefzadeh et al, 2022c ). In addition, compared to males, following ischemia, females have reduced myocardial IR injury ( Besík et al, 2007 ) and infarct size ( Bae and Zhang, 2005 ), as well as higher eNOS and neural NOS (nNOS) expression ( Sun et al, 2006 ) and lower apoptosis ( Chen et al, 2013 ; Medzikovic et al, 2023 ) in heart tissue. Therefore, the current study was designed to investigate whether the long-term (9 months) nitrate administration provides resistance against myocardial IR injury in OVX rats.…”