Increased Myocardial MARK4 Expression in Patients with Heart Failure and Sleep-Disordered Breathing

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide, underscoring the urgent need for novel therapeutic targets and strategies. The kinase MARK4 (MAP (microtubule-associated proteins)/microtubule affinity-regulating kinase 4) regulates microtubule-associated proteins pivotal for cell polarity, protein stability, and intracellular signaling. Animal models of heart failure revealed elevated MARK4 levels, which correlated with impaired cardiac contractility. However, the involvement of MARK4 and its potential as a molecular drug target has not yet been explored in the myocardium of cardiovascular patients. We investigated the MARK4 mRNA expression in human myocardial biopsies of 152 high-risk cardiovascular patients undergoing cardiac surgery. Comprehensive echocardiography as well as testing for sleep-disordered breathing (SDB), a critical comorbidity in heart failure, were assessed preoperatively. We observed a substantial upregulation of myocardial MARK4 expression in patients with impaired cardiac contractility, resulting in an inverse correlation with the left ventricular ejection fraction. Myocardial MARK4 expression also correlated with echocardiographic E/e', a central parameter of diastolic dysfunction. Mechanistically, our analyses revealed that MARK4 expression increases in SDB and under hypoxic conditions, as evidenced by significant correlations between myocardial MARK4 expression and factors like mean oxygen saturation, time with oxygen saturation below 90%, and the oxygen desaturation index. Multivariable regression analysis revealed that both left ventricular ejection fraction and mean oxygen saturation were independently associated with dysregulated MARK4 levels, even when controlling for important clinical covariables as potential confounders. Taken together, our findings demonstrate that MARK4 expression is highly increased in the myocardium of cardiovascular high-risk patients, suggesting it is a potential molecular target against cardiovascular diseases.