Prevention of heart failure with preserved ejection fraction (HFpEF): reexamining microRNA-21 inhibition in the era of oligonucleotide-based therapeutics.

Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of cases of heart failure, which is the most common cause of hospitalization in US patients over the age of 65. HFpEF pathogenesis is increasingly believed to be due to pathological hypertrophy and fibrosis of the myocardium that may be a result of systemic inflammation from comorbid conditions such as hypertension, diabetes mellitus, chronic obstructive pulmonary disease, anemia, chronic kidney disease and others. It is believed that oxidative stress triggers a process of pathological hypertrophy and fibrosis in cardiac endothelial cells, which leads to increased left ventricle filling pressures and, eventually, symptoms of heart failure. Numerous recent major clinical trials that have examined various therapies aimed at improving mortality in HFpEF have emerged empty-handed and thus the search for effective management strategies continues. Over the last several years, there have been many new developments in the field of antisense oligonucleotide-based therapeutics, which involves using noncoding nucleic acid particles such as microRNA and small interfering RNA to repress the expression of specific messenger RNA. In this article, we review the concept of using oligonucleotide-based therapeutics to prevent or treat HFpEF by targeting a specific microRNA that has been implicated in the pathogenesis of myocardial fibrosis and hypertrophy, microRNA-21 (miR-21). We review the various evidence that implicates miR-21 in the process of myocardial fibrosis and discuss recent attempts to use antimiR-21 compounds to prevent fibrosis. We also discuss proposed methods for screening patients at high risk for HFpEF for diastolic dysfunction in order to determine which patients.