Abstract
Diastolic heart failure, also referred to as heart failure with preserved ejection fraction (HFpEF), is a complex cardiovascular clinical syndrome that is a growing health burden worldwide. Patients present with high abnormal left ventricular filling pressures but normal ejection fraction that can progress to diastolic heart failure and death. The causes of diastolic dysfunction are varied, and pharmacotherapies are limited to managing the symptoms of the disease. At the level of the myocyte, cytoskeletal disarray and mitochondrial dysfunction are common features associated with diastolic disease. Understanding the mechanisms of abnormal diastolic filling pressures is necessary to identify novel treatments, which remains an area of significant unmet need. In this article, we discuss the mechanisms of maladaptive feedback contributing to increased extracellular stiffness, cytoskeletal disarray, and mitochondrial dysfunction in diastolic heart failure. Since the mechanisms are complex, understanding the contributing factors provides opportunities for the development of novel drug targets. These will be discussed and examined in the context of current therapy.