Mitochondria are the power plants of the cell, and when their activity falters, cell and tissue function suffers as a consequence. Unfortunately mitochondrial dysfunction is a feature of aging, and is connected to the progression and severity of numerous age-related conditions. The research here examines age-related mitochondrial decline in the context of heart failure. As is appropriate for this new era of intervention in the aging process, the focus is on what might be done about this. At the very least, the evidence suggests that even early approaches that can only somewhat restore mitochondrial function in the old, such as NAD+ upregulation or mitochondrially targeted antioxidants, might produce benefits in heart failure patients. Better methodologies capable of greater restoration of mitochondrial function are very much required, however.
The burden of heart failure (HF) in terms of health care expenditures, hospitalizations, and mortality is substantial and growing. The failing heart has been described as "energy-deprived" and mitochondrial dysfunction is a driving force associated with this energy supply-demand imbalance. Existing HF therapies provide symptomatic and longevity benefit by reducing cardiac workload through heart rate reduction and reduction of preload and afterload but do not address the underlying causes of abnormal myocardial energetic nor directly target mitochondrial abnormalities.
Numerous studies in animal models of HF as well as myocardial tissue from explanted failed human hearts have shown that the failing heart manifests abnormalities of mitochondrial structure, dynamics, and function that lead to a marked increase in the formation of damaging reactive oxygen species (ROS) and a marked reduction in on demand adenosine triphosphate (ATP) synthesis. Correcting mitochondrial dysfunction to enhance the energy supply of the failing heart to meet the desired energy needs offers considerable potential to improve cardiac function, reduce symptoms, and improve exercise tolerance in HF, and ultimately offer improved quality of life and survival for patients, and reduce the overall economic burden of this condition.
Elamipretide (SS-31) is a water-soluble, aromatic-cationic mitochondria-targeting tetrapeptide that readily penetrates and transiently localizes to the inner mitochondrial membrane and associates with cardiolipin to restore mitochondrial bioenergetics. Studies in dogs with coronary microembolization-induced chronic HF showed that 3 months of treatment with daily subcutaneous injections of elamipretide improved left ventricle (LV) systolic function and prevented progressive LV dilation without affecting heart rate, blood pressure, or systemic vascular resistance. Elamipretide also elicited a normalization of mitochondrial function evidenced by improved respiration, normalization of membrane potential, reduced ROS formation, and improved maximum rate of ATP synthesis.