Expert consensus document: Mitochondrial function as a therapeutic target in heart failure

Abstract

Heart failure is a pressing worldwide public-health problem with millions of patients having worsening heart failure. Despite all the available therapies, the condition carries a very poor prognosis. Existing therapies provide symptomatic and clinical benefit, but do not fully address molecular abnormalities that occur in cardiomyocytes. This shortcoming is particularly important given that most patients with heart failure have viable dysfunctional myocardium, in which an improvement or normalization of function might be possible. Although the pathophysiology of heart failure is complex, mitochondrial dysfunction seems to be an important target for therapy to improve cardiac function directly. Mitochondrial abnormalities include impaired mitochondrial electron transport chain activity, increased formation of reactive oxygen species, shifted metabolic substrate utilization, aberrant mitochondrial dynamics, and altered ion homeostasis. In this Consensus Statement, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria.

Figures

Figure 1. Energy supply–demand matching in health and heart failure

The delicate balance between cardiac demands for energy and supply of energy is tipped in heart failure, in which energy supply cannot match demand. Next-generation therapeutics can improve on existing standard-of-care therapies by bolstering mitochondrial energy production. ACE, angiotensin-converting enzyme; ARB, angiotensin II-receptor blocker; ETC, electron transport chain; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; ROS, reactive oxygen species.

Figure 2. Impaired mitochondrial capacity and function in heart failure

Decreased capacity of mitochondria to generate and transfer energy within heart cells results in energy deficits, which influences all cellular processes that require energy, most notably the processes of contraction and relaxation.

Figure 3. Mitochondrial contribution across multifaceted symptoms of heart failure

Aberrant mitochondrial energy production is involved in many symptoms commonly found in patients with heart failure, including skeletal muscle dysfunction and renal pathologies. LV, left ventricular.

Figure 4. Impaired mitochondrial energy production along the inner membrane

Enzyme complexes responsible for energy production are packed into the mitochondrial inner membrane, often with the help of phospholipids such as cardiolipin. Failing mitochondria often display altered morphology, decreased ATP-generating capacity, heightened production of reactive oxygen species (ROS), abnormal cardiolipin levels, and impaired supercomplexes.