The pathophysiology of heart failure is complex, but mitochondrial dysfunction is an emerging therapeutic target to improve cardiac function. 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.
Mitochondria and the heart
The importance of mitochondria in cardiovascular pathophysiology and the potential of targeting mitochondrial dysfunction for clinical interventions to improve cardiac function have been increasingly recognized over the past decade. Nature Reviews Cardiology brings together a collection of the most recent articles from Nature Research journals that highlight the role of mitochondria in the heart, from mitochondrial energy production to redox signalling or mitochondrial calcium efflux, and the new opportunities for mitochondria-targeted therapies in cardiac diseases, for example, to modify the defect in energy substrate utilization associated with heart failure or to mitigate ischaemia–reperfusion injury.
Strategies to reduce myocardial infarct size beyond early reperfusion have thus far yielded disappointing results in clinical trials. In this Review, Kloner and co-workers discuss several new approaches to preserve the reperfused myocardium, including those that target mitochondrial bioenergetics and autophagy.
Mitochondrial metabolism is essential for the dynamic regulation of cardiac and vascular tissues, and the relevance of basic mitochondrial biology in cardiovascular disease is being increasingly recognized. In this Review, the authors explore the physical interaction between mitochondria and sarco/endoplasmic reticulum, discussing how the communication between these two organelles is involved in cardiovascular pathologies.
Autophagy is a ubiquitous cellular catabolic process responsive to energy stress. Activation of autophagy is cardioprotective in some settings (ischaemia and ischaemic preconditioning), but sustained autophagy has been linked with cardiopathology in other settings (prolonged pressure overload and heart failure). In this Review, induction of autophagy associated with cardiac benefit or detriment is considered, and prospects for pharmacological intervention are discussed.
In this Perspectives article, Ormerod et al. propose that dynamic left ventricular systolic dysfunction provoked by obstruction in hypertrophic cardiomyopathy is a manifestation of inefficient cardiac energy utilization. This mid-systolic drop in left ventricular Doppler ejection velocities has been termed the 'lobster claw abnormality'. Energy insufficiency is also present in nonobstructive hypertrophic cardiomyopathy, and this paradigm might suggest novel therapies.
Ischaemic conditioning is an endogenous cardioprotective strategy that involves the application of brief cycles of ischaemia and reperfusion either directly to the heart, or to a remote organ or tissue, and which has been shown to reduce infarct size. In this Review, Hausenloy and Yellon summarize the various forms of ischaemic conditioning and pharmacological cardioprotection, and highlight the challenges of translating these methods into the clinical setting.
Derailment of cellular protein homeostasis (proteostasis) and loss of protein quality control (PQC) are central factors in ageing and contribute to cardiovascular disease. In this Review, Henning and Brundel describe the mechanisms by which PQC can fail. Targeting PQC to maintain cardiac proteostasis offers a novel therapeutic strategy to promote cardiac health and combat cardiac disease.
Nicotinamide adenine dinucleotide (NAD+) depletion contributes to the pathogenesis of cardiac and renal diseases. Here, the authors review the roles of NAD+ in the heart and kidney and discuss the mechanisms by which NAD+ supplementation might have therapeutic efficacy, with a focus on the role of mitochondrial sirtuins.