Review Articles

Mitochondrial dysfunction has a major role in the pathogenesis of multiple cardiovascular disorders. In this Review, Galluzzi and colleagues discuss the therapeutic potential of mitochondria-targeting agents in the treatment of cardiovascular disease, examine the obstacles that have limited their development thus far, and identify strategies for the development of these promising therapeutic tools.

The benefits of regular exercise extend beyond its effect on cardiovascular disease (CVD) risk factors. In this Review, the authors outline the non-traditional mechanisms underlying the benefits of exercise in CVD and highlight the importance of a holistic view of exercise in cardiovascular health.

This Review summarizes the current understanding on the roles of the Hippo–YAP pathway in cardiac development, growth, homeostasis, disease, and regeneration, with a particular focus on the roles of the Hippo–YAP pathway in endogenous cardiac muscle renewal, including the pivotal role of this pathway in regulating cardiomyocyte proliferation, differentiation, stress response, and mechanical signalling.

Inflammageing is a chronic, pro-inflammatory state that develops with age and is a risk factor for cardiovascular disease, comorbidities, frailty, and death. In this Review, Ferrucci and Fabbri discuss whether therapies to modulate inflammageing can reduce the age-related decline in health.

Various intrinsic and extrinsic factors influence the balance between cellular renewal and senescence in the ageing heart. In this Review, Gude and colleagues discuss these factors, including environment, lifestyle, genetics and epigenetics, inflammation, and oxidative stress, and how they might be therapeutically targeted.

Alterations in mitochondrial function, which are amplified by defective mitochondrial quality control (MQC) mechanisms, are major contributing factors to cardiac senescence. In this Review, the authors discuss the mechanisms linking defective MQC to organelle dysfunction in the context of cardiac ageing and consider how these pathways might be targeted for the prevention and treatment of age-related heart dysfunction.

In this Review, a panel of leading experts in antithrombotic pharmacotherapy discuss the principles guiding the role of acetylsalicylic acid (aspirin)-free strategies in the prevention and management of cardiovascular disease, along with their implications for clinical trial design and development.

Familial hypercholesterolaemia (FH) is the most commonly encountered genetic condition that predisposes to premature cardiovascular disease. In this Review, Berberich and Hegele revisit the genetic complexity of FH and discuss our revised understanding of the mechanisms of FH and the implications for screening, diagnosis, and patient management.

The epicardium is a multipotent cardiac progenitor tissue that serves as a crucial signalling centre for heart development and repair. This Review describes recent advances in our understanding of the biology of the epicardium and discusses the potential to harness the properties of the epicardium to develop therapeutic strategies for heart repair and regeneration.

In patients with heart failure, derangements of substrate utilization and intermediate metabolism, an energetic deficit, and oxidative stress are thought to underlie contractile dysfunction and disease progression. In this Review, Bertero and Maack describe the physiological processes of cardiac energy metabolism and their pathological alterations in heart failure and diabetes mellitus, and discuss promising treatments targeting substrate utilization or oxidative stress in mitochondria.

In this Review, Christoffels and colleagues detail the transcriptional networks that control development and homeostasis of the cardiac conduction system. The pathophysiological consequences of aberrations in these networks are also discussed, with potential insights into the generation of biological pacemakers.

This Review discusses the advances in therapeutic approaches for cardiac repair and regeneration, including cell-based therapies as well as the use of secretory factors, such as microRNAs and exosomes, direct reprogramming strategies, and gene editing to control cardiac remodelling and redirect the adult heart to a regenerative state, and highlights the future prospects of preclinical and clinical trials of heart regeneration.

Cellular, molecular, and functional changes occur in the endothelium during ageing. Ungvari and colleagues explore the links between oxidative and nitrative stress and the conserved molecular pathways affecting endothelial dysfunction and impaired angiogenesis during ageing, and also speculate on how these pathological processes might be therapeutically targeted.

Cardiovascular ageing and the atherosclerotic process begin very early in life and progress over decades of exposure to suboptimal metabolic and hormonal risk factors. In this Review, Fontana discusses how various approaches, including calorie restriction, intermittent fasting, regular physical activity, and mindfulness-based stress-reduction exercises, can slow the effects of cardiovascular ageing and promote cardiometabolic health.

Matrix metalloproteinases (MMPs) are a family of 25 enzymes that proteolytically process extracellular matrix and inflammatory proteins, making them highly relevant in ischaemic remodelling after myocardial infarction. In this Review, Lindsey focuses on systems biology approaches to integrate the roles of MMPs in left ventricular remodelling, using MMP9 as an example.

Endothelial-to-mesenchymal transition (EndoMT) is critical for the formation of the cardiac valves and contributes postnatally to the development of cardiovascular diseases. However, progress in lineage-tracing technology has challenged the role of EndoMT in cardiac fibrosis. In this Review, Li and colleagues discuss the caveats of using lineage tracing to investigate cell-lineage conversion and reassess the role of EndoMT in cardiovascular development and diseases.

The conflicting results of cell therapy clinical trials for heart regeneration have led to some confusion over the efficacy of this approach. This Review summarizes the main outcomes of these studies and gives perspectives for future cell-based regenerative trials largely based on the primary therapeutic target: regeneration of lost myocardium by exogenous cells or promotion of intrinsic repair though paracrine signalling.

Reduction in salt consumption has long been recommended to lower blood pressure (BP) and the risk of cardiovascular disease (CVD). A linear relationship between salt intake and CVD risk has recently been challenged in some cohort studies; however, methodological issues exist with these studies. In this Review, He and MacGregor discuss the relationship between salt intake, BP, and CVD risk, and describe the benefits and challenges of reducing the population intake of salt.

This Review highlights the pathophysiology underlying changes in coronary blood flow and the role of functional assessment in patients with high-gradient, high-flow aortic stenosis. Michail and colleagues also discuss factors that influence the immediate and long-term consequences of stenosis treatment.

This Review summarizes the growing body of evidence implicating cathepsin activities in the pathogenesis of several cardiovascular diseases, outlining the potential of cathepsins as biomarkers of disease progression and discussing clinical trials of cathepsin inhibitors in other diseases that highlight opportunities for developing novel therapies targeting cathepsins in cardiovascular diseases.