Reviews & Analysis

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.

Early studies showing that KIT⁺ cardiac progenitor cells (CPCs) could differentiate into cardiomyocytes generated excitement regarding their potential therapeutic application. Subsequent studies called their functional relevance into question, and while claims for a contribution of KIT⁺ CPCs to myocardial regeneration continue, two new studies confirm the doubts about their relevance to cardiomyogenesis and provide unexpected new insights.

The immaturity of stem cell-derived cardiomyocytes has impeded their use for in vitro disease modelling, cardiotoxicity assays, and cell-replacement therapy. Ronaldson-Bouchard and colleagues report unparalleled in vitro maturation of stem cell-derived cardiomyocytes. This advance promises to unlock the translational potential of these cells.

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.

Hiramoto and colleagues examine the current status of interventions for peripheral artery disease, focusing on disease staging, treatment goals, and factors that influence outcomes. Persistent unmet needs and emerging approaches (including cell-based and gene-based therapies) are also highlighted.

Adult cardiac hypertrophy initially develops as an adaptive response to an increased workload, but this physiological growth can ultimately lead to pathological hypertrophy and disease. In this Review, Nakamura and Sadoshima summarize the characteristics and underlying mechanisms of physiological and pathological hypertrophy, and discuss possible therapeutic strategies targeting these pathways to prevent or reverse pathological hypertrophy.

This Review describes the relationship between urban and transport planning and the city environment, the main cardiovascular risk factors (including physical activity, hypertension, and obesity), and cardiovascular disease and mortality. Improved city planning that promotes physical activity, reduces levels of air pollution and noise, and increases green space could decrease the burden of cardiovascular disease.

In this Review, Katritsis and colleagues discuss the major factors underlying the clinical decision to perform revascularization in patients with stable coronary artery disease and examine the use and limitations of existing evidence on the choice for, and preferred methods of, revascularization, namely, CABG surgery versus percutaneous coronary intervention.

Hyperlipidaemia is an important risk factor for coronary artery disease. Chadwick and colleagues report significantly reduced blood lipid levels following CRISPR-based in vivo genome editing in mice to introduce loss-of-function mutations in Angptl3, encoding a lipoprotein lipase inhibitor. Treatment was effective in both wild-type and Ldlr^−/− mice and had a similar effect to that of Pcsk9-targeted genome editing, without causing off-target mutations.

In this Review, Serruys and colleagues describe the pathophysiology of unprotected left main coronary artery disease, discuss novel diagnostic approaches in light of new imaging techniques, and describe risk stratification models to help in the decision-making process for determining the best revascularization strategy in these patients.

Advances in breast cancer therapy mean that more women are surviving cancer but are at increased risk of cardiovascular disease (CVD). In a statement released by the AHA, Mehta and colleagues summarize the intersection between breast cancer and CVD, and highlight the importance of vigilance in preventive measures.