Cardiometabolism

In this Review, Moore and co-workers provide an overview of the mechanisms and functions of microRNAs and long non-coding RNAs in vascular biology and the regulation of lipid metabolism, as well as the effects of non-coding RNAs on atherosclerotic plaque formation and progression.

Heart failure (HF) and obesity are growing global health problems, and excess body weight is associated with an increased risk of HF across the spectrum of left ventricular ejection fraction. In this Review, Meems et al. explore the pathophysiological mechanisms linking these two conditions and how management strategies targeting obesity could also improve HF-related outcomes.

In this Review, Mericskay and colleagues discuss the role of cardiac intermediary metabolism in heart failure, describing the perturbations in cardiac energy metabolism that occur in heart failure with reduced ejection fraction and cardiometabolic heart failure with preserved ejection fraction, and highlighting potential treatments to target intermediary metabolism in these patients.

In this Review, the authors discuss the cellular and molecular mechanisms of immunometabolism in heart failure and highlight potential approaches for non-invasive monitoring and for the treatment of patients with heart failure.

Glycogen has an important role in cardiac development and function. In this Review, Pinós and colleagues discuss the cardiovascular manifestations of glycogen storage diseases caused by rare inherited deficiencies of enzymes involved either in glycogen synthesis or breakdown, or in glycolysis. Interventions, including gene therapies, for these conditions are also summarized.

In this Review, the authors describe the metabolic programmes that control endothelial cell function in the cardiovascular system, discuss the role of endothelial cell metabolism in different cardiovascular diseases, and highlight the therapeutic potential and challenges of targeting endothelial cell metabolism to treat cardiovascular diseases.

In this Review, Yvan-Charvet and colleagues discuss how cardiovascular risk factors and metabolic modifiers of atherosclerosis influence metabolism-dependent haematopoietic stem cell skewing (haematometabolism) and efferocyte reprogramming (efferotabolism) and highlight potential therapeutic strategies to reduce the risk of atherosclerosis by rebalancing haematopoiesis and efferocytosis.

In this Review, Khan and Jandeleit-Dahm discuss pathological mechanisms involved in atherosclerosis development and progression in patients with diabetes mellitus and highlight novel therapeutic targets to treat atherosclerosis in these patients.

In this Review, the authors describe the bidirectional crosstalk between lysosome biology and immune cell function and polarization, focusing on immunometabolic reprogramming in the context of atherosclerosis and highlighting knowledge gaps and potential therapeutic strategies targeting immune cell lysosomes.

Various dietary patterns have been proposed to improve cardiometabolic health. In this Review, Pagidipati et al. emphasize the commonalities between recommendations on what to eat (Mediterranean, Dietary Approaches to Stop Hypertension and low-carbohydrate or ketogenic diets) and the possible benefits of time-restricted eating and intermittent fasting.

In this Review, the authors describe the changes in metabolism that predispose individuals to developing atrial fibrillation (AF) and highlight the potential of available and emerging therapeutic strategies that target metabolic remodelling to treat AF.

In this Review, Ritterhoff and Tian describe the metabolic reprogramming that occurs in cardiac hypertrophy and heart failure; discuss the contribution of metabolism to energy-generating and non-energy-generating functions, including signalling, protein function and gene expression regulation; and highlight the role of metabolism in non-cardiomyocytes and the potential to develop metabolic therapies for heart failure.

Individuals with type 2 diabetes mellitus are at high risk of developing cardiovascular disease (CVD). In the context of type 2 diabetes mellitus, Wong and Sattar discuss established and novel mechanisms of CVD, risk assessment and patient stratification, and strategies to reduce multiple risk factors to prevent CVD.

In this Review, the authors discuss current treatment regimens for lowering plasma LDL cholesterol levels to reduce the risk of cardiovascular disease, highlight treatment gaps and challenges, as well as describe opportunities raised by novel available therapies and potential future therapeutic approaches.

Glucagon-like peptide 1 (GLP1) receptor agonists reduce the rate of major adverse cardiovascular events in people with type 2 diabetes mellitus. In this Review, Ussher and Drucker discuss the possible mechanisms of cardiovascular benefit of GLP1 receptor agonists and highlight the novel GLP1-based multi-agonists currently in development.

In this Review, Lucia and colleagues explain why obesity is an evolutionarily novel condition, summarize the epidemiological evidence for its detrimental cardiometabolic consequences, discuss the major mechanisms involved in the association between obesity and the risk of cardiometabolic diseases, and examine the evidence for potential ‘healthy’ phenotypes associated with obesity.

Aldehyde dehydrogenase 2 (ALDH2), a key enzyme for the detoxification of alcohol-derived acetaldehyde, has been implicated in the pathogenesis of various types of cardiovascular disease. In this Review, Xu and colleagues present the latest evidence showing a link between the inactivating ALDH2 rs671 polymorphism and an increased or decreased risk of cardiovascular disease such as coronary artery disease.

In this Review, Packer summarizes the latest advances in our understanding of the mechanisms that underlie the benefits of sodium–glucose cotransporter 2 (SGLT2) inhibitors in heart failure, identifies specific pathways that are likely to mediate a direct effect of SGLT2 inhibitors on cardiomyocytes and proposes a novel conceptual framework that explains the findings from experimental studies and clinical trials.

In this Review, McGarrah and White outline the major factors regulating branched-chain amino acid (BCAA) abundance and metabolic fate, highlight molecular mechanisms connecting impaired BCAA homeostasis to cardiovascular disease and discuss the epidemiological evidence connecting BCAAs with various cardiovascular disease states.

Since the discovery of ferroptosis a decade ago, this iron-dependent form of regulated cell death has been implicated in the pathogenesis of cardiovascular disease. In this Review, Fudi Wang and colleagues discuss the link between the metabolic pathways of iron signalling and ferroptosis in the context of the cardiovascular system and describe the potential of ferroptosis inhibitors in the treatment of cardiovascular disease.

In this Review, the authors discuss the roles of non-canonical WNT signalling in cardiovascular disease. They provide an overview of non-canonical WNT signalling, describe its links to the pathogenesis of atherosclerosis, heart failure and arrhythmias, and explore the clinical potential of targeting individual components of non-canonical WNT signalling in cardiovascular disease.

In this Review, the authors explore metabolic dysregulation as an important theme in cardio-oncology. They discuss metabolic reprogramming in cardiovascular disease and cancer and the possibility that therapeutically targeting metabolic and immunometabolic changes in patients with cancer might also reduce their risk of cardiovascular disease.

In this Review, Borén and colleagues provide an overview of the pathways involved in triglyceride-rich lipoprotein (TRL) assembly and intravascular processing, and discuss how the dysregulation of triglyceride transport can result in hypertriglyceridaemia.

In this Review, Iacobellis provides a comprehensive overview of the role of epicardial adipose tissue (EAT) in cardiovascular disease, including coronary artery disease, heart failure and atrial fibrillation, discusses imaging techniques for EAT assessment and highlights the therapeutic potential of targeting EAT in cardiovascular disease.

Peripartum cardiomyopathy (PPCM) is a rare form of heart failure that presents in late pregnancy or early in the postpartum period. In this Review, Hoes and colleagues discuss the known risk factors for PPCM, including genetic variants and pre-eclampsia, and describe the potential pathogenic mechanisms underlying the development of PPCM such as disrupted metabolic homeostasis in the heart owing to pregnancy-induced hormone fluctuations.

In this Review, Mehta and Shapiro discuss the mechanisms by which apolipoproteins regulate lipoprotein metabolism and thereby influence vascular biology and atherosclerotic disease. Advances in the understanding of apolipoprotein biology and their translation into therapeutic agents to reduce the risk of cardiovascular disease are also highlighted.

Fatty acids affect the pathogenesis of atherosclerosis, and accumulating evidence shows that fatty acids also modulate T cell functions and processes. This Review summarizes the effects of circulating fatty acids on the metabolism, activation, proliferation and polarization of T cells and how these changes influence the subsequent functions of T cells in the pathogenesis of atherosclerosis.

Novel peroxisome proliferator-activated receptor (PPAR) agonists are providing new opportunities in the management of metabolic and cardiovascular diseases. In this Review, Staels and colleagues discuss the physiological regulation and actions of the PPAR family and their modulation of the atherogenic lipid profile, atherosclerosis and cardiac remodelling.

In this Review, Gotto and colleagues summarize the evolution of our understanding of HDL structure and function, current models of atheroprotection by HDL involving reverse cholesterol transport, and their identification of a correlation between the bioavailability of free cholesterol contained in HDL and atherogenesis.

The metabolism of lipids accumulated in blood vessel walls and the heart produces sphingolipids, such as ceramides, which are associated with the development of diabetes mellitus, atherosclerosis, hypertension and heart failure. In this Review, the authors discuss ceramides as drivers of cardiovascular disease and therapeutic strategies to lower plasma and cardiac levels of ceramides.

According to a study published in Nature, the gut microbial metabolite imidazole propionate can induce atherosclerosis in atheroprone mice, further highlighting the role of microbiome-informed precision medicine to treat cardiovascular disease.

Seyed Soheil Saeedi Saravi discusses the seminal study that linked a gut microbial metabolite to atherosclerotic cardiovascular disease and opened the way to mechanistic studies assessing how the gut microbiota influences host cardiovascular health.

A new study in science Translational Medicine demonstrates that the atheroprotective effects of PPARα agonists are associated with their anti-inflammatory properties rather than their lipid-lowering activity, highlighting the importance of targeting inflammation in managing the residual risk of cardiovascular disease

A new study shows that activation of vagal sensory neurons expressing the oxytocin receptor in the cardiovascular and gastrointestinal tissues of mice mediates cardiometabolic changes resembling those from a hibernation-like, hypometabolic state.

A new study shows how obesity can disrupt a cholesterol metabolism in a particular subset of metabolically protective regulatory T cells in visceral adipose tissue.

Activation of the bile acid receptor TGR5 inhibits CD36-mediated fatty acid uptake in cardiomyocytes and protects against cardiac lipotoxicity and the development of diabetic cardiomyopathy in mice, according to a new study.

The metabolic maturation of mammalian cardiomyocytes that occurs during the early postnatal period shapes the epigenetic landscape of cardiomyocytes and creates a barrier for cell division, but reversing this remodelling process can restore the reparative capacity of the heart in mice, according to a study published in Nature.

Lipophagy is a type of selective autophagy that targets lipid droplets for degradation. Since the discovery of lipophagy in 2009, research has uncovered a central role for this process in cellular lipid metabolism, including in atherogenic foam cells. Therefore, increasing lipophagy might be a therapeutic target to reverse lipid build-up in atherosclerosis.

More than 50% of patients with chronic heart failure present with iron deficiency, which is associated with reduced quality of life and worse prognosis. Intravenous iron supplementation therapy has been shown to improve clinical outcomes in these patients.

The totality of evidence from large-scale, randomized, controlled clinical trials and mechanistic studies in the laboratory has provided six crucial lessons about the emerging role of SGLT2 inhibitors to prevent the onset of heart failure in patients at high risk and slow the progression of heart failure in patients with established disease.

Human genetic studies combined with biotechnological advances have guided and accelerated the development of PCSK9-targeting therapies. In this Clinical Outlook, we highlight present and future approaches for PCSK9 inhibition to reduce LDL-cholesterol levels and the risk of atherosclerotic cardiovascular disease.

The essential omega-6 polyunsaturated fatty acid γ-linolenic acid present in maternal milk coordinates cardiac adaptation and survival in newborn mice, according to a new study.

In a mouse model of atherosclerosis, a selective monoclonal antibody that blocks the binding of LDL to activin receptor-like kinase 1 reduced plaque formation in the aorta.

In treatment-naive patients with essential hypertension, supplementation with prebiotic acetylated and butyrylated high amylose maize starch significantly reduces systolic blood pressure levels compared with placebo.

A synthetic Ganoderma meroterpene derivative protects against obesity-associated atherosclerosis in mice by increasing the abundance of the gut commensal bacterium Parabacteroides merdae and increasing branched-chain amino acid degradation.

Inhibition of asialoglycoprotein receptor 1 (ASGR1) reduces cholesterol levels by promoting cholesterol excretion to bile and faeces.

Transient inhibition of the glucocorticoid receptor promotes cardiomyocyte proliferation and heart regeneration after myocardial infarction in the adult mouse heart.

Activating the serine biosynthesis pathway might be a potential strategy for the treatment of dilated cardiomyopathy, according to a phenotypic screening study.

The results of two early-phase trials of novel lipid-lowering agents targeting ANGPTL3 and lipoprotein(a) might help to combat the residual risk of cardiovascular events in patients treated with statins and/or PCSK9 inhibitors to lower LDL-cholesterol levels.