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Background Cardiovascular disease (CVD) is the leading cause of mortality worldwide, with men and women experiencing distinct differences in risk, symptom presentation, and health outcomes. Despite established evidence of these differences, women remain underrepresented in cardiovascular research, leading to persistent disparities in clinical care and outcomes. Main body Important sex differences in CVD risk and risk factors exist. For example, women face a disproportionately higher CVD risk from metabolic disorders such as diabetes. However, the underlying reasons have not been fully explained. Women are also more likely to present with atypical or non-classic CVD symptoms, resulting in under-recognition, diagnostic delays, and less intensive management. Despite this, most current research findings and guidelines are based predominantly on males, limiting their relevance for women. The lack of sex-specific evidence extends to risk prediction models and treatment approaches. Existing models have not considered women’s specific risk factors. Prevention and treatment strategies often rely on “one-size-fits-all” standards that fail to address women’s unique needs. Addressing these gaps requires clinical research intentionally designed to incorporate sex differences at every stage, from participant recruitment and risk stratification to the development of tailored prediction tools and therapies, and prioritize sex-specific questions. Increasing women’s representation as both participants and principal investigators in clinical trials is essential; evidence shows that studies led by women are more likely to enroll female participants. Promoting women’s leadership can help ensure that women’s perspectives and needs are fully integrated into cardiovascular research and healthcare. Conclusions Achieving equity in cardiovascular health requires the integration of sex-specific perspectives across research, risk assessment, prevention, treatment, and leadership. These efforts are essential to close persistent knowledge gaps and improve the quality and equity of cardiovascular care for all.

Air pollution is well recognized as a major risk factor for chronic non-communicable diseases and has been estimated to contribute more to global morbidity and mortality than all other known environmental risk factors combined. Although air pollution contains a heterogeneous mixture of gases, the most robust evidence for detrimental effects on health is for fine particulate matter (particles ≤2.5 µm in diameter (PM2.5)) and ozone gas and, therefore, these species have been the main focus of environmental health research and regulatory standards. The evidence to date supports a strong link between the risk of cardiovascular events and all-cause mortality with PM2.5 across a range of exposure levels, including to levels below current regulatory standards, with no ‘safe’ lower exposure levels at the population level. In this comprehensive Review, the empirical evidence supporting the effects of air pollution on cardiovascular health are examined, potential mechanisms that lead to increased cardiovascular risk are described, and measures to reduce this risk and identify key gaps in our knowledge that could help address the increasing cardiovascular morbidity and mortality associated with air pollution are discussed.A strong relationship exists between exposure to air pollution and cardiovascular events. In this Review, Rajagopalan and colleagues summarize the evidence supporting the detrimental effects of air pollution on cardiovascular health and describe the potential mechanisms involved in air pollution-mediated cardiovascular mortality.

Cardiovascular disease (CVD) is the leading cause of death in China. To develop effective and timely strategies to cope with the challenges of CVD epidemics, we need to understand the current epidemiological features of the major types of CVD and the implications of these features for the prevention and treatment of CVD. In this Review, we summarize eight important features of the epidemiology of CVD in China. Some features indicate a transition in CVD epidemiology owing to interrelated changes in demography, environment, lifestyle, and health care, including the rising burden from atherosclerotic CVD (ischaemic heart disease and ischaemic stroke), declining mortality from haemorrhage stroke, varied regional epidemiological trends in the subtypes of CVD, increasing numbers of patients with moderate types of ischaemic heart disease and ischaemic stroke, and increasing ageing of patients with CVD. Other features highlight the problems that need particular attention, including the high proportion of out-of-hospital death of patients with ischaemic heart disease with insufficient prehospital care; the wide gaps between guideline-recommended goals and levels of lifestyle indicators; and the huge number of patients with undiagnosed, untreated, or uncontrolled hypertension, hypercholesterolaemia, or diabetes mellitus.

Sedentary behaviour — put simply, too much sitting, as a distinct concept from too little exercise — is a novel determinant of cardiovascular risk. This definition provides a perspective that is complementary to the well-understood detrimental effects of physical inactivity. Sitting occupies the majority of the daily waking hours in most adults and has become even more pervasive owing to the COVID-19 pandemic. The potential for a broad cardiovascular health benefit exists through an integrated approach that involves ‘sitting less and moving more’. In this Review, we first consider observational and experimental evidence on the adverse effects of prolonged, uninterrupted sitting and the evidence identifying the possible mechanisms underlying the associated risk. We summarize the results of randomized controlled trials demonstrating the feasibility of changing sedentary behaviour. We also highlight evidence on the deleterious synergies between sedentary behaviour and physical inactivity as the underpinnings of our case for addressing them jointly in mitigating cardiovascular risk. This integrated approach should not only reduce the specific risks of too much sitting but also have a positive effect on the total amount of physical activity, with the potential to more broadly benefit the health of individuals living with or at risk of developing cardiovascular disease.In this Review, Dunstan and colleagues make a case for an approach to preventing and managing cardiovascular disease that involves sitting less and moving more, which will build on the well-established role of exercise in cardiovascular disease prevention and rehabilitation.

Epidemiological studies have found that transportation noise increases the risk of cardiovascular morbidity and mortality, with high-quality evidence for ischaemic heart disease. According to the WHO, ≥1.6 million healthy life-years are lost annually from traffic-related noise in Western Europe. Traffic noise at night causes fragmentation and shortening of sleep, elevation of stress hormone levels, and increased oxidative stress in the vasculature and the brain. These factors can promote vascular dysfunction, inflammation and hypertension, thereby elevating the risk of cardiovascular disease. In this Review, we focus on the indirect, non-auditory cardiovascular health effects of transportation noise. We provide an updated overview of epidemiological research on the effects of transportation noise on cardiovascular risk factors and disease, discuss the mechanistic insights from the latest clinical and experimental studies, and propose new risk markers to address noise-induced cardiovascular effects in the general population. We also explain, in detail, the potential effects of noise on alterations of gene networks, epigenetic pathways, gut microbiota, circadian rhythm, signal transduction along the neuronal–cardiovascular axis, oxidative stress, inflammation and metabolism. Lastly, we describe current and future noise-mitigation strategies and evaluate the status of the existing evidence on noise as a cardiovascular risk factor.In this Review, Münzel and colleagues summarize the epidemiological evidence on transportation noise pollution as a cardiovascular risk factor, discussing mechanistic insights for the adverse cardiovascular effects of noise pollution and highlighting new risk markers of noise-induced cardiovascular effects as well as promising noise-mitigation strategies.

Peroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα increases cellular fatty acid uptake, esterification and trafficking, and regulates lipoprotein metabolism genes. PPARδ stimulates lipid and glucose utilization by increasing mitochondrial function and fatty acid desaturation pathways. By contrast, PPARγ promotes fatty acid uptake, triglyceride formation and storage in lipid droplets, thereby increasing insulin sensitivity and glucose metabolism. PPARs also exert antiatherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates reduce insulin resistance and dyslipidaemia, respectively. PPARs are also physiological master switches in the heart, steering cardiac energy metabolism in cardiomyocytes, thereby affecting pathological heart failure and diabetic cardiomyopathy. Novel PPAR agonists in clinical development are providing new opportunities in the management of metabolic and cardiovascular diseases.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.

A large body of evidence indicates that mitochondrial dysfunction has a major role in the pathogenesis of multiple cardiovascular disorders. Over the past 2 decades, extraordinary efforts have been focused on the development of agents that specifically target mitochondria for the treatment of cardiovascular disease. Despite such an intensive wave of investigation, no drugs specifically conceived to modulate mitochondrial functions are currently available for the clinical management of cardiovascular disease. In this Review, we discuss the therapeutic potential of targeting mitochondria in patients with cardiovascular disease, examine the obstacles that have restrained the development of mitochondria-targeting agents thus far, and identify strategies that might empower the full clinical potential of this approach.

Cardiovascular diseases (CVDs), such as ischaemic heart disease, cardiomyopathy, atherosclerosis, hypertension, stroke and heart failure, are among the leading causes of morbidity and mortality worldwide. Although specific CVDs and the associated cardiometabolic abnormalities have distinct pathophysiological and clinical manifestations, they often share common traits, including disruption of proteostasis resulting in accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER). ER proteostasis is governed by the unfolded protein response (UPR), a signalling pathway that adjusts the protein-folding capacity of the cell to sustain the cell’s secretory function. When the adaptive UPR fails to preserve ER homeostasis, a maladaptive or terminal UPR is engaged, leading to the disruption of ER integrity and to apoptosis. ER stress functions as a double-edged sword, with long-term ER stress resulting in cellular defects causing disturbed cardiovascular function. In this Review, we discuss the distinct roles of the UPR and ER stress response as both causes and consequences of CVD. We also summarize the latest advances in our understanding of the importance of the UPR and ER stress in the pathogenesis of CVD and discuss potential therapeutic strategies aimed at restoring ER proteostasis in CVDs.In this Review, Ren and colleagues summarize the latest advances in understanding the unfolded protein response and endoplasmic reticulum stress in the pathogenesis of cardiovascular disease and discuss potential therapeutic strategies aimed at restoring endoplasmic reticulum proteostasis in cardiovascular diseases.

Accumulating knowledge on the biology and function of the adipose tissue has led to a major shift in our understanding of its role in health and disease. The adipose tissue is now recognized as a crucial regulator of cardiovascular health, mediated by the secretion of several bioactive products, including adipocytokines, microvesicles and gaseous messengers, with a wide range of endocrine and paracrine effects on the cardiovascular system. The adipose tissue function and secretome are tightly controlled by complex homeostatic mechanisms and local cell–cell interactions, which can become dysregulated in obesity. Systemic or local inflammation and insulin resistance lead to a shift in the adipose tissue secretome from anti-inflammatory and anti-atherogenic towards a pro-inflammatory and pro-atherogenic profile. Moreover, the interplay between the adipose tissue and the cardiovascular system is bidirectional, with vascular-derived and heart-derived signals directly affecting adipose tissue biology. In this Review, we summarize the current knowledge of the biology and regional variability of adipose tissue in humans, deciphering the complex molecular mechanisms controlling the crosstalk between the adipose tissue and the cardiovascular system, and their possible clinical translation. In addition, we highlight the latest developments in adipose tissue imaging for cardiovascular risk stratification and discuss how therapeutic targeting of the adipose tissue can improve prevention and treatment of cardiovascular disease.

Ageing and inflammation strongly drive the risk of cardiovascular disease. Work over the past decade has uncovered a common condition characterized by the positive selection of certain somatic mutations in haematopoietic stem cells in ageing humans. This phenomenon, known as clonal haematopoiesis of indeterminate potential (CHIP), occurs most commonly as a result of mutations in the transcriptional regulators DNMT3A, TET2 and ASXL1. CHIP is associated with a variety of adverse outcomes, including haematological cancer and death. Surprisingly, CHIP is also associated with a doubling of the risk of atherosclerotic cardiovascular disease. Studies in mice support the causality of this relationship. Mutations in TET2, which are among the most commonly found mutations in CHIP, lead to increased expression of inflammatory genes in innate immune cells, potentially explaining the link between mutations and increased cardiovascular risk. Therapies targeting the mutant clones or the increased inflammatory mediators might be useful for ameliorating the risk of cardiovascular disease. We propose that the mutations leading to clonal haematopoiesis contribute to the increased inflammation seen in ageing and thereby explain some of the age-related risk of cardiovascular disease.Clonal haematopoiesis of indeterminate potential (CHIP) commonly occurs as a result of mutations in transcriptional regulators and is associated with a doubling of the risk of atherosclerotic cardiovascular disease. Jaiswal and Libby propose that CHIP contributes to the increased inflammation seen in ageing and thereby explains some of the age-related risk of cardiovascular disease.