Atherosclerosis is the leading cause of cardiovascular morbidity and mortality worldwide. Beyond genetic predisposition, epigenetic mechanisms, such as DNA methylation, histone modifications and non-coding RNAs, have an...Atherosclerosis is the leading cause of cardiovascular morbidity and mortality worldwide. Beyond genetic predisposition, epigenetic mechanisms, such as DNA methylation, histone modifications and non-coding RNAs, have an integral role in the development, progression and complications of atherosclerosis. Global and locus-specific changes in DNA methylation regulate cell proliferation and inflammatory activation, whereas histone post-transcriptional modifications (primarily acetylation and methylation) regulate atherosclerosis-related gene networks relevant to lipid metabolism, cell plasticity and inflammation. Long non-coding RNAs further modulate vascular remodelling by shaping cell-specific transcriptomes and guiding epigenetic enzymes and their activity, whereas microRNAs exert post-transcriptional gene regulation and non-canonical functions. In this Review, we provide an overview of epigenetic regulation in atherosclerosis, focusing on how these dynamic, reversible modifications orchestrate gene expression in vascular endothelial cells, vascular smooth muscle cells and immune cells. We highlight how technological advances and the integration of multimodal datasets have progressed this research field and describe the cell-specific contributions of genetically associated loci. Finally, we discuss preclinical study findings and the translational efforts towards the development of epigenetic drugs as promising interventions to attenuate atherosclerotic plaque progression and inflammation, shedding light on the challenges of specificity, delivery and long-term safety. Achieving clinical applicability will enable precision medicine approaches to transform atherosclerosis therapy.
Genetic cardiomyopathies caused by pathogenic variants in nuclear DNA (nDNA) that encodes contractile sarcomere proteins are among the best understood of all the cardiomyopathies. By contrast, mitochondrial cardiomyopath...Genetic cardiomyopathies caused by pathogenic variants in nuclear DNA (nDNA) that encodes contractile sarcomere proteins are among the best understood of all the cardiomyopathies. By contrast, mitochondrial cardiomyopathy is caused by a dysfunction in mitochondrial oxidative phosphorylation due to pathogenic variants in either nDNA or the maternal mitochondrial DNA (mtDNA). Unlike contractile protein defects, which generally follow predictable Mendelian inheritance patterns, mitochondrial cardiomyopathy is genetically complex as a result of the distinctive characteristics of the mitochondrial genome, which influence patterns of maternal inheritance, heteroplasmy and tissue-specific variations in mtDNA variant load. Both single-gene nDNA and mtDNA variants can impair cardiac energetics, resulting in a wide clinical spectrum ranging from severe, childhood-onset to milder, adult-onset cardiomyopathy. Furthermore, the intricate metabolic demands of the heart mean that mitochondrial dysfunction can be influenced by a broad array of genetic and environmental modifiers. A greater recognition of these complexities and the integration of genomic sequencing, novel biomarkers and functional imaging have advanced diagnostic and therapeutic approaches. Emerging treatment strategies, such as metabolic supplementation, gene therapy and genome editing, are under investigation. In this Review, we synthesize the molecular and clinical landscape of mitochondrial cardiomyopathy, highlighting the ongoing challenges and prospects of precision medicine in this rapidly evolving field.
Adipose tissue is increasingly recognized as an immunological and metabolic organ composed of multiple specialized depots that exert diverse effects on cardiometabolic health. Beyond total adiposity, the distribution and...Adipose tissue is increasingly recognized as an immunological and metabolic organ composed of multiple specialized depots that exert diverse effects on cardiometabolic health. Beyond total adiposity, the distribution and phenotypic state of regional adipose tissue depots, including visceral, subcutaneous and epicardial adipose tissue, contribute to shaping overall cardiovascular risk. These depots communicate with the vasculature and myocardium through endocrine, paracrine, vasocrine and neural pathways to mediate cardiovascular inflammation and remodelling. Advances in cardiac CT, MRI, dual-energy X-ray absorptiometry and artificial intelligence technologies in the past 5 years have resulted in highly reproducible measurements of adipose tissue volume, quality, density and radiomics. Emerging multiomics data now reveal how specific adipose tissue patterns correspond to pathways of inflammation and the development of cardiovascular disease. In this Review, we synthesize the current evidence across adipose depots, highlighting how their collective biology, more so than quantity alone, shapes cardiometabolic risk. Furthermore, we highlight emerging insights into adipose depot-specific biology, imaging phenotyping, ethnicity-related and sex-related differences, and potential therapeutic modulation. We also introduce the 'unified adipose tissue' model that conceptualizes all adipose tissue depots as components of a unified system, in which the biology rather than the total mass of adipose tissue drives cardiometabolic disease.
Dilated cardiomyopathy, defined by left ventricular dilatation and systolic dysfunction, is a major cause of heart failure, heart transplantation and sudden cardiac death, especially in young and middle-aged adults. Dila...Dilated cardiomyopathy, defined by left ventricular dilatation and systolic dysfunction, is a major cause of heart failure, heart transplantation and sudden cardiac death, especially in young and middle-aged adults. Dilated cardiomyopathy of non-ischaemic aetiology is more common than once thought, with current prevalence estimated at around 1 in 220 based on cardiac magnetic resonance imaging studies, and the prevalence is twice as high in men than in women. However, the true prevalence could be even higher when early or subclinical forms of the disease are considered. Advances in genetic technologies over the past three decades have led to improved understanding of the genetic basis of non-ischaemic dilated cardiomyopathy and the identification of pathogenic variants in 30-40% of patients. The genetic architecture of this disease is complex and heterogeneous. Rather than being a strictly monogenic disorder, dilated cardiomyopathy results from a combination of monogenic and polygenic factors, along with gene-environment interactions as critical modifiers of disease penetrance and phenotype. A deeper understanding of the genetic factors and epidemiological landscape of dilated cardiomyopathy is crucial for improving clinical management and optimizing screening protocols and public health strategies.
Cardiovascular diseases remain a global health challenge, with >600 million cases reported annually. Atherosclerosis is a common pathology that underlies various cardiovascular diseases, such as myocardial infarction and...Cardiovascular diseases remain a global health challenge, with >600 million cases reported annually. Atherosclerosis is a common pathology that underlies various cardiovascular diseases, such as myocardial infarction and stroke. Both the innate and adaptive immune systems have crucial roles in the progression of atherosclerosis. CD8 T cells are the most clonally expanded adaptive immune cells in human atherosclerotic plaques, but whether these cells are pro-atherogenic or atheroprotective during the different stages of atherosclerosis development and progression is unclear. In this Review, we summarize the latest knowledge on the role of CD8 T cells in atherosclerosis. We discuss the phenotypic, functional and transcriptional features of CD8 T cells in atherosclerosis and shed light on their involvement in comorbidities to understand the landscape of CD8 T cells during the progression of atherosclerosis. We also highlight key research gaps and questions that need to be addressed to improve our understanding of the functions of CD8 T cells in atherosclerosis. Targeting CD8 T cells could provide potential therapeutic avenues to prevent and mitigate adverse cardiovascular events in patients with atherosclerosis and coronary heart disease.