Showing papers in "Nature Reviews Cardiology in 2020"

COVID-19 and the cardiovascular system.

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through ACE2 receptors, leading to coronavirus disease (COVID-19)-related pneumonia, while also causing acute myocardial injury and chronic damage to the cardiovascular system. Therefore, particular attention should be given to cardiovascular protection during treatment for COVID-19.

COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives.

Abstract: Coronavirus disease 2019 (COVID-19), caused by a strain of coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic that has affected the lives of billions of individuals. Extensive studies have revealed that SARS-CoV-2 shares many biological features with SARS-CoV, the zoonotic virus that caused the 2002 outbreak of severe acute respiratory syndrome, including the system of cell entry, which is triggered by binding of the viral spike protein to angiotensin-converting enzyme 2. Clinical studies have also reported an association between COVID-19 and cardiovascular disease. Pre-existing cardiovascular disease seems to be linked with worse outcomes and increased risk of death in patients with COVID-19, whereas COVID-19 itself can also induce myocardial injury, arrhythmia, acute coronary syndrome and venous thromboembolism. Potential drug-disease interactions affecting patients with COVID-19 and comorbid cardiovascular diseases are also becoming a serious concern. In this Review, we summarize the current understanding of COVID-19 from basic mechanisms to clinical perspectives, focusing on the interaction between COVID-19 and the cardiovascular system. By combining our knowledge of the biological features of the virus with clinical findings, we can improve our understanding of the potential mechanisms underlying COVID-19, paving the way towards the development of preventative and therapeutic solutions.

Myocardial ischaemia-reperfusion injury and cardioprotection in perspective.

Abstract: Despite the increasing use and success of interventional coronary reperfusion strategies, morbidity and mortality from acute myocardial infarction are still substantial. Myocardial infarct size is a major determinant of prognosis in these patients. Therefore, cardioprotective strategies aim to reduce infarct size. However, a perplexing gap exists between the many preclinical studies reporting infarct size reduction with mechanical and pharmacological interventions and the poor translation into better clinical outcomes in patients. This Review revisits the pathophysiology of myocardial ischaemia-reperfusion injury, including the role of autophagy and forms of cell death such as necrosis, apoptosis, necroptosis and pyroptosis. Other cellular compartments in addition to cardiomyocytes are addressed, notably the coronary microcirculation. Preclinical and clinical research developments in mechanical and pharmacological approaches to induce cardioprotection, and their signal transduction pathways, are discussed. Additive cardioprotective interventions are advocated. For clinical translation into treatments for patients with acute myocardial infarction, who typically are of advanced age, have comorbidities and are receiving several medications, not only infarct size reduction but also attenuation of coronary microvascular obstruction, as well as longer-term targets including infarct repair and reverse remodelling, must be considered to improve patient outcomes. Future clinical trials must focus on patients who really need adjunct cardioprotection, that is, those with severe haemodynamic alterations.

Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine

Abstract: Our knowledge of pluripotent stem cell (PSC) biology has advanced to the point where we now can generate most cells of the human body in the laboratory. PSC-derived cardiomyocytes can be generated routinely with high yield and purity for disease research and drug development, and these cells are now gradually entering the clinical research phase for the testing of heart regeneration therapies. However, a major hurdle for their applications is the immature state of these cardiomyocytes. In this Review, we describe the structural and functional properties of cardiomyocytes and present the current approaches to mature PSC-derived cardiomyocytes. To date, the greatest success in maturation of PSC-derived cardiomyocytes has been with transplantation into the heart in animal models and the engineering of 3D heart tissues with electromechanical conditioning. In conventional 2D cell culture, biophysical stimuli such as mechanical loading, electrical stimulation and nanotopology cues all induce substantial maturation, particularly of the contractile cytoskeleton. Metabolism has emerged as a potent means to control maturation with unexpected effects on electrical and mechanical function. Different interventions induce distinct facets of maturation, suggesting that activating multiple signalling networks might lead to increased maturation. Despite considerable progress, we are still far from being able to generate PSC-derived cardiomyocytes with adult-like phenotypes in vitro. Future progress will come from identifying the developmental drivers of maturation and leveraging them to create more mature cardiomyocytes for research and regenerative medicine.

Counter-regulatory renin-angiotensin system in cardiovascular disease

Abstract: The renin-angiotensin system is an important component of the cardiovascular system. Mounting evidence suggests that the metabolic products of angiotensin I and II - initially thought to be biologically inactive - have key roles in cardiovascular physiology and pathophysiology. This non-canonical axis of the renin-angiotensin system consists of angiotensin 1-7, angiotensin 1-9, angiotensin-converting enzyme 2, the type 2 angiotensin II receptor (AT2R), the proto-oncogene Mas receptor and the Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the classical renin-angiotensin system. This counter-regulatory renin-angiotensin system has a central role in the pathogenesis and development of various cardiovascular diseases and, therefore, represents a potential therapeutic target. In this Review, we provide the latest insights into the complexity and interplay of the components of the non-canonical renin-angiotensin system, and discuss the function and therapeutic potential of targeting this system to treat cardiovascular disease.

Reappraising the role of inflammation in heart failure.

Abstract: The observation that heart failure with reduced ejection fraction is associated with elevated circulating levels of pro-inflammatory cytokines opened a new area of research that has revealed a potentially important role for the immune system in the pathogenesis of heart failure. However, until the publication in 2019 of the CANTOS trial findings on heart failure outcomes, all attempts to target inflammation in the heart failure setting in phase III clinical trials resulted in neutral effects or worsening of clinical outcomes. This lack of positive results in turn prompted questions on whether inflammation is a cause or consequence of heart failure. This Review summarizes the latest developments in our understanding of the role of the innate and adaptive immune systems in the pathogenesis of heart failure, and highlights the results of phase III clinical trials of therapies targeting inflammatory processes in the heart failure setting, such as anti-inflammatory and immunomodulatory strategies. The most recent of these studies, the CANTOS trial, raises the exciting possibility that, in the foreseeable future, we might be able to identify those patients with heart failure who have a cardio-inflammatory phenotype and will thus benefit from therapies targeting inflammation. Inflammation has an important role in the pathogenesis of acute and chronic heart failure. This Review summarizes the latest findings on the role of the innate and adaptive immune systems in the pathogenesis of heart failure, and highlights the results of phase III clinical trials of therapies targeting inflammatory processes in this condition, such as anti-inflammatory and immunomodulatory strategies.

T cell subsets and functions in atherosclerosis

Abstract: Atherosclerosis is a chronic inflammatory disease of the arterial wall and the primary underlying cause of cardiovascular disease. Data from in vivo imaging, cell-lineage tracing and knockout studies in mice, as well as clinical interventional studies and advanced mRNA sequencing techniques, have drawn attention to the role of T cells as critical drivers and modifiers of the pathogenesis of atherosclerosis. CD4+ T cells are commonly found in atherosclerotic plaques. A large body of evidence indicates that T helper 1 (TH1) cells have pro-atherogenic roles and regulatory T (Treg) cells have anti-atherogenic roles. However, Treg cells can become pro-atherogenic. The roles in atherosclerosis of other TH cell subsets such as TH2, TH9, TH17, TH22, follicular helper T cells and CD28null T cells, as well as other T cell subsets including CD8+ T cells and γδ T cells, are less well understood. Moreover, some T cells seem to have both pro-atherogenic and anti-atherogenic functions. In this Review, we summarize the knowledge on T cell subsets, their functions in atherosclerosis and the process of T cell homing to atherosclerotic plaques. Much of our understanding of the roles of T cells in atherosclerosis is based on findings from experimental models. Translating these findings into human disease is challenging but much needed. T cells and their specific cytokines are attractive targets for developing new preventive and therapeutic approaches including potential T cell-related therapies for atherosclerosis. Accumulating evidence supports the critical role of T cells as drivers and modifiers of atherosclerosis. In this Review, Ley and colleagues describe the latest advances in our understanding of the role of T cell subsets in atherosclerosis, discuss the process of T cell homing to atherosclerotic plaques and highlight potential T cell-related therapies for atherosclerosis.

Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence

Abstract: The pathogenesis and clinical features of diabetic cardiomyopathy have been well-studied in the past decade, but effective approaches to prevent and treat this disease are limited. Diabetic cardiomyopathy occurs as a result of the dysregulated glucose and lipid metabolism associated with diabetes mellitus, which leads to increased oxidative stress and the activation of multiple inflammatory pathways that mediate cellular and extracellular injury, pathological cardiac remodelling, and diastolic and systolic dysfunction. Preclinical studies in animal models of diabetes have identified multiple intracellular pathways involved in the pathogenesis of diabetic cardiomyopathy and potential cardioprotective strategies to prevent and treat the disease, including antifibrotic agents, anti-inflammatory agents and antioxidants. Some of these interventions have been tested in clinical trials and have shown favourable initial results. In this Review, we discuss the mechanisms underlying the development of diabetic cardiomyopathy and heart failure in type 1 and type 2 diabetes mellitus, and we summarize the evidence from preclinical and clinical studies that might provide guidance for the development of targeted strategies. We also highlight some of the novel pharmacological therapeutic strategies for the treatment and prevention of diabetic cardiomyopathy.

SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control

Abstract: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective antidiabetic therapies in patients with type 2 diabetes mellitus and are associated with improved glycaemic control as well as with reductions in body mass and blood pressure. In large cardiovascular outcome trials in patients with diabetes, SGLT2 inhibitors improve cardiovascular and renal outcomes, including hospitalization for heart failure, with this benefit extending to patients without diabetes who have heart failure with reduced ejection fraction. The possible mechanisms of benefit are being extensively investigated because they are unlikely to be related to improved glycaemic control. Early natriuresis with a reduction in plasma volume, a consequent rise in haematocrit, improved vascular function, a reduction in blood pressure and changes in tissue sodium handling are all likely to have a role. Additional mechanisms of SGLT2 inhibitors that might be beneficial include a reduction in adipose tissue-mediated inflammation and pro-inflammatory cytokine production, a shift towards ketone bodies as the metabolic substrate for the heart and kidneys, reduced oxidative stress, lowered serum uric acid level, reduced glomerular hyperfiltration and albuminuria, and suppression of advanced glycation end-product signalling. Further outcome trials and mechanistic studies, including in patients with heart failure with preserved ejection fraction or non-diabetic kidney disease, might identify other possible mechanisms of benefit of SGLT2-inhibitor therapy.

Evaluation and management of heart failure with preserved ejection fraction.

Abstract: Heart failure with preserved ejection fraction (HFpEF) has grown to become the dominant form of heart failure worldwide, in tandem with ageing of the general population and the increasing prevalences of obesity, diabetes mellitus and hypertension. The clinical syndrome of HFpEF is heterogeneous and must be distinguished from heart failure with reduced ejection fraction as well as other aetiologies that have different treatment strategies. The diagnosis of HFpEF is challenging and ultimately relates to the conceptual definition of heart failure as a clinical syndrome characterized by symptoms that are associated with a reduced capacity of the heart to pump blood adequately at normal filling pressures during diastole. Clinical trials to date have been largely unsuccessful in identifying effective treatments for HFpEF but evidence supports the use of diuretics, mineralocorticoid antagonists and lifestyle interventions. Pathophysiological heterogeneity in the presentation of HFpEF is substantial, and ongoing studies are underway to evaluate the optimal methods to classify patients into phenotypically homogeneous subpopulations to facilitate better individualization of treatment. Heart failure with preserved ejection fraction (HFpEF) is the predominant form of heart failure among elderly patients. In this Review, Borlaug describes the challenges of diagnosing HFpEF, summarizes the current recommendations for treatment and describes a new strategy of categorizing patients with HFpEF into phenotypically homogeneous subgroups to facilitate the individualization of treatment.

Environmental determinants of cardiovascular disease: lessons learned from air pollution.

Abstract: 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.

NADPH oxidases and oxidase crosstalk in cardiovascular diseases: novel therapeutic targets.

Abstract: Reactive oxygen species (ROS)-dependent production of ROS underlies sustained oxidative stress, which has been implicated in the pathogenesis of cardiovascular diseases such as hypertension, aortic aneurysm, hypercholesterolaemia, atherosclerosis, diabetic vascular complications, cardiac ischaemia-reperfusion injury, myocardial infarction, heart failure and cardiac arrhythmias. Interactions between different oxidases or oxidase systems have been intensively investigated for their roles in inducing sustained oxidative stress. In this Review, we discuss the latest data on the pathobiology of each oxidase component, the complex crosstalk between different oxidase components and the consequences of this crosstalk in mediating cardiovascular disease processes, focusing on the central role of particular NADPH oxidase (NOX) isoforms that are activated in specific cardiovascular diseases. An improved understanding of these mechanisms might facilitate the development of novel therapeutic agents targeting these oxidase systems and their interactions, which could be effective in the prevention and treatment of cardiovascular disorders.

Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia

Abstract: Remarkable progress has been made in the development of new therapies for cancer, dramatically changing the landscape of treatment approaches for several malignancies and continuing to increase patient survival. Accordingly, adverse effects of cancer therapies that interfere with the continuation of best-possible care, induce life-threatening risks or lead to long-term morbidity are gaining increasing importance. Cardiovascular toxic effects of cancer therapeutics and radiation therapy are the epitome of such concerns, and proper knowledge, interpretation and management are needed and have to be placed within the context of the overall care of individual patients with cancer. Furthermore, the cardiotoxicity spectrum has broadened to include myocarditis with immune checkpoint inhibitors and cardiac dysfunction in the setting of cytokine release syndrome with chimeric antigen receptor T cell therapy. An increase in the incidence of arrhythmias related to inflammation such as atrial fibrillation can also be expected, in addition to the broadening set of cancer therapeutics that can induce prolongation of the corrected QT interval. Therefore, cardiologists of today have to be familiar not only with the cardiotoxicity associated with traditional cancer therapies, such as anthracycline, trastuzumab or radiation therapy, but even more so with an ever-increasing repertoire of therapeutics. This Review provides this information, summarizing the latest developments at the juncture of cardiology, oncology and haematology.

Endothelial responses to shear stress in atherosclerosis: a novel role for developmental genes

Abstract: Flowing blood generates a frictional force called shear stress that has major effects on vascular function. Branches and bends of arteries are exposed to complex blood flow patterns that exert low or low oscillatory shear stress, a mechanical environment that promotes vascular dysfunction and atherosclerosis. Conversely, physiologically high shear stress is protective. Endothelial cells are critical sensors of shear stress but the mechanisms by which they decode complex shear stress environments to regulate physiological and pathophysiological responses remain incompletely understood. Several laboratories have advanced this field by integrating specialized shear-stress models with systems biology approaches, including transcriptome, methylome and proteome profiling and functional screening platforms, for unbiased identification of novel mechanosensitive signalling pathways in arteries. In this Review, we describe these studies, which reveal that shear stress regulates diverse processes and demonstrate that multiple pathways classically known to be involved in embryonic development, such as BMP–TGFβ, WNT, Notch, HIF1α, TWIST1 and HOX family genes, are regulated by shear stress in arteries in adults. We propose that mechanical activation of these pathways evolved to orchestrate vascular development but also drives atherosclerosis in low shear stress regions of adult arteries. The shear stress generated by flowing blood has major effects on vascular function, with low shear stress promoting vascular dysfunction and atherosclerosis. This Review describes the latest findings on how endothelial cells decode complex shear stress environments to regulate physiological and pathophysiological responses, highlighting the role of pathways involved in embryonic development.

Neutrophils as regulators of cardiovascular inflammation.

Abstract: Neutrophils have traditionally been viewed as bystanders or biomarkers of cardiovascular disease. However, studies in the past decade have demonstrated the important functions of neutrophils during cardiovascular inflammation and repair. In this Review, we discuss the influence of traditional and novel cardiovascular risk factors on neutrophil production and function. We then appraise the current knowledge of the contribution of neutrophils to the different stages of atherosclerosis, including atherogenesis, plaque destabilization and plaque erosion. In the context of cardiovascular complications of atherosclerosis, we highlight the dichotomous role of neutrophils in pathogenic and repair processes in stroke, heart failure, myocardial infarction and neointima formation. Finally, we emphasize how detailed knowledge of neutrophil functions in cardiovascular homeostasis and disease can be used to generate therapeutic strategies to target neutrophil numbers, functional status and effector mechanisms.

Cardiac natriuretic peptides

Abstract: Investigations into the mixed muscle-secretory phenotype of cardiomyocytes from the atrial appendages of the heart led to the discovery that these cells produce, in a regulated manner, two polypeptide hormones - the natriuretic peptides - referred to as atrial natriuretic factor or atrial natriuretic peptide (ANP) and brain or B-type natriuretic peptide (BNP), thereby demonstrating an endocrine function for the heart. Studies on the gene encoding ANP (NPPA) initiated the field of modern research into gene regulation in the cardiovascular system. Additionally, ANP and BNP were found to be the natural ligands for cell membrane-bound guanylyl cyclase receptors that mediate the effects of natriuretic peptides through the generation of intracellular cGMP, which interacts with specific enzymes and ion channels. Natriuretic peptides have many physiological actions and participate in numerous pathophysiological processes. Important clinical entities associated with natriuretic peptide research include heart failure, obesity and systemic hypertension. Plasma levels of natriuretic peptides have proven to be powerful diagnostic and prognostic biomarkers of heart disease. Development of pharmacological agents that are based on natriuretic peptides is an area of active research, with vast potential benefits for the treatment of cardiovascular disease.

Native and bioengineered extracellular vesicles for cardiovascular therapeutics

Abstract: Extracellular vesicles (EVs) are a heterogeneous group of natural particles that are relevant to the treatment of cardiovascular diseases. These endogenous vesicles have certain properties that allow them to survive in the extracellular space, bypass biological barriers and deliver their biologically active molecular cargo to recipient cells. Moreover, EVs can be bioengineered to increase their stability, bioactivity, presentation to acceptor cells and capacity for on-target binding at both cell-type-specific and tissue-specific levels. Bioengineering of EVs involves the modification of the donor cell before EV isolation or direct modification of the EV properties after isolation. The therapeutic potential of native EVs and bioengineered EVs has been only minimally explored in the context of cardiovascular diseases. Efforts to harness the therapeutic potential of EVs will require innovative approaches and a comprehensive integration of knowledge gathered from decades of research into molecular-compound delivery. In this Review, we outline the endogenous properties of EVs that make them natural delivery agents as well as the features that can be improved by bioengineering. We also discuss the therapeutic applications of native and bioengineered EVs to cardiovascular diseases and examine the opportunities and challenges that need to be addressed to advance this research area, with an emphasis on clinical translation. Extracellular vesicles are a heterogeneous group of natural particles that can deliver their biologically active molecular cargo to recipient cells. In this Review, the authors outline the endogenous properties of extracellular vesicles that make them natural delivery agents and the features that can be improved by bioengineering for the treatment of cardiovascular diseases.

Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease

Abstract: 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.

Transcriptional and epigenetic regulation of macrophages in atherosclerosis.

Abstract: Monocytes and macrophages provide defence against pathogens and danger signals. These cells respond to stimulation in a fast and stimulus-specific manner by utilizing complex cascaded activation by lineage-determining and signal-dependent transcription factors. The complexity of the functional response is determined by interactions between triggered transcription factors and depends on the microenvironment and interdependent signalling cascades. Dysregulation of macrophage phenotypes is a major driver of various diseases such as atherosclerosis, rheumatoid arthritis and type 2 diabetes mellitus. Furthermore, exposure of monocytes, which are macrophage precursor cells, to certain stimuli can lead to a hypo-inflammatory tolerized phenotype or a hyper-inflammatory trained phenotype in a macrophage. In atherosclerosis, macrophages and monocytes are exposed to inflammatory cytokines, oxidized lipids, cholesterol crystals and other factors. All these stimuli induce not only a specific transcriptional response but also interact extensively, leading to transcriptional and epigenetic heterogeneity of macrophages in atherosclerotic plaques. Targeting the epigenetic landscape of plaque macrophages can be a powerful therapeutic tool to modulate pro-atherogenic phenotypes and reduce the rate of plaque formation. In this Review, we discuss the emerging role of transcription factors and epigenetic remodelling in macrophages in the context of atherosclerosis and inflammation, and provide a comprehensive overview of epigenetic enzymes and transcription factors that are involved in macrophage activation.

Molecular genetic framework underlying pulmonary arterial hypertension

Abstract: Pulmonary arterial hypertension (PAH) is a rare, progressive disorder typified by occlusion of the pulmonary arterioles owing to endothelial dysfunction and uncontrolled proliferation of pulmonary artery smooth muscle cells and fibroblasts. Vascular occlusion can lead to increased pressure in the pulmonary arteries, often resulting in right ventricular failure with shortness of breath and syncope. Since the identification of BMPR2, which encodes a receptor in the transforming growth factor-β superfamily, the development of high-throughput sequencing approaches to identify novel causal genes has substantially advanced our understanding of the molecular genetics of PAH. In the past 6 years, additional pathways involved in PAH susceptibility have been described through the identification of deleterious genetic variants in potassium channels (KCNK3 and ABCC8) and transcription factors (TBX4 and SOX17), among others. Although familial PAH most often has an autosomal-dominant pattern of inheritance, cases of incomplete penetrance and evidence of genetic heterogeneity support a model of PAH as a Mendelian disorder with complex disease features. In this Review, we outline the latest advances in the detection of rare and common genetic variants underlying PAH susceptibility and disease progression. These findings have clinical implications for lung vascular function and can help to identify mechanistic pathways amenable to pharmacological intervention.

Cardiovascular effects and safety of (non-aspirin) NSAIDs.

Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective, widely used analgesics. For the past 2 decades, considerable attention has been focused on their cardiovascular safety. After early studies indicating an association between NSAID use and increased risks of heart failure and elevated blood pressure, subsequent studies found a link between NSAID use and an increased risk of thrombotic events. Selective cyclooxygenase 2 (COX2) inhibitors (also known as coxibs) have been associated with the greatest risk of adverse vascular effects but concern also relates to non-selective NSAIDs, especially those with strong COX2 inhibition such as diclofenac. Although NSAID use is discouraged in patients with cardiovascular disease, pain-relief medication is often required and, in the absence of analgesics that are at least as effective but safer, NSAIDs are frequently prescribed. Furthermore, non-prescription use of NSAIDs, even among people with underlying cardiovascular risks, is largely unsupervised and varies widely between countries. As concern mounts about the disadvantages of alternatives to NSAIDs (such as opioids) for pain management, the use of NSAIDs is likely to rise. Given that the pharmaceutical development pipeline lacks new analgesics, health-care professionals, patients and medicine regulatory authorities are focused on optimizing the safe use of NSAIDs. In this Review, we summarize the current evidence on the cardiovascular safety of NSAIDs and present an approach for their use in the context of holistic pain management.

Single-cell RNA sequencing in cardiovascular development, disease and medicine.

Abstract: Advances in single-cell RNA sequencing (scRNA-seq) technologies in the past 10 years have had a transformative effect on biomedical research, enabling the profiling and analysis of the transcriptomes of single cells at unprecedented resolution and throughput. Specifically, scRNA-seq has facilitated the identification of novel or rare cell types, the analysis of single-cell trajectory construction and stem or progenitor cell differentiation, and the comparison of healthy and disease-related tissues at single-cell resolution. These applications have been critical in advances in cardiovascular research in the past decade as evidenced by the generation of cell atlases of mammalian heart and blood vessels and the elucidation of mechanisms involved in cardiovascular development and stem or progenitor cell differentiation. In this Review, we summarize the currently available scRNA-seq technologies and analytical tools and discuss the latest findings using scRNA-seq that have substantially improved our knowledge on the development of the cardiovascular system and the mechanisms underlying cardiovascular diseases. Furthermore, we examine emerging strategies that integrate multimodal single-cell platforms, focusing on future applications in cardiovascular precision medicine that use single-cell omics approaches to characterize cell-specific responses to drugs or environmental stimuli and to develop effective patient-specific therapeutics.

Drug-eluting coronary stents: insights from preclinical and pathology studies

Abstract: Implantation of drug-eluting stents (DES) is the dominant treatment strategy for patients with symptomatic coronary artery disease. However, the first-generation DES had substantial drawbacks, including delayed healing, local hypersensitivity reactions and neoatherosclerosis, which all led to a steady increase in major adverse cardiovascular events over time. Subsequently, newer-generation DES were introduced with thinner struts, different scaffold designs (to improve deliverability while maintaining radial strength), different durable and biodegradable polymers - and in some cases no polymer (to improve vascular biocompatibility) - and new antiproliferative drug types and doses. Currently, >30 different DES are commercially available in Europe, with fewer available in the USA but with many new entrants coming onto the US market in the next few years. Never before have cardiologists been faced with so many choices of stent, each with its own unique design. In this Review, we detail preclinical and pathology studies for each stent design, examining thromboresistance, speed of neointimal coverage and completeness of healing, including endothelialization. We conclude by discussing how these design characteristics might affect the potential for shortening the minimum duration of dual antiplatelet therapy needed after coronary intervention.

Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease.

Abstract: Lysine acetylation is a conserved, reversible, post-translational protein modification regulated by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs; also known as histone deacetylases (HDACs)) that is involved in many cellular signalling pathways and diseases. Studies in animal models have revealed a regulatory role of reversible lysine acetylation in hypertension, vascular diseases, arrhythmia, heart failure and angiogenesis. Evidence from these studies indicates a therapeutic role of KDAC inhibitors (also known as HDAC inhibitors) in cardiovascular diseases. In this Review, we describe the diverse roles of KATs and KDACs in both the normal and the diseased heart. Among KDACs, class II and class III HDACs seem to have a protective role against both cardiac damage and vessel injury, whereas class I HDACs protect against vessel injury but have deleterious effects on the heart. These observations have important implications for the clinical utility of HDAC inhibitors as therapeutic agents for cardiovascular diseases. In addition, we summarize the latest data on nonacetylation acylations in the context of cardiovascular disease.

Genetics of dilated cardiomyopathy: practical implications for heart failure management

Abstract: Given the global burden of heart failure, strategies to understand the underlying cause or to provide prognostic information are critical to reducing the morbidity and mortality associated with this highly prevalent disease. Cardiomyopathies often have a genetic cause, and the field of heart failure genetics is progressing rapidly. Through a deliberate investigation, evaluation for a familial component of cardiomyopathy can lead to increased identification of pathogenic genetic variants. Much research has also been focused on identifying markers of risk in patients with cardiomyopathy with the use of genetic testing. Advances in our understanding of genetic variants have been slightly offset by an increased recognition of the heterogeneity of disease expression. Greater breadth of genetic testing can increase the likelihood of identifying a variant of uncertain significance, which is resolved only rarely by cellular functional validation and segregation analysis. To increase the use of genetics in heart failure clinics, increased availability of genetic counsellors and other providers with experience in genetics is necessary. Ultimately, through ongoing research and increased clinical experience in cardiomyopathy genetics, an improved understanding of the disease processes will facilitate better clinical decision-making about the therapies offered, exemplifying the implementation of precision medicine. In this Review, Rosenbaum and colleagues give a broad perspective on the genetic causes of dilated cardiomyopathy to provide a context for a discussion of the pragmatic use of genetic testing in heart failure clinics for patients presenting with new-onset dilated cardiomyopathy.

Congestion in Heart Failure: A Contemporary Look at Physiology, Diagnosis and Treatment

Abstract: Congestion is the main reason for hospitalization in patients with acute decompensated heart failure and is an important target for therapy. However, achieving complete decongestion can be challenging. Furthermore, residual congestion before discharge from hospital is associated with a high risk of early rehospitalization and death. An improved understanding of the pathophysiology of congestion is of great importance in finding better and more personalized therapies. In this Review, we describe the two different forms of congestion - intravascular congestion and tissue congestion - and hypothesize that differentiating between and specifically treating these two different forms of congestion could improve the outcomes of patients with acute decompensated heart failure. Although the majority of these patients have a combination of both intravascular and tissue congestion, one phenotype can dominate. Each of these two forms of congestion has a different pathophysiology and requires a different diagnostic approach. We provide an overview of novel and established biomarkers, imaging modalities and mechanical techniques for identifying each type of congestion. Treatment with loop diuretics, the current cornerstone of decongestive treatment, reduces circulating blood volume and thereby reduces intravascular congestion. However, the osmolality of the circulating blood decreases with the use of loop diuretics, which might result in less immediate translocation of fluid from the tissues (lungs, abdomen and periphery) to the circulation when the plasma refill rate is exceeded. By contrast, aquaretic drugs (such as vasopressin antagonists) predominantly cause water excretion, which increases the osmolality of the circulating blood, potentially improving translocation of fluid from the tissues to the circulation and thereby relieving tissue congestion.

Saphenous vein grafts in contemporary coronary artery bypass graft surgery.

Abstract: Myocardial ischaemia resulting from obstructive coronary artery disease is a major cause of morbidity and mortality in the developed world. Coronary artery bypass graft (CABG) surgery is the gold-standard treatment in many patients with complex multivessel coronary artery disease or left main disease. Despite substantial improvements in the outcome of patients undergoing CABG surgery in the past decade, graft patency remains the 'Achilles' heel' of this procedure. Whereas the use of the left internal mammary artery as a conduit is associated with the highest 10-year patency rate (>90%), saphenous vein grafts - the most commonly used conduit in CABG surgery - fail in 40-50% of treated patients by 10 years after surgery. Vein graft disease (VGD) and failure result from complex pathophysiological processes that can lead to complete occlusion of the graft, affecting long-term clinical outcomes. Optimal harvesting techniques, intraoperative preservation strategies and intraoperative patency control have important roles in the prevention of VGD. In addition, several studies published in the past decade have reported similar mid-term patency rates between vein grafts and arterial grafts when veins are used as a composite graft based on the internal mammary artery. In this Review, we present the latest evidence on the utilization of saphenous vein grafts for CABG surgery and provide an overview of the current practices for the prevention of VGD and vein graft failure.

Pregnancy and cardiovascular disease.

Abstract: Cardiovascular disease complicates 1–4% of pregnancies — with a higher prevalence when including hypertensive disorders — and is the leading cause of maternal death. In women with known cardiovascular pathology, such as congenital heart disease, timely counselling is possible and the outcome is fairly good. By contrast, maternal mortality is high in women with acquired heart disease that presents during pregnancy (such as acute coronary syndrome or aortic dissection). Worryingly, the prevalence of acquired cardiovascular disease during pregnancy is rising as older maternal age, obesity, diabetes mellitus and hypertension become more common in the pregnant population. Management of cardiovascular disease in pregnancy is challenging owing to the unique maternal physiology, characterized by profound changes to multiple organ systems. The presence of the fetus compounds the situation because both the cardiometabolic disease and its management might adversely affect the fetus. Equally, avoiding essential treatment because of potential fetal harm risks a poor outcome for both mother and child. In this Review, we examine how the physiological adaptations during pregnancy can provoke cardiometabolic complications or exacerbate existing cardiometabolic disease and, conversely, how cardiometabolic disease can compromise the adaptations to pregnancy and their intended purpose: the development and growth of the fetus. In this Review, Roos-Hesselink and colleagues describe how the physiological adaptations during pregnancy can induce cardiometabolic complications or an exacerbation of existing cardiometabolic disease, and discuss the epidemiology, pathophysiology, diagnosis and management of cardiometabolic diseases acquired or presenting during pregnancy, including hypertensive disorders, gestational diabetes mellitus, thromboembolic disorders and peripartum cardiomyopathy.

Assessment of mitral valve regurgitation by cardiovascular magnetic resonance imaging

Abstract: Mitral regurgitation (MR) is a common valvular heart disease and is the second most frequent indication for heart valve surgery in Western countries. Echocardiography is the recommended first-line test for the assessment of valvular heart disease, but cardiovascular magnetic resonance imaging (CMR) provides complementary information, especially for assessing MR severity and to plan the timing of intervention. As new CMR techniques for the assessment of MR have arisen, standardizing CMR protocols for research and clinical studies has become important in order to optimize diagnostic utility and support the wider use of CMR for the clinical assessment of MR. In this Consensus Statement, we provide a detailed description of the current evidence on the use of CMR for MR assessment, highlight its current clinical utility, and recommend a standardized CMR protocol and report for MR assessment.

Clinical quantitative cardiac imaging for the assessment of myocardial ischaemia

Abstract: Cardiac imaging has a pivotal role in the prevention, diagnosis and treatment of ischaemic heart disease. SPECT is most commonly used for clinical myocardial perfusion imaging, whereas PET is the clinical reference standard for the quantification of myocardial perfusion. MRI does not involve exposure to ionizing radiation, similar to echocardiography, which can be performed at the bedside. CT perfusion imaging is not frequently used but CT offers coronary angiography data, and invasive catheter-based methods can measure coronary flow and pressure. Technical improvements to the quantification of pathophysiological parameters of myocardial ischaemia can be achieved. Clinical consensus recommendations on the appropriateness of each technique were derived following a European quantitative cardiac imaging meeting and using a real-time Delphi process. SPECT using new detectors allows the quantification of myocardial blood flow and is now also suited to patients with a high BMI. PET is well suited to patients with multivessel disease to confirm or exclude balanced ischaemia. MRI allows the evaluation of patients with complex disease who would benefit from imaging of function and fibrosis in addition to perfusion. Echocardiography remains the preferred technique for assessing ischaemia in bedside situations, whereas CT has the greatest value for combined quantification of stenosis and characterization of atherosclerosis in relation to myocardial ischaemia. In patients with a high probability of needing invasive treatment, invasive coronary flow and pressure measurement is well suited to guide treatment decisions. In this Consensus Statement, we summarize the strengths and weaknesses as well as the future technological potential of each imaging modality.