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The purpose of this study was to determine the long-term pattern of plasma aldosterone concentration (PAC) trajectories and to explore the relationship between PAC trajectory patterns and cardiovascular disease (CVD) risk in patients with hypertension. Participants were surveyed three times between 2010 and 2016, and latent mixed modeling was employed to determine the trajectory of PAC over the exposure period (2010–2016). A Cox regression analysis was used to examine the association between PAC trajectory patterns and the risk of CVD (stroke and myocardial infarction). Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were calculated and reported. During a median follow-up of 4.10 (3.37–4.50) years, 82 incident CVD cases (33 myocardial infarction cases and 49 stroke cases) were identified. Among all three PAC models, the high-stability PAC pattern exhibited the highest risk of CVD. After full adjustment for all covariables, HRs were 2.19 (95% CI 1.59–3.01) for the moderate-stable pattern and 2.56 (95% CI 1.68–3.91) for the high-stable pattern in comparison to the low-stable pattern. Subgroup and sensitivity analyses verified this association. The presence of a high-stable PAC trajectory pattern is associated with an elevated risk of CVD in hypertensive patients. Nevertheless, more studies are warranted to confirm these findings.

Endothelial cells and mesenchymal cells are two different cell types with distinct morphologies, phenotypes, functions, and gene profiles. Accumulating evidence, notably from lineage-tracing studies, indicates that the two cell types convert into each other during cardiovascular development and pathogenesis. During heart development, endothelial cells transdifferentiate into mesenchymal cells in the endocardial cushion through endothelial-to-mesenchymal transition (EndoMT), a process that is critical for the formation of cardiac valves. Studies have also reported that EndoMT contributes to the development of various cardiovascular diseases, including myocardial infarction, cardiac fibrosis, valve calcification, endocardial elastofibrosis, atherosclerosis, and pulmonary arterial hypertension. Conversely, cardiac fibroblasts can transdifferentiate into endothelial cells and contribute to neovascularization after cardiac injury. However, progress in genetic lineage tracing has challenged the role of EndoMT, or its reversed programme, in the development of cardiovascular diseases. In this Review, we discuss the caveats of using genetic lineage-tracing technology to investigate cell-lineage conversion; we also reassess the role of EndoMT in cardiovascular development and diseases and elaborate on the molecular signals that orchestrate EndoMT in pathophysiological processes. Understanding the role and mechanisms of EndoMT in diseases will unravel the therapeutic potential of targeting this process and will provide a new paradigm for the development of regenerative medicine to treat cardiovascular diseases.

Observational studies have suggested that insulin resistance (IR) is associated with hypertension and various cardiovascular diseases. However, the presence of a causal relationship between IR and cardiovascular disease remains unclear. Here, we applied Mendelian randomization (MR) approaches to address the causal association between genetically determined IR and the risk of cardiovascular diseases. Our primary genetic instruments comprised 53 SNPs associated with IR phenotype from a GWAS of up to 188,577 participants. Genetic association estimates for hypertension and venous thromboembolism (VTE) were extracted from UK Biobank, estimates for atrial fibrillation (AF) were extracted from the hitherto largest GWAS meta-analysis on AF, estimates for heart failure were extracted from HERMES Consortium, estimates for peripheral artery disease (PAD) and aortic aneurysm were extracted from the FinnGen Study. The main analyses were performed using the random-effects inverse-variance weighted approach, and complemented by sensitivity analyses and multivariable MR analyses. Corresponding to 55% higher fasting insulin adjusted for body mass index, 0.46 mmol/L lower high-density lipoprotein cholesterol and 0.89 mmol/L higher triglyceride, one standard deviation change in genetically predicted IR was associated with increased risk of hypertension (odds ratio (OR) 1.06, 95% CI 1.04–1.08; P  = 1.91 × 10 –11 ) and PAD (OR 1.90, 95% CI 1.43–2.54; P  = 1.19 × 10 –5 ). Suggestive evidence was obtained for an association between IR and heart failure (OR per SD change in IR: 1.19, 95% CI 1.01–1.41, P  = 0.041). There was no MR evidence for an association between genetically predicted IR and atrial fibrillation, VTE, and aortic aneurysm. Results were widely consistent across all sensitivity analyses. In multivariable MR, the association between IR and PAD was attenuated after adjustment for lipids ( P  = 0.347) or BMI ( P  = 0.163). Our findings support that genetically determined IR increases the risk of hypertension and PAD.

The antiarrhythmic and cardiac electrophysiological effects of SZV-2649 that contains a 2,6-diiodophenoxy moiety but lacks the benzofuran ring system present in amiodarone, were studied in mammalian cell line, rat and dog cardiac preparations. SZV-2649 exerted antiarrhythmic effects against coronary artery occlusion/reperfusion induced ventricular arrhythmias in rats and in acetylcholine- and burst stimulation induced atrial fibrillation in dogs. SZV-2649 inhibited hERG and GIRK currents in HEK cells (IC 50 : 342 and 529 nM, respectively). In canine ventricular myocytes, SZV-2649 (10 µM) decreased the densities of I Kr , and I to outward and I NaL and I CaL inward currents. The compound (2.5–10 µM) elicited Class IB type V max reducing and Class III type action potential duration prolonging effects in dog right ventricular muscle preparations. In canine atrial muscle, SZV-2629 (2.5–10 µM) moderately prolonged action potential duration and this effect was greatly augmented in preparations pretreated with 1 µM carbachol. In conclusion, SZV-2649, has antiarrhythmic effects based on its multiple ion channel blocking properties. Since its chemical structure substantially differs from that of amiodarone, it is expected that SZV-2649 would exhibit fewer adverse effects than the currently used most effective multichannel inhibitor drug amiodarone and may be a promising molecule for further development.

Cardiomyocytes exit the cell cycle and become terminally differentiated soon after birth. Therefore, in the adult heart, instead of an increase in cardiomyocyte number, individual cardiomyocytes increase in size, and the heart develops hypertrophy to reduce ventricular wall stress and maintain function and efficiency in response to an increased workload. There are two types of hypertrophy: physiological and pathological. Hypertrophy initially develops as an adaptive response to physiological and pathological stimuli, but pathological hypertrophy generally progresses to heart failure. Each form of hypertrophy is regulated by distinct cellular signalling pathways. In the past decade, a growing number of studies have suggested that previously unrecognized mechanisms, including cellular metabolism, proliferation, non-coding RNAs, immune responses, translational regulation, and epigenetic modifications, positively or negatively regulate cardiac hypertrophy. In this Review, we summarize the underlying molecular mechanisms of physiological and pathological hypertrophy, with a particular emphasis on the role of metabolic remodelling in both forms of cardiac hypertrophy, and we discuss how the current knowledge on cardiac hypertrophy can be applied to develop novel therapeutic strategies to prevent or reverse pathological hypertrophy.

Increases in calorie consumption and sedentary lifestyles are fuelling a global pandemic of cardiometabolic diseases, including coronary artery disease, diabetes mellitus, cardiomyopathy and heart failure. These lifestyle factors, when combined with genetic predispositions, increase the levels of circulating lipids, which can accumulate in non-adipose tissues, including blood vessel walls and the heart. The metabolism of these lipids produces bioactive intermediates that disrupt cellular function and survival. A compelling body of evidence suggests that sphingolipids, such as ceramides, account for much of the tissue damage in these cardiometabolic diseases. In humans, serum ceramide levels are proving to be accurate biomarkers of adverse cardiovascular disease outcomes. In mice and rats, pharmacological inhibition or depletion of enzymes driving de novo ceramide synthesis prevents the development of diabetes, atherosclerosis, hypertension and heart failure. In cultured cells and isolated tissues, ceramides perturb mitochondrial function, block fuel usage, disrupt vasodilatation and promote apoptosis. In this Review, we discuss the body of literature suggesting that ceramides are drivers — and not merely passengers — on the road to cardiovascular disease. Moreover, we explore the feasibility of therapeutic strategies to lower ceramide levels to improve cardiovascular health.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.

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.The cardiotoxicity spectrum of cancer therapies has broadened and is gaining increasing importance with an ever-growing repertoire of therapeutics. This Review provides an updated overview of cardiotoxicity and arrhythmias associated with cancer therapies, summarizing the latest developments at the juncture of cardiology, oncology and haematology and the emerging field of cardio-oncology.

Platelets — blood cells continuously produced from megakaryocytes mainly in the bone marrow — are implicated not only in haemostasis and arterial thrombosis, but also in other physiological and pathophysiological processes. This Review describes current evidence for the heterogeneity in platelet structure, age, and activation properties, with consequences for a diversity of platelet functions. Signalling processes of platelet populations involved in thrombus formation with ongoing coagulation are well understood. Genetic approaches have provided information on multiple genes related to normal haemostasis, such as those encoding receptors and signalling or secretory proteins, that determine platelet count and/or responsiveness. As highly responsive and secretory cells, platelets can alter the environment through the release of growth factors, chemokines, coagulant factors, RNA species, and extracellular vesicles. Conversely, platelets will also adapt to their environment. In disease states, platelets can be positively primed to reach a pre-activated condition. At the inflamed vessel wall, platelets interact with leukocytes and the coagulation system, interactions mediating thromboinflammation. With current antiplatelet therapies invariably causing bleeding as an undesired adverse effect, novel therapies can be more beneficial if directed against specific platelet responses, populations, interactions, or priming conditions. On the basis of these novel concepts and processes, we discuss several initiatives to target platelets therapeutically.

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.In this Review, Soehnlein and colleagues discuss the role of neutrophils in cardiovascular inflammation and repair, describing the effect of cardiovascular risk factors on neutrophil production and function, appraising the contribution of neutrophils to the different stages of atherosclerosis and its clinical manifestations, and highlighting the evolving therapeutic strategies for targeting neutrophil numbers, functional status and effector mechanisms.

Cardiovascular diseases (CVDs) are a leading global cause of mortality. Hypertension (HTN) is a primary risk factor for developing and progressing CVDs, like cardiac hypertrophy and renal dysfunction. The use of experimental models to better understand the mechanisms linking HTN, cardiac hypertrophy, and renal dysfunction is essential. We aim to investigate whether cardiac hypertrophy induced by the aortic constriction model (TAC), combined with sodium oxalate (OXA) gavage, can serve as a novel model of cardiac hypertrophy with cardiorenal dysfunction. Four groups of C57BL/6 mice were randomized: SHAM (sham surgery and vehicle gavage), TAC (TAC surgery and vehicle gavage), OXA (sham surgery and OXA gavage), and TAC + OXA (TAC surgery and OXA gavage). In the eighth week, the TAC group exhibited elevated systolic carotid pressure, cardiac hypertrophy, increased end-diastolic volume and LV internal diameter, and renal inflammation, but did not exhibit renal dysfunction. OXA gavage intensely increased autonomic modulation as a whole (SD-PI: SHAM = 5.97 ± 1.31 vs. OXA = 15.55 ± 4.03, p  < 0.01), caused an increase in the gene expression of SERCA2, changed the LV relaxation phase and induced renal injury, but did not cause an increase in carotid pressure or cardiac hypertrophy. The combination of TAC with OXA gavage in the TAC + OXA group caused increased carotid pressures, cardiac hypertrophy, pulmonary congestion, loss of baroreflex sensitivity (alpha index: SHAM = 3.64 ± 1.0 vs. TAC + OXA = 0.68 ± 0.13, p  < 0.04), increased expression of SERCA2 and induced renal dysfunction. Conclusion: The combination of TAC with OXA gavage generated a novel model of cardiac hypertrophy with cardiorenal dysfunction, with a greater state of cardiac decompensation than when TAC and OXA are used separately, and caused significant renal dysfunction, a situation not observed in the TAC model or the OXA gavage model.