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Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and d-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.In this Consensus Statement, the authors delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess thrombotic risk in these patients. Consensus recommendations are made about the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombosis and in-hospital mortality.

Essential hypertension (EH) is a multifactorial disease of the cardiovascular system that is influenced by the interplay of genetic, epigenetic, and environmental factors. The molecular dynamics underlying EH etiopathogenesis is unknown; however, earlier studies have revealed EH-associated genetic variants. Nevertheless, this finding alone is not sufficient to explain the variability in blood pressure, suggesting that other risk factors are involved, such as epigenetic modifications. Therefore, this review highlights the potential contribution of well-defined epigenetic mechanisms in EH, specifically, DNA methylation, post-translational histone modifications, and microRNAs. We further emphasize global and gene-specific DNA methylation as one of the most well-studied hallmarks among all epigenetic modifications in EH. In addition, post-translational histone modifications, such as methylation, acetylation, and phosphorylation, are described as important epigenetic markers associated with EH. Finally, we discuss microRNAs that affect blood pressure by regulating master genes such as those implicated in the renin-angiotensin-aldosterone system. These epigenetic modifications, which appear to contribute to various cardiovascular diseases, including EH, may be a promising research area for the development of novel future strategies for EH prevention and therapeutics.

In the PLATO trial of ticagrelor versus clopidogrel for treatment of acute coronary syndromes, ticagrelor reduced the composite outcome of cardiovascular death, myocardial infarction, and stroke, but increased events of major bleeding related to non-coronary artery bypass graft (CABG). CYP2C19 and ABCB1 genotypes are known to influence the effects of clopidogrel. In this substudy, we investigated the effects of these genotypes on outcomes between and within treatment groups. DNA samples obtained from patients in the PLATO trial were genotyped for CYP2C19 loss-of-function alleles (*2, *3, *4, *5, *6, *7, and *8), the CYP2C19 gain-of-function allele *17, and the ABCB1 single nucleotide polymorphism 3435C→T. For the CYP2C19 genotype, patients were stratified by the presence or absence of any loss-of-function allele, and for the ABCB1 genotype, patients were stratified by predicted gene expression (high, intermediate, or low). The primary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, or stroke after up to 12 months' treatment with ticagrelor or clopidogrel. 10 285 patients provided samples for genetic analysis. The primary outcome occurred less often with ticagrelor versus clopidogrel, irrespective of CYP2C19 genotype: 8·6% versus 11·2% (hazard ratio 0·77, 95% CI 0·60–0·99, p=0·0380) in patients with any loss-of-function allele; and 8·8% versus 10·0% (0·86, 0·74–1·01, p=0·0608) in those without any loss-of-function allele (interaction p=0·46). For the ABCB1 genotype, event rates for the primary outcome were also consistently lower in the ticagrelor than in the clopidogrel group for all genotype groups (interaction p=0·39; 8·8% vs 11·9%; 0·71, 0·55–0·92 for the high-expression genotype). In the clopidogrel group, the event rate at 30 days was higher in patients with than in those without any loss-of-function CYP2C19 alleles (5·7% vs 3·8%, p=0·028), leading to earlier separation of event rates between treatment groups in patients with loss-of-function alleles. Patients on clopidogrel who had any gain-of-function CYP2C19 allele had a higher frequency of major bleeding (11·9%) than did those without any gain-of-function or loss-of-function alleles (9·5%; p=0·022), but interaction between treatment and genotype groups was not significant for any type of major bleeding. Ticagrelor is a more efficacious treatment for acute coronary syndromes than is clopidogrel, irrespective of CYP2C19 and ABCB1 polymorphisms. Use of ticagrelor instead of clopidogrel eliminates the need for presently recommended genetic testing before dual antiplatelet treatment. AstraZeneca.

Immunotherapy is one of the most effective therapeutic options for cancer patients. Five specific classes of immunotherapies, which includes cell-based chimeric antigenic receptor T-cells, checkpoint inhibitors, cancer vaccines, antibody-based targeted therapies, and oncolytic viruses. Immunotherapies can improve survival rates among cancer patients. At the same time, however, they can cause inflammation and promote adverse cardiac immune modulation and cardiac failure among some cancer patients as late as five to ten years following immunotherapy. In this review, we discuss cardiotoxicity associated with immunotherapy. We also propose using human-induced pluripotent stem cell-derived cardiomyocytes/ cardiac-stromal progenitor cells and cardiac organoid cultures as innovative experimental model systems to (1) mimic clinical treatment, resulting in reproducible data, and (2) promote the identification of immunotherapy-induced biomarkers of both early and late cardiotoxicity. Finally, we introduce the integration of omics-derived high-volume data and cardiac biology as a pathway toward the discovery of new and efficient non-toxic immunotherapy.

Variation in and irreversibility of platelet inhibition with clopidogrel has led to controversy about its optimum dose and timing of administration in patients with acute coronary syndromes. We compared ticagrelor, a more potent reversible P2Y12 inhibitor with clopidogrel in such patients. At randomisation, an invasive strategy was planned for 13 408 (72·0%) of 18 624 patients hospitalised for acute coronary syndromes (with or without ST elevation). In a double-blind, double-dummy study, patients were randomly assigned in a one-to-one ratio to ticagrelor and placebo (180 mg loading dose followed by 90 mg twice a day), or to clopidogrel and placebo (300–600 mg loading dose or continuation with maintenance dose followed by 75 mg per day) for 6–12 months. All patients were given aspirin. The primary composite endpoint was cardiovascular death, myocardial infarction, or stroke. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00391872. 6732 patients were assigned to ticagrelor and 6676 to clopidogrel. The primary composite endpoint occurred in fewer patients in the ticagrelor group than in the clopidogrel group (569 [event rate at 360 days 9·0%] vs 668 [10·7%], hazard ratio 0·84, 95% CI 0·75–0·94; p=0·0025). There was no difference between clopidogrel and ticagrelor groups in the rates of total major bleeding (691 [11·6%] vs 689 [11·5%], 0·99 [0·89–1·10]; p=0·8803) or severe bleeding, as defined according to the Global Use of Strategies To Open occluded coronary arteries, (198 [3·2%] vs 185 [2·9%], 0·91 [0·74–1·12]; p=0·3785). Ticagrelor seems to be a better option than clopidogrel for patients with acute coronary syndromes for whom an early invasive strategy is planned. AstraZeneca.

The prevalence of both atrial fibrillation (AF) and diabetes mellitus (DM) are rising, and these conditions often occur together. Also, DM is an independent risk factor for stroke in patients with AF. We aimed to examine the safety and efficacy of rivaroxaban vs warfarin in patients with nonvalvular AF and DM in a prespecified secondary analysis of the ROCKET AF trial. We stratified the ROCKET AF population by DM status, assessed associations with risk of outcomes by DM status and randomized treatment using Cox proportional hazards models, and tested for interactions between randomized treatments. For efficacy, primary outcomes were stroke (ischemic or hemorrhagic) or non–central nervous system embolism. For safety, the primary outcome was major or nonmajor clinically relevant bleeding. The 5,695 patients with DM (40%) in ROCKET AF were younger, were more obese, and had more persistent AF, but fewer had previous stroke (the CHADS2 score includes DM and stroke). The relative efficacy of rivaroxaban and warfarin for prevention of stroke and systemic embolism was similar in patients with (1.74 vs 2.14/100 patient-years, hazard ratio [HR] 0.82) and without (2.12 vs 2.32/100 patient-years, HR 0.92) DM (interaction P = .53). The safety of rivaroxaban vs warfarin regarding major bleeding (HRs 1.00 and 1.12 for patients with and without DM, respectively; interaction P = .43), major or nonmajor clinically relevant bleeding (HRs 0.98 and 1.09; interaction P = .17), and intracerebral hemorrhage (HRs 0.62 and 0.72; interaction P = .67) was independent of DM status. Adjusted exploratory analyses suggested 1.3-, 1.5-, and 1.9-fold higher 2-year rates of stroke, vascular mortality, and myocardial infarction in DM patients. The relative efficacy and safety of rivaroxaban vs warfarin was similar in patients with and without DM, supporting use of rivaroxaban as an alternative to warfarin in diabetic patients with AF.

We investigated stroke outcomes in normal weight (body mass index [BMI] 18.50 to 24.99 kg/m2), overweight (BMI 25.00 to 29.99 kg/m2), and obese (BMI ≥30 kg/m2) patients with atrial fibrillation treated with rivaroxaban and warfarin. We compared the incidence of stroke and systemic embolic events as well as bleeding events in normal weight (n = 3,289), overweight (n = 5,535), and obese (n = 5,206) patients in a post hoc analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial. Stroke and systemic embolic event rates per 100 patient-years were 2.93 in the normal weight group (reference group), 2.28 in the overweight group (adjusted hazard ratio [HR] 0.81, 95% CI 0.66 to 0.99, p = 0.04) and 1.88 in the obese group (adjusted HR 0.69, 95% CI 0.55 to 0.86, p <0.001). The risk of stroke was statistically significantly lower for obese patients with BMI ≥35 than that for normal weight patients in both the rivaroxaban and warfarin groups (rivaroxaban: HR 0.62, 95% CI 0.40 to 0.96, p = 0.033; warfarin: HR 0.48, 95% CI 0.31 to 0.74, p <0.001). In conclusion, in patients with atrial fibrillation treated with anticoagulant therapy, increased BMI was associated with decreased stroke risk. Warfarin and the novel anticoagulant rivaroxaban are effective in stroke prevention in all subgroups of obese patients.

The autonomic nervous system (ANS) is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common observation among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] in the acute and chronic phases of the disease is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Because abnormalities in the ANS can contribute to each of these symptoms, herein a review of autonomic dysfunction in SARS-COV-2 infection is provided to guide diagnostic testing, patient care and research initiatives.Graphic abstractThe autonomic nervous system is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common collection of signs and symptoms among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Abnormalities in the autonomic nervous system (ANS) can contribute to each of these identifiers, potentially offering a unifying pathobiology for acute, subacute and the long-term sequelae of SARS-CoV-2 infection (PASC) and a target for intervention.