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Indeed, patients with TTS clinically present like patients with ST-segment elevation myocardial infarction (STEMI) with angina pectoris with or without, dyspnoea, and often with similar electrocardiographic (ECG) changes. As pyruvate levels decreased and hexokinase increased, glucose metabolism also switched from the classical pyruvate production to glucose-6-phosphate (G6P) with consequent elevation of G6P and fructose-6-phosphate levels in the myocardium. The ATP depletion in turn results in PCr depletion and inhibits glycolysis.[11] Of note, Borchert I et al i . created iPSC-derived cardiomyocytes from patients with TTS and replicated its cardiac phenotype. [Extracted from the article]

The article discusses that English physician William Withering, inspired by an old herb woman in Shropshire, published his seminal monograph. It mentions that the Foxglove and some of its medical uses with practical remarks on dropsy, and other diseases," in which he described the clinical effects of an extract of the foxglove plant on patients with a condition that he called dropsy.

This article discusses the relationship between heart failure (HF) and respiratory tract infections, specifically lower respiratory tract infections (LRTI). The burden of comorbidities in patients with HF exposes them to a higher risk of non-cardiovascular events, including infections. LRTIs, such as pneumonia, are common in patients with HF and can lead to HF decompensation or be a consequence of it, increasing the risk of hospitalizations and mortality. The article also explores the potential protective role of HF drugs, specifically empagliflozin, in preventing LRTIs. The study found that empagliflozin was associated with a lower risk of incident LRTI compared to a placebo. However, there was no impact on the incidence of COVID-19. Further research is needed to confirm these findings and explore the impact of SGLT2 inhibitors on LRTI risk in patients with HF. [Extracted from the article]

Background: The aging gene p66Shc, is an important mediator of oxidative stress-induced vascular dysfunction and disease. In cultured human aortic endothelial cells (HAEC), p66Shc deletion increases endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) bioavailability via protein kinase B. However, the putative role of the NO pathway on p66Shc activation remains unclear. This study was designed to elucidate the regulatory role of the eNOS/NO pathway on p66Shc activation. Methods and Results: Incubation of HAEC with oxidized low density lipoprotein (oxLDL) led to phosphorylation of p66Shc at Ser-36, resulting in an enhanced production of superoxide anion (O2-). In the absence of oxLDL, inhibition of eNOS by small interfering RNA or L-NAME, induced p66Shc phosphorylation, suggesting that basal NO production inhibits O2- production. oxLDL-induced, p66Shc-mediated O2- was prevented by eNOS inhibition, suggesting that when cells are stimulated with oxLDL eNOS is a source of reactive oxygen species. Endogenous or exogenous NO donors, prevented p66Shc activation and reduced O2- production. Treatment with tetrahydrobiopterin, an eNOS cofactor, restored eNOS uncoupling, prevented p66Shc activation, and reduced O2- generation. However, late treatment with tetrahydropterin did not yield the same result suggesting that eNOS uncoupling is the primary source of reactive oxygen species. Conclusions: The present study reports that in primary cultured HAEC treated with oxLDL, p66Shc-mediated oxidative stress is derived from eNOS uncoupling. This finding contributes novel information on the mechanisms of p66Shc activation and its dual interaction with eNOS underscoring the importance eNOS uncoupling as a putative antioxidant therapeutical target in endothelial dysfunction as observed in cardiovascular disease. [ABSTRACT FROM AUTHOR]

Cardiovascular Research, 2022, https://doi.org/10.1093/cvr/cvac069 In the originally published version of this manuscript, figure 1 was missing. This error has been corrected (online). [Extracted from the article]

Background: Inflammatory processes can trigger acute coronary syndromes (ACS) which may increase core body temperature (BT), a widely available low‐cost marker of systemic inflammation. Herein, we aimed to delineate baseline characteristics of ST‐segment elevation myocardial infarction (STEMI) and non‐ST‐segment elevation ACS (NSTE‐ACS) patients stratified by initial BT and to assess its predictive utility towards major adverse cardiovascular events (MACE) after the index ACS. Methods: From 2012 until 2017, a total of 1044 ACS patients, 517 with STEMI and 527 with NSTE‐ACS, were prospectively recruited at the University Hospital Zurich. BT was measured by digital tympanic thermometer along with high‐sensitivity C‐reactive protein (hs‐CRP) and cardiac troponin‐T (hs‐cTnT) levels prior to coronary angiography. Patients were stratified according to initial BT and uni‐ and multivariable regression models were fit to assess associations of BT with future MACE risk. Results: Among patients with STEMI, BT was not predictive of 1‐year MACE, but a U‐shaped relationship between BT and MACE risk was noted in those with NSTE‐ACS (p =.029), translating into a 2.4‐fold (HR, 2.44, 95% CI, 1.16–5.16) increased 1‐year MACE risk in those with BT >36.8°C (reference: 36.6–36.8°C). Results remained robust in multivariable‐adjusted analyses accounting for sex, age, diabetes, renal function and hs‐cTnT. However, when introducing hs‐CRP, the BT‐MACE association did not prevail. Conclusions: In prospectively recruited patients with ACS, initial BT shows a U‐shaped relationship with 1‐year MACE risk among those with NSTE‐ACS, but not in those with STEMI. BT is a broadly available low‐cost marker to identify ACS patients with high inflammatory burden, at high risk for recurrent ischaemic events, and thus potentially suitable for an anti‐inflammatory intervention. Registration: ClinicalTrials.gov Identifier: NCT01000701. [ABSTRACT FROM AUTHOR]

Calcium antagonists are potent vasodilators and are widely used in the treatment of hypertension and angina pectoris. The currently available compounds belong to three classes: (1) dihydropyridines (e.g. nifedipine, amlodipine and felodipine), (2) phenylalkylamines (e.g. verapamil) and (3) benzothiazepines (e.g. diltiazem). The three classes differ in their pharmacological profile and safety. For example, verapamil and diltiazem lower heart rate, while dihydropyridines increase it or leave it unchanged. With most of the latter compounds, a marked activation of the sympathetic nervous system has been noted. Most compounds exhibit negative inotropic effects, particularly the first-generation molecules, which is disadvantageous in patients with impaired left-ventricular function. The most common side effects of these drugs are flushing, headache and edema. With verapamil, constipation may represent a problem in certain patients. Hence, in spite of a large number of calcium antagonists available, there remains a need for new compounds with enhanced efficacy and improved tolerability. A new compound should lack any negative inotropism, avoid any increase in sympathetic outflow or heart rate and exhibit a high degree of vascular selectivity. Furthermore, a low incidence of side effects, particularly ankle edema and optimal pharmacokinetics allowing once-daily dosing would be desirable. Mibefradil is a new calcium antagonist with promising pharmacological and clinical properties. The compound has a high bioavailability, lacks negative inotropic effects at therapeutic concentrations, does not exhibit reflex tachycardia during vasodilation and actually slightly decreases heart rate. It is a potent direct vasodilator efficacious in hypertension and chronic angina pectoris, elicits endothelium-dependent relaxations and facilitates the effects of nitric oxide in vascular smooth muscle. The drug is a particularly efficacious vasodilator in intramyocardial coronary arteries which may be important for its anti-ischemic effects and the lack of steal in the coronary circulation. Furthermore, mibefradil has antiproliferative properties in human vascular smooth muscle cells in culture. As a unique property, mibefradil blocks T-type calcium channels and hence represents a new class of calcium channel blockers. In patients with hypertension, mibefradil has a high efficacy in controlling blood pressure. The drug does not cause constipation and has a low incidence of ankle edema. A large trial is under way to further delineate the properties of this new calcium antagonist in patients with heart failure. [ABSTRACT FROM AUTHOR]

Keywords: plaque rupture; erosion; coronary dissection; Takotsubo syndrome; myocarditis EN plaque rupture erosion coronary dissection Takotsubo syndrome myocarditis 322 322 1 06/16/21 20210401 NES 210401 1. Patients with Takotsubo, on the other hand, should receive primarily tender loving care until their left ventricular function normalizes within days or weeks, except for patients presenting after cardio-pulmonary resuscitation, syncope or cardiogenic shock, for which acute cardiac care management is required. Accordingly, while such patients should not undergo primary PCI, they should receive the same aggressive secondary preventions as STEMI or NSTEMI patients, respectively. Of note, while patients with STEMI and non-STEMI should undergo primary or urgent PCI, respectively, and must receive aggressive secondary prevention focusing on their cardiovascular risk factors, patients with MINOCA should, obviously, only receive the latter. [Extracted from the article]

Nogo-A is a transmembrane protein with multiple functions in the central nervous system (CNS), including restriction of neurite growth and synaptic plasticity. Thus far, Nogo-A has been predominantly considered a cell contact-dependent ligand signaling via cell surface receptors. Here, we show that Nogo-A can be secreted by cultured cells of neuronal and glial origin in association with extracellular vesicles (EVs). Neuron- and oligodendrocyte-derived Nogo-A containing EVs inhibited fibroblast spreading, and this effect was partially reversed by Nogo-A receptor S1PR2 blockage. EVs purified from HEK cells only inhibited fibroblast spreading upon Nogo-A over-expression. Nogo-A-containing EVs were found in vivo in the blood of healthy mice and rats, as well as in human plasma. Blood Nogo-A concentrations were elevated after acute stroke lesions in mice and rats. Nogo-A active peptides decreased barrier integrity in an in vitro blood-brain barrier model. Stroked mice showed increased dye permeability in peripheral organs when tested 2 weeks after injury. In the Miles assay, an in vivo test to assess leakage of the skin vasculature, a Nogo-A active peptide increased dye permeability. These findings suggest that blood borne, possibly EV-associated Nogo-A could exert long-range regulatory actions on vascular permeability. [ABSTRACT FROM AUTHOR]

LoDoCo2 was designed as a multicentre, event-driven, double-blind RCT in which patients with chronic CAD on conventional therapy and tolerant to colchicine were enrolled during a run-in phase of 30 days. Am Heart J. 2019; 218 (LDLc): 46 - 56. 11 The LoDoCo2 Trial: A randomised controlled trial on the effect of low dose Colchicine for secondary prevention of cardiovascular disease in patients with established, stable coronary artery disease. [Extracted from the article]

Epigenetic processing takes centre stage in cardiometabolic diseases (obesity, metabolic syndrome, type 2 diabetes, hypertension), where it participates in adiposity, inflammation, endothelial dysfunction, vascular insulin resistance and atherosclerosis. Epigenetic modifications, defined as heritable changes in gene expression that do not entail mutation in the DNA sequence, are mainly induced by environmental stimuli (stress, pollution, cigarette smoking) and are gaining considerable interest due to their causal role in cardiovascular disease, and their amenability to pharmacological intervention. Importantly, epigenetic modifications acquired during life can be transmitted to the offspring and exert their biological effects across multiple generations. Indeed, such transgenerational transmission of epigenetic signals may contribute to anticipating cardiovascular and metabolic disease phenotypes already in children and young adults. A deeper understanding of environmental factors and their effects on the epigenetic machinery and transcriptional programs is warranted to develop effective mechanism-based therapeutic strategies. The clinical application of epigenetic drugs—also known as "epi-drugs"—is currently exploding in the field of cardiovascular disease. The present review describes the main epigenetic networks underlying cardiometabolic alterations and sheds light on specific points of intervention for pharmacological reprogramming in this setting. [ABSTRACT FROM AUTHOR]

• In a population of non-institutionalized 75 years-old subjects, lncRNA H19 predicts all-cause mortality over a follow-up of 14 years. • lncRNA H19 is differentially expressed in males and females, and it is a possible feature of sex differences in lifespan. • low-levels of lncRNA NKILA are associated with an increased risk of lacunar stroke, detected by magnetic resonance, over a follow-up of 7.5 years. Differential expression of long non-coding RNAs (lncRNAs) is a hallmark of cardiovascular aging, cerebrovascular diseases, and neurodegenerative disorders. This research article investigates the association between a panel of lncRNAs and the risk of death and ischemic stroke in a cohort of non-institutionalized elderly subjects. A total of 361 healthy individuals aged 75 years old, prospectively recruited in the Vienna Transdanube Aging (VITA) cohort, were included. Expression of lncRNAs at baseline was assessed using quantitative polymerase chain reaction PCR with pre-amplification reaction, using 18S for normalization. The primary endpoint was all-cause mortality; the secondary endpoint was the incidence of new ischemic brain lesions. Death was assessed over a 14-year follow-up, and ischemic brain lesions were evaluated by magnetic resonance imaging (MRI) over a 90-month follow-up. Ischemic brain lesions were divided into large brain infarcts (Ø ≥ 1.5 cm) or lacunes (Ø < 1.5 cm) The primary endpoint occurred in 53.5 % of the study population. The incidence of the secondary endpoint was 16 %, with a 3.3 % being large brain infarcts, and a 12.7 % lacunes. After adjustment for potential confounders, the lncRNA H19 predicted the incidence of the primary endpoint (HR 1.194, 95 % C.I. 1.012–1.409, p = 0.036), whereas the lncRNA NKILA was associated with lacunar stroke (HR 0.571, 95 % C.I. 0.375–0.868, p = 0.006). In a prospective cohort of non-institutionalized elderly subjects, high levels of lncRNA H19 are associated with a higher risk of death, while low levels of lncRNA NKILA predict an increased risk of lacunar stroke. [Display omitted] [ABSTRACT FROM AUTHOR]

An increasing number of individuals are at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and eventually premature death. The sodium-glucose co-transporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated overview of the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With landmark randomized controlled trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (i.e. at systemic, vascular, cardiac, and renal levels), we provide insights into the key mechanisms that may underlie their beneficial effects, including gliflozins' role in the modulation of inflammation, oxidative stress, cellular energy metabolism, and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, collectively contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrhythmias are presented and potential implications for future research and clinical practice are comprehensively reviewed. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes (T2DM) have a significantly higher risk of developing cardiovascular disease (CVD)-namely myocardial infarction, heart failure, and stroke. Despite clear advances in the prevention and treatment of CVD, the impact of T2DM on CVD outcome remains high and continues to escalate. Available evidence indicates that the risk of macrovascular complications increases with the severity of hyperglycemia, thus suggesting that the relation between metabolic disturbances and vascular damage is approximately linear. Although current antidiabetic drugs are highly effective for the management of hyperglycemia, most T2DM patients remain exposed to a substantial and concrete risk of CVD. Over the last decade many glucose-lowering agents have been tested for their safety and efficacy in T2DM with CVD. Noteworthy, most of these studies failed to show a significant benefit in terms of CV morbidity and mortality, despite intensive glycemic control. The recent trials Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME); Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6); Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER); and Insulin Resistance Intervention After Stroke (IRIS) have shed some light on this important clinical issue, thus showing a convincing effect of empagliflozin, liraglutide, and pioglitazone on CVD outcomes. Here we provide a critical and updated overview of the main glucose-lowering agents and their risk/benefit ratio for the prevention of CVD in patients with T2DM. [ABSTRACT FROM AUTHOR]

Aim: Heart failure with preserved ejection fraction (HFpEF) remains under‐diagnosed in clinical practice despite accounting for nearly half of all heart failure (HF) cases. Accurate and timely diagnosis of HFpEF is crucial for proper patient management and treatment. In this study, we explored the potential of natural language processing (NLP) to improve the detection and diagnosis of HFpEF according to the European Society of Cardiology (ESC) diagnostic criteria. Methods and results: In a retrospective cohort study, we used an NLP pipeline applied to the electronic health record (EHR) to identify patients with a clinical diagnosis of HF between 2010 and 2022. We collected demographic, clinical, echocardiographic and outcome data from the EHR. Patients were categorized according to the left ventricular ejection fraction (LVEF). Those with LVEF ≥50% were further categorized based on whether they had a clinician‐assigned diagnosis of HFpEF and if not, whether they met the ESC diagnostic criteria. Results were validated in a second, independent centre. We identified 8606 patients with HF. Of 3727 consecutive patients with HF and LVEF ≥50% on echocardiogram, only 8.3% had a clinician‐assigned diagnosis of HFpEF, while 75.4% met ESC criteria but did not have a formal diagnosis of HFpEF. Patients with confirmed HFpEF were hospitalized more frequently; however the ESC criteria group had a higher 5‐year mortality, despite being less comorbid and experiencing fewer acute cardiovascular events. Conclusions: This study demonstrates that patients with undiagnosed HFpEF are an at‐risk group with high mortality. It is possible to use NLP methods to identify likely HFpEF patients from EHR data who would likely then benefit from expert clinical review and complement the use of diagnostic algorithms. [ABSTRACT FROM AUTHOR]

Aims The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a transforming growth factor-β superfamily member that shares 90% homology with myostatin (MSTN), remains controversial. Here, we aimed to probe the role of GDF11 in acute myocardial infarction (MI), a frequent cause of heart failure and premature death during ageing. Methods and results In contrast to endogenous Mstn , myocardial Gdf11 declined during the course of ageing and was particularly reduced following ischaemia/reperfusion (I/R) injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by recombinant GDF11 delivery (0.1 mg/kg body weight over 30 days) prior to myocardial I/R augmented myocardial infarct size in C57BL/6 mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. While intrinsic cardioprotective signalling pathways remained unaffected by high circulating GDF11, targeted transcriptomics and immunomapping studies focusing on GDF11-associated downstream targets revealed attenuated Nkx2-5 expression confined to CD105-expressing cells, with pro-apoptotic activity, as assessed by caspase-3 levels, being particularly pronounced in adjacent cells, suggesting an indirect effect. By harnessing a highly specific and validated liquid chromatography-tandem mass spectrometry–based assay, we show that in prospectively recruited patients with MI circulating GDF11 but not MSTN levels incline with age. Moreover, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event, with circulating GDF11 emerging as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels. Conclusion Our data challenge the initially reported heart rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice and humans alike. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of cardioprotective mechanisms and thus poor outcomes of elderly patients following acute MI. [ABSTRACT FROM AUTHOR]

Aims: Cardiac sarcoidosis (CS) is a potentially fatal condition that varies in its clinical presentation. Here, we describe baseline characteristics at presentation along with prognosis and predictors of outcome in a sizable and deeply phenotyped contemporary cohort of CS patients. Methods and results: Consecutive CS patients seen at one institution were retrospectively enrolled after undergoing laboratory testing, electrocardiogram, echocardiography, cardiac magnetic resonance (CMR) imaging and 18F‐flourodeoxyglucose positron emission tomography (FDG‐PET) at baseline. The composite endpoint consisted of all‐cause mortality, aborted sudden cardiac death, major ventricular arrhythmic events, heart failure hospitalization and heart transplantation. A total of 319 CS patients were studied (67% male, 55.4 ± 12 years). During a median follow‐up of 2.2 years (range: 1 month–11 years), 8% of patients died, while 33% reached the composite endpoint. The annualized mortality rate was 2.7% and the 5‐ and 10‐year mortality rates were 6.2% and 7.5%, respectively. Multivariate analysis showed serum brain natriuretic peptide (BNP) levels (hazard ratio [HR] 2.41, 95% confidence interval [CI] 1.34–4.31, p = 0.003), CMR left ventricular ejection fraction (LVEF) (HR 0.96, 95% CI 0.94–0.98, p < 0.0001) and maximum standardized uptake value of FDG‐PET (HR 1.11, 95% CI 1.04–1.19, p = 0.001) to be independent predictors of outcome. These findings remained robust for different patient subgroups. Conclusion: Cardiac sarcoidosis is associated with significant morbidity and mortality, particularly in those with cardiac involvement as the first manifestation. Higher BNP levels, lower LVEF and more active myocardial inflammation were independent predictors of outcomes. [ABSTRACT FROM AUTHOR]

Aims: Health‐related quality of life (HRQoL) is highly relevant in cancer and often assessed with the EORTC QLQ‐C30. Cardiovascular HRQoL in cancer can be measured with the ESC HeartQoL questionnaire. We compared these instruments and examined their prognostic value. Methods and results: Summary scores for EORTC QLQ‐C30 (0–100 points) and ESC HeartQoL (0–3 points) questionnaires were prospectively assessed in 290 patients with mostly advanced cancer (stage 3/4: 81%, 1‐year mortality: 36%) and 50 healthy controls (similar age and sex). Additionally, physical function and activity assessments were performed. Both questionnaires demonstrated reduced HRQoL in patients with cancer versus controls (EORTC QLQ‐C30: 67 ± 20 vs. 91 ± 11, p < 0.001; ESC HeartQoL: 1.8 ± 0.8 vs. 2.7 ± 0.4, p < 0.001). The instruments were strongly correlated with each other (summary scores [r = 0.76], physical [r = 0.81], and emotional subscales [r = 0.75, all p < 0.001]) and independently associated with all‐cause mortality (best cut‐offs: EORTC QLQ‐C30 <82.69: hazard ratio [HR] 2.33, p = 0.004; ESC HeartQoL <1.50: HR 1.85, p = 0.004 – adjusted for sex, age, left ventricular ejection fraction, N‐terminal pro‐B‐type natriuretic peptide [NT‐proBNP], high‐sensitivity troponin T, cancer stage/type), with no differences in the strength of the association by sex (p‐interaction > 0.9). Combining both questionnaires identified three risk groups with highest mortality in patients below both cut‐offs (vs. patients above both cut‐offs: HR 3.60, p < 0.001). Patients with results below both cut‐offs, showed higher NT‐proBNP and reduced physical function and activity. Conclusions: The EORTC QLQ‐C30 and ESC HeartQoL – assessing cancer and cardiovascular HRQoL – are both associated with increased mortality in cancer patients, with even greater stratification by combing both. Reduced HRQoL scores were associated with elevated cardiovascular biomarkers and decreased functional status. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) presents a great burden for elderly patients, their caregivers, and health systems. Structural and functional alterations of vessels accumulate throughout life, culminating in increased risk of developing CVD. The growing elderly population worldwide highlights the need to understand how aging promotes CVD in order to develop new strategies to confront this challenge. This review provides examples of some major unresolved clinical problems encountered in daily cardiovascular practice as we care for elderly patients. Next, the authors summarize the current understanding of the mechanisms implicated in cardiovascular aging, and the potential for targeting novel pathways implicated in endothelial dysfunction, mitochondrial oxidative stress, chromatin remodeling, and genomic instability. Lastly, the authors consider critical aspects of vascular repair, including autologous transplantation of bone marrow-derived stem cells in elderly patients. [ABSTRACT FROM AUTHOR]

Aims Enhancing SIRT1 activity exerts beneficial cardiovascular effects. In diabetes, plasma SIRT1 levels are reduced. We aimed to investigate the therapeutic potential of chronic recombinant murine SIRT1 (rmSIRT1) supplementation to alleviate endothelial and vascular dysfunction in diabetic mice (db/db). Methods and results Left internal mammary arteries obtained from patients undergoing coronary artery bypass grafting with or without a diagnosis of diabetes were assayed for SIRT1 protein levels. Twelve-week-old male db/db mice and db/+ controls were treated with vehicle or rmSIRT1 intraperitoneally for 4 weeks, after which carotid artery pulse wave velocity (PWV) and energy expenditure/activity were assessed by ultrasound and metabolic cages, respectively. Aorta, carotid, and mesenteric arteries were isolated to determine endothelial and vascular function using the myograph system. Arteries obtained from diabetic patients had significantly lower levels of SIRT1 relative to non-diabetics. In line, aortic SIRT1 levels were reduced in db/db mice compared to db/+ mice, while rmSIRT1 supplementation restored SIRT1 levels. Mice receiving rmSIRT1 supplementation displayed increased physical activity and improved vascular compliance as reflected by reduced PWV and attenuated collagen deposition. Aorta of rmSIRT1-treated mice exhibited increased endothelial nitric oxide (eNOS) activity, while endothelium-dependent contractions of their carotid arteries were significantly decreased, with mesenteric resistance arteries showing preserved hyperpolarization. Ex vivo incubation with reactive oxygen species (ROS) scavenger Tiron and NADPH oxidase inhibitor apocynin revealed that rmSIRT1 leads to preserved vascular function by suppressing NADPH oxidase (NOX)-related ROS synthesis. Chronic rmSIRT1 treatment resulted in reduced expression of both NOX1 and NOX4, in line with a reduction in aortic protein carbonylation and plasma nitrotyrosine levels. Conclusions In diabetic conditions, arterial SIRT1 levels are significantly reduced. Chronic rmSIRT1 supplementation improves endothelial function and vascular compliance by enhancing eNOS activity and suppressing NOX-related oxidative stress. Thus, SIRT1 supplementation may represent novel therapeutic strategy to prevent diabetic vascular disease. [ABSTRACT FROM AUTHOR]

Arterial thrombosis is the main underlying mechanism of acute atherothrombosis. Combined antiplatelet and anticoagulant regimens prevent thrombosis but increase bleeding rates. Mast cell-derived heparin proteoglycans have local antithrombotic properties, and their semisynthetic dual AntiPlatelet and AntiCoagulant (APAC) mimetic may provide a new efficacious and safe tool for arterial thrombosis. We investigated the in vivo impact of intravenous APAC (0.3–0.5 mg/kg; doses chosen according to pharmacokinetic studies) in two mouse models of arterial thrombosis and the in vitro actions in mouse platelets and plasma. Platelet function and coagulation were studied with light transmission aggregometry and clotting times. Carotid arterial thrombosis was induced either by photochemical injury or surgically exposing vascular collagen after infusion of APAC, UFH or vehicle. Time to occlusion, targeting of APAC to the vascular injury site and platelet deposition on these sites were assessed by intra-vital imaging. Tissue factor activity (TF) of the carotid artery and in plasma was captured. APAC inhibited platelet responsiveness to agonist stimulation (collagen and ADP) and prolonged APTT and thrombin time. After photochemical carotid injury, APAC-treatment prolonged times to occlusion in comparison with UFH or vehicle, and decreased TF both in carotid lysates and plasma. Upon binding from circulation to vascular collagen-exposing injury sites, APAC reduced the in situ platelet deposition. Intravenous APAC targets arterial injury sites to exert local dual antiplatelet and anticoagulant actions and attenuates thrombosis upon carotid injuries in mice. Systemic APAC provides local efficacy, highlighting APAC as a novel antithrombotic to reduce cardiovascular complications. [Display omitted] • APAC is an antiplatelet agent and inhibits platelet aggregation to collagen and ADP in mice. • APAC is an anticoagulant and prolongs coagulation times in plasma. • Intravenous APAC decreases platelet-driven thrombi by targeting to arterial injury sites. • APAC decreases circulating and vascular tissue factor activity after arterial injury. • Systemic APAC acts as a local antithrombotic to reduce cardiovascular complications at injury sites. [ABSTRACT FROM AUTHOR]

Patients with acute coronary syndromes (ACS) remain at risk of cardiovascular disease (CVD) recurrences. Peripheral artery disease (PAD) may identify a very high risk (VHR) group who may derive greater benefit from intensified secondary prevention. Among ACS-patients enrolled in the prospective multi-center Special Program University Medicine (SPUM), we assessed the impact of PAD on major cardiovascular events (MACE: composite of myocardial infarction, stroke and all-cause death) and major bleeding. Multivariate analysis tested the relation of each significant variable with MACE, as well as biomarkers of inflammation and novel markers of atherogenesis. Out of 4787 ACS patients, 6.0% (n = 285) had PAD. PAD-patients were older (p < 0.001), with established CVD and signs of increased persistent inflammation (hs-CRP; 23.6 ± 46.5 vs 10.4 ± 27.2 mg/l, p < 0.001 and sFlt-1; 1399.5 ± 1501.3 vs 1047.2 ± 1378.6 ng/l, p = 0.018). In-hospital-death (3.2% vs 1.4%, p = 0.022) and -MACE (5.6% vs 3.0%, p = 0.017) were higher in PAD-patients. MACE at 1 year (18.6% vs 7.9%,p < 0.001) remained increased even after adjustment for confounders (Adj. HR 1.53, 95% CI: 1.14–2.08, p = 0.005). Major bleeding did not differ between groups (Adj. HR 1.18; 95% CI 0.71–1.97, p = 0.512). Although PAD predicted MACE, PAD-patients were prescribed less frequently for secondary prevention at discharge. In this real-world ACS patient cohort, concomitant PAD is a marker of VHR and is associated with increased and persistent inflammation, higher risk for MACE without an increased risk of major bleeding. Therefore, a history of PAD may be useful to identify those ACS patients at VHR who require more aggressive secondary prevention. • PAD is an easy identifiable marker of residual very high risk in ACS. • PAD in ACS is associated with increased risk of MACE but not of major bleeding. • PAD patients presented persistent increased inflammation. • PAD patients are often undertreated despite a higher residual risk. [ABSTRACT FROM AUTHOR]

Low-density lipoprotein (LDL)-cholesterol (LDL-C) promotes atherosclerotic cardiovascular disease (ASCVD), with changes in LDL electronegativity modulating its pro-atherogenic/pro-thrombotic effects. Whether such alterations associate with adverse outcomes in patients with acute coronary syndromes (ACS), a patient population at particularly high cardiovascular risk, remains unknown. This is a case-cohort study using data from a subset of 2619 ACS patients prospectively recruited at four university hospitals in Switzerland. Isolated LDL was chromatographically separated into LDL particles with increasing electronegativity (L1-L5), with the L1-L5 ratio serving as a proxy of overall LDL electronegativity. Untargeted lipidomics revealed lipid species enriched in L1 (least) vs. L5 (most electronegative subfraction). Patients were followed at 30 days and 1 year. The mortality endpoint was reviewed by an independent clinical endpoint adjudication committee. Multivariable-adjusted hazard ratios (aHR) were calculated using weighted Cox regression models. Changes in LDL electronegativity were associated with all-cause mortality at 30 days (aHR, 2.13, 95% CI, 1.07–4.23 per 1 SD increment in L1/L5; p=.03) and 1 year (1.84, 1.03–3.29; p=.04), with a notable association with cardiovascular mortality (2.29; 1.21–4.35; p=.01; and 1.88; 1.08–3.28; p=.03). LDL electronegativity superseded several risk factors for the prediction of 1-year death, including LDL-C, and conferred improved discrimination when added to the updated GRACE score (area under the receiver operating characteristic curve 0.74 vs. 0.79, p=.03). Top 10 lipid species enriched in L1 vs. L5 were: cholesterol ester (CE) (18:2), CE (20:4), free fatty acid (FA) (20:4), phosphatidyl-choline (PC) (36:3), PC (34:2), PC (38:5), PC (36:4), PC (34:1), triacylglycerol (TG) (54:3), and PC (38:6) (all p <.001), with CE (18:2), CE (20:4), PC (36:3), PC (34:2), PC (38:5), PC (36:4), TG (54:3), and PC (38:6) independently associating with fatal events during 1-year of follow-up (all p <.05). Reductions in LDL electronegativity are linked to alterations of the LDL lipidome, associate with all-cause and cardiovascular mortality beyond established risk factors, and represent a novel risk factor for adverse outcomes in patients with ACS. These associations warrant further validation in independent cohorts. [Display omitted] • Reduced low-density lipoprotein (LDL) electronegativity associates independently with mortality risk at 30 days and 1 year after the acute event. • LDL electronegativity supersedes several risk factors for the prediction of 1-year death, including LDL-cholesterol. • When added to the GRACE risk score, it enhances the discriminatory performance of the score. • LDL particles of different electronegativity have a distinct lipidome, with potential implications for their athero-/thrombogenicity. • LDL electronegativity is a novel and independent determinant of mortality risk in patients with established atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

Takotsubo syndrome (TTS) accounts for between 1 and 4% of cases presenting clinically as an acute coronary syndrome. It typically presents as a transient cardiac phenotype of left ventricular dysfunction with spontaneous recovery. More dramatic presentations may include cardiogenic shock or cardiac arrest. Despite progress in the understanding of the condition since its first description in 1990, considerable questions remain into understanding underlying pathomechanisms. In this review article, we describe the current published data on potential underlying mechanisms associated with the onset of TTS including sympathetic nervous system over-stimulation, structural and functional alterations in the central nervous system, catecholamine secretion, alterations in the balance and distribution of adrenergic receptors, the additive impact of hormones including oestrogen, epicardial coronary or microvascular spasm, endothelial dysfunction, and genetics as potentially contributing to the cascade of events leading to the onset. These pathomechanisms provide suggestions for novel potential therapeutic strategies in patients with TTS including the role of cognitive behavioural therapy, beta-blockers, and endothelin-A antagonists. The underlying mechanism of TTS remains elusive. In reality, physical or emotional stressors likely trigger through the amygdala and hippocampus a central neurohumoral activation with the local and systemic secretion of excess catecholamine and other neurohormones, which exert its effect on the myocardium through a metabolic switch, altered cellular signalling, and endothelial dysfunction. These complex pathways exert a regional activation in the myocardium through the altered distribution of adrenoceptors and density of autonomic innervation as a protective mechanism from myocardial apoptosis. More research is needed to understand how these different complex mechanisms interact with each other to bring on the TTS phenotype. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Long noncoding RNAs (lncRNAs) are involved in diabetogenesis in experimental models, yet their role in humans is unclear. We investigated whether circulating lncRNAs associate with incident type 2 diabetes in older adults. RESEARCH DESIGN AND METHODS: A preselected panel of lncRNAs was measured in serum of individuals without diabetes (n = 296) from the Vienna Transdanube Aging study, a prospective community-based cohort study. Participants were followed up over 7.5 years. A second cohort of individuals with and without type 2 diabetes (n = 90) was used to validate our findings. RESULTS: Four lncRNAs (ANRIL, MIAT, RNCR3, and PLUTO) were associated with incident type 2 diabetes and linked to hemoglobin A1c trajectories throughout the 7.5-year follow-up. Similar results (for MIAT and PLUTO also in combined analysis) were obtained in the validation cohort. CONCLUSIONS: We found a set of circulating lncRNAs that independently portends incident type 2 diabetes in older adults years before disease onset. [ABSTRACT FROM AUTHOR]

Body wasting in patients with cancer can affect the heart. The frequency, extent, and clinical and prognostic importance of cardiac wasting in cancer patients is unknown. This study prospectively enrolled 300 patients with mostly advanced, active cancer but without significant cardiovascular disease or infection. These patients were compared with 60 healthy control subjects and 60 patients with chronic heart failure (ejection fraction <40%) of similar age and sex distribution. Cancer patients presented with lower left ventricular (LV) mass than healthy control subjects or heart failure patients (assessed by transthoracic echocardiography: 177 ± 47 g vs 203 ± 64 g vs 300 ± 71 g, respectively; P < 0.001). LV mass was lowest in cancer patients with cachexia (153 ± 42 g; P < 0.001). Importantly, the presence of low LV mass was independent of previous cardiotoxic anticancer therapy. In 90 cancer patients with a second echocardiogram after 122 ± 71 days, LV mass had declined by 9.3% ± 1.4% (P < 0.001). In cancer patients with cardiac wasting during follow-up, stroke volume decreased (P < 0.001) and resting heart rate increased over time (P = 0.001). During follow-up of on average 16 months, 149 patients died (1-year all-cause mortality 43%; 95% CI: 37%-49%). LV mass and LV mass adjusted for height squared were independent prognostic markers (both P < 0.05). Adjustment of LV mass for body surface area masked the observed survival impact. LV mass below the prognostically relevant cutpoints in cancer was associated with reduced overall functional status and lower physical performance. Low LV mass is associated with poor functional status and increased all-cause mortality in cancer. These findings provide clinical evidence of cardiac wasting–associated cardiomyopathy in cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Aims Low-grade inflammation couples dysmetabolic states to insulin resistance and atherosclerotic cardiovascular (CV) disease (ASCVD). Selective sodium–glucose co-transporter 2 (SGLT-2) inhibition by empagliflozin improves clinical outcomes in patients with ASCVD independently of its glucose lowering effects. Yet, its mechanism of action remains largely undetermined. Here, we aimed to test whether empagliflozin affects arterial thrombus formation in baseline (BSL) conditions or low-grade inflammatory states, a systemic milieu shared among patients with ASCVD. Methods and results Sixteen-week-old C57BL/6 mice were randomly assigned to acute administration of empagliflozin (25 mg/kg body weight) or vehicle, of which a subgroup was pre-treated biweekly over 4 weeks with super-low-dose lipopolysaccharide (LPS; 5 ng/kg body weight), before carotid thrombosis was induced by photochemical injury. The between-group difference in Doppler-flow probe detected time-to-occlusion remained within the predefined equivalence margin (Δ = |10.50|), irrespective of low-grade inflammation (95% confidence interval, –9.82 to 8.85 and –9.20 to 9.69), while glucose dropped by 1.64 and 4.84 mmoL/L, respectively. Ex vivo platelet aggregometry suggested similar activation status, corroborated by unchanged circulating platelet-factor 4 plasma levels. In concert, carotid PAI-1 expression and tissue factor (TF) activity remained unaltered upon SGLT-2 inhibition, and no difference in plasma D-dimer levels was detected, suggesting comparable coagulation cascade activation and fibrinolytic activity. In human aortic endothelial cells pre-treated with LPS, empagliflozin neither changed TF activity nor PAI-1 expression. Accordingly, among patients with established ASCVD or at high CV risk randomized to a daily dose of 10 mg empagliflozin signatures of thrombotic (i.e. TF) and fibrinolytic activity (i.e. PAI-1) remained unchanged, while plasma glucose declined significantly during 3 months of follow-up. Conclusion SGLT-2 inhibition by empagliflozin does not impact experimental arterial thrombus formation, neither under BSL conditions nor during sustained low-grade inflammation, and has no impact on proxies of thrombotic/fibrinolytic activity in patients with ASCVD. The beneficial pleiotropic effects of empagliflozin are likely independent of pathways mediating arterial thrombosis. [ABSTRACT FROM AUTHOR]

Inflammation is a major mediator of atherosclerosis and plays a pivotal role for both innate and adaptive immunity in the onset and the progression of atherosclerosis. Novel insights into how the adaptive immune system is activated and propagates atherosclerosis elucidate the intricate interplay of different subsets of lymphocytes and their mediators as a central feature of vascular inflammation. The recognition of an inherent anti-inflammatory component of the adaptive immune system mediated by regulatory T (Treg) cells outline a novel concept: the expansion of regulatory T cells to reduce atherosclerosis. Based on a variety of research results, this concept represents a new therapeutic option in patients with atherosclerosis. [ABSTRACT FROM AUTHOR]

Arterial thrombosis may be initiated by endothelial inflammation or denudation, activation of blood-borne elements or the coagulation system. Tissue factor (TF), a central trigger of the coagulation cascade, is regulated by the pro-inflammatory NF-κB-dependent pathways. Sirtuin 6 (SIRT6) is a nuclear member of the sirtuin family of NAD+-dependent deacetylases and is known to inhibit NF-κB signaling. Its constitutive deletion in mice shows early lethality with hypoglycemia and accelerated aging. Of note, the role of SIRT6 in arterial thrombosis remains unknown. Thus, we hypothesized that endothelial SIRT6 protects from arterial thrombosis by modulating inhibition of NF-κB-associated pathways. Using a laser-induced carotid thrombosis model, in vivo arterial occlusion occurred 45% faster in 12-week-old male endothelial-specific Sirt6 −/− mice as compared to Sirt6 fl/fl controls (n ≥ 9 per group; p = 0.0012). Levels of procoagulant TF were increased in animals lacking endothelial SIRT6 as compared to control littermates. Similarly, in cultured human aortic endothelial cells, SIRT6 knockdown increased TF mRNA, protein and activity. Moreover, SIRT6 knockdown increased mRNA levels of NF-κB-associated genes tumor necrosis factor alpha (TNF- α), poly [ADP-ribose] polymerase 1 (PARP-1), vascular cell adhesion molecule 1 (VCAM-1), and cyclooxygenase-2 (COX-2); at the protein level, COX-2, VCAM-1, TNF-α, and cleaved PARP-1 remained increased after Sirt6 knockdown. Endothelium-specific Sirt6 deletion promotes arterial thrombosis in mice. In cultured human aortic endothelial cells , SIRT6 silencing enhances TF expression and activates pro-inflammatory pathways including TNF-α, cleaved PARP-1, VCAM-1 and COX-2. Hence, endogenous endothelial SIRT6 exerts a protective role in experimental arterial thrombosis. [Display omitted] • Loss of endothelial Sirt6 accelerates arterial thrombotic occlusion in vivo. • SIRT6 knockdown increases TF expression and activity in aortic endothelial cells. • SIRT6 knockdown activates pro-inflammatory cytokines in aortic endothelial cells. [ABSTRACT FROM AUTHOR]

Introduction: People with diabetes smoke at similar rates as those without diabetes, with cardiovascular consequences. Smoking cessation rates were compared between people with and without diabetes 1 year after an acute coronary syndrome (ACS).Aims and Methods: People with ACS who smoked and were part of an observational prospective multicenter study in Switzerland were included from 2007 to 2017 and followed for 12 months. Seven-day point prevalence abstinence was assessed at 12 months follow-up. Association between diabetes and smoking cessation was assessed using multivariable-adjusted logistical regression model.Results: 2457 people with ACS who smoked were included, the mean age of 57 years old, 81.9% were men and 13.3% had diabetes. At 1 year, smoking cessation was 35.1% for people with diabetes and 42.6% for people without diabetes (P-value .01). After adjustment for age, sex, and educational level, people with diabetes who smoked were less likely to quit smoking compared with people without diabetes who smoked (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.59-0.98, P-value = .037). The multivariable-adjusted model, with further adjustments for personal history of previous cardiovascular disease and cardiac rehabilitation attendance, attenuated this association (OR 0.85, 95% CI 0.65-1.12, P-value = .255). Among people with diabetes, cardiac rehabilitation attendance was a positive predictor of smoking cessation, and personal history of cardiovascular disease was a negative predictor of smoking cessation.Conclusions: People with diabetes who smoke are less likely to quit smoking after an ACS and need tailored secondary prevention programs. In this population, cardiac rehabilitation is associated with increased smoking cessation.Implications: This study provides new information on smoking cessation following ACSs comparing people with and without diabetes. After an ACS, people with diabetes who smoked were less likely to quit smoking than people without diabetes. Our findings highlight the importance of tailoring secondary prevention to people with diabetes. [ABSTRACT FROM AUTHOR]

Background Atherosclerosis is a major cause of mortality in patients with diabetes. However, novel breakthrough therapies have yet to be approved in this setting. Prolyl-isomerase-1 (Pin1) is emerging as a key molecule implicated in vascular oxidative stress and inflammation. In the present study, we investigate whether pharmacological inhibition of Pin1 may protect against diabetes-induced oxidative stress, endothelial dysfunction and vascular inflammation. Methods and Results Experiments were performed in human aortic endothelial cells (HAECs) exposed to normal (5 mmol/L) or high glucose (25 mmol/L) concentrations, in the presence of Pin1 inhibitor Juglone (10 μM) or vehicle (< 1% ethanol). In parallel, streptozotocin-induced diabetic mice were treated with Juglone i.p. every other day for 30 days (1 mg/Kg). Organ chamber experiments were performed in aortic rings to assess endothelium-dependent relaxations to acetylcholine (Ach 10 − 9 to 10 − 6 mol/L). Mitochondrial oxidative stress, organelle integrity as well as NF-kB-dependent inflammatory signatures were determined both in HAECs and aortas from diabetic mice. In HAECs, ambient hyperglycemia increased mitochondrial superoxide anion generation while treatment with Juglone prevented this phenomenon. Pharmacological inhibition of Pin1 also preserved mitochondrial integrity, nitric oxide availability and endothelial expression of adhesion molecules. Interestingly enough, endothelial dysfunction, oxidative stress and NF-kB-driven inflammation were significantly attenuated in diabetic mice chronically treated with Juglone as compared to vehicle-treated animals. Conclusion Pharmacological inhibition of Pin1 by Juglone prevents hyperglycemia-induced vascular dysfunction. Taken together, our findings may set the stage for novel therapeutic approaches to prevent vascular complications in patients with diabetes. [ABSTRACT FROM AUTHOR]

Over 10 million doses of COVID‐19 vaccines based on RNA technology, viral vectors, recombinant protein, and inactivated virus have been administered worldwide. Although generally very safe, post‐vaccine myocarditis can result from adaptive humoral and cellular, cardiac‐specific inflammation within days and weeks of vaccination. Rates of vaccine‐associated myocarditis vary by age and sex with the highest rates in males between 12 and 39 years. The clinical course is generally mild with rare cases of left ventricular dysfunction, heart failure and arrhythmias. Mild cases are likely underdiagnosed as cardiac magnetic resonance imaging (CMR) is not commonly performed even in suspected cases and not at all in asymptomatic and mildly symptomatic patients. Hospitalization of symptomatic patients with electrocardiographic changes and increased plasma troponin levels is considered necessary in the acute phase to monitor for arrhythmias and potential decline in left ventricular function. In addition to evaluation for symptoms, electrocardiographic changes and elevated troponin levels, CMR is the best non‐invasive diagnostic tool with endomyocardial biopsy being restricted to severe cases with heart failure and/or arrhythmias. The management beyond guideline‐directed treatment of heart failure and arrhythmias includes non‐specific measures to control pain. Anti‐inflammatory drugs such as non‐steroidal anti‐inflammatory drugs, and corticosteroids have been used in more severe cases, with only anecdotal evidence for their effectiveness. In all age groups studied, the overall risks of SARS‐CoV‐2 infection‐related hospitalization and death are hugely greater than the risks from post‐vaccine myocarditis. This consensus statement serves as a practical resource for physicians in their clinical practice, to understand, diagnose, and manage affected patients. Furthermore, it is intended to stimulate research in this area. [ABSTRACT FROM AUTHOR]

Background: The Global Registry of Acute Coronary Events (GRACE) 2.0 score was developed and validated in predominantly male patient populations. We aimed to assess its sex-specific performance in non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and to develop an improved score (GRACE 3.0) that accounts for sex differences in disease characteristics.Methods: We evaluated the GRACE 2.0 score in 420 781 consecutive patients with NSTE-ACS in contemporary nationwide cohorts from the UK and Switzerland. Machine learning models to predict in-hospital mortality were informed by the GRACE variables and developed in sex-disaggregated data from 386 591 patients from England, Wales, and Northern Ireland (split into a training cohort of 309 083 [80·0%] patients and a validation cohort of 77 508 [20·0%] patients). External validation of the GRACE 3.0 score was done in 20 727 patients from Switzerland.Findings: Between Jan 1, 2005, and Aug 27, 2020, 400 054 patients with NSTE-ACS in the UK and 20 727 patients with NSTE-ACS in Switzerland were included in the study. Discrimination of in-hospital death by the GRACE 2.0 score was good in male patients (area under the receiver operating characteristic curve [AUC] 0·86, 95% CI 0·86-0·86) and notably lower in female patients (0·82, 95% CI 0·81-0·82; p<0·0001). The GRACE 2.0 score underestimated in-hospital mortality risk in female patients, favouring their incorrect stratification to the low-to-intermediate risk group, for which the score does not indicate early invasive treatment. Accounting for sex differences, GRACE 3.0 showed superior discrimination and good calibration with an AUC of 0·91 (95% CI 0·89-0·92) in male patients and 0·87 (95% CI 0·84-0·89) in female patients in an external cohort validation. GRACE 3·0 led to a clinically relevant reclassification of female patients to the high-risk group.Interpretation: The GRACE 2.0 score has limited discriminatory performance and underestimates in-hospital mortality in female patients with NSTE-ACS. The GRACE 3.0 score performs better in men and women and reduces sex inequalities in risk stratification.Funding: Swiss National Science Foundation, Swiss Heart Foundation, Lindenhof Foundation, Foundation for Cardiovascular Research, and Theodor-Ida-Herzog-Egli Foundation. [ABSTRACT FROM AUTHOR]

The article focuses on Takotsubo cardiomyopathy (TTC), and states that its major characteristic is transient, reversible, systolic dysfunction of the left ventricle. Topics discussed include higher prevalence of the disease in women, primarily in primarily postmenopausal women, cardiac biomarkers and types of TTC, and coronary angiography and echocardiography in patients with TTC.

We report the case of a 38-year patient who presented in our outpatient clinic for cardiac evaluation and assessment as volunteer firefighter. The patient had an asymptomatic sinustachycardia, which was diagnosed at the age of 15. After we excluded secondary etiologies, as well as a postural orthostatic tachycardia syndrome (POTS) diagnosis of inappropriate sinus tachycardia (1ST) was confirmed. A metoprolol therapy was established, however to resistant tachycardia, we suggested a combined therapy of Bisoprolol and Ivabradin, which resulted successfully in normocard sinus rhythm. [ABSTRACT FROM AUTHOR]

Tafamidis is a molecular chaperone that stabilizes the transthyretin (TTR) homo-tetramer, preventing its dissociation and consequent deposition as amyloid fibrils in organ tissues. Tafamidis reduces mortality and the incidence of hospitalization for cardiovascular causes in patients with TTR amyloid (ATTR) cardiomyopathy. As ATTR cardiomyopathy is associated with a high risk of thromboembolic complications, we hypothesized that tafamidis may have a direct ancillary anti-thrombotic effect. Primary human aortic endothelial cells (HAECs) were treated with tafamidis at clinically relevant concentrations and with plasma of patients, before and after the initiation of treatment with tafamidis. The expression of TF was induced by incubation with Tumor Necrosis Factor α (TNFα). Intracellular expression of tissue factor (TF) was measured by western blot. TF activity was measured by a colorimetric assay. Gene expressions of TF were measured by quantitative polymerase chain reaction. Treatment with tafamidis dose-dependently reduced the expression and activity of TNFα-induced TF. This effect was confirmed in cells treated with patients' plasma. Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation was significantly inhibited by tafamidis. Incubation of HAECs with tafamidis and the STAT3 activator colivelin partially rescued the expression of TF. Treatment with tafamidis lowers the thrombotic potential in human primary endothelial cells by reducing TF expression and activity. This previously unknown off-target effect may provide a novel mechanistic explanation for the lower number of thromboembolic complications in ATTR cardiomyopathy patients treated with tafamidis. [ABSTRACT FROM AUTHOR]

Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare premature aging genetic disorder caused by a point mutation in the lamin A gene, LMNA. Children with HGPS display short lifespans and typically die due to myocardial infarction or ischemic stroke, both acute cardiovascular events that are tightly linked to arterial thrombosis. Despite this fact, the effect of the classic HGPS LMNA gene mutation on arterial thrombosis remains unknown. Heterozygous Lmna G609G knock-in (Lmna G609G/+ ) mice, yielding an equivalent classic mutation observed in HGPS patients (c.1824C>T; pG608G mutation in the human LMNA gene) and corresponding wild-type (WT) control littermates underwent photochemically laser-induced carotid injury to trigger thrombosis. Coagulation and fibrinolytic factors were measured. Furthermore, platelet activation and reactivity were investigated. Lmna G609G/+ mice displayed accelerated arterial thrombus formation, as underlined by shortened time to occlusion compared to WT littermates. Levels of factors involved in the coagulation and fibrinolytic system were comparable between groups, while Lmna G609G/+ animals showed higher plasma levels of thrombin-antithrombin complex and lower levels of antithrombin. Bone marrow analysis showed larger megakaryocytes in progeric mice. Lastly, enhanced platelet activation upon adenosine diphosphate, collagen-related peptide, and thrombin stimulation was observed in Lmna G609G/+ animals compared to the WT group, indicating a higher platelet reactivity in progeric animals. LMNA mutation in HGPS mice accelerates arterial thrombus formation, which is mediated, at least in part, by enhanced platelet reactivity, which consequently augments thrombin generation. Given the wide spectrum of antiplatelet agents available clinically, further investigation is warranted to consider the most suitable antiplatelet regimen for children with HGPS to mitigate disease mortality and morbidity. • Hutchinson-Gilford progeria syndrome (HGPS) mouse model displays accelerated arterial thrombus formation. • Extrinsic coagulation and fibrinolytic pathways are not affected by the HGPS classic LMNA mutation. • Platelets isolated from HGPS animals show intensified reactivity upon stimulation. • HGPS animals display increased levels of circulating thrombin-antithrombin complex. [ABSTRACT FROM AUTHOR]