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Right ventricular (RV) function has proven to be a prognostic factor in heart failure with reduced and preserved ejection fraction and in pulmonary hypertension. RV function is also a cornerstone in the management of novel clinical issues, such as mechanical circulatory support devices or grown-up congenital heart disease patients. Despite the notable amount of circumferentially oriented myofibers in the subepicardial layer of the RV myocardium, the non-longitudinal motion directions are often neglected in the everyday assessment of RV function by echocardiography. However, the complex RV contraction pattern incorporates different motion components along three anatomically relevant axes: longitudinal shortening with traction of the tricuspid annulus towards the apex, radial motion of free wall often referred as the “bellows effect”, and anteroposterior shortening of the chamber by stretching the free wall over the septum. Advanced echocardiographic techniques, such as speckle-tracking and 3D echocardiography allow an in-depth characterization of RV mechanical pattern, providing better understanding of RV systolic and diastolic function. In our current review, we summarize the existing knowledge regarding RV mechanical adaptation to pressure- and/or volume-overloaded states and also other physiologic or pathologic conditions.

In a randomized trial, 398 patients with heart failure and atrial fibrillation were assigned to either catheter ablation or medical therapy. Catheter ablation significantly reduced the primary outcome of death from any cause or hospitalization for worsening heart failure.

Key Points Most acute coronary events result from sudden luminal thrombosis due to rupture of an atherosclerotic plaque Modern computed tomography (CT) scanners enable robust coronary plaque characterization and quantification Large plaque volume, low CT attenuation, napkin-ring sign, positive remodelling, and spotty calcification are all associated with plaques vulnerable to rupture Computational fluid dynamic simulation enables plaque-specific endothelial shear stress and fractional flow reserve assessment, and thus permits functional characterization of plaques Coupling individual plaque morphology with plaque-specific functional data will enable new noninvasive detection of vulnerable plaques with CT Catastrophic acute coronary events are often the result of ruptured atherosclerotic plaques and subsequent luminal thrombosis. Preventing such an event seems to be the only effective strategy to reduce mortality and morbidity of coronary artery disease. This Review highlights how computed tomography angiography might be combined with fluid dynamic assessment to identify rupture-prone plaques in patients with coronary artery disease. Most acute coronary syndromes are caused by sudden luminal thrombosis due to atherosclerotic plaque rupture or erosion. Preventing such an event seems to be the only effective strategy to reduce mortality and morbidity of coronary heart disease. Coronary lesions prone to rupture have a distinct morphology compared with stable plaques, and provide a unique opportunity for noninvasive imaging to identify vulnerable plaques before they lead to clinical events. The submillimeter spatial resolution and excellent image quality of modern computed tomography (CT) scanners allow coronary atherosclerotic lesions to be detected, characterized, and quantified. Large plaque volume, low CT attenuation, napkin-ring sign, positive remodelling, and spotty calcification are all associated with a high risk of acute cardiovascular events in patients. Computation fluid dynamics allow the calculation of lesion-specific endothelial shear stress and fractional flow reserve, which add functional information to plaque assessment using CT. The combination of morphologic and functional characteristics of coronary plaques might enable noninvasive detection of vulnerable plaques in the future.

•The PEG-containing mRNA/LNP Covid-19 vaccines can rarely cause anaphylaxis.•A causal role of anti-PEG IgG/IgM in these reactions has been raised but not yet proven.•Such antibodies are present in the blood of most humans, with very high levels in some.•Anti-PEG antibody super-carriers have increased risk for reactions to PEGylated vaccines.•The PEG in these vaccines can induce anti-PEG antibodies in some individuals. A small fraction of recipients who receive polyethylene-glycol (PEG)-containing COVID-19 mRNA-LNP vaccines (Comirnaty and Spikevax) develop hypersensitivity reactions (HSRs) or anaphylaxis. A causal role of anti-PEG antibodies (Abs) has been proposed, but not yet been proven in humans.We used ELISA for serial measurements of SARS-CoV-2 neutralizing Ab (anti-S) and anti-PEG IgG/IgM Ab levels before and after the first and subsequent booster vaccinations with mRNA-LNP vaccines in a total of 291 blood donors. The HSRs in 15 subjects were graded and correlated with anti-PEG IgG/IgM, just as the anti-S and anti-PEG Ab levels with each other. The impacts of gender, allergy, mastocytosis and use of cosmetics were also analyzed. Serial testing of two or more plasma samples showed substantial individual variation of anti-S Ab levels after repeated vaccinations, just as the levels of anti-PEG IgG and IgM, which were over baseline in 98–99 % of unvaccinated individuals. About 3-4 % of subjects in the strongly left-skewed distribution had 15–45-fold higher values than the median, referred to as anti-PEG Ab supercarriers. Both vaccines caused significant rises of anti-PEG IgG/IgM with >10-fold rises in about ∼10 % of Comirnaty, and all Spikevax recipients. The anti-PEG IgG and/or IgM levels in the 15 vaccine reactors (3 anaphylaxis) were significantly higher compared to nonreactors. Serial testing of plasma showed significant correlation between the booster injection-induced rises of anti-S and anti-PEG IgGs, suggesting coupled anti-S and anti-PEG immunogenicity.Conclusions: The small percentage of people who have extremelevels of anti-PEG Ab in their blood may be at increased risk for HSRs/anaphylaxis to PEGylated vaccines and other PEGylated injectables. This risk might be further increased by the anti-PEG immunogenicity of these vaccines. Screening for anti-PEG Ab “supercarriers” may help predicting reactors and thus preventing these adverse phenomena.

Aims/hypothesisLarge cardiovascular outcome trials demonstrated that the cardioprotective effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors might reach beyond glucose-lowering action. In this meta-analysis, we sought to evaluate the potential infarct size-modulating effect of SGLT2 inhibitors in preclinical studies.MethodsIn this preregistered meta-analysis (PROSPERO: CRD42020189124), we included placebo-controlled, interventional studies of small and large animal models of myocardial ischaemia–reperfusion injury, testing the effect of SGLT2 inhibitor treatment on myocardial infarct size (percentage of area at risk or total area). Standardised mean differences (SMDs) were calculated and pooled using random-effects method. We evaluated heterogeneity by computing Τ2 and I2 values. Meta-regression was performed to explore prespecified subgroup differences according to experimental protocols and their contribution to heterogeneity was assessed (pseudo-R2 values).ResultsWe identified ten eligible publications, reporting 16 independent controlled comparisons on a total of 224 animals. Treatment with SGLT2 inhibitor significantly reduced myocardial infarct size compared with placebo (SMD = −1.30 [95% CI −1.79, −0.81], p < 0.00001), referring to a 33% [95% CI 20%, 47%] difference. Heterogeneity was moderate (Τ2 = 0.58, I2 = 60%). SGLT2 inhibitors were only effective when administered to the intact organ system, but not to isolated hearts (p interaction <0.001, adjusted pseudo-R2 = 47%). While acute administration significantly reduced infarct size, chronic treatment was superior (p interaction <0.001, adjusted pseudo-R2 = 85%). The medications significantly reduced infarct size in both diabetic and non-diabetic animals, favouring the former (p interaction = 0.030, adjusted pseudo-R2 = 12%). Treatment was equally effective in rats and mice, as well as in a porcine model. Individual study quality scores were not related to effect estimates (p = 0.33). The overall effect estimate remained large even after adjusting for severe forms of publication bias.Conclusions/interpretationThe glucose-lowering SGLT2 inhibitors reduce myocardial infarct size in animal models independent of diabetes. Future in vivo studies should focus on clinical translation by exploring whether SGLT2 inhibitors limit infarct size in animals with relevant comorbidities, on top of loading doses of antiplatelet agents. Mechanistic studies should elucidate the potential relationship between the infarct size-lowering effect of SGLT2 inhibitors and the intact organ system.

In a randomized trial, 1905 patients with left main coronary artery disease were assigned to either percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG). At 5 years, the rates of the composite of death, stroke, or myocardial infarction were not significantly different between the two groups.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce major adverse cardiovascular events (MACE) in type 2 diabetic (T2DM) patients. Pharmacological selectivity of these agents to SGLT2 over SGLT1 is highly variant, with unknown clinical relevance. Genetically reduced SGLT1—but not SGLT2—activity correlates with lower risk of heart failure and mortality, therefore additional non-selective SGLT1 inhibition might be beneficial. In this prespecified meta-analysis, we included 6 randomized, placebo-controlled cardiovascular outcome trials of SGLT2 inhibitors assessing MACE in 57,553 patients with T2DM. Mixed-effects meta-regression revealed that pharmacological selectivity of SGLT2 inhibitors (either as continuous or dichotomized variable) had no significant impact on most outcomes. However, lower SGLT2 selectivity correlated with significantly lower risk of stroke (pseudo-R 2  = 78%; p = 0.011). Indeed, dual SGLT1/2 inhibitors significantly reduced the risk of stroke (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.64–0.94), unlike selective agents (p for interaction = 0.018). The risk of diabetic ketoacidosis and genital infections was higher in both pharmacological groups versus placebo. However, hypotension occurred more often with non-selective SGLT2 inhibitors (odds ratio [OR], 1.87; 95% CI, 1.20–2.92) compared with selective agents (p for interaction = 0.044). In conclusion, dual SGLT1/2 inhibition reduces stroke in high-risk T2DM patients but has limited additional effect on other clinical outcomes.

This study compared administration of the antiplatelet agent ticagrelor in the ambulance with administration in the cath lab in patients with ST-segment elevation MI. Prehospital administration did not improve coronary reperfusion before PCI but did reduce the risk of stent thrombosis. Effective antiplatelet therapy combining the inhibition of both thromboxane A 2 –dependent platelet aggregation and P2Y 12 receptors is necessary in patients undergoing percutaneous coronary intervention (PCI), particularly those with ST-segment elevation myocardial infarction (STEMI). Studies in this patient population have shown that the more intense P2Y 12 -receptor inhibition achieved with the use of prasugrel, ticagrelor, or cangrelor, as compared with clopidogrel, is associated with better clinical outcomes and a lower risk of stent thrombosis. 1 – 5 The benefit was obtained with in-hospital administration of these drugs, and it is not known whether earlier administration would be as safe and . . .

Background The sodium–glucose cotransporter-2 (SGLT2) inhibitor canagliflozin has been shown to reduce major cardiovascular events in type 2 diabetic patients, with a pronounced decrease in hospitalization for heart failure (HF) especially in those with HF at baseline. These might indicate a potent direct cardioprotective effect, which is currently incompletely understood. We sought to characterize the cardiovascular effects of acute canagliflozin treatment in healthy and infarcted rat hearts. Methods Non-diabetic male rats were subjected to sham operation or coronary artery occlusion for 30 min, followed by 120 min reperfusion in vivo. Vehicle or canagliflozin (3 µg/kg bodyweight) was administered as an intravenous bolus 5 min after the onset of ischemia. Rats underwent either infarct size determination with serum troponin-T measurement, or functional assessment using left ventricular (LV) pressure–volume analysis. Protein, mRNA expressions, and 4-hydroxynonenal (HNE) content of myocardial samples from sham-operated and infarcted rats were investigated. In vitro organ bath experiments with aortic rings from healthy rats were performed to characterize a possible effect of canagliflozin on vascular function. Results Acute treatment with canagliflozin significantly reduced myocardial infarct size compared to vehicle (42.5 ± 2.9% vs. 59.3 ± 4.2%, P = 0.006), as well as serum troponin-T levels. Canagliflozin therapy alleviated LV systolic and diastolic dysfunction following myocardial ischemia–reperfusion injury (IRI), and preserved LV mechanoenergetics. Western blot analysis revealed an increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric-oxide synthase (eNOS), which were not disease-specific effects. Canagliflozin elevated the phosphorylation of Akt only in infarcted hearts. Furthermore, canagliflozin reduced the expression of apoptotic markers (Bax/Bcl-2 ratio) and that of genes related to myocardial nitro-oxidative stress. In addition, treated hearts showed significantly lower HNE positivity. Organ bath experiments with aortic rings revealed that preincubation with canagliflozin significantly enhanced endothelium-dependent vasodilation in vitro, which might explain the slight LV afterload reducing effect of canagliflozin in healthy rats in vivo. Conclusions Acute intravenous administration of canagliflozin after the onset of ischemia protects against myocardial IRI. The medication enhances endothelium dependent vasodilation independently of antidiabetic action. These findings might further contribute to our understanding of the cardiovascular protective effects of canagliflozin reported in clinical trials.

High inter-individual variability in tacrolimus clearance is attributed to genetic polymorphisms of CYP3A enzymes. However, due to CYP3A phenoconversion induced by non-genetic factors, continuous changes in tacrolimus-metabolizing capacity entail frequent dose-refinement for optimal immunosuppression. In heart transplant recipients, the contribution of patients’ CYP3A-status ( CYP3A5 genotype and CYP3A4 expression) to tacrolimus blood concentration and dose-requirement was evaluated in the early and late post-operative period. In low CYP3A4 expressers carrying CYP3A5*3/*3 , the dose-corrected tacrolimus level was significantly higher than in normal CYP3A4 expressers or in those with CYP3A5*1 . Modification of the initial tacrolimus dose was required for all patients: dose reduction by 20% for low CYP3A4 expressers, a 40% increase for normal expressers and a 2.4-fold increase for CYP3A5*1 carriers. The perioperative high-dose corticosteroid therapy was assumed to ameliorate the low initial tacrolimus-metabolizing capacity during the first month. The fluctuation of CYP3A4 expression and tacrolimus blood concentration (C 0 /D) was found to be associated with tapering and cessation of corticosteroid in CYP3A5 non-expressers, but not in those carrying CYP3A5*1 . Although monitoring of tacrolimus blood concentration cannot be omitted, assaying recipients’ CYP3A-status can guide optimization of the initial tacrolimus dose, and can facilitate personalized tacrolimus therapy during steroid withdrawal in the late post-operative period.