Systemic levels of trimethylamine N-oxide (TMAO), a pro-atherogenic and pro-thrombotic metabolite produced from gut microbiota metabolism of dietary trimethylamine (TMA)-containing nutrients such as choline or carnitine, predict incident cardiovascular event risks in stable primary and secondary prevention subjects. However, the prognostic value of TMAO in the setting of acute coronary syndromes (ACS) remains unknown. We investigated the relationship of TMAO levels with incident cardiovascular risks among sequential patients presenting with ACS in two independent cohorts. In the Cleveland Cohort, comprised of sequential subjects (n = 530) presenting to the Emergency Department (ED) with chest pain of suspected cardiac origin, an elevated plasma TMAO level at presentation was independently associated with risk of major adverse cardiac events (MACE, including myocardial infarction, stroke, need for revascularization, or death) over the ensuing 30-day (4th quartile (Q4) adjusted odds ratio (OR) 6.30, 95% confidence interval (CI), 1.89–21.0, P < 0.01) and 6-month (Q4 adjusted OR 5.65, 95%CI, 1.91–16.7; P < 0.01) intervals. TMAO levels were also a significant predictor of the long term (7-year) mortality (Q4 adjusted HR 1.81, 95%CI, 1.04–3.15; P < 0.05). Interestingly, TMAO level at initial presentation predicted risk of incident MACE over the near-term (30 days and 6 months) even among subjects who were initially negative for troponin T (< 0.1 ng/mL) (30 days, Q4 adjusted OR 5.83, 95%CI, 1.79–19.03; P < 0.01). The prognostic value of TMAO was also assessed in an independent multicentre Swiss Cohort of ACS patients (n = 1683) who underwent coronary angiography. Trimethylamine N-oxide again predicted enhanced MACE risk (1-year) (adjusted Q4 hazard ratios: 1.57, 95% CI, 1.03–2.41; P <0.05). Plasma TMAO levels among patients presenting with chest pain predict both near- and long-term risks of incident cardiovascular events, and may thus provide clinical utility in risk stratification among subjects presenting with suspected ACS.

Calcific aortic valve disease (CAVD) is a highly prevalent condition that comprises a disease continuum, ranging from microscopic changes to profound fibro-calcific leaflet remodelling, culminating in aortic stenosis, heart failure, and ultimately premature death. Traditional risk factors, such as hypercholesterolaemia and (systolic) hypertension, are shared among atherosclerotic cardiovascular disease and CAVD, yet the molecular and cellular mechanisms differ markedly. Statin-induced low-density lipoprotein cholesterol lowering, a remedy highly effective for secondary prevention of atherosclerotic cardiovascular disease, consistently failed to impact CAVD progression or to improve patient outcomes. However, recently completed phase II trials provide hope that pharmaceutical tactics directed at other targets implicated in CAVD pathogenesis offer an avenue to alter the course of the disease non-invasively. Herein, we delineate key players of CAVD pathobiology, outline mechanisms that entail compromised endothelial barrier function, and promote lipid homing, immune-cell infiltration, and deranged phospho-calcium metabolism that collectively perpetuate a pro-inflammatory/pro-osteogenic milieu in which valvular interstitial cells increasingly adopt myofibro-/osteoblast-like properties, thereby fostering fibro-calcific leaflet remodelling and eventually resulting in left ventricular outflow obstruction. We provide a glimpse into the most promising targets on the horizon, including lipoprotein(a), mineral-binding matrix Gla protein, soluble guanylate cyclase, dipeptidyl peptidase-4 as well as candidates involved in regulating phospho-calcium metabolism and valvular angiotensin II synthesis and ultimately discuss their potential for a future therapy of this insidious disease.

Clinical medicine requires the integration of various forms of patient data including demographics, symptom characteristics, electrocardiogram findings, laboratory values, biomarker levels, and imaging studies. Decision-making on the optimal management should be based on a high probability that the envisaged treatment is appropriate, provides benefit, and bears no or little potential harm. To that end, personalized risk–benefit considerations should guide the management of individual patients to achieve optimal results. These basic clinical tasks have become more and more challenging with the massively growing data now available; artificial intelligence and machine learning (AI/ML) can provide assistance for clinicians by obtaining and comprehensively preparing the history of patients, analysing face and voice and other clinical features, by integrating laboratory results, biomarkers, and imaging. Furthermore, AI/ML can provide a comprehensive risk assessment as a basis of optimal acute and chronic care. The clinical usefulness of AI/ML algorithms should be carefully assessed, validated with confirmation datasets before clinical use, and repeatedly re-evaluated as patient phenotypes change. This review provides an overview of the current data revolution that has changed and will continue to change the face of clinical medicine radically, if properly used, to the benefit of physicians and patients alike.

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.

Cardiovascular diseases (CVDs), specifically lipid-driven atherosclerotic CVDs, remain the number one cause of death worldwide. The lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1), a scavenger receptor that promotes endothelial dysfunction by inducing pro-atherogenic signalling and plaque formation via the endothelial uptake of oxidized LDL (oxLDL) and electronegative LDL, contributes to the initiation, progression, and destabilization of atheromatous plaques, eventually leading to the development of myocardial infarction and certain forms of stroke. In addition to its expression in endothelial cells, LOX-1 is expressed in macrophages, cardiomyocytes, fibroblasts, dendritic cells, lymphocytes, and neutrophils, further implicating this receptor in multiple aspects of atherosclerotic plaque formation. LOX-1 holds promise as a novel diagnostic and therapeutic target for certain CVDs; therefore, understanding the molecular structure and function of LOX-1 is of critical importance. In this review, we highlight the latest scientific findings related to LOX-1, its ligands, and their roles in the broad spectrum of CVDs. We describe recent findings from basic research, delineate their translational value, and discuss the potential of LOX-1 as a novel target for the prevention, diagnosis, and treatment of related CVDs.

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. 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. 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. 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. Swiss National Science Foundation, Swiss Heart Foundation, Lindenhof Foundation, Foundation for Cardiovascular Research, and Theodor-Ida-Herzog-Egli Foundation.