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Aims: To investigate whether manganese-enhancedmagnetic resonance imagingcan assess functional pancreatic beta-cellmass in people with type 1 diabetes mellitus.Methods: In a prospective case–controlstudy, 20 people with type 1 diabetesmellitus (10 with low (≥50 pmol/L) and 10 with very low (concentrations) and 15 healthy volunteers underwent manganese-enhancedmagnetic resonance imaging of the pancreas following an oral glucose load. Scan-rescanreproducibility was performed in 10 participants.Results: Mean pancreatic manganese uptake was 31 ± 6 mL/100 g of tissue/minin healthy volunteers (median 32 [interquartile range 23–36]years, 6 women),falling to 23 ± 4 and 13 ± 5 mL/100 g of tissue/min (p ≤ 0.002 for both) in peoplewith type1 diabetes mellitus (52 [44–61]years, 6 women) and low or very lowplasma C-peptideconcentrations respectively. Pancreatic manganese uptakecorrelated strongly with plasma C-peptideconcentrations in people with type1diabetes mellitus (r = 0.73, p < 0.001) but not in healthy volunteers (r = −0.054,p = 0.880). There were no statistically significant correlations between manganeseuptake and age, body-massindex, or glycated haemoglobin. There was strongintra-observer(mean difference: 0.31 (limits of agreement −1.42 to 2.05) mL/100 gof tissue/min; intra-classcorrelation, ICC = 0.99), inter-observer(−1.23 (−5.74 to3.27) mL/100 g of tissue/min; ICC = 0.85) and scan-rescan(−0.72 (−2.9 to 1.6)mL/100 g of tissue/min; ICC = 0.96) agreement for pancreatic manganese uptake.Conclusions: Manganese-enhancedmagnetic resonance imaging provides a potentialreproducible non-invasivemeasure of functional beta-cellmass in people with type1 diabetes mellitus. This holds major promise for investigating type 1 diabetes, monitoringdisease progression and assessing novel immunomodulatory interventions.

Patients with type 2 diabetes mellitus are at a higher risk of developing heart failure compared with the healthy population. In recent landmark clinical trials, sodium-glucose co-transporter 2 (SGLT2) inhibitor therapies improve blood glucose control and also reduce cardiovascular events and heart failure hospitalisations in patients with type 2 diabetes. Intriguingly, such clinical benefits have also been seen in patients with heart failure in the absence of type 2 diabetes although the underlying mechanisms are not clearly understood. Potential pathways include improved glycaemic control, diuresis, weight reduction and reduction in blood pressure, but none fully explain the observed improvements in clinical outcomes. More recently, novel mechanisms have been proposed to explain these benefits that include improved cardiomyocyte calcium handling, enhanced myocardial energetics, induced autophagy and reduced epicardial fat. We provide an up-to-date review of cardiac-specific SGLT2 inhibitor–mediated mechanisms and highlight studies currently underway investigating some of the proposed mechanisms of action in cardiovascular health and disease.

The Authors’ reply We would like to thank Yalta et al 1 for their interest in our review. We share their enthusiasm for the potential metabolic benefits of sodium-glucose co-transporter 2 (SGLT-2) inhibition. We agree with Yalta et al that in patients with type 2 diabetes or heart failure, there is dysregulated fatty acid oxidation and impaired glucose uptake causing myocardial dysfunction. In this setting of restricted fuel selection and low energetic reserve, ketone bodies are a super-fuel producing Adenosine triphosphate (ATP) more efficiently than free fatty acids or glucose, which usually serve as fuels for …

Background Myocardial injury is associated with adverse outcomes in patients with COVID-19. However, the prognostic role of myocardial injury in COVID-19 compared to other acute illnesses and the underlying mechanisms of injury are poorly understood. Methods In a prospective, multi-centre, cohort study conducted in secondary and tertiary care hospitals in Scotland, all consecutive patients with suspected COVID-19 underwent cardiac troponin (ARCHITECTSTAT high-sensitive troponin I (hs-cTnI) assay; Abbott Laboratories) testing in plasma that was surplus to clinical requirements. The results were not reported unless required by the attending clinician. We evaluated the prevalence of myocardial injury, mechanisms and outcomes in all patients. In those with any hs-cTnI concentration above the sex-specific 99th centile the diagnosis was adjudicated according to the 4th Universal Definition of Myocardial Infarction. The primary outcome of all-cause mortality was compared in those with and without myocardial injury and COVID-19 by cox regression adjusted for age, sex, renal function and co-morbidities. Results A total of 2,916 (median age 69 [interquartile range, IQR 54–79] years, 53% women) consecutive patients with suspected COVID-19 were followed up for 228 [IQR 203–249] days. Myocardial injury occurred in 26% (750/2,916) with a median troponin concentration of 66 [35–178] ng/L; the prevalence was 41% (46/112) and 25% (704/2,804) in those with and without COVID-19, respectively. The most common mechanism was acute non-ischaemic myocardial injury occurring in 80% (37/46) and 71% (502/704) of patients with and without COVID-19, respectively. Type 1 myocardial infarction (2% and 4%), type 2 myocardial infarction (7% and 14%) and chronic myocardial injury (11% and 11%) were less common and only one patient had confirmed myocarditis. In patients with myocardial injury mortality was increased compared to those without (P Conclusion Myocardial injury is common in hospitalised patients with suspected COVID-19 whether or not COVID-19 was the cause of their presentation. The majority of patients had acute non-ischaemic myocardial injury rather than a defined cardiac condition. Despite this the presence of myocardial injury was an independent predictor of death in all hospitalised patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): British Heart Foundation Kaplan-Meier curve for all-cause death

ObjectivesTo determine the contribution of comorbidities on the reported widespread myocardial abnormalities in patients with recent COVID-19.MethodsIn a prospective two-centre observational study, patients hospitalised with confirmed COVID-19 underwent gadolinium and manganese-enhanced MRI and CT coronary angiography (CTCA). They were compared with healthy and comorbidity-matched volunteers after blinded analysis.ResultsIn 52 patients (median age: 54 (IQR 51–57) years, 39 males) who recovered from COVID-19, one-third (n=15, 29%) were admitted to intensive care and a fifth (n=11, 21%) were ventilated. Twenty-three patients underwent CTCA, with one-third having underlying coronary artery disease (n=8, 35%). Compared with younger healthy volunteers (n=10), patients demonstrated reduced left (ejection fraction (EF): 57.4±11.1 (95% CI 54.0 to 60.1) versus 66.3±5 (95 CI 62.4 to 69.8)%; p=0.02) and right (EF: 51.7±9.1 (95% CI 53.9 to 60.1) vs 60.5±4.9 (95% CI 57.1 to 63.2)%; p≤0.0001) ventricular systolic function with elevated native T1 values (1225±46 (95% CI 1205 to 1240) vs 1197±30 (95% CI 1178 to 1216) ms;p=0.04) and extracellular volume fraction (ECV) (31±4 (95% CI 29.6 to 32.1) vs 24±3 (95% CI 22.4 to 26.4)%; pConclusionsPatients demonstrate right but not left ventricular dysfunction. Previous reports of left ventricular myocardial abnormalities following COVID-19 may reflect pre-existing comorbidities.Trial registration numberNCT04625075.

Background Widespread abnormalities of the myocardium have been reported in patients with COVID-19. However, these patients often have substantial co-morbidities and it is essential to understand whether cardiac abnormalities represent pre-existing disease or are the consequence of COVID-19. Objective To determine the contribution and cardiac impact of co-morbidities in patients who have recovered from COVID-19. Methods In a prospective observational study, adult patients hospitalized with confirmed COVID-19 were recruited from the Edinburgh Heart Centre between May and November 2020 and compared to healthy and co-morbidity-matched volunteers. Patients underwent gadolinium and manganese-enhanced magnetic resonance imaging and coronary computed tomography angiography. Results Twenty-three patients (54±11 years, 20 male) who recovered from COVID-19 were recruited. Half (n=11, 48%) required admission to the intensive care unit and a third (n=7, 31%) received non-invasive or invasive ventilation. Patients had a high prevalence of known cardiovascular disease (n=18, 78%), associated risk factors (n=11, 45%) and coronary artery disease (n=8, 35%). Compared with younger healthy volunteers (n=10), myocardial native T1 values (1202±25 versus 1162±27 ms, P=0.008, figure 1) and extracellular volume fraction (31.9±1.7 versus 29.8±0.5 %, P=0.001, figure 1) were higher with no differences in manganese uptake. Compared to co-morbidity-matched volunteers (n=20), there were no differences in native T1 values (1202±25 versus 1196±39 ms, P=0.61, figure 1), extracellular volume fraction (31.9±1.7 versus 31.0±0.5 %, P=0.11), presence of late gadolinium enhancement or manganese uptake. These findings remained irrespective of COVID-19 disease severity, presence of concomitant myocardial injury or coronary artery disease. Conclusions Patients who have recovered following hospitalization with COVID-19 have no evidence of a major excess in myocardial injury or dysfunction compared to co-morbidity-matched volunteers. The presence of co-morbidities likely explains many of the previously reported myocardial abnormalities. Conflict of Interest None

In an era of incremental gains in preventative cardiology, the ongoing pursuit of reduction in ischaemic events has led to advances in the antiplatelet armamentarium that is available for use after percutaneous coronary intervention (PCI). The protection offered by antithrombotic may be enhanced by extending their duration of use, or through the application of more potent drugs—longer, stronger or both. The corollary, of course, is the potential for increased bleeding, which may carry significant associated morbidity and mortality. What combination and duration of aspirin, clopidogrel, ticagrelor or prasugrel is optimal in a given patient? This is a nuanced question that is pertinent in both acute and chronic coronary syndromes. Current guidelines broadly recommend the use of dual antiplatelet therapy (DAPT) for at least 12 months in patients undergoing PCI for an acute coronary syndrome (ACS) and at least 6 months in chronic coronary syndrome, with the proviso that shorter duration DAPT may be considered in patients at high risk of bleeding.1 2 Within these boundaries, clinicians must gauge the ischaemic and bleeding risk of an individual patient in order to optimise their DAPT regime. The advent of potent P2Y12 inhibitors and iterative improvements in drug-eluting stents (DES), the latest of which have thinner struts, improved drug delivery and are associated with lower rates of stent thrombosis and restenosis, have raised the possibility of a shorter duration of DAPT after PCI, with the goal of minimising bleeding while offering non-inferior protection from ischaemic events. Multiple randomised trials have studied various combinations of drugs and DAPT duration, including short-term DAPT followed by aspirin monotherapy and short-term DAPT followed by P2Y12 inhibitor monotherapy.3–5 Although somewhat heterogenous, collectively, these data suggest that short-term DAPT may be considered as a safe option in selected individuals. The authors of the current paper conducted one …

ObjectiveIn a proof-of-concept study, to quantify myocardial viability in patients with acute myocardial infarction using manganese-enhanced MRI (MEMRI), a measure of intracellular calcium handling.MethodsHealthy volunteers (n=20) and patients with ST-elevation myocardial infarction (n=20) underwent late gadolinium enhancement (LGE) using gadobutrol and MEMRI using manganese dipyridoxyl diphosphate. Patients were scanned ≤7 days after reperfusion and rescanned after 3 months. Differential manganese uptake was described using a two-compartment model.ResultsAfter manganese administration, healthy control and remote non-infarcted myocardium showed a sustained 25% reduction in T1 values (mean reductions, 288±34 and 281±12 ms). Infarcted myocardium demonstrated less T1 shortening than healthy control or remote myocardium (1157±74 vs 859±36 and 835±28 ms; both p2=0.72 vs 0.55; p0.1) myocardium.ConclusionsThrough visualisation of intracellular calcium handling, MEMRI accurately differentiates infarcted, stunned and viable myocardium, and correlates with myocardial dysfunction better than LGE. MEMRI holds major promise in directly assessing myocardial viability, function and calcium handling across a range of cardiac diseases.Trial registration numbersNCT03607669; EudraCT number 2016-003782-25.

Background Cardiovascular magnetic resonance (CMR) is increasingly used for risk stratification in aortic stenosis (AS). However, the relative prognostic power of CMR markers and their respective thresholds remains undefined. Objectives Using machine learning, the study aimed to identify prognostically important CMR markers in AS and their thresholds of mortality. Methods Patients with severe AS undergoing AVR (n = 440, derivation; n = 359, validation cohort) were prospectively enrolled across 13 international sites (median 3.8 years’ follow-up). CMR was performed shortly before surgical or transcatheter AVR. A random survival forest model was built using 29 variables (13 CMR) with post-AVR death as the outcome. Results There were 52 deaths in the derivation cohort and 51 deaths in the validation cohort. The 4 most predictive CMR markers were extracellular volume fraction, late gadolinium enhancement, indexed left ventricular end-diastolic volume (LVEDVi), and right ventricular ejection fraction. Across the whole cohort and in asymptomatic patients, risk-adjusted predicted mortality increased strongly once extracellular volume fraction exceeded 27%, while late gadolinium enhancement >2% showed persistent high risk. Increased mortality was also observed with both large (LVEDVi >80 mL/m2) and small (LVEDVi ≤55 mL/m2) ventricles, and with high (>80%) and low (≤50%) right ventricular ejection fraction. The predictability was improved when these 4 markers were added to clinical factors (3-year C-index: 0.778 vs 0.739). The prognostic thresholds and risk stratification by CMR variables were reproduced in the validation cohort. Conclusions Machine learning identified myocardial fibrosis and biventricular remodeling markers as the top predictors of survival in AS and highlighted their nonlinear association with mortality. These markers may have potential in optimizing the decision of AVR.

Aims The aim of this study is to quantify altered myocardial calcium handling in non-ischaemic cardiomyopathy using magnetic resonance imaging. Methods and results Patients with dilated cardiomyopathy (n = 10) or hypertrophic cardiomyopathy (n = 17) underwent both gadolinium and manganese contrast-enhanced magnetic resonance imaging and were compared with healthy volunteers (n = 20). Differential manganese uptake (Ki) was assessed using a two-compartment Patlak model. Compared with healthy volunteers, reduction in T1 with manganese-enhanced magnetic resonance imaging was lower in patients with dilated cardiomyopathy [mean reduction 257 ± 45 (21%) vs. 288 ± 34 (26%) ms, P Conclusion The rate of manganese uptake in both dilated and hypertrophic cardiomyopathy provides a measure of altered myocardial calcium handling. This holds major promise for the detection and monitoring of dysfunctional myocardium, with the potential for early intervention and prognostication.

Summary Young stroke patients should be investigated thoroughly to look for cardiac and extra-cardiac sources of emboli. We present a patient who was investigated for a cardiac source of emboli following an ischemic stroke. She was found to have a small patent foramen ovale (PFO), but due to the late appearances of bubbles on the bubble study it was thought that this was an incidental finding. Further investigation confirmed a PAVM was the source of emboli causing her stroke. Learning points: Paradoxical embolus is a rare complication of a pulmonary arterio-venous malformation (PAVM). Young stroke patients should be investigated for intra and extra-cardiac shunts, in particular, patent foramen ovale (PFO), ideally with a bubble study. Consider an extra-cardiac source of embolism when bubbles are seen in arriving late into the left heart.

Aims To assess contemporary pre-test probability estimates for obstructive coronary artery disease in patients with stable chest pain. Methods and results In this substudy of a multicentre randomized controlled trial, we compared 2019 European Society of Cardiology (ESC)-endorsed pre-test probabilities with observed prevalence of obstructive coronary artery disease on computed tomography coronary angiography (CTCA). We assessed associations between pre-test probability, 5-year coronary heart disease death or non-fatal myocardial infarction and study intervention (standard care vs. CTCA). The study population consisted of 3755 patients (30–75 years, 46% women) with a median pre-test probability of 11% of whom 1622 (43%) had a pre-test probability of >15%. In those who underwent CTCA (n = 1613), the prevalence of obstructive disease was 22%. When divided into deciles of pre-test probability, the observed disease prevalence was similar but higher than the corresponding median pre-test probability [median difference 2.3 (1.3–5.6)%]. There were more clinical events in patients with a pre-test probability >15% compared to those at 5–15% and 15% (2.8% vs. 5.3%, log rank P = 0.01), although this interaction was not statistically significant on multivariable modelling. Conclusion The updated 2019 ESC guideline pre-test probability recommendations tended to slightly underestimate disease prevalence in our cohort. Pre-test probability is a powerful predictor of future coronary events and helps select those who may derive the greatest absolute benefit from CTCA.

Aortic stenosis is the most prevalent valvular heart disease worldwide, and rates are increasing with the growing and more elderly population. Although the precise mechanisms that underpin aortic valve stenosis are incompletely understood, pathological valvular calcification has emerged as a key instigator in mediating the biomechanical stiffening that can lead to symptoms, the need for aortic valve replacement, and death if left untreated. Here, we review the currently understood processes leading to aortic valve calcification, summarise the contemporary imaging assessments of valve calcification, and highlight how these might improve patient care and accelerate our pathological understanding and the development of an effective medical therapy.

Importance Recent European guidance supports a diminished role for exercise electrocardiography (ECG) in the assessment of suspected stable angina. Objective To evaluate the utility of exercise ECG in contemporary practice and assess the value of combined functional and anatomical testing. Design, Setting, and Participants This is a post hoc analysis of the Scottish Computed Tomography of the Heart (SCOT-HEART) open-label randomized clinical trial, conducted in 12 cardiology chest pain clinics across Scotland for patients with suspected angina secondary to coronary heart disease. Between November 18, 2010, and September 24, 2014, 4146 patients aged 18 to 75 years with stable angina underwent clinical evaluation and 1417 of 1651 (86%) underwent exercise ECG prior to randomization. Statistical analysis was conducted from October 10 to November 5, 2019. Interventions Patients were randomized in a 1:1 ratio to receive standard care plus coronary computed tomography (CT) angiography or to receive standard care alone. The present analysis was limited to the 3283 patients who underwent exercise ECG alone or in combination with coronary CT angiography. Main Outcomes and Measures The primary clinical end point was death from coronary heart disease or nonfatal myocardial infarction at 5 years. Results Among the 3283 patients (1889 men; median age, 57.0 years [interquartile range, 50.0-64.0 years]), exercise ECG had a sensitivity of 39% and a specificity of 91% for detecting any obstructive coronary artery disease in those who underwent subsequent invasive angiography. Abnormal results of exercise ECG were associated with a 14.47-fold (95% CI, 10.00-20.41;P Conclusions and Relevance This study suggests that abnormal results of exercise ECG are associated with coronary revascularization and the future risk of adverse coronary events. However, coronary CT angiography more accurately detects coronary artery disease and is more strongly associated with future risk compared with exercise ECG. Trial Registration ClinicalTrials.gov Identifier:NCT01149590

We assessed myocardial calcium handling in patients with acute and established myocardial withmanganese-enhanced magnetic resonance imaging (MEMRI). Patients (n=20) with acute myocardial infarction and healthy volunteers (n=20) underwent gadolinium delayed enhanced MRI (DEMRI) and MEMRI (

We assessed myocardial calcium handling in patients with non-ischaemic cardiomyopathy usingmanganese-enhanced magnetic resonance imaging (MEMRI). Healthy volunteers (HV; n=20, 13 male, 42±11 yr), patients with hypertrophic (HCM; n=17, 10 male, 57±10 yr) or dilated (DCM; n=10, 6 male, 54±10 yr)