Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial.

Background: Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism RS9349379 enhances expression of the endothelin-1 gene (EDN1) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral ET-A receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown. Methods: Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the RS9349379 single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo. Results: A total of 118 participants (mean ±SD; years of age 63.5 [9.2 ]; 71 [60.2% ] females; 25 [21.2% ] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, -4.26 seconds [95 ] CI, -19.60 to 11.06] P=0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; P<0.001). Conclusions: Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common.

MyI-Net: Fully Automatic Detection and Quantification of Myocardial Infarction from Cardiovascular MRI Images.

Myocardial infarction (MI) occurs when an artery supplying blood to the heart is abruptly occluded. The "gold standard" method for imaging MI is cardiovascular magnetic resonance imaging (MRI) with intravenously administered gadolinium-based contrast (with damaged areas apparent as late gadolinium enhancement [LGE]). However, no "gold standard" fully automated method for the quantification of MI exists. In this work, we propose an end-to-end fully automatic system (MyI-Net) for the detection and quantification of MI in MRI images. It has the potential to reduce uncertainty due to technical variability across labs and the inherent problems of data and labels. Our system consists of four processing stages designed to maintain the flow of information across scales. First, features from raw MRI images are generated using feature extractors built on ResNet and MoblieNet architectures. This is followed by atrous spatial pyramid pooling (ASPP) to produce spatial information at different scales to preserve more image context. High-level features from ASPP and initial low-level features are concatenated at the third stage and then passed to the fourth stage where spatial information is recovered via up-sampling to produce final image segmentation output into: (i) background, (ii) heart muscle, (iii) blood and (iv) LGE areas. Our experiments show that the model named MI-ResNet50-AC provides the best global accuracy (97.38%), mean accuracy (86.01%), weighted intersection over union (IoU) of 96.47%, and bfscore of 64.46% for the global segmentation. However, in detecting only LGE tissue, a smaller model, MI-ResNet18-AC, exhibited higher accuracy (74.41%) than MI-ResNet50-AC (64.29%). New models were compared with state-of-the-art models and manual quantification. Our models demonstrated favorable performance in global segmentation and LGE detection relative to the state-of-the-art, including a four-fold better performance in matching LGE pixels to contours produced by clinicians.

Long COVID and cardiovascular disease: a prospective cohort study.

BACKGROUND: Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known. OBJECTIVES: To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors. METHODS: In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health. RESULTS: From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86). CONCLUSION: Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need. TRAIL REGISTRATION NUMBER: ISRCTN10980107.

The role of cardiac magnetic resonance imaging in the assessment of heart failure with preserved ejection fraction.

Heart failure (HF) is a major cause of morbidity and mortality worldwide. Current classifications of HF categorize patients with a left ventricular ejection fraction of 50% or greater as HF with preserved ejection fraction or HFpEF. Echocardiography is the first line imaging modality in assessing diastolic function given its practicality, low cost and the utilization of Doppler imaging. However, the last decade has seen cardiac magnetic resonance (CMR) emerge as a valuable test for the sometimes challenging diagnosis of HFpEF. The unique ability of CMR for myocardial tissue characterization coupled with high resolution imaging provides additional information to echocardiography that may help in phenotyping HFpEF and provide prognostication for patients with HF. The precision and accuracy of CMR underlies its use in clinical trials for the assessment of novel and repurposed drugs in HFpEF. Importantly, CMR has powerful diagnostic utility in differentiating acquired and inherited heart muscle diseases presenting as HFpEF such as Fabry disease and amyloidosis with specific treatment options to reverse or halt disease progression. This state of the art review will outline established CMR techniques such as transmitral velocities and strain imaging of the left ventricle and left atrium in assessing diastolic function and their clinical application to HFpEF. Furthermore, it will include a discussion on novel methods and future developments such as stress CMR and MR spectroscopy to assess myocardial energetics, which show promise in unraveling the mechanisms behind HFpEF that may provide targets for much needed therapeutic interventions.

MRI and CT coronary angiography in survivors of COVID-19.

OBJECTIVES: To determine the contribution of comorbidities on the reported widespread myocardial abnormalities in patients with recent COVID-19. METHODS: In 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. RESULTS: In 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)%; p<0.0003) but reduced myocardial manganese uptake (6.9±0.9 (95% CI 6.5 to 7.3) vs 7.9±1.2 (95% CI 7.4 to 8.5) mL/100 g/min; p=0.01). Compared with comorbidity-matched volunteers (n=26), patients had preserved left ventricular function but reduced right ventricular systolic function (EF: 51.7±9.1 (95% CI 53.9 to 60.1) vs 59.3±4.9 (95% CI 51.0 to 66.5)%; p=0.0005) with comparable native T1 values (1225±46 (95% CI 1205 to 1240) vs 1227±51 (95% CI 1208 to 1246) ms; p=0.99), ECV (31±4 (95% CI 29.6 to 32.1) vs 29±5 (95% CI 27.0 to 31.2)%; p=0.35), presence of late gadolinium enhancement and manganese uptake. These findings remained irrespective of COVID-19 disease severity, presence of myocardial injury or ongoing symptoms. CONCLUSIONS: Patients demonstrate right but not left ventricular dysfunction. Previous reports of left ventricular myocardial abnormalities following COVID-19 may reflect pre-existing comorbidities. TRIAL REGISTRATION NUMBER: NCT04625075.

Cardiovascular magnetic resonance: applications and practical considerations for the general cardiologist.

Cardiovascular magnetic resonance (CMR) is a rapidly evolving non-invasive imaging modality offering comprehensive, multiparametric assessment of cardiac structure and function in a variety of clinical situations. Cine imaging with CMR is the gold standard non-invasive imaging technique for the quantification of ventricular volumes and systolic function. It also affords superior visualisation of apical and right ventricular morphological abnormalities. In coronary artery disease, CMR stress perfusion imaging identifies functionally significant coronary artery disease with high sensitivity and specificity, and international guidelines recommend CMR perfusion imaging in patients with chest pain at intermediate-high risk of coronary disease. Late gadolinium enhancement (LGE) imaging is the most sensitive imaging technique for identifying infarction/viability. In non-ischaemic cardiomyopathy, LGE imaging plays vital diagnostic and prognostic roles in a number of cardiomyopathies (eg, hypertrophic and dilated cardiomyopathies, and amyloidosis). In vivo tissue characterisation with CMR enables the identification of oedema/inflammation in acute coronary syndromes/myocarditis and the diagnosis of chronic fibrotic conditions (eg, in hypertrophic and dilated cardiomyopathy, aortic stenosis and amyloidosis). CMR T2* imaging uniquely offers non-invasive assessment of iron overload states, facilitating diagnosis and management. A multiparametric CMR approach also enables differentiation of cardiac masses/tumours and is a useful adjunct to echocardiography in the assessment of valve disease. The emergence of automated, inline, quantitative methodologies will expand the scope of CMR and reduce its cost in forthcoming years.

Daily remote ischaemic conditioning following acute myocardial infarction: a randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning (rIC) is a cardioprotective tool which has shown promise in preclinical and clinical trials in the context of acute ischaemia. Repeated rIC post myocardial infarction may provide additional benefits which have not previously been tested clinically. METHODS: The trial assessed the role of daily rIC in enhancing left ventricular ejection fraction (LVEF) recovery in patients with impaired LVEF (<45%) after ST segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (P-PCI). Patients were recruited from four UK hospitals and randomised to receive either 4 weeks of daily rIC or sham conditioning using the autoRIC Device (CellAegis) starting on day 3 post P-PCI. The primary endpoint was the improvement in LVEF over 4 months assessed by cardiac MRI (CMR). Seventy-three patients (38 cases, 35 controls) completed the study. RESULTS: The treatment and control groups were well matched at baseline including for mean LVEF (42.8% vs 44.3% respectively, p=0.952). There was no difference in the improvement in LVEF over 4 months between the treatment and control groups (4.8%±7.8% vs 4.6%±5.9% respectively, p=0.924). No differences were seen in the secondary outcome measures including changes in infarct size and left ventricular end-diastolic and systolic volumes, major adverse cardiac and cerebral event, mean Kansas City Cardiomyopathy Questionnaire score and change in N-terminal pro-brain natriuretic peptide levels. CONCLUSIONS: Daily rIC starting on day 3 and continued for 4 weeks following successful P-PCI for STEMI did not improve LVEF as assessed by CMR after 4 months when compared with a matched control group. TRIAL REGISTRATION NUMBER: NCT0166461.