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Abstract Metformin is an antihyperglycemic used to treat type 2 diabetes mellitus (T2DM). Patients with T2DM are at increased risk of cardiovascular disease. We explored the association between metformin use and cardiovascular magnetic resonance (CMR) derived stress myocardial blood flow (MBF), myocardial perfusion reserve (MPR) and major adverse cardiovascular events (MACE; all cause death, MI, stroke, heart failure hospitalisation and coronary revascularisation) in patients with T2DM. Multi-centre study of patients with T2DM, and healthy controls, underwent quantitative myocardial perfusion CMR using an artificial intelligence supported process. Multivariable regression analysis, and cox proportional hazard models of propensity score weighted patients quantified associations between metformin use, MBF, MPR, all cause death and MACE. Analysis included 572 patients with T2DM (68% prescribed metformin) with median follow-up 851 days (IQR 935 − 765). Metformin use was associated with an increase of MPR of 0.12 [0.08–0.40], p = 0.004. There were 82 MACE events (14.3%) including 25 (4.4%) deaths of which 16 were in those not prescribed metformin (8.7%), compared to 9 in patients prescribed metformin (2.3%): adjusted hazard ratio 0.24 (95% CI 0.08–0.70, p = 0.009). MACE events were similar between groups. This multicentre, inverse probability weighting propensity score analysis study showed that in patients with T2DM, metformin use is associated with higher MPR and improved all cause survival.

Abstract Background Cardiac magnetic resonance (CMR) in the four-chamber plane offers comprehensive insight into the volumetrics of the heart. We aimed to develop an artificial intelligence (AI) model of time-resolved segmentation using the four-chamber cine. Methods A fully automated deep learning algorithm was trained using retrospective multicentre and multivendor data of 814 subjects. Validation, reproducibility, and mortality prediction were evaluated on an independent cohort of 101 subjects. Results The mean age of the validation cohort was 54 years, and 66 (65%) were males. Left and right heart parameters demonstrated strong correlations between automated and manual analysis, with a ρ of 0.91−0.98 and 0.89−0.98, respectively, with minimal bias. All AI four-chamber volumetrics in repeatability analysis demonstrated high correlation (ρ = 0.99−1.00) and no bias. Automated four-chamber analysis underestimated both left ventricular (LV) and right ventricular (RV) volumes compared to ground-truth short-axis cine analysis. Two correction factors for LV and RV four-chamber analysis were proposed based on systematic bias. After applying the correction factors, a strong correlation and minimal bias for LV volumetrics were observed. During a mean follow-up period of 6.75 years, 16 patients died. On stepwise multivariable analysis, left atrial ejection fraction demonstrated an independent association with death in both manual (hazard ratio (HR) = 0.96, p = 0.003) and AI analyses (HR = 0.96, p

Abstract Background Pulmonary transit time (PTT) can be measured automatically from arterial input function (AIF) images of dual sequence first-pass perfusion imaging. PTT has been validated against invasive cardiac catheterisation correlating with both cardiac output and left ventricular filling pressure (both important prognostic markers in heart failure). We hypothesized that prolonged PTT is associated with clinical outcomes in patients with heart failure. Methods We recruited outpatients with a recent diagnosis of non-ischaemic heart failure with left ventricular ejection fraction (LVEF)

Abstract Background Use of electronic methods to support informed consent (‘eConsent’) is increasingly popular in clinical research. This commentary reports the approach taken to implement electronic consent methods and subsequent experiences from a range of studies at the Leeds Clinical Trials Research Unit (CTRU), a large clinical trials unit in the UK. Main text We implemented a remote eConsent process using the REDCap platform. The process can be used in trials of investigational medicinal products and other intervention types or research designs. Our standard eConsent system focuses on documenting informed consent, with other aspects of consent (e.g. providing information to potential participants and a recruiter discussing the study with each potential participant) occurring outside the system, though trial teams can use electronic methods for these activities where they have ethical approval. Our overall process includes a verbal consent step prior to confidential information being entered onto REDCap and an identity verification step in line with regulator guidance. We considered the regulatory requirements around the system’s generation of source documents, how to ensure data protection standards were upheld and how to monitor informed consent within the system. We present four eConsent case studies from the CTRU: two randomised clinical trials and two other health research studies. These illustrate the ways eConsent can be implemented, and lessons learned, including about differences in uptake. Conclusions We successfully implemented a remote eConsent process at the CTRU across multiple studies. Our case studies highlight benefits of study participants being able to give consent without having to be present at the study site. This may better align with patient preferences and trial site needs and therefore improve recruitment and resilience against external shocks (such as pandemics). Variation in uptake of eConsent may be influenced more by site-level factors than patient preferences, which may not align well with the aspiration towards patient-centred research. Our current process has some limitations, including the provision of all consent-related text in more than one language, and scalability of implementing more than one consent form version at a time. We consider how enhancements in CTRU processes, or external developments, might affect our approach.

Background: Left atrial (LA) assessment is an important marker of adverse cardiovascular outcomes. Cardiovascular magnetic resonance (CMR) accurately quantifies LA volume and function based on biplane long-axis imaging. We aimed to validate single-plane-derived LA indices against the biplane method to simplify the post-processing of cine CMR. Methods: In this study, 100 patients from Leeds Teaching Hospitals were used as the derivation cohort. Bias correction for the single plane method was applied and subsequently validated in 79 subjects. Results: There were significant differences between the biplane and single plane mean LA maximum and minimum volumes and LA ejection fraction (EF) (all p < 0.01). After correcting for biases in the validation cohort, significant correlations in all LA indices were observed (0.89 to 0.98). The area under the curve (AUC) for the single plane to predict biplane cutoffs of LA maximum volume ≥ 112 mL was 0.97, LA minimum volume ≥ 44 mL was 0.99, LA stroke volume (SV) ≤ 21 mL was 1, and LA EF ≤ 46% was 1, (all p < 0.001). Conclusions: LA volumetric and functional assessment by the single plane method has a systematic bias compared to the biplane method. After bias correction, single plane LA volume and function are comparable to the biplane method.

(1) Background and Objectives: Flow assessment using cardiovascular magnetic resonance (CMR) provides important implications in determining physiologic parameters and clinically important markers. However, post-processing of CMR images remains labor- and time-intensive. This study aims to assess the validity and repeatability of fully automated segmentation of phase contrast velocity-encoded aortic root plane. (2) Materials and Methods: Aortic root images from 125 patients are segmented by artificial intelligence (AI), developed using convolutional neural networks and trained with a multicentre cohort of 160 subjects. Derived simple flow indices (forward and backward flow, systolic flow and velocity) and complex indices (aortic maximum area, systolic flow reversal ratio, flow displacement, and its angle change) were compared with those derived from manual contours. (3) Results: AI-derived simple flow indices yielded excellent repeatability compared to human segmentation (p < 0.001), with an insignificant level of bias. Complex flow indices feature good to excellent repeatability (p < 0.001), with insignificant levels of bias except flow displacement angle change and systolic retrograde flow yielding significant levels of bias (p < 0.001 and p < 0.05, respectively). (4) Conclusions: Automated flow quantification using aortic root images is comparable to human segmentation and has good to excellent repeatability. However, flow helicity and systolic retrograde flow are associated with a significant level of bias. Overall, all parameters show clinical repeatability.

Abstract Aims Left ventricular filling pressure (LVFP) can be estimated from cardiovascular magnetic resonance (CMR). We aimed to investigate whether CMR‐derived LVFP is associated with signs, symptoms, and prognosis in patients with recently diagnosed heart failure (HF). Methods and results This study recruited 454 patients diagnosed with HF who underwent same‐day CMR and clinical assessment between February 2018 and January 2020. CMR‐derived LVFP was calculated, as previously, from long‐ and short‐axis cines. CMR‐derived LVFP association with symptoms and signs of HF was investigated. Patients were followed for median 2.9 years (interquartile range 1.5–3.6 years) for major adverse cardiovascular events (MACE), defined as the composite of cardiovascular death, HF hospitalization, non‐fatal stroke, and non‐fatal myocardial infarction. The mean age was 62 ± 13 years, 36% were female (n = 163), and 30% (n = 135) had raised LVFP. Forty‐seven per cent of patients had an ejection fraction

Abstract Left ventricular fibrosis can be identified by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) in some veteran athletes. We aimed to investigate prevalence of ventricular fibrosis in veteran athletes and associations with cardiac arrhythmia. 50 asymptomatic male endurance athletes were recruited. They underwent CMR imaging including volumetric analysis, bright blood (BB) and dark blood (DB) LGE, motion corrected (MOCO) quantitative stress and rest perfusion and T1/T2/extracellular volume mapping. Athletes underwent 12-lead electrocardiogram (ECG) and 24-h ECG. Myocardial fibrosis was identified in 24/50 (48%) athletes. All fibrosis was mid-myocardial in the basal-lateral left ventricular wall. Blood pressure was reduced in athletes without fibrosis compared to controls, but not athletes with fibrosis. Fibrotic areas had longer T2 time (44 ± 4 vs. 40 ± 2 ms, p

Abstract Background When feasible, guidelines recommend mitral valve repair (MVr) over mitral valve replacement (MVR) to treat primary mitral regurgitation (MR), based upon historic outcome studies and transthoracic echocardiography (TTE) reverse remodeling studies. Cardiovascular magnetic resonance (CMR) offers reference standard biventricular assessment with superior MR quantification compared to TTE. Using serial CMR in primary MR patients, we aimed to investigate cardiac reverse remodeling and residual MR post-MVr vs MVR with chordal preservation. Methods 83 patients with ≥ moderate-severe MR on TTE were prospectively recruited. 6-min walk tests (6MWT) and CMR imaging including cine imaging, aortic/pulmonary through-plane phase contrast imaging, T1 maps and late-gadolinium-enhanced (LGE) imaging were performed at baseline and 6 months after mitral surgery or watchful waiting (control group). Results 72 patients completed follow-up (Controls = 20, MVr = 30 and MVR = 22). Surgical groups demonstrated comparable baseline cardiac indices and co-morbidities. At 6-months, MVr and MVR groups demonstrated comparable improvements in 6MWT distances (+ 57 ± 54 m vs + 64 ± 76 m respectively, p = 1), reduced indexed left ventricular end-diastolic volumes (LVEDVi; − 29 ± 21 ml/m2 vs − 37 ± 22 ml/m2 respectively, p = 0.584) and left atrial volumes (− 23 ± 30 ml/m2 and − 39 ± 26 ml/m2 respectively, p = 0.545). At 6-months, compared with controls, right ventricular ejection fraction was poorer post-MVr (47 ± 6.1% vs 53 ± 8.0% respectively, p = 0.01) compared to post-MVR (50 ± 5.7% vs 53 ± 8.0% respectively, p = 0.698). MVR resulted in lower residual MR-regurgitant fraction (RF) than MVr (12 ± 8.0% vs 21 ± 11% respectively, p = 0.022). Baseline and follow-up indices of diffuse and focal myocardial fibrosis (Native T1 relaxation times, extra-cellular volume and quantified LGE respectively) were comparable between groups. Stepwise multiple linear regression of indexed variables in the surgical groups demonstrated baseline indexed mitral regurgitant volume as the sole multivariate predictor of left ventricular (LV) end-diastolic reverse remodelling, baseline LVEDVi as the most significant independent multivariate predictor of follow-up LVEDVi, baseline indexed LV end-systolic volume as the sole multivariate predictor of follow-up LV ejection fraction and undergoing MVR (vs MVr) as the most significant (p

Abstract Background Measurement of peak velocities is important in the evaluation of heart failure. This study compared the performance of automated 4D flow cardiac MRI (CMR) with traditional transthoracic Doppler echocardiography (TTE) for the measurement of mitral inflow peak diastolic velocities. Methods Patients with Doppler echocardiography and 4D flow cardiac magnetic resonance data were included retrospectively. An established automated technique was used to segment the left ventricular transvalvular flow using short-axis cine stack of images. Peak mitral E-wave and peak mitral A-wave velocities were automatically derived using in-plane velocity maps of transvalvular flow. Additionally, we checked the agreement between peak mitral E-wave velocity derived by 4D flow CMR and Doppler echocardiography in patients with sinus rhythm and atrial fibrillation (AF) separately. Results Forty-eight patients were included (median age 69 years, IQR 63 to 76; 46% female). Data were split into three groups according to heart rhythm. The median peak E-wave mitral inflow velocity by automated 4D flow CMR was comparable with Doppler echocardiography in all patients (0.90 ± 0.43 m/s vs 0.94 ± 0.48 m/s, P = 0.132), sinus rhythm-only group (0.88 ± 0.35 m/s vs 0.86 ± 0.38 m/s, P = 0.54) and in AF-only group (1.33 ± 0.56 m/s vs 1.18 ± 0.47 m/s, P = 0.06). Peak A-wave mitral inflow velocity results had no significant difference between Doppler TTE and automated 4D flow CMR (0.81 ± 0.44 m/s vs 0.81 ± 0.53 m/s, P = 0.09) in all patients and sinus rhythm-only groups. Automated 4D flow CMR showed a significant correlation with TTE for measurement of peak E-wave in all patients group (r = 0.73, P

Abstract Background The underlying pathophysiology of post-coronavirus disease 2019 (long-COVID-19) syndrome remains unknown, but increased cardiometabolic demand and state of mitochondrial dysfunction have emerged as candidate mechanisms. Cardiovascular magnetic resonance (CMR) provides insight into pathophysiological mechanisms underlying cardiovascular disease and 31-phosphorus CMR spectroscopy (31P-CMRS) allows non-invasive assessment of the myocardial energetic state. The main aim of the study was to assess whether long COVID-19 syndrome is associated with abnormalities of myocardial structure, function, perfusion and energy metabolism. Methods Prospective case–control study. A total of 20 patients with a clinical diagnosis of long COVID-19 syndrome (seropositive) and no prior underlying cardiovascular disease (CVD) and 10 matching healthy controls underwent 31P-CMRS and CMR at 3T at a single time point. All patients had been symptomatic with acute COVID-19, but none required hospital admission. Results Between the long COVID-19 syndrome patients and matched contemporary healthy controls there were no differences in myocardial energetics (phosphocreatine to ATP ratio), in cardiac structure (biventricular volumes), function (biventricular ejection fractions, global longitudinal strain), tissue characterization (T1 mapping and late gadolinium enhancement) or perfusion (myocardial rest and stress blood flow, myocardial perfusion reserve). One patient with long COVID-19 syndrome showed subepicardial hyperenhancement on late gadolinium enhancement imaging compatible with prior myocarditis, but no accompanying abnormality in cardiac size, function, perfusion, extracellular volume fraction, native T1, T2 or cardiac energetics. Conclusions In this prospective case–control study, the overwhelming majority of patients with a clinical long COVID-19 syndrome with no prior CVD did not exhibit any abnormalities in myocardial energetics, structure, function, blood flow or tissue characteristics.

Abstract Objectives Mitral regurgitation (MR) and microvascular obstruction (MVO) are common complications of myocardial infarction (MI). This study aimed to investigate the association between MR in ST-elevation MI (STEMI) subjects with MVO post-reperfusion. STEMI subjects undergoing primary percutaneous intervention were enrolled. Cardiovascular magnetic resonance (CMR) imaging was performed within 48-hours of initial presentation. 4D flow images of CMR were analysed using a retrospective valve tracking technique to quantify MR volume, and late gadolinium enhancement images of CMR to assess MVO. Results Among 69 patients in the study cohort, 41 had MVO (59%). Patients with MVO had lower left ventricular (LV) ejection fraction (EF) (42 ± 10% vs. 52 ± 8%, P 2.5 ml. We conclude that in patients with reperfused STEMI, the degree of acute MR is associated with the degree of MVO.

Background and Objectives: Cardiovascular magnetic resonance (CMR) is emerging as an important imaging tool for sub-phenotyping and estimating left ventricular (LV) filling pressure (LVFP). The N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) is released from cardiac myocytes in response to mechanical load and wall stress. This study sought to investigate if CMR-derived LVFP is associated with the serum levels of NT-proBNP and, in addition, if it provides any incremental prognostic value in heart failure (HF). Materials and Methods: This study recruited 380 patients diagnosed with HF who underwent same-day CMR and clinical assessment between February 2018 and January 2020. CMR-derived LVFP was calculated, as previously, from long- and short-axis cines. During CMR assessment, serum NT-proBNP was measured. The pathological cut-offs were defined as follows: NT-proBNP ≥ 125 pg/mL and CMR LVFP > 15 mmHg. The incidence of HF hospitalisation was treated as a clinical outcome. Results: In total, 305 patients had NT-proBNP ≥ 125 pg/mL. Patients with raised NT-proBNP were older (54 ± 14 vs. 64 ± 11 years, p < 0.0001). Patients with raised NT-proBNP had higher LV volumes and mass. In addition, CMR LVFP was higher in patients with raised NT-proBNP (13.2 ± 2.6 vs. 15.4 ± 3.2 mmHg, p < 0.0001). The serum levels of NT-proBNP were associated with CMR-derived LVFP (R = 0.42, p < 0.0001). In logistic regression analysis, this association between NT-proBNP and CMR LVFP was independent of all other CMR variables, including LV ejection fraction, LV mass, and left atrial volume (coefficient = 2.02, p = 0.002). CMR LVFP demonstrated an independent association with the incidence of HF hospitalisation above NT-proBNP (hazard ratio 2.7, 95% confidence interval 1.2 to 6, p = 0.01). Conclusions: A CMR-modelled LVFP is independently associated with serum NT-proBNP levels. Importantly, it provides an incremental prognostic value over and above serum NT-proBNP levels.

Background. Ischaemia with nonobstructive coronary arteries is most commonly caused by coronary microvascular dysfunction but remains difficult to diagnose without invasive testing. Myocardial blood flow (MBF) can be quantified noninvasively on stress perfusion cardiac magnetic resonance (CMR) or positron emission tomography but neither is routinely used in clinical practice due to practical and technical constraints. Quantification of coronary sinus (CS) flow may represent a simpler method for CMR MBF quantification. 4D flow CMR offers comprehensive intracardiac and transvalvular flow quantification. However, it is feasibility to quantify MBF remains unknown. Methods. Patients with acute myocardial infarction (MI) and healthy volunteers underwent CMR. The CS contours were traced from the 2-chamber view. A reformatted phase contrast plane was generated through the CS, and flow was quantified using 4D flow CMR over the cardiac cycle and normalised for myocardial mass. MBF and resistance (MyoR) was determined in ten healthy volunteers, ten patients with myocardial infarction (MI) without microvascular obstruction (MVO), and ten with known MVO. Results. MBF was quantified in all 30 subjects. MBF was highest in healthy controls (123.8 ± 48.4 mL/min), significantly lower in those with MI (85.7 ± 30.5 mL/min), and even lower in those with MI and MVO (67.9 ± 29.2 mL/min/) (P

Abstract Background Adenosine stress perfusion cardiovascular magnetic resonance (CMR) is commonly used in the assessment of patients with suspected ischaemia. Accepted protocols recommend administration of adenosine at a dose of 140 µg/kg/min increased up to 210 µg/kg/min if required. Conventionally, adequate stress has been assessed using change in heart rate, however, recent studies have suggested that these peripheral measurements may not reflect hyperaemia and can be blunted, in particular, in patients with heart failure. This study looked to compare stress myocardial blood flow (MBF) and haemodynamic response with different dosing regimens of adenosine during stress perfusion CMR in patients and healthy controls. Methods 20 healthy adult subjects were recruited as controls to compare 3 adenosine perfusion protocols: standard dose (140 µg/kg/min for 4 min), high dose (210 µg/kg/min for 4 min) and long dose (140 µg/kg/min for 8 min). 60 patients with either known or suspected coronary artery disease (CAD) or with heart failure and different degrees of left ventricular (LV) dysfunction underwent adenosine stress with standard and high dose adenosine within the same scan. All studies were carried out on a 3 T CMR scanner. Quantitative global myocardial perfusion and haemodynamic response were compared between doses. Results In healthy controls, no significant difference was seen in stress MBF between the 3 protocols. In patients with known or suspected CAD, and those with heart failure and mild systolic impairment (LV ejection fraction (LVEF) ≥ 40%) no significant difference was seen in stress MBF between standard and high dose adenosine. In those with LVEF

Abstract Aims The clinical reliability of echocardiographic surrogate markers of left ventricular filling pressures (LVFPs) across different cardiovascular pathologies remains unanswered. The main objective was to evaluate the evidence of how effectively different echocardiographic indices estimate true LVFP. Methods and results Design: this is a systematic review and meta‐analysis. Data source: Scopus, PubMed and Embase. Eligibility criteria for selecting studies were those that used echocardiography to predict or estimate pulmonary capillary wedge pressure or left ventricular end‐diastolic pressures. Twenty‐seven studies met criteria. Only eight studies (30%) reported both correlation coefficient and bias between non‐invasive and invasively measured LVFPs. The majority of studies (74%) recorded invasive pulmonary capillary wedge pressure as a surrogate for left ventricular end‐diastolic pressures. The pooled correlation coefficient overall was r = 0.69 [95% confidence interval (CI) 0.63–0.75, P

Abstract Objectives Four-dimensional flow CMR allows for a comprehensive assessment of the blood flow kinetic energy of the ventricles of the heart. In comparison to standard two-dimensional image acquisition, 4D flow CMR is felt to offer superior reproducibility, which is important when repeated examinations may be required. The objective was to evaluate the inter-observer and intra-observer reproducibility of blood flow kinetic energy assessment using 4D flow of the left ventricle in 20 healthy volunteers across two centres in the United Kingdom and the Netherlands. Data description This dataset contains 4D flow CMR blood flow kinetic energy data for 20 healthy volunteers with no known cardiovascular disease. Presented is kinetic energy data for the entire cardiac cycle (global), the systolic and diastolic components, in addition to blood flow kinetic energy for both early and late diastolic filling. This data is available for reuse and would be valuable in supporting other research, such as allowing for larger sample sizes with more statistical power for further analysis of these variables.

Abstract Background Patients with coexistent chronic heart failure (CHF) and diabetes mellitus (DM) demonstrate greater exercise limitation and worse prognosis compared with CHF patients without DM, even when corrected for cardiac dysfunction. Understanding the origins of symptoms in this subgroup may facilitate development of targeted treatments. We therefore characterized the skeletal muscle phenotype and its relationship to exercise limitation in patients with diabetic heart failure (D‐HF). Methods In one of the largest muscle sampling studies in a CHF population, pectoralis major biopsies were taken from age‐matched controls (n = 25), DM (n = 10), CHF (n = 52), and D‐HF (n = 28) patients. In situ mitochondrial function and reactive oxygen species, fibre morphology, capillarity, and gene expression analyses were performed and correlated to whole‐body exercise capacity. Results Mitochondrial respiration, content, coupling efficiency, and intrinsic function were lower in D‐HF patients compared with other groups (P < 0.05). A unique mitochondrial complex I dysfunction was present in D‐HF patients only (P < 0.05), which strongly correlated to exercise capacity (R2 = 0.64; P < 0.001). Mitochondrial impairments in D‐HF corresponded to higher levels of mitochondrial reactive oxygen species (P < 0.05) and lower gene expression of anti‐oxidative enzyme superoxide dismutase 2 (P < 0.05) and complex I subunit NDUFS1 (P < 0.05). D‐HF was also associated with severe fibre atrophy (P < 0.05) and reduced local fibre capillarity (P < 0.05). Conclusions Patients with D‐HF develop a specific skeletal muscle pathology, characterized by mitochondrial impairments, fibre atrophy, and derangements in the capillary network that are linked to exercise intolerance. These novel preliminary data support skeletal muscle as a potential therapeutic target for treating patients with D‐HF.

Abstract Background Using cardiovascular magnetic resonance imaging (CMR), it is possible to detect diffuse fibrosis of the left ventricle (LV) in patients with atrial fibrillation (AF), which may be independently associated with recurrence of AF after ablation. By conducting CMR, clinical, electrophysiology and biomarker assessment we planned to investigate LV myocardial fibrosis in patients undergoing AF ablation. Methods LV fibrosis was assessed by T1 mapping in 31 patients undergoing percutaneous ablation for AF. Galectin-3, coronary sinus type I collagen C terminal telopeptide (ICTP), and type III procollagen N terminal peptide were measured with ELISA. Comparison was made between groups above and below the median for LV extracellular volume fraction (ECV), followed by regression analysis. Results On linear regression analysis LV ECV had significant associations with invasive left atrial pressure (Beta 0.49, P = 0.008) and coronary sinus ICTP (Beta 0.75, P

Abstract Background Previous studies in heart failure with reduced ejection fraction (HFrEF) suggest that skeletal muscle mitochondrial impairments are associated with exercise intolerance in men. However, the nature of this relationship in female patients remains to be elucidated. This study aimed to determine the relationship between skeletal muscle mitochondrial impairments and exercise intolerance in male and female patients with HFrEF. Methods Mitochondrial respiration, enzyme activity, and gene expression were examined in pectoralis major biopsies from age‐matched male (n = 45) and female (n = 11) patients with HFrEF and healthy‐matched male (n = 24) and female (n = 11) controls. Mitochondrial variables were compared between sex and related to peak exercise capacity. Results Compared with sex‐matched controls, complex I mitochondrial oxygen flux was 17% (P = 0.030) and 29% (P = 0.013) lower in male and female patients with HFrEF, respectively, which correlated to exercise capacity (r = 0.71; P > 0.0001). Female HFrEF patients had a 32% (P = 0.023) lower mitochondrial content compared with controls. However, after adjusting for mitochondrial content, male patients demonstrated lower complex I function by 15% (P = 0.030). Expression of key mitochondrial genes regulating organelle dynamics and maintenance (i.e. optic atrophy 1, peroxisome proliferator‐activated receptor γ coactivator‐1α, NADH:ubiquinone oxidoreductase core subunit S1/S3, and superoxide dismutase 2) were selectively lower in female HFrEF patients. Conclusions These data provide novel evidence that HFrEF induces divergent sex‐specific mitochondrial phenotypes in skeletal muscle that predispose towards exercise intolerance, impacting mitochondrial ‘quantity' in female patients and mitochondrial ‘quality' in male patients. Therapeutic strategies to improve exercise tolerance in HFrEF should consider targeting sex‐specific mitochondrial abnormalities in skeletal muscle.

Background: Four-dimensional (4D) flow cardiovascular magnetic resonance imaging (MRI) is an emerging technique used for intra-cardiac blood flow assessment. The role of 4D flow cardiovascular MRI in the assessment of trans-valvular flow in patients with atrial fibrillation (AF) has not previously been assessed. The purpose of this study was to assess the feasibility, image quality, and internal validity of 4D flow cardiovascular MRI in the quantification of trans-valvular flow in patients with AF. Methods: Patients with AF and healthy controls in sinus rhythm underwent cardiovascular MRI, including 4D flow studies. Quality assurance checks were done on the raw data and streamlines. Consistency was investigated by trans-valvular flow assessment between the mitral valve (MV) and the aortic valve (AV). Results: Eight patients with AF (88% male, mean age 62±13 years, mean heart rate (HR) 83±16 beats per minute (bpm)) were included and compared with ten healthy controls (70% male, mean age 41±20 years, mean HR 68.5±9 bpm). All scans were of either good quality with minimal blurring artefacts, or excellent quality with no artefacts. No significant bias was observed between the AV and MV stroke volumes in either healthy controls (–4.8, 95% CI –15.64 to 6.04; P=0.34) or in patients with AF (1.64, 95% CI –4.7 to 7.94; P=0.56). A significant correlation was demonstrated between MV and AV stroke volumes in both healthy controls (r=0.87, 95% CI 0.52 to 0.97; P=0.001) and in AF patients (r=0.82, 95% CI 0.26 to 0.97; P=0.01). Conclusions: In patients with AF, 4D flow cardiovascular MRI is feasible with good image quality, allowing for quantification of trans-valvular flow.

Background Spironolactone may have prognostic benefit in selected patients with heart failure with preserved ejection fraction. This study assessed the myocardial tissue effects of spironolactone in heart failure with preserved ejection fraction. Methods and Results A 1:1 randomized controlled study of 6 months of spironolactone versus control in heart failure with preserved ejection fraction. The primary outcome was change in myocardial extracellular volume fraction by cardiovascular magnetic resonance as a surrogate of diffuse fibrosis. Of 55 randomized patients, 40 (20 women; age, 75.2±5.9 years) completed follow‐up (19 treatment, 21 control). A significant change in extracellular volume over the study period was not seen (treatment, 28.7±3.7% versus 27.7±3.4% [P=0.14]; controls, 27.6±3.4% versus 28.3±4.4% [P=0.14]); however, the rate of extracellular volume expansion was decreased by spironolactone (−1.0±2.4% versus 0.8±2.2%). Indexed left ventricular mass decreased with treatment (104.4±26.6 versus 94.0±20.6 g/m2; P=0.001) but not in controls (101.4±29.4 versus 104.0±32.8 g/m2; P=0.111). Extracellular mass decreased by 13.8% (15.1±4.8 versus 13.0±3.4 g/m2; P=0.003), and cellular mass decreased by 8.3% (37.6±10.0 versus 34.3±7.9 g/m2; P=0.001) with spironolactone, but was static in controls. Conclusions Spironolactone did not lead to significant change in extracellular volume. However, spironolactone did decrease rate of extracellular expansion, with a decrease in the mass of both cellular and extracellular myocardial compartments. These data point to the mechanism of action of spironolactone in heart failure with preserved ejection fraction, including a direct tissue effect with a reduction in rate of myocardial fibrosis.

Abstract Background Myocardial infarction (MI) leads to complex changes in left ventricular (LV) haemodynamics that are linked to clinical outcomes. We hypothesize that LV blood flow kinetic energy (KE) is altered in MI and is associated with LV function and infarct characteristics. This study aimed to investigate the intra-cavity LV blood flow KE in controls and MI patients, using cardiovascular magnetic resonance (CMR) four-dimensional (4D) flow assessment. Methods Forty-eight patients with MI (acute-22; chronic-26) and 20 age/gender-matched healthy controls underwent CMR which included cines and whole-heart 4D flow. Patients also received late gadolinium enhancement imaging for infarct assessment. LV blood flow KE parameters were indexed to LV end-diastolic volume and include: averaged LV, minimal, systolic, diastolic, peak E-wave and peak A-wave KEiEDV. In addition, we investigated the in-plane proportion of LV KE (%) and the time difference (TD) to peak E-wave KE propagation from base to mid-ventricle was computed. Association of LV blood flow KE parameters to LV function and infarct size were investigated in all groups. Results LV KEiEDV was higher in controls than in MI patients (8.5 ± 3 μJ/ml versus 6.5 ± 3 μJ/ml, P = 0.02). Additionally, systolic, minimal and diastolic peak E-wave KEiEDV were lower in MI (P

Abstract Background Non-invasive assessment of myocardial ischaemia is a cornerstone of the diagnosis of coronary artery disease. Measurement of myocardial blood flow (MBF) using positron emission tomography (PET) is the current reference standard for non-invasive quantification of myocardial ischaemia. Dynamic myocardial perfusion cardiovascular magnetic resonance (CMR) offers an alternative to PET and a recently developed method with automated inline perfusion mapping has shown good correlation of MBF values between CMR and PET. This study assessed the repeatability of myocardial perfusion mapping by CMR in healthy subjects. Methods Forty-two healthy subjects were recruited and underwent adenosine stress and rest perfusion CMR on two visits. Scans were repeated with a minimum interval of 7 days. Intrastudy rest and stress MBF repeatability were assessed with a 15-min interval between acquisitions. Interstudy rest and stress MBF and myocardial perfusion reserve (MPR) were measured for global myocardium and regionally for coronary territories and slices. Results There was no significant difference in intrastudy repeated global rest MBF (0.65 ± 0.13 ml/g/min vs 0.62 ± 0.12 ml/g/min, p = 0.24, repeatability coefficient (RC) =24%) or stress (2.89 ± 0.56 ml/g/min vs 2.83 ± 0.64 ml/g/min, p = 0.41, RC = 29%) MBF. No significant difference was seen in interstudy repeatability for global rest MBF (0.64 ± 0.13 ml/g/min vs 0.64 ± 0.15 ml/g/min, p = 0.80, RC = 32%), stress MBF (2.71 ± 0.61 ml/g/min vs 2.55 ± 0.57 ml/g/min, p = 0.12, RC = 33%) or MPR (4.24 ± 0.69 vs 3.73 ± 0.76, p = 0.25, RC = 36%). Regional repeatability was good for stress (RC = 30–37%) and rest MBF (RC = 32–36%) but poorer for MPR (RC = 35–43%). Within subject coefficient of variation was 8% for rest and 11% for stress within the same study, and 11% for rest and 12% for stress between studies. Conclusions Fully automated, inline, myocardial perfusion mapping by CMR shows good repeatability that is similar to the published PET literature. Both rest and stress MBF show better repeatability than MPR, particularly in regional analysis.

Abstract Background We aimed to investigate in patients with type 2 diabetes whether aortic stiffness is: (i) associated with glycaemic control, (ii) associated with adverse outcomes and (iii) can be reversed on treatment with RAAS inhibition. Methods Patients with type 2 diabetes (N = 94) and low vascular risk underwent assessment of cardiovascular risk and CMR assessment of ascending aortic distensibility (AAD), descending aortic distensibility (DAD) and aortic pulse wave velocity (PWV). Of these patients a subgroup with recent onset microalbuminuria (N = 25) were treated with renin–angiotensin–aldosterone system (RAAS) inhibition and imaging repeated after 1 year. All 94 patients were followed up for 2.4 years for major adverse cardiovascular disease (CVD) events including myocardial infarction detected on late gadolinium enhancement CMR. Results Ascending aortic distensibility, DAD and PWV all had a significant association with age and 24 h systolic blood pressure but only AAD had a significant association with glycaemic control, measured as HbA1c (Beta − 0.016, P = 0.04). The association between HbA1c and AAD persisted even after correction for age and hypertension. CVD events occurred in 19/94 patients. AAD, but not DAD or PWV, was associated with CVD events (hazard ratio 0.49, 95% confidence interval 0.25–0.95, P = 0.01). On treatment with RAAS inhibition, AAD, but not DAD or PWV, showed significant improvement from 1.51 ± 1.15 to 1.97 ± 1.07 10−3 mmHg−1, P = 0.007. Conclusions Ascending aortic distensibility measured by CMR is independently associated with poor glycaemic control and adverse cardiovascular events. Furthermore it may be reversible on treatment with RAAS inhibition. AAD is a promising marker of cardiovascular risk in asymptomatic patients with type 2 diabetes and has potential use as a surrogate cardiovascular endpoint in studies of novel hypoglycaemic agents. Clinical trials registration https://clinicaltrials.gov/ct2/show/NCT01970319

Abstract Background Expansion of the myocardial extracellular volume (ECV) is a surrogate measure of focal/diffuse fibrosis and is an independent marker of prognosis in chronic heart disease. Changes in ECV may also occur after myocardial infarction, acutely because of oedema and in convalescence as part of ventricular remodelling. The objective of this study was to investigate changes in the pattern of distribution of regional (normal, infarcted and oedematous segments) and global left ventricular (LV) ECV using semi-automated methods early and late after reperfused ST-elevation myocardial infarction (STEMI). Methods Fifty patients underwent cardiovascular magnetic resonance (CMR) imaging acutely (24 h–72 h) and at convalescence (3 months). The CMR protocol included: cines, T2-weighted (T2 W) imaging, pre−/post-contrast T1-maps and LGE-imaging. Using T2 W and LGE imaging on acute scans, 16-segments of the LV were categorised as normal, oedema and infarct. 800 segments (16 per-patient) were analysed for changes in ECV and wall thickening (WT). Results From the acute studies, 325 (40.6%) segments were classified as normal, 246 (30.8%) segments as oedema and 229 (28.6%) segments as infarct. Segmental change in ECV between acute and follow-up studies (Δ ECV) was significantly different for normal, oedema and infarct segments (0.8 ± 6.5%, −1.78 ± 9%, −2.9 ± 10.9%, respectively; P

BackgroundPatients with type 2 diabetes mellitus and elevated urinary albumin:creatinine ratio (ACR) have increased risk of heart failure. We hypothesized this was because of cardiac tissue changes rather than silent coronary artery disease. Methods and ResultsIn a case‐controlled observational study 130 subjects including 50 ACR+ve diabetes mellitus patients with persistent microalbuminuria (ACR >2.5 mg/mol in males and >3.5 mg/mol in females, ≥2 measurements, no previous renin–angiotensin–aldosterone therapy, 50 ACR−ve diabetes mellitus patients and 30 controls underwent cardiovascular magnetic resonance for investigation of myocardial fibrosis, ischemia and infarction, and echocardiography. Thirty ACR+ve patients underwent further testing after 1‐year treatment with renin–angiotensin–aldosterone blockade. Cardiac extracellular volume fraction, a measure of diffuse fibrosis, was higher in diabetes mellitus patients than controls (26.1±3.4% and 23.3±3.0% P=0.0002) and in ACR+ve than ACR−ve diabetes mellitus patients (27.2±4.1% versus 25.1±2.9%, P=0.004). ACR+ve patients also had lower E′ measured by echocardiography (8.2±1.9 cm/s versus 8.9±1.9 cm/s, P=0.04) and elevated high‐sensitivity cardiac troponin T 18% versus 4% ≥14 ng/L (P=0.05). Rate of silent myocardial ischemia or infarction were not influenced by ACR status. Renin–angiotensin–aldosterone blockade was associated with increased left ventricular ejection fraction (59.3±7.8 to 61.5±8.7%, P=0.03) and decreased extracellular volume fraction (26.5±3.6 to 25.2±3.1, P=0.01) but no changes in diastolic function or high‐sensitivity cardiac troponin T levels. ConclusionsAsymptomatic diabetes mellitus patients with persistent microalbuminuria have markers of diffuse cardiac fibrosis including elevated extracellular volume fraction, high‐sensitivity cardiac troponin T, and diastolic dysfunction, which may in part be reversible by renin–angiotensin–aldosterone blockade. Increased risk in these patients may be mediated by subclinical changes in tissue structure and function. Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT01970319.