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OBJECTIVE To confirm the presence of subclinical cardiovascular dysfunction in working-age adults with type 2 diabetes (T2D) and determine whether this is improved by a low-energy meal replacement diet (MRP) or exercise training. RESEARCH DESIGN AND METHODS This article reports on a prospective, randomized, open-label, blinded end point trial with nested case-control study. Asymptomatic younger adults with T2D were randomized 1:1:1 to a 12-week intervention of 1) routine care, 2) supervised aerobic exercise training, or 3) a low-energy (∼810 kcal/day) MRP. Participants underwent echocardiography, cardiopulmonary exercise testing, and cardiac magnetic resonance (CMR) at baseline and 12 weeks. The primary outcome was change in left ventricular (LV) peak early diastolic strain rate (PEDSR) as measured by CMR. Healthy volunteers were enrolled for baseline case-control comparison. RESULTS Eighty-seven participants with T2D (age 51 ± 7 years, HbA1c 7.3 ± 1.1%) and 36 matched control participants were included. At baseline, those with T2D had evidence of diastolic dysfunction (PEDSR 1.01 ± 0.19 vs. 1.10 ± 0.16 s−1, P = 0.02) compared with control participants. Seventy-six participants with T2D completed the trial (30 routine care, 22 exercise, and 24 MRP). The MRP arm lost 13 kg in weight and had improved blood pressure, glycemia, LV mass/volume, and aortic stiffness. The exercise arm had negligible weight loss but increased exercise capacity. PEDSR increased in the exercise arm versus routine care (β = 0.132, P = 0.002) but did not improve with the MRP (β = 0.016, P = 0.731). CONCLUSIONS In asymptomatic working-age adults with T2D, exercise training improved diastolic function. Despite beneficial effects of weight loss on glycemic control, concentric LV remodeling, and aortic stiffness, a low-energy MRP did not improve diastolic function.

Key Points Question What is the prevalence of fibromuscular dysplasia, aneurysms, dissection, and tortuosity in extracoronary arteries of patients who developed a spontaneous coronary artery dissection (SCAD)? Findings In this case series including 173 patients with SCAD, using magnetic resonance angiography with blinded interpretation of the findings, 32% of the patients had fibromuscular dysplasia, 8% had aneurysms, and 2% had dissections; the prevalence of arterial tortuosity was similar in cases and controls. Extracoronary vascular events over a median 5-year follow-up were rare. Meaning The findings of this blinded analysis suggest that, in patients with SCAD, severe multivessel fibromuscular dysplasia, aneurysms, and dissections are infrequent and seldom associated with clinically evident vascular events., Importance Spontaneous coronary artery dissection (SCAD) has been associated with fibromuscular dysplasia (FMD) and other extracoronary arterial abnormalities. However, the prevalence, severity, and clinical relevance of these abnormalities remain unclear. Objective To assess the prevalence and spectrum of FMD and other extracoronary arterial abnormalities in patients with SCAD vs controls. Design, Setting, and Participants This case series included 173 patients with angiographically confirmed SCAD enrolled between January 1, 2015, and December 31, 2019. Imaging of extracoronary arterial beds was performed by magnetic resonance angiography (MRA). Forty-one healthy individuals were recruited to serve as controls for blinded interpretation of MRA findings. Patients were recruited from the UK national SCAD registry, which enrolls throughout the UK by referral from the primary care physician or patient self-referral through an online portal. Participants attended the national SCAD referral center for assessment and MRA. Exposures Both patients with SCAD and healthy controls underwent head-to-pelvis MRA (median time between SCAD event and MRA, 1 [IQR, 1-3] year). Main Outcome and Measures The diagnosis of FMD, arterial dissections, and aneurysms was established according to the International FMD Consensus. Arterial tortuosity was assessed both qualitatively (presence or absence of an S curve) and quantitatively (number of curves ≥45%; tortuosity index). Results Of the 173 patients with SCAD, 167 were women (96.5%); mean (SD) age at diagnosis was 44.5 (7.9) years. The prevalence of FMD was 31.8% (55 patients); 16 patients (29.1% of patients with FMD) had involvement of multiple vascular beds. Thirteen patients (7.5%) had extracoronary aneurysms and 3 patients (1.7%) had dissections. The prevalence and degree of arterial tortuosity were similar in patients and controls. In 43 patients imaged with both computed tomographic angiography and MRA, the identification of clinically significant remote arteriopathies was similar. Over a median 5-year follow-up, there were 2 noncardiovascular-associated deaths and 35 recurrent myocardial infarctions, but there were no primary extracoronary vascular events. Conclusions and Relevance In this case series with blinded analysis of patients with SCAD, severe multivessel FMD, aneurysms, and dissections were infrequent. The findings of this study suggest that, although brain-to-pelvis imaging allows detection of remote arteriopathies that may require follow-up, extracoronary vascular events appear to be rare., This case series examines the prevalence of fibromuscular dysplasia and other extracoronary events in patients who develop spontaneous coronary artery dissection.

Introduction Left atrial (LA) strain has been shown to be an independent predictor of cardiovascular events in many conditions and superior to conventional measures of LA function (LA volumes and emptying fraction). The effects of low-energy diet or exercise on cardiovascular function in younger adults with type 2 diabetes (DIASTOLIC) study has previously demonstrated an improvement in left ventricle peak early diastolic strain rate in response to aerobic exercise in patients with type-2 diabetes (T2D). However, the effect of lifestyle intervention on LA function, assessed by cardiac magnetic resonance (CMR) imaging, is unknown. Methods The DIASTOLIC study was a prospective, randomised, open-label, blind endpoint trial, that randomised 90 obese participants with T2D (aged 18–65 years) to a 12-week intervention of: (i) routine care, (ii) aerobic exercise training, or (iii) low energy (≈810kcal/day) meal replacement plan (MRP). CMR was performed at baseline and week-12. Images were analysed using Medis v3.1. LA strain (LAS) was assessed using Feature Tracking (QStrain v2.0), corresponding to LA reservoir (LAS-r), conduit (LAS-cd), and booster pump (LAS-bp) using 4- and 2-chamber standard steady-state free precession cine images, and average values calculated. LA emptying fraction (LAEF) was calculated using biplane area-length method (QMass v8.1) for total, passive and active EF. Results 73 participants with T2D completed the trial and had analysable LA images (28 routine care, 22 exercise and 23 MRP). There was no significant change in CMR measured standard LA volumetric function (LAV/LAEF) and echocardiogram measured LV filling pressures (E/e') in any groups. The routine care arm showed no significant change in body mass index (BMI) or LAS (see Table). In the MRP group, there were significant reductions in BMI (4.8 kg/m2), mean systolic blood pressure (SBP) (13mmHg), and a significant increase in LAS-r and LAS-bp (29.9±7.0 to 32.3±7.0,p=0.036 and 14.6±5.3 to 17.2±3.7,p=0.034). The exercise arm showed a small reduction in BMI (0.8kg/m2), with no significant change in BP or LAS. Conclusion There was significant improvement in LAS post-lifestyle intervention in young adults with T2D, despite no change in volumetric measurements. MRP led to weight loss and improved SBP, with associated improved LA filling and contraction. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute for Health Research (NIHR) a career development fellowship.

Background Efficient matching of energy supply to demand is essential for maintaining normal cardiac function. Altered cardiac metabolism may contribute to the development of cardiac dysfunction by impairing metabolic flexibility in type 2 diabetes (T2D). Purpose We aimed to evaluate the effect of T2D on myocardial substrate preferences in response to acute increases in cardiac workload and the effects on contractile function utilising simultaneous coronary sinus (CS) and aorta blood sampling and cardiac magnetic resonance (CMR) imaging Methods Eligible participants without obstructive coronary artery disease (>50% luminal coronary artery stenosis on coronary angiography) underwent transmyocardial arteriovenous blood sampling. Metabolites in paired coronary sinus and arterial samples were quantified to determine myocardial fuel selection at rest and during a stress protocol with intravenous dobutamine. Free fatty acid (FFA), glucose, 3-hydroxybutyric acid (3HBA) and lactate utilisation at rest and haemodynamic stress was calculated as an extraction fraction % (EF). Participants underwent dobutamine stress multiparametric CMR imaging at 3.0 Tesla (Skyra, Siemens, Germany) on a separate visit within 21 days to quantify cardiac volumes, function and perfusion. Results Two thousand and sixty-one participants were screened and due to stringent inclusion and exclusion criteria for this mechanistic study, three T2D patients and five matching controls were enrolled. Baseline demographics and metabolic and CMR results are documented in Table 1. At peak stress levels there was a significant increase in FFA use from rest to stress in controls only (p=0.002). There were no significant differences in FA or glucose uptake between T2D patients and controls at rest or stress. 3HBA EF was significantly increased in T2D during stress (25.04% vs 5.31%, p=0.007). Mean FFA and 3-HBA changes calculated as extraction fraction at stress and rest are illustrated in Figure 1. Conclusions We demonstrate for the first time in vivo that the diabetic heart switches to ketone bodies during increased workloads as a significant fuel source. At present, it is unknown whether enhanced ketone body metabolism in T2D is beneficial, maladaptive, or a bystander. As the energetic properties of ketones are favourable, increased myocardial ketone oxidation could be an adaptive change designed to compensate for defects in myocardial energy metabolism in diabetes. Further, larger studies are warranted. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation - Clinical Research Training FellowshipWellcome Trust Seed Grant Table 1Figure 1

Background Systolic strain and peak-early diastolic strain rate (PEDSR) measure subclinical cardiac dysfunction. These parameters can be derived from cardiovascular magnetic resonance (CMR) cine images using new software packages, but the comparative test-retest reproducibility of these software in disease states is unknown. This study compared the test-retest reproducibility of strain measures derived from two software packages (feature-tracking software (FT) and tissue-tracking (TT)) in disease populations with preserved ejection fractions. Methods This was a prospective study of 10 patients with aortic stenosis (AS), 10 haemodialysis patients and 10 diabetic patients at 1.5 and 3-Tesla. 30 subjects underwent test-retest reproducibility scans of global circumferential strain (GCS), global longitudinal strain (GLS), circumferential-PEDSR and longitudinal-PEDSR calculated using TT and FT software. Results Test-retest reproducibility of GCS and GLS were similar for FT and TT across patient groups. Coefficient of variability (CoV) for FT-derived GCS 8.1%, 5% and 7.9% for AS, diabetic and haemodialysis patients, compared to 3.3%, 9.2% and 5.4% for TT-derived GCS, with CoV for FT-derived GLS 8%, 6.4% and 8.2% for AS, diabetic and haemodialysis patients, compared to 5.3%, 4.8% and 7% for TT-derived GLS). Reproducibility of FT-derived circumferential and longitudinal-PEDSR was worse than TT-derived circumferential and longitudinal-PEDSR (CoV for FT-derived circumferential-PEDSR 18.2%, 18% and 17.4% for AS, diabetic and haemodialysis patients, compared to 6.1%, 11.7% and 11% for TT-derived circumferential-PEDSR with CoV for FT-derived longitudinal PEDSR 18.2%, 18.9%, 18.3% for AS, diabetic and haemodialysis patients, compared to 8.9%, 9.1% and 11.4% for TT-derived longitudinal-PEDSR). Bland-Altman analysis revealed no systematic bias with tighter limits of agreement for TT-derived strain measures. Conclusions Reproducibility of GCS and GLS are excellent with FT and TT software across diseases. TT had superior test-retest reproducibility for quantification of longitudinal and circumferential-PEDSR than FT-derived PEDSR across diseases.

Objective: People with T2D have increased risk of heart failure, with fibro-inflammatory pathways implicated in the pathogenesis. This secondary analysis assessed the relationship between multiple fibro-inflammatory biomarkers and cardiovascular (CV) structure and function in patients with T2D and asymptomatic nondiabetic controls and the impact of two lifestyle interventions, exercise training or meal replacement plan (MRP). Methods: Data was derived from a randomised controlled trial (RCT), including a nested case-control study. Adults with T2D and no CV disease were randomized (1:1:1) to a 12-week intervention of 1) supervised aerobic exercise training, 2) a low-energy (∼810 kcal/day) MRP or 3) standard care. Fasting bloods for fibro-inflammatory biomarkers and cardiac MRI (CMR) were undertaken pre- and post-intervention. Principal component analysis (PCA) was performed to visualise this multivariate dataset in a 3D space to understand the relationship between CMR outcomes of interest (e.g., cardiac geometry, systolic and diastolic function), key demographic variables (age, sex, ethnicity and smoking status) and the fibro-inflammatory biomarkers (total of 68 variables) between cases and controls and pre-post intervention. Results: At baseline 36 controls and 83 T2D were compared of which 76 participants completed the RCT. People with T2D had an adverse fibro-inflammatory profile compared to controls’. The PCA 3D-visulisation containing demographics, biomarkers and CMR data shows almost complete separation between controls and those with T2D. Following MRP there was a marked shift in the PCA but not for the exercise intervention. Conclusion: Alterations in fibro-inflammatory pathways impact CV structure and function before the onset of symptomatic heart failure in people with T2D. The MRP improved this fibro-inflammatory profile but not exercise. Longer term studies are required to determine whether the MRP can reduce symptomatic heart failure. Disclosure E. M. Brady: Other Relationship; Self; Bristol Myers Squibb Pharmaceutical company. E. Mirkes: None. K. Parke: None. G. S. Gulsin: None. L. Athithan: None. J. Henson: None. T. Yates: None. M. J. Davies: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Boehringer Ingelheim Limited (UK), Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi, Other Relationship; Self; AstraZeneca, NIHR Leicester Biomedical Research Centre, Novo Nordisk, Speaker's Bureau; Self; Astra Zeneca Pharma India Ltd, Boehringer Ingelheim (China), Boehringer Ingelheim (Philippines), Inc., Boehringer Ingelheim International GmbH, Boehringer Ingelheim Limited (UK), Boehringer Ingelheim Saudi Arabia Trading, Boehringer Ingelheim Singapore Pte. Ltd, Boehringer Ingelheim Sp. Z o. o., Eli Lilly and Company, Napp Pharmaceuticals, Novo Nordisk, Novo Nordisk A/S, S. C. Sanofi Romania SRL, Sanofi K. K. G. P. Mccann: None. P. Kanagala: None. L. Ng: None. Funding National Institute for Health Research (CDF2014-07-045 to G.P.M.)

Background Identifying coronary artery disease (CAD) in patients with end-stage renal disease (ESRD) is challenging. Adenosine stress native T1 mapping with cardiovascular magnetic resonance (CMR) may accurately detect obstructive CAD and microvascular dysfunction in the general population. This study assessed the feasibility and reliability of adenosine stress native T1 mapping in patients on haemodialysis. Methods The feasibility of undertaking rest and adenosine stress native T1 mapping using the single-shot Modified Look-Locker inversion recovery (MOLLI) sequence was assessed in 58 patients on maintenance haemodialysis using 3 T CMR. Ten patients underwent repeat stress CMR within 2 weeks for assessment of test-retest reliability of native T1, stress T1 and delta T1 (ΔT1). Interrater and intrarater agreement were assessed in 10 patients. Exploratory analyses were undertaken to assess associations between clinical variables and native T1 values in 51 patients on haemodialysis. Results Mean age of participants was 55 ± 15 years, 46 (79%) were male, and median dialysis vintage was 21 (8; 48) months. All patients completed the scan without complications. Mean native T1 rest, stress and ΔT1 were 1261 ± 57 ms, 1297 ± 50 ms and 2.9 ± 2.5%, respectively. Interrater and intrarater agreement of rest T1, stress T1 and ΔT1 were excellent, with intraclass correlation coefficients (ICC) > 0.9 for all. Test-retest reliability of rest and stress native T1 were excellent or good (CoV 1.2 and 1.5%; ICC, 0.79 and 0.69, respectively). Test-retest reliability of ΔT1 was moderate to poor (CoV 27.4%, ICC 0.55). On multivariate analysis, CAD, diabetes mellitus and resting native T1 time were independent determinants of ΔT1 (β = − 0.275, p = 0.019; β = − 0.297, p = 0.013; β = − 0.455; p Conclusions Rest and adenosine stress native T1 mapping is feasible and well-tolerated amongst patients with ESRD on haemodialysis. Although rater agreement of the technique is excellent, test-retest reliability of ΔT1 is moderate to poor. Prospective studies should evaluate the relationship between this technique and established methods of CAD assessment and association with outcomes.

IntroductionDespite their young age and relatively short duration of disease, younger adults with type 2 diabetes (T2D) already have diastolic dysfunction and may be at risk of incipient heart failure. Whether weight loss or exercise training improve cardiac dysfunction in people with T2D remains to be established.Methods and analysisProspective, randomised, open-label, blind endpoint trial. The primary aim of the study is to determine if diastolic function can be improved by either a meal replacement plan or a supervised exercise programme, compared with guideline-directed care. A total of 90 obese participants with T2D (aged 18–65 years), diabetes duration Ethics and disseminationThe study has full ethical approval, and data collection was completed in August 2018. The study results will be submitted for publication within 6 months of completion.Trial registration numberNCT02590822; Pre-results.

Background Arterial stiffness has been implicated in the pathophysiology of Heart Failure with Preserved Ejection Fraction (HFpEF) and has been postulated to be related to adverse left ventricular (LV) remodelling. Purpose To determine whether arterial stiffness measured by cfPWV (Oscillometry) and Aortic distensibility (AoD) are independently related to LV remodeling in HFpEF. Methods We prospectively recruited 140 patients with HFpEF who underwent VICORDER® assessment of cfPWV and a multiparametric cardiac MRI which included a cine, perpendicular to the thoracic aorta at the pulmonary artery bifurcation with simultaneous blood pressure recording. Images were analysed using Circle CVi and aortic images were analysed in Java Image Manipulation. Aortic (Ao) distensibility was calculated using the formula Distensibility = (Ao max – Ao min)/(Ao min × pulse pressure). Results 134 (65 males) of the patients had either cfPWV or distensibility measured using MRI, with an average age of 73±9.4 years, mean BP 144.7±24.9/74.0±13.9 mmHg. 73 patients (54.4%) with a diagnosis of diabetes, 121 patients (90.2%) with known hypertension, average BMI of 33.7±7.0. Mean cfPWV was 9.57±2.42 and aortic distensibility was 1.13±0.70 in the ascending and 1.28±1.02 in the descending aorta. Average measures for LV remodelling and function were: LV Mass Index 52.35±14.83 g/m 2 ; LV Mass/Volume 0.96±0.19 and ejection fraction 56.11%±5.48%. Aortic stiffness (data for ascending aortic distensibility and cfPWV shown respectively) was not significantly related to any measure of LV remodelling: LV Mass r=0.023, p=0.824 and r=0.036, p=0.703; LV Mass Index r=−0.063, p=0.531 and r=0.110, p=0.243; LV Mass/Volume r=0.111, p=0.272 and r=0.068, p=0.467. Factors that showed a significant effect in the univariate analysis were gender, presence of diabetes, level of HbA1c and average heart rate, but in the multivariate analysis, only gender remained significant. Conclusion In patients with established HFpEF, aortic stiffness measured by CMR or oscillometry, is not associated with adverse LV remodelling. Whether aortic stiffness is related to pre-symptomatic LV remodelling warrants further study. Funding acknowledgement This research was funded by the NIHR Leicester Cardiovascular Biomedical Research Centre

Individuals with type 2 diabetes have a three- to fivefold increased risk of developing heart failure. Diabetic cardiomyopathy is typified by left ventricular (LV) concentric remodeling, which is a recognized predictor of adverse cardiovascular events. Although the mechanisms underlying LV remodeling in type 2 diabetes are unclear, progressive aortic stiffening may be a key determinant. The aim of this study was to assess the relationship between aortic stiffness and LV geometry in younger adults with type 2 diabetes, using multiparametric cardiovascular MRI. We prospectively recruited 80 adults (aged 18–65 years) with type 2 diabetes and no cardiovascular disease and 20 age- and sex-matched healthy control subjects. All subjects underwent comprehensive bio-anthropometric assessment and cardiac MRI, including measurement of aortic stiffness by aortic distensibility (AD). Type 2 diabetes was associated with increased LV mass, concentric LV remodeling, and lower AD compared with control subjects. On multivariable linear regression, AD was independently associated with concentric LV remodeling in type 2 diabetes. Aortic stiffness may therefore be a potential therapeutic target to prevent the development of heart failure in type 2 diabetes.

Background:Type 2 diabetes (T2D) is associated with an increased risk of heart failure (HF) and cardiovascular mortality. A large-scale meta-analysis on HF found that diabetes was more frequent in women than men, and diabetes appeared to have attenuated the otherwise protective effect of female sex on progression of cardiomyopathy. The exact underlying mechanisms for this remain unclear. Here, we aimed to determine the effect of sex on the phenotypic expression of diabetic heart disease in patients with T2D.Methods:A total of 62 male [mean age 44 ± 8 years, body mass index (BMI) 33 ± 5 kg/m2, mean HBA1c of 7.8 ± 1.8%] and 67 female (44 ± 10 years, BMI 35 ± 6 kg/m2, HBA1c 7.6 ± 1.2%) T2D patients on oral glucose-lowering treatment, and 16 male (48 ± 17 years, BMI 25 ± 3 kg/m2) and 14 female (50 ± 10 years, BMI 25 ± 4 kg/m2) controls were recruited. Left ventricular (LV) volumes, mass, function and deformation, and left atrial (LA) volumes and function were assessed using cardiac magnetic resonance imaging (CMR).Results:Participants in all groups were of similar age, and there were no significant differences in blood pressure (BP), diabetes duration or metabolic profile between the two diabetes groups. Concentric remodeling was present in both sexes ( p Conclusion:Male sex adversely affects the phenotypic expression of diabetic heart disease. The striking differences in the cardiac phenotype between male and female patients with T2D promote awareness of gender-specific risk factors in search of treatment and prevention of diabetes-associated HF.Condensed Abstract:We aimed to determine the effect of sex on the phenotypic expression of diabetic heart disease in patients with T2D. While our findings support the notion that in T2D, male sex adversely affects the phenotypic expression of diabetic heart disease, this is in apparent conflict with the previous large-scale study showing diabetes attenuates the otherwise protective effect of female sex on progression of cardiomyopathy. Further longitudinal studies looking at gender differences in clinical outcomes in T2D patients are needed. These sex-related differences promote awareness of sex-specific risk factors in search of treatment and prevention of diabetes-associated HF.