MECHANISMS IN ENDOCRINOLOGY: Diabetic cardiomyopathy: pathophysiology and potential metabolic interventions state of the art review

Heart failure is a major cause of morbidity and mortality in type 2 diabetes. Type 2 diabetes contributes to the development of heart failure through a variety of mechanisms, including disease-specific myocardial structural, functional and metabolic changes. This review will focus on the contemporary contributions of state of the art non-invasive technologies to our understanding of diabetic cardiomyopathy, including data on cardiac disease phenotype, cardiac energy metabolism and energetic deficiency, ectopic and visceral adiposity, diabetic liver disease, metabolic modulation strategies and cardiovascular outcomes with new classes of glucose-lowering therapies

Dilated Cardiomyopathy: Phosphorus 31 MR Spectroscopy at 7 T

Purpose To test whether the increased signal-to-noise ratio of phosphorus 31 (31P) magnetic resonance (MR) spectroscopy at 7 T improves precision in cardiac metabolite quantification in patients with dilated cardiomyopathy (DCM) compared with that at 3 T. Materials and Methods Ethical approval was obtained, and participants provided written informe consent. In a prospective study, 31P MR spectroscopy was performed at 3 T and 7 T in 25 patients with DCM. Ten healthy matched control subjects underwent 31P MR spectroscopy at 7 T. Paired Student t tests were performed to compare results between the 3-T and 7-T studies. Results The phosphocreatine (PCr) signal-to-noise ratio increased 2.5 times at 7 T compared with that at 3 T. The PCr to adenosine triphosphate (ATP) concentration ratio (PCr/ATP) was similar at both field strengths (mean ± standard deviation, 1.48 ± 0.44 at 3 T vs 1.54 ± 0.39 at 7 T, P = .49), as expected. The Cramér-Rao lower bounds in PCr concentration (a measure of uncertainty in the measured ratio) were 45% lower at 7 T than at 3 T, reflecting the higher quality of 7-T 31P spectra. Patients with dilated cardioyopathy had a significantly lower PCr/ATP than did healthy control subjects at 7 T (1.54 ± 0.39 vs 1.95 ± 0.25, P = .005), which is consistent with previous findings. Conclusion 7-T cardiac 31P MR spectroscopy is feasible in patients with DCM and gives higher signal-to-noise ratios and more precise quantification of the PCr/ATP than that at 3 T. PCr/ATP was significantly lower in patients with DCM than in control subjects at 7 T, which is consistent with previous findings at lower field strengths

Cardiac magnetic resonance left ventricular filling pressure is linked to symptoms, signs and prognosis in heart failure

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 < 40% during CMR assessment. Patients with raised LVFP were more likely to have pleural effusions [hazard ratio (HR) 3.2, P = 0.003], orthopnoea (HR 2.0, P = 0.008), lower limb oedema (HR 1.7, P = 0.04), and breathlessness (HR 1.7, P = 0.01). Raised CMR-derived LVFP was associated with a four-fold risk of HF hospitalization (HR 4.0, P < 0.0001) and a three-fold risk of MACE (HR 3.1, P < 0.0001). In the multivariable model, raised CMR-derived LVFP was independently associated with HF hospitalization (adjusted HR 3.8, P = 0.0001) and MACE (adjusted HR 3.0, P = 0.0001). Conclusions Raised CMR-derived LVFP is strongly associated with symptoms and signs of HF. In addition, raised CMR-derived LVFP is independently associated with subsequent HF hospitalization and MACE

The interplay between metabolic alterations, diastolic strain rate and exercise capacity in mild heart failure with preserved ejection fraction

Background: Heart failure (HF) is characterized by altered myocardial substrate metabolism which can lead to myocardial triglyceride accumulation (steatosis) and lipotoxicity. However its role in mild HF with preserved ejection fraction (HFpEF) is uncertain. We measured myocardial triglyceride content (MTG) in HFpEF and assessed its relationships with diastolic function and exercise capacity. Methods: 27 HFpEF (clinical features of HF, left ventricular EF >50%, evidence of mild diastolic dysfunction and evidence of exercise limitation as assessed by cardiopulmonary exercise test) and 14 controls underwent 1H-magnetic resonance spectroscopy (1H-MRS) to measure MTG (lipid/water, %), 31P-MRS to measure myocardial energetics (phosphocreatine-to-adenosine triphosphate - PCr/ATP) and feature-tracking magnetic resonance imaging for diastolic strain rate. Results: When compared to controls, HFpEF had 2.3 fold higher in MTG (1.45±0.25% vs. 0.64±0.16%, p=0.009) and reduced PCr/ATP (1.60±0.09 vs. 2.00±0.10, p=0.005). HFpEF had significantly reduced diastolic strain rate and maximal oxygen consumption (VO2 max), which both correlated significantly with elevated MTG and reduced PCr/ATP. On multivariate analyses, MTG was independently associated with diastolic strain rate while diastolic strain rate was independently associated with VO2 max. Conclusions: Myocardial steatosis is pronounced in mild HFpEF, and is independently associated with impaired diastolic strain rate which is itself related to exercise capacity. Steatosis may adversely affect exercise capacity by indirect effect occurring via impairment in diastolic function. As such, myocardial triglyceride may become a potential therapeutic target to treat the increasing number of patients with HFpEF.This work was supported by Chest Heart and Stroke Association, Scotland. MM acknowledges support from the National University of Malaysia and Ministry of Higher Education Malaysia. SN and OR acknowledge support from the Oxford NIHR Biomedical Research Centre and the Oxford British Heart Foundation Centre of Research Excellence. JES is a Senior BHF Basic Science Research Fellow (FS/11/50/29038). CTR is funded by a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society [098436/Z/12/Z/B]. OR is a BHF Clinical Intermediate Research Fellow FS/16/70/32157

Ectopic and Visceral Fat Deposition in Lean and Obese Patients With Type 2 Diabetes

Background: Type 2 diabetes (T2D) and obesity are associated with nonalcoholic fatty liver disease, cardiomyopathy, and cardiovascular mortality. Both show stronger links between ectopic and visceral fat deposition, and an increased cardiometabolic risk compared with subcutaneous fat. Objectives: This study investigated whether lean patients (Ln) with T2D exhibit increased ectopic and visceral fat deposition and whether these are linked to cardiac and hepatic changes. Methods: Twenty-seven obese patients (Ob) with T2D, 15 Ln-T2D, and 12 normal-weight control subjects were studied. Subjects underwent cardiac computed tomography, cardiac magnetic resonance imaging (MRI), proton and phosphorus MR spectroscopy, and multiparametric liver MR, including hepatic proton MRS, T1- and T2*-mapping yielding “iron-corrected T1” [cT1]. Results: Diabetes, with or without obesity, was associated with increased myocardial triglyceride content (p = 0.01), increased hepatic triglyceride content (p = 0.04), and impaired myocardial energetics (p = 0.04). Although cardiac structural changes, steatosis, and energetics were similar between the T2D groups, epicardial fat (p = 0.04), hepatic triglyceride (p = 0.01), and insulin resistance (p = 0.03) were higher in Ob-T2D. Epicardial fat, hepatic triglyceride, and insulin resistance correlated negatively with systolic strain and diastolic strain rates, which were only significantly impaired in Ob-T2D (p < 0.001 and p = 0.006, respectively). Fibroinflammatory liver disease (elevated cT1) was only evident in Ob-T2D patients. cT1 correlated with hepatic and epicardial fat (p < 0.001 and p = 0.01, respectively). Conclusions: Irrespective of body mass index, diabetes is related to significant abnormalities in cardiac structure, energetics, and cardiac and hepatic steatosis. Obese patients with T2D show a greater propensity for ectopic and visceral fat deposition

Clinical translation of three-dimensional scar, diffusion tensor imaging, four-dimensional flow, and quantitative perfusion in cardiac MRI: a comprehensive review

Cardiovascular magnetic resonance (CMR) imaging is a versatile tool that has established itself as the reference method for functional assessment and tissue characterisation. CMR helps to diagnose, monitor disease course and sub-phenotype disease states. Several emerging CMR methods have the potential to offer a personalised medicine approach to treatment. CMR tissue characterisation is used to assess myocardial oedema, inflammation or thrombus in various disease conditions. CMR derived scar maps have the potential to inform ablation therapy—both in atrial and ventricular arrhythmias. Quantitative CMR is pushing boundaries with motion corrections in tissue characterisation and first-pass perfusion. Advanced tissue characterisation by imaging the myocardial fibre orientation using diffusion tensor imaging (DTI), has also demonstrated novel insights in patients with cardiomyopathies. Enhanced flow assessment using four-dimensional flow (4D flow) CMR, where time is the fourth dimension, allows quantification of transvalvular flow to a high degree of accuracy for all four-valves within the same cardiac cycle. This review discusses these emerging methods and others in detail and gives the reader a foresight of how CMR will evolve into a powerful clinical tool in offering a precision medicine approach to treatment, diagnosis, and detection of disease

Validation of time-resolved, automated peak trans-mitral velocity tracking: Two center four-dimensional flow cardiovascular magnetic resonance study

Objective: We aim to validate four-dimensional flow cardiovascular magnetic resonance (4D flow CMR) peak velocity tracking methods for measuring the peak velocity of mitral inflow against Doppler echocardiography.  Method: Fifty patients were recruited who had 4D flow CMR and Doppler Echocardiography. After transvalvular flow segmentation using established valve tracking methods, peak velocity was automatically derived using three-dimensional streamlines of transvalvular flow. In addition, a static planar method was used at the tip of mitral valve to mimic Doppler technique.  Results: Peak E-wave mitral inflow velocity was comparable between TTE and the novel 4D flow automated dynamic method (1.02±0.41 m/s vs 1.02±0.36 m/s; P=0.77) however there was a statistically significant difference when compared with the static planar method (0.93±0.37 m/s; P=0.04). Mean A-wave peak velocity was also comparable across TTE and the automated dynamic streamline (0.87±0.39 m/s vs 0.87±0.36 m/s; P=0.99). A significant difference was seen with the static planar method (0.78±0.36 m/s; P=0.04). E/A ratio was comparable between TTE and both the automated dynamic and static planar method (1.22±0.52 vs 1.20±0.34; p=0.76 and 1.36±0.81; p=0.25 respectively). Both novel 4D flow methods showed good correlation with TTE for E-wave (dynamic method; r=0.70; P<0.001 and static planar method; r=0.67; P<0.001) and A-wave velocity measurements (dynamic method; r=0.83; P<0.001 and static method; r=0.71; P<0.001). The automated dynamic method demonstrated excellent intra/inter-observer reproducibility for all parameters.  Conclusion: Automated dynamic peak velocity tracing method using 4D flow CMR is comparable to Doppler echocardiography for mitral inflow assessment and has excellent reproducibility for clinical use

Multimodality imaging approach to left ventricular dysfunction in diabetes: an expert consensus document from the European Association of Cardiovascular Imaging.

peer reviewedHeart failure (HF) is among the most important and frequent complications of diabetes mellitus (DM). The detection of subclinical dysfunction is a marker of HF risk and presents a potential target for reducing incident HF in DM. Left ventricular (LV) dysfunction secondary to DM is heterogeneous, with phenotypes including predominantly systolic, predominantly diastolic, and mixed dysfunction. Indeed, the pathogenesis of HF in this setting is heterogeneous. Effective management of this problem will require detailed phenotyping of the contributions of fibrosis, microcirculatory disturbance, abnormal metabolism, and sympathetic innervation, among other mechanisms. For this reason, an imaging strategy for the detection of HF risk needs to not only detect subclinical LV dysfunction (LVD) but also characterize its pathogenesis. At present, it is possible to identify individuals with DM at increased risk HF, and there is evidence that cardioprotection may be of benefit. However, there is insufficient justification for HF screening, because we need stronger evidence of the links between the detection of LVD, treatment, and improved outcome. This review discusses the options for screening for LVD, the potential means of identifying the underlying mechanisms, and the pathways to treatment