Oliver J. Rider

Cardiac energetics, oxygenation, and perfusion during increased workload in patients with type 2 diabetes mellitus

Aims Patients with type 2 diabetes mellitus (T2DM) are known to have impaired resting myocardial energetics and impaired myocardial perfusion reserve, even in the absence of obstructive epicardial coronary artery disease (CAD). Whether or not the pre-existing energetic deficit is exacerbated by exercise, and whether the impaired myocardial perfusion causes deoxygenation and further energetic derangement during exercise stress, is uncertain. Methods and results Thirty-one T2DM patients, on oral antidiabetic therapies with a mean HBA1c of 7.4 ± 1.3%, and 17 matched controls underwent adenosine stress cardiovascular magnetic resonance for assessment of perfusion [myocardial perfusion reserve index (MPRI)] and oxygenation [blood-oxygen level-dependent (BOLD) signal intensity change (SIΔ)]. Cardiac phosphorus-MR spectroscopy was performed at rest and during leg exercise. Significant CAD (>50% coronary stenosis) was excluded in all patients by coronary computed tomographic angiography. Resting phosphocreatine to ATP (PCr/ATP) was reduced by 17% in patients (1.74 ± 0.26, P = 0.001), compared with controls (2.07 ± 0.35); during exercise, there was a further 12% reduction in PCr/ATP (P = 0.005) in T2DM patients, but no change in controls. Myocardial perfusion and oxygenation were decreased in T2DM (MPRI 1.61 ± 0.43 vs. 2.11 ± 0.68 in controls, P = 0.002; BOLD SIΔ 7.3 ± 7.8 vs. 17.1 ± 7.2% in controls, P < 0.001). Exercise PCr/ATP correlated with MPRI (r = 0.50, P = 0.001) and BOLD SIΔ (r = 0.32, P = 0.025), but there were no correlations between rest PCr/ATP and MPRI or BOLD SIΔ. Conclusion The pre-existing energetic deficit in diabetic cardiomyopathy is exacerbated by exercise; stress PCr/ATP correlates with impaired perfusion and oxygenation. Our findings suggest that, in diabetes, coronary microvascular dysfunction exacerbates derangement of cardiac energetics under conditions of increased workload.

Assessment of Metformin Induced Changes in Cardiac and Hepatic Redox State Using Hyperpolarized[1-13C]Pyruvate.

Metformin improves cardiovascular outcomes in type 2 diabetes, but its exact mechanisms of action remain controversial. We used hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy to determine the effects of metformin treatment on heart and liver pyruvate metabolism in rats in vivo. Both oral treatment for 4 weeks and a single intravenous metformin infusion significantly increased the cardiac [1-13C]lactate:[1-13C]pyruvate ratio but had no effect on the [1-13C]bicarbonate + 13CO2:[1-13C]pyruvate ratio, an index of pyruvate dehydrogenase flux. These changes were paralleled by a significant increase in the heart and liver cytosolic redox state, estimated from the [lactate]:[pyruvate] ratio but not the whole-cell [NAD+]/[NADH] ratio. Hyperpolarized MRI localized the increase in cardiac lactate to the left ventricular myocardium, implying a direct myocardial effect, though metformin had no effect on systolic or diastolic cardiac function. These findings demonstrate the ability of hyperpolarized pyruvate magnetic resonance spectroscopy to detect metformin-induced changes in cytosolic redox biology, suggest that metformin has a previously unrecognized effect on cardiac redox state, and help to refine the design of impending hyperpolarized magnetic resonance studies in humans.

Pericardial, But Not Hepatic, Fat by CT Is Associated With CV Outcomes and Structure: The Multi-Ethnic Study of Atherosclerosis.

OBJECTIVESnThe study sought to determine the associations between local (pericardial) fat and incident cardiovascular disease (CVD) events and cardiac remodeling independent of markers of overall adiposity.nnnBACKGROUNDnThe impact of pericardial fat-a local fat depot encasing the heart-on myocardial function andxa0long-term CV prognosis independent of systemic consequences of adiposity or hepatic fat is an area of activexa0debate.nnnMETHODSnWe studied 4,234 participants enrolled in the MESA (Multi-Ethnic Study of Atherosclerosis) study with concomitant cardiac magnetic resonance imaging and computed tomography (CT) measurements for pericardial fat volume and hepatic attenuation (a measure of liver fat). Poisson and Cox regression were used to estimate the annualized risk of incident hard atherosclerotic CVD (ASCVD), all-cause death, heart failure, all-cause CVD, hard coronary heart disease, and stroke as a function of pericardial and hepatic fat. Generalized additive models were used to assess the association between cardiac magnetic resonance indices of left ventricular (LV) structure and function and pericardial fat. Models were adjusted for relevant clinical, demographic, and cardiometabolic covariates.nnnRESULTSnMESA study participants with higher pericardial and hepatic fat were more likely to be older, were more frequently men, and had a higher prevalence of cardiometabolic risk factors (including dysglycemia, dyslipidemia, hypertension), as well as adiposity-associated inflammation. Over a median 12.2-year follow-up (interquartile range: 11.6 to 12.8 years), pericardial fat was associated with a higher rate of incident hard ASCVD (standardized hazard ratio: 1.22; 95% confidence interval: 1.10 to 1.35; pxa0= 0.0001). Hepatic fat by CT was not significantly associated with hard ASCVD (standardized hazard ratio: 0.96; 95% confidence interval: 0.86 to 1.08; pxa0= 0.52). Higher pericardial fat was associatedxa0with greater indexed LV mass (37.8 g/m2.7 vs. 33.9 g/m2.7, highest quartile vs. lowest quartile; pxa0< 0.01), LV mass-to-volume ratio (1.2 vs. 1.1, highest quartile vs. lowest quartile; pxa0< 0.01). In adjusted models, a higher pericardial fat volume was associated with greater LV mass (pxa0< 0.0001) and concentricity (pxa0<xa00.0001).nnnCONCLUSIONSnPericardial fat is associated with poorer CVD prognosis and LV remodeling, independent of insulin resistance, inflammation, and CT measures of hepatic fat.

Metabolic remodeling in hypertrophied and failing myocardium: a review

The energy starvation hypothesis proposes that maladaptive metabolic remodeling antedates, initiates, and maintains adverse contractile dysfunction in heart failure (HF). Better understanding of the cardiac metabolic phenotype and metabolic signaling could help identify the role metabolic remodeling plays within HF and the conditions known to transition toward HF, including pathological hypertrophy. In this review, we discuss metabolic phenotype and metabolic signaling in the contexts of pathological hypertrophy and HF. We discuss the significance of alterations in energy supply (substrate utilization, oxidative capacity, and phosphotransfer) and energy sensing using observations from human and animal disease models and models of manipulated energy supply/sensing. We aim to provide ways of thinking about metabolic remodeling that center around metabolic flexibility, capacity (reserve), and efficiency rather than around particular substrate preferences or transcriptomic profiles. We show that maladaptive metabolic remodeling takes multiple forms across multiple energy-handling domains. We suggest that lack of metabolic flexibility and reserve (substrate, oxidative, and phosphotransfer) represents a final common denominator ultimately compromising efficiency and contractile reserve in stressful contexts.

Measurement of myocardial native T1 in cardiovascular diseases and norm in 1291 subjects

BackgroundNative T1-mapping provides quantitative myocardial tissue characterization for cardiovascular diseases (CVD), without the need for gadolinium. However, its translation into clinical practice is hindered by differences between techniques and the lack of established reference values. We provide typical myocardial T1-ranges for 18 commonly encountered CVDs using a single T1-mapping technique – Shortened Look-Locker Inversion Recovery (ShMOLLI), also used in the large UK Biobank and Hypertrophic Cardiomyopathy Registry study.MethodsWe analyzed 1291 subjects who underwent CMR (1.5-Tesla, MAGNETOM-Avanto, Siemens Healthcare, Erlangen, Germany) between 2009 and 2016, who had a single CVD diagnosis, with mid-ventricular T1-map assessment. A region of interest (ROI) was placed on native T1-maps in the “most-affected myocardium”, characterized by the presence of late gadolinium enhancement (LGE), or regional wall motion abnormalities (RWMA) on cines. Another ROI was placed in the “reference myocardium” as far as possible from LGE/RWMA, and in the septum if no focal abnormality was present. To further define normality, we included native T1 of healthy subjects from an existing dataset after sub-endocardial pixel-erosions.ResultsNative T1 of patients with normal CMR (938xa0±xa021xa0ms) was similar compared to healthy subjects (941xa0±xa023xa0ms). Across all patient groups (57xa0±xa019xa0yrs., 65% males), focally affected myocardium had significantly different T1 value compared to reference myocardium (all pxa0<xa00.001). In the affected myocardium, cardiac amyloidosis (1119xa0±xa061xa0ms) had the highest native T1 compared to normal and all other CVDs, while iron-overload (795xa0±xa058xa0ms) and Anderson-Fabry disease (863xa0±xa023xa0ms) had the lowest native reference T1 (all pxa0<xa00.001). Future studies designed to detect the large T1 differences between affected and reference myocardium are estimated to require small sample-sizes (nxa0<xa050). However, studies designed to detect the small T1 differences between reference myocardium in CVDs and healthy controls can require several thousand of subjects.ConclusionsWe provide typical T1-ranges for common clinical cardiac conditions in the largest cohort to-date, using ShMOLLI T1-mapping at 1.5xa0T. Sample-size calculations from this study may be useful for the design of future studies and trials that use T1-mapping as an endpoint.

Improvements in ECG accuracy for diagnosis of left ventricular hypertrophy in obesity

Objectives The electrocardiogram (ECG) is the most commonly used tool to screen for left ventricular hypertrophy (LVH), and yet current diagnostic criteria are insensitive in modern increasingly overweight society. We propose a simple adjustment to improve diagnostic accuracy in different body weights and improve the sensitivity of this universally available technique. Methods Overall, 1295 participants were included—821 with a wide range of body mass index (BMI 17.1–53.3u2005kg/m2) initially underwent cardiac magnetic resonance evaluation of anatomical left ventricular (LV) axis, LV mass and 12-lead surface ECG in order to generate an adjustment factor applied to the Sokolow–Lyon criteria. This factor was then validated in a second cohort (n=520, BMI 15.9–63.2u2005kg/m2). Results When matched for LV mass, the combination of leftward anatomical axis deviation and increased BMI resulted in a reduction of the Sokolow–Lyon index, by 4u2005mm in overweight and 8u2005mm in obesity. After adjusting for this in the initial cohort, the sensitivity of the Sokolow–Lyon index increased (overweight: 12.8% to 30.8%, obese: 3.1% to 27.2%) approaching that seen in normal weight (37.8%). Similar results were achieved in the validation cohort (specificity increased in overweight: 8.3% to 39.1%, obese: 9.4% to 25.0%) again approaching normal weight (39.0%). Importantly, specificity remained excellent (>93.1%). Conclusions Adjusting the Sokolow–Lyon index for BMI (overweight +4u2005mm, obesity +8u2005mm) improves the diagnostic accuracy for detecting LVH. As the ECG, worldwide, remains the most widely used screening tool for LVH, implementing these findings should translate into significant clinical benefit.

The relative contribution of metabolic and structural abnormalities to diastolic dysfunction in obesity

Background:Obesity causes diastolic dysfunction, and is one of the leading causes of heart failure with preserved ejection fraction. Myocardial relaxation is determined by both active metabolic processes such as impaired energetic status and steatosis, as well as intrinsic myocardial remodelling. However, the relative contribution of each to diastolic dysfunction in obesity is currently unknown.Methods:Eighty adult subjects (48 male) with no cardiovascular risk factors across a wide range of body mass indices (18.4–53.0u2009kgu2009m−2) underwent magnetic resonance imaging for abdominal visceral fat, left ventricular geometry (LV mass:volume ratio) and diastolic function (peak diastolic strain rate), and magnetic resonance spectroscopy for PCr/ATP and myocardial triglyceride content.Results:Increasing visceral obesity was related to diastolic dysfunction (peak diastolic strain rate, r=−0.46, P=0.001). Myocardial triglyceride content (β=−0.2, P=0.008), PCr/ATP (β=−0.22, P=0.04) and LV mass:volume ratio (β=−0.61, P=0.04) all independently predicted peak diastolic strain rate (model R2 0.36, P<0.001). Moderated multiple regression confirmed the full mediating roles of PCr/ATP, myocardial triglyceride content and LV mass:volume ratio in the relationship between visceral fat and peak diastolic strain rate. Of the negative effect of visceral fat on diastolic function, 40% was explained by increased myocardial triglycerides, 39% by reduced PCr/ATP and 21% by LV concentric remodelling.Conclusions:Myocardial energetics and steatosis are more important in determining LV diastolic function than concentric hypertrophy, accounting for more of the negative effect of obesity on diastolic function than LV geometric remodelling. Targeting these metabolic processes is an attractive strategy to treat diastolic dysfunction in obesity.

The Role of Cardiovascular Magnetic Resonance Imaging in Heart Failure

Cardiovascular imaging is key for the assessment of patients with heart failure. Today, cardiovascular magnetic resonance imaging plays an established role in the assessment of patients with suspected and confirmed heart failure syndromes, in particular identifying aetiology. Its role in informing prognosis and guiding decisions around therapy are evolving. Key strengths include its accuracy; reproducibility; unrestricted field of view; lack of radiation; multiple abilities to characterise myocardial tissue, thrombus and scar; as well as unparalleled assessment of left and right ventricular volumes. T2* has an established role in the assessment and follow-up of iron overload cardiomyopathy and a role for T1 in specific therapies for cardiac amyloid and Anderson-Fabry disease is emerging.

Left Atrial Volumes in Health and Disease Measured Using Cardiac Magnetic Resonance.

> It is not the size of a man, but the size of his heart that matters. n> n> —Evander HolyfieldThe left atrium (LA) plays an important mechanical role in cardiac performance. There are 3 discrete phasic functions within the cardiac cycle: first, the LA acts as a reservoir for storing pulmonary venous return during left ventricular (LV) contraction; second, it acts as a conduit because blood is passively transferred into the LV; third, active LA contraction in LV end-diastole contributes significantly to LV filling. It is also responsible for secreting natriuretic peptides in response to stretch, thus, helping to mediate fluid and hemodynamic homeostasis.nnSee Article by Zemrak et al nnGiven these various and important functions, it is unsurprising that disturbances of LA morphology are associated with important cardiovascular comorbidities, such as stroke,1 heart failure,2 atrial fibrillation (AF),3 and even premature mortality.4 Overall, LA size has been the most widely investigated atrial characteristic and has been found to be consistently increased in association with these and other cardiovascular complications. Given the enormous and increasing combined public health impact of these diseases, there is significant clinical interest in LA imaging as a potential biomarker to not only identify individuals at increased risk (suggested by the presence of LA remodeling), but also guide potential treatments and assess the therapeutic response—that is, reverse LA remodeling.5nnThe traditional metric of LA size has been the anteroposterior LA diameter in ventricular end-systole (ie, maximal atrial dimension within the cardiac cycle), measured from a parasternal long-axis M-mode echocardiographic view. This approach has advantages, given the widespread availability of echocardiography and the ease and reproducibility of this particular measurement. However, the LA is a morphologically complex chamber, and overall volume is more accurately estimated using the biplane area–length method, which combines LA areas and lengths …

Hyperpolarised magnetic resonance for in vivo real-time metabolic imaging.

Although non-invasive perfusion and viability imaging often provide the gateway to coronary revascularisation, current non-invasive imaging methods only report the surrogate markers of inducible hypoperfusion and presence or absence of myocardial scar, rather than actually visualising areas of ischaemia and/or viable myocardium. This may lead to suboptimal revascularisation decisions. Normally respiring (viable) cardiomyocytes convert pyruvate to acetyl-CoA and CO2/bicarbonate (via pyruvate dehydrogenase), but under ischaemic conditions characteristically shift this conversion to lactate (by lactate dehydrogenase). Imaging pyruvate metabolism thus has the potential to improve upon current imaging techniques. Using the novel hyperpolarisation technique of dynamic nuclear polarisation (DNP), the magnetic resonance signal of injected [1-13C]pyruvate can be transiently magnified >10 000 times over that seen in conventional MR spectroscopy, allowing the characteristic metabolic signatures of ischaemia (lactate production) and viability (CO2/bicarbonate production) to be directly imaged. As such DNP imaging of the downstream metabolism of [1-13C]pyruvate could surpass the diagnostic capabilities of contemporary ischaemia and viability testing. Here we review the technique, and with brief reference to the salient biochemistry, discuss its potential applications within cardiology. These include ischaemia and viability testing, and further characterisation of the altered metabolism seen at different stages during the natural history of heart failure.