Although diabetic cardiomyopathy is widely recognized, there are no specific treatments available. Altered myocardial substrate selection has emerged as a candidate mechanism behind the development of cardiac dysfunction in diabetes. As pyruvate dehydrogenase (PDH) activity appears central to the balance of substrate use, we aimed to investigate the relationship between PDH flux and myocardial function in a rodent model of type 2 diabetes and to explore whether or not increasing PDH flux, with dichloroacetate, would restore the balance of substrate use and improve cardiac function. All animals underwent in vivo hyperpolarized [1][2][3][4][5][6][7][8][9][10][11][12][13] C]pyruvate magnetic resonance spectroscopy and echocardiography to assess cardiac PDH flux and function, respectively. Diabetic animals showed significantly higher blood glucose levels (10.8 6 0.7 vs. 8.4 6 0.5 mmol/L), lower PDH flux (0.005 6 0.001 vs. 0.017 6 0.002 s -1 ), and significantly impaired diastolic function (transmitral early diastolic peak velocity/early diastolic myocardial velocity ratio [E/E9] 12.2 6 0.8 vs. 20 6 2), which are in keeping with early diabetic cardiomyopathy. Twenty-eight days of treatment with dichloroacetate restored PDH flux to normal levels (0.018 6 0.002 s -1 ), reversed diastolic dysfunction (E/E9 14 6 1), and normalized blood glucose levels (7.5 6 0.7 mmol/L). The treatment of diabetes with dichloroacetate therefore restored the balance of myocardial substrate selection, reversed diastolic dysfunction, and normalized blood glucose levels. This suggests that PDH modulation could be a novel therapy for the treatment and/or prevention of diabetic cardiomyopathy.It is now firmly established that type 2 diabetes contributes to an increased risk for the development of heart failure (1). Although some of this risk can be attributed to increased coronary artery disease and hypertension, it is becoming clear that patients with type 2 diabetes are also at risk for the development of "diabetic cardiomyopathy" (2-5), which manifests across a spectrum from subclinical left ventricular (LV) diastolic dysfunction (i.e., transmitral early diastolic peak velocity/early diastolic myocardial velocity ratio [E/E9]) to overt systolic failure (6). As the incidence of type 2 diabetes is rapidly increasing, understanding the pathophysiology behind diabetic cardiomyopathy and developing new treatment strategies is of increasing clinical importance.Cardiac metabolism and altered substrate use are now emerging as candidate mechanisms underpinning diabetic cardiomyopathy and, as such, are targets for novel treatments (7,8). The cardiac metabolic changes in type 2 diabetes are linked to an increase in circulating fatty acid levels that results from insulin insensitivity and a failure to suppress adipose tissue hormone-sensitive lipase (9). This increase in fatty acid availability, and consequently increased cardiac usage, is thought to result in a loss of efficiency between substrate use and ATP production in the diabetic heart (10). Chan...

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BackgroundMyocardial T1 relaxation times have been reported to be markedly abnormal in diverse myocardial pathologies, ascribed to interstitial changes, evaluated by T1 mapping and calculation of extracellular volume (ECV). T1 mapping is sensitive to myocardial water content of both intra- and extracellular in origin, but the effect of intravascular compartment changes on T1 has been largely neglected. We aimed to assess the role of intravascular compartment on native (pre-contrast) T1 values by studying the effect of adenosine-induced vasodilatation in patients with severe aortic stenosis (AS) before and after aortic valve replacement (AVR).Methods42 subjects (26 patients with severe AS without obstructive coronary artery disease and 16 controls) underwent cardiovascular magnetic resonance at 3 T for native T1-mapping (ShMOLLI), first-pass perfusion (myocardial perfusion reserve index-MPRI) at rest and during adenosine stress, and late gadolinium enhancement (LGE).ResultsAS patients had increased resting myocardial T1 (1196 ± 47 ms vs. 1168 ± 27 ms, p = 0.037), reduced MPRI (0.92 ± 0.31 vs. 1.74 ± 0.32, p < 0.001), and increased left ventricular mass index (LVMI) and LGE volume compared to controls. During adenosine stress, T1 in AS was similar to controls (1240 ± 51 ms vs. 1238 ± 54 ms, p = 0.88), possibly reflecting a similar level of maximal coronary vasodilatation in both groups. Conversely, the T1 response to stress was blunted in AS (ΔT1 3.7 ± 2.7% vs. 6.0 ± 4.2% in controls, p = 0.013). Seven months after AVR (n = 16) myocardial T1 and response to adenosine stress recovered towards normal. Native T1 values correlated with reduced MPRI, aortic valve area, and increased LVMI.ConclusionsOur study suggests that native myocardial T1 values are not only influenced by interstitial and intracellular water changes, but also by changes in the intravascular compartment. Performing T1 mapping during or soon after vasodilator stress may affect ECV measurements given that hyperemia alone appears to substantially alter T1 values.

The 7T provides a new tool to explore aortic 4D flow, yielding higher SNR that can be used to push the boundaries of acceleration and resolution. Field strength and contrast enhancement at all fields provide significant improvements in SNR.

ObjectivesThe aim of this study was to determine if hyperpolarized [1,4–13C2]malate imaging could measure cardiomyocyte necrosis after myocardial infarction (MI).BackgroundMI is defined by an acute burst of cellular necrosis and the subsequent cascade of structural and functional adaptations. Quantifying necrosis in the clinic after MI remains challenging. Magnetic resonance-based detection of the conversion of hyperpolarized [1,4–13C2]fumarate to [1,4–13C2]malate, enabled by disrupted cell membrane integrity, has measured cellular necrosis in vivo in other tissue types. Our aim was to determine whether hyperpolarized [1,4–13C2]malate imaging could measure necrosis after MI.MethodsIsolated perfused hearts were given hyperpolarized [1,4–13C2]fumarate at baseline, immediately after 20 min of ischemia, and after 45 min of reperfusion. Magnetic resonance spectroscopy measured conversion into [1,4–13C2]malate. Left ventricular function and energetics were monitored throughout the protocol, buffer samples were collected and hearts were preserved for further analyses. For in vivo studies, magnetic resonance spectroscopy and a novel spatial-spectral magnetic resonance imaging sequence were implemented to assess cardiomyocyte necrosis in rats, 1 day and 1 week after cryo-induced MI.ResultsIn isolated hearts, [1,4–13C2]malate production became apparent after 45 min of reperfusion, and increased 2.7-fold compared with baseline. Expression of dicarboxylic acid transporter genes were negligible in healthy and reperfused hearts, and lactate dehydrogenase release and infarct size were significantly increased in reperfused hearts. Nonlinear regression revealed that [1,4–13C2]malate production was induced when adenosine triphosphate was depleted by >50%, below 5.3 mmol/l (R2 = 0.904). In vivo, the quantity of [1,4–13C2]malate visible increased 82-fold over controls 1 day after infarction, maintaining a 31-fold increase 7 days post-infarct. [1,4–13C2]Malate could be resolved using hyperpolarized magnetic resonance imaging in the infarct region one day after MI; [1,4–13C2]malate was not visible in control hearts.ConclusionsMalate production in the infarcted heart appears to provide a specific probe of necrosis acutely after MI, and for at least 1 week afterward. This technique could offer an alternative noninvasive method to measure cellular necrosis in heart disease, and warrants further investigation in patients.

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Metformin improves cardiovascular outcomes in type 2 diabetes, but its exact mechanisms of action remain controversial. We used hyperpolarized [1-C]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-C]lactate:[1-C]pyruvate ratio but had no effect on the [1-C]bicarbonate + CO:[1-C]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.

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