Myocardial Oxidative Metabolism Research Articles

Myocardial External Efficiency in Asymptomatic Severe Primary Mitral Regurgitation Using 11C-Acetate PET.

Subjects with asymptomatic moderate-to-severe or severe primary mitral regurgitation are closely observed for signs of progression or symptoms requiring surgical intervention. The role of myocardial metabolic function in progression of mitral regurgitation is poorly understood. We used 11C-acetate PET to noninvasively measure myocardial mechanical external efficiency (MEE), which is the energetic ratio of external cardiac work and left ventricular (LV) oxygen consumption. Methods: Forty-seven patients in surveillance with mitral regurgitation and no or minimal symptoms prospectively underwent PET, echocardiography, and cardiac MRI on the same day. PET was used to simultaneously measure cardiac output, LV mass, and oxygen consumption to establish MEE. PET findings were compared between patients and healthy volunteers (n = 9). MEE and standard imaging indicators of regurgitation severity, LV volumes, and function were studied as predictors of time to surgical intervention. Patients were followed a median of 3.0 y (interquartile range, 2.0-3.8 y), and the endpoint was reached in 22 subjects (47%). Results: MEE in patients reaching the endpoint (23.8% ± 5.0%) was lower than in censored patients (28.5% ± 4.5%, P = 0.002) or healthy volunteers (30.1% ± 4.9%, P = 0.001). MEE with a cutoff lower than 25.7% was significantly associated with the outcome (hazard ratio, 7.5; 95% CI, 2.7-20.6; P < 0.0001) and retained independent significance when compared with standard imaging parameters. Conclusion: MEE independently predicted time to progression requiring valve surgery in patients with asymptomatic moderate-to-severe or severe primary mitral regurgitation. The study suggests that inefficient myocardial oxidative metabolism precedes clinically observed progression in mitral regurgitation.

Characterization of myocardial oxidative metabolism and myocardial external efficiency in high-risk alcohol cardiotoxicity and alcoholic cardiomyopathy via dynamic 11C-Acetate positron emission tomography

IntroductionThe purpose of this study was to evaluate subjects with high-risk alcohol cardiotoxicity and patients with alcoholic cardiomyopathy (ACM) via dynamic 11C-Acetate positron emission tomography (PET) imaging as a myocardial oxidative metabolic probe. Methods and ResultsWe recruited 37 subjects with chronic alcohol consumption [18 with moderate consumption (MC), 19 with heavy consumption (HC)], 5 ACM patients, and 12 healthy controls to receive dynamic 11C-Acetate PET scans. PET imaging data were analyzed to calculate kinetic parameters (e.g., Kmono, K1 and k2) based on the mono-exponential and one-tissue compartmental models. Myocardial oxygen consumption (MVO2) and myocardial external efficiency (MEE) were then derived from these kinetic parameters. MVO2 was significantly lowered in the HC group and in ACM patients (0.121± 0.018 and 0.111 ± 0.017 mL·g−1·min−1, respectively) compared with those in healthy controls and MC subjects (0.144 ± 0.023 and 0.146 ± 0.027 mL·g−1·min−1, respectively; P < .01). MEE was significantly reduced in ACM patients (13.0% ± 4.3%) compared with those of healthy controls (22.4% ± 4.6%, P < .01), MC subjects (20.1% ± 4.5%, P < .05), and HC subjects (22.3% ± 4.5%, P < .001). ConclusionFunctional assessment via dynamic 11C-Acetate PET imaging may represent a clinically feasible probe for identifying cohorts with high-risk cardiotoxicity due to addictive alcohol consumption and ACM.

Evaluation of Non-infarct-Related Arteries Using C-11 Acetate PET in STEMI With Multivessel Disease.

BACKGROUNDWe analyzed whether C-11 acetate positron emission tomography (PET) can be used for the evaluation of non-infarct-related artery (NIRA) in patients with ST-elevation myocardial infarction (STEMI) and multivessel disease.METHODSWe prospectively enrolled 31 patients with STEMI and at least one NIRA stenosis (diameter stenosis [DS] ≥ 50%). C-11 acetate PET was performed after successful revascularization for the infarct-related artery (IRA). Myocardial blood flow (MBF) and oxidative metabolism (kmono) were measured and compared between NIRA vs. IRA, stenotic (DS ≥ 50%) vs. non-stenotic (DS < 50%) NIRAs, and NIRAs with significant stenosis (DS ≥ 70% or fractional flow reserve [FFR] ≤ 0.80) vs. those without (neither DS ≥ 70% nor FFR ≤ 0.80). The correlations between PET and angiographic parameters were also analyzed.RESULTSMBF and kmono were significantly higher in NIRAs than those in IRAs. Stenotic NIRAs showed significantly reduced stress MBF, myocardial flow reserve (MFR), relative flow reserve (RFR) (0.72 ± 0.12 vs. 0.82 ± 0.14; p = 0.001), and stress kmono, as compared to those in non-stenotic NIRAs. NIRAs with significant stenosis had significantly lower stress MBF, MFR, and RFR (0.70 ± 0.10 vs. 0.80 ± 0.14; p = 0.001). RFR showed the best, but modest linear correlation with DS of NIRA stenosis (r = −0.429, p = 0.001). RFR > 0.81 could effectively exclude the presence of significant NIRA stenosis.CONCLUSIONSC-11 acetate PET could be a feasible alternative noninvasive modality in patients with STEMI and multivessel disease, by excluding the presence of significant NIRA stenosis.

Autologous skeletal myoblast patch implantation prevents the deterioration of myocardial ischemia and right heart dysfunction in a pressure-overloaded right heart porcine model.

Right ventricular dysfunction is a predictor for worse outcomes in patients with congenital heart disease. Myocardial ischemia is primarily associated with right ventricular dysfunction in patients with congenital heart disease and may be a therapeutic target for right ventricular dysfunction. Previously, autologous skeletal myoblast patch therapy showed an angiogenic effect for left ventricular dysfunction through cytokine paracrine effects; however, its efficacy in right ventricular dysfunction has not been evaluated. Thus, this study aimed to evaluate the angiogenic effect of autologous skeletal myoblast patch therapy and amelioration of metabolic and functional dysfunction, in a pressure-overloaded right heart porcine model. Pulmonary artery stenosis was induced by a vascular occluder in minipigs; after two months, autologous skeletal myoblast patch implantation on the right ventricular free wall was performed (n = 6). The control minipigs underwent a sham operation (n = 6). The autologous skeletal myoblast patch therapy alleviated right ventricular dilatation and ameliorated right ventricular systolic and diastolic dysfunction. 11C-acetate kinetic analysis using positron emission tomography showed improvement in myocardial oxidative metabolism and myocardial flow reserve after cell patch implantation. On histopathology, a higher capillary density and vascular maturity with reduction of myocardial ischemia were observed after patch implantation. Furthermore, analysis of mRNA expression revealed that the angiogenic markers were upregulated, and ischemic markers were downregulated after patch implantation. Thus, autologous skeletal myoblast patch therapy ameliorated metabolic and functional dysfunction in a pressure-overloaded right heart porcine model, by alleviating myocardial ischemia through angiogenesis.

Abstract 16976: Derangements in Cardiac Oxidative Metabolism in Humans With Dilated Cardiomyopathy

Introduction: Dilated cardiomyopathy (DCM) is associated with impaired myocardial perfusion reserve and impaired myocardial oxidative metabolism. However, the association between myocardial perfusion reserve and oxidative metabolism, is not fully understood. Hypothesis: Reduced myocardial perfusion reserve is associated with reduced myocardial oxidative metabolism. Methods: Using non-invasive cardiac imaging, we studied 8 DCM patients and 14 normal subjects. Myocardial perfusion reserve index (MPRI) was calculated using cardiac magnetic resonance as the normalized rate of myocardial signal augmentation following gadolinium contrast injection between rest and regadenoson induced stress. Resting oxidative metabolism was calculated as the myocardial mono-exponential decay rate (Kmono) of [ 11 C]acetate by positron emission tomography normalized per unit demand (rate-pressure product, RPP) (Kmono/RPP). Results: MPRI was lower in DCM compared to controls (1.25 ± 0.22 vs 1.59 ± 0.49, p=0.038). Similarly, Kmono/RPP was lower in DCM compared with normal subjects (0.6x10e-3 ± 0.15 x10e-3 vs 1.2x10e-3 ± 0.9x10e-3, p&lt;0.0001). There was a linear relation between Kmono and RPP in normal subjects. However, DCM patients showed no increase in Kmono regardless of RPP (Figure 1A). Kmono/RPP was not significantly related to MPRI in either group (Figure 1B). Conclusions: Patients with DCM exhibit markedly impaired myocardial oxidative metabolism compared to normal subjects. However, this impairment was not quantitatively related to impaired myocardial perfusion reserve. Of the various mechanisms that could explain decrease in oxidative metabolism in DCM, these data suggest that reduced myocardial perfusion is not the principal driver of impaired oxidative metabolism.

Abstract 13717: Autologous Skeletal Myoblast Patch Remodeled Swine Pressure-overloaded Right Heart by Amelioration in Myocardial Ischemia

Introduction: Myocardial ischemia (MI) is majorly seen in the right ventricular (RV) dysfunction in patients with congenital heart disease secondary to residual hemodynamic stressors in form of pressure-overloaded, suggesting therapeutic target for RV dysfunction may be how to control MI. Autologous skeletal myoblast patch showed the angiogenetic effect for left ventricular dysfunction by cytokine paracrine effects, which are expected to be sufficiently effective against pressure-overloaded RV dysfunction. Hypothesis: An autologous skeletal myoblast patch alleviates the MI in a pressure-overloaded right heart in swine model, leading to amelioration of metabolic and functional dysfunction. Methods: Five-month-old mini-pigs underwent pulmonary artery banding. Two months after banding, myoblast patch derived from autologous skeletal muscles were placed on the epicardium of RV free wall. Groups were as follows: control (C, n=6), sheet implantation (S, n=6). Two months after sheet implantation, cardiac function exam and C11-Acetate positron emission tomography (PET) were done, and hearts were dissected for histologic and real-time polymerase chain reaction (RT-PCR) analysis. Results: Two months after sheet implantation, RV dysfunction was significantly ameliorated in group S than group C (RVEF; S 44.9+/-2.2 vs C 31.9+/-2.1 % [p=0.0042]). PET revealed the deterioration of myocardial blood flow (Rest/Stress; S 3.22+/-0.39 vs C 2.13+/-0.92 min -1 [p=0.0421]) and myocardial oxidative metabolism (K mono -Rest/Stress: S 3.17+/-0.69 vs C 2.03+/-0.65 min -1 [p=0.0421]) were suppressed in group S than group C. In histologic analysis, group S presented more angiogenesis in CD31 expression (S 18.3+/-1.5 vs C 10.7+/-2.8 units/cells [p=0.0122]). In RT-PCR analysis, mRNA expression of vascular endothelial growth factor (S 1.28+/-0.35 vs C 0.75+/-0.17 folds [p=0.030]), hepatocyte growth factor (S 1.70+/-0.79 vs C 0.74+/-0.10 folds [p=0.030]), and chemokine stromal cell-derived factor-1 (S 1.49+/-0.97 vs C 0.35+/-0.20 folds [p=0.030]) were upregulated in group S than group C. Conclusions: Autologous skeletal myoblast patch ameliorated metabolic and functional dysfunction in a swine model of pressure-overloaded right heart by alleviation of MI.

Targeted Deletion of Interleukin-6 in a Mouse Model of Chronic Inflammation Demonstrates Opposing Roles in Aging: Benefit and Harm.

Chronic inflammation (CI) in older adults is associated with reduced health span and life span. Interleukin-6 (IL-6) is one CI marker that is strongly associated with adverse health outcomes and mortality in aging. We have previously characterized a mouse model of frailty and chronic inflammatory pathway activation (IL-10tm/tm, IL-10 KO) that demonstrates the upregulation of numerous proinflammatory cytokines, including IL-6. We sought to identify a more specific role for IL-6 within the context of CI and aging and developed a mouse with targeted deletion of both IL-10 and IL-6 (IL-10tm/tm/IL-6tm/tm, DKO). Phenotypic characteristics, cytokine measurements, cardiac myocardial oxygen consumption, physical function, and survival were measured in DKO mice and compared to age- and gender-matched IL-10 KO and wild-type mice. Our findings demonstrate that selective knockdown of IL-6 in a frail mouse with CI resulted in the reversal of some of the CI-associated changes. We observed increased protective mitochondrial-associated lipid metabolites, decreased cardiac oxaloacetic acid, improved myocardial oxidative metabolism, and better short-term functional performance in DKO mice. However, the DKO mice also demonstrated higher mortality. This work shows the pleiotropic effects of IL-6 on aging and frailty.

FOXO1 contributes to diabetic cardiomyopathy via inducing imbalanced oxidative metabolism in type 1 diabetes.

Forkhead box protein O1 (FOXO1), a nuclear transcription factor, is preferably activated in the myocardium of diabetic mice. However, its role and mechanism in the development of diabetic cardiomyopathy in non‐obese insulin‐deficient diabetes are unclear. We hypothesized that cardiac FOXO1 over‐activation was attributable to the imbalanced myocardial oxidative metabolism and mitochondrial and cardiac dysfunction in type 1 diabetes. FOXO1‐selective inhibitor AS1842856 was administered to streptozotocin‐induced diabetic (D) rats, and cardiac functions, mitochondrial enzymes PDK4 and CPT1 and mitochondrial function were assessed. Primary cardiomyocytes isolated from non‐diabetic control (C) and D rats were treated with or without 1 µM AS1842856 and underwent Seahorse experiment to determine the effects of glucose, palmitate and pyruvate on cardiomyocyte bioenergetics. The results showed diabetic hearts displayed elevated FOXO1 nuclear translocation, concomitant with cardiac and mitochondrial dysfunction (manifested as elevated mtROS level and reduced mitochondrial membrane potential) and increased cell apoptosis (all P < .05, D vs C). Diabetic myocardium showed impaired glycolysis, glucose oxidation and elevated fatty acid oxidation and enhanced PDK4 and CPT1 expression. AS1842856 attenuated or prevented all these changes except for glycolysis. We concluded that FOXO1 activation, through stimulating PDK4 and CPT1, shifts substrate selection from glucose to fatty acid and causes mitochondrial and cardiac dysfunction.

Myocardial tissue and metabolism characterization in men with alcohol consumption by cardiovascular magnetic resonance and 11C-acetate PET/CT

BackgroundChronic alcohol consumption initially leads to asymptomatic left ventricular dysfunction, but can result in myocardial impairment and heart failure if ongoing. This study sought to characterize myocardial tissues and oxidative metabolism in asymptomatic subjects with chronic alcohol consumption by quantitative cardiovascular magnetic resonance (CMR) and 11C-acetate positron emission tomography (PET)/computed tomography (CT).MethodsThirty-four male subjects (48.8 ± 9.1 years) with alcohol consumption > 28 g/day for > 10 years and 35 age-matched healthy male subjects (49.5 ± 9.7 years) underwent CMR and 11C-acetate PET/CT. Native and post T1 values and extracellular volume (ECV) from CMR and Kmono and K1 from PET imaging were measured. Quantitative measurements by CMR and PET imaging were compared between subjects with moderate to heavy alcohol consumption and healthy controls, and their correlations were also analyzed.ResultsCompared to healthy controls, subjects with alcohol consumption showed significantly shorter native T1 (1133 ± 65 ms vs. 1186 ± 31 ms, p < 0.001) and post T1 (477 ± 42 ms vs. 501 ± 38 ms, p = 0.008) values, greater ECV (28.2 ± 2.2% vs. 26.9 ± 1.3%, p = 0.003), marginally lower Kmono (57.6 ± 12.1 min− 1 × 10− 3 vs. 63.0 ± 11.7 min− 1 × 10− 3, p = 0.055), and similar K1 (0.82 ± 0.13 min− 1 vs. 0.83 ± 0.15 min− 1, p = 0.548) after adjusting for confounding factors. There were no significant differences in CMR measurements and K1 between subjects with heavy and moderate alcohol consumption (all p > 0.05). In contrast, subjects with heavy alcohol consumption showed significantly lower Kmono values compared to those with moderate alcohol consumption (52.9 ± 12.1 min− 1 × 10− 3 vs. 63.7 ± 9.2 min− 1 × 10− 3, p = 0.012). Strong and moderate correlations were found between K1 and ECV in healthy controls (r = 0.689, p = 0.013) and subjects with moderate alcohol consumption (r = 0.518, p = 0.048), respectively.ConclusionAsymptomatic men with heavy alcohol consumption have detectable structural and metabolic changes in myocardium on CMR and 11C-acetate PET/CT. Compared with quantitative CMR, 11C-acetate PET/CT imaging may be more sensitive for detecting differences in myocardial damage among subjects with moderate to heavy alcohol consumption.

P3361Pathophysiology measured with positron emission tomography is equally impaired in hypertrophic and non-hypertrophic regions in hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease with regard to clinical manifestations. It is characterized by an asymmetric pattern of hypertrophy of the left ventricle. However, less is known about pathophysiological distribution of the abnormalities. Positron emission tomography (PET) provides quantitative assessment of myocardial blood flow (MBF), oxidative metabolism, and sympathetic innervation using the following tracers: 15O-water, 11C-acetate, and 11C-HED. Purpose The purpose of the present study was to investigate if physiological parameters measured with PET are more impaired in hypertrophic regions compared to non-hypertrophic regions. Methods We examined 25 HCM patients using a Discovery MI PET/CT with 15O-water, 11C-acetate, and 11C-HED. Wall thickness (WT) was calculated from the 11C-acetate scan for basal and mid segments (n=12) in the 17-segment model and hypertrophic regions were defined as segments &gt;15 mm. 15O-water PET was performed during rest and adenosine induced stress. Quantification of MBF, oxygen consumption (MVO2) and retention index of 11C-HED (RIHED) was done in aQuant software. Comparison of parameters in hypertrophic regions to non-hypertrophic regions was done using Mann-Whitney U- test and Bland-Altman analysis with repeatability coefficient defined as 2 times the standard-deviation of differences. Results One patient had all segments &gt;15mm and one patient had all segments &lt;15mm and were therefore excluded from analysis. WT was 18.2±1.9 mm in hypertrophic regions and 12.2±1.5 mm in non-hypertrophic regions. None of the PET-parameters showed a significant difference between hypertrophic and non-hypertrophic regions, see table 1. Table 1 MBFREST MBFSTRESS MVO2 RIHED Hypertrophic segments (mm) 0.70±0.20 1.74±0.92 0.092±0.026 0.12±0.037 Non-hypertrophic segments (mm) 0.68±0.18 1.71±0.87 0.094±0.025 0.12±0.036 p-value 0.767 0.851 0.956 0.684 Repeatability coefficient (%) 25.4 35.4 13.3 16.2 Mean ± standard deviation for PET-parameters in hypertrophic and non-hypertrophic segments. Relative repeatability coefficient (%) between regions and p-value for Mann-Whitney U-test. Conclusion Pathophysiology in terms of myocardial blood flow at rest and stress, oxygen consumption and sympathetic innervation are not significantly different in hypertrophic segments compared to non-hypertrophic segments in patients with HCM. Thus, the disease is not confined to hypertrophied areas but spread throughout the left ventricle. Acknowledgement/Funding Selanders stiftelse, Regionala forskningsrådet

Metabolic Alterations in Myocardial Metabolism during Ex Situ Heart Perfusion

Purpose Ex situ heart perfusion (ESHP) is a novel method for preservation of the donated heart in a semi-physiologic state and provides the opportunity to evaluate pre-transplant function. Because of the well-described extraordinary metabolic requirements of the heart, efficient metabolic support is critical for optimal preservation of function and viability. Our aim was to determine changes in energy metabolism/energy substrates during extended ex situ perfusion of hearts in two different perfusion modes, working mode (WM) and non-working mode (NWM). Methods 17 female domestic breed pigs (37-47 kg) were included. Hearts were perfused on a custom ESHP apparatus (12 hours, NWM n=6 and WM n=7) with insulin and glucose infusions for metabolic support. Cardiac function, and changes in myocardial oxidative metabolism, glucose utilization, lactate, free fatty acids (FFA) and triglycerides (TG) were evaluated during ESHP. The enzymatic activity of pyruvate kinase was assessed using immunoassay techniques. The results were compared with baseline values (in vivo, n=4). Results Cardiac function declined over time but it was better preserved in WM (cardiac index change, p=0.02). Glucose utilization increased overtime in both groups (WM p=0.04, NWM p=0.04). Venous and arteriovenous lactate did not change over time and were not different between WM and NWM. FFA concentrations declined considerably during ESHP in both groups (WM p Conclusion Our data suggests functional decline during ESHP has a metabolic basis and is therefore reversible. Furthermore, a strategy of insulin and glucose appears insufficient for maintenance of metabolic integrity during ESHP and there is decoupling of glycolysis and the TCA cycle at the level of pyruvate kinase. Further research is required to determine the causative factors underpinning these alterations and optimal methods to abrogate their effects to ensure optimal preservation of contractile function during ESHP.

Myocardial Infarction With Nonobstructive Coronary Arteries Assessed by 11C-Acetate Cardiac PET

C-acetate PET can quantify myocardial blood flow and oxidative metabolism (kmono) with a single imaging study. We present a 63-year-old man with myocardial infarction with nonobstructive coronary arteries due to vasospasm, who underwent C-acetate PET after antispastic medication. By quantifying myocardial blood flow and kmono, C-acetate PET could detect the initial ischemic insult by vasospasm and sufficient amount of remaining viable myocardium, while excluding significant inducible ischemia. We suggest that C-acetate PET can be a clinically valuable tool for assessing the pathophysiology of myocardial infarction with nonobstructive coronary arteries.

Test–retest repeatability of myocardial oxidative metabolism and efficiency using standalone dynamic 11C-acetate PET and multimodality approaches in healthy controls

BackgroundMyocardial efficiency measured by 11C-acetate positron emission tomography (PET) has successfully been used in clinical research to quantify mechanoenergetic coupling. The objective of this study was to establish the repeatability of myocardial external efficiency (MEE) and work metabolic index (WMI) by non-invasive concepts. Methods and ResultsTen healthy volunteers (63 ± 4 years) were examined twice, one week apart, using 11C-acetate PET, cardiovascular magnetic resonance (CMR), and echocardiography. Myocardial oxygen consumption from PET was combined with stroke work data from CMR, echocardiography, or PET to obtain MEE and WMI for each modality. Repeatability was estimated as the coefficient of variation (CV) between test and retest. MEECMR, MEEEcho, and MEEPET values were 21.9 ± 2.7%, 16.4 ± 3.7%, and 23.8 ± 4.9%, respectively, P < .001. WMICMR, WMIEcho, and WMIPET values were 4.42 ± 0.90, 4.07 ± 0.63, and 4.58 ± 1.13 mmHg × mL/m2 × 106, respectively, P = .45. Repeatability for MEECMR was superior compared with MEEEcho but did not differ significantly compared with MEEPET (6.3% vs 12.9% and 9.4%, P = .04 and .25). CV values for WMICMR, WMIEcho, and WMIPET were 10.0%, 14.8%, and 12.0%, respectively, (P = .53). ConclusionsNon-invasive measurements of MEE using 11C-acetate PET are highly repeatable. A PET-only approach did not differ significantly from CMR/PET and might facilitate further clinical research due to lower costs and broader applicability.

Repeatable and reproducible measurements of myocardial oxidative metabolism, blood flow and external efficiency using 11C-acetate PET

BackgroundNon-invasive approaches to investigate myocardial efficiency can help track the progression of heart failure (HF). This study evaluates the repeatability and reproducibility of 11C-acetate positron emission tomography (PET) imaging of oxidative metabolism. Methods and resultsDynamic 11C-acetate PET scans were performed at baseline and followup (47 ± 22 days apart) in 20 patients with stable HF with reduced ejection fraction. Two observers blinded to patients’ clinical data used FlowQuant® to evaluate test–retest repeatability, as well as intra- and inter-observer reproducibility of 11C-acetate tracer uptake and clearance rates, for the measurement of myocardial oxygen consumption (MVO2), myocardial external efficiency (MEE), work metabolic index (WMI), and myocardial blood flow. Reproducibility and repeatability were evaluated using intra-class-correlation (ICC) and Bland–Altman coefficient-of-repeatability (CR). Test–retest correlations and repeatability were better for MEE and WMI compared to MVO2. All intra- and inter-observer correlations were excellent (ICC = 0.95-0.99) and the reproducibility values (CR = 3%-6%) were significantly lower than the test–retest repeatability values (22%-54%, P < 0.001). Repeatability was improved for all parameters using a newer PET–computed tomography (CT) scanner compared to older PET-only instrumentation. Conclusion11C-acetate PET measurements of WMI and MEE exhibited excellent test–retest repeatability and operator reproducibility. Newer PET–CT scanners may be preferred for longitudinal tracking of cardiac efficiency.

Human Cardiac 31P-MR Spectroscopy at 3 Tesla Cannot Detect Failing Myocardial Energy Homeostasis during Exercise.

Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) is a unique non-invasive imaging modality for probing in vivo high-energy phosphate metabolism in the human heart. We investigated whether current 31P-MRS methodology would allow for clinical applications to detect exercise-induced changes in (patho-)physiological myocardial energy metabolism. Hereto, measurement variability and repeatability of three commonly used localized 31P-MRS methods [3D image-selected in vivo spectroscopy (ISIS) and 1D ISIS with 1D chemical shift imaging (CSI) oriented either perpendicular or parallel to the surface coil] to quantify the myocardial phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio in healthy humans (n = 8) at rest were determined on a clinical 3 Tesla MR system. Numerical simulations of myocardial energy homeostasis in response to increased cardiac work rates were performed using a biophysical model of myocardial oxidative metabolism. Hypertrophic cardiomyopathy was modeled by either inefficient sarcomere ATP utilization or decreased mitochondrial ATP synthesis. The effect of creatine depletion on myocardial energy homeostasis was explored for both conditions. The mean in vivo myocardial PCr/ATP ratio measured with 3D ISIS was 1.57 ± 0.17 with a large repeatability coefficient of 40.4%. For 1D CSI in a 1D ISIS-selected slice perpendicular to the surface coil, the PCr/ATP ratio was 2.78 ± 0.50 (repeatability 42.5%). With 1D CSI in a 1D ISIS-selected slice parallel to the surface coil, the PCr/ATP ratio was 1.70 ± 0.56 (repeatability 43.7%). The model predicted a PCr/ATP ratio reduction of only 10% at the maximal cardiac work rate in normal myocardium. Hypertrophic cardiomyopathy led to lower PCr/ATP ratios for high cardiac work rates, which was exacerbated by creatine depletion. Simulations illustrated that when conducting cardiac 31P-MRS exercise stress testing with large measurement error margins, results obtained under pathophysiologic conditions may still lie well within the 95% confidence interval of normal myocardial PCr/ATP dynamics. Current measurement precision of localized 31P-MRS for quantification of the myocardial PCr/ATP ratio precludes the detection of the changes predicted by computational modeling. This hampers clinical employment of 31P-MRS for diagnostic testing and risk stratification, and warrants developments in cardiac 31P-MRS exercise stress testing methodology.

Effects of exenatide on cardiac function, perfusion, and energetics in type 2 diabetic patients with cardiomyopathy: a randomized controlled trial against insulin glargine

BackgroundMultiple bloodglucose-lowering agents have been linked to cardiovascular events. Preliminary studies showed improvement in left ventricular (LV) function during glucagon-like peptide-1 receptor agonist administration. Underlying mechanisms, however, are unclear. The purpose of this study was to investigate myocardial perfusion and oxidative metabolism in type 2 diabetic (T2DM) patients with LV systolic dysfunction as compared to healthy controls. Furthermore, effects of 26-weeks of exenatide versus insulin glargine administration on cardiac function, perfusion and oxidative metabolism in T2DM patients with LV dysfunction were explored.Methods and resultsTwenty-six T2DM patients with LV systolic dysfunction (cardiac magnetic resonance (CMR) derived LV ejection fraction (LVEF) of 47 ± 13%) and 10 controls (LVEF of 59 ± 4%, P < 0.01 as compared to patients) were analyzed. Both myocardial perfusion during adenosine-induced hyperemia (P < 0.01), and coronary flow reserve (P < 0.01), measured by [15O]H2O positron emission tomography (PET), were impaired in T2DM patients as compared to healthy controls. Myocardial oxygen consumption and myocardial efficiency, measured using [11C]acetate PET and CMR derived stroke volume, were not different between the groups. Eleven patients in the exenatide group and 12 patients in the insulin glargine group completed the trial. Systemic metabolic control was improved after both treatments, although, no changes in cardiac function, perfusion and metabolism were seen after exenatide or insulin glargine.ConclusionsT2DM patients with LV systolic dysfunction did not have altered myocardial efficiency as compared to healthy controls. Exenatide or insulin glargine had no effects on cardiac function, perfusion or oxidative metabolism.Trial registration NCT00766857

Left ventricular hypertrophy does not prevent heart failure in experimental hypertension

BackgroundLeft ventricular hypertrophy (LVH) secondary to hypertension has been accepted to prevent heart failure (HF) while paradoxically increasing cardiovascular morbi-mortality. ObjectivesTo evaluate whether antihypertensive treatment inhibits LVH, restores beta-adrenergic response and affects myocardial oxidative metabolism. MethodsNinety spontaneously hypertensive rats (SHR) were distributed into groups and treated (mg/kg, p.o.) with: losartan 30 (L), hydralazine 11 (H), rosuvastatin 10 (R), carvedilol 20 (C). Hypertension control group comprised 18 normotensive rats (Wistar-Kyoto, WKY). Following euthanasia at 16months, contractility was measured in 50% of rats (Langendorff system) before and after isoproterenol (Iso) 10−9M, 10−7M and 10−5M stimulation. Left ventricular weight (LVW) was measured in the remaining hearts, and normalized by BW. Expression of thioredoxin 1 (Trx-1), peroxyredoxin 2 (Prx-2), glutaredoxin 3 (Grx-3), caspase-3 and brain natriuretic peptide (BNP) was determined. ResultsSystolic blood pressure (mmHg): 154±3 (L), 137±1 (H), 190±3 (R)*, 206±3 (SHR)*, 183±1 (C)**, and 141±1 (WKY) (*p<0.05 vs. L, H, WKY, **p<0.05 vs. L, H, WKY, SHR). LVW/BW was higher in SHR and R (p<0.05). Groups SHR, R and C evidenced baseline contractile depression. Response to Iso 10−5M was similar in WKY and L. Expression of Trx-1, Prx-2 and Grx-3 increased in C, H, R and L (p<0.01). ConclusionsPresent findings argue against the traditional idea and support that LVH might not be required to prevent HF. Increased expression of thioredoxins by antihypertensive treatment might be involved in protection from HF.

A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate.

Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac energy substrate usage during sunitinib treatment, hypothesising that these changes could represent a strategy for the early detection of cardiotoxicity. Balb/CJ mice or Sprague-Dawley rats were treated orally for 4 weeks with 40 or 20 mg/kg/day sunitinib. Cardiac positron emission tomography (PET) was implemented to investigate alterations in myocardial glucose and oxidative metabolism. Following treatment, blood pressure increased, and left ventricular ejection fraction decreased. Cardiac [18F]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [11C]Acetate-PET showed decreased myocardial perfusion following treatment. Electron microscopy revealed significant lipid accumulation in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top myocardial signalling pathways perturbed. Sunitinib treatment results in an increased reliance on glycolysis, increased myocardial lipid deposition and perturbed mitochondrial function, indicative of a fundamental energy crisis resulting in compromised myocardial energy metabolism and function. Our findings suggest that a cardiac PET strategy may represent a rational approach to non-invasively monitor metabolic pathway remodeling following sunitinib treatment.

Left ventricular metabolism, function, and sympathetic innervation in men and women with type 1 diabetes

BackgroundIn type I diabetes (T1DM), alterations in LV function may occur due to changes in innervation, metabolism, and efficiency. ObjectivesWe evaluated the association between sympathetic nerve function, oxidative metabolism, resting blood flow, LV efficiency and function in healthy diabetics, and assessed gender differences. MethodsCross-sectional study of 45 subjects with T1DM, 60% females, age 34 ± 13 years, and 10 age-matched controls. Positron emission tomography (PET) imaging with [11C]acetate and [11C]meta-hydroxyephedrine was performed, in addition to cardiac magnetic resonance imaging. ResultsThere were no significant differences in LV function, innervation, or oxidative metabolism between T1DM and controls. Cardiac oxidative metabolism was positively associated with higher levels of sympathetic activation, particularly in women. Diabetic women had significantly lower efficiency compared with diabetic men. Resting flow was significantly higher in diabetic women compared with diabetic men, and tended to be higher in female controls as well. ConclusionsMeasures of myocardial function, metabolism, blood flow, and sympathetic activation were preserved in young, otherwise healthy, T1DM patients. However, T1DM women presented with greater myocardial oxidative metabolism requirements than men. Ongoing studies are evaluating changes over time.

Effect of levosimendan therapy on myocardial infarct size and left ventricular function after acute coronary occlusion

BackgroundLevosimendan is an inotropic agent with cardioprotective and vasodilating properties used for the management of acutely decompensated heart failure. We studied the effects of levosimendan treatment on the size of...