Myocardial High-energy Phosphate Metabolism Research Articles

Abstract 13305: Energetic Basis of Recovered Ejection Fraction in Human Heart Failure

Introduction: Left ventricular ejection fraction (LVEF) improvement in HFrEF patients is classified as heart failure with improved ejection fraction (HFimpEF) and is associated with better long-term outcomes than persistent HFrEF. HFimpEF is difficult to predict and underlying mechanisms remain poorly understood. Hypothesis: Better myocardial high-energy phosphate metabolism at baseline predicts future LVEF recovery and outcomes in a general HFrEF population Methods: We measured cardiac energetics, the ratio of the two main high-energy phosphates, phosphocreatine and ATP (PCr/ATP), and the rate of ATP synthesis through the primary cardiac energy reserve reaction creatine kinase (“CK flux”), in 37 nonischemic HFrEF patients (LVEF ≤40%) with 31 P cardiac magnetic resonance spectroscopy (MRS) at 3T. Baseline transthoracic echocardiogram (TTE) was obtained prior to 31 P MRS and follow-up consecutive TTEs with the two highest LVEFs meeting HFimpEF criteria (LVEF >40% and ≥10% increase over baseline LVEF) over a median follow-up of 6.9 years were averaged and used to classify HFimpEF. Results: There were no significant differences in demographics, HF etiology, baseline TTE metrics, or medications between persistent HFrEF (n=22) and eventual HFimpEF (n=15). Cardiac CK flux was significantly higher at baseline in patients who later recovered to HFimpEF than in those who remained HFrEF (p=0.031). Better baseline cardiac CK flux was associated with increases in LVEF (p=0.025) and decreases in LV end-diastolic diameter (p=0.016) over time. By both dichotomous and continuous metrics, better preserved CK flux was associated with future HFimpEF. Fourteen subjects (38%), all persistent HFrEF, experienced cardiac death, transplant, or LVAD and had significantly lower baseline CK flux than outcome-free patients (p=0.017). Cardiac PCr/ATP was not associated with eventual HFimpEF, outcomes, or changes in TTE indices. Conclusion: Better preserved cardiac CK flux is associated with future LVEF recovery and LV reverse remodeling while lower CK flux is associated with worse cardiac outcomes in HFrEF patients. Interventions restoring CK flux, and possibly other energy-generating metabolic reactions, may elicit myocardial recovery in HFrEF patients.

Effects of weight loss on myocardial energetics and diastolic function in obesity.

A reduced myocardial phosphocreatine/adenosine triphosphate (PCr/ATP) ratio is linked to both diastolic dysfunction and heart failure. Although obesity is well known to cause diastolic dysfunction a link to impaired cardiac energetics has only recently been established. We assessed whether or not long-term weight loss in obesity, which is known to reduce mortality, is accompanied by both improved cardiac energetics and diastolic function. Normal weight (BMI 22 ± 2; n = 18) and obese subjects (BMI 34 ± 4; n = 13) underwent cine-MRI (1.5 Tesla) to determine left ventricular diastolic function using volume-time curve analysis, and (31)P-MR spectroscopy (3 Tesla) to assess cardiac energetics (PCr/ATP ratio). Obese subjects (n = 13) underwent repeat assessment after 1 year of supervised weight loss. Obesity, in the absence of identifiable cardiovascular risk factors, was associated with significantly impaired myocardial high energy phosphate metabolism (PCr/ATP ratio, normal; 2.03 ± 0.27 vs. obese; 1.58 ± 0.47, p = 0.002) and significantly lower peak diastolic filling rate (normal; 4.8 ± 0.8 vs. obese; 3.8 ± 0.7 EDV/s, p = 0.01). Weight loss (on average 9 kg, 55% excess weight) over 1 year resulted in a 24% increase in PCr/ATP ratio (p = 0.01) and an 18% improvement in peak diastolic filling rate (p = 0.01). Myocardial PCr/ATP ratio remained positively correlated with peak diastolic filling rate after weight loss (r = 0.63, p = 0.02). In obesity, weight loss improves impaired cardiac energetics and myocardial relaxation. Improved myocardial energetics appear to play a key role in diastolic functional recovery accompanying weight loss.

Correlation of cardiovascular risk scores with myocardial high-energy phosphate metabolism

The aim of our current work was to prove the association of myocardial high-energy phosphate metabolism measured by MR spectroscopy with validated cardiovascular risk scores, such as the European Systematic COronary Risk Evaluation (SCORE) Project [1], the German PROspective CArdiovascular Munster (PROCAM) Study [2] and the US Framingham Heart and Offspring Studies [3]. We used the ratio of phosphocreatinine (PCr) to β-adenosine-triphosphate (β-ATP) as a surrogate for the energy metabolism of the myocardium [4,5]. PCr-β-ATP ratios are reduced in patients with coronary heart disease [4,5], hypertension [6], and our previous studies suggested cardiovascular risk factors such as hypercholesterolemia [7], diabetes [8] or age [9] to be involved in this process. Therefore we hypothesized a relationship between established primary-event risk scores [1–3] and myocardial high-energy phosphate metabolism. Fasting blood samples of ninety-nine healthy asymptomatic volunteers without history of coronary heart disease were obtained to evaluate cardiovascular risk factors. All of the volunteers underwent cycle ergometry and echocardiography to exclude a latent coronary insufficiency and/or a reduced left ventricular function. Tabulated cardiovascular risk factors and parameters are shown in Table 1. For each patient the cardiovascular risk was assessed by:

Different effects of rosuvastatin and simvastatin on myocardial high-energy phosphate metabolism

In the last decade a variety of non-lipid lowering effects of statins has been described. The aim of the study was to compare the effects of a lipophilic and a hydrophilic statin on human myocardial high-energy phosphate (HEP) metabolism measured with 31-phosphorus-magnetic resonance spectroscopy (MRS). 21 male patients with moderate to severe hypercholesterolemia were included. Patients were divided into 2 groups in a blinded fashion: group 1 received 10mg rosuvastatin, group 2 was put on 40mg simvastatin.

Reduced in vivo high-energy phosphates precede Adriamycin-induced cardiac dysfunction

Adriamycin (ADR) is an established, life-saving antineoplastic agent, the use of which is often limited by cardiotoxicity. ADR-induced cardiomyopathy is often accompanied by depressed myocardial high-energy phosphate (HEP) metabolism. Impaired HEP metabolism has been suggested as a potential mechanism of ADR cardiomyopathy, in which case the bioenergetic decline should precede left ventricular (LV) dysfunction. We tested the hypothesis that murine cardiac energetics decrease before LV dysfunction following ADR (5 mg/kg ip, weekly, 5 injections) in the mouse. As a result, the mean myocardial phosphocreatine-to-ATP ratio (PCr/ATP) by spatially localized (31)P magnetic resonance spectroscopy decreased at 6 wk after first ADR injection (1.79 + or - 0.18 vs. 1.39 + or - 0.30, means + or - SD, control vs. ADR, respectively, P < 0.05) when indices of systolic and diastolic function by magnetic resonance imaging were unchanged from control values. At 8 wk, lower PCr/ATP was accompanied by a reduction in ejection fraction (67.3 + or - 3.9 vs. 55.9 + or - 4.2%, control vs. ADR, respectively, P < 0.002) and peak filling rate (0.56 + or - 0.12 vs. 0.30 + or - 0.13 microl/ms, control vs. ADR, respectively, P < 0.01). PCr/ATP correlated with peak filling rate and ejection fraction, suggesting a relationship between cardiac energetics and both LV systolic and diastolic dysfunction. In conclusion, myocardial in vivo HEP metabolism is impaired following ADR administration, occurring before systolic or diastolic abnormalities and in proportion to the extent of eventual contractile abnormalities. These observations are consistent with the hypothesis that impaired HEP metabolism contributes to ADR-induced myocardial dysfunction.

Altered Myocardial Substrate Metabolism and Decreased Diastolic Function in Nonischemic Human Diabetic Cardiomyopathy: Studies With Cardiac Positron Emission Tomography and Magnetic Resonance Imaging

This study was designed to evaluate myocardial substrate and high-energy phosphate (HEP) metabolism in asymptomatic men with well-controlled, uncomplicated type 2 diabetes with verified absence of cardiac ischemia, and age-matched control subjects, and to assess the association with myocardial function. Metabolic abnormalities, particularly an excessive exposure of the heart to circulating nonesterified fatty acids and myocardial insulin resistance are considered important contributors to diabetic cardiomyopathy in animal models of diabetes. The existence of myocardial metabolic derangements in uncomplicated human type 2 diabetes and their possible contribution to myocardial dysfunction still remain undetermined. In 78 insulin-naive type 2 diabetes men (age 56.5 +/- 5.6 years, body mass index 28.7 +/- 3.5 kg/m(2), glycosylated hemoglobin A(1c) 7.1 +/- 1.0%; expressed as mean +/- SD) without cardiac ischemia and 24 normoglycemic control subjects (age 54.5 +/- 7.1 years, body mass index 27.0 +/- 2.5 kg/m(2), glycosylated hemoglobin A(1c) 5.3 +/- 0.2%), we assessed myocardial left ventricular (LV) function by magnetic resonance imaging, and myocardial perfusion and substrate metabolism by positron emission tomography using H(2)(15)O, carbon (11)C-palmitate, and 18-fluorodeoxyglucose 2-fluoro-2-deoxy-D-glucose. Cardiac HEP metabolism was assessed by phosphorous P 31 magnetic resonance spectroscopy. In patients, compared with control subjects, LV diastolic function (E/A ratio: 1.04 +/- 0.25 vs. 1.26 +/- 0.36, p = 0.003) and myocardial glucose uptake (260 +/- 128 nmol/ml/min vs. 348 +/- 154 nmol/ml/min, p = 0.015) were decreased, whereas myocardial nonesterified fatty acid uptake (88 +/- 31 nmol/ml/min vs. 68 +/- 18 nmol/ml/min, p = 0.021) and oxidation (85 +/- 30 nmol/ml/min vs. 63 +/- 19 nmol/ml/min, p = 0.007) were increased. There were no differences in myocardial HEP metabolism or perfusion. No association was found between LV diastolic function and cardiac substrate or HEP metabolism. Patients versus control subjects showed impaired LV diastolic function and altered myocardial substrate metabolism, but unchanged HEP metabolism. We found no direct relation between cardiac diastolic function and parameters of myocardial metabolism.

Correlation of cardiac performance with cellular energetic components in the oxygen-deprived turtle heart

The relationship between cardiac energy metabolism and the depression of myocardial performance during oxygen deprivation has remained enigmatic. Here, we combine in vivo (31)P-NMR spectroscopy and MRI to provide the first temporal profile of in vivo cardiac energetics and cardiac performance of an anoxia-tolerant vertebrate, the freshwater turtle (Trachemys scripta) during long-term anoxia exposure (approximately 3 h at 21 degrees C and 11 days at 5 degrees C). During anoxia, phosphocreatine (PCr), unbound levels of inorganic phosphate (effective P(i)(2-)), intracellular pH (pH(i)), and free energy of ATP hydrolysis (dG/dxi) exhibited asymptotic patterns of change, indicating that turtle myocardial high-energy phosphate metabolism and energetic state are reset to new, reduced steady states during long-term anoxia exposure. At 21 degrees C, anoxia caused a reduction in pH(i) from 7.40 to 7.01, a 69% decrease in PCr and a doubling of effective P(i)(2-). ATP content remained unchanged, but the free energy of ATP hydrolysis (dG/dxi) decreased from -59.6 to -52.5 kJ/mol. Even so, none of these cellular changes correlated with the anoxic depression of cardiac performance, suggesting that autonomic cardiac regulation may override putative cellular feedback mechanisms. In contrast, during anoxia at 5 degrees C, when autonomic cardiac control is severely blunted, the decrease of pH(i) from 7.66 to 7.12, 1.9-fold increase of effective P(i)(2-), and 6.4 kJ/mol decrease of dG/dxi from -53.8 to -47.4 kJ/mol were significantly correlated to the anoxic depression of cardiac performance. Our results provide the first evidence for a close, long-term coordination of functional cardiac changes with cellular energy status in a vertebrate, with a potential for autonomic control to override these immediate relationships.

A Conserved Role for Phosphatidylinositol 3-Kinase but Not Akt Signaling in Mitochondrial Adaptations that Accompany Physiological Cardiac Hypertrophy

Physiological cardiac hypertrophy is associated with mitochondrial adaptations that are characterized by activation of PGC-1alpha and increased fatty acid oxidative (FAO) capacity. It is widely accepted that phosphatidylinositol 3-kinase (PI3K) signaling to Akt1 is required for physiological cardiac growth. However, the signaling pathways that coordinate physiological hypertrophy and metabolic remodeling are incompletely understood. We show here that activation of PI3K is sufficient to increase myocardial FAO capacity and that inhibition of PI3K signaling prevents mitochondrial adaptations in response to physiological hypertrophic stimuli despite increased expression of PGC-1alpha. We also show that activation of the downstream kinase Akt is not required for the mitochondrial adaptations that are secondary to PI3K activation. Thus, in physiological cardiac growth, PI3K is an integrator of cellular growth and metabolic remodeling. Although PI3K signaling to Akt1 is required for cellular growth, Akt-independent pathways mediate the accompanying mitochondrial adaptations.

Short-Term Caloric Restriction Induces Accumulation of Myocardial Triglycerides and Decreases Left Ventricular Diastolic Function in Healthy Subjects

Diabetes and obesity are associated with increased plasma nonesterified fatty acid (NEFA) levels, myocardial triglyceride accumulation, and myocardial dysfunction. Because a very low-calorie diet (VLCD) also increases plasma NEFA levels, we studied the effect of a VLCD on myocardial triglyceride content and cardiac function in healthy subjects. Fourteen healthy nonobese men underwent (1)H-magnetic resonance spectroscopy (MRS) to determine myocardial and hepatic triglyceride content, (31)P-MRS to assess myocardial high-energy phosphate (HEP) metabolism (phosphocreatine/ATP), and magnetic resonance imaging of myocardial function at baseline and after a 3-day VLCD. After the dietary intervention, plasma NEFA levels increased compared with those at baseline (from 0.5 +/- 0.1 to 1.1 +/- 0.1 mmol/l, P < 0.05). Concomitantly, myocardial triglyceride content increased by approximately 55% compared with that at baseline (from 0.38 +/- 0.05 to 0.59 +/- 0.06%, P < 0.05), whereas liver triglyceride content decreased by approximately 32% (from 2.2 +/- 0.5 to 1.5 +/- 0.4%, P < 0.05). The VLCD did not change myocardial phosphocreatine-to-ATP ratio (2.33 +/- 0.15 vs. 2.33 +/- 0.08, P > 0.05) or systolic function. Interestingly, deceleration of the early diastolic flow across the mitral valve decreased after the VLCD (from 3.37 +/- 0.20 to 2.91 +/- 0.16 ml/s(2) x 10(-3), P < 0.05). This decrease in diastolic function was significantly correlated with the increase in myocardial triglyceride content. Short-term VLCD induces accumulation of myocardial triglycerides. In addition, VLCD decreases left ventricular diastolic function, without alterations in myocardial HEP metabolism. This study documents diet-dependent physiological variations in myocardial triglyceride content and diastolic function in healthy subjects.

Impact of Exercise Capacity on Myocardial High-Energy Phosphate Metabolism

31-Phosphorous magnetic resonance spectroscopy (31P MRS) is a unique tool to investigate IN VIVO high-energy phosphates (HEP) in the human heart. We hypothesized that physical capacity may be associated with myocardial HEP status. Healthy, male volunteers (n = 105, mean age 51 +/- 7 years) underwent bicycle ergometry with a stepwise increasing workload to determine maximal working capacity (MWC). Heart rate (HR) and blood pressure (BP) were measured continuously during exercise and 4 minutes of recovery. Further 31-Phosphorous 2-dimensional chemical shift imaging (31P 2D CSI) MRS was performed to assess myocardial HEP metabolism by determining phosphocreatinine to beta-ATP ratios (PCr/b-ATP) using a 1.5 tesla scanner. Volunteers with MWC > 230 Watt had significantly higher PCr/b-ATP ratios than those with MWC < 200 Watt (1.93 +/- 0.36 vs. 1.59 +/- 0.35; p < 0.001). Additionally, those with a recovery systolic (S)BP < 195 mmHg had significantly higher ratios than those with a recovery SBP > 195 mmHg (1.74 +/- 0.3 vs. 1.51 +/- 0.2; p < 0.05). We observed a linear correlation between the PCr/b-ATP ratio and MWC (r = 0.411; p < 0.001) and recovery SBP (r = - 0.290; p < 0.01). After statistical correction for age, these correlations remained significant. In this study, we observed a correlation of parameters of physical fitness determined by bicycle exercise testing and cardiac PCr/b-ATP ratios.

Magnetic resonance tomography and spectroscopy investigations of the human heart

The use of cardiac magnetic resonance (CMR) has emerged in the last decades. Technical innovations provide fast and high-quality imaging sequences and CMR is often proposed as a gold-standard for the in vivo evaluation of cardiac function, morphologic details and infarct size. Also the 31-phosphorous magnetic resonance spectroscopy (MRS) is a unique tool to investigate the human myocardial high-energy phosphate (HEP) metabolism in vivo. PCr/b-ATP ratio examined by MRS is mainly used as an index for cardiac energy metabolism. We have described decreased PCr/b-ATP ratios in patients with diabetes mellitus, hypercholesterolemia and hemochromatosis. The use of CMR to study the effects of ischemia time on the evolution of myocardial infarct characteristics after an acute myocardial infarction (AMI) treated with a primary angioplasty (p-PTCA) is a promising new application of this technique. Results of this study will further help to clarify the impact of ischemia time on myocardial regional functional recovery after p-PTCA.

Myocardial energy metabolism in ischemic preconditioning and cardioplegia: A metabolic control analysis

For both, cardioplegia (CP) and ischemic preconditioning (IP), increased ischemic tolerance with reduction in infarct size is well documented. These cardioprotective effects are related to a limitation of high energy phosphate (HEP) depletion. As CP and IP have to be assumed to act by different mechanisms, their effects on myocardial HEP metabolism cannot be assumed to be identical. Therefore, a systematic analysis of myocardial HEP metabolism for both procedures and their combination was performed, addressing the question whether there are different effects on myocardial HEP metabolism by IP and CP. In this study, metabolic control analysis was used to analyze the regulation of HEP metabolism. In open chest pigs subjected to 45 min LAD occlusion (index ischemia), CP and IP preserved myocardial ATP (control (C) 0.14 +/- 0.05 micromol/g wwt; CP: 0.95 +/- 0.14, IP: 0.61 +/- 0.12; p<0.05 C vs. CP and IP) and reduced myocardial necrosis (infarct size IA/RA: C: 90.0 +/- 3.0%; CP: 0.0 +/- 0.0% but patchy necroses; IP: 5.05 +/- 2.1%; p<0.05 C vs. CP and IP). The effects on HEP metabolism, however, were different: CP acted predominantly by slowing down the breakdown of phosphocreatine (PCr) during early phases of ischemia (C: DeltaPCr 0-2 min: 5.24 +/- 0.32 micromol/g wwt; CP: DeltaPCr 0-2 min: 3.38 +/- 0.23 micromol/g wwt, p<0.05 vs. C), leaving ATP breakdown during later stages unaffected (C: DeltaATP 5-45 min: 1.77 +/- 0.11 micromol/g wwt CP: DeltaATP 5-45 min: 1.59 +/- 0.28 micromol/g wwt, n.s. vs. C). In contrast to CP, in IP PCr breakdown was even increased (IP: DeltaPCr 0-2 min: 7.06 +/- 0.34 micromol/g wwt, p<0.05 vs. C), but ATP depletion greatly attenuated (IP: DeltaATP 5-45 min: 0.48 +/- 0.10 micromol/g wwt, p<0.05 vs. C and CP). Combining IP and CP yielded an additive effect with slowing down the breakdown of both PCr (IP+CP: DeltaPCr 0-2 min: 5.09+/- 0.35 micromol/g wwt, p<0.05 vs. C and IP) and ATP (IP+CP: DeltaATP 5-45 min: 0.56 +/- 0.48 micromol/g wwt, p<0.05 vs. C and CP), resulting in a higher ATP content at the end of index ischemia (1.86 +/- 0.46 micromol/g wwt, p<0.05 vs. C, CP and IP). Compared to IP, combining IP+CP achieved also a further reduction in infarct size (IA/RA: 0.0 +/- 0.0%, p<0.05 vs IP) and--compared to CP--a disappearance of the patchy necroses. The concept of major differences in myocardial HEP metabolism during CP and IP is further supported at a molecular level by metabolic control analysis. CP but not IP slowed down the CK reaction velocity at high PCr levels. In contrast to CP exerting a continuous decline in vATPase for any given ATP level, in IP myocardium ATPase reaction velocity was even increased at higher ATP contents, whereas a marked decrease in ATPase reaction velocity was found if ATP levels decreased. The equilibrium of the CK-reaction remained unchanged following CP, whereas IP induced a changing CK equilibrium, which was the more shifted towards PCr the more myocardial HEP content decreased. The data demonstrate different effects of CP and IP on myocardial HEP metabolism, i.e. PCr and ATP breakdown as well as the apparent equilibrium of the creatine kinase (CK)-reaction. For these reasons the combination of the two protective interventions has an additive effect.

1088-121 Improved myocardial high-energy phosphate metabolism induces by partial free fatty acid inhibition in patients with heart failure

1088-121 Improved myocardial high-energy phosphate metabolism induces by partial free fatty acid inhibition in patients with heart failure

Diastolic dysfunction is associatedwith altered myocardial metabolism inasymptomatic normotensive patientswith well-controlled type 2 diabetes mellitus

ObjectivesThis study evaluated myocardial function in relation to high-energy phosphate (HEP) metabolism in asymptomatic patients with uncomplicated type 2 diabetes mellitus using magnetic resonance (MR) techniques. BackgroundMyocardial dysfunction may occur in patients with type 2 diabetes mellitus in the absence of coronary artery disease or left ventricular (LV) hypertrophy. The mechanisms underlying this diabetic cardiomyopathy are largely unknown, but may involve altered myocardial energy metabolism. MethodsWe assessed myocardial systolic and diastolic function and HEP metabolism in 12 asymptomatic normotensive male patients with recently diagnosed, well-controlled type 2 diabetes and 12 controls, using MR imaging and phosphorus-31-nuclear MR spectroscopy (31P-MRS) on a 1.5 T clinical scanner; 31P-MR spectra were quantified, and myocardial HEP metabolism was expressed as phosphocreatine to adenosine-triphosphate (PCr/ATP) ratio. ResultsNo differences were found in LV mass and systolic function between patients and controls. However, early (E) acceleration peak, deceleration peak, peak filling rate, and transmitral early-to-late diastolic peak flow (E/A) ratio, all indexes of diastolic function, were significantly decreased in patients compared with controls (p < 0.02). In addition, myocardial PCr/ATP in patients was significantly lower than in controls (1.47 vs. 1.88, p < 0.01). Inverse associations were found between myocardial PCr/ATP and E acceleration peak, E deceleration peak, and E peak filling rate (all, p < 0.05). ConclusionsThese results indicate that altered myocardial energy metabolism may contribute to LV diastolic functional changes in patients with recently diagnosed, well-controlled and uncomplicated type 2 diabetes.

Mitochondrial creatine kinase is critically necessary for normal myocardial high-energy phosphate metabolism.

The individual functional significance of the various creatine kinase (CK) isoenzymes for myocardial energy homeostasis is poorly understood. Whereas transgenic hearts lacking the M subunit of CK (M-CK) show unaltered cardiac energetics and left ventricular (LV) performance, deletion of M-CK in combination with loss of sarcomeric mitochondrial CK (ScCKmit) leads to significant alterations in myocardial high-energy phosphate metabolites. To address the question as to whether this alteration is due to a decrease in total CK activity below a critical threshold or due to the specific loss of ScCKmit, we studied isolated perfused hearts with selective loss of ScCKmit (ScCKmit(-/-), remaining total CK activity approximately 70%) using (31)P NMR spectroscopy at two different workloads. LV performance in ScCKmit(-/-) hearts (n = 11) was similar compared with wild-type hearts (n = 9). Phosphocreatine/ATP, however, was significantly reduced in ScCKmit(-/-) compared with wild-type hearts (1.02 +/- 0.05 vs. 1.54 +/- 0.07, P < 0.05). In parallel, free [ADP] was higher (144 +/- 11 vs. 67 +/- 7 microM, P < 0.01) and free energy release for ATP hydrolysis (DeltaG(ATP)) was lower (-55.8 +/- 0.5 vs. -58.5 +/- 0.5 kJ/mol, P < 0.01) in ScCKmit(-/-) compared with wild-type hearts. These results demonstrate that M- and B-CK containing isoenzymes are unable to fully substitute for the loss of ScCKmit. We conclude that ScCKmit, in contrast to M-CK, is critically necessary to maintain normal high-energy phosphate metabolite levels in the heart.

Myocardial energetics in cardiac hypertrophy.

1. This review is presented with the intent of illustrating the representative studies of functional and myocardial energetic consequences of hearts with postinfarction left ventricular (LV) remodelling or with concentric hypertrophy and diastolic LV dysfunction in porcine models. 2. Both eccentric and concentric cardiac hypertrophy are associated with the abnormal myocardial energetics that are most severe in hearts with congestive heart failure (CHF). Presently, these abnormalities cannot be satisfactorily explained to be the cause(s) of the dysfunction of failing hearts or cause the progress from compensated cardiac hypertrophy to CHF. 3. Mechanisms governing abnormal myocardial high-energy phosphate (HEP) metabolism in hearts with cardiac hypertrophy and CHF are unclear. Myocardial energy metabolism studies use both kinetic and thermodynamic models. The thermodynamic studies examine the myocardial steady state levels of high- and low-energy phosphate, which indicate myocardial energy state or phosphorylation potential that is defined by the ratio of [ATP]/([ADP][Pi]). The kinetics studies examine the reaction velocity that is regulated by: (i) quantity and activity of the key enzymes; (ii) the concentrations of all the substrates and products; and (iii) the Michaelis-Menten constants of each substrate of the reaction. 4. Significant alterations in myocardial concentrations of phosphocreatine (PCr), ATP and ADP, myocardial oxidative phosphorylation (OXPHOS) protein expression and substrate preference are found in hearts with postinfarction LV remodelling and CHF. However, to define a causal relationship is a different matter. 5. Future studies of animal models of LV hypertrophy or heart failure using gene manipulation may provide additional insights to answer the persisting question of whether limitations of ATP synthetic or transport capacities contribute to the pathogenesis of LV remodelling or failure.

Cardiac metabolism and function in patients with multiple sclerosis: a combined 31P-MR-spectroscopy and MRI study.

Involvement of the autonomic system in multiple sclerosis (MS) may concur with dysfunction of the cardiovascular system. The introduction of potentially cardiotoxic immunosuppressive drugs like Mitoxantrone into the treatment of MS warrants proper assessment of preexisting heart disease. However, systematic analyses of functional and metabolic derangements in MS are missing. Using quantitative 31P-MR-spectroscopy (MRS) and MR-imaging (MRI) metabolic and functional parameters were analyzed in patients with MS in comparison to healthy volunteers. 14/15 patients with MS could be included in the study, as the MRS examination of one patient had to be excluded from analysis due to movement during the examination. Using chemical shift imaging (CSI) and AMARES, phosphocreatine (PCr) to adenosine triphosphate (ATP) ratios, characterizing myocardial high-energy phosphate metabolism, were determined. Additionally, absolute concentrations of PCr and ATP were calculated by SLOOP (Spatial Localization with Optimal Pointspread Function). Analysis of functional changes was performed by Cine-MRI. 14 healthy volunteers matched for age and gender served as control. A significant decrease of absolute PCr concentration was observed in patients with MS compared to matched volunteers (p < 0.05), whereas ATP concentrations showed no significant changes (p = 0.27). Metabolite ratios calculated by SLOOP or AMARES showed a tendency to be reduced in patients, however, did not reach significance (p = 0.08, SLOOP; p = 0.47, AMARES). Using volunteers' mean values +/- 2 x SD as cut off value revealed PCr changes in 5 of 14 patients, whereas only 2 also had pathologic PCr/ATP ratios. Functional analysis by MRI depicted depressed left ventricular ejection fraction in 4 patients. The reduction in cardiac high-energy phosphates in some patients with MS points to a subclinical involvement of the heart. This may be important for treatment with potentially cardiotoxic drugs. Longitudinal studies are need to understand the clinical relevance of our findings.

Effects of augmented delivery of pyruvate on myocardial high-energy phosphate metabolism at high workstate.

This study was performed to determine whether the fall in myocardial high-energy phosphates (HEP) that occurs during high workstates can be ascribed to either inadequate glycolytic pyruvate generation and conversion to acyl-CoA or limitation of long-chain fatty acid transport into the mitochondria. This was tested by using infusions of either pyruvate or butyrate in anesthetized dogs. Pyruvate was used because it bypasses the glycolytic sequence of reactions, activates pyruvate dehydrogenase, and increases mitochondrial NADH concentration ([NADH(m)]) in isolated myocardium, whereas butyrate enters the mitochondria without need for transport by the rate-limiting, palmitoyl-carnitine transporter. Increasing blood pyruvate from 0.16 +/- 0.016 mM to >3 mM did not alter baseline HEP levels determined with (31)P nuclear magnetic resonance, but caused an increase in the rate-pressure product and a modest increase in myocardial oxygen consumption (MVO(2)). Infusion of dobutamine + dopamine (each 20 microg x kg(-1) x min(-1) iv) increased MVO(2) and caused decreases of myocardial phosphocreatine (PCr)/ATP. Pyruvate partially reversed the decrease of HEP levels produced by catecholamine stimulation, whereas butyrate had no effect. Neither pyruvate nor butyrate caused an increase of MVO(2) during catecholamine infusion. Deoxymyoglobin was not detected by (1)H magnetic resonance spectroscopyy in any group. The data demonstrate that carbon substrate availability to the mitochondria is not the only cause of the reduction of PCr/ATP that occurs at high workstates. Supplemental pyruvate (but not butyrate) attenuated the reduction of PCr/ATP during the high workstates; this may have resulted from direct effects on intermediary metabolism or from other effects such as the free radical scavenging activity of pyruvate.

Aortic valve replacement in patients with aortic valve stenosis improves myocardial metabolism and diastolic function.

To evaluate whether functional and metabolic changes recover after aortic valve replacement (AVR). Eighteen men with aortic valve stenosis (mean pressure gradient +/- SD, 79.9 mm Hg +/- 15.1) underwent magnetic resonance (MR) imaging and phosphorus 31 MR spectroscopy. In nine patients who underwent AVR, MR imaging and spectroscopy were repeated 40 weeks +/- 12 after AVR. Ten age-matched healthy men were control subjects. Before AVR, the myocardial phosphocreatine (PCr)-to-adenosine triphosphate (ATP) ratio in the 18 patients was 1.24 +/- 0.17 and 1.43 +/- 0.14 in the control group (P <.01). In nine patients who underwent follow-up MR spectroscopy, the ratio increased from 1.28 +/- 0.17 to 1.47 +/- 0.14 (P <.05) following AVR. Before AVR, early acceleration peak corrected for cardiac output was (0.043 +/- 0.008) x 10(-3) sec(-1) in patients and (0.081 +/- 0.033) x 10(-3) sec(-1) in the control group (P <.05). After 40 weeks +/- 12, the mean early acceleration peak corrected for cardiac output in the nine patients increased significantly to (0.055 +/- 0.006) x 10(-3) sec(-1) (P <.05), although it was still significantly lower than that of the control group (P <.05). Before AVR, a significant correlation was found between the myocardial PCr-ATP ratio and left ventricular diastolic function (n = 18; P <.05). Severe aortic valve stenosis leads to a decreased myocardial PCr-ATP ratio and impairment of left ventricular diastolic function; following AVR, the ratio normalizes completely, whereas function improves significantly. There is an association between altered myocardial high-energy phosphate metabolism and impaired left ventricular diastolic function.

High-energy phosphate metabolism and creatine kinase in failing hearts: a new porcine model.

This study aimed to create a pig model of heart failure secondary to severe aortic stenosis and to examine the relationship between the alterations in myocardial high-energy phosphate (HEP) metabolism and protein expression of creatine kinase (CK) isoforms. Sixteen pigs with left ventricular hypertrophy (LVH) secondary to ascending aortic banding and 10 normal pigs (N) were studied. Myocardial protein levels of CK isoforms (Western blot), HEP levels, and CK kinetics ((31)P MR spectroscopy) were measured under basal conditions. Nine of the 16 animals with LVH developed congestive heart failure (CHF), as evidenced by ascites (100 to 2000 mL). LV weight/body weight ratio (g/kg) was 2.18+/-0.15 in N hearts, 3.04+/-0.14 in hearts with LVH (P<0.01), and 4.23+/-0.36 in hearts with CHF (P<0.01 versus LVH). Right ventricle weight/body weight ratio and LV end-diastolic pressure were significantly higher in hearts with CHF (each P<0.01 versus N or LVH). Myocardial phosphocreatine/ATP ratios and the CK forward flux rates were decreased in LVH hearts, most severely in hearts with CHF. CK-M/beta-actin ratios were 2.21+/-12 (N), 1.69+/-0.15 (LVH), and 1.39+/-0.27 (CHF, P<0.05 versus N). CK-mitochondria (CK-Mt)/beta-actin ratios were 1.40+/-0.09 (N), 1.24+/-0.09 (LVH), and 1.02+/-0.08 (CHF, P<0.05 versus N or LVH). The severity of the reduction of CK flux rate was linearly related to the severity of the decrease of CK-Mt/beta-actin (r=0.68, P<0.01). In this new model of heart failure/hypertrophy, the abnormal myocardial HEP metabolism is related to the decreased CK-Mt protein level, which in turn is related to the severity of the hypertrophy.