Cardiac High-energy Phosphate Research Articles

Abstract 9199: A Novel Small Molecule Troponin Activator Increases Cardiac Contractile Function Without Negative Impact on Energetics or Diastolic Function

Background: Current heart failure (HF) therapies improve cardiac energy balance and prolong survival by unloading the failing heart without targeting the underlying problem of reduced cardiac contractility. Traditional inotropic medications, also termed calcitropes, stimulate contractility via energetically costly augmentation of calcium cycling and worsen patient survival. Myotropes are a new class of agents that activate the sarcomere directly, independent of cAMP and calcium. We hypothesize that a novel myotrope, troponin activator (TA1), increases contractility without the deleterious myocardial energetic impact of calcitrope dobutamine (DOB). Methods: We determined the pharmacodynamics of TA1 ex vivo and in vivo in anesthetized normal rats. Isolated rat hearts were perfused with incremental concentrations of TA1 or DOB to compare their effect on cardiac contractility and high-energy phosphate concentrations using 31 P NMR spectroscopy. Results: A dose dependent increase in contractility was observed in vivo by echocardiography after acute administration of TA1. In isolated hearts, increasing concentrations of TA1 and DOB similarly increased rate pressure product (RPP), which is a product of developed pressure (DevP) and heart rate (HR). At equivalent doses (DOB 120 nM, TA1 60 nM), TA1 increased DevP more and HR less compared to DOB. DOB decreased phosphocreatine (PCr) to ATP ratio and free energy of ATP hydrolysis (ΔG ~ATP ) and elevated left ventricular end-diastolic pressure (LVEDP). In contrast, the TA1 increased RPP without any effect on HR, LVEDP, PCr/ATP ratio or ΔG ~ATP . Conclusions: Here we describe a novel myotrope, TA1, that increased myocardial contractility by sensitizing the sarcomere to calcium without impairing diastolic function or depleting the cardiac energy reserve. Since energetic depletion negatively correlates with long term survival, TA1 may represent a superior alternative to traditional inotropes in HF management.

Abstract 10080: Myocardial Physiological Responses to the Third Trimester of Healthy Pregnancy

Background: Pregnancy requires significant cardiometabolic adaptation and is therefore considered a “stress test” for future cardiovascular disease. Cardiovascular magnetic resonance (CMR) allows evaluation of cardiac structure, function and tissue characteristics with excellent reproducibility. There is scarcity of CMR data on pregnancy-associated cardiovascular adaptive changes. Moreover, no studies to date assessed the physiological impact of pregnancy on cardiac high energy phosphate metabolism, measured as the phosphocreatine (PCr)/ATP ratio, using 31 Phosphorus magnetic resonance spectroscopy ( 31 P-MRS). Objectives: We aimed to investigate the physiological effects of pregnancy in women in the third trimester of a healthy singleton pregnancy on cardiac energetics, function and tissue characteristics using 31 P-MRS and CMR at 3T. Methods: Thirty pregnant women and fifteen age-matching nulliparous healthy female controls were recruited. Results: Clinical characteristics and CMR/ 31 P-MRS results are provided in Table1.Resting heart rates and cardiac output were higher in pregnancy, with no significant differences in left-ventricular volumes, mass or ejection fraction, diastolic function (mitral in-flow E/A), global longitudinal strain or MAPSE. There were subtle reductions in cardiac PCr/ATP in pregnancy. Compared to non-pregnant controls, myocardial T1 was 2% higher in pregnant women, whilst T2 was 5% lower. Conclusions: Healthy pregnancy was associated with no significant changes in cardiac size, mass or function. Consistent with the haemodynamic changes in pregnancy, subtle reductions in cardiac energetics were detected, though these remained within normal range.CMR is well tolerated in pregnancy and may play a role in assessing cardiac involvement in women at risk of perinatal complications, offering the opportunity of early initiation of risk modifying treatment and prevention of adverse maternal cardiovascular outcomes.

Myocardial glucose and fatty acid metabolism is altered and associated with lower cardiac function in young adults with Barth syndrome

BackgroundBarth syndrome (BTHS) is a rare X-linked condition resulting in cardiomyopathy, however; the effects of BTHS on myocardial substrate metabolism and its relationships with cardiac high-energy phosphate metabolism and left ventricular (LV) function are unknown. We sought to characterize myocardial glucose, fatty acid (FA), and leucine metabolism in BTHS and unaffected controls and examine their relationships with cardiac high-energy phosphate metabolism and LV function. Methods/ResultsYoung adults with BTHS (n = 14) and unaffected controls (n = 11, Control, total n = 25) underwent bolus injections of 15O-water and 1-11C-glucose, palmitate, and leucine and concurrent positron emission tomography imaging. LV function and cardiac high-energy phosphate metabolism were examined via echocardiography and 31P magnetic resonance spectroscopy, respectively. Myocardial glucose extraction fraction (21 ± 14% vs 10 ± 8%, P = .03) and glucose utilization (828.0 ± 470.0 vs 393.2 ± 361.0 μmol·g−1·min−1, P = .02) were significantly higher in BTHS vs Control. Myocardial FA extraction fraction (31 ± 7% vs 41 ± 6%, P < .002) and uptake (0.25 ± 0.04 vs 0.29 ± 0.03 mL·g−1·min−1, P < .002) were significantly lower in BTHS vs Control. Altered myocardial metabolism was associated with lower cardiac function in BTHS. ConclusionsMyocardial substrate metabolism is altered and may contribute to LV dysfunction in BTHS.Clinical Trials #: NCT01625663.

Association between cardiac high-energy phosphate metabolism and whole body metabolism in healthy female adults.

Decline in cardiac high-energy phosphate metabolism [phosphocreatine-to-ATP (PCr/ATP) ratio] and whole body metabolism increase the risk of heart failure and metabolic diseases. The aim of the present study was to assess the relationship between PCr/ATP ratio and measures of body metabolic function. A total of 35 healthy women (56+/-14.0 years of age) underwent cardiac 31P magnetic resonance spectroscopy to assess PCr/ATP ratio - an index of cardiac high-energy phosphate metabolism. Fasting and 2-hour glucose levels were assessed using oral glucose tolerance test. Indirect calorimetry was performed to determine oxygen consumption and resting metabolic rate. There were no significant relationships between PCr/ATP ratio and resting metabolic rate (r=-0.09, p=0.62), oxygen consumption (r=-0.11, p=0.54), fasting glucose levels (r=-0.31, p=0.07), and 2-hour plasma glucose (r=-0.10, p=0.58). Adjusted analysis for covariates including age, body mass index, fat mass, and physical activity, had no significant influence on the relationship between PCr/ATP ratio and body metabolism. In conclusion, the lack of relationship between cardiac PCr/ATP ratio, glucose control and metabolic rate may suggest that overall metabolic function does not influence cardiac high-energy phosphate metabolism.

Enhanced cardiac hypoxic injury in atherogenic dyslipidaemia results from alterations in the energy metabolism pattern

ObjectiveDyslipidaemia is a major risk factor for myocardial infarction that is known to correlate with atherosclerosis in the coronary arteries. We sought to clarify whether metabolic alterations induced by dyslipidaemia in cardiomyocytes collectively constitute an alternative pathway that escalates myocardial injury. MethodsDyslipidaemic apolipoprotein E and low-density lipoprotein receptor (ApoE/LDLR) double knockout (ApoE−/−/LDLR−/−) and wild-type C57BL/6 (WT) mice aged six months old were studied. Cardiac injury under reduced oxygen supply was evaluated by 5 min exposure to 5% oxygen in the breathing air under electrocardiogram (ECG) recording and with the assessment of troponin I release. To address the mechanisms LC/MS was used to analyse the cardiac proteome pattern or in vivo metabolism of stable isotope-labelled substrates and HPLC was applied to measure concentrations of cardiac high-energy phosphates. Furthermore, the effect of blocking fatty acid use with ranolazine on the substrate preference and cardiac hypoxic damage was studied in ApoE−/−/LDLR−/− mice. ResultsHypoxia induced profound changes in ECG ST-segment and troponin I leakage in ApoE−/−/LDLR−/− mice but not in WT mice. The evaluation of the cardiac proteomic pattern revealed that ApoE−/−/LDLR−/− as compared with WT mice were characterised by coordinated increased expression of mitochondrial proteins, including enzymes of fatty acids' and branched-chain amino acids' oxidation, accompanied by decreased expression levels of glycolytic enzymes. These findings correlated with in vivo analysis, revealing a reduction in the entry of glucose and enhanced entry of leucine into the cardiac Krebs cycle, with the cardiac high-energy phosphates pool maintained. These changes were accompanied by the activation of molecular targets controlling mitochondrial metabolism. Ranolazine reversed the oxidative metabolic shift in ApoE−/−/LDLR−/− mice and reduced cardiac damage induced by hypoxia. ConclusionsWe suggest a novel mechanism for myocardial injury in dyslipidaemia that is consequent to an increased reliance on oxidative metabolism in the heart. The alterations in the metabolic pattern that we identified constitute an adaptive mechanism that facilitates maintenance of metabolic equilibrium and cardiac function under normoxia. However, this adaptation could account for myocardial injury even in a mild reduction of oxygen supply.

The creatine kinase system as a therapeutic target for myocardial ischaemia–reperfusion injury

Restoring blood flow following an acute myocardial infarction saves lives, but results in tissue damage due to ischaemia–reperfusion injury (I/R). Ameliorating this damage is a major research goal to improve recovery and reduce subsequent morbidity due to heart failure. Both the ischaemic and reperfusion phases represent crises of cellular energy provision in which the mitochondria play a central role. This mini-review will explore the rationale and therapeutic potential of augmenting the creatine kinase (CK) energy shuttle, which constitutes the primary short-term energy buffer and transport system in the cardiomyocyte. Proof-of-principle data from several transgenic mouse models have demonstrated robust cardioprotection by either raising myocardial creatine levels or by overexpressing specific CK isoforms. The effect on cardiac function, high-energy phosphates and myocardial injury will be discussed and possible directions for future research highlighted. We conclude that the CK system represents a viable target for therapeutic intervention in I/R injury; however, much needed translational studies will require the development of new pharmacological tools.

Metabolic Modulation of Cardiac Metabolism in Heart Failure.

Heart failure (HF) is associated with metabolic changes that cause a progressive impairment of cardiac and skeletal muscle high-energy phosphate production. As a consequence of the impaired cardiac metabolism, other processes are activated in the failing heart that further exacerbate the progression of HF. The reduced production of high-energy phosphates has important implications for both systole and diastole in HF with both preserved and reduced left ventricular function. The aim of this review is to summarise the state-of-the-art on metabolic therapy in HF with a particular focus on trimetazidine. Metabolic agents optimise cardiac substrate metabolism without exerting negative haemodynamic effects. In particular, as studies with metabolic agents modulating cardiac metabolism have consistently demonstrated, this approach is effective in improving symptoms, functional capacity and prognosis in people with HF when added to optimal medical therapy. Therefore, the modulation of cardiac metabolism is an important therapeutic approach to the treatment of HF, especially in patients where it is of ischaemic or metabolic origin. Although further studies are needed, metabolic agents might be a new, effective strategy for the treatment of HF.

Oral Coenzyme Q10 Supplementation Does Not Prevent Cardiac Alterations During a High Altitude Trek to Everest Base Camp

Exposure to high altitude is associated with sustained, but reversible, changes in cardiac mass, diastolic function, and high-energy phosphate metabolism. Whilst the underlying mechanisms remain elusive, tissue hypoxia increases generation of reactive oxygen species (ROS), which can stabilize hypoxia-inducible factor (HIF) transcription factors, bringing about transcriptional changes that suppress oxidative phosphorylation and activate autophagy. We therefore investigated whether oral supplementation with an antioxidant, Coenzyme Q10, prevented the cardiac perturbations associated with altitude exposure. Twenty-three volunteers (10 male, 13 female, 46±3 years) were recruited from the 2009 Caudwell Xtreme Everest Research Treks and studied before, and within 48 h of return from, a 17-day trek to Everest Base Camp, with subjects receiving either no intervention (controls) or 300 mg Coenzyme Q10 per day throughout altitude exposure. Cardiac magnetic resonance imaging and echocardiography were used to assess cardiac morphology and function. Following altitude exposure, body mass fell by 3 kg in all subjects (p<0.001), associated with a loss of body fat and a fall in BMI. Post-trek, left ventricular mass had decreased by 11% in controls (p<0.05) and by 16% in Coenzyme Q10-treated subjects (p<0.001), whereas mitral inflow E/A had decreased by 18% in controls (p<0.05) and by 21% in Coenzyme Q10-treated subjects (p<0.05). Coenzyme Q10 supplementation did not, therefore, prevent the loss of left ventricular mass or change in diastolic function that occurred following a trek to Everest Base Camp.

Cardiac high-energy phosphate metabolism alters with age as studied in 196 healthy males with the help of 31-phosphorus 2-dimensional chemical shift imaging.

Recently published studies have elucidated alterations of mitochondrial oxidative metabolism during ageing. The intention of the present study was to evaluate the impact of ageing on cardiac high-energy phosphate metabolism and cardiac function in healthy humans. 31-phosphorus 2-dimensional chemical shift imaging (31P 2D CSI) and echocardiography were performed in 196 healthy male volunteers divided into groups of 20 to 40 years (I, n = 43), 40 to 60 years (II, n = 123) and >60 years (III, n = 27) of age. Left ventricular PCr/β-ATP ratio, myocardial mass (MM), ejection fraction and E/A ratio were assessed. Mean PCr/β-ATP ratios were significantly different among the three groups of volunteers (I, 2.10±0.37; II, 1.77±0.37; III, 1.45±0.28; all p<0.001). PCr/β-ATP ratios were inversely related to age (r2 = −0.25; p<0.001) with a decrease from 2.65 by 0.02 per year of ageing. PCr/β-ATP ratios further correlated with MM (r = −0.371; p<0.001) and E/A ratios (r = 0.213; p<0.02). Moreover, E/A ratios (r = −0.502, p<0.001), MM (r = 0.304, p<0.001), glucose-levels (r = 0.157, p<0.05) and systolic blood pressure (r = 0.224, p<0.005) showed significant correlations with age. The ejection fraction did not significantly differ between the groups. This study shows that cardiac PCr/β-ATP ratios decrease moderately with age indicating an impairment of mitochondrial oxidative metabolism due to age. Furthermore, MM increases, and E/A ratio decreases with age. Both correlate with left-ventricular PCr/β-ATP ratios. The findings of the present study confirm numerous experimental studies showing an impairment of cardiac mitochondrial function with age.

Sub-normothermic preservation of donor hearts for transplantation using a novel solution, Somah: A comparative pre-clinical study

Hearts preserved ex vivo at extreme hypothermia (4°C) undergo time-dependent irreversible injury. Our studies using a novel solution, Somah, suggest that hearts are viably preserved at 21°C. In this study we evaluate the relative efficacy of Somah for preservation of hearts at 21°C when compared with the clinically used Celsior and University of Wisconsin (UWS) solutions. Porcine hearts arrested by cardioplegia at 21°C using Somah, Celsior or UWS solution were stored in the respective solutions at 21°C (n = 5) for 5 hours and then reperfused ex vivo for functional assessment. We assessed development of edema, cardiac tissue high-energy phosphate (HEP; ATP + creatine phosphate) levels and release of cardiac enzymes. Alterations in left ventricular wall thicknesses and functional parameters were examined by 2-dimensional (2D) echocardiography. Changes in myocardial oxygen consumption (MVO2) and lactate utilization were assessed at reperfusion. Heart weights were unaltered during 5-hour storage in all groups. After storage, HEP levels were 28.33 ± 5.51, 10.20 ± 2.78 and 5.92 ± 1.46 nmol/liter per milligram protein (p < 0.001) in the Somah, Celsior and UWS group hearts, respectively. Upon reanimation, 2D echocardiography showed edema in the Celsior and UWS hearts; prompt attainment of physiologic function was associated with rapid establishment of aerobic metabolism not requiring stimulatory interventions in the Somah hearts, but not in the Celsior/UWS hearts. Percent fractional area change, ejection fraction and stroke volume were significantly higher (p < 0.001) in Somah hearts than in Celsior and UWS group hearts. Increased synthesis of HEP, rapid metabolic switch and optimal function together provide evidence that hearts procured for transplantation are preserved in a superior viable condition at 21°C with Somah, but not with other commonly used clinical preservation solutions.

Exercise-Induced Decrease in Myocardial High-Energy Phosphate Metabolites in Patients With Chagas Heart Disease

BackgroundThe influence of exercise on cardiac metabolic response in patients with Chagas disease is incompletely understood. Methods and ResultsChanges in cardiac energetic metabolism were investigated in Chagas disease patients before and during isometric handgrip exercise with 31P magnetic resonance spectroscopy (MRS). Twenty-eight patients (10 with systolic dysfunction: group I; 10 with normal systolic function and electrocardiogram (ECG) abnormalities: group II; and 8 asymptomatic without ECG abnormalities: group III) and 8 healthy control subjects (group C) were evaluated by electrocardiogram, echocardiogram, functional tests for coronary artery disease, and image-selected localized cardiac 31P-MRS. The myocardial phosphocreatine to [β-phosphate]adenosine triphosphate ratio (PCr/β-ATP) was measured at rest and during isometric handgrip exercise. Exercise testing or 99mTc–sestamibi scintigraphy were negative for myocardial ischemia in all individuals. At rest, cardiac PCr/β-ATP was decreased in all Chagas groups (1.23 ± 0.37) versus group C (1.88 ± 0.08; P < .001) and was lower in group I (0.89 ± 0.24) versus groups II (1.44 ± 0.23) and III (1.40 ± 0.37; P < .001). There was no stress-induced change in cardiac PCr/β-ATP (1.88 ± 0.08 at rest vs 1.89 ± 0.08 during exercise; P = NS) in group C. Mean cardiac PCr/β-ATP was 0.89 ± 0.24 and 0.56 ± 0.21 at rest and during exercise, respectively, in group I (37% decrease; P < .001). In group II, PCr/β-ATP was 1.44 ± 0.23 at rest and 0.97 ± 0.37 during exercise (33% decrease; P < .001). In group III, PCr/β-ATP was 1.40 ± 0.37 at rest and 0.60 ± 0.19 during exercise (57% decrease; P < .001). ConclusionsMyocardial high-energy phosphates are reduced at rest in Chagas heart disease patients, and the reduction is greater in patients with left ventricular dysfunction. Regardless of left ventricular function, Chagas patients exhibit an exercise-induced decline in cardiac high-energy phosphates consistent with myocardial ischemia, suggesting the possibility that this metabolic approach may offer a tool to probe new interventions in Chagas disease patients.

Systematic Evaluation of Key L-Carnitine Homeostasis Mechanisms during Postnatal Development in Rat

BackgroundThe conditionally essential nutrient, L-carnitine, plays a critical role in a number of physiological processes vital to normal neonatal growth and development. We conducted a systematic evaluation of the developmental changes in key L-carnitine homeostasis mechanisms in the postnatal rat to better understand the interrelationship between these pathways and their correlation to ontogenic changes in L-carnitine levels during postnatal development.MethodsmRNA expression of heart, kidney and intestinal L-carnitine transporters, liver γ-butyrobetaine hydroxylase (Bbh) and trimethyllysine hydroxylase (Tmlh), and heart carnitine palmitoyltransferase (Cpt) were measured using quantitative RT-PCR. L-Carnitine levels were determined by HPLC-UV. Cpt and Bbh activity were measured by a spectrophotometric method and HPLC, respectively.ResultsSerum and heart L-carnitine levels increased with postnatal development. Increases in serum L-carnitine correlated significantly with postnatal increases in renal organic cation/carnitine transporter 2 (Octn2) expression, and was further matched by postnatal increases in intestinal Octn1 expression and hepatic γ-Bbh activity. Postnatal increases in heart L-carnitine levels were significantly correlated to postnatal increases in heart Octn2 expression. Although cardiac high energy phosphate substrate levels remained constant through postnatal development, creatine showed developmental increases with advancing neonatal age. mRNA levels of Cpt1b and Cpt2 significantly increased at postnatal day 20, which was not accompanied by a similar increase in activity.ConclusionsSeveral L-carnitine homeostasis pathways underwent significant ontogenesis during postnatal development in the rat. This information will facilitate future studies on factors affecting the developmental maturation of L-carnitine homeostasis mechanisms and how such factors might affect growth and development.

Exercise training in dilated cardiomyopathy improves rest and stress cardiac function without changes in cardiac high energy phosphate metabolism

ObjectiveTo determine the effects of short-term exercise training on cardiac function and metabolism during rest and physical exercise in patients with heart failure from dilated cardiomyopathy (DCM).DesignPatients with DCM (n=15,...

BGP-15, a PARP-inhibitor, prevents imatinib-induced cardiotoxicity by activating Akt and suppressing JNK and p38 MAP kinases

In this study, we investigate the cardiotoxic effects of the well-known cytostatic agent imatinib mesylate (Gleevec), and presented evidence for the cardioprotective effect of BGP-15 which is a novel insulin sensitizer. The cardiotoxic effect of imatinib mesylate was assessed in Langendorff rat heart perfusion system. The cardiac high-energy phosphate levels (creatine phosphate (PCr) and ATP) were monitored in situ by (31)P NMR spectroscopy. The protein oxidation, lipid peroxidation, and the activation of signaling pathways were determined from the freeze-clamped hearts. Prolonged treatment of the heart with imatinib mesylate (20 mg/kg) resulted in cardiotoxicity, which were characterized by the depletion of high-energy phosphates (PCr and ATP), and significantly increased protein oxidation and lipid peroxidation. Imatinib mesylate treatment-induced activation of MAP kinases (including ERK1/2, p38, and JNK) and the phosphorylation of Akt and GSK-3beta. BGP-15 (200 μM) prevented the imatinib mesylate-induced oxidative damages, attenuated the depletion of high-energy phosphates, altered the signaling effect of imatinib mesylate by preventing p38 MAP kinase and JNK activation, and induced the phosphorylation of Akt and GSK-3beta. The suppressive effect of BGP-15 on p38 and JNK activation could be significant because these kinases contribute to the cell death and inflammation in the isolated perfused heart.

Allopurinol Acutely Increases Adenosine Triphospate Energy Delivery in Failing Human Hearts

This study tested the hypothesis that acute administration of the xanthine oxidase (XO) inhibitor allopurinol improves cardiac high-energy phosphate concentrations in human heart failure (HF) and increases the rate of adenosine triphosphate (ATP) synthesis through creatine kinase (CK), the primary myocardial energy reserve. Studies of patients and animal models implicate impaired myocardial high-energy phosphate availability in HF. The XO reaction is a critical terminal step in ATP and purine degradation and an important source of reactive oxygen species. Thus, XO inhibition is a potentially attractive means to improve energy metabolism in the failing human heart. We randomized 16 patients with nonischemic cardiomyopathy in a double-blind fashion to allopurinol (300 mg intravenously) or placebo infusion, 4-to-1, the latter for purposes of blinding only. The myocardial concentrations of ATP and creatine phosphate (PCr) and the rate of ATP synthesis through CK (CK flux) were determined by (31)P magnetic resonance spectroscopy. Allopurinol infusion increased mean cardiac PCr/ATP and PCr concentration by ∼11% (p < 0.02), and mean CK flux by 39% (2.07 ± 1.27 μmol/g/s to 2.87 ± 1.82 μmol/g/s, p < 0.007). Calculated cytosolic adenosine diphosphate concentration decreased, whereas the free energy of ATP hydrolysis (ΔG(∼ATP)) increased with allopurinol. The increased CK flux was disproportionate to substrate changes, indicating increased CK enzyme activity. Intravenous administration of the XO inhibitor allopurinol acutely improves the relative and absolute concentrations of myocardial high-energy phosphates and ATP flux through CK in the failing human heart, offering direct evidence that myofibrillar CK energy delivery can be pharmaceutically augmented in the failing human heart. (Intravenous Allopurinol in Heart Failure; NCT00181155).

Hypoxia tolerance in elasmobranchs. II. Cardiovascular function and tissue metabolic responses during progressive and relative hypoxia exposures

Cardiovascular function and metabolic responses of the heart and other tissues during hypoxia exposure were compared between the hypoxia-tolerant epaulette shark (Hemiscyllium ocellatum) and the hypoxia-sensitive shovelnose ray (Aptychotrema rostrata). In both species, progressive hypoxia exposure caused increases in stroke volume and decreases in heart rate, cardiac output, cardiac power output (CPO, an assessment of cardiac energy demand) and dorsal aortic blood pressure, all of which occurred at or below each species' critical P(O2) for whole-animal O(2) consumption rate, M(O2) (P(crit)). In epaulette sharks, which have a lower P(crit) than shovelnose rays, routine levels of cardiovascular function were maintained to lower water P(O2) levels and the changes from routine levels during hypoxia exposure were smaller compared with those for the shovelnose ray. The maintenance rather than depression of cardiovascular function during hypoxia exposure may contribute to the superior hypoxia tolerance of the epaulette shark, presumably by improving O(2) delivery and waste removal. Compared with shovelnose rays, epaulette sharks were also better able to maintain a stable cardiac high-energy phosphate pool and to minimize metabolic acidosis and lactate accumulation in the heart (despite higher CPO) and other tissues during a 4 h exposure to 40% of their respective P(crit) (referred to as a relative hypoxia exposure), which results in similar hypoxaemia in the two species (∼16% Hb-O(2) saturation). These different metabolic responses to relative hypoxia exposure suggest that variation in hypoxia tolerance among species is not solely dictated by differences in O(2) uptake and transport but also by tissue-specific metabolic responses. In particular, lower tissue [lactate] accumulation in epaulette sharks than in shovelnose rays during relative hypoxia exposure suggests that enhanced extra-cardiac metabolic depression occurs in the former species. This could facilitate strategic utilization of available O(2) for vital organs such as the heart, potentially explaining the greater hypoxic cardiovascular function of epaulette sharks.

A high-fat diet impairs cardiac high-energy phosphate metabolism and cognitive function in healthy human subjects

High-fat, low-carbohydrate diets are widely used for weight reduction, but they may also have detrimental effects via increased circulating free fatty acid concentrations. We tested whether raising plasma free fatty acids by using a high-fat, low-carbohydrate diet results in alterations in heart and brain in healthy subjects. Men (n = 16) aged 22 ± 1 y (mean ± SE) were randomly assigned to 5 d of a high-fat, low-carbohydrate diet containing 75 ± 1% of calorie intake through fat consumption or to an isocaloric standard diet providing 23 ± 1% of calorie intake as fat. In a crossover design, subjects undertook the alternate diet after a 2-wk washout period, with results compared after the diet periods. Cardiac (31)P magnetic resonance (MR) spectroscopy and MR imaging, echocardiography, and computerized cognitive tests were used to assess cardiac phosphocreatine (PCr)/ATP, cardiac function, and cognitive function, respectively. Compared with the standard diet, subjects who consumed the high-fat, low-carbohydrate diet had 44% higher plasma free fatty acids (P < 0.05), 9% lower cardiac PCr/ATP (P < 0.01), and no change in cardiac function. Cognitive tests showed impaired attention (P < 0.01), speed (P < 0.001), and mood (P < 0.01) after the high-fat, low-carbohydrate diet. Raising plasma free fatty acids decreased myocardial PCr/ATP and reduced cognition, which suggests that a high-fat diet is detrimental to heart and brain in healthy subjects.

Mitochondrial Fe-S cluster biogenesis, frataxin and the modulation of susceptibility to drug-induced cardiomyopathy

The role of energy deficits in the development and progression of heart failure is well-established and cardiac high-energy phosphate levels correlate directly with survival in cardiomyopathy patients [1]. In light of these clinical observations it has been posited that the modulation of mitochondrial function may be a feasible strategy to ameliorate heart failure. Aspects of mitochondrial function that have been manipulated to investigate this include: modulation of energy substrate utilization; activation of mitochondrial biogenesis; induction of mitochondrial antioxidant defenses and suppression of mitochondrial death programs including apoptosis and mitochondrial permeability transition. As briefly discussed below, targeting distinct aspects of these programs result in variable levels of success and suggest that our understanding of the role of the mitochondria in the pathophysiology remains incomplete. Pharmacologic approaches to modulate mitochondrial function have, to date, been limited and have recently been reviewed [2,3]. To identify potential novel therapeutic targets, genetic approaches have been used to directly modulate mitochondrial programming with the subsequent assessment of cardiac effects. These include the genetic augmentation of PGC-1α, the master regulator of mitochondrial biogenesis. Here, somewhat counterintuitively, acute and chronic upregulation of PGC-1α results in deleterious cardiac phenotype [4,5]. In contrast, the overexpression of mitochondrial transcription factor A ameliorates the development of ischemia-induced heart failure [6]. The genetic modulation of substrate utilization similarly exhibit divergent effects. The upregulation of atranscription factor promoting fatty acid oxidation, a known major cardiac source of energy, is detrimental [7], whereas the promotion of glucose uptake enhances cardiac tolerance to ischemia [8]. Other approaches include augmentation of anti-oxidant enzymes, e.g., by the upregulation of cardiac manganese superoxide. These transgenic mice are protected against doxorubicin-induced [9] and diabetic cardiomyopathy [10]. Augmentation of cardiac anti-apoptotic programming by the overexpression of Bcl-2 similarly restores mitochondrial function and reduces cardiomyopathy in desmin null mice [11]. In light of incomplete characterization of proteins involved in the mitochondrial permeability transition (MPT) the genetic modulation of this program to prevent cardiomyopathy has to my knowledge not being explored. However, pharmacologic inhibition of MPT by cyclosporine A attenuates cardiomyopathy and mitochondrial genomic mutagenesis in mice harboring a cardiac specific defect in mitochondrial DNA proofreading [12]. Taken together, these pharmacologic and genetic approaches are beginning to discern distinct levels at which mitochondrial reprogramming may have beneficial effects in preventing the development and progression of heart failure. An intriguing new finding, by Shultz et al is published in AGING regarding the induction of frataxin. Mutations in frataxin result in the development of Friedreich's Ataxia, an inherited neurodegenerative disease associated with the development of severe cardiomyopathy. Frataxin, itself is involved in mitochondrial iron-sulphur cluster biogenesis which functions, in part, to incorporate appropriate amounts of iron into mitochondrial proteins including aconitase and succinate dehydrogenase [13]. Whether frataxin functions as an iron-chaperone protein or plays a regulatory role in controlling iron and sulphur flux within mitochondria is not yet completely characterized. Nevertheless, the study by Shultz and colleagues [14] shows that increased cardiac frataxin enhances tricarboxylic acid cycle function resulting in increased cardiac ATP, NADH, NADPH and reduced glutathione levels. This array of features is consistent with an enhanced bioenergetic capacity and increased antioxidant defenses. The authors go on to demonstrate that overexpression of frataxin is cardioprotective against doxorubicin-induced cardiomyopathy. This intriguing study shows that the modulation of the mitochondria at the fundamental level of integrating cofactors required for protein functional integrity have beneficial effects in disease processes that are exacerbated by mitochondrial dysfunction. This study further highlights the complexity of mitochondrial function and adds a new level of regulation operational in the pathophysiology of heart failure that may be amenable to therapeutic modulation.

Cardiac response to hypobaric hypoxia: persistent changes in cardiac mass, function, and energy metabolism after a trek to Mt. Everest Base Camp

We postulated that changes in cardiac high-energy phosphate metabolism may underlie the myocardial dysfunction caused by hypobaric hypoxia. Healthy volunteers (n=14) were studied immediately before, and within 4 d of return from, a 17-d trek to Mt. Everest Base Camp (5300 m). (31)P magnetic resonance (MR) spectroscopy was used to measure cardiac phosphocreatine (PCr)/ATP, and MR imaging and echocardiography were used to assess cardiac volumes, mass, and function. Immediately after returning from Mt. Everest, total body weight had fallen by 3% (P<0.05), but left ventricular mass, adjusted for changes in body surface area, had disproportionately decreased by 11% (P<0.05). Alterations in diastolic function were also observed, with a reduction in peak left ventricular filling rates and mitral inflow E/A, by 17% (P<0.05) and 24% (P<0.01), respectively, with no change in hydration status. Compared with pretrek, cardiac PCr/ATP ratio had decreased by 18% (P<0.01). Whether the abnormalities were even greater at altitude is unknown, but all had returned to pretrek levels after 6 mo. The alterations in cardiac morphology, function, and energetics are similar to findings in patients with chronic hypoxia. Thus, a decrease in cardiac PCr/ATP may be a universal response to periods of sustained low oxygen availability, underlying hypoxia-induced cardiac dysfunction in healthy human heart and in patients with cardiopulmonary diseases.

Development and validation of a short 31P cardiac magnetic resonance spectroscopy protocol

Introduction Cardiac 31P-MRS is the only non-invasive in vivo technique for the determination of cardiac high energy phosphate metabolism. Changes in cardiac phosphocreatine to adenosine triphosphate ratios (PCr/ATP) occur in common cardiac pathologies and have diagnostic, prognostic and therapeutic utility. However, long acquisition times (20 minutes or more, depending on heart rate) required to achieve sufficient signal to noise ratios for reliable interpretation have limited the clinical utility of 31P-MRS studies in patients with severe cardiac disease.