1Altered cardiac metabolism and function (diabetic cardiomyopathy) has been observed in diabetes. We hypothesize that cardiac efficiency, the ratio of cardiac work (pressurevolume area [PVA]) and myocardial oxygen consumption (MVO 2 ), is reduced in diabetic hearts. Experiments used ex vivo working hearts from control db/؉, db/db (type 2 diabetes), and db/؉ mice given streptozotocin (STZ; type 1 diabetes). PVA and ventricular function were assessed with a 1.4-F pressure-volume catheter at low (0.3 mmol/l) and high (1.4 mmol/l) fatty acid concentrations with simultaneous measurements of MVO 2 . Substrate oxidation and mitochondrial respiration were measured in separate experiments. Diabetic hearts showed decreased cardiac efficiency, revealed as an 86 and 57% increase in unloaded MVO 2 in db/db and STZ-administered hearts, respectively. The slope of the PVA-MVO 2 regression line was increased for db/db hearts after elevation of fatty acids, suggesting that contractile inefficiency could also contribute to the overall reduction in cardiac efficiency. The end-diastolic and end-systolic pressure-volume relationships in db/db hearts were shifted to the left with elevated end-diastolic pressure, suggesting left ventricular remodeling and/or myocardial stiffness. Thus, by means of pressure-volume technology, we have for the first time documented decreased cardiac efficiency in diabetic hearts caused by oxygen waste for noncontractile purposes. Diabetes 55: 466 -473, 2006 C ardiac efficiency is the ratio between energy output (work) and energy input (myocardial oxygen consumption [MVO 2 ]) for the heart. Currently, the most accepted definition of total cardiac work is pressure-volume area (PVA), the sum of external mechanical work and the potential energy triangle (1). Importantly, MVO 2 is linearly related to PVA. Extrapolation of this linear relationship to 0 work gives unloaded (PVA independent) MVO 2 , the oxygen cost of excitation-contraction coupling and basal metabolism.Furthermore, the inverse slope of the MVO 2 -PVA relationship defines the contractile efficiency.Recently, How et al. (2) demonstrated that pressurevolume loops and resulting determinations of PVA can be obtained with ex vivo perfused working mouse hearts, using a combined micromanometer (pressure)-conductance (volume) catheter. A fiber-optic oxygen probe gave simultaneous measurements of MVO 2 . An elevation in perfusate fatty acid concentration resulted in augmented fatty acid oxidation and reduced cardiac efficiency (increased MVO 2 with no change in work), manifested as increased unloaded MVO 2 (2).Perfused hearts from db/db mice, a monogenic model of type 2 diabetes with obesity and insulin resistance, have been characterized as having an early increase in fatty acid oxidation that precedes the onset of contractile dysfunction (3). Because elevated rates of fatty acid oxidation produce a decrease in cardiac efficiency in control hearts (2), the objective of the current investigation was to test the hypothesis that cardiac efficiency will be r...

How, Ole-Jakob, Ellen Aasum, Stanley Kunnathu, David L. Severson, Eivind S. P. Myhre, and Terje S. Larsen. Influence of substrate supply on cardiac efficiency, as measured by pressure-volume analysis in ex vivo mouse hearts. Am J Physiol Heart Circ Physiol 288: H2979 -H2985, 2005. First published March 11, 2005 doi:10.1152/ajpheart.00084.2005In the present study, we tested the reliability of measurements of pressure-volume area (PVA) and oxygen consumption (MV O2) in ex vivo mouse hearts, combining the use of a miniaturized conductance catheter and a fiber-optic oxygen sensor. Second, we tested whether we could reproduce the influence of increased myocardial fatty acid (FA) metabolism on cardiac efficiency in the isolated working mouse heart model, which has already been documented in large animal models. The hearts were perfused with crystalloid buffer containing 11 mM glucose and two different concentrations of FA bound to 3% BSA. The initial concentration was 0.3 Ϯ 0.1 mM, which was subsequently raised to 0.9 Ϯ 0.1 mM. End-systolic and end-diastolic pressure-volume relationships were assessed by temporarily occluding the preload line. Different steadystate PVA-MV O2 relationships were obtained by changing the loading conditions (pre-and afterload) of the heart. There were no apparent changes in baseline cardiac performance or contractile efficiency (slope of the PVA-MV O2 regression line) in response to the elevation of the perfusate FA concentration. However, all hearts (n ϭ 8) showed an increase in the y-intercept of the PVA-MV O2 regression line after elevation of the palmitate concentration, indicating an FA-induced increase in the unloaded MV O2. Therefore, in the present model, unloaded MV O2 is not independent of metabolic substrate. This is, to our knowledge, the first report of a PVA-MV O2 relationship in ex vivo perfused murine hearts, using a pressure-volume catheter. The methodology can be an important tool for phenotypic assessment of the relationship among metabolism, contractile performance, and cardiac efficiency in various mouse models. oxygen consumption; pressure-volume area; cardiac metabolism; compliance; steady state PHENOTYPING OF THE MURINE heart has become essential to understand the physiological effects (at the organ level) of various manipulations of the mouse genome. The use of ex vivo perfused working hearts (5, 19) is a valuable experimental approach to assess cardiac phenotype with respect to mechanical as well as metabolic function. Moreover, the ex vivo model enables strict control of cardiac loading and substrate supply and offers, in addition, the possibility to measure oxidation rates of exogenous myocardial substrates (1,2,4,29). Thus the ex vivo mouse heart should be an excellent model to study the coupling of mechanical work and the energy requirement of the heart in various disease states, such as diabetes, ventricular hypertrophy, and heart failure.Cardiac efficiency is the ratio between cardiac work and myocardial oxygen consumption (MV O 2 ). A physiologically rele...

Hafstad AD, Khalid AM, How OJ, Larsen TS, Aasum E. Glucose and insulin improve cardiac efficiency and postischemic functional recovery in perfused hearts from type 2 diabetic (db/db) mice. Am J Physiol Endocrinol Metab 292: E1288 -E1294, 2007. First published January 9, 2007; doi:10.1152/ajpendo.00504.2006.-Hearts from type 2 diabetic (db/db) mice demonstrate altered substrate utilization with high rates of fatty acid oxidation, decreased functional recovery following ischemia, and reduced cardiac efficiency. Although db/db mice show overall insulin resistance in vivo, we recently reported that insulin induces a marked shift toward glucose oxidation in isolated perfused db/db hearts. We hypothesize that such a shift in metabolism should improve cardiac efficiency and consequently increase functional recovery following low-flow ischemia. Hearts from db/db and nondiabetic (db/ϩ) mice were perfused with 0.7 mM palmitate plus either 5 mM glucose (G), 5 mM glucose and 300 U/ml insulin (GI), or 33 mM glucose and 900 U/ml insulin (HGHI). Substrate oxidation and postischemic recovery were only moderately affected by GI and HGHI in db/ϩ hearts. In contrast, GI and particularly HGHI markedly increased glucose oxidation and improved postischemic functional recovery in db/db hearts. Cardiac efficiency was significantly improved in db/db, but not in db/ϩ hearts, in the presence of HGHI. In conclusion, insulin and glucose normalize cardiac metabolism, restore efficiency, and improve postischemic recovery in type 2 diabetic mouse hearts. These findings may in part explain the beneficial effect of glucose-insulin-potassium therapy in diabetic patients with cardiac complications. glucose; insulin; myocardial oxygen consumption; pressure-volume area TYPE 2 DIABETES IS THE MOST prevalent form (90%) of diabetes, resulting from a combination of insulin resistance and, eventually, a ␤-cell secretory defect. Increased cardiovascular disease is the most common complication of diabetes (10). Both clinical (4) and experimental (2, 35) studies have shown that type 2 diabetes and/or insulin resistance is associated with reduced myocardial tolerance to ischemia, which may explain the increased morbidity of ischemic heart disease in diabetes (10). Type 2 diabetes and/or insulin resistance are associated with increased cardiac fatty acid oxidation (FA ox ) and a concomitant decrease in glucose utilization (2,5,9,33). This change in substrate utilization has been considered a metabolic maladaptation that may contribute to the development of cardiac dysfunction and/or reduced ischemic tolerance in type 2 diabetes. In line with this notion, transgenic mice with increased cardiac fatty acid (FA) uptake/utilization show a diabetic phenotype with reduced ventricular function and/or reduced postischemic recovery (3, 6).There has been a long-standing interest in metabolic modulation as a means to improve functional recovery following myocardial ischemia, and administration of glucose and insulin, as part of glucose-insulin-potassium (GIK) treatment, ...

Background— Omecamtiv mecarbil (OM) is a novel inotropic agent that prolongs systolic ejection time and increases ejection fraction through myosin ATPase activation. We hypothesized that a potentially favorable energetic effect of unloading the left ventricle, and thus reduction of wall stress, could be counteracted by the prolonged contraction time and ATP-consumption. Methods and Results— Postischemic left ventricular dysfunction was created by repetitive left coronary occlusions in 7 pigs (7 healthy pigs also included). In both groups, systolic ejection time and ejection fraction increased after OM (0.75 mg/kg loading for 10 minutes, followed by 0.5 mg/kg/min continuous infusion). Cardiac efficiency was assessed by relating myocardial oxygen consumption to the cardiac work indices, stroke work, and pressure–volume area. To circumvent potential neurohumoral reflexes, cardiac efficiency was additionally assessed in ex vivo mouse hearts and isolated myocardial mitochondria. OM impaired cardiac efficiency; there was a 31% and 23% increase in unloaded myocardial oxygen consumption in healthy and postischemic pigs, respectively. Also, the oxygen cost of the contractile function was increased by 63% and 46% in healthy and postischemic pigs, respectively. The increased unloaded myocardial oxygen consumption was confirmed in OM-treated mouse hearts and explained by an increased basal metabolic rate. Adding the myosin ATPase inhibitor, 2,3-butanedione monoxide abolished all surplus myocardial oxygen consumption in the OM-treated hearts. Conclusions— Omecamtiv mecarbil, in a clinically relevant model, led to a significant myocardial oxygen wastage related to both the contractile and noncontractile function. This was mediated by that OM induces a continuous activation in resting myosin ATPase.

IntroductionWe developed a minimally invasive, closed chest pig model with the main aim to describe hemodynamic function during surface cooling, steady state severe hypothermia (one hour at 25°C) and surface rewarming.MethodsTwelve anesthetized juvenile pigs were acutely catheterized for measurement of left ventricular (LV) pressure-volume loops (conductance catheter), cardiac output (Swan-Ganz), and for vena cava inferior occlusion. Eight animals were surface cooled to 25°C, while four animals were kept as normothermic time-matched controls.ResultsDuring progressive cooling and steady state severe hypothermia (25°C) cardiac output (CO), stroke volume (SV), mean arterial pressure (MAP), maximal deceleration of pressure in the cardiac cycle (dP/dtmin), indexes of LV contractility (preload recruitable stroke work, PRSW, and maximal acceleration of pressure in the cardiac cycle, dP/dtmax) and LV end diastolic and systolic volumes (EDV and ESV) were significantly reduced. Systemic vascular resistance (SVR), isovolumetric relaxation time (Tau), and oxygen content in arterial and mixed venous blood increased significantly. LV end diastolic pressure (EDP) remained constant. After rewarming all the above mentioned hemodynamic variables that were depressed during 25°C remained reduced, except for CO that returned to pre-hypothermic values due to an increase in heart rate. Likewise, SVR and EDP were significantly reduced after rewarming, while Tau, EDV, ESV and blood oxygen content normalized. Serum levels of cardiac troponin T (TnT) and tumor necrosis factor-alpha (TNF-α) were significantly increased.ConclusionsProgressive cooling to 25°C followed by rewarming resulted in a reduced systolic, but not diastolic left ventricular function. The post-hypothermic increase in heart rate and the reduced systemic vascular resistance are interpreted as adaptive measures by the organism to compensate for a hypothermia-induced mild left ventricular cardiac failure. A post-hypothermic increase in TnT indicates that hypothermia/rewarming may cause degradation of cardiac tissue. There were no signs of inadequate global oxygenation throughout the experiments.