Influence of substrate supply on cardiac efficiency, as measured by pressure-volume analysis in ex vivo mouse hearts

Abstract

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...

Increased Myocardial Oxygen Consumption Reduces Cardiac Efficiency in Diabetic Mice

“…Cannulation and instrumentation of the heart. After intraperitoneal injection of heparin (100 units), animals were anesthetized with sodium pentobarbital, after which the heart was quickly excised and cannulated for perfusion in the working mode, using Krebs-Henseleit buffer (KHB) buffer with 11 mmol/l glucose as well as albumin-bound fatty acids as energy substrates (2). A 1.4-F micromanometer-conductance catheter (Millar Instru-ments, Houston, TX) was inserted into the left ventricle via the apex of the heart, while a fiber-optic oxygen probe (FOXY-AL300; Ocean Optics, Duiven, the Netherlands) was placed in the pulmonary trunk for on-line recording of the partial oxygen pressure in the coronary effluent ( Fig.…”

“…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 .…”

“…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).…”

“…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 reduced in diabetic db/db hearts because of enhanced rates of fatty acid oxidation (3). Accordingly, db/db hearts were perfused with both low and high concentrations of fatty acids (palmitate) in the perfusate.…”

Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation

“…Under normal resting conditions, fatty acid oxidation is the predominant source of energy for cardiac power generation (60 -80%); however, studies in humans (39), dogs (30,31), and pigs (25) in vivo and in isolated perfused rat (3,21) and mouse (20) hearts show that, with high rates fatty acid oxidation, the external power is reduced for a given MV O 2 (3,30,39). In the failing heart or during acute ischemia and/or reperfusion, pharmacological treatment with agents that inhibit myocardial fatty acid oxidation (5,6) or directly activate carbohydrate oxidation (2,28,41) increases LV function without affecting MV O 2 and, therefore, improves LV mechanical efficiency (defined as the ratio of external LV power to LV energy expenditure).…”