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1Faculty of Medicine, Department of Medical Physiology, Institute of Medical Biology, University of Tromsø, Tromsø, Norway; and 2Faculty of Medicine, Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada
Submitted 27 January 2005 ; accepted in final form 6 March 2005
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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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 ± 0.1 mM, which was subsequently raised to 0.9 ± 0.1 mM. End-systolic and end-diastolic pressure-volume relationships were assessed by temporarily occluding the preload line. Different steady-state PVA-MO2 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-MO2 regression line) in response to the elevation of the perfusate FA concentration. However, all hearts (n = 8) showed an increase in the y-intercept of the PVA-MO2 regression line after elevation of the palmitate concentration, indicating an FA-induced increase in the unloaded MO2. Therefore, in the present model, unloaded MO2 is not independent of metabolic substrate. This is, to our knowledge, the first report of a PVA-MO2 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
Cardiac efficiency is the ratio between cardiac work and myocardial oxygen consumption (MO2). A physiologically relevant measurement of cardiac efficiency requires the use of a work term that correlates closely with MO2. To date, the most accepted definition of total cardiac mechanical work is Suga’s (31, 32) concept of the pressure-volume area (PVA), which he defined as the sum of external work and the "potential energy triangle." Kameyama et al. (16) demonstrated that PVA correlated nicely with MO2 in isovolumetrically contracting (Langendorff perfused) mouse hearts. Until recently, technical hurdles limited measurements of PVA with pressure-volume (P-V) technology to larger animals. However, the new 1.4-Fr combined micromanometer (pressure)-conductance (volume) catheter has now been successfully applied to mice in vivo (10, 13), demonstrating both the precision and reproducibility of this technology in obtaining high-quality recordings of P-V loops. In addition, Grieve et al. (14) and Layland et al. (20) have recently described the application of this catheter for analysis of cardiac function in the isolated murine ejecting heart. The main purpose of the present study was to establish and use the miniaturized P-V catheter technology to assess the relationship between PVA and MO2 (by the use of a fiber-optic oxygen probe; see Ref. 33) in the ex vivo working mouse heart, a model that allows for strict control of important hemodynamic factors and substrate availability (14, 19). We also wanted to validate the technology by examining whether an elevation of the fatty acid (FA) supply to the heart (by increasing the FA concentration in the perfusate) would reduce cardiac efficiency, detected as an increase in unloaded MO2, as previously demonstrated in large animal models (17, 24).
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Cannulation and instrumentation of the heart. An intraperitoneal injection of heparin (100 U) was administered 10 min before death. The animals were anesthetized with an intraperitoneal injection (10 mg) of pentobarbital sodium, after which the heart was quickly excised and the aorta cannulated with an 18-gauge plastic cannula for an initial Langendorff perfusion to wash out blood from the coronary vasculature. Oxygenated Krebs-Henseleit bicarbonate buffer (KHB, 37.5°C, pH 7.4) containing 11 mM glucose was used for this procedure. During this time, the left atrium was cannulated with a 16-gauge steel cannula with connection to the preload reservoir, and a 1.4-Fr micromanometer-conductance catheter (Millar Instruments, Houston, TX) was inserted in the left ventricle via the apex of the heart. Finally, a fiber-optic oxygen probe (FOXY-AL300; Ocean Optics, Duiven, Netherlands) was placed in the pulmonary trunk for online recording of the partial oxygen pressure of the coronary effluate. The heart was subsequently switched to the working (left ventricle ejecting) mode by opening the connection between the left atrium and the preload reservoir. In the working mode, hearts were perfused with KHB buffer (gassed with 95% oxygen using a surface oxygenator) containing 11 mM glucose and FA bound to 3% BSA (fraction V; Sigma) as energy substrates.
Experimental protocol.
During stabilization, the initial filling pressure (preload) was set to 8 mmHg, whereas the afterload column was set to a height corresponding to 55 mmHg. The hearts were initially perfused with KHB buffer containing 0.3 ± 0.1 mmol/l FA, which was the endogenous FA content in the albumin preparation. A temporary occlusion of the preload line was first performed to determine end-systolic and end-diastolic pressure-volume relationships (ESPVR and EDPVR, respectively). Thereafter, a set of steady-state PVA-MO2 relationships was obtained by varying the loading conditions of the heart over a wide range (from low pre- and afterload settings of 3 and 35 mmHg, respectively, to high settings of 10 and 65 mmHg). The heart was again allowed to stabilize for 
5 min at the baseline loading conditions (8 mmHg preload and 55 mmHg afterload) to obtain baseline hemodynamic values. The concentration of palmitate was subsequently increased over a 5-min period by gradually replacing most of the initial buffer with a preheated and pregassed buffer with an FA (palmitate) concentration of 1.2 mmol/l so that the final FA concentration became 0.9 mmol/l. After the change of buffer, new measurements of baseline hemodynamics were conducted. New series of steady-state PVA-MO2 relationships were then performed as described above.
Baseline measurements of left ventricular function. The ventricular function at baseline loading conditions was determined before and immediately after the buffer replacement. Left ventricular (LV) end-diastolic and end-systolic volumes and stroke volume (i.e., the difference between the end-diastolic and end-systolic volume) were calculated from the P-V loop, which was recorded by a PowerLab, Chart 5 data acquisition system (AD Instruments) and analyzed by the software accompanying the Millar P-V catheter (PVAN 2.9). Likewise, LV end-diastolic and end-systolic pressures, the first derivative of the pressure with respect to time (dP/dt), and tau (relaxation index) were determined from the P-V record. Coronary flow (CF) was measured by timed collections of the effluent dropping from the heart, aortic flow (AF) was determined by a drop counter at the outlet of the afterload line, whereas cardiac output (CO) was calculated as the sum of AF and CF. Finally, stroke work (SW) was calculated as the area enclosed by the P-V loop.
Measurement of PVA.
The micromanometer part of the P-V catheter was calibrated by a two-point calibration (0 and 100 mmHg), using a water column with a hydrostatic pressure equivalent to 100 mmHg. In addition, pressure recordings were adjusted for variations in the daily barometric pressure. LV volume was assessed by the conductance catheter and calculated as V(t) = (1/
) x (L2/
) x [G(t) – Gp] in accordance with previous studies (3, 30). V(t) is the total volume and is a factor relating conductance volumes to true volumes. In this study, was calculated as the ratio between the directly measured stroke volume (CO divided by heart rate) and stroke volume obtained by the conductance catheter. L is the interelectrode distance, whereas is the buffer resistivity. G(t) is the instantaneous conductance and Gp is the instantaneous conductance by the myocardium, or parallel conductance. The resistivity of the buffer () was stable during the whole experiment, making L2/ a constant. Some of the electrical field generated by the conductance catheter will always pass into the myocardium. This parallel conductance (Gp) causes an extra artificial volume named parallel volume, Vp. Vp was determined by injection of a 30-µl bolus of KHB containing 1% NaCl in the left ventricle via the preload cannula. This intervention caused a transient increase in conductance and produced an offset of the volume signal, which can be used for assessing parallel conductance (3). Parallel conductance was measured only in the hearts referred to in Figs. 1–3. PVA, the sum of SW and potential energy (PE), was calculated according to the formula PVA = SW + [PES x (VES – V0)/2] – [PED x (VED – V0)/4] in accordance with Korvald et al. (18), where PES is end-systolic pressure, VES is end-systolic volume, PED is end-diastolic pressure, V0 is theoretical volume where no pressure is generated, and VED is end-diastolic volume.
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O2.
Myocardial MO2 was calculated by the following equation: MO2 = [PO2 (oxygenated perfusate) – PO2 (coronary effluent)] x Bunsen solubility coefficient of O2 x CF. PO2 was measured by the use of a fiber-optic oxygen sensor (FOXY-AL300; Ocean Optics) that was connected to a spectrophotometer (USB2000-FL-450; Ocean Optics). This methodology has been described in detail by Zhao et al. (33). It employs a luminescence-based fiber-optic sensor with an oxygen-sensitive ruthenium-containing dye attached to the distal tip. The luminescence of the ruthenium complex is quenched by oxygen and has been shown to follow a second-order polynomial algorithm. The oxygen sensor was calibrated daily by a three-point calibration using KHB buffer (37°C) gassed with N2 (0% O2/100% N2), air (21% O2/79% N2), or carbogen (95% O2/5% CO2). The oxygen saturation of the buffer entering the heart was measured in several pilot experiments at the start and end of each experiment and was consistently found to be 82% of the barometric pressure. The fact that the buffer reaching the heart had a lower oxygen tension (82%) than the theoretical value of 95% is most likely because of the use of a surface oxygenator with an albumin-containing solution and probably some diffusional loss of oxygen from the tubing connecting the oxygenator and the atrial cannula. Oxygen saturation of the coronary effluent was measured by placing the sensor in the opening of the pulmonary trunk. In this way, we could continuously record PO2 in the coronary effluent and easily determine the steady-state PO2 values after alterations in the workload of the heart.
Measurement of FA oxidation. Rates of FA oxidation were determined in separately perfused hearts by measuring the amount of 3H2O released from [9,10-3H]palmitate over a 60-min perfusion period. Samples of perfusate were taken every 10 min for determinations of metabolite (3H2O) content. Hearts were perfused with 0.3 mmol/l palmitate for the first 30 min and 0.9 mmol/l palmitate for the last 30 min of the perfusion period (buffer was replaced as described under Experimental protocol). At the end of the perfusion, hearts were frozen, and total dry mass of the ventricles was determined.
Statistics. Metabolic and functional parameters obtained at low vs. high FA concentrations were compared statistically by Student’s t-test for paired data. A statistical significant difference between means was indicated by a P value <0.05.
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RESULTS |
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P-V loop configuration in ex vivo working mouse heart is strongly dependent on the compliance volume and the size of the aortic cannula.
During the initial tests of the 1.4-Fr P-V catheter, it became clear that both the volume of air in the compliance chamber above the heart and the length of the aortic cannula significantly influenced the configuration of the P-V loops. Figure 2 shows P-V loops from two different hearts, one being perfused with a long (15-mm) aortic cannula, whereas the other was perfused with a very short (3-mm) cannula. The long cannula created an extra resistance to flow (on top of the resistance provided by the hydrostatic pressure), which was translated into an increase in the effective afterload by 15 mmHg. Figure 3 shows the influence of compliance (volume of air in the compliance chamber) on P-V relationships using compliance volumes of 0.3, 0.5, and 1.3 ml; families of P-V loops were obtained from the same heart by temporarily closing the preload line. At the highest compliance (1.3 ml), ventricular pressure was relatively constant during the ejection phase so that determination of ESPVR and V0 became difficult. Reduction of the compliance to 0.5 ml produced an auxotonic configuration of the P-V loops, which resembles the in vivo P-V loop configuration. At the lowest compliance (0.3 ml), ventricular pressure increased very steeply during the ejection phase, and stroke volume (distance between the ascending and descending limbs of the P-V loop) was significantly reduced because of reduced emptying of the left ventricle. Accordingly, the amount of PE increased relative to the amount of energy used for external work (SW), and the heart was gradually exhausted during this condition. Thus these experiments demonstrate that it is essential to define an optimal compliance for the ex vivo mouse heart because of its impact on the ventricular performance (PE vs. SW, ESPVR). Based on these findings, all perfusions in the present study employed a short cannula (5 mm), as well as the 0.5-ml compliance volume, and under these conditions hearts were functionally stable for 2 h.
Increased myocardial FA oxidation resulting from elevated FA supply causes increased MO2 without affecting LV function, i.e., increased FA oxidation leads to reduced cardiac efficiency.
Figure 4 shows rates of FA oxidation in isolated mouse hearts that were perfused initially with a low FA concentration of 0.3 mmol/l and after elevating the FA concentration to 0.9 mmol/l. As can be seen, FA oxidation increased more than fourfold because of the elevation of the FA supply.
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O2 and PVA in a representative heart that was perfused under high and low FA concentrations. As can be seen, MO2 was linearly related to PVA at both FA concentrations. The regression line was, however, shifted upward in a parallel fashion as a consequence of the elevation in FA, indicating an increased unloaded MO2.
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O2 increased significantly, as indicated by a marked fall of PO2 in the coronary effluate. Because CF was unaltered, the drop in PO2 indicates increased myocardial O2 extraction. Taken together, the increased MO2 and unaltered work performance in response to the elevated FA supply are indicative of decreased cardiac efficiency.
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O2 and PVA were obtained from each heart while being perfused first at low and subsequently at high FA concentration. Moreover, each heart was exposed to a wide range of workloads, as produced by changing the loading conditions (both pre- and afterload). The results from the individual experiments are shown in Table 3, whereas the pooled data are shown in Fig. 6. In every experiment, the y-intercept for the relationship between MO2 and PVA was increased in response to the elevation in FA concentration. Thus the average MO2 value was 27% higher during high vs. low FA supply. On the other hand, the slope of the relation, reflecting the contractile efficiency, was not significantly influenced by the elevation of the FA.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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O2, and, consequently, reduced cardiac efficiency may result from either a reduction in cardiac work or an increase in oxygen consumption. Measurement of PVA, which is the work term that correlates best with MO2, was until a few years ago restricted to large animals. In the present study, we show that PVA, as well as myocardial MO2, can be measured with confidence in the ex vivo mouse heart. Moreover, we have confirmed using this system that an elevated FA supply to the heart causes increased FA oxidation and MO2, leading to decreased cardiac efficiency, whereas cardiac performance was unaffected (8, 17, 24).
Loading conditions (i.e., pre- and afterload), compliance, and resistance in the artificial circulatory system may profoundly affect cardiac function of the ex vivo working mouse heart. Thus, not surprisingly, the ex vivo P-V relationships obtained in the present study were slightly different from those recently reported by Grieve et al. (14); with the auxotonic ejection conditions chosen for the present study, peak systolic pressure nearly coincided with the end-systolic pressure, whereas peak systolic pressure was obtained immediately after contraction in Grieve’s study, reaching values nearly two times as high as the end-systolic pressure. Based on the results shown in Figs. 2 and 3, we suggest that these differences are related to the difference in compliance volumes between the two setups (0.5 vs. 1.5 ml). Otherwise, values of volume-related indexes, such as end-systolic and end-diastolic volumes, as well as stroke volume (Fig. 1) were quite similar to those reported in the ex vivo study by Grieve et al. (14). The values of functional indexes (CO, SW, contractility, and relaxation indexes) obtained in this study (Table 1) were similar or slightly higher than those reported previously for isolated working murine hearts (1, 4, 15). Thus these data suggest that insertion of the catheter through the apex does not significantly impair the ventricular function. However, in comparison with the hemodynamic function reported for mouse hearts in vivo (9, 11–13, 23), the current ex vivo preparation exhibited consistently lower function. Georgakopoulos and coworkers (13) reported heart rate values >600 beats/min and a contractility index (dP/dtmax) close to 12,000 mmHg/s in intact anesthetized mice, which are approximately two times the values obtained for the corresponding parameters in the present ex vivo heart preparation. In addition to the obvious physical limitations of the artificial perfusion setup, this difference in performance could be related to the total lack of neurohumoral stimuli of the ex vivo heart. In support of this view, we observed, in accordance with Grieve et al. (14), a consistent leftward shift in the P-V loops after administration of isoprenaline (data not shown). In contrast, the shift between baseline and isoprenaline-stimulated mouse hearts is not observed in vivo, and, in addition, the in vivo preparation shows a rightward shift after 
-blockade with propranolol (13). It is suggested, therefore, that the isolated murine heart resembles a neurohumorally blocked heart, resulting in moderate ventricular dilatation, but contractility can be further blunted by administration of propranolol (14). Finally, the absence of hemoglobin in the crystalloid buffer could contribute to ex vivo and in vivo differences (7).
In accordance with previous studies by Mjøs (24) and Belke et al. (5), we found that LV performance was unaffected by elevating the substrate FA concentration. Therefore, despite the increase in MO2 associated with the change of buffer, one can conclude that the myocardial oxygen supply was not a limiting factor. Furthermore, the elevated FA concentrations did not provoke any arrhythmogenic action, as was reported in a study on isolated rat hearts (21). The only consistent response after the elevation of FA was an increased myocardial oxygen extraction from the coronary effluate (Table 2). Because CF was unchanged in the present study, the increased oxygen extraction was the direct effect of an increased MO2. Mjøs (24), who increased the FA concentration in the circulatory system of intact dogs, reported a similar effect. Furthermore, the increased MO2 after elevating the FA concentration led to a decreased cardiac efficiency, since cardiac work (PVA) was unchanged (Table 2). This finding is in contrast to a recent study conducted by Mazumder et al. (22). These authors reported decreased cardiac efficiency in control mice as a result of a fall in cardiac power while MO2 was unchanged after elevation of FA in the perfusate.
Cardiac inefficiency can be a result of impaired contractile efficiency (slope of regression line in Fig. 5) or, alternatively, caused by metabolic factors such as an increased oxygen cost of excitation-contraction coupling, elevated basal metabolic rate, or changes in substrate supply (8, 24). The latter change will appear as an increased y-intercept (Fig. 5), which is the oxygen cost for the unloaded heart. As shown in Fig. 6 and Table 3, there was a significant 27% increase in the y-intercept after elevation of the FA supply, although the slope of the regression was unchanged.
This increase in the unloaded MO2 could not solely be explained by a switch in metabolism from glucose to FA utilization, since the differences in phosphorylation-to-oxidation ratios between FA and glucose oxidation could account for a maximally 11% increase in the oxygen consumption (production of a given amount of ATP requires 11% more oxygen when the myocardium oxidizes FA, compared with oxidation of glucose; see Ref. 27). The 27% increase in unloaded MO2 therefore requires explanation from alternative metabolic mechanisms. One possibility is that the FA oxidation is uncoupled from oxidative phosphorylation in the respiratory chain during excessive FA supply. FA-induced uncoupling of oxidative phosphorylation has been shown to increase oxygen consumption without a corresponding increase in the production of ATP (6). In a recent publication by Murray et al. (25), increased mitochondrial content of uncoupling proteins was suggested as a likely mechanism of uncoupling. Another explanation of the increased MO2 in the unloaded heart is that high levels of FA may trigger intracellular futile metabolic cycles (27). During high levels of intracellular FA, the triacylgycerol-FA cycle has been shown to increase oxygen consumption up to 30% (26).
Relevance.
Because of technical hurdles, measurement of cardiac efficiency has previously been limited to larger animals. The fast-progressing development of transgenic murine models has raised many new questions in fields like phenotyping of ventricular function and myocardial substrate utilization. The current method could be an important tool for studies of cardiac efficiency under controlled loadings and substrate conditions. The major advantages with the isolated setup are 1) no neurohumoral influence, 2) direct pharmacological interventions can easily be done by addition of drugs to the buffer, and 3) the isolated setup allows direct measurements of CF and "arteriovenous" differences in oxygen content. These factors make assessment of MO2 more direct and accurate compared with in vivo setups. It also allows freedom of choice regarding the effects of, i.e., loading and substrate supply beyond the normal physiological range. However, it should be stressed that phenotyping of ventricular function ex vivo could differ from in vivo assessments. Therefore sophisticated data on ventricular function that can be obtained with the current technology should also be tested in vivo. Interestingly, it was recently reported (28) that obese women with insulin resistance exhibited decreased myocardial efficiency, i.e., cardiac work was unchanged but MO2 was increased, which was linked with increased FA uptake. Moreover, the dependence on FA utilization increased with increasing insulin resistance and cannot be completely explained by an increase in serum FA concentrations. Therefore, the present validation of cardiac efficiency measurements in mice means that this protocol can be extended to diabetic animal models, with direct relevance to human diabetes and insulin resistance.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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) and high (
) FA concentration. Intercept represents unloaded M