The structural left ventricular (LV) remodeling and contractile dysfunction of hearts with postinfarction LV remodeling are benefited by angiotensin II type 1 receptor (AT1) blocker. However, the myocardial bioenergetic consequences of AT1 blocker in these hearts are not known. To investigate, we used a porcine model of postinfarction LV remodeling produced by ligation of the left circumflex coronary artery. After infarction, 7 pigs received olmesartan medoxomil (2 mg/kg) for comparison against 9 untreated and 10 normal pigs. Measurements of hemodynamics, myocardial perfusion, and myocardial bioenergetics were taken 7 weeks postinfarction. The treated group had an LV-to-body weight ratio significantly lower than the untreated group (2.69±0.70, 2.96±0.51, 3.66±0.60 g/kg for control, treated, and untreated groups, respectively). The untreated group had a mean aortic pressure significantly higher than the control (73±16, 86±14, and 94±20 mm Hg, respectively). The subendocardial phosphocreatine-to-ATP ratios of the treated group were significantly higher than that of the untreated group. The untreated group, but not the treated group, had significant reductions in mitochondrial F0F1-ATPase subunits compared with controls. Congestive heart failure as evidenced by significant ascites (100 to 2000 mL) developed in 4 of the 9 untreated animals, but was absent in the treated group. Animals with heart failure demonstrated reductions in both mitochondrial F0F1-ATPase expression and myocardial high-energy phosphate levels. Thus, severe LV dysfunction and accompanying abnormal myocardial bioenergetic phenotype were prevented by the AT1 antagonist olmesartan medoxomil.
Departments of Medicine and Radiology, University of Minnesota Health Sciences, Minneapolis, MN 55455
Supported by US Public Health Service Grants HL50470, HL61353, HL67828, and HL71970.
Reprints: Jianyi Zhang, MD, PhD, University of Minnesota Academic Health Center, Mayo Mail Code 508, 420 Delaware Street SE, Minneapolis, MN 55455 (e-mail: email@example.com)
Received for publication December 14, 2005; accepted March 15, 2006
The current address for Koichi Ochiai, Yo Murakami, and Toshio Shimada is Department of Cardiology, Shimane University School of Medicine, Izumo, Shimane 693–8501, Japan.
The authors Koichi Ochiai, Qingsong Hu, and Joseph Lee contributed equally to this manuscript.
Acute myocardial infarction instigates complex alterations in the geometric, structural, and biochemical architecture of both infarct and noninfarct regions of the heart. Such changes profoundly alter left ventricular (LV) structure and function. LV dilatation, scar expansion, and hypertrophy of remote noninfarct myocardium give poor cardiac performance and can lead to heart failure. On the molecular level, the postinfarcted heart exhibits perturbations in both high-energy phosphate (HEP) metabolism and mitochondrial F0F1-ATPase expression.1–3 We previously reported a porcine model of postinfarction LV remodeling.3 The significant characteristics of this model were LV chamber dilation, reduced systolic performance, increased systolic and diastolic wall stresses, depressed myocardial HEP levels, and alterations in both myocardial oxidative phosphorylation regulation and carbon substrate utilization.1–3
Disturbances in myocardial energy metabolism are chiefly characterized by changes to the phosphocreatine-to-ATP ratio (PCr/ATP), which can be considered an important predictor of mortality in patients with heart failure.4 In our previously reported porcine model PCr/ATP was significantly decreased within the hypertrophied myocardium in amounts proportional to the severity of cardiac dysfunction.1,3,5–7 In human studies, decreased myocardial PCr/ATP was seen in patients presenting with angina,8 mitral regurgitation,9 and cardiomyopathy.4 In the latter study, PCr/ATP ratios provided prognostic information and predicted survival better than LV ejection fraction or New York Heart Association classifications.4
The renin-angiotensin-aldosterone system (RAAS) plays an important role in pathologic postinfarction events such as LV remodeling. RAAS antagonists, namely angiotensin II type 1 receptor (AT1) blockers (ARBs) and angiotensin I converting enzyme (ACE) inhibitors, are used primarily for treating hypertension. However, there is increasing evidence of their potential for treating a wider range of cardiovascular disease including myocardial infarction.10,11 The effect of ARBs on myocardial HEP metabolism and mitochondrial F0F1-ATPase remains unknown. In the present study, we hypothesized that hearts undergoing postinfarction LV remodeling would benefit from the administration of olmesartan medoxomil, an ARB also known as CS-866. In particular, using a swine model of postinfarction LV remodeling, we hypothesized that olmesartan treatment would prevent the development of heart failure, attenuate pathologic LV remodeling, and protect both myocardial HEP metabolism and mitochondrial F0F1-ATPase levels.
Studies were based on 26 Yorkshire pigs. All procedures and protocols were approved by the University of Minnesota Animal Care Committee. The investigation conformed to the Guide for the Care and Use of Laboratory Animals by the Institute of Laboratory Animal Research.12
The study groups consisted of (a) 7 pigs given myocardial infarction and oral treatment of 2 mg/kg/d olmesartan medoxomil (Benicar, Sankyo Pharma Inc, Parsippany, NJ) sized-matched with (b) 9 pigs given myocardial infarction but no treatment, and (c) 10 size-matched normal pigs. After production of infarction, olmesartan administration was maintained for 7 weeks followed by terminal studies. Dose selection was based on a previous drug kinetic study of olmesartan medoxomil.13,14 In a pilot study of 3 animals given 1 mg/kg/d myocardial hypertrophy and heart failure were not successfully prevented. A subsequent dose increase to 2 mg/kg/d proved effective and was used for this work.
Production of Myocardial Infarction
A swine model of postinfarction LV remodeling was produced similar to our previous work.2,3,5 Briefly, Yorkshire pigs at ∼45 days of age were anesthetized with sodium pentobarbital (25 to 30 mg/kg IV), intubated, and mechanically ventilated. The heart was exposed through a left thoracotomy in the third intercostal space and suspended in a pericardial cradle. The proximal left circumflex coronary artery (0.5 cm) was dissected free and completely occluded using a 3-0 silk ligature. The animals were observed in the open chest state for 60 minutes and electrically defibrillated in the event of ventricular fibrillation. The chest was then closed and evacuated of pneumothorax. The animals were given standard postoperative care including analgesia until they were active and eating normally. Animals were returned to the laboratory for terminal studies 7 weeks after infarction.
Animal Preparation for Spectroscopic and Hemodynamic Measurements
Animals were anesthetized with pentobarbital (loading dose of 30 mg/kg IV, maintenance dose of 4 mg/kg/h), intubated, and mechanically ventilated with oxygen-supplemented air to maintain arterial blood gases within physiologic range. To avoid death in subjects suspected as having congestive heart failure (CHF), lower loading doses of pentobarbital (∼15 mg/kg IV) were used.
Catheters were installed for accessing the ascending aorta (Ao), inferior vena cava, LV, left atrium, and interventricular vein (IVV). Catheters were 3.0 mm outer diameter polyvinyl chloride, flushed with heparinized normal saline to prevent clotting, and secured using silk sutures after placement. The Ao catheter was placed through the right femoral artery and advanced into the ascending aorta. Two inferior vena cava catheters were placed through the left external jugular vein at the level of the cervical vertebrae. The heart was exposed via sternotomy and suspended in a pericardial cradle. The LV catheter was fed through the apical dimple. The LA catheter was fed through the left atrial appendage. The IVV cathether was fed by needle through the epicardium into the IVV lumen and secured. To restore the heart to its normal position the pericardial cradle was released.
A single loop transmit/receive radiofrequency coil for magnetic resonance spectroscopy (MRS) was sutured onto the LV wall segment supplied by the left anterior descending coronary artery. The animals were placed into a polyethylene-lined Lucite cradle, and the MRS coil leads were soldered to a balanced-tuned circuit external and parallel to the craniocaudal axis. The entire assembly was then positioned within a 4.7 T magnet.
Physiologically normal arterial blood gases and pH were maintained by adjusting the proportion of oxygen supplied by mechanical ventilation. Hemodynamic parameters (Ao and LV pressure versus time) were monitored using pressure transducers leveled with the heart and logged using a multichannel direct writing recorder (Coulbourne Instruments, Allentown, PA). The large range of LV end diastolic pressures (LVEDP) throughout the study was accommodated by toggling between the normal and high gain recorder settings. Periodic blood gas analyses of Ao and IVV blood were logged for later in use calculating myocardial oxygen consumption.
MRS: Spatially Localized 31P MRS
Measurements were performed in a 40-cm-bore, 4.7 T magnet interfaced to a Spectroscopy Imaging System Corporation (SISCO) console as previously described.6,15 MRS data acquisition was gated to the LV pressure signal, and mechanical ventilation was gated to the cardiac cycle between data acquisitions. Spectra were acquired in late diastole with a pulse repetition time of 6 to 7 seconds. This repetition time permitted full relaxation for ATP and inorganic phosphate resonances and 90% relaxation for PCr resonances. PCr resonance intensities were corrected for this minor saturation; the correlation factor was determined for each heart from 2 spectra recorded consecutively without transmural differentiation, one with 15-second repetition time to allow full relaxation and the other with the 6 to 7-second repetition time used in all the other measurements.6,7
Radiofrequency transmission and signal detection were performed with a 25-mm-diameter surface coil.6,7 The coil was cemented to a 0.7-mm-thick, 38-mm-diameter disc of silicone rubber centered on a reference capillary of 15 μL of 3 M phosphonoacetic acid. Chemical shifts were measured relative to PCr, which was assigned a chemical shift of −2.55 ppm relative to 85% phosphoric acid at 0 ppm.
Spatial localization across the LV wall was performed using the RAPP-ISIS/FSW (rotating-frame experiment using adiabatic plane-rotation pulses for phase modulation—imaging selected in vivo spectroscopy/Fourier series window) method.15 Detailed data regarding voxel profiles, voxel volume, and extensive documentation of the accuracy of the spatial localization obtained in phantom studies and in vivo have been published elsewhere.15 Each set of spatially localized transmural spectra were acquired in 10 minutes. A total of 96 scans were accumulated within each 10-minute block.
Resonance intensities were quantified with integration routines in VNMR 6.1 software (Varian Associates; Palo Alto, CA). ATP-γ was used for ATP determination. Because data were acquired with the transmitter frequency positioned between the ATP-γ and PCr resonances, the off resonance effects on these peaks were negligible. The numeric values for PCr and ATP in each voxel were expressed as ratios of PCr/ATP.
Myocardial Blood Flow Measurements
The distribution of blood flow across the wall of the LV was estimated using 15-μm diameter microspheres labeled with different radioisotopes: 141Ce, 51Cr, 85Sr, 95Nb, and 46Sc.31 Microspheres were agitated in an ultrasonic mixer and a vortex agitator for at least 15 minutes before injection. Blood flow measurements were obtained by injecting 3×106 microspheres through the left atrial catheter and flushing with 10 mL of normal saline. A reference arterial blood specimen was withdrawn from the ascending aorta at a rate of 15 mL/min beginning 5 seconds before the injection and continuing for 90 seconds. Subsequent to the termination of the study, blood flow was determined from tissue samples as described below.
Biopsy and Tissue Preparation
Myocardial biopsies were obtained from the region beneath the surface coil with drill biopsy precooled in liquid nitrogen and stored at −80°C for later ATPase measurement. Each pig was subsequently euthenized with sodium pentobarbital. The heart was excised and fixed in 10% formalin. The LV was divided into transverse rings 1 cm in thickness with one ring centered under the surface coil. Myocardium from the LV was sectioned into 3 transmural layers of equal thickness. Regional blood flow was determined by counting the radioactivity in each section using a γ spectrometer with multichannel analyzer. The radioactivity in each energy window, background activity and tissue sample weights were entered into a computer, which calculated the corrected counts for each isotope. Knowing the rate of withdrawal of the reference blood specimen (Qr) and the radioactivity of the reference sample (Cr), myocardial blood flow (Qm) was determined from myocardial radioactivity (Cm) as: Qm=Qr×Cm/Cr. Blood flow was expressed mL/min/g (wet weight) of myocardium.
Oxygen Consumption Measurements
Blood specimens were withdrawn anaerobically into iced syringes from the aortic and coronary sinus catheters (3 mL each). pO2, pCO2, and pH were measured with a blood gas analyzer (model 1304, Instrumentation Laboratory, Lexington, MA) calibrated with known gas mixtures. Hemoglobin content was determined by the cyanmethemoglobin method. Blood oxygen content was calculated as hemoglobin×1.34% O2 saturation+(0.0031×pO2), using oxygen dissociation curve for dog blood.7 Myocardial oxygen consumption rate was computed as the product of myocardial blood flow and the oxygen content difference between aortic and coronary sinus blood.
Mitochondrial ATPase Subunit Protein Levels
Frozen heart samples (∼100 mg) were powdered in a liquid nitrogen cooled mortar, homogenized in 1 mL of ice-cold buffer (0.25 M sucrose, 50 mM Tris-HCl, 10 mM sodium azide, pH 8.5), incubated for 1 hour at room temperature and then centrifuged at 10,000g for 10 minutes at room temperature. The supernatants were used for Western blotting, and protein concentration was determined by a modified Lowry analysis (Sigma, Protein Assay Kit). Total protein extract (15 mcg) was loaded into a standard discontinuous 12% polyacrylamide/sodium dodecyl sulfate gel run at 200 V for 90 minutes. Proteins were transferred to Bio-Rad nitrocellulose membranes. Transfer efficiency was assessed by staining the gel pretransfer and posttransfer with Coomassie blue. Nonspecific binding sites were blocked by incubating the membrane in 5% nonfat milk buffer overnight. The antibodies 7B3 (against α-subunit-F1-ATPase), 19D3 (β-subunit-F1-ATPase), 2B1B1 [oligomycin sensitivity-conferring protein (OSCP) subunit], and 2H10 (the IF1 subunit) were produced as previously described.1 The primary antibody was diluted in antibody buffer [1% nonfat milk in 0.1% Tris-buffered saline Tween-20 (TTBS)] and incubated with the membranes for 2 hours on a rotating cylinder. The membrane was washed 3 times with TTBS buffer for 30 minutes. Appropriate horseradish peroxidase-labeled secondary antibodies (goat antimouse) were then incubated with membrane for 1 hour. The membrane was again washed 3 times in TTBS buffer before a 1-minute incubation with enhanced chemiluminescent substrate (Amersham). Light emission was detected by exposure to Kodak RX autoradiography film. Signal densities were quantified using a Bio-Rad laser densitometric scanner and normalized to the intensities of the same amount of β-actin protein.
After situating animals within the 4.7 T magnet, data were collected to measure hemodynamics, blood gases, 31P spectra of HEP, and myocardial blood flow. Afterward, animals were sacrificed for tissue collection.
Hemodynamic data were measured directly from the chart recordings. The integrated numeric values for PCr and ATP during each experimental condition were expressed as PCr/ATP. All data are expressed as mean±SD. One-way ANOVA identified the presence of any difference in group means. The Scheffe multiple comparison test evaluated the significance of pairwise differences between group means. Differences were considered statistically significant at a value of P<0.05.
All animals receiving left circumflex coronary artery ligation sustained transmural infarction. Key anatomic findings are summarized in Table 1. The LV-to-body weight ratio (LVW/BW, g/kg) increased 36% in untreated hearts (P<0.05), but did not differ significantly (P>0.05) in hearts receiving olmesartan compared with the control group (Table 1). Compared with the normal group, the right ventricle-to-body weight ratio increased 110% in untreated hearts (P<0.05) and increased 58% in treated hearts. Only the untreated group developed significant ascites (437±406 mL) in contrast to the treated group (21±2 mL) and control (Table 1).
Hemodynamic data are shown in Table 2. The untreated group had aortic systolic, diastolic, and mean aortic pressures significantly higher than that of the control group (Table 2, P<0.05).
The untreated group LV systolic pressure tended to be higher, but there were no significant differences between groups. In contrast, LVEDP were significantly higher in both infarct groups than normal controls. Moreover, the untreated group LVEDP was significantly higher than the treated group (P<0.05).
Heart rate, LV systolic pressure, and the rate pressure product did not differ significantly between groups.
Myocardial Blood Flow and Oxygen Consumption
Myocardial blood flow and oxygen consumption data are summarized in Table 3. Under the basal conditions, the myocardial blood flow and myocardial oxygen consumption tended to be higher in hearts with postinfarction LV remodeling, but the difference was not significant (P>0.05). There were no significant differences between the treated and untreated groups at high cardiac workstates (HCWs) (Table 3).
Figure 1 illustrates sets of typical transmurally differentiated spectra acquired from control, untreated, and treated animals. In the figure, the voxel labeled EPI corresponds to the subepicardial layer. MID corresponds to the midmyocardium. ENDO corresponds to the subendocardial layer, with little penetration into the LV cavity, and is the voxel most distant from the coil. We have shown previously that these 3 voxels have no overlap.15
All the spectroscopy data are summarized in Table 4. The PCr/ATP ratios of the untreated group throughout all layers were significantly lower than both treated and normal groups (Table 4, P<0.05). PCr/ATP ratios were significantly higher in the midmyocardial to subendocardial layer of the treated group than the untreated group (P<0.05, Table 4). At very HCWs, myocardial PCr/ATP decreased in all groups, which was lowest in the subendocardial layers of the untreated group (Table 4), Myocardial ΔPi/PCr did not differ between the groups under the baseline, and increased significantly only in the untreated group (P<0.05, Table 4).
Mitochondrial Protein Levels of mtATPase Subunits
Figure 2 shows representative Western blots of mitochondrial α, OSCP, IF1, β ATPase, and β actin from normal, LV remodeling, and AT1 blockade treated hearts. All the quantified protein data are summarized in Table 5. Untreated hearts exhibited significant reductions in all 4 mitochondrial ATPases (Fig. 2, Table 5), with the most severe change in the periscar area of failing hearts (data not shown). Mitochondrial ATPase protein expression did not differ significantly between control and treated hearts in the β and OSCP subunits.
This study tested the hypothesis that chronic oral olmesartan medoxomil administration would attenuate pathologic LV remodeling, preserve both PCr/ATP and mitochondrial ATPase levels in the myocardium and also prevent the development of heart failure in a porcine model of postinfarction LV remodeling. This hypothesis is supported by our findings. The major findings in the present study are that: (1) the AT1 antagonist olmesartan prevented myocardial hypertrophy and heart failure after myocardial infarction, (2) olmesartan improved HEP metabolism in the myocardium remote from the LV scar, and (3) olmesartan prevented reduction of mitochondrial ATPase expression after myocardial infarction.
Characteristics of the Animal Model
Swine have inherently poor coronary collateral development. When given coronary artery occlusion they sustain transmural myocardial infarction that is subsequently replaced by scar. Using this experimental model we previously observed LV dilation and dysfunction in all animals within 8 weeks after coronary ligation.1–3 Compared with that in healthy swine, LV diastolic wall stress increased in animals with LV remodeling (LVR) and was most severe in animals progressing to CHF.1–3 The ejection fractions were significantly reduced in hearts with LVR. The model of this previous work also exhibited abnormalities in HEP metabolism. In animals with compensated LVR, the PCr/ATP ratio was reduced significantly in the subendocardial layer of the noninfarct remote area compared with controls. In animals with CHF, the PCr/ATP ratio was decreased in all transmural layers compared with normal controls.1–3
In the present study we employed the same porcine model of myocardial infarction, but also introduced the olmesartan medoxomil treatment with the goal of preventing the pathologic myocardial remodeling and perturbations in HEP metabolism. Animals with LV infarction that were denied olmesartan treatment experienced significantly elevated LVW/BW ratio, elevated mean aortic pressure indicating increased peripheral arterial resistance, elevated LVEDP, impaired HEP metabolism, and progression to heart failure. No such significant deteriorations were observed in animals receiving olmesartan medoxomil treatment, and in that regard these treated animals were instead similar to the healthy controls. Thus, the AT1 antagonist olmesartan medoxomil was beneficial in preserving hemodynamics and myocardial HEP metabolism in the face of myocardial infarction.
AT1 Antagonist and Postinfarction Remodeling
In the face of transmural myocardial infarction, the remote viable myocardium hypertrophies to compensate for the loss of functional LV mass. In our porcine model, the overgrowth of remote viable myocardium far outweighs any reduction of mass in the infarct scar tissue and results in increased LVW/BW.1–3
Myocardial infarction activates the RAAS, resulting in a complex cascade that spans the heart and other organs such as the kidneys and brain.16,17 The multiple events underlying these processes are not yet fully understood, but there is increasing knowledge about mechanisms that link the RAAS with myocardial infarction and the progression to heart failure. The intracardiac RAAS influences collagen deposition and extracellular matrix remodeling in the myocardium.18 The hypertrophy of remote viable myocardium has been shown to be signaled by the translocation and angiotensin-AT1-receptor-dependent activation of protein kinase C.19 The AT1a receptor has been implicated in cell infiltration, cytokine production, and neovascularization in infarcted myocardium.20 AT1 receptor blockade was shown to enhance vasorelaxation in heart failure by increasing nitric oxide bioavailability.21
The olmesartan-induced beneficial effect in myocardial bioenergetic could be a result of a primary effect on myocytes via activation of protein kinase c,19 or a result of the intracardiac RAAS influences collagen deposition and extracellular matrix remodeling in the myocardium.18 Using a rat model of postinfarction LV remodeling, Hugel et al22 demonstrated that improvement of myocardial bioenergetics was caused by either an ACE inhibitor or a β blocker treatment, which were both associated with decrease of blood pressure. In the present study, ARB treatment resulted in the decrease of preload and after-load (Table 2), and consequently a decrease of LV wall stresses. These changes by necessity would decrease in myocardial energy demand, which in turn would result in the improvement in balance of myocardial delivery and demand. We cannot exclude the beneficial effects from the contribution of the aforementioned primary effects of olmesartan treatment on myocytes or extracellular matrix. However, to prove this primary effect requires detailed in vitro studies to define the molecular beneficial signaling systems that are triggered by the ARB, which are beyond the scope of the present study.
Myocardial HEP Changes
Consistent with our previous reports, the present study showed that postinfarction remodeling of the heart is characterized by significant PCr/ATP depression suggesting an energy inefficient heart. Animals not receiving treatment experienced significant depression of PCr/ATP throughout all transmural layers. In contrast, animals receiving olmesartan medoxomil were protected from such severe bioenergetic deterioration; PCr/ATP in the treated group was significantly elevated across the entire LV wall compared with the untreated group and did not differ significantly in the epicardial layer compared with the controls. Because of its low myocardial levels (20 to 80 μM), free myocardial ADP concentration [ADP] was not measurable by 31P MRS. However, [ADP] can be calculated from the equilibrium of creatine kinase (CK):
where Keq=1.66×109 M−1.23 PCr/ATP is considered directly proportional to phosphorylation potential [ATP]/[ADP][Pi]. Accordingly, the decreased PCr/ATP ratio indicated an increase in myocardial-free ADP level and decrease of free energy released per unit of ATP use (ΔG), which is associated with LV dysfunction.24 Decreased PCr/ATP significantly correlates with reduced CK activity and reduced mtATPase.1 Thus, hearts with depressed PCr/ATP were functionally impaired in both HEP transport and HEP synthesis (mediated by CK and mtATPase, respectively). The significantly lower PCr/ATP ratio in untreated pigs reflects that mitochondrial ATP machinery is less efficient and requires higher driving forces of myocardial free ADP.
This beneficial effect ARB treatment induced improvement in myocardial energetic efficiency could be more pronounced during an oxidative stress such as at HCWs secondary to catecholamine stimulation. A further reduction in energetic efficiency at HCWs of failing hearts was observed before using the same animal model.2 In the present study the myocardial PCr/ATP further decreased at HCWs, which is most severe in the subendocardial layers of the untreated LV remodeling hearts (P<0.05 vs. control or AT (+) hearts, Table 4) suggesting that the abnormal myocardial bioenergetic phenotype were improved by the AT1 antagonist olmesartan medoxomil. This improvement in myocardial bioenergetics at the HCW was independent of the differences in LV pressure, myocardial blood flow, and oxygen consumption, as there were no significant differences between the groups with or without olmesartan treatment (Tables 2 and 3, respectively). These data suggest a primary olmesartan effect on myocytes might also contribute to the beneficial effects in myocardial bioenergetics.
Mitochondrial ATPase Changes
Consistent with our previous work, the present study showed that postinfarction remodeling of the heart is characterized by significant mtATPase depression.1 Animals not receiving treatment experienced significant reduction of mtATPase subunits in the heart. In contrast, animals receiving olmesartan medoxomil were protected from such bioenergetic deterioration. Compared with controls, mtATPase in the treated group was not significantly different in the β or the OSCP subunits. Compared with the untreated group, mtATPase in the treated group was significantly higher in the α and IF1 subunits. This is the first report of mtATPase protection using an AT1 blockade and suggests there could be a mechanistic link between the AT1 receptor cascade and mtATPase regulation.
HEP Metabolism With RAAS Blocking
In the present study, RAAS antagonism by an ARB improved HEP abnormalities after myocardial infarction. There is little previous work that has evaluated RAAS antagonism for myocardial infarction through HEP levels. The little work that does exist largely focuses on RAAS antagonism using ACE inhibitors. Nonetheless, such work provides preliminary evidence that RAAS antagonism could be useful in maintaining myocardial HEP metabolism in the face of myocardial infarction. Quinapril treatment in a rat model of myocardial infarction showed improvements in HEP metabolism, energy reserve via the creatine kinase reaction, and contractile performance.22 ACE inhibition using captopril, enalapril, and trandolapril in a rat model of postinfarction LV remodeling preserved myocardial HEP levels via effects associated with increased mitochondrial oxidation.25 ACE inhibition via quinapril prevented depression of phosphocreatine in viable remote myocardium in a rat model of myocardial infarction.26
AT1 antagonists are expected to have comparable effects in improving HEP metabolism in the acute postischemic myocardium.27 An ARB (CV-11974) preserved HEP metabolism in perfused isolated rabbits hearts subjected to acute ischemia-reperfusion injury.28–30 However, reports regarding HEP metabolism and chronic ARB treatment for myocardial infarction are entirely absent.
Taken together, the findings in this study suggest that the significant depression of myocardial HEP levels and mitochondrial ATPase subunit expression1 are caused by increased diastolic wall stresses in the dysfunctional LV. At the cellular level, the mechanical overdistention of myocytes may signal or trigger these bioenergetic changes. This abnormal myocardial bioenergetic phenotype can be prevented by chronic ARB administration, which significantly unloaded the dysfunctional LV.
In conclusion, RAAS antagonism via chronic administration of the ARB olmesartan medoxomil prevented both the pathologic myocardial remodeling and subsequent progression to heart failure. These benefits were accompanied by the preservation of myocardial HEP and mitochondrial ATPase levels.
1. Liu J, Wang C, Murakami Y, et al. Mitochondrial ATPase and high-energy phosphates in failing hearts. Am J Physiol Heart Circ Physiol. 2001;281:H1319–H1326.
2. Murakami Y, Zhang Y, Cho YK, et al. Myocardial oxygenation during high work states in hearts with postinfarction remodeling. Circulation. 1999;99:942–948.
3. Zhang J, Wilke N, Wang Y, et al. Functional and bioenergetic consequences of postinfarction left ventricular remodeling in a new porcine model. MRI and 31 P-MRS study. Circulation. 1996;94:1089–1100.
4. Neubauer S, Horn M, Cramer M, et al. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation. 1997;96:2190–2196.
5. Ye Y, Gong G, Ochiai K, et al. High-energy phosphate metabolism and creatine kinase in failing hearts: a new porcine model. Circulation. 2001;103:1570–1576.
6. Zhang J, Merkle H, Hendrich K, et al. Bioenergetic abnormalities associated with severe left ventricular hypertrophy. J Clin Invest. 1993;92:993–1003.
7. Zhang J, Toher C, Erhard M, et al. Relationships between myocardial bioenergetic and left ventricular function in hearts with volume-overload hypertrophy. Circulation. 1997;96:334–343.
8. Buchthal SD, den Hollander JA, Merz CN, et al. Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms. N Engl J Med. 2000;342:829–835.
9. Conway MA, Bottomley PA, Ouwerkerk R, et al. Mitral regurgitation: impaired systolic function, eccentric hypertrophy, and increased severity are linked to lower phosphocreatine/ATP ratios in humans. Circulation. 1998;97:1716–1723.
10. Capasso JM, Li P, Meggs LG, et al. Efficacy of angiotensin-converting enzyme inhibition and AT1 receptor blockade on cardiac pump performance after myocardial infarction in rats. J Cardiovasc Pharmacol. 1994;23:584–593.
11. Schieffer B, Wirger A, Meybrunn M, et al. Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat. Circulation. 1994;89:2273–2282.
12. Institute of Laboratory Animal Resources (US). Guide for the Care and Use of Laboratory Animals. Washington, DC: National Academy Press; 1996.
13. Puchler K, Nussberger J, Laeis P, et al. Blood pressure and endocrine effects of single doses of CS-866, a novel angiotensin II antagonist, in salt-restricted hypertensive patients. J Hypertens. 1997;15:1809–1812.
14. Schwocho LR, Masonson HN. Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects. J Clin Pharmacol. 2001;41:515–527.
15. Liu H, Zhang J. An efficient MR phosphorous spectroscopic localization technique for studying ischemic heart. J Magn Reson Imaging. 1999;10:892–898.
16. Meggs LG, Coupet J, Huang H, et al. Regulation of angiotensin II receptors on ventricular myocytes after myocardial infarction in rats. Circ Res. 1993;72:1149–1162.
17. Tan J, Wang H, Leenen FH. Increases in brain and cardiac AT1 receptor and ACE densities after myocardial infarct in rats. Am J Physiol Heart Circ Physiol. 2004;286:H1665–H1671.
18. Lijnen PJ, Petrov VV. Role of intracardiac renin-angiotensin-aldosterone system in extracellular matrix remodeling. Methods Find Exp Clin Pharmacol. 2003;25:541–564.
19. Simonis G, Dahlem MH, Hohlfeld T, et al. A novel activation process of protein kinase C in the remote, non-ischemic area of an infarcted heart is mediated by angiotensin-AT1 receptors. J Mol Cell Cardiol. 2003;35:1349–1358.
20. Toko H, Zou Y, Minamino T, et al. Angiotensin II type 1a receptor is involved in cell infiltration, cytokine production, and neovascularization in infarcted myocardium. Arterioscler Thromb Vasc Biol. 2004;24:664–670.
21. Thai H, Wollmuth J, Goldman S, et al. Angiotensin subtype 1 receptor (AT1) blockade improves vasorelaxation in heart failure by up-regulation of endothelial nitric-oxide synthase via activation of the AT2 receptor. J Pharmacol Exp Ther. 2003;307:1171–1178.
22. Hugel S, Horn M, de Groot M, et al. Effects of ACE inhibition and beta-receptor blockade on energy metabolism in rats postmyocardial infarction. Am J Physiol. 1999;277:H2167–H2175.
23. Lawson JW, Veech RL. Effects of pH and free Mg2+ on the Keq of the creatine kinase reaction and other phosphate hydrolyses and phosphate transfer reactions. J Biol Chem. 1979;254:6528–6537.
24. Tian R, Ingwall JS. Energetic basis for reduced contractile reserve in isolated rat hearts. Am J Physiol. 1996;270:H1207–H1216.
25. Sanbe A, Tanonaka K, Kobayasi R, et al. Effects of long-term therapy with ACE inhibitors, captopril, enalapril and trandolapril, on myocardial energy metabolism in rats with heart failure following myocardial infarction. J Mol Cell Cardiol. 1995;27:2209–2222.
26. Horn M, Neubauer S, Frantz S, et al. Preservation of left ventricular mechanical function and energy metabolism in rats after myocardial infarction by the angiotensin-converting enzyme inhibitor quinapril. J Cardiovasc Pharmacol. 1996;27:201–210.
27. Werrmann JG, Cohen SM. Comparison of effects of angiotensin-converting enzyme inhibition with those of angiotensin II receptor antagonism on functional and metabolic recovery in postischemic working rat heart as studied by [31P] nuclear magnetic resonance. J Cardiovasc Pharmacol. 1994;24:573–586.
28. Kawabata H, Ryomoto T, Ishikawa K. Cardioprotection with angiotensin converting enzyme inhibitor and angiotensin II type 1 receptor antagonist is not abolished by nitric oxide synthase inhibitor in ischemia-reperfused rabbit hearts. Hypertens Res. 2001;24:403–409.
29. Kawabata H, Ryomoto T, Ishikawa K. Effect of angiotensin converting enzyme inhibitor and angiotensin II type 1 receptor antagonist on metabolism and contraction in ischemia-reperfused rabbit heart. Jpn Circ J. 2000;64:276–282.
30. Kawabata H, Ryomoto T, Ishikawa K. Role of cardiac ATP-sensitive K+ channels induced by angiotensin II type 1 receptor antagonist on metabolism, contraction and relaxation in ischemia-reperfused rabbit heart. Jpn Circ J. 2001;65:451–456.
31. Domenech RJ, Hoffman JI, Noble MI, et al. Total and regional coronary blood flow measured by radioactive microspheres in conscious and anesthetized dogs. Circ Res. 1969;25:581–596.
32. Liao R, Jain M, Cui L, et al. Cardiac-specific overexpression of GLUT1 prevents the development of heart failure attributable to pressure overload in mice. Circulation. 2002;106:2125–2131.
33. Spindler M, Engelhardt S, Niebler R, et al. Alterations in the myocardial creatine kinase system precede the development of contractile dysfunction in beta(1)-adrenergic receptor transgenic mice. J Mol Cell Cardiol. 2003;35:389–397.
Keywords:© 2006 Lippincott Williams & Wilkins, Inc.
high-energy phosphates; myocardial infarction; heart failure; hypertrophy; nuclear magnetic resonance spectroscopy; myocardial energetics