Am J Physiol Heart Circ Physiol 294: H2313-H2321, 2008.
First published March 7, 2008; doi:10.1152/ajpheart.01288.2007
0363-6135/08 $8.00
Relationships between regional myocardial wall stress and bioenergetics in hearts with left ventricular hypertrophy
Julia Feygin,1,2
Qinsong Hu,2
Cory Swingen,2 and
Jianyi Zhang1,2
Departments of 1Biomedical Engineering and 2Division of Cardiology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
Submitted 2 November 2007
; accepted in final form 6 March 2008
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ABSTRACT
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This study utilized porcine models of postinfarction left ventricular (LV) remodeling [myocardial infarction (MI); n = 8] and concentric LV hypertrophy secondary to aortic banding (AoB; n = 8) to examine the relationships between regional myocardial contractile function (tagged MRI), wall stress (MRI and LV pressure), and bioenergetics (31P-magnetic resonance spectroscopy). Physiological assessments were conducted at a 4-wk time point after MI or AoB surgery. Comparisons were made with size-matched normal animals (normal; n = 8). Both MI and AoB instigated significant LV hypertrophy. Ejection fraction was not significantly altered in the AoB group, but significantly decreased in the MI group (P < 0.01 vs. normal and AoB). Systolic and diastolic wall stresses were approximately two times greater than normal in the infarct region and border zone. Wall stress in the AoB group was not significantly different from that in normal hearts. The infarct border zone demonstrated profound bioenergetic abnormalities, especially in the subendocardium, where the ratio of PCr/ATP decreased from 1.98 ± 0.16 (normal) to 1.06 ± 0.30 (MI; P < 0.01). The systolic radial thickening fraction and the circumferential shortening fraction in the anterior wall were severely reduced (MI, P < 0.01 vs. normal). The radial thickening fraction and circumferential shortening fraction in the AoB group were not significantly different from normal. The severely elevated wall stress in the infarct border zone was associated with a significant increase in chemical energy demand and abnormal myocardial energy metabolism. Such severe metabolic perturbations cannot support normal cardiac function, which may explain the observed regional contractile abnormalities in the infarct border zone.
myocardial infarction; left ventricular remodeling; metabolism
POSTINFARCTION LEFT VENTRICULAR (LV) remodeling often leads to the evolution of heart failure. However, the mechanisms contributing to the transition from compensated ventricular remodeling to congestive heart failure (CHF) remain unclear. Tethering of the border zone (BZ) to the infarct causes an increase in the radius of curvature of the surrounding viable myocardium, thereby increasing wall stress and stress-associated energy demands in viable myocardium in the infarct BZ (7). Using a porcine model of postinfarction LV remodeling, we previously observed significant bioenergetic abnormalities in remote, noninfarcted myocardial regions in animals with overt CHF, whereas only modest alterations were observed in the remote myocardial regions of animals undergoing compensated LV remodeling (7). We have recently reported that the abnormal myocardial bioenergetic state, as represented by high-energy phosphate (HEP) content and the phosphocreatine (PCr)-to-ATP ratio (PCr/ATP), is markedly more severe in the infarct BZ compared with remote myocardial regions in the same hearts (7). We hypothesized that, over time, the bioenergetic and contractile abnormalities of the BZ, which are triggered by elevated regional wall stress, may extend laterally and eventually involve the entire LV, thereby leading to global LV dysfunction and the development of CHF. If this hypothesis is correct, then hearts with concentric LV hypertrophy (LVH) containing a small chamber cavity and thicker LV wall should have normal regional LV wall stress and relatively less severe abnormalities in myocardial bioenergetics. In the present study, we, therefore, compared a porcine model of eccentric LVH secondary to a myocardial infarction (MI) to a porcine model of concentric LVH secondary to aortic banding (AoB). Myocardial wall stress and contractile function were assessed with cine and tagged MRI; myocardial bioenergetics was assessed with 31P-NMR spectroscopy.
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METHODS
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All experiments were performed in accordance with the animal use guidelines of the University of Minnesota, and the experimental protocol was approved by the University of Minnesota Research Animal Resources Committee. The investigation conformed to the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication no. 85-23, revised 1985).
Induction of MI.
Details of the animal model of postinfarction LV remodeling have been described previously (9, 24). Briefly, young Yorkshire swine (45 days old, 
10 kg) were anesthetized with pentobarbital (30 mg/kg iv), intubated, and ventilated with a respirator with supplemental oxygen. Arterial blood gases were maintained within the physiological range by adjustments of the respiratory settings and oxygen flow. A left thoracotomy was performed, and 0.5 cm of the left anterior descending coronary artery (LAD) distal to the second diagonal branch was dissected free and totally occluded with a ligature. After coronary ligation, animals were observed in the open-chest state for 60 min. When ventricular fibrillation occurred, electrical defibrillation was performed immediately. The chest was then closed, but, if the heart was dilated, the pericardium was left open. The animals were given standard postoperative care, including analgesia, until they ate normally and resumed full activity. Animals returned to the laboratory 3.5 and 4 wk later for MRI and 31P-magnetic resonance (MR) spectroscopic studies, respectively.
Induction of LVH with AoB.
Details of the animal model of LVH have been described previously (4, 20). Briefly, young Yorkshire swine (45 days old, 10 kg) were anesthetized with pentobarbital (30 mg/kg iv), intubated, and ventilated with a respirator with supplemental oxygen. Arterial blood gases were maintained within the physiological range by adjustments of the respiratory settings and oxygen flow. A right thoracotomy was performed in the third intercostals space, and the ascending aorta (Ao) (1.5 cm above the aortic valve) was mobilized and encircled with a polyethylene band 2.5 mm in width. While LV and distal aortic pressures were simultaneously measured, the band was tightened until a 70-mmHg peak systolic pressure gradient was achieved across the narrowing. The chest was then closed, pneumothorax was evacuated, and the animals were allowed to recover. LVH occurred progressively as the area of aortic constriction remained fixed in the face of normal body growth. Animals returned to the laboratory 3.5 and 4 wk later for MRI and 31P-MR spectroscopic studies, respectively.
Tagged- and cine-MRI protocol.
MRI was performed 25 days following surgery on a 1.5-T clinical scanner (Siemens Sontata, Siemens Medical Systems, Islen, NJ) using a phased-array four-channel surface coil and ECG gating. Animals were anesthetized with 1% isoflurane and positioned in a supine position within the scanner. The protocol consisted of 1) localizing scouts to identify the long and short axis of the heart; 2) short- and long-axis cine for the measurement of global cardiac function; 3) short-axis imaging with myocardial tagging in three slices for the measurement of regional myocardial strain; and 4) delayed contrast enhancement for the assessment of scar size and position. Steady-state free precession "True-FISP" cine imaging used the following MR parameters, repetition time (TR) = 3.1 ms, echo time (TE) = 1.6 ms, flip angle = 79°, matrix size = 256 x 120, field of view = 340 mm x 265 mm, slice thickness = 6 mm (4-mm gap between slices), and 16–20 phases were acquired across the cardiac cycle. Global function and regional wall thickness data were computed from the short-axis cine images using MASS (Medis Medical Imaging Systems, Leiden, The Netherlands) for the manual segmentation of the endocardial and epicardial surfaces at both end diastole (ED) and end systole (ES) from base to apex.
The tagging preparation consisted of nonselective radio-frequency pulses separated by encoding gradients for spatial modulation of magnetization, resulting in a tag-line separation of 6 mm. Three short-axis slices were prescribed at a basal, midventricular, and apical level, identical to the cine image positions. At each slice location, two sets of cine images were acquired with tag lines in orthogonal directions with the following scan parameters: TR = 6.5 ms, TE = 2.1 ms, flip angle = 14°, matrix size = 256 x 128, field of view = 320 mm x 320 mm, slice thickness = 6 mm, and a minimum of 14 cardiac phases. Tagged images were acquired for resting conditions only. Tagging data were analyzed using the HARP analysis package (HARP version 2.0, Nael Osman, John Hopkins Medical School), as described elsewhere (14, 15). Two-dimensional myocardial strains were assessed offline in six circumferential myocardial segments per short-axis slice. Transmural strains were calculated between the reference ED and ES state as the fractional change in length in the circumferential and radial directions.
Infarct size.
At the completion of the open-chest MR spectroscopy and hemodynamic measurements, animals were killed by an overdose of pentobarbital, and the heart explanted. The LV was opened at the lateral wall from base to apex, and a photograph was taken for infarct size measurement. Infarct size was expressed as a percentage of LV surface area by an image analysis system (NIH image J program, http://rsb.info.nih.gov/ij).
Surgical preparation for open-chest MR spectroscopy study.
Animals were anesthetized with pentobarbital (loading dose of 30 mg/kg iv, maintenance dose of 4 mg·kg–1·h–1), intubated, and mechanically ventilated with oxygen-supplemented air to maintain arterial blood gases within the physiological range. Three-millimeter outer diameter polyvinyl chloride catheters were inserted into the ascending Ao, inferior vena cava, and LV. Catheters were flushed with heparinized normal saline to prevent clotting and secured using silk sutures after placement. The Ao catheter was placed via the left internal carotid artery at the level of the cervical vertebrae. Two inferior vena cava catheters were placed through the left external jugular vein. The heart was exposed via a sternotomy and suspended in a pericardial cradle. The LV catheter was introduced through the apical dimple.
A 28-mm-diameter single-loop transmit/receive radio-frequency coil for magnetic resonance spectroscopy was sutured onto the anterior wall of the LV such that most of the coil was directly over the scar and a small portion of the coil was over the infarct BZ. Scar tissue does not contain HEPs, and, therefore, the entire NMR signal was obtained from the infarct BZ. To restore the heart to its normal position, the pericardial cradle was released. The animals were placed into a polyethylene-lined Lucite cradle, and the 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 superconducting magnet.
Hemodynamic measurements.
Aortic and LV pressures were measured using pressure transducers positioned at midchest level and recorded on an eight-channel recorder (11, 20, 22, 23). Ventilation rate, volume, and inspired oxygen content were adjusted to maintain physiological values for arterial PO2, PCO2, and pH. Aortic and LV pressures were monitored continuously throughout the study (11, 20, 22, 23). Hemodynamic measurements were acquired simultaneously with the spectra.
Spatially localized 31P-MR spectroscopy technique.
Spatially localized 31P-NMR spectroscopy was performed using the rotating-frame experiment using adiabatic plane-rotation pulses for phase modulation (RAPP)-imaging selected in vivo spectroscopy (ISIS)/Fourier series window (FSW) method (11, 20, 22, 23). Detailed experiments documenting voxel profiles, voxel volumes, and spatial resolution attained by this method have been published previously. In this application of RAPP-ISIS/FSW, the signal origin was first restricted to a 12 x 12-mm two-dimensional column perpendicular to the LV wall. The signal was later localized into three-well resolved and five partially resolved layers along the column and hence across the LV wall. Localization along the column was based on B1 phase encoding and employed a nine-term Fourier series window, as previously described (11, 20, 22, 23). Whole wall spectra were obtained with the image-selected in vivo (ISIS) technique, defining a column 12 x 12 mm2 perpendicular to the heart wall. The calibration of spectroscopic parameters was facilitated by placing a polyethylene capillary filled with 15 µl of 3 M/l phosphonoacetic acid into the inner diameter of the surface coil. This phosphonoacetic acid standard was used only for calculating the 90° pulse length of the RAPP-ISIS method (11, 20, 22, 23). The position of the voxels relative to the coil was set according to the B1 strength at the coil center, which was experimentally determined in each case by measuring the 90° pulse length for the phosphonoacetic acid standard contained in the reference capillary at the coil center. NMR data acquisition was gated to the cardiac and respiratory cycles using the cardiac cycle as the master clock to drive both the respirator and the spectrometer, as previously described (11, 20, 22, 23). The surface coil was constructed from a single-turn copper wire, 28 mm in diameter, with each side of the coil leads soldered to a 33-pF capacitor. Complete transmural data sets were obtained in 10-min time blocks using a TR of 6–7 s to allow for full relaxation for ATP and inorganic phosphate and 95% relaxation of the PCr resonance (11, 20, 22, 23). The PCr/ATP were calculated for each transmurally differentiated spectra set, as previously described (11, 20, 22, 23). All resonance intensities were quantified using integration routines provided by the SISCO software.
Data analysis.
Data were analyzed with one-way analysis of variance for repeated measurements. A value of P < 0.05 was considered significant. When significant results were found, individual comparisons were made using the Bonferroni correction. Values are means ± SE.
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RESULTS
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Anatomic data.
Table 1 summarizes the anatomic data from eight normal animals, eight animals with postinfarction LV remodeling (MI group), and eight animals with AoB (AoB group). Infarct size in the MI group was calculated and expressed as the ratio of scar surface area to LV surface area. LAD occlusion produced an infarct on the anterior wall, which encompassed 13 ± 3% of the LV. MI and AoB instigated significant LVH, as assessed by the LV weight (LVW)-to-body weight (BW) ratio (LVW/BW) (P < 0.05, Table 1). The LVW/BW increased from 2.6 ± 0.1 g/kg (normal) to 3.3 ± 0.3 and 3.7 ± 0.2 g/kg in MI and AoB, respectively (P < 0.05, Table 1).
MI hearts were characterized by a thin wall and dilated LV; however, the total LV mass (determined during postmortem assessments) of dilated hearts was still greater than that of normal hearts. These observations are in agreement with earlier reports that disaggregated myocytes from dilated MI hearts were characterized by elongated myocytes with the same or slightly reduced cross-sectional areas (11). Although AoB hearts tended to have a higher LVW/BW, the severity of myocyte hypertrophy was likely similar between the two groups, considering the 13% loss of LV mass in the MI hearts.
LV ejection fraction and hemodynamics.
LV ejection fraction (EF) was measured from CINE MRI images. After 4 wk, EF was not significantly decreased from normal in the AoB group (normal: 55.3 ± 3.1% vs. AoB: 49.5 ± 2.1%), but was significantly decreased in the MI group (MI: 30.4 ± 2.3%, P < 0.01 vs. normal and AoB, Table 2, Fig. 1A). Systemic hemodynamic variables were not statistically different between the three groups of animals. LV systolic pressure was observed to be elevated in AoB animals; however, this observation was not statistically significant. Importantly, LV ED pressure was not elevated in either group, indicating both groups of animals were still undergoing compensated LVH 4 wk after MI or AoB.
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Fig. 1. Myocardial structure and contractile function. A: global myocardial function was assessed by the ejection fraction (EF). Myocardial wall thickness was assessed during diastole (B) and systole (C). Regional myocardial function was assessed throughout left ventricular (LV) ring by measuring radial thickening fraction (TF; D), circumferential shortening fraction (SF; E), systolic wall stress (F), and diastolic wall stress (G). MI, myocardial infarction; AoB, aortic banding; AN, anterior wall; AP, anterior papillary region; LAT, lateral wall; PP, posterior papillary region; PO, posterior wall; SP, septal wall; IZ, infarct zone; BZ, border zone. Values are means ± SE. *P < 0.01 vs. normal;  P < 0.05 vs. normal; #P < 0.01 vs. MI; ^P < 0.05 vs. MI. The infarct region and BZ were localized in the AN segment.
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MRI analysis of LV wall thickness.
LV structure was assessed in three horizontal short-axis rings from the midventricular level of the LV. Each ring was divided into six regions, according to the coronary artery perfusion pattern, as depicted in Fig. 2. Papillary muscle tissue was avoided in wall thickness measurements. Short-axis cine MRI analyses revealed that animals in the MI group developed significant diastolic wall thinning in the anterior region (Table 3, Fig. 1B; P < 0.01 vs. normal). Systolic wall thickness was decreased throughout the entire LV ring, being most severe in the anterior wall (Table 3, Fig. 1C; P < 0.01 vs. normal). Both systolic and diastolic thickness were increased in the AoB group (Table 3, Fig. 2; P < 0.05 vs. normal).
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Fig. 2. Regional analysis by MRI. LV structure was assessed in three horizontal short-axis rings from the central portion of the LV. Each ring was divided into six regions, according to the coronary artery perfusion pattern. In the MI group, the scar and BZ were localized in the anterior region of the LV. RV, right ventricle.
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MRI measured LV function.
Regional myocardial contractile function was assessed by calculating the radial thickening fraction and circumferential shortening fraction (tagged MRI) in the six different segments from three horizontal short-axis rings from the midventricular level of the LV. Radial thickening fraction (TF) was calculated by the equation TF% = (EST – EDT)/EDT x 100%, where EST is ES thickness, and EDT is ED thickness. Circumferential shortening fraction (SF) was calculated by the equation SF% = (ls – ld)/ld x 100%, where ls is systolic length, and ld is diastolic length along the circumferential direction.
The analysis revealed that animals in the MI group developed significant contractile dyskinesis in the anterior region of the LV, where the infarct region and BZ were localized. The radial thickening fraction in the anterior wall was reduced by almost 98% from 40.5 ± 3.1% (normal) to 0.2 ± 1.8% (MI, P < 0.01, Table 4, Fig. 1D). The reduction in radial thickening fraction was much less severe in myocardial regions remote from the scar [posterior wall: 36.7 ± 3.1% (normal) vs. 25.4 ± 1.5% (MI), P < 0.05, Table 4, Fig. 1D]. Moreover, negative radial thickening fractions were observed in a number of pigs in the MI group, indicating that infarct region and BZ were "bulging" outward during systole and not contributing to ventricular contraction. The circumferential shortening fraction was decreased in the anterior wall [–16.7 ± 0.8% (normal) to –5.4 ± 0.1% (MI), P < 0.01, Table 4, Fig. 1E], but was not significantly changed in remote myocardial regions in the posterior wall. The radial thickening fraction and circumferential shortening fraction in the AoB group were not significantly different from normal.
Wall stress.
LV wall stress (
) in different LV segments was calculated according to the Laplace law, as previously described, using the following equation: = PR/(2T) (16), where P is LV pressure measured with a pressure transducer in a fluid filled catheter, R is chamber radius, and T is wall thickness measured from CINE MRI images in the particular region of the LV. Systolic and diastolic wall stresses were approximately two times greater than normal in the infarct region and BZ [systolic wall stress: 157 ± 11 mmHg (normal) vs. 297 ± 17 mmHg (MI), P < 0.01, Table 5, Fig. 1F, diastolic wall stress: 11 ± 1 mmHg (normal) vs. 25 ± 3 mmHg (MI), P < 0.01, Table 5, Fig. 1G]. Systolic and diastolic wall stresses in remote myocardial regions along the posterior wall were also elevated, but to a lesser extent. Wall stress was not elevated in the AoB group.
Myocardial bioenergetics.
Figure 3A illustrates typical transmurally differentiated 31P-NMR spectra obtained from a normal heart, the infarct BZ of an MI heart, and the anterior wall of an AoB heart. The infarct BZ demonstrated profound bioenergetic abnormalities, especially in the subendocardium, where the PCr/ATP decreased from 1.98 ± 0.16 (normal) to 1.06 ± 0.30 (MI; P < 0.01, Table 6, Fig. 3B). It should be noted that, although the PCr/ATP was not measured in remote myocardial regions, in previous experiments using the same animal model, our laboratory observed only modest alterations in the PCr/ATP in remote myocardium of animals with compensated postinfarction LV remodeling (7, 24). The subendocardial PCr/ATP was moderately decreased in the AoB group (PCr/ATP: 1.62 ± 0.08); however, the bioenergetic abnormalities were not nearly as severe as in the infarct BZ (Table 6, Fig. 3B). Correlations between the regional wall stress and BZ myocardial bioenergetics are depicted in Fig. 4. Elevated wall stress was associated with increased regional energy demand and bioenergetic abnormalities (Fig. 4).
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Fig. 3. 31P-NMR spectroscopy. A: representative transmurally differentiated 31P-NMR spectra obtained from the subendocardium (ENDO) and subepicardium (EPI) of a normal heart (normal), an infarcted heart (MI), and a heart with AoB. Vertical scale was adjusted in each spectrum for optimal visualization of the resonance peaks. Therefore, only the PCr-to-ATP ratios are compared in this figure. Resonance peaks correspond to 2,3-diphosphorglycerate (2,3-DPG) from the erythrocytes in the ventricular cavity; inorganic phosphate (Pi), phosphocreatine (PCr), and the three phosphates on ATP. B: The PCr/ATP was calculated by integrating the area under the PCr and ATP- peaks. The PCr/ATP was severely decreased in the infarct BZ of MI hearts, especially on the ENDO surface, while only a moderate depletion in the PCr/ATP was observed in the AoB group. *P < 0.01 vs. normal; #P < 0.01 vs. MI.
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Fig. 4. Correlation between regional variables. A: AN systolic wall stress. B: AN diastolic wall stress. Correlations between the AN stress and BZ myocardial bioenergetics. The observed relationships between alterations in regional wall stress and abnormalities in myocardial bioenergetics suggest that elevated wall stress increases the regional energy demand and results in bioenergetic abnormalities. The observed functional and bioenergetic heterogeneity also suggests that the underlying mechanism behind the progression from compensated postinfarction LV remodeling to congestive heart failure involves the lateral expansion of functional and bioenergetic abnormalities from the infarct BZ to the entire myocardium.
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Because a mature LV scar is very thin, an obvious question concerns the partial volume effect of the thinned LV scar. Due to the relatively low signal-to-noise ratio of 31P-MR spectroscopy, HEP levels in the scar tissue are too low to be detected within the defined sample region of interest (defined by the ISIS method as 17 x 17 mm2). Consequently, the HEP signals obtained from the surface coil positioned adjacent to the infarct represent BZ myocardium with essentially no contribution from the scar tissue.
In principle, the deeper voxels (i.e., more distant from the epicardial surface) contain contributions from LV cavity blood because of partial volume effects in which the voxel contains both the LV wall and the LV chamber. This is recognizable by the presence of 2,3-diphosphoglycerate resonances in the 3 ppm region of the spectra (7, 21). The presence of both blood and cardiac muscle in the same voxel has the potential to distort ATP levels and PCr/ATP, because blood contains ATP but not PCr. The ATP contribution from blood to the endocardial spectrum PCr/ATP has been previously examined and found to be trivial (7, 21). In the present study, the contribution of blood in the NMR region of interest might be greater because of the thinner wall in the infarct BZ. To assess this possibility, the blood ATP contribution was examined with a phantom filled with fresh heparinized blood using the identical spectrometer setup. Prominent resonance peaks of 2,3-diphosphoglycerate appeared at 3 ppm. No ATP resonance was detected, demonstrating that the contribution of LV cavity blood ATP to the endocardial PCr/ATP was negligible.
Correlations between regional variables.
Correlations between the three regional variables (anterior wall stress, BZ myocardial bioenergetics, and anterior wall contractile function) are depicted in Fig. 4. Elevated wall stress increases the regional energy demand and results in bioenergetic abnormalities (Fig. 4). Abnormalities in the three regional variables were found to be significantly linearly related. The observed relationships between alterations in regional wall stress, abnormalities in myocardial bioenergetics, and the impaired regional contractile function suggest a "vicious cycle" that is initiated by the elevated wall stress in the overstretched cardiomyocytes within the infarct region and BZ.
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DISCUSSION
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The main finding of the present study is that the severely elevated wall stress in the infarct BZ was associated with a significant increase in chemical energy demand and abnormal myocardial energy metabolism. Such severe metabolic perturbations cannot support normal cardiac function, which may explain the observed contractile abnormalities. In addition, the dysfunctional cardiomyocytes in the infarct BZ are overstretched, which acts to induce strain-mediated apoptotic signaling systems (21, 22). These data support the hypothesis that a progressive radial expansion of functional and bioenergetic abnormalities from the infarct BZ to the entire LV contributes to the onset of severe LV dysfunction in hearts with postinfarction LV remodeling and the evolution of CHF.
Comparison between concentric and eccentric LVH.
In postinfarction LV remodeling, it is hypothesized that the evolution of heart failure my be related to the progressive expansion of contractile and bioenergetic dysfunction from the region of viable myocardium that surrounds the infarct BZ to the entire LV (7). As a consequence of being mechanically "tethered" to the infarct, the viable myocardial tissue in the BZ increases its radius of curvature, thereby increasing its wall stress and stress-associated energy demands (5, 10, 18). Since the BZ is also mechanically tethered to myocardial tissue, which is more distal to the infarct region, the progressive dysfunction in BZ may adversely affect function of the myocardial tissue to which it is connected, leading to a lateral expansion of functional and bioenergetic abnormalities throughout the LV wall.
In the MI group of the present study, permanent LAD ligation caused a 13 ± 3% infarct on the anterior wall of the LV, resulting in eccentric hypertrophy with chamber dilatation and severe wall thinning. Although this level of MI resulted in compensated postinfarction LV remodeling, significant functional and bioenergetic alterations were observed (Tables 4–6). Pigs in the MI group developed contractile abnormalities and elevated wall stress throughout the LV. However, the abnormalities were most severe in the infarct region and BZ (Figs. 1 and 3). Interestingly, the abnormalities of myocardial wall stress and myocardial bioenergetics were found to be related (Fig. 4), implying that the detrimental cascade of events may be initiated by the elevated wall stress in overstretched cardiomyocytes within the infarct region and BZ.
This study also utilized a porcine model of concentric hypertrophy for comparison with postinfarction hearts, to determine whether the increased BZ wall stress causes regional myocardial bioenergetic abnormalities. Concentric LVH was induced by AoB and resulted in a significant increase in LV wall thickness. In pigs with concentric LVH, the thicker LV wall acted to normalize LV wall stress (Fig. 1). Interestingly, the severity of hypertrophy was similar between the hearts of concentric and eccentric LVH (Table 1, LVW/BW); however, the bioenergetic abnormalities, which were manifested by the decrease of PCr/ATP, were much more severe in the BZ of the MI hearts (Table 6). These data further support the concept that regional myocardial wall stress contributed to the myocardial bioenergetic abnormalities in hearts with postinfarction LV remodeling (Fig. 4). These data also imply that different mechanisms contribute to the transition from compensated LVH to CHF in hearts with eccentric LVH than hearts with concentric LVH.
It should be noted that the correlation among bioenergetics with these estimates of wall stress and direct measures of contractile function do not prove that impaired energetics cause regional dysfunction. There are likely other differences among these eccentric and concentric LVH models that can also affect contractility, including calcium handling, myocardial blood flow, and molecular remodeling.
Postinfarction LV remodeling and BZ contractile dysfunction.
Postinfarction LV remodeling often leads to a dilated LV, even if the coronary occlusions are treated (2). After an acute MI (AMI), the entire LV is exposed to significantly increased wall stresses and chamber dilatation that is most severe in BZ. Cardiomyocyte hypertrophy begins shortly after MI to restore normal LV wall stress and cardiac function. However, despite initial compensation, the underlying loss of contractile mass in the infarct region causes a mechanical overstretch on surviving cardiomyocytes in the BZ (13). Overstretch of cardiomyocytes is coupled to increased reactive oxygen species production, increased oxidative stress, further chamber dilatation mediated by the renin-angiotensin system, overexpression of the apoptosis-mediating Fas molecule, cardiomyocyte apoptosis, and impairment in force development (1, 3). This combination of adverse events, consequently, worsens the contractile function in the BZ and may instigate the progression to heart failure.
In a study using an ovine MI model and echo contrast imaging, Jackson et al. (8) observed that the radial displacement of the infarct region during systole forced the adjacent myocardium to curve outward. This resulted in a decreased local radius of curvature and more than doubled computed systolic wall stress in the infarct BZ (8). The elevated wall stress in the infarct BZ of MI pigs in the present study mirrors these findings (Table 5, Fig. 2). Because the viable myocardial tissue in BZ is mechanically tethered to the dysfunctional infarct region, early increases in BZ wall stress that result from geometric changes in this region of the myocardium have been implicated as an important mechanism for inciting the development of adverse ventricular remodeling and the subsequent development of CHF (5, 8).
Myocardial bioenergetics.
In the present study, the bioenergetic efficiency in the infarct BZ was assessed by the PCr/ATP. The PCr/ATP reflects the mitochondrial oxidative phosphorylation regulation, myocardial energy efficiency (6), and extent of LV dysfunction (12, 22). Because the creatine kinase reaction is nearly in equilibrium in the in vivo heart, a lower PCr/ATP indicates elevated levels of myocardial free ADP. The phosphorylation potential (
G) for hydrolysis of ATP is proportional to ATP/ADP and inorganic phosphate; therefore, elevated levels of ADP result in a significantly lower G and less energy made available for each unit of ATP that is utilized (6, 17). Consequently, hearts with a lower PCr/ATP are energetically less efficient (6, 17).
Using an in vivo canine model of severe LVH, we reported that severity of the reduction in PCr/ATP is linearly related to the severity of LVH and that failing hearts had the lowest PCr/ATP (23). We also found that a reduced PCr/ATP is linearly related to the decrease in LV EF in hearts with postinfarction LV remodeling (22). It has been observed clinically that a reduction in the PCr/ATP is a good predictor of mortality in patients with dilated cardiomyopathies (12).
The myocardial bioenergetic efficiency, as reflected by the PCr/ATP, was severely reduced in the infarct BZ of pigs in the MI group (Table 6, Figs. 3 and 4). These bioenergetic alterations were remarkably more profound than in remote myocardial regions of the same MI hearts or in AoB hearts with concentric hypertrophy (Table 6, Figs. 3 and 4). Moreover, the reduction in the BZ PCr/ATP was more severe than what our laboratory previously reported in remote myocardial regions of failing hearts (24), suggesting that the spared myocardium in the infarct BZ had a severely reduced energetic capacity, operated at a very low energetic state, and likely are most vulnerable to oxidative stresses.
Limitations.
The material properties of the LV scar can significantly impact wall stress calculation in the infarct zone (IZ) (5, 18, 19). Four weeks after AMI, the necrotic AMI tissue changes to a thinned mature scar. The scarring could significantly reduce extensibility because of the increased stiffness of the LV scar and, consequently, reduces wall stress of IZ as well as the BZ (5, 18, 19). Because of the material properties of the stiffness of the infarct have not been considered, the wall stress in IZ could be overestimated. However, the focus of the present study is the BZ, and an overstretched BZ myocyte (11) likely results from the increase of BZ wall stress. The material properties of IZ and BZ are beyond the scope of the present study. Future experiments are warranted incorporating material property measurements into the regional wall stresses alterations to provide insights in further understanding of a ventricle with postinfarction LV remodeling.
Conclusion.
The present study demonstrates that, in postinfarction LV remolding, the LV should not be considered as a homogeneous organ. The functional and bioenergetic abnormalities observed in the infarct BZ of heart undergoing compensated LV remodeling were much more severe than what has been observed in remote myocardium (24). The detrimental cascade of events leading to metabolic perturbations and contractile dysfunction was likely initiated by the elevated wall stress in the overstretched cardiomyocytes within the infarct region and BZ. The data indicate that a new heart failure prevention therapeutic target may start with the prevention of systolic LV bulging and reduction of the elevated wall stress in the infarct region and BZ to prevent the abnormal myocardial bioenergetics and BZ extension.
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GRANTS
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This work was supported by US Public Health Service Grants HL50470, HL61353, and HL67828 (to J. Zhang), and American Heart Association Predoctoral Fellowship 0610077Z (to J. Feygin).
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FOOTNOTES
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Address for reprint requests and other correspondence: J. Zhang, Dept. of Medicine and Biomedical Engineering, Univ. of Minnesota, 401 East River Rd., Minneapolis, MN 55455 (e-mail: zhang047{at}umn.edu)
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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REFERENCES
|
|---|
- Blaufarb IS, Sonnenblick EH. The renin-angiotensin system in left ventricular remodeling. Am J Cardiol 77: 8C–16C, 1996.[CrossRef][Medline]
- Bolognese L, Neskovic AN, Parodi G, Cerisano G, Buonamici P, Santoro GM, Antoniucci D. Left ventricular remodeling after primary coronary angioplasty: patterns of left ventricular dilation and long-term prognostic implications. Circulation 106: 2351–2357, 2002.[Abstract/Free Full Text]
- Cheng W, Li B, Kajstura J, Li P, Wolin MS, Sonnenblick EH, Hintze TH, Olivetti G, Anversa P. Stretch-induced programmed myocyte cell death. J Clin Invest 96: 2247–2259, 1995.[Web of Science][Medline]
- Gong G, Liu J, Liang P, Guo T, Hu Q, Ochiai K, Hou M, Ye Y, Wu X, Mansoor A, From AH, Ugurbil K, Bache RJ, Zhang J. Oxidative capacity in failing hearts. Am J Physiol Heart Circ Physiol 285: H541–H548, 2003.[Abstract/Free Full Text]
- Guccione JM, Moonly SM, Moustakidis P, Costa KD, Moulton MJ, Ratcliffe MB, Pasque MK. Mechanism underlying mechanical dysfunction in the border zone of left ventricular aneurysm: a finite element model study. Ann Thorac Surg 71: 654–662, 2001.[Abstract/Free Full Text]
- Hamman BL, Bittl JA, Jacobus WE, Allen PD, Spencer RS, Tian R, Ingwall JS. Inhibition of the creatine kinase reaction decreases the contractile reserve of isolated rat hearts. Am J Physiol Heart Circ Physiol 269: H1030–H1036, 1995.[Abstract/Free Full Text]
- Hu Q, Wang X, Lee J, Mansoor A, Liu J, Zeng L, Swingen C, Zhang G, Feygin J, Ochiai K, Bransford TL, From AH, Bache RJ, Zhang J. Profound bioenergetic abnormalities in peri-infarct myocardial regions. Am J Physiol Heart Circ Physiol 291: H648–H657, 2006.[Abstract/Free Full Text]
- Jackson BM, Gorman JH 3rd, Salgo IS, Moainie SL, Plappert T, St. John-Sutton M, Edmunds LH Jr, Gorman RC. Border zone geometry increases wall stress after myocardial infarction: contrast echocardiographic assessment. Am J Physiol Heart Circ Physiol 284: H475–H479, 2003.[Abstract/Free Full Text]
- Liu J, Wang C, Murakami Y, Gong G, Ishibashi Y, Prody C, Ochiai K, Bache RJ, Godinot C, Zhang J. Mitochondrial ATPase and high-energy phosphates in failing hearts. Am J Physiol Heart Circ Physiol 281: H1319–H1326, 2001.[Abstract/Free Full Text]
- Moustakidis P, Maniar HS, Cupps BP, Absi T, Zheng J, Guccione JM, Sundt TM, Pasque MK. Altered left ventricular geometry changes the border zone temporal distribution of stress in an experimental model of left ventricular aneurysm: a finite element model study. Circulation 106: I168–I175, 2002.[Web of Science][Medline]
- Murakami Y, Zhang Y, Cho YK, Mansoor AM, Chung JK, Chu C, Francis G, Ugurbil K, Bache RJ, From AH, Jerosch-Herold M, Wilke N, Zhang J. Myocardial oxygenation during high work states in hearts with postinfarction remodeling. Circulation 99: 942–948, 1999.[Abstract/Free Full Text]
- Neubauer S, Horn M, Cramer M, Harre K, Newell JB, Peters W, Pabst T, Ertl G, Hahn D, Ingwall JS, Kochsiek K. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 96: 2190–2196, 1997.[Abstract/Free Full Text]
- Olivetti G, Capasso JM, Meggs LG, Sonnenblick EH, Anversa P. Cellular basis of chronic ventricular remodeling after myocardial infarction in rats. Circ Res 68: 856–869, 1991.[Abstract/Free Full Text]
- Osman NF, Kerwin WS, McVeigh ER, Prince JL. Cardiac motion tracking using CINE harmonic phase (HARP) magnetic resonance imaging. Magn Reson Med 42: 1048–1060, 1999.[CrossRef][Web of Science][Medline]
- Osman NF, McVeigh ER, Prince JL. Imaging heart motion using harmonic phase MRI. IEEE Trans Med Imaging 19: 186–202, 2000.[CrossRef][Web of Science][Medline]
- Regen DM, Anversa P, Capasso JM. Segmental calculation of left ventricular wall stresses. Am J Physiol Heart Circ Physiol 264: H1411–H1421, 1993.[Abstract/Free Full Text]
- Tian R, Ingwall JS. Energetic basis for reduced contractile reserve in isolated rat hearts. Am J Physiol Heart Circ Physiol 270: H1207–H1216, 1996.[Abstract/Free Full Text]
- Walker JC, Ratcliffe MB, Zhang P, Wallace AW, Fata B, Hsu EW, Saloner D, Guccione JM. MRI-based finite-element analysis of left ventricular aneurysm. Am J Physiol Heart Circ Physiol 289: H692–H700, 2005.[Abstract/Free Full Text]
- Wall ST, Walker JC, Healy KE, Ratcliffe MB, Guccione JM. Theoretical impact of the injection of material into the myocardium: a finite element model simulation. Circulation 114: 2627–2635, 2006.[Abstract/Free Full Text]
- Ye Y, Gong G, Ochiai K, Liu J, Zhang J. High-energy phosphate metabolism and creatine kinase in failing hearts: a new porcine model. Circulation 103: 1570–1576, 2001.[Abstract/Free Full Text]
- Zhang J, Duncker DJ, Xu Y, Zhang Y, Path G, Merkle H, Hendrich K, From AH, Bache RJ, Ugurbil K. Transmural bioenergetic responses of normal myocardium to high workstates. Am J Physiol Heart Circ Physiol 268: H1891–H1905, 1995.[Abstract/Free Full Text]
- Zhang J, McDonald KM. Bioenergetic consequences of left ventricular remodeling. Circulation 92: 1011–1019, 1995.[Abstract/Free Full Text]
- Zhang J, Merkle H, Hendrich K, Garwood M, From AH, Ugurbil K, Bache RJ. Bioenergetic abnormalities associated with severe left ventricular hypertrophy. J Clin Invest 92: 993–1003, 1993.[Web of Science][Medline]
- Zhang J, Wilke N, Wang Y, Zhang Y, Wang C, Eijgelshoven MH, Cho YK, Murakami Y, Ugurbil K, Bache RJ, From AH. Functional and bioenergetic consequences of postinfarction left ventricular remodeling in a new porcine model. MRI and 31 P-MRS study. Circulation 94: 1089–1100, 1996.[Abstract/Free Full Text]
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