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J Thorac Cardiovasc Surg 2008;135:991-998
© 2008 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Regional remodeling strain and its association with myocardial apoptosis after myocardial infarction in an ovine model

Department of Surgery, University of Maryland, Baltimore, Md

Received for publication May 30, 2007; revisions received October 5, 2007; accepted for publication December 6, 2007.

^_* Address for reprints: Bartley P. Griffith, MD, University of Maryland School of Medicine, Department of Surgery, 22 S Greene St, N4W94, Baltimore, MD 21201. (Email: bgriffith{at}smail.umaryland.edu).

	Abstract

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Objective: Progressive left ventricular remodeling after myocardial infarction has been viewed as an important contributor to progressive heart failure. The objective of this study was to investigate the relationship between myocardial apoptosis and strain during progressive cardiac remodeling.

Methods: Before creation of an anterolateral left ventricular infarction by ligation of diagonal arteries, 16 sonomicrometry transducers were placed in the left ventricular free wall of 8 sheep to assess regional deformation in the infarct, adjacent, and normally perfused remote myocardial regions over 8 weeks' duration. Hemodynamic, echocardiographic and sonomicrometric data were collected before infarction and then 30 minutes and 2, 6, and 8 weeks after infarction. At the end of the study, regional myocardial tissues were collected for apoptotic signaling proteins.

Results: At terminal study, an increase in left ventricular end-diastolic pressure of 8.1 ± 0.1 mm Hg, a decrease in ejection fraction from 54.19% ± 5.68% to 30.55% ± 2.72%, and an end-diastolic volume increase of 46.08 ± 5.02 mL as compared with the preinfarct values were observed. The fractional contraction at terminal study correlated with the relative abundance of apoptotic protein expressions: cytochrome c (r ² = 0.02, P < .05), mitochondrial Bax (r ² = 0.27, P < .05), caspase-3 (r ² = 0.31, P < .05), and poly (adenosine diphosphate–ribose) polymerase (r ² = 0.30, P < .05). These myocardial apoptotic activities also correlated with remodeling strain: cytochrome c (r ² = 0.02, P < .05), mitochondrial Bax (r ² = 0.28, P < .05), caspase-3 (r ² = 0.43, P < .05), and poly (adenosine diphosphate–ribose) polymerase (r ² = 0.37, P < .05).

Conclusion: Increase in regional remodeling strain led to an increase in myocardial apoptosis and regional contractile dysfunction in heart failure.

	Introduction

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Cardiac remodeling after myocardial infarction (MI) is characterized by progressive global left ventricular (LV) dilatation and systolic dysfunction associated with an increased risk of congestive heart failure.^1,2 Post-MI remodeling has been described as a change in the structural properties between the ischemic zone and the nonischemic zone that leads to increases in regional wall stress, myocyte cell loss, side-to-side myocyte slippage, chronic lengthening, and hypertrophy of myocytes.^3,4 Increased mechanical stresses in the myocardium during cardiac remodeling have been shown to activate stretch-activated signaling pathways and apoptotic molecular events.^5,6

Studies have shown that myocyte apoptosis occurs in the infarct, peri-infarct (adjacent), and remote zone of myocardium after MI.⁷ Apoptosis is programmed cell death characterized by cell shrinkage, membrane blebbing, and DNA fragmentation.^8,9 Both intrinsic and extrinsic pathways of apoptosis leading to cell death have been described. The intrinsic pathway relies on the release of mitochondrial cytochrome c into the cytosol whereas the extrinsic pathway relies on ligation of membrane-bound death receptors. Induction of either pathway leads to the activation of the aspartate-specific cysteine proteases such as caspase-3 and cleavage of poly (adenodiphosphate–ribose) polymerase (PARP).^10,11

The objective of this study was to correlate changes in remodeling strain (end-diastolic dimensional stretch) and fractional contraction with molecular changes observed in the infarct, adjacent, and remote regions of the myocardium in a post-MI model of cardiac remodeling.

	Methods

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Study Design
Eight Dorsett hybrid sheep (male; weight, 60–70 kg) bred for laboratory use (Thomas Morris, Reisterstown, Md) were instrumented with subsequent creation of an anterolateral MI by coronary ligation. Four noninstrumented animals served as healthy tissue controls. LV geometry and function were measured with an echocardiogram. Sonomicrometry transducers were placed in the free wall of the LV to quantify the regional myocardial contractile function. At the time of terminal study, LV myocardial tissue samples from the excised heart from each animal were harvested in ice-cold solution and separated into the infarct region, adjacent region (which was defined as less than 2 cm from the edge of the infarct), and remote region for analysis of protein expression. All the animals received treatment in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (National Institutes of Health publication 85-23, revised 1996). The surgical procedures and postoperative care were carried out according to the approved protocol by the Institutional Animal Care and Use Committee of the University of Maryland at Baltimore.

Surgical Protocol
In each animal, anesthesia was induced with thiopental sodium (10 mg/kg) and maintained by mechanical ventilation with 1% to 2% isoflurane mixed with oxygen (Draeger anesthesia monitor; North American Draeger, Telford, Pa). Surface electrocardiogram, arterial blood pressure, pulse oximeter, and esophageal temperature were continuously monitored during the surgical operation. The instrumented group underwent a left anterolateral thoracotomy with polypropylene snares placed around the first and second diagonal coronary arteries of the left anterior descending artery (LAD) and tunneled subcutaneously. The snares were momentarily tightened (<30 seconds) to demarcate the border of the future infarct. Sixteen sonomicrometry transducers (2 mm; Sonometrics Corporation, London, Ontario, Canada) were placed in the free wall of the LV. The transducers were placed in 3 groups, each having 5 transducers placed circumferentially from anterior wall to posterior LV wall. One transducer was placed at the LV apex. An ultrasound flow probe (20 mm; Transonic Systems, Inc, Ithaca, NY) was placed around the main pulmonary artery for cardiac output monitoring.

Infarction
Ten days after the initial operation, the sheep were reanesthetized. The subcutaneous snares were permanently tightened to cause an anterolateral MI and the animal was supported with epinephrine infusion according to MI protocol described previously.¹² The pre-MI and post-MI data (sonomicrometry, echocardiogram, and hemodynamics) were collected.

Data Collection and Analysis
Hemodynamic, echocardiographic, and sonomicrometry data were collected in the pre-MI and post-MI periods and 2, 6, and 8 weeks after MI. The hemodynamic parameters were measured with a Millar pressure transducer (Millar Instruments, Inc, Houston, Tex) placed in the LV cavity through the aortic valve via the femoral artery with the aid of a fluoroscope. Parameters measured included heart rate, systolic and diastolic arterial pressure, mean arterial pressure, and LV end-diastolic pressure (LVEDP). Cardiac output was measured with the transonic flow probe placed around the main pulmonary artery with the flowmeter. Transdiaphragmatic echocardiographic data were collected with a Sonos 5500 machine with a sterile covered transducer (Philips Medical, Andover, Mass). LV end-systolic and end-diastolic volumes, wall motion abnormalities, and ejection fractions were measured as previously described.¹³ Sonomicrometry data were collected with a commercially available digital sonomicrometry system (Sonometrics Corporation) to determine 3-dimensional motion and deformation of the LV free wall. Sonomicrometry data were used to calculate the fractional contraction (end-systolic strain) from end-diastole to end-systole over a cardiac cycle to quantify the regional contractile function of the myocardium. The end-diastolic and end-systolic time points were determined from the pressure and flow waveforms. Negative fractional contraction values as percent change over diastolic reference indicate functional contraction and positive values indicate dysfunctional dilatation during systole. The remodeling strain calculated between the geometries at end-diastole at one data collection time point and at end-diastole at the pre-MI measurement was used to quantify the progression of LV remodeling. We described the calculation of these strains previously.¹² In brief, an area strain measure was used and calculated by comparing the area change of the paired triangles between different time points. Strain measurements were then calculated from the collected sonomicrometry transducer coordinate data to compile (1) fractional strain during cardiac contraction and (2) remodeling strain over the progression of myocardial remodeling as described above.

Immunohistochemistry Staining
The tissues sampled from the 3 regions (remote, adjacent, and infarct) were fixed in formalin for 24 hours, embedded in paraffin, and 5-µm sections were obtained. The sections were then deparaffinized with xylene and rehydrated with a series of graded alcohol. The immunochemistry of cleaved caspase-3 was performed as previously described.¹⁴

Terminal Deoxynucleotidyl Transferase-mediated dUTP Nick-end Labeling Analysis
Apoptotic cells were detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) with a commercially available apoptosis detection kit (Roche Diagnostics, Indianapolis, Ind). Histologic sections were prepared and stained according to the manufacturer's instructions. Positive control was prepared with DNase I (3 µg/ml) (Roche Diagnostics) to induce DNA strand fragments. Negative control was obtained by omitting terminal transferase during the labeling procedure. For cell death, tissue sections were semiquantitatively evaluated by light microscopy (Carl Zeiss, Inc, Oberkochen, Germany).

Western Blot Analysis
Protein extraction and Western blotting were performed as described previously.¹² Primary antibodies used were anti–caspase-3, anti–cleaved caspase-3 (Asp175), anti-PARP, anti-VDAC (mitochondrial porin; Cell Signaling Technology, Danvers, Mass), anti-Bax, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) antibodies (Santa Cruz Biotechnology, Santa Cruz, Calif).

Isolation of Myocardial Cytosolic Fraction of Cytochrome c
Mitochondria were isolated from remote and adjacent regions of the LV myocardium by a mitochondria-isolation kit for tissue (Pierce, Rockford, Ill). Isolation of cytosolic fraction of cytochrome c was performed as described previously.¹⁵ The soluble cystolic fraction was assayed for cytochrome c. Western blot was performed with specific anti–cytochrome c and GAPDH antibodies (Santa Cruz Biotechnology) under the conditions recommended by the manufacturer.

Statistical Analysis
All data are expressed as the mean ± SEM. One-way repeated-measures analysis of variance (ANOVA) was used to compare temporal changes in hemodynamic, echocardiographic, and strain data as well as the abundance of protein expression. One-way ANOVA was used to compare regional changes in strain data. All ANOVAs were performed by multiple comparisons with the least significant difference correction. The significance level was set at .05. Protein expression was correlated with the regional strain to explore the association of the strain with protein expression.

	Results

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Hemodynamics
The heart rate, mean arterial pressure, and cardiac output remained unchanged during the course of the study, but the LVEDP progressively increased over the 10-week period. The LVEDP at baseline, 30 minutes after MI, 2 weeks after MI, 6 weeks after MI, and at terminal study were 1.4 ± 0.4, 1.4 ± 0.3, 3.9 ± 0.7 (P < .05), 6.9 ± 0.7 (P < .05), and 8.1 ± 0.8 mm Hg (P < .05), respectively.

Echocardiographic analysis
Figure 1 summarizes the echocardiographic data at the different study time points. Results from the measurement of cardiac function showed increases in LV end-diastolic volume from 86.39 ± 11.02 mL to 132.47 ± 16.04 mL (P < .05) and LV end-systolic volume from 40.49 ± 8.15 mL to 93.46 ± 12.85 mL (P < .05) with a decrease in ejection fraction from 54.19% ± 5.68% to 30.55% ± 2.72 % (P < .05) during the study period.

View larger version (16K): [in this window] [in a new window]   Figure 1. Summary of changes observed in left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and ejection fraction (EF) over time on echocardiogram. Increase in LVEDV and LVSV with decrease in EF show a global LV chamber dilatation and systolic dysfunction. All values are given as mean ± standard error of the mean. Symbols *, , , and indicate P 0.05 as compared with preinfarct, postinfarct, 2 weeks, and 6 weeks, respectively.

TUNEL Analysis
Figure 2 shows photographs of typical TUNEL-stained sections of tissue from remote, adjacent, and infarct regions of the LV myocardium. The nucleus of apoptotic cells stains brown. The number of TUNEL-positive cells in the infarct and adjacent regions of the myocardium was higher than in the remote and normal tissues.

View larger version (45K): [in this window] [in a new window]   Figure 2. The infarct region shows a greater number of TUNEL-positive cells and the highest caspase-3 intensity. The adjacent region shows a lesser number of TUNEL-stained cells with a mild caspase-3 activity and remote region shows the fewest TUNEL-positive cells with minimal caspase-3 staining. Normal tissue is not shown but stained similar to the remote region of the LV myocardium.

Mitochondrium-mediated Apoptotic Protein Expression
The infarct region showed more than a 2-fold increase in expression of mitochondrial Bax, cleaved caspase-3, and PARP as compared with the remote region ( Figure 3). There was no significant regional change in the protein expression of cytochrome c. Although the infarct region showed the most alteration in the expression of cleaved caspase-3 and PARP from normal, the remote region exhibited some level of caspase-3 and PARP activity.

View larger version (43K): [in this window] [in a new window]   Figure 3. A, Representative Western blot. B, Relative abundance of protein expression: Poly (ADP-ribose) polymerase (PARP), caspase-3, and cytochrome c (Cyto c) normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and mitochondria Bax (Mito Bax) normalized to mitochondrial porin (VDAC). Symbols * and indicate P .05 as compared with tissue in the adjacent region and the infarction region of the LV myocardium, respectively. All values are given as mean ± SEM.

View larger version (21K): [in this window] [in a new window]   Figure 4. Normalized cytochrome c, mitochondrial Bax, caspase-3 and poly (ADP-ribose) polymerse versus fractional contraction. For abbreviations, see Figure 3.

View larger version (20K): [in this window] [in a new window]   Figure 5. Normalized cytochrome c, mitochondrial Bax, caspase-3, and poly (ADP-ribose) polymerase versus remodeling strain. For abbreviations, see Figure 3.

	Discussion

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There is increasing evidence that increased wall stress from myocardial stretch (strain) during cardiac remodeling induces the apoptotic pathway, and apoptotic cell loss contributes to progressive ventricular dilation and systolic dysfunction.^5,6,20 Apoptosis can be induced by stimuli with membrane death receptor or by mitochondrium-mediated pathway via the release of cytochrome c, resulting in the downstream activation of caspase-3, an important molecule in the determination phase of apoptosis.²¹ The pathway of interest is via the mitochondrial origin, and on induction of apoptosis, the mitochondrial membrane destabilizes with translocation of cytosol Bax into the mitochondria and altering the release of cytochrome c into the cytosol.²² Cytochrome c then activates caspase-9 and caspase-3 sequentially with resultant cleavage of PARP leading to apoptosis.^23,24

In the present study, apoptosis was documented histologically with the TUNEL assay and protein expression of mediators by Western blot. Significantly higher levels of proapoptotic Bax, cytochrome c, caspase-3, and PARP proteins were seen in the adjacent region than remote region of the myocardium. Results from our strain measurement indicate that there are regional strain differences in the remote, adjacent, and infarct regions of the myocardium after MI during cardiac remodeling. Although there was a general increasing trend in the remodeling strain, the largest increase was found to be in the infarct region. The fractional contraction was noted to be decreasing from remote to the infarct region. In this study, we investigated the relationship of both the fractional contraction and remodeling strain (areal dilatation) to alterations in apoptotic protein expression (mitochondrial Bax, cytochrome c, caspase-3, and PARP) during cardiac remodeling. Our results show a direct correlation between apoptosis versus fractional contraction and remodeling strain during cardiac remodeling after MI. This observation is supported by the regional distribution of apoptosis being significantly higher in the infarct region, in which strain (mechanical stress) is typically higher than that in the adjacent and remote regions of the myocardium. The remodeling changes were consistent with global changes in vivo in LVDEP, echocardiogram-confirmed LV end-diastolic volume, ejection fraction, and wall motion abnormalities. Significant cardiac remodeling was observed by 8 weeks after MI in our ovine model as the LV chamber enlarged, and significant increase in mechanical wall stress (strain) induced with decreased fractional contraction in the adjacent region of the myocardium and with compensatory hypercontractility in the remote region.²⁵ These changes during cardiac remodeling are associated with an increase in angiotensin II, catecholamines, and various cytokines and stretch stress, all of which are potential inducers of apoptosis leading to cardiac functional impairment.²⁶ Our study indicates that regional activation of apoptosis correlates strongly with fractional contraction and remodeling strain during cardiac remodeling. We speculate that myocardial wall stretch (strain) through mechanotransduction is the initial driving force and impetus behind myocardial apoptotic signaling cascade and myocardial cell death after MI during progression of cardiac remodeling into heart failure. Various studies have shown reversal of cardiac remodeling and restoration of cardiac protein expression and function by reducing myocardial strain in post-MI heart failure models through LV assist devices, passive constraints, and ventricular endocardial restoration procedures.^27-29 It is our hope that reducing myocardial strain by mechanically unloading the LV during cardiac remodeling will inhibit progressive apoptosis in the adjacent and remote regions of the myocardium.

	Figure E1

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Summary of changes observed in fractional contraction and in infarct, remote, and adjacent zones of LV myocardium at different study time points. The infarct region shows loss of contractile immediately after the MI becoming akinetic. Adjacent region shows a statistically significant loss of functional contraction by 2 weeks and becomes hypokinetic by 6 to 8 weeks. The remote region shows preserved contractile function by the end of the study. All values are given as mean ± SEM. Symbols * and indicate P .05 as compared with remote and adjacent regions, respectively. Symbols and indicate P .05 as compared with preinfarct and 6 weeks, respectively.

	Figure E2

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Summary of changes observed in remodeling strain in infarct, remote, and adjacent zones of LV myocardium at different study time points. The infarct displays the greatest remodeling strain. The difference in the degree of remodeling between the adjacent and the remote zones is statistically significant at both 6 weeks and time of termination. All values are given as mean ± SEM. Symbols * and indicate P .05 as compared with remote and adjacent regions, respectively. Symbols , , and # indicate P .05 as compared with postinfarct, 2 weeks, and 6 weeks, respectively.

	Footnotes

 
The study was supported in part by McGowan Charitable Fund, National Institute of Health Grant R01HL081106 and National Institutes of Health Training Grant HL0772751.

Read at the Eighty-seventh Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5–9, 2007.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Guangming Cheng Sina L. Moainie Bartley P. Griffith Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yankey, G. K. Articles by Griffith, B. P. Search for Related Content PubMed Articles by Yankey, G. K. Articles by Griffith, B. P. Related Collections Cardiac - physiology Congestive Heart Failure Molecular biology Myocardial infarction Related Article