Ann Thorac Surg 1998;65:390-396
© 1998 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Superior Recovery of Hypertrophied Rat Myocardium After Cardioplegic Arrest
Seth D. Blank, MD,
Joseph A. Lahorra, MD,
Robert S. McDonald, MD,
Alvin G. Denenberg, MS,
James S. Titus,
David F. Torchiana, MD,
Willard M. Daggett, MD,
Gillian A. Geffin, MB, BS
Departments of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
Accepted for publication July 20, 1997.
Dr Daggett, Surgical Cardiovascular Unit, Massachusetts General Hospital BUL-119, Fruit St, Boston, MA 02114.
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Abstract
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Background. Although cardioplegic protection of the hypertrophied heart remains a clinical challenge, we have previously observed enhanced recovery in rat hearts with pressure-overload hypertrophy induced by aortic banding. We investigated whether this unexpected result is found in other models of hypertrophy.
Methods. Hearts with hypertrophy induced by aortic banding or administration of desoxycorticosterone acetate were each compared with age-matched sham-operated and nonoperated controls. Spontaneously hypertensive rats and Wistar-Kyoto controls were also compared. We evaluated left ventricular isomyosin distribution by gel electrophoresis and recovery of isolated working rat hearts arrested at 8°C for 2 hours.
Results. The percentage of V3 isomyosin in hearts with hypertrophy from aortic banding or administration of desoxycorticosterone acetate was increased compared with the control groups. Recovery of aortic flow in all three groups of hypertrophied hearts was at least as good or better than their respective controls. There were no significant differences in ATP or glycogen between hypertrophied and control hearts before or after arrest.
Conclusions. Enhanced recovery of hypertrophied hearts is not specific to a single model. This level of recovery may be supported by induction of a "fetal genetic program," exemplified in the rat by the shift in isomyosin from predominantly V1 to the more efficient V3 isoform, which occurs in pressure-overloaded hearts.
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Introduction
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Protection of the hypertrophied myocardium during cardiac operations has been a clinical challenge since Cooley and colleagues [1] first reported the phenomenon of the "stone heart" in 1972. This phenomenon represents ischemic contracture—the result of inadequate myocardial protection with consequent high-energy phosphate depletion. Despite modern techniques of hypothermic cardioplegia, patients with myocardial hypertrophy undergoing cardiac operations remain at increased risk of suboptimal myocardial protection [2] [3].
Our initial studies of the efficacy of hypothermic cardioplegic arrest in hypertrophied hearts were performed using a rat model of left ventricular hypertrophy (LVH) produced by abdominal aortic constriction [4]. Contrary to expectations, these hypertrophied hearts had significantly better functional recovery after hypothermic arrest than nonoperated and sham-operated controls.
In the current study, to see whether enhanced recovery after cardioplegic arrest was particular to the model of LVH that we had used or whether it was a more general phenomenon, we investigated three different models of LVH: hypertrophy produced by abdominal aortic constriction, by hyperaldosteronism, and in spontaneously hypertensive and hypertrophic rats (SHR). These models of LVH were evaluated by their left ventricular (LV) dry weight to body weight ratio and by LV isomyosin distribution. Cardioplegic arrest of the isolated perfused rat hearts was induced by a multidose cold oxygenated crystalloid solution that has been well characterized previously in the laboratory and, with some modifications, is in current clinical use [5]. Myocardial protection was assessed from recovery of aortic flow at constant left atrial and mean aortic pressure and from preservation of high-energy phosphates and glycogen.
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Material and Methods
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Models of Myocardial Hypertrophy
Male Sprague Dawley rats (Charles River Laboratories, Wilmington, MA) weighing 150 to 180 g were randomly assigned to one of four groups. Hypertrophy was induced by (1) left nephrectomy and desoxycorticosterone implant (DOCA), or (2) abdominal aortic banding (BAND). Control groups comprised rats undergoing sham abdominal aortic banding (SHAM) or no operation (NONOP). For these surgical procedures, which were followed by recovery, rats were anesthetized with intramuscular ketamine (5 mL/kg) and acepromazine (0.5 mg/kg) and they underwent a midline laparotomy.
Rats in the DOCA group underwent left nephrectomy, and before skin closure a silicone elastomer wafer containing desoxycorticosterone was placed subcutaneously, lateral to the midline incision. The implant was prepared in the following manner: one gram of desoxycorticosterone (Sigma Chemical Co, St. Louis, MO) was mixed with 2 g of silicone elastomer (RTV3110; Dow Corning Co, Midland, MI) and a hardening agent (Catalyst 4, Dow Corning Co), spread into a thin sheet, and allowed to harden. The sheet was then divided into small wafers weighing 120 mg each, which provided a dose of 150 mg/kg [6].
In the BAND group, a 5-0 nonabsorbable suture was tied around the aorta between the right and left renal arteries over a 25-gauge needle [4]. The needle was then removed, leaving the aorta narrowed. Rats in the SHAM group underwent laparotomy alone.
All rats had free access to standard laboratory rat food and tap water for the first week after operation. After 1 week, the DOCA group was given 0.9% sodium chloride with 40 mEq/L potassium chloride ad libitum instead of tap water. Potassium chloride was added to counteract the hypokalemic effect of the induced hyperaldosteronism. All other rats remained on regular rat chow and water ad libitum.
Spontaneously hypertensive (SHR) and age-matched Wistar-Kyoto (WKY) rats were obtained from Charles River Laboratory at 95 to 115 days of age and were studied within 1 to 3 days of their arrival.
Left ventricular dry weight-to-body weight ratio (LVDW/BW) was measured in hearts obtained from rats anesthetized with pentobarbital (65 mg/kg). The atria, great vessels, and right ventricular free wall were removed and the LV including the intraventricular septum was dried at 80°C for 48 hours.
Left ventricular isomyosin distribution was determined in additional hearts from rats in the BAND and DOCA groups and their control groups to characterize the models of LVH created in the laboratory. A few SHR and WKY hearts were also studied. Hearts were harvested, 7 weeks after operation in appropriate groups, after anesthesia with pentobarbital (65 mg/kg intraperitoneally). After removal of the atria, great vessels, and right ventricle, the LVs were compressed by metal paddles cooled in liquid nitrogen for storage at -70°C. Tissue was then homogenized and prepared for electrophoretic separation of LV isomyosins by the method of Hoh and associates [7] with modifications. A 10- to 40-mg sample was extracted for 72 hours at 4°C in 50 mmol/L Na4P2O7 buffer with 5 mmol/L dithiothreitol, 5 mmol/L ethylene glycol-bis(ß-aminoethyl ether)-N,N,N',N'-tetraacetic acid, and 50% glycerol at pH 8.8. Electrophoresis was performed on cylindrical 4% polyacrylamide gels at 84 V for 16 hours at 2°C in 20 mmol/L Na4P2O7 buffer with 10% glycerol and 3.5 mmol/L L-cysteine at pH 8.8 using a Pharmacia GE-4 electrophoresis apparatus. Rabbit skeletal myosin (Boston Biomedical Research Institute, Boston, MA) was used as a reference band. The gels were stained in a Hoeffer DD-105 diffusion-destainer with 0.1% Coomassie Blue R for 6 hours and destained in 45% methanol and 10% acetic acid for 16 hours. Transmittance through the gels was determined by converting a video image (COHU video camera; Coherent, Inc, Auburn, CA) into gray-scale values using Image Pro software (Media Cybernetics, Silver Spring, MD). The relative amounts of V1, V2, and V3 isomyosins, expressed as percentages, were calculated from the area under each isomyosin transmittance peak. Left ventricular V2 isomyosin content was divided equally between V1 and V3 so that 
[8]. Most gels were scanned two to four times and results were averaged for each gel. Most LV samples were run on at least two gels and results were averaged for each sample.
Cardioplegic Arrest and Recovery in Isolated Perfused Hearts
We studied hearts from rats in the DOCA, BAND, and SHAM groups 7 weeks after operation and hearts from rats in the NONOP group of the same age. Rats from SHR and WKY groups were studied at 13.5 to 17 weeks of age. All animals were anesthetized with sodium pentobarbital (65 mg/kg) intraperitoneally and then anticoagulated with 100 units of heparin injected into a femoral vein. The hearts were excised and immediately placed in ice-cold Krebs-Henseleit buffer (containing 11.2 mmol/L glucose and 1.2 mmol/L ionized calcium) and mounted on a perfusion apparatus as in an earlier study [4]. During an initial 10-minute period of Langendorff perfusion, while hearts were perfused with the same buffer at 37°C bubbled with 95% oxygen and 5% carbon dioxide, the left atrium was cannulated, and the pulmonary artery was incised to promote coronary venous drainage and for insertion of a temperature probe. The working mode was then established by perfusing the left atrium with oxygenated Krebs-Henseleit buffer at a pressure of 16 cm H2O and allowing the LV to eject into a recirculating circuit against a pressure of 95 cm H2O. Aortic flow was measured by a flowmeter calibrated by timed volumetric collection. Heart rate was obtained from an aortic pressure tracing recorded on a strip chart. Myocardial temperature was held at 37°C during the Langendorff and work periods by flowing heated water to jacketing around the perfusion apparatus and the heart. Continuous bubbling of the Krebs-Henseleit buffer with 95% oxygen and 5% carbon dioxide produced a PO2 greater than 500 mm Hg, a pH of 7.40, and a PCO2 of 40 mm Hg measured at 37°C (Model 170 blood gas analyzer, Ciba Corning, Medfield, MA).
After 15 minutes of work, baseline measurements of aortic flow and heart rate were recorded, cold water replaced warm water in the jacketing, and then the aortic and left atrial cannulae were clamped and the hearts in all groups were immediately arrested with 15 mL cold cardioplegic solution infused through the aortic root at a pressure of 60 cm H2O. The solution contained (mmol/L) Na+, 109.3; K+, 20; ionized Ca2+, 0.1; Cl-, 103.5; HCO3-, 27; Mg2+, 16; SO42-, 16; glucose, 27.8; and mannitol, 54.9. The cardioplegic solution was infused from a reservoir above the heart in which the solution was cooled to 4°C and continuously oxygenated with 98% oxygen and 2% carbon dioxide to produce an oxygen tension greater than 800 mm Hg, a pH of 7.40, and a carbon dioxide tension of 40 mm Hg when measured at 37°C. Hearts remained arrested at 8 ± 2°C for 2 hours, during which time 10 mL cardioplegic solution was infused at a pressure of 60 cm H2O every 15 minutes in all groups. Myocardial temperature was recorded at the beginning and end of each infusion. At the end of the arrest period, hearts were reperfused with Krebs-Henseleit buffer at 37°C, initially in the Langendorff mode for 15 minutes and then in the working mode for 30 minutes, during which time aortic flow and heart rate were measured every 5 minutes.
Myocardial Metabolites
Hearts for measurement of myocardial adenosine triphosphate (ATP), phosphocreatine (PCr), and glycogen content were obtained at three points (sacrifice times) in the cardioplegic protocol: (1) excised immediately after attaining full anesthesia without mounting on the perfusion apparatus (immediate sacrifice), (2) after perfusion and collection of baseline data (prearrest), and (3) at the end of the arrest period just before reperfusion (end arrest). After compression and freezing by metal paddles cooled to the temperature of liquid nitrogen, the hearts were stored at -70°C. The frozen tissue was assayed for ATP and PCr by high-pressure liquid chromatography and for glycogen by the hexokinase technique, with glycogen content expressed as nmol glycosyl units/mg of protein, as described previously [4].
Data Analysis
Hearts from SHAM and NONOP controls were compared with each other; BAND and DOCA hearts were each compared with SHAM and NONOP controls; SHR and WKY hearts were compared with each other. Functional recovery was determined from aortic flow during reperfusion expressed as a percentage of prearrest aortic flow. Data underwent analysis of variance. Myocardial metabolite contents underwent two-way analysis of variance with group and sacrifice time as factors. When indicated by the tail probability of the F statistics, planned comparisons were undertaken by paired or unpaired t test as appropriate. Probability values less than 0.05 were taken to indicate statistical significance. Data are presented as means ± standard errors of the mean.
All animals received humane care as outlined in the "Guide for the Care and Use of Laboratory Animals" (NIH publication 85-23, revised 1985).
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Results
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Left Ventricular Hypertrophy
Rats from the NONOP and SHAM groups did not differ with respect to LV dry weight, body weight, or LVDW/BW (Table 1). Rats from the DOCA group weighed less than rats from the control groups, but because their LV dry weights were similar, the DOCA rats developed substantial relative LVH; they had 66% and 68% increases in LVDW/BW compared with NONOP and SHAM rats, respectively. The body weights of BAND, SHAM, and NONOP rats were similar, but the LV dry weight and LVDW/BW of BAND rats were increased: BAND rats had an 18% increase in LVDW/BW compared with SHAM rats. The LV dry weight of SHR rats was substantially above that of WKY rats so that despite a significantly greater body weight, SHR rats had a 19% increase in LVDW/BW compared with WKY rats. There was no evidence of heart failure in any animal at the time of sacrifice.
Left Ventricular Isomyosin Distribution
Representative gels after electrophoretic separation of LV isomyosins are displayed in Fig 1. The percentage of V3 isomyosin for hearts from DOCA, BAND, SHAM, and NONOP rats is shown in Fig 2. The percentage of V3 isomyosin of hearts from SHAM (14% ± 2%) and NONOP rats (9% ± 3%) did not differ significantly. Hearts from BAND rats had nearly double the percentage of V3 (28% ± 3%) of those from SHAM rats, as did those from DOCA rats (26% ± 5%). Fig 1 also illustrates the greater percentage of V3 in an SHR than a WKY heart.
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Isomyosins from rat left ventricles (LV) after electrophoretic separation. Note that the amount of V3 isomyosin is increased in the hearts of rats subjected to aortic banding (Band) or desoxycorticosterone acetate (DOCA) administration compared with hearts from the sham-operated (Sham) or nonoperated (Nonop) rats, and in the heart from the spontaneously hypertensive (SHR) rat as compared with that from the Wistar-Kyoto (WKY) rat.
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Cardioplegic Arrest
There were no significant group differences in myocardial temperatures during arrest. The duration of all cardioplegic infusions was significantly longer in the DOCA group than in the SHAM or NONOP groups. The duration of the initial cardioplegic infusion was 123 ± 7 seconds in hearts from DOCA rats, 89 ± 4 seconds in hearts from SHAM rats (p = 0.0003 versus DOCA), and 83 ± 4 seconds in hearts from NONOP rats (p < 0.00001 versus DOCA, not significant versus SHAM). The duration of the cardioplegic infusions in hearts from BAND rats (97 ± 4 seconds for the initial infusion) tended to be greater than in the control groups, significantly so for the second infusion versus the SHAM or NONOP groups (p < 0.05), and for third and fifth infusions versus the NONOP group (p < 0.05). There were no significant differences in cardioplegic infusion duration between SHR and WKY rats.
Functional Recovery
There were no significant group differences in aortic flow or heart rate in the control period, except that SHR rats had slower heart rates than WKY rats (Table 2). Recovery of aortic flow was essentially the same in the SHAM and NONOP groups (Fig 3). Recovery of aortic flow in all groups of hypertrophied hearts was at least as good or better than in their respective control groups throughout working reperfusion (Fig 3). Hearts from DOCA rats had an average recovery of aortic flow of 79% ± 7% for the entire period compared with 60% ± 3% for SHAM and 59% ± 4% for NONOP groups (p = 0.001, DOCA versus SHAM plus NONOP). Hearts from DOCA rats were significantly better than those from SHAM or NONOP rats at 5, 20, 25, and 30 minutes. Hearts from BAND rats recovered an average of 70% ± 3% (p = 0.053, BAND versus SHAM plus NONOP; not significant) and were significantly better than those from SHAM or NONOP groups at 20 and 25 minutes. Aortic flow in SHR hearts recovered an average of 71% ± 2% compared with 60% ± 7% for WKY hearts (not significant) and were significantly better than hearts from WKY rats at 5 minutes. Heart rate recovery throughout the period of working reperfusion was between 89% and 109% of the respective prearrest rate in all groups.
Myocardial Metabolites
There were no significant differences in ATP content attributable to group or sacrifice time except that ATP increased in hearts from NONOP rats and decreased in hearts from SHR rats during the prearrest period (Table 3). There were no significant group differences in PCr at immediate sacrifice, prearrest, or end arrest. Levels of PCr tended to increase during prearrest perfusion in all groups except WKY rats, significantly so in DOCA and BAND rats. During arrest, the increase in PCr was significant in hearts from BAND and NONOP groups but not in other groups. There were no significant differences in glycogen content attributable to group or sacrifice time.
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Comment
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An increased hemodynamic load results in myocyte hypertrophy and hyperplasia of other cellular elements initially compensating for the increased load, but some aspects of the response to overload are harmful rather than adaptive [9]. As hypertrophy develops, capillary density decreases and ultimately hypertrophy progresses to cardiac failure.
Hemodynamic overload induces a "fetal program" regulated by specific genes, which alters the proportions of different isoforms of many enzymes, including myosin, to resemble the isoform distribution in the neonatal period [10]. The myosin molecule includes two heavy chains containing the catalytic sites for ATP hydrolysis [11]. The myosin isoforms V1 and V3 are differentiated by the amino acid sequence of the heavy chains [7]. During fetal life, V3 predominates in mammalian ventricles but V1 appears or increases around the time of birth [12]. During adult life, V1 predominates in the small fast hearts of rats and mice but V3 predominates in larger species [12] including man [12] [13]. In hemodynamically overloaded small hearts, including those of rats [8] [14] and rabbits [15], isomyosin distribution regresses, increasing the proportion of V3.
Molecular differences between the myosin isoforms are thought to confer economy in the face of increased loading [16] [17] [18] [19]. One ATP molecule is hydrolyzed each time a crossbridge between a myosin molecule and actin filament cycles through attachment and detachment, generating force or motion [16]. With V3 as compared with V1, the duration of crossbridge attachment is believed to be prolonged, increasing the individual crossbridge tension–time integral per molecule of ATP hydrolyzed [16] [17]. This mechanism may contribute to the greater mechanical efficiency of the hypertrophied heart as a whole [17] [18] [19].
Similar functional changes occur in hypertrophy in humans as in rabbits; in both species myothermal techniques show an increase in the tension–time integral of individual crossbridges [17]. Because in overloaded human hearts—in contrast to rats, rabbits, and mice—any increase in the proportion of V3 is negligible [13], other mechanisms must underlie the enhanced economy, possibly including a reduction of the ATP consumed by Ca2+ cycling [17].
In our study, there was substantial hypertrophy in hearts from DOCA rats and modest hypertrophy in hearts from BAND and SHR rats as indicated by the increases in the LVDW/BW (Table 1). Both the experimentally induced models of hypertrophy (BAND and DOCA groups) displayed the expected increase in the percentage of V3 isomyosin [8] [14] (Fig 1Fig 2). Hearts from SHR rats are known to have more V3 than do those from WKY rats [14], as illustrated in representative hearts in Fig 1. As reflected by aortic flow, hearts from DOCA rats recovered substantially better than sham-operated or nonoperated controls; there was significant improvement in the recovery of hearts from BAND rats versus those from controls, confirming our earlier results [4], and to a lesser extent of hearts from SHR rats compared with WKY rats (Fig 3). Therefore, improved recovery of hypertrophied hearts after hypothermic cardioplegic arrest is not particular to hypertrophy induced by aortic banding but appears to be a more general phenomenon. The reason for the limited enhancement of recovery in hearts from SHR rats is unclear but could reflect less increase in V3.
Hypertrophied hearts subjected to ischemia or hypoxia are prone to diastolic dysfunction [20] [21], which cannot be evaluated in the model we used. However, if left ventricular filling of the hypertrophied hearts were impaired by increased ventricular diastolic stiffness, their postarrest aortic flow would be unlikely to compare favorably with that of control hearts. Hypothermic cardioplegia can protect hypertrophied hearts against impaired diastolic dysfunction [20] and presumably did so in our study.
Improved recovery is unexpected in the light of clinical observations [1] [2] [3] but may result from a number of factors. Clearly, the in vitro crystalloid-perfused rat heart differs from human hearts undergoing operations. Our rat hearts were not compromised by the presence of coronary artery disease; the degree of hypertrophy was relatively modest and had not progressed to the point of heart failure. Rapid induction and maintenance of hypothermia as well as the use of adequate volumes of cardioplegia are considered essential for good myocardial protection in patients with hypertrophied hearts with their increased mass and the diminished vascularity characteristic of hypertrophy [3]. These conditions are easily attained in cardioplegia of the isolated rat heart; in our study, relative cardioplegic volumes and the degree of hypothermia met or exceeded clinical recommendations. However, effective protection cannot explain the enhanced recovery we observed. Although we cannot rule out the possibility that preconditioning of the hypertrophied hearts during the study improved their resistance to ischemia, it is not supported by the observation in this and our previous study [4] that prearrest ATP was not depleted.
Economy of performance may be of importance not only as an adaptation to overload but also to the level of recovery after ischemia. After a period of ischemia too short to cause necrosis, mechanical function is depressed (stunning) but there is disproportionately little reduction in myocardial oxygen consumption or even an increase [22]. In other words, mechanical efficiency is impaired [22]. Both large and small hearts display this phenomenon [22] [23]. In line with these observations, we previously found that mechanical efficiency, expressed as the ratio of cardiac output to myocardial oxygen consumption at constant aortic pressure, was decreased in rat hearts after cardioplegic arrest [4]. Efficiency as well as function was best preserved in the hypertrophied hearts [4]. It is tempting to suggest that the superior recovery in hypertrophied hearts in this and our earlier study [4] is partly explained by the presence of increased V3 isomyosin, the more efficient isoform, and other features of the "fetal program." The enhanced glycolytic potential of hypertrophied myocardium may also be protective during ischemia [24].
Studies in humans and in animal models disagree as to whether baseline high-energy phosphates are depleted, thereby increasing the susceptibility of hypertrophied hearts to ischemia, as observed clinically [1] [2] [3]. Possible reasons for the discordant findings have been discussed previously [4]. In this and our earlier study, baseline high-energy phosphates and glycogen were not depressed by hypertrophy [4]. Normal myocardial ATP levels have been reported in rats with LVH produced by aortic banding [18] or DOCA and high salt diet [21], and in SHR rats [19], as in this study. The initially low PCr values may reflect brief hypoxia related to opening the chest of the rats in the absence of mechanical ventilation, apparently an insufficient insult to deplete ATP. The increase in PCr during prearrest perfusion may reflect recovery from this. It is unclear why hearts from SHR and WKY rats appear less affected.
In hearts from DOCA and BAND rats, the duration of cardioplegic infusions—of equal volume and administered at near constant pressure with zero downstream pressure in all groups—was prolonged. The LV dry weights of hearts from DOCA and BAND rats were similar or greater than in the control groups. Therefore coronary vascular resistance per unit LV dry weight is increased in these arrested hypertrophied hearts, in general accord with the diminished vascularity reported by others [9] [18]. However, there was no evidence of decreased coronary vascular resistance in hearts from SHR rats compared with those from WKY rats in our study.
In summary, we found a shift to the V3 form of ventricular isomyosin with LVH. Although the coincidence of good recovery and increased V3 does not prove a causal relationship, the greater efficiency of this isoform could partly explain enhanced functional recovery observed in the hypertrophied hearts after hypothermic arrest. The many other changes in hypertrophy might also contribute. Increased mechanical efficiency with hypertrophy appears to occur in a wide range of species including rats and humans. Although the rat is limited as a model of human LVH because the human heart does not display the same myosin isoform shift, other molecular strategies appear to underlie the increased mechanical efficiency of the hypertrophied human heart.
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Acknowledgments
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This study was supported in part by grants HL12322 and HL12777 from the National Institutes of Health, and by generous gifts from Mr. and Mrs. Milton J. Silverman and the Leon S. Newton Foundation. We thank Ellen O. Weinberg, MD, for assistance with the DOCA model, Katsuhide Mabuchi, PhD, for assistance with myosin electrophoresis, Carmelo Bondi and Christopher Butler for chemical analyses, Diane Barbarisi and Angela Devid for technical assistance, and John L. Boucher, Linda Dell’Olio, and Marie Estime for preparation of the manuscript.
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References
|
|---|
- Cooley DA, Reul GJ, Wukasch DC Ischemic contracture of the heart: stone heart. Am J Cardiol 1972;29:575-577.[Medline]
- Warner KG, Khuri SF, Kloner RA, et al. Structural and metabolic correlates of cell injury in the hypertrophied myocardium during valve replacement. J Thorac Cardiovasc Surg 1987;93:741-754.[Abstract]
- Levitsky S Myocardial protection of the hypertrophied heart [Editorial]. Ann Thorac Surg 1986;41:2-3.[Medline]
- Munfakh NA, Steinberg JB, Titus JS, et al. Protection of the hypertrophied myocardium by crystalloid cardioplegia. J Surg Res 1991;51:447-456.[Medline]
- Hendren WG, O’Keefe DD, Geffin GA, Denenberg AG, Love TR, Daggett WM Maximal oxygenation of dilute blood cardioplegic solution. Ann Thorac Surg 1994;58:1558-1559.[Medline]
- Miller AW, II, Bohr DF, Schork AM, Terris JM Hemodynamic responses to DOCA in young pigs. Hypertension 1979;1:591-597.[Abstract/Free Full Text]
- Hoh JFY, McGrath PA, Hale PT Electrophoretic analysis of multiple forms of rat cardiac myosin: effects of hypophysectomy and thyroxine replacement. J Mol Cell Cardiol 1978;10:1053-1076.[Medline]
- Martin AF, Paul RJ, McMahon EG Isomyosin transitions in ventricles of aldosterone-salt hypertensive rats. Hypertension 1986;8:128-132.[Abstract/Free Full Text]
- Hamrell B, Alpert N Cellular basis of the mechanical properties of hypertrophied myocardium. In: Fozzard HA, ed. The heart and cardiovascular system. New York: Raven Press, 1986:1507-1524.
- Izumo S, Lompré AM, Matsuoka R, et al. Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy. Interaction between hemodynamic and thyroid-hormone induced signals. J Clin Invest 1987;79:970-977.
- Harrington WF, Rodgers ME Myosin. Annu Rev Biochem 1984;53:35-73.[Medline]
- Lompre AM, Mercadier JJ, Wisnewsky C, et al. Species and age-dependent changes in the relative amounts of cardiac myosin isoenzymes in mammals. Dev Biol 1981;84:286-290.
- Mercadier JJ, Bouveret P, Gorza L, et al. Myosin isoenzymes in normal and hypertrophied human ventricular myocardium. Circ Res 1983;53:52-62.[Abstract/Free Full Text]
- Mercadier JJ, Lompré AM, Wisnewsky C, et al. Myosin isoenzyme changes in several models of rat cardiac hypertrophy. Circ Res 1981;49:525-532.[Abstract/Free Full Text]
- Litten RZ, III, Martin BJ, Low RB, Alpert NR Altered myosin isozyme patterns from pressure-overloaded and thyrotoxic hypertrophied rabbit hearts. Circ Res 1982;50:856-864.[Abstract/Free Full Text]
- VanBuren P, Harris DE, Alpert NR, Warshaw DM Cardiac V1 and V3 myosins differ in their hydrolytic and mechanical activities in vitro. Circ Res 1995;77:439-444.[Abstract/Free Full Text]
- Alpert NR, Mulieri LA, Hasenfuss G, Holubarsch C Myocyte reorganization in hypertrophied and failing hearts. Eur Heart J 1995;16(Suppl C):2-7.
- Aufferman W, Wu ST, Derugin N, et al. 31P magnetic resonance spectroscopy of pressure overload hypertrophy in rats: effect of reduced perfusion pressure. Cardiovasc Res 1990;24:57-64.[Abstract/Free Full Text]
- Tubau JF, Wikman-Coffelt JF, Massie BM, Sievers R, Parmley WW Improved myocardial efficiency in the working perfused heart of the spontaneously hypertensive rat. Hypertension 1987;10:396-403.[Abstract/Free Full Text]
- Menasché P, Grousset C, Apstein CS, Marotte F, Mouas C, Piwnica A Increased injury of hypertrophied myocardium with ischemic arrest: preservation with hypothermia and cardioplegia. Am Heart J 1985;110:1204-1209.[Medline]
- Wexler LF, Lorell BH, Momomura S, Weinberg EO, Ingwall JS, Apstein CS Enhanced sensitivity to hypoxia-induced diastolic dysfunction in pressure-overload left ventricular hypertrophy in the rat: role of high energy phosphate depletion. Circ Res 1988;62:766-775.[Abstract/Free Full Text]
- Burkhoff D Myocardial energetics and the postischemic heart. Ann Thorac Surg 1990;49:525-527.[Medline]
- Soei LK, Sassen LMA, Fan DS, van Veen T, Krams R, Verdouw PD Myofibrillar Ca2+ sensitization predominantly enhances function and mechanical efficiency of stunned myocardium. Circulation 1994;90:959-969.[Abstract/Free Full Text]
- Bishop SP, Altschuld RA Evidence for increased glycolytic metabolism in cardiac hypertrophy and congestive heart failure. In: Alpert NR, ed. Cardiac hypertrophy. New York: Academic Press, 1971:567-585.
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Abstract
Introduction
