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Ann Thorac Surg 1997;63:1353-1360
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Rapid Cooling Contracture With Cold Cardioplegia

Cardiac Surgical Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

Accepted for publication December 5, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Cold cardioplegia can induce rapid cooling contracture. The relations of cardioplegia-induced cooling contracture to myocardial temperature or myocyte calcium are unknown.

Methods. Twelve crystalloid-perfused isovolumic rat hearts received three 2-minute cardioplegic infusions (1 mmol/L calcium) at 4°, 20°, and 37°C in random order, each followed by 10 minutes of beating at 37°C. Finally, warm induction of arrest by a 1-minute cardioplegic infusion at 37°C was followed by a 1-minute infusion at 4°C. Indo-1 was used to measure the intracellular Ca²⁺ concentration in 6 of these hearts. Additional hearts received hypoxic, glucose-free cardioplegia at 4° or 37°C.

Results. After 1 minute of cardioplegia at 4°, 20°, and 37°C, left ventricular developed pressure rose rapidly to 54% ± 3%, 43% ± 3%, and 18% ± 1% of its prearrest value, whereas the intracellular Ca²⁺ concentration reached 166% ± 23%, 94% ± 4%, and 37% ± 10% of its prearrest transient. Coronary flow was 5.7 ± 0.2, 8.7 ± 0.3, and 12.6 ± 0.6 mL/min, respectively. Warm cardioplegia induction at 37°C reduced left ventricular developed pressure and [Ca²⁺]_i during subsequent 4°C cardioplegia by 16% (p = 0.001) and 34% (p = 0.03), respectively. Adenosine triphosphate and phosphocreatine contents were lower after 4°C than after 37°C hypoxic, glucose-free cardioplegia.

Conclusions. Rapid cooling during cardioplegia increases left ventricular pressure, [Ca²⁺]_i, and coronary resistance, and is energy consuming. The absence of rapid cooling contracture may be a benefit of warm heart operations and warm induction of cardioplegic arrest.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Hypothermia has been a cornerstone of myocardial protection since the inception of cardiac surgery, facilitating rapid arrest and improving tolerance to ischemia. However, good clinical results with warm heart operations [1] have generated interest in the adverse effects of cooling. Hypothermia impairs the Na⁺-K⁺ adenosine triphosphatase (ATPase) [2], mitochondrial adenosine triphosphate (ATP) translocase [3], and sarcoplasmic reticular (SR) Ca²⁺-ATPase [4], as well as oxygen-hemoglobin dissociation [5], thus hindering cell volume control, energy metabolism, Ca²⁺ sequestration, and oxygen delivery. The functional and clinical significance of these effects is unknown. The Warm Heart Investigators [1] found that warm blood cardioplegia during coronary artery bypass grafting significantly reduced the incidence of low output syndrome and enzymatic myocardial infarction when compared with cold blood cardioplegia in a randomized trial; profoundly cooling the heart worsened the outcome as measured by these variables.

Rapid cooling contracture (RCC), a nondepolarizing myocardial contracture induced by rapid cooling, is a potentially deleterious effect of cold heart operations. Rebeyka and associates [6] showed that RCC induced in isolated rabbit hearts by cooling before hypothermic cardioplegic arrest impaired postarrest systolic and diastolic function and was associated with greater cellular necrosis. Williams and colleagues [7] found that rapid core cooling before total circulatory arrest for repair of congenital cardiac defects in infants was detrimental to survival and postulated that RCC played a role. We have described RCC in crystalloid-perfused rat hearts [8] and in blood-perfused canine hearts [8, 9] during infusion of cold calcium-containing cardioplegic solutions. Cardioplegia-induced RCC was associated with ATP depletion during arrest and impaired left ventricular systolic and diastolic function after arrest [8, 9].

Rapid cooling contracture is believed to be caused by a temperature-dependent release of calcium from the SR [10–12]. Rebeyka and associates [6] and Williams and colleagues [7] attributed the poor recovery associated with RCC to preischemic calcium loading. A better understanding of what precipitates or prevents RCC is important for clinical cardiac operations, in which the adequacy of myocardial protection is often equated with the rapidity and depth of cooling [1]. In this study, we report the relations of developed pressure, myocyte calcium ([Ca²⁺]_i), coronary flow, and myocardial high-energy phosphates to myocardial temperature during cardioplegia-induced RCC in isolated crystalloid-perfused rat hearts.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Male Sprague-Dawley rats weighing 300 to 500 g were anesthetized with 65 mg/kg sodium pentobarbital intraperitoneally and were given 100 U of heparin through the femoral vein. Beating hearts were excised rapidly and perfused at 37°C through the aortic root at 100 cm H₂O through a water-jacketed perfusion system with HEPES-buffered Tyrode's solution, continuously equilibrated with 100% oxygen (Table 1). The left atrial appendage was incised, the left ventricle was vented, and a water-filled balloon-tipped catheter attached to a pressure transducer was passed across the mitral valve into the left ventricle. The balloon volume was adjusted to an end-diastolic pressure of 10 mm Hg. An incision in the pulmonary artery allowed egress of coronary effluent and placement of a temperature probe in the right ventricle. Hearts were paced at a constant rate of 250 or 300 beats/min (Grass Stimulator, Quincy, MA) by an electrode clipped to the left atrial appendage after the right atrium was excised to abolish sinus rhythm. Peak and end-diastolic left ventricular pressures, heart rate, and myocardial temperature were recorded continuously on a multichannel strip-chart recorder. Coronary flow was measured by timed volumetric collections. Stable measurements after 10 minutes of isovolumic beating were considered prearrest baseline values. Hearts were arrested by clamping the aortic perfusion line and delivering cardioplegic solution through a side arm in the aortic cannula at 65 cm H₂O at a randomly chosen temperature of 4°, 20°, or 37°C. Simultaneously, the temperature of the water jacket around the heart was changed from 37°C to that of the cardioplegic solution, if hypothermic. The cardioplegic solution, continuously equilibrated with 100% oxygen, was buffered with HEPES to simplify pH control at different temperatures (see Table 1). After 2 minutes of infusion of cardioplegic solution, aortic perfusion with oxygenated Tyrode's perfusate was resumed at 37°C, restoring the heart to the isovolumic beating mode. The intraventricular balloon volume was again adjusted to produce an end-diastolic pressure of 10 mm Hg. The sequence of 10 minutes of isovolumic beating at 37°C followed by 2 minutes of cardioplegic solution infusion was performed three times, administering cardioplegic solution at 4°, 20°, and 37°C in random order to each heart. A fourth and final period of arrest was induced by administering cardioplegic solution at 37°C for 1 minute, followed immediately by cardioplegic solution at 4°C for 1 minute. Left ventricular developed pressure, expressed as a percentage of prearrest developed pressure (%dP), coronary flow, and myocardial temperature were recorded during each cardioplegic arrest period.

The excitation beam of a 100-W mercury lamp (UVP) was filtered at 365 ± 7.5 nm (Omega Optical, Brattleboro, VT) and focused onto the left ventricular epicardium of indo-1-loaded hearts through a bifurcated quartz fiberoptic cable. Visible epicardial vessels were excluded from the focal point. Emitted fluorescence was collected by the fiberoptic cable, split by a dichroic mirror, and filtered at 405 ± 17.5 nm and 495 ± 10 nm (Omega Optical, Brattleboro, VT) at separate photomultiplier tubes. Fluorescence intensity at 405 nm and 495 nm, and the ratio of these fluorescence intensities (F_405/495), were calculated by an electronic ratio circuit (Biomedical Instrumentation Group, University of Pennsylvania, Philadelphia, PA) and recorded on the multichannel strip-chart recorder. The binding of calcium to indo-1 shifts the fluorescence excitation spectra to shorter wavelengths, such that F_405/495 is proportional to [Ca²⁺]_i [13, 14]. In theory, the F_405/495 ratio negates the effect of motion artifact on the indo-1 signal in a beating-heart preparation [13]. However, during the first seconds of infusion of cardioplegic solution, there often was excessive random movement of the preparation; therefore, [Ca²⁺]_i during cardioplegia was formally measured only after 1 and 2 minutes of cardioplegic solution infusion when there was no movement. [Ca²⁺]_i recorded during arrest was expressed as a percentage of the [Ca²⁺]_i transient associated with peak developed pressure before arrest (%dCa), with the prearrest diastolic F_405/495 ratio assigned a value of zero.

Differences in energy consumption during arrest at different temperatures were studied in additional hearts, perfused at 37°C as described previously but arrested only once with cardioplegic solution delivered at 4°C (n = 12) or 37°C (n = 8). The perfusate was a Krebs-Henseleit bicarbonate solution continuously equilibrated with 95% O₂ and 5% CO₂. The cardioplegic solution, also buffered with bicarbonate, was nitrogenated with 98% N₂ and 2% CO₂ and was glucose free to accentuate differences in energy consumption (see Table 1) [8]. Either after 15 minutes of perfusion (prearrest baseline, n = 6) or at the end of infusion of the nitrogenated cardioplegic solution, the atria of these hearts were removed and the ventricles were frozen with aluminum clamps cooled in liquid nitrogen; these were stored at -70°C. Samples were analyzed for myocardial ATP and phosphocreatine (PCr) contents by high-pressure liquid chromatography [15], modified by the use of iced 0.6 N perchloric acid for homogenization and by neutralization of the homogenate by 1.0 mol/L K₂HPO₄ after 30 minutes at 4°C.

Data from the four prearrest periods in hearts receiving multiple doses of cardioplegic solution were subjected to analysis of variance with repeated measures. Cardioplegic arrest data were subjected to linear regression analysis. High-energy phosphate data were assessed by analysis of variance. When analysis of variance rejected the hypothesis of equal means, planned comparisons of pairs of means were performed by the paired or unpaired t test, as appropriate. Values of p less than 0.05 were considered significant. Data are presented as mean ± standard error of the mean.

All rats received humane care in compliance with the "Guide For the Care and Use of Laboratory Animals" formulated by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 85-23, revised 1985).

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Baseline data from all four prearrest periods were similar. Indo-1 had no significant effect on any variable before or during arrest. Therefore, data from all four prearrest periods from both indo-free and indo-loaded hearts were pooled (n = 47) to give a baseline left ventricular systolic pressure, diastolic pressure, and coronary flow of 106.0 ± 2.3 mm Hg, 9.3 ± 0.2 mm Hg, and 21.6 ± 0.2 mL/min, respectively. Myocardial temperature, obtained similarly, was 36.9° ± 0.02°C.

A representative simultaneous recording of left ventricular pressure and the indo-1 F_405/495 signal (Fig 1) from a beating heart shows the rapid rise of [Ca²⁺]_i preceding the onset of ventricular contraction, peaking before end-systole and gradually returning to baseline. This time course and morphology are typical of [Ca²⁺]_i transients recorded from the surface of indo-1-loaded, isolated perfused hearts [13].

View larger version (63K): [in this window] [in a new window]   Fig 1. . Representative recording of left ventricular pressure and the indo-1 F405/495 signal in the beating, isolated perfused isovolumic rat heart. Note the rapid rise of [Ca2+]i preceding the onset of ventricular contraction, peaking before end-systole and gradually returning to baseline.

View larger version (66K): [in this window] [in a new window]   Fig 2. . Representative recordings of myocardial temperature, left ventricular pressure, and the indo-1 F405/495 signal during infusion of cardioplegic solution at 4°C (A) and 37°C (B). Note the rapid rise of left ventricular pressure and [Ca2+]i, correlating with the rapid decrease in myocardial temperature with cardioplegia at 4°C.

View larger version (24K): [in this window] [in a new window]   Fig 3. . Linear regressions of percentage of the [Ca2+]i transient associated with peak developed pressure before arrest (%dCa), left ventricular developed pressure as a percentage of prearrest developed pressure (%dP), and coronary flow on myocardial temperature after 1 and 2 minutes of perfusion with cardioplegic solution at 4°, 20°, and 37°C. For all six regressions, p 0.0001. For myocardial temperature versus %dCa, correlation coefficient r = -0.785 and -0.802 at 1 and 2 minutes, respectively. For myocardial temperature versus %dP, r = -0.875 and -0.894 at 1 and 2 minutes, respectively. For myocardial temperature versus coronary flow, r = 0.889 and 0.675 at 1 and 2 minutes, respectively.

View larger version (23K): [in this window] [in a new window]   Fig 4. . Linear regressions of left ventricular developed pressure as a percentage of prearrest developed pressure (%dP) to percentage of the [Ca2+]i transient associated with peak developed pressure before arrest (%dCa) after 1 and 2 minutes of perfusion with cardioplegic solution at 4°, 20°, and 37°C. Correlation coefficient r = 0.845 and 0.865 at 1 and 2 minutes, respectively. p < 0.0001 for both regressions. The inset shows the relation of %dP to log(%dCa) (pooled 1- and 2-minute arrest data) described by a sigmoid curve: y = 15.9 + (56.4 - 15.9)/(1 + e ((83.3 - x)/17.7)); r = 0.935.

Peak %dP increased with decreasing cardioplegia temperature in hearts arrested once with anoxic glucose-free cardioplegic solution (Fig 5). In these hearts, the time taken to infuse the 15-mL cardioplegia dose was longer with the cardioplegic solution at 4°C than at 37°C, demonstrating higher coronary vascular resistance during arrest at the lower temperature (see Fig 5). Myocardial ATP and PCr contents were significantly depressed at end-arrest with cardioplegia at 4°C as compared with baseline; only the PCr content was significantly depressed at end-arrest with cardioplegia at 37°C as compared with baseline (Fig 6). Myocardial ATP and PCr contents were decreased more markedly in those hearts arrested at 4°C than in those arrested at 37°C (see Fig 6).

View larger version (16K): [in this window] [in a new window]   Fig 5. . Duration of infusions of 15 mL of anoxic, glucose-free cardioplegic solution at 4° or 37°C and peak left ventricular developed pressure as a percentage of prearrest developed pressure (%dP) during these infusions. Data are mean ± standard error of the mean, n = 4 to 12. The 4° and 37°C values are significantly different from each other for duration (p < 0.0001) and %dP (p < 0.0001).

View larger version (32K): [in this window] [in a new window]   Fig 6. . Myocardial adenosine triphosphate (ATP) and phosphocreatine (PCr) contents in nmol/mg protein before arrest and after infusion of 15 mL of anoxic, glucose-free cardioplegic solution at 4° or 37°C. Data are mean ± standard error of the mean, n = 6 to 12. Both ATP and PCr were decreased at end-arrest at 4°C as compared with baseline (p = 0.0407 and p = 0.0000, respectively); PCr was decreased at end-arrest at 37°C as compared with baseline (p = 0.0007). Both ATP and PCr were lower after arrest at 4°C than at 37°C (p = 0.0152 and p = 0.0053, respectively).

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Rapid cooling contracture was originally described in guinea pig [10] and rabbit [11] papillary muscle preparations and has been further characterized in isolated guinea pig myocytes [12]. Such contracture occurring during rapid cooling before cardioplegic arrest has been reported in the isolated rabbit heart [6] and may occur in some infant hearts [7]. In this and previous studies, we have described RCC induced by the infusion of cold calcium-containing cardioplegic solutions in isolated crystalloid-perfused rat hearts [8] and in blood-perfused canine hearts [8, 9].

Rapid cooling contracture appears to be mediated by a rapid temperature-dependent rise in [Ca²⁺]_i. A rapid increase in [Ca²⁺]_i preceding peak contraction during RCC in isolated guinea pig myocytes loaded with indo-1 [12] and a temperature-dependent rise in [Ca²⁺]_i during cooling of indo-1-loaded rat myocytes have been reported [18].

We measured [Ca²⁺]_i during cardioplegia-induced RCC using the calcium fluorophore indo-1. In vitro calibrations performed by Bers and associates [12] indicated that cooling slightly decreases the affinity of calcium for indo-1; thus, indo-1 might underestimate [Ca²⁺]_i at colder temperatures. Our own in vitro experiments showed no significant effect of cooling on the indo-1 fluorescence ratio (unpublished data). The presence of indo-1 did not alter prearrest ventricular function or the cardioplegia-induced RCC phenomenon.

In this study, peak %dP occurred during the first 10 to 11 seconds of infusion of cardioplegic solution, a period when myocardial temperature and [Ca²⁺]_i were changing rapidly. Peak %dP increased with decreasing cardioplegic solution temperature, but with cold cardioplegia, this peak occurred before the minimum myocardial temperature or peak [Ca²⁺]_i was attained. The temperature-dependent myofilament calcium sensitivity of skinned rabbit ventricular trabeculae is greater during temperature change than at steady-state temperatures [19]. This phenomenon could explain why the peak %dP occurred before myocardial temperature and [Ca²⁺]_i plateaued. The early peak in left ventricular pressure attained during cardioplegic solution infusion was eliminated during infusion of 4°C cardioplegic solution when preceded by arrest with 37°C cardioplegic solution.

There was a direct inverse relation between %dCa and myocardial temperature and between %dP and myocardial temperature after 1 and 2 minutes of cardioplegic solution infusion, when myocardial temperature and [Ca²⁺]_i had stabilized (see Fig 3). The sigmoid-shaped %dCa-%dP relation (see Fig 4, inset) resembles and, perhaps, is analogous to the force-pCa²⁺ (-log[Ca²⁺]) relation described for isolated cardiac trabeculae [20] and myocytes [21]. Figure 4 demonstrates that during cardioplegic arrest, %dCa always exceeded %dP, suggesting that rat cardiac myofilament calcium sensitivity or maximal calcium-stimulated tension decreased with cardioplegic arrest. The direction and magnitude of the temperature dependence of myofilament calcium sensitivity and maximal calcium-stimulated tension vary among species and muscle types and are not known for rat myocardium [20, 21].

It is possible that the F_405/495 signal represents elevated [Ca²⁺]_i in other organelles or cardiac cell types and not just that in the myofilament microenvironment. Lorell and co-workers [22] noted that stimulation of endothelial cells by bradykinin causes a dose-dependent increase in endothelial [Ca²⁺]_i, possibly confounding the measurement of myocyte calcium. Although we cannot exclude a possible contribution of other cell types to the fluorescence measured from an intact heart preparation, our results are consistent with those obtained during cooling of indo-1-loaded isolated myocytes [12, 22].

Rapid cooling contracture is not associated with depolarization sufficient for voltage-dependent activation of contracture or gated entry of calcium from the extracellular space [10, 12]. Several lines of evidence implicate the SR as the source of calcium released in RCC. Pretreatment with caffeine [11] or ryanodine [12] prevents calcium uptake by the SR and abolishes RCC. Calculations by Bers and colleagues [12] indicated that the entire SR calcium content is released very rapidly (half-maximal in 150 ms) during RCC [12]. The exact mechanism of calcium release is unknown, but an SR rapid calcium release channel has been described [12, 19].

We noted a 16% decrease in the %dP and a 34% decrease in the %dCa when cardioplegic solution infusion at 4°C was preceded by normothermic arrest for 1 minute, as compared with arrest at 4°C without preceding normothermic arrest. Myocardial cooling was equivalent in both situations. This decrement in contracture amplitude is consistent with the rest decay phenomenon of RCC. Rest decay is a decrease in RCC magnitude that occurs progressively with periods of precooling quiescence [11, 12]. Rest decay is accelerated in the presence of caffeine and ryanodine and is prevented when transarcolemmal sodium-calcium exchange is inhibited during the precooling rest period by a sodium-free superfusate [11, 12]. It is therefore proposed that rest decay is due to a decrease in the SR calcium store that results when the SR calcium leak [20] is uncompensated by stimulation-dependent loading and the leaked calcium is pumped out of the myocyte by sodium-calcium exchange [12].

In this study, serial cardioplegia-induced RCCs without intervening ischemia were not detrimental to myocardial function. Prearrest systolic and end-diastolic pressures showed minimal deterioration over the course of an experiment involving four brief contractures. In addition, the regression curves for pressure developed during cardioplegia-induced RCC from each of the cardioplegic periods were not statistically different from each other. Bridge [11] also found that papillary muscle preparations suffered no apparent injury after many successive brief RCCs. However, RCC has been reported to be deleterious in both experimental and clinical settings. Rebeyka and associates [6] noted that, when followed by ischemia, RCC induced by cooling before ischemic arrest in isolated rabbit hearts impaired recovery. Williams and colleagues [7] found that rapid core cooling before circulatory arrest for repair of congenital cardiac defects in infants was detrimental to survival and proposed that RCC played a role.

Rapid cooling contracture is energy consuming. In this study, myocardial ATP and PCr were depressed more markedly after arrest with anoxic glucose-free cardioplegic solution at 4°C than after arrest with the same solution at 37°C. In a previous study in isolated blood-perfused canine hearts undergoing 75 minutes of cold continuous blood cardioplegia, we found that RCC was associated with a decline in myocardial ATP and PCr measured by ³¹P nuclear magnetic resonance spectroscopy [9]. Those hearts receiving continuous cold blood cardioplegia also had poorer postarrest recovery of left ventricular peak pressure and diastolic compliance and relaxation than did hearts receiving continuous warm blood cardioplegia [9]. We have also found that rat hearts developing serial RCCs during 2 hours of multidose cardioplegic ischemic arrest had greater depletion of ATP and PCr at end-arrest and poorer functional recovery upon reperfusion than did hearts in which RCC was avoided by the use of an acalcemic cardioplegic solution [8]. The addition of magnesium to the cardioplegic solution inhibited RCC [8].

The elevated cytosolic calcium content associated with RCC may contribute to myocardial stunning. Stunning is a state of reversible contractile and metabolic dysfunction insufficient to cause myocyte death; clinical cardioplegic arrest is often followed by temporary pump dysfunction attributed to stunning [23]. Calcium overload during ischemia and reperfusion is thought to play a central role in the pathophysiology of stunning [24, 25]. Elevation of [Ca²⁺]_i by cardioplegia-induced RCC in an ischemic setting could promote these calcium-mediated processes and stunning.

Rapid cooling contracture is associated with elevated coronary vascular resistance. Coronary flow was directly related to myocardial temperature in this study. Rebeyka and associates [6] noted that cardioplegic infusion pressure was increased in those hearts undergoing cooling before ischemic cardioplegic arrest. Increased coronary vascular resistance from vascular compression by myocardial contracture may cause inequities of cardioplegia distribution or delay mechanical arrest.

Thus, cardioplegia-induced RCC is associated with consumption of high-energy phosphates, calcium loading, and increased coronary vascular resistance. These processes may injure the myocardium, particularly if associated with ischemia. In this study, an interval of normothermic arrest decreased the magnitude of RCC and the associated calcium elevation. The Warm Heart Investigators [1], in a randomized study of 1,732 patients undergoing coronary bypass, found that the incidences of postoperative low output syndrome and enzymatic myocardial infarction were significantly reduced by warm heart operations as compared with cold blood cardioplegia. Although the difference did not attain statistical significance, mortality was lower in the group undergoing warm heart operations, at 1.4% versus 2.5% in the cold group [1]. We postulate that cardioplegia-induced RCC and its associated energy consumption, calcium overload, and increased coronary vascular resistance may be avoided by warm induction and warm heart operations, thus possibly reducing the incidence or the severity of stunning.

In summary, we have demonstrated that during cardioplegic arrest, the contractile elements of the heart remain mechanically active. Rapid cooling contracture induced by cold cardioplegia may exacerbate ischemic injury by elevating [Ca²⁺]_i, consuming energy, and compromising coronary distribution. These effects conflict with the goals of myocardial protection. The prevention of RCC may be an underlying benefit of warm cardioplegia induction and warm heart operations.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study was supported in part by grants HL12322 and HL12777 from the National Institutes of Health, and by generous gifts from Mr Anthony A. Borgatti, Jr, Mr and Mrs Milton J. Silverman, and the Leon S. Newton Foundation. Doctor Lahorra was supported by the Dudley P. Allen Surgical Scholarship of the Case Western Reserve University Department of Surgery.

We thank Rombout Kruse and Cheng-zai Lu for their extensive assistance. We also thank Alvin G. Denenberg for chemical analyses, Diane Barbarisi for technical assistance, and Linda Dell'Olio, Anne Manning, and Marie Estime for manuscript preparation.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Torchiana, Cardiac Surgical Unit, Massachusetts General Hospital, Boston, MA 02114.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract 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 Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Joseph A. Lahorra David F. Torchiana Willard M. Daggett Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lahorra, J. A. Articles by Daggett, W. M. Search for Related Content PubMed PubMed Citation Articles by Lahorra, J. A. Articles by Daggett, W. M.