increased injury of hypertrophied myocardium with ischemic arrest: preservation with hypothermia and...

Groves et al. December, 1985

American Heart Journal

The authors are indebted to Drs. J. Greg Perkins, and Franklin Handel for their support, and Becky Rendon, and Carole Becker for their assistance in preparing this manuscript.

REFERENCES

1. Rubin LJ, Peter RH: Oral hydralazine therapy for primary pulmonary hypertension. N Engl J Med 302:69, 1980.

2. McKay CR, Chatterjee K, Raff GL, Brundage BH, Parmley WW: Comparative hemodynamic and clinical responses to Isuprel, diazoxide and hydralazine in severe precapillary pulmonary hypertension. Am J Cardiol 47:422, 1981,

3. Lupi-Herrera E, Sandoval J, Seoane M, Bialostozky D: The role of hydralazine therapy for pulmonary arterial hypertension of unknown cause. Circulation 65:645, 1982.

4. McGoon MD, Seward JB, Vlietstra RE, Choo MH, Moyer TP, Reeder GS: Haemodynamic response to intravenous hydralazine in patients with pulmonary hypertension. Br Heart J 50:579, 1983.

5. Rich S, Ganz R, Levy P: Comparative actions of hydralazine, nifedipine and amrinone in primary pulmonary hypertension. Am J Cardiol 52:1104, 1983.

6. Rubin LJ, Handel F, Peter RH: The effects of oral hydralazine on right ventricular end-diastolic pressure in patients with right ventricular failure. Circulation 65:1369, 1982.

7. Rubin LJ, Lazar JD: Influence of prostaglandin synthesis inhibitors on pulmonary vasodilatory effects of hydralazine

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in dogs with hypoxic pulmonary vasoconstriction. J Clin Invest 67:193, 1981. Packer M, Greenberg B, Massie B, Dash H: Deleterious effects of hydralazine in patients with pulmonary hypertension. N Engl J Med 306:1326, 1982. Kronzon I, Cohen M, Winer HE: Adverse effect of hydralazine in patients with primary pulmonary hypertension. JAMA 24733112, 1982. Rubino JM. Schroeder JS: Diazoxide in treatment of urimarv pulmonary ‘hypertension. Br Heart J 42:362, 1979. X ” Buch J, Wennevold A: Hazards of diazoxide in pulmonary hypertension. Br Heart J 46:401, 1981. Cohen ML. Kronzon I: Adverse hemodvnamic effects of phentolamine in primary pulmonary hypertension. Ann Intern Med 95:591, 1981. Hermiller JB, Bambach D, Thompson MJ, Huss P, Fontana ME, Magorien RD, Unverferth DV, Leier CV: Vasodilators and prostaglandin inhibitors in primary pulmonary hypertension. Ann Intern Med 97:480, 1982. Rubin LJ, Groves BM, Reeves JT, Frosolono MF, Handel F, Cato AE: Prostacyclin-induced acute pulmonary vasodilation in primary pulmonary hypertension. Circulation 66:334, 1982. Van Grondelle A, Ditchey RV, Groves BM, Wagner WW, Reeves JT: Thermodilution method overestimates low cardiac output in humans. Am J Physiol 14:H690, 1983.

Increased injury of hypertrophied myocardium with ischemic arrest: Preservation with hypothermia and cardioplegia

Many patients undergoing cardiac surgery have some degree of myocardial hypertrophy. To assess the response of hypertrophied myocardium to simulated cardiac surgery, left ventricular hypertrophy was induced in rats by aortic banding, and ventricular function was measured by means of the isolated, isovolumic heart perfusion technique. The hypertrophied hearts had a greater susceptibility to ischemic injury than nonhypertrophied control hearts, as manifested by a greater degree of diastolic contracture during the recovery period after 30 minutes of tschemic arrest at 37” C. Hypothermia without cardioplegia during a l-hour arrest did not completely preserve diastolic function in the hypertrophied hearts, but cardiopiegia combined with hypothermia completely protected the hypertrophied hearts against 2 hours of ischemia. The results suggest a need for both hypothermic and cardioplegic preservation techniques in patients with myocardial hypertrophy who have cardiac surgical procedures requiring a significant period of myocardial ischemia. (AM HEART J 110:1204, 1985.)

Philippe Menasche, M.D., Christian Grousset, Ph.D., Carl S. Apstein, M.D., Franqoise Marotte, Christian Mouas, and Armand Piwnica, M.D. Paris, France

From the Department of Cardiovascular Surgery and INSERM U-127, Preservation of the myocardium during surgically Hospital Lariboisiere. induced ischemic arrest is commonly achieved by a *Supported in part by United States Public Health Service grant HL23406 combination of hypothermia and administration of and RCDA HLOO425 (Dr. Apstein). cardioplegic solutions. Most experimental studies of Received for publication Jan. 4, 1985; revision received May 28, 1985; accepted July 1, 1985.

myocardial preservation during cardiac surgery have

Reprint requests: Philippe Menasche, M.D., Service de Chirurgie Cardio- been carried out in normal animals with normal, Vasculaire, Hopital Lariboisiere, Rue Ambroise Pare, 75475 Paris Cedex nonhypertrophied hearts. However, patients un- 10, France. dergoing valve replacement or coronary artery

Volume 110 Number 6 Cardioplegia in hypertrophied hearts 1205

Table 1. Degree of left ventricular hypertrophy and related values of preischemic coronary flow in hearts of all experimental groups

Ischemia Coefficient of hypertrophy p Value

Preischemic coronary f7on (mllminlgm) p Value

30-minute &hernia Normothermic arrest

Sham Hypertrophied

Hypothermic arrest

36% <O.OOl 11.8 + 0.7

6.9 -+ 0.5 <0.001

Sham Hypertrophied

120-minute &hernia Hypothermic arrest

Sham Hypertrophied

Cardioplegic arrest Sham

Hypertrophied

11.8 + 0.7 45 SC <O.OOl

6.9 + 0.5 <0.001

37 00 <O.OOl 11.2 I 0.4

7.8 +- 0.5 <O.OOl

31% <O.OOl 12.1 + 0.5

8.0 rf- 0.5 <0.001

bypass procedures frequently have left ventricular hypertrophy as a result of the valve lesion, the frequent association of hypertension and coronary artery disease, or the presence of a previous myocardial infarction.’ The presence of left ventricular hypertrophy is associated with an increased inci- dence of ischemic contracture and subendocardial necrosis and a poorer postoperative course compared to nonhypertrophied hearts2

Accordingly, the present study was done to assess the influence of a pressure-overload type of hypertrophy on the myocardial response to a period of global ischemia and reperfusion. Initial studies done at 37’ C demonstrated that such hypertrophied myocardium had a poorer postischemic recovery of mechanical function than nonhypertrophied hearts, particularly in regard to diastolic chamber distensibility. A second series of studies was then done to determine if hypothermic cardioplegia was equally efficacious in preserving mechanical function in hypertrophied and nonhypertrophied hearts after ischemia and reperfusion.

METHODS

Hypertrophy model. Male Wistar rats, weighing approximately 180 gm, were anesthetized with an intraperitoneal injection of sodium pentobarbital, 75 mg. Fol- lowing midline laparotomy, a partially occluding Week hemoclip was positioned around the upper part of the abdominal aorta to produce coarctation.3 Rats were studied approximately 8 weeks following this procedure. Significant left ventricular hypertrophy was confirmed by comparing the ratio of left ventricular weight to body weight in rata with aortic banding to that of sham- operated control rats.

Perfused heart model. Sixty-eight isolated rat hearts were studied by means of a Langendorff perfusion column. Anesthesia was achieved with intraperitoneal sodium pen-

tobarbital, 150 mg, after which median sternotomy was performed and the heart rapidly excised. The hearts were then transferred to the perfusion column and retrograde perfusion was established at a pressure of 100 cm H,O by means of nonrecirculating Krebs-Henseleit bicarbonate buffer bubbled with a 95% O,-5% CO, gas mixture. Coronary perfusion pressure was held constant throughout the preischemia and recovery phases. Left ventricular pacing was maintained at a constant rate of 320 bpm throughout the preischemia and reperfusion periods; the pacemaker was turned off during the period of ischemia. The left atria1 wall was partially excised and a latex balloon was inserted into the left ventricular cavity through the mitral valve. This balloon was connected by a short, rigid, fluid-filled tube and a three-way stopcock to a Statham P 23 Id pressure transducer. The balloon was filled with saline solution to produce a left ventricular end-diastolic pressure of 10 * 1 mm Hg. Balloon volume was held constant throughout the experiment. Left ventricular systolic function was assessed by recording developed pressure (peak systolic minus end-diastolic pressure) and its first derivative, maximum positive dP/dt (Schlum- berger OM-4502 four-channel recorder; Gould-St&ham 13-4615-71 differentiator). Coronary flow was measured by timed collection of the coronary venous effluent. Diastolic function was assessed by monitoring isovolumic left ventricular diastolic pressure as a measure of diastolic chamber distensibility.

Perfusion sequence. After a 20-minute stabilization period, during which time control measurements of ventricular function were made, total global ischemia was induced by interrupting aortic root perfusion. Except for protocol I, part of which was conducted at normothermia (37’ C), all other experiments were done under hypothermic conditions during the period of ischemic arrest. To achieve the desired level of myocardial cooling, the hearts were kept in a sealed water-jacketed chamber at 15’ C via a cooling circuit which was separate from the rest of the perfusion apparatus. In groups receiving cadioplegic solution, the 4O C cardioplegic solution was infused through a

1206 Menasche et al. December, 1985


ISCHEMIA I DEVELOPED PRESSURE

REPERFUSION

mmHg/sec

2500

2000

1500

1000

500

:

r

I

I

I

1

C

POSITIVE dP/dt (max)

mmHg DIASTOLIC PRESSURE

3 w,;:

20

t =e:

%-+

I , I I I 1 1 1

5 10 15 20 25 30 35 40 45 Time (min)

Fig. 1. Comparative effects of 30 minutes of normothermic (37O C) or hypothermic (15’ C) global ischemia on the recovery of developed pressure, maximum positive dP/dt, and diastolic pressure in sham-operated control and hypertrophied hearts. Control measurements (C) were obtained during a 20-minute stabilization period. The period of ischemia was followed by 45 minutes of normothermic reperfusion. Each series consisted of seven to eight hearts. Data are mean 2 SEM. There was no significant difference in the baseline values of any parameters between the four groups. See text for statistical results.

side arm on the aortic cannula at a pressure of 55 cm H,O. The solution was delivered over a 2-minute period at the onset of ischemia and thereafter at 30-minute intervals.

After the ischemic period, 45 minutes of normothermic reperfusion was done in all groups by reinstating retrograde aortic root flow at 37O C. Measurements of ventricular function were made at 5-minute intervals with the balloon filled to the same volume as during the preischemic period.

Experimental groups. The normal and hypertrophied hearts underwent three experimental protocols, differen- tiated by the duration of the ischemic period and the type

of protection used during arrest. In protocol I, hearts were subjected to 30 minutes of global ischemia under either normothermic (37’ C) or hypothermic (15’ C) conditions. In protocols II and III, the period of ischemia was extended to 120 minutes. In protocol II, hearts were protected either by hypothermia alone (15O C) and in protocol III by the combination of hypothermia and multidose cardioplegia. The composition of the cardioplegic solution was as follows: NaCl, 100 mM/L; KCl, 15 mM/L; MgClz, 16 mM/L; CaCl,, 0.25 mM/L; and glutamic acid, 2.942 gm/L. The solution was made hyperosmolar (370 mOsm/L) by the addition of mannitol (12.5 gmL) and its pH was adjusted to 7.4 (at 20’ C). Each experimental group consisted of six to eight hearts.

Statistics. Statistical analysis was performed by means of two-way analysis of variance; whenever F ratio values were significant, multiple linear contrasts were performed and the resultant p values were adjusted by means of the Bonferroni method.4*5 Differences were considered to be significant at the p < 0.05 level. All data are expressed as mean k SEM.

RESULTS

As shown in Table I, significant left ventricular hypertrophy was present in all banded animals. Absolute heart weights were 33% greater in the aortic banded group than in the control group: 1.75 + 0.06 gm (n = 31) vs 1.32 f 0.02 gm (n = 31), p < 0.001. None of the rats with ventricular hypertrophy displayed any sign of heart failure at the time of study. Prearrest values of coronary flow, normal- ized for left ventricular weight, were significantly lower in the pressure-overloaded hearts of all groups (Table I). Since all hearts were perfused at a constant coronary perfusion pressure of 100 cm H,O, the lower coronary flow rate8 in the hypertrophied hearts indicate a relatively higher coronary resistance or tone than that in the normal subjects. Measurements of left ventricular contractile function were similar in normal and hypertrophied hearts during the prearrest periods (Fig. 1 and 2), except in hearts subjected to protocol II where baseline values of these indices were higher in sham-operated hearts (Fig. 2).

Protocol I (30-minute ischemia at normo- or hypothermia). This protocol was designed to assess the basic response of hypertrophied myocardium to a brief ischemic period. The results are shown in Fig. 1. All hearts subjected to normothermic ischemia had a poor recovery of contractile function. The indices of systolic function (developed pressure and maximum positive dP/dt) were depressed to a similar extent (approximately 50% of prearrest values) in normal and hypertrophied hearts. However, diastolic chamber stiffness, as assessed by isovolumic diastolic pressure, was increased more in hypertrophied

Volume 110 Number 6 Cardioplegia in hypertrophifzd hearts 1207

hearts, as evidenced by significantly higher postischemic values of diastolic pressure 0, < 0.001 vs control hearts). The use of hypothermia during the ischemic period improved the recovery of contractile function in both normal and hypertrophied hearts 0, < 0.001 for all parameters in the two groups for hypothermia vs normothermia). However, the hypertrophied hearts still had a slightly greater degree of contracture, as assessed by significantly higher diastolic pressures, than the sham-operated group 0, < 0.001) throughout the period of reperfusion.

Protocol II (120-minute hypothermic ischemia without cardioplegia). This protocol was designed to assess the recovery of hypertrophied hearts made ischemic under conditions simulating those of clinical cardiac surgery. As shown in Fig. 2, all hearts subjected to 2 hours of hypothermic ischemia without cardioplegia failed to resume contractile activity during the initial 10 minutes of reperfusion. Subsequently there were significant differences in the recovery of systolic and diastolic function between the hypertrophied and normal hearts. The hypertrophied hearts had a poorer recovery of diastolic chamber distensibility as evidenced by an increase in diastolic pressure of 17.7 ~fr 3.3 mm Hg above the prearrest control value of 11.6 -t 1.2 mm Hg in the hypertrophied group, while in the normal hearts, diastolic pressure only increased by 7.0 ? 2.6 mm Hg above the preischemic control of 9.8 + 1.2 mm Hg. The difference between the two groups for diastolic pressure was significant at the 0.001 level throughout reperfusion. In contrast, contractile function was better preserved in the group of hypertrophied hearts: after 45 minutes of reflow, developed pressure recovered to 50.6 + 6.8% of prearrest values in normal hearts and to 67.4 + 8.3% in hypertrophied hearts (p < 0.02). Similarly, maximum positive dP/ dt in the control group recovered to 56.9 + 6.7% compared to 70.5 + 9.0% in the hypertrophied group (p = NS). The absolute recovery of developed pressure and dP/dt was similar for both groups; however, the hypertrophied hearts had better recov- eries of these parameters when expressed relative to their respective preischemic values. In both groups, there was a significant trend for developed pressure and maximum positive dP/dt to decline throughout the 45minute period of reperfusion 07 < 0.001).

Protocol Ill (120-minute hypothermic ischemia with cardioplegia). The addition of cardioplegia to hypothermia resulted in all hearts immediately recover- ing pump function at the onset of reperfusion (Fig. 2). In both the normal and hypertrophied hearts, the recovery of all mechanical parameters was signifi-

ISCHEMIA REPERFUSION

mmHg k‘ 1 1 DEVELOPED PRESSURE T

POSITIVE dP/dt Imax)

5 10 15 20 25 30 35 40 45 mmHg

40 DIASTOLIC PRESSURE T : - / I _

30 : T

i- A-k_** &-A ‘-i-A

20

i

,. *

+--+ ,f,,.,,,, 5 10 15 20 25 30 35 40 45 Time (min)

Fig. 2. Comparative effects of 2 hours of hypothermic (15’ C) global ischemia without or with cardioplegia on the recovery of developed pressure, maximum positive dP/dt, and diastolic pressure in sham-operated control and hypertrophied hearts. Control measurements (C) were obtained during a 20-minute stabilization period. During the following 120 minutes of ischemia, hearts receiving cardioplegia were injected with the cardioplegic solution at the onset of arrest and at 30-minute intervals thereafter. The period of ischemia was followed by 45 minutes of normothermic reperfusion. Each series consisted of eight hearts. Data are mean t SEM. In series of hearts protected by hypothermia alone, control values of developed pressure and maximum positive dP/dt were higher in sham-operated than in hypertrophied hearts (p < 0.05 and <O.Ol, respectively). In contrast, there was no difference between the baseline values of these parameters in the corresponding subsets receiving hypothermic cardioplegia. See text for statistical results.

cantly better (p < 0.001) than in the corresponding group that received hypothermic protection without cardioplegia. Particularly striking was the effect of cardioplegic protection on the recovery of diastolic distensibility in the hypertrophied group. In both groups, the combination of hypothermia and cardio-

1208 Menasche et al. December, 1985


plegia resulted in a recovery of contractile function of 80%) as assessed by developed pressure or (+) dP/dt, and postrecovery diastolic pressure was only 2 mm Hg above the preischemic control values (Fig. a.

Although these data indicate slightly incomplete recovery relative to the preischemic values, they should also be compared to the performance maintained by normal, well-oxygenated hearts perfused for an equal period of time. Accordingly, a group of six normal rat hearts was perfused with oxygenated Krebs-Henseleit buffer for 3 hours (equivalent to the initial stabilization period, 2 hours of ischemia, and 45 minutes of recovery). After 3 hours of perfusion, developed pressure had decreased to 77 + 3 % , (+) dP/dt had decreased to 80 ZL 4% of their initial values, and end-diastolic pressure had increased by 3 f 0.1 mm Hg. These data indicate a decline in these parameters of contractile function of approximately 7 %/hour of perfusion with the use of this experimental model, despite well-oxygenated conditions. Thus both the hypertrophied and nonhypertrophied hearts, when protected with cardioplegia and hypothermia during the 120 minutes of ischemia, recovered completely when compared to a group of hearts which had been perfused for 3 hours under well-oxygenated conditions.

DISCUSSION

Sensitivity of the hypertrophied myocardium to ischemic injury. Our results confirm those of previous studies6s7 showing that the hypertrophied myocardi- urn is more sensitive to a period of normothermic ischemic arrest and reperfusion than is normal myocardium. Diastolic function, as assessed by the extent of contracture during the recovery period, was impaired in the hypertrophied hearts to a relatively greater extent than was systolic function. Hypothermia without cardioplegia did not completely preserve diastolic function in the hypertrophied hearts, but hypothermia with cardioplegia completely protected the hypertrophied hearts against 2 hours of ischemia.

The hypertrophied hearts had a lower coronary perfusion rate (per gram of myocardium) than the normal hearts during the preischemic control period (Table I). This indicated that the hypertrophied hearts had a higher coronary vascular resistance than the normal hearts, since all hearts were perfused at a constant coronary perfusion pressure of 100 cm H,O. The lower coronary perfusion rate in the hypertropied hearts was probably secondary to coronary autoregulation, which in turn reflected a reduced oxygen demand per gram of myocardium in

the hypertrophied hearts. We assumed that by virture of their hypertrophy and increased in wall thickness, the pressure-overloaded hypertrophied hearts had a reduction in active systolic stress development and consequently a proportional decrease in myocardial oxygen demand. Thus, the observation that, despite a lesser degree of oxygen demand-supply imbalance, these hearts had a poorer recovery of function than sham-operated control hearts suggests that hypertrophied myocardium is intrinsically more sensitive to ischemic arrest than is normal myocardium.

Protective effects of cardioplegia. In hypertrophied hearts that did not receive cardioplegia, increased ischemic injury was primarily manifested by a rise in diastolic contracture during the recovery period. It is likely that this change in diastolic chamber distensibility was related to either a greater decrease in high-energy phosphate levels during the period of ischemic arrest or a greater increase in cytosolic Ca2+ relative to the normal hearts’s8 Consequently, at least two mechanisms can be put forward to account for the protective effects of cardioplegia on diastolic function of hypertrophied myocardium.

The first mechanism is preservation of tissue high-energy prosphates. Such an issue could be critical since hypertrophied myocardium has been reported to have lower high-energy phosphate stores present at the onset of ischemia’ and to undergo accelerated ischemia-induced decline in adenosine thiphosphate (ATP) levels as a consequence of increased wall tension.8 The lack of ATP could than cause contracture, either directly through rigor bond formation or by impairing homeostatic mechanisms that regulate the intracellular distribution of Ca2+.g*10 By means of phosphorus-31 nuclear magnetic resonance spectroscopy, we” have previously shown that the cardioplegic solution used in the present study significantly preserved high-energy phosphate levels during elective ischemic arrest. Thus, the decrease in the extent of contracture observed in cardioplegically protected hypertrophied hearts could be explained by a better mainte- nance of intracellular ATP levels as a result of the cardioplegic protection. This reasoning is also con- sistent with results of previous investigations12 where preischemic enhancement of ATP levels was shown to delay the onset of contracture in hypertrophied hearts subjected to global ischemia.

Alternatively, the increased sensitivity of hypertrophied hearts to ischemic damage could be primarily related to a failure of the intracellular calcium sequestering sites to regulate the cytosolic calcium concentration.13 An increase in the cytosolic

Volume 110 Number 6 Cardioplegia in hypertrophicd hearts 1209

calcium level would result in an increase in diastolic contracture as we observed. Hypothermic ischemia is known to result in a rise in the cytoplasmic content of ionized calcium.14 There is both experi- mentall l6 and clinicall evidence that cardiac overload is associated with a decrease in the rate of calcium binding and calcium uptake in the sarco- plasmic reticulum and possibly also by the mitochondria. Thus one might speculate that hypertrophied hearts subjected to ischemic arrest are prone to develop more diastolic contracture than normal hearts because the accumulation rate of calcium in the cytosol is greater than that in normal hearts, leading to an increased diastolic fiber tension in the hypertrophied hearts.g In this case, the protective effects of the cardioplegic solution would be related to its ionic composition which was designed to reduce calcium entry into the myocyte.” As previously mentioned a greater preservation of intracellular high-energy phosphate levels would also be expected to limit abnormality of intracellular calcium levels by maintaining sarcolemmal and sarco- plasmic reticular calcium pump function and there- by reducing postischemic myocardial diastolic stiffness. Our data cannot distinguish among these possible mechanisms.

Clinical implications. Regardless of mechanism, our results clearly show that the increased susceptibility of hypertrophied myocardium to develop increased diastolic chamber distensibility after a period of ischemia can be prevented by applying hypothermic and cardioplegic protection. Although these techniques are now widely employed, there are still some proponents” of the use of hypothermic protection alone during coronary artery bypass grafting procedures. Our results strongly argue against such a management since left ventricular hypertrophy is commonly encountered in this large subset of patients.’

content in hypertrophied ventricles of animal and man. The biological basis for increased sensitivity t.k, ischemic injury. Ann Surg 196:278, 1982.

2. Buckberg GB: Left ventricular subendocardial necrosis. Ann Thorac Surg 24:379, 1977.

3. Mercadier JJ, Lompre AM, Wisnewsky C. Samuel Jl,, Berco- vici J, Swynghedauw B, Schwartz K: Myosin isoenzyme changes in several models of rat cardiac hypert,rophy. (lirc Res 49:525, 1981.

4. Zar JH: Two-factor analysis of variance. In McElroy WI). Swanson CP, editors: Biostatistical analysis. Englewood Cliffs, NJ, 1974, Prentice-Hall, Inc, p 163.

5. Wallenstein S, Zucker CL, Fleiss JL: Some statistical methods useful in circulation research. Circ Res 47:1, 1980.

6. Hearse DJ, Stewart DA, Greene DG: Myocardial susceptibility to ischemic damage: A comparative study of disease models in the rat. Eur J Cardiol 7:437, 1978.

7. Attarian DE, Jones RN, Currie WD, Hill RC, Sink dD, Olsen CO, Chitwood WR Jr, Wechsler AS: Characteristics of chron- ic left ventricular hypertrophy induced by subcoronary val- vular aortic stenosis. II. Resnonse to ischemia. J Thorax Cardiovasc Surg 61:389, 1981.*

8. Sink JD, Pellom GL, Currie WD, Hill R(!. Olsen CO, donrs RN, Wechsler AS: Response of hypertrophied myocardium to ischemia. Correlation with biochemical and physiological parameters. J. Thorac Cardiovasc Surg 613865, 1981.

9. Bourdillon PDV, Poole-Wilson PA: Effect+ of ischemia and reperfusion on calcium exchange and mechanical function in isolated rabbit myocardium. Cardiovasc Res 15:121, 1981.

10. Lewis MJ, Grey AC, Henderson AH: Lleterminants of hypoxic contracture in isolated heart, muscle preparations. Cardio- vast Res 13:86, 1979.

Il. Pernot, AC, Ingwall JS, Menasche P. (;rousset C, Berrot M, Piwnica A, Fossel ET: Evaluation of higtr-energy phosphate metabolism during cardioplegic arrest and reperfusion. A phosphorus-31 nuclear magnetic resonant e study. Circula- tion 67:1296, 1983.

12. Peyton RR, Van Trigt P, Pellon GL. ,Jones RN, Sink JI). Wechsler AS: Improved tolerance to ischrmia in hypertrophied myocardium by preischemic enhancement of adenosine triphosphate. J Thorac Cardiovasc Surg 84:11, 1982.

13. Lentz RW, Harrison CE, Dewey JD. Barnhorst DA, Daniel- son GD, Pluth JR: Functional evaluation ol’ cardiac sarco- plasmic reticulum and mitochondria in human pathologic states. J Mol Cell Cardiol 10:3, 1978.

14. Hearse D,J, Braimbridge MV, Jynge P: Protection of the ischemic myocardium: Cardioplegia. New \I.ork, 1981, Raven Press, p 167.

15. Dhalla NS, Das PK Sharma GP: Subcellular basis of cardiac contractile failure. J Mol Cell Cardiol 10::%3, 1978.

16. Sordahl LA, McCollum WB, Wood WG, Schwartz i\: Mito- chondria and sarconlasmic reticulum function in cardiac

~CCC”C. Is .CC hvpertrophy and failure. Am J Phvsiol 224:497, 1973.

1. Peyton RB, Jones RN, Attarian D, Sink JD, Van Trigt P, Currie WD, Wechsler AS: Depressed high-energy phosphate

17. Skins CW: Noncardioplegic myocaidial prrservation for cor- onarv revascularization. ,J Thorac Cardiovapc Sure 88:17-t. 1984:

increased injury of hypertrophied myocardium with ischemic arrest: preservation with hypothermia and...

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