Right and left ventricular metabolites

J

THORAC CARDIOVASC SCRG

1988;96:725-9

Right and left ventricular metabolites Current methods of cardioplegic delivery may delay the recovery of right ventricular metabolism and function. To evaluate right and left ventricular metabolism, we performed biopsies in 37 patients undergoing elective coronary bypass operation with aortic root blood cardioplegia. Right ventricular temperatures were warmer than left ventricular temperatures during cardioplegic arrest (right ventricle: 16.80 ± 3.8 0 C, left ventricle: 14.30 ± 3.7 0 C, p = 0.02). Adenosine triphosphate concentrations were lower in the right ventricle than in the left ventricle before cardioplegic arrest (right ventricle: 13.8 ± 7.8 mmoljkg, left ventricle: 21.5 ± 8.7 mmoljkg, p = 0.02). After reperfusion, right ventricular adenosine triphosphate concentrations feD to low levels (10 ± 6 mmoljkg). Postoperative left and right ventricular high energy phosphate concentrations (the sum of adenosine triphosphate and creatine phosphate levels) correlated inversely with myocardial temperatures during cardioplegia (r = -0.29, p = 0.048). Aortic root cardioplegia did not cool the right ventricle as weD as it did the left ventricle. The lower preoperative high energy phosphate concentrations may have increased the susceptibility of the right ventricle to ischemic injury. Alternative methods of myocardial preservation may improve right ventricular cooling and protection.

Kevin H. Teoh, MD, John C. Mullen, MD, Richard D. Weisel, MD, George T. Christakis, MD, M. Mindy Madonik, BSc, Joan Ivanov, RN, and Donald A. G. Mickle, MD, Toronto, Ontario, Canada

Rtoperative right ventricular dysfunction may limit hemodynamic recovery and contribute to postoperative mortality and morbidity after coronary revascularization 1.2 or mitral valve replacement. 3.4 Although antegrade blood cardioplegia provided excellent myocardial protection for the left ventricle,' we found that right ventricular systolic function was depressed after the use of blood cardioplegia for elective coronary artery bypass operations." To evaluate potential mechanisms for delayed recovery of right ventricular function, we performed left and right ventricular biopsies in patients undergoing an elective coronary artery bypass operation with blood cardioplegia.

From the Division of Cardiovascular Surgery and the Department of Clinical Biochemistry. the Toronto General Hospital, and the University of Toronto. Toronto, Ontario, Canada. Supported by the Medical Research Council of Canada (Grant MA-9829). Received for publication Oct. 28, 1987. Accepted for publication April 11. 1988. Address for reprints: Richard D. Weisel. MD, Cardiovascular Surgery. Toronto General Hospital. 200 Elizabeth St.. Eaton North 13-224. Toronto. Ontario M5G 2C4. Canada.

Methods Patient population. Thirty-seven patients scheduled for elective coronary artery bypass operation agreed to participate in this study and signed a consent form approved by our Institutional Human Experimentation Committee. All patients had stable angina pectoris, preserved left ventricular function (ejection fraction greater than 30% on preoperative cineventriculograrn), and double- or triple-vessel coronary artery disease including a right coronary artery stenosis. Operative technique. Anesthesia was induced and maintained with fentanyl citrate (100 ~g/kg); isoflurane was added when necessary. Cardiopulmonary bypass was instituted with an ascending aortic and a two-stage right atrial cannula. Moderate hemodilution (hematocrit level 22(!r to 24%) and moderate systemic hypothermia (nasopharyngeal temperature 25° C) were used during bypass. Topical cooling was not used. Blood cardioplegic solution was administered with the Buckberg-Shiley system (Shiley Inc., Irvine, Calif.), which delivered oxygenated blood and a crystalloid solution at a ratio of 2 to l .' The physical and biochemical composition of the blood cardioplegic solution has been described in previous reports. 57 Initially, 1000 ml of this solution was infused into the aortic root at a pressure of 70 mm Hg and a temperature of 8 c ± 1c C to achieve arrest. Proximal and distal anastomoses were constructed during a single prolonged cross-clamp period." Blood cardioplegic solution (100 ml) was infused into each vein graft after completion of each distal anastomosis, and 400 ml was infused into the aortic root at a pressure of 60 mm Hg after the completion of each proximal anastomosis. The right coronary artery was bypassed with a vein graft as the first

725

The Journal of Thoracic and Cardiovascular Surgery

7 2 6 Teoh et al.

Table I. Clinical information

Myocardial Temperature

20

DLV

DRv

37 55 ± 10 10/19/8 17/12/8 117 ± 24

Patients Age (yr) NYHA class II/III/IV LV grade 1/2/3 CPB time (min) Cross-clamp time (min)

.p 005 LV different than RV

64 ± 20

Left ventricular (LV) grade was derived from the left ventricular ejection fraction (L VEF): grade I = LVEF >60'if. grade 2 = LVEF 40% to 60%, grade 3 = LVEF 20'; to 40'if. l\YHA. New York Heart Association: CPB. cardiopulmonary bypass.

Cardioplegia Infusion Fig. 1. Right ventricular (RV) temperatures were significantly warmer than left ventricular (LV) temperatures after each infusion of cardioplegic solution.

distal anastomosis to improve right ventricular protection. Systemic rewarming was begun during the construction of the final distal anastomosis. The left ventricle was vented through the aortic root between infusion of cardioplegic solution. Before release of the aortic cross-clamp, 500 ml of 37 C blood cardioplegic solution was infused into the aortic root at a pressure of 50 mm Hg (a hot shot).' After cross-clamp release, flow rates were maintained between 2.0 and 2.5 L/min/m 2 and arterial pressures were maintained between 50 and 70 mm Hg. Measurements. Myocardial temperatures were measured with needle thermistors (Shiley Inc.) after each aortic root cardioplegic infusion. Left ventricular temperatures were measured in the distribution of the left anterior descending, circumflex, and right coronary arteries, and the mean of the three measurements was recorded as the left ventricular temperature for each cardioplegic infusion. The mean left ventricular temperature at the site of the biopsy was calculated as the mean of the temperature measurements from that location after each cardioplegic infusion. Right ventricular temperatures were measured in the free wall. The mean right ventricular temperature was calculated as the mean of the free wall temperature measurement after each infusion of cardiaplegic solution. Transmural right and left ventricular biopsies specimens were obtained with a Tru-Cut biopsy needle (Travenol Labs, Deerfield, 111.) during cardiopulmonary bypass at 37° C before cross-clamp application, immediately after cross-clamp release, and after 20 minutes of reperfusion. Left ventricular biopsy specimens were obtained from the region subserved by the most stenotic vessel." , and the right ventricular specimens were obtained from the free wall. Specimens were not taken from areas of myocardial scarring. The biopsy specimens were immediately immersed in liquid nitrogen and subsequently freeze-dried. The tissue concentrations of adenosine triphosphate (ATP), creatine phosphate (CP), and lactate were C

assayed with spectrofluorometric techniques.* The results are expressed as millimoles per kilogram dry weight of myocardial muscle. Statistical analysis. The Statistical Analysis System programs (SAS Institute Inc., Cary, N.C.) were used for statistical analysis. Twa-way, repeated measures analyses of variance were performed to test the effects of location and time for myocardial temperatures and tissue metabolites, and Duncan's multiple range test was used to specify differences. A linear regression analysis was performed to correlate the mean myocardial temperatures and the high energy phosphate measurements after reperfusion for the left ventricle, the right ventricle, and both ventricles together. Statistical significance was assumed for probability values less than 0.05. The mean and standard deviation are presented in the tables and text, and the mean and standard error are illustrated in the figures.

Results The clinical profile of the patients is presented in Table L There were no hospital deaths and no patient had a perioperative myocardial infarction. One patient required inotropic support for more than 30 minutes to maintain the systolic blood pressure greater than 80 mm Hg (a transient low output syndrome). The myocardial temperatures after each infusion of cardioplegic solution are depicted in Fig. I. The right ventricular temperatures were consistently warmer than the left ventricular temperatures (location, p = 0.0001). Although the myocardial temperatures gradually rose between cardioplegic infusions in both ventricles, right ventricular temperatures were always warmer than left ventricular temperatures. In addition, the mean of the temperature measurements after each cardioplegic infusion was warmer in the right ventricle than in the left ventricle (right ventricle: 16.8 ± 3.8 left ventricle: 14.3 ± 3.7 C, P = 0,02). The myocardial concentrations of ATP, CP, and high energy phosphates (the sum of the ATP and CP measurements) are depicted in Fig. 2. The ATP concentrations were lower in the right ventricle than in the left 0

0

0

,

0

*Grenier Selective Analyzer II, Grenier Electronics, Langenthal, Switzerland, and Perkin-Elmer 650-1 OS fluorescence spectrophotometer, Perkin-Elmer, Norwalk, Conn.)

Volume 96 Number 5

Right ventricular metabolism 7 2 7

November 1988

Table II. Myocardial lactate concentrations (mmoljkg) Left ventricle Right ventricle

ATP

25

Before XCL

XCL off

Reperfusion

27 ± 21 37 ± 27

52 ± 35* 52 ± 34*

45 ± 32 46 ± 34

DLV

*

20

[JRV

*p

005 LV different than RV

Myocardial lactate concentrations rose significantly during aortic cross-clamping (XCl) in both ventricles (time. p = 0.01).

'p < 0.05 dilTerent from before cross-clamping by Duncan's test.

(location, p = 0.001). ATP concentrations were lower in the right ventricle before cardioplegia (p = 0.02 by Duncan's test), when only three patients (8%) had higher ATP concentrations in the right ventricle than in the left ventricle. ATP concentrations fell in both the right and left ventricles (time, p = 0.0001 overall, p = 0.01 for the left ventricle, and p = 0.001 for the right ventricle). In addition, the fall in ATP levels may have been greater in the right ventricle than in the left because the interaction between location and time was also significant (p = 0.02). After reperfusion, ATP concentrations were low in the right ventricle (10 ± 6 mmoljkg) and only seven patients (19%) had higher ATP concentrations in the right ventricle than in the left. The CP concentrations fell significantly with time in both groups (time, p = 0.04), and the CP concentrations tended to be lower in the right ventricle after reperfusion, but the differences did not achieve statistical significance (location, p = 0.10, P = 0.02 by Duncan's test). High energy phosphate concentrations (the sum of ATP and CP concentrations) fell in both ventricles (time, p = 0.0001) and were lower in the right ventricle than in the left (location, p = 0.02). Left and right ventricular high energy phosphate concentrations fell to extremely low levels (18 ± 15 mmoljkg) after reperfusion in the right ventricle. Left and right ventricular high energy phosphate concentrations after reperfusion correlated inversely (r = -0.29, P = 0.048) with the mean of the myocardial temperature measurements at the biopsy site during cardioplegic arrest. The correlations were not significant for only the left or the right ventricle. Myocardial lactate concentrations were not significantly different between ventricles (Table II) although before cardioplegia, 27 patients (73%) had higher lactate concentrations in the right ventricle than in the left. Myocardial lactate concentrations rose significantly during aortic cross-clamping and fell during reperfusion (time, p = 0.0 I) in both the left and right ventricles.

Discussion In this study, aortic root cardioplegia produced warmer right ventricular temperatures than left ventricular

CP

Ol

~

::::::

o

E

E

High Energy Phosphates

40

*

PRE XCL

XCL OFF

REPERFUSION

Fig. 2. Left and right ventricular concentrations of ATP, CP, and high energy phosphates (ATP and CP) before aortic occlusion (PRE XCL). after cross-clamp release (XCL OFF), and after 20 minutes of reperfusion are illustrated. Right ventricular (RV) ATP and high energy phosphate concentrations were significantly lower than left ventricular (L V) concentrations before cardioplegia and fell to low levels during reperfusion.

temperatures during cardioplegic arrest. Each patient had a right coronary artery stenosis, and right ventricular protection was more difficult in these patients. In addition, the ventral position of the right ventricle and

The Journal of Thoracic and Cardiovascular

7 2 8 Teoh et al.

the warming effect of systemic venous return and noncoronary collateral blood flow may have contributed to the rewarming. Myocardial high energy phosphate concentrations decreased in both ventricles after cardioplegia and reperfusion. In a previous study, we found that blood cardioplegia provided better preservation of left ventricular high energy phosphates than did crystalloid cardioplegia.' In this study, the fall in high energy phosphates in the left ventricle may have resulted from the rise in left ventricular temperatures after the third cardioplegic infusion (perhaps because of systemic rewarming during the last distal anastomosis) The fall in right ventricular high energy phosphates may have been due to the warm right ventricular temperatures during cardioplegic arrest. Topical hypothermia may be necessary to improve left and right ventricular protection. An alternate explanation for the fall in high energy phosphates during reperfusion could be persistent ischemic anaerobic metabolism after cross-clamp removal. We have previously demonstrated myocardial platelet and leukocyte deposition? and persistent anaerobic metabolism" during the first hour after cross-clamp removal. Improved methods of intraoperative protection may preserve high energy phosphate concentrations during reperfusion. High energy phosphate concentrations were lower in the right ventricle than in the left ventricle before cardioplegic arrest. The reason for the lower concentrations remains obscure, but may reflect the metabolic adaptation of the right ventricle to less pressure work. The lower right ventricular ATP concentrations were unlikely to have been due to chronic right ventricular ischemia, because all patients had both right and left coronary artery stenoses. ATP provides energy for the maintenance of cellular integrity during ischemia. Low concentrations of ATP preoperatively may have increased the susceptibility of the right ventricle to ischemia. Peyton and associates!I found diminished subendocardial high energy phosphate concentrations in animals and human beings with left ventricular hypertrophy. They suggested that the lower high energy phosphate concentrations increased the susceptibility of the hypertrophied ventricles to ischemia. In animals, the lower concentrations were associated with a shorter time to ischemic contracture. In human subjects, these investigators found a higher incidence of postoperative ventricular dysfunction. II The low levels of high energy phosphates may have rendered the right ventricle more susceptible to ischemic injury during cardioplegic arrest. High energy phosphate concentrations in the right

Surgery

ventricle fell to low levels 20 minutes after cross-clamp release. Low levels have been associated with ischemic contracture in animals and ventricular dysfunction in human subjects.":" The low concentrations of ATP (10 mmoljkg) and high energy phosphates (18 mmoljkg) in the right ventricle after reperfusion may have contributed to the postoperative right ventricular dysfunction web previously reported. Inadequate right ventricular cooling and low postoperative high energy phosphates may have contributed to postoperative right ventricular dysfunction. Interventions intended to cool the right ventricle during cardioplegia may preserve high energy phosphates and improve postoperative right ventricular function. Both topical hypothermia I~ and profound systemic hypothermia" (with the venae cavae snared) have been demonstrated to enhance the cooling of the right ventricle during cardioplegic arrest. Retrograde coronary sinus cardioplegia may improve both right and left ventricular protection. 16. 17 However, right atrial retrograde cardioplegia may provide the best cooling and protection of the right atrium and right ventricle. IS We wish to extend our appreciation to Ms. Eslyn Kespcr for preparation of the manuscript. We also wish to extend our appreciation to the nurses and perfusionists of the cardiovascular operating rooms for their invaluable assistance. REFERENCES 1. Christakis GT, Fremes SE, Weisel RD. et al. Right ventricular dysfunction following cold potassium cardioplegia. J THORAC CARDIOVASC SCRG 1985;90:243-50. 2. Rabinovitch MA, Elstein J, Chiu RCJ, et al. Selective right ventricular dysfunction after coronary bypass grafting. J THORAC CARDIOVASC SURG 1983;86:444-6. 3. Christakis GT, Kormos RL, Weisel RD, et al. Morbidity and mortality in mitral valve surgery. Circulation 1985;72 (Pt 2):11120-8. 4. Teoh KH, Christakis GT, Weisel RD. et al. The determinants of mortality and morbidity after multiple valve surgery. Ann Thorac Surg 1987;43:353-8. 5. Fremes SE, Christakis GT, Weisel RD, et al. A clinical trial of blood and crystalloid cardioplegia. J THoRO\c CARDIOVASC SURG 1984;88:726-41. 6. Mullen JC, Fremes SE, Weisel RD, et al. Right ventricular function: a comparison between blood and crystalloid cardioplegia. Ann Thorac Surg 1987;43:17-24. 7. Teoh KH, Christakis GT. Weisel RD, et al. Accelerated myocardial metabolic recovery with terminal warm blood cardioplegia. J THoRAc CARDIOVASC SLiRG 1986;91 :88895. 8. Weisel RD, Fremes SE, Baird RJ, Ivanov J. Madonik MM, Mickle DAG. Improved myocardial protection with blood and crystalloid cardioplegia. J Vase Surg 1984; 1:656-9.

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9. Teoh KH, Christakis GT, Weisel RD, et al. Prevention of myocardial platelet deposition and thrornboxane release with dipyridamole. Circulation 1986;74(Pt 2): III 145-52. 10. Teoh KH, Mickle DAG, Weisel RD, et al. Improving myocardial metabolic and functional recovery after cardioplegic arrest. J THORAC CARDIOVASC SURG 1988; 95:788-98. 11. Peyton RB, Jones RN, Attarian D, et al. Depressed high-energy phosphate content in hypertrophied ventricles of animals and man: the biologic basis for increased sensitivity to ischemic injury. Ann Surg 1982; 196:27884. 12. Attarian DE, Jones RN, Currie WD, et al. Characteristics of chronic left ventricular hypertrophy induced by subcoronary valvular aortic stenosis. II. Response to ischemia. J THORAC CARDlOVASC SURG 1985;81:389-95. 13. Sink JD, Pellom GL, Currie WD, et al. Response of hypertrophic myocardium to ischemia: correlation with biochemical and physiological parameters. J THORAC CARDIOVASC SURG 1981;81:865- 72.

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14. Landymore RW, Tice D, Trehan N, Spencer F. Importance of topical hypothermia to ensure uniform myocardial cooling during coronary artery bypass. J THORi\C CARDlOVASC SURG 1981;82:832-6. 15. Grover FL, Fewel JG, Ghiodoni JJ, Trinkle JK. Does lower systemic temperature enhance cardioplegic myocardial protection? J THoRAc CARDIOVASC SURG 1981;81:1120. 16. Gundry SR, Kirsh MM. A comparison of retrograde cardioplegia versus antegrade cardioplegia in the presence of coronary artery obstruction. Ann Thorac Surg 1984; 38:124-7. 17. Bolling SF, Flaherty JT, Bulkley BH, Gott VL, Gardner T J. Improved myocardial preservation during global ischemia by continuous retrograde coronary sinus perfusion. J THORAC CARDIOVASC SURG 1983;86:659-66. 18. Fabiani IN, Deloche A, Swanson J, Carpentier A. Retrograde cardioplegia through the right atrium. Ann Thorac Surg 1986;41:101-2.