A. Jain

A. Khanna

A.J. Demetris

Atkinson

Brand

D. Kramer

G. Ziady

J.J. Fung

Nomoto

Ohara

Park

T.E. Starzl

English

PubMed

Khanna, A

Jain, A

Ziady, G

Demetris, AJ

Fung, JJ

Kramer, D

Starzl, TE

Name not available

Cardiac changes at autopsy in adult liver transplant recipients under tacrolimus

D-Scholarship@Pitt

i • f ~f Cardiac Changes at Autopsy in Adult Liver Transplant Recipients Under Tacrolimus A. Khanna, A. Jain, G. Ziady, A.J. Demetris, J.J. Fung, D. Kramer, and T.E. Starzl TACROLIMUS (FK506) is being used as immunosup-pressant in solid organ transplantation. However, its nephrotoxic and neurotoxic effects are well recognized. Recently reversible hypertrophic cardiomyopathy under tacrolimus has been described in five children. 1 In order to evaluate myocardial toxicity of the drug. we examined the cardiac findings at autopsy in adults and children following primary liver transplantation (OLTx) under tacrolimus and compared them with autopsy findings of patients who died of end-stage liver disease without OLTx and tacrolimus. MATERIALS AND METHODS Patients who received OL Tx between August 1989 and December 1<)92 (834 adults. age> 18 years) were followed through April 1995. Sixty-seven (2<)%) of 228 patients who died during the follow-up period underwent autopsy (study group). Cardiac findings at autopsy were compared with 72 adults who died of end-stage liver disease without OL Tx and Tacrolimus (control group). The param-eters studied were weight of the heart. left (LV) and right (RV) ventricular wall thickness. circumferences of tricuspid (TV). pul-monary (PV). mitral (MV). and aortic (A V) valves. and macro-scopic and microscopic appearances of the cardiac musculature. The prescnce of associated problems of hypertension. coronary artery disease. and infective endocarditis was taken into account. A\I hearts were subjected to formalin fixation for 12 to 24 hours followed hy cutting according to "flow of hlood method. "2 DEMOGRAPHICS Mean age in the study group (51.3 :::: !3 years) and the control group (52.5 = 13.7 years) were comparahle. There were more maks in the study group (M = -l-l. F = 23) compared to the control group (M .\9. F = 33). The mean period of exposure to tacrolimus in the study group was h.I :::: S.C! months. RESULTS Mean weight of the heart. wall thickness of both ventricles, and circumference of all valves are shown in Table 1. The mean weight of the heart in both the groups is comparable (458:!: 105 g study group and 470 :!: 109.5 g control group). The average weight of the heart in both groups was increased as compared to normal popUlation (275 ± 75 g). None of the patients in either group had had any congenital or acquired valvular abnormality. Mean R V wall thickness in both the groups were com-parable and normal (RV = 0.47 :!: 0.2 em study group. 0.5 ± 0.2 cm control group, 0.4 to 0.5 em normal popula-tion). Mean LV wall thickness. however. was increased in both groups as compared to the normal population (LV = 1.65 :!: 0.4 cm study group. 1.6 :!: 0.3 cm control group, 0.8 to 1.5 em normal population). Table 2 shows left ventricle wall thickness in both groups of patients. The circumfer-ences of valves were comparable as shown in Table 1. Mean TV circumference 12 :!: 1.3 em in the study group as compared to 12 :!: 1.2 cm in the control group, PV 8.1 ± 1.1 cm compared to 8.1 :!: 1.1 em in control group, the corresponding numbers for MV and A V being 10.5 :!: 1.3 cm against 10 :!: 1.2 cm. and 7.7 :!: 1.2 cm against 7.4 :!: 0.9 From the Diviston of Transplantation Surgery (AK. A.J .• J.J.F .. T.E.S.), Cardiology (G.Z.), Pathology (A.J.D.), and Critical Care Medicine (DK), Thomas E. Starzi Transplantation Institute, University of Pittsburgh School of Medicine. Pittsburgh, Penn-sylvania. Address reprint requests to A. Khanna. Division of Transplan-tation Surgery, Thomas E. Starzi Transplantation Institute, Uni-versity of Pittsburgh School of Medicine. 4-C Falk Clinic, 3601 5th Avenue, Pittsburgh, PA 15213. Table 1. Cardiac Changes at Autopsy in Adult Liver Transplant Recipients Under Tacrolimus Study Group (A) N 67 Wall thickness Valve Circumference Weight Igi RV LV rv PV MV AV Mean -158 0.47 1.65 12 8.1 10.5 77 SD 105 0.2 0.4 1.3 11 1.3 i .2 Median .\40 0.4 1.55 12 8 10.5 ?6 RV rloht ventrtCle: LV left ventncle: TV tncusplc valve: PV pulmonary valve; 0041-1315/97/$17.00 PII S0041-1345(96)00254-0 532 MV Control Group (S) N 72 Wall thickness Valve Circumference Weight (g) RV LV TV PV MV AV 470.2 0.5 16 12 8 10 (-1 109.5 0.2 0.3 1.2 1.1 1.2 0.9 460 0.4 1.6 12 8 10 7.5 mitral valve: AV aortiC valve. '9 1997 by ElseVier Science Inc. 655 Avenue of the Americas. New York. NY 10010 CARDIAC CHANGES AT AUTOPSY IN LIVER TX UNDER TACROLIMUS 533 em ";1.3 >1.3-<2.0 2:2.0 Table 2. Group (A) n (%) 11 (18) 38 (63) 11 (18) LV Wall Thickness Group (6) n(%) 13 (18) 42 (61) 15 (20) cm. respectively. These are normal when compared with the dimensions in normal population. TV = 10 to 12.5 cm. PV = 7 to 9 cm. MV = 8 to 10.5 cm and AV = 8 to 10 cm. The incidence of myocardial infarction. coronary artery disease and. infective endocarditis was noted to be 12%. 45%. and 16% in the study group and 8o/r. 58%. and 4% in the control group. respectively. DISCUSSION Liver failure and chronic liver disease are associated with peripheral vasodilatation and increased cardiac output he-modynamic changes which affect the myocardium causing hypertrophy. This has been well established and also con-firmed in a series by Park et al:' They based their study on echocardiography findings in 73 liver failure patients before and after liver transplantation and confirmed that there is a tendency to myocardial hypertrophy. chamber enlargement. and increased cardiac output in patients with chronic liver disease. Echocardiography on these patients performed at 5 weeks to 15 months posttransplant showed reduction in LV end diastolic dimensions in all except one (P < .2). There was also a reduction in stroke volume index from 53 mLlm2 to 34 mLim2 and in mean cardiac index from 5.S Llmin/m 2 to 3.11 Limin/m 2 after OL Tx (P < .00 I). In our study. an increase in weight of heart and LV thickness were comparable in ooth the groups. This could be uue to a number of reasons. Liver failure. t'luiu status. repeat blood transfusions. and steroid therapy j contribute to a hyperdvnamic state that can cause mYOl.:ardial hyper-trophy. It would have been helpful if we had pre- and posttransplant echocaruiograms in the study anu control population. This woulu have helpeu us compare these with ~lutopsy uimensillns. Assm;iated renal uysfunction. hypertension. and infusions of colloids (intravcnous albumin and packed cell transfu-sion) would alkc! the hemodynamic status and c(lulu contrlhute to the development of cardiac hvpertrophy. The illlpnllcment rcportcd hy ,\tkinson ct all ill P:ltiCllt, with l'ardiolllvopathv aftcr withdrawal of q~lcrolimus mav have hl'cn attributable III part til these ilctor~K yticrll~iDopic c\;lllllllalillll 01 Ihc IIlHll'arlilUlll l'onlirmed the prc'l'I1L'c 01 hypertrophy in our patients. Cardiotoxic side effects have not been reported in the cxperimental toxicologic evalua-tion of FK 506 in rats. dogs. and baboons.5 Tacrolimus in high doses (0.4 mg/kg IV q d) has been known to cause myocardial necrosis in rabbits. This is reversible upon stopping the drug. h However. this experimental study did not show any evidence of hypertrophic cardiomyopathy induced by Tacrolimus. CONCLUSION Liver failure is associated with cardiac changes that essen-tially include myocardial hypertrophy and increase in heart weight and dimensions. namely thickness of ventricles and circumferences of valves. The effect is related to hemody-namic changes accompanying liver failure. OLTx amelio-rates the hyperdynamic state. thus improving the hemody-namic status which may cause regression of cardiac dimensions (repeat echoeardiograms after 3 months). Car-diac hypertrophy. however. may persist after liver trans-plantation due to augmentation effect of steroids these patients routinely receive and failure of portosystemic shunts to close. It would be naive attribute these changes to a specific therapeutic agent. This study confirms that cardiac findings at autopsy in primary OL Tx recipients treated with Tacrolimus and pa-tients with end-stage liver disease without OL Tx and Ta-crolimus arc comparable for weight of the heart. wall thickness. valve circumference. and evidence of myocardial infarction. The rate of infective endocarditis was higher in the study group. The rate of coronary artery disease was higher in the control group. Left ventricle hypertrophy was found in X07r of the patients in both groups and is due to liver failure and hemodynamic changes associated with it rather than a direct dfect of drug therapy. ACKNOWLEDGMENT The authors aeknowkdge the help of Vishal Jain in preparation of tahles and ligun: in this manuscript. REFERENCES I. Atkinson p, J<lubert Cr. Barron A. et al: Lancet 345:894. 11)1)5 2. Walker Bruec F. Sciliant RC. In Hurst's The Heart. ~th Ed. p77 .'. Park Sc. Beerman LI3. (iartner Jc. d al: Am J Cardiol R~:i1T~K I'IS:, 4. Brand I'Ll'. l't al: Aeta 1':lcdiatr s2:1J 14. 1<)<)3 '. OIl:lr<l K. Billilll!t()11 R. J;lIllC' RW. ct <II: Transplant Proc 22:S.'. 1'1'111 II. ~EFnelyyl S. Fllji\\;!,-a II. lhn r. l'l :11: Transplant Pro, 21J:S55. lqq4 

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Transplantation Proceedings

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Cardiac changes at autopsy in adult liver transplant recipients under tacrolimus

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