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European Journal of Heart Failure 2002 4(5):583-586; doi:10.1016/S1388-9842(02)00091-0
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© 2002 European Society of Cardiology

Simultaneous angiotensin converting enzyme inhibition moderates ventricular dysfunction caused by doxorubicin

Mikhail Vaynblata,*, Himansu R. Shahb, Dinesh Bhaskarana, Geeta Ramdevb, Wellington J. Davis, IIIa, Joseph N. Cunningham, Jr.a,b and Mario Chiavarellib

a Division of Cardiovascular Surgery, Department of Surgery, Maimomides Medical Center, Administration Building, Rm D, Department of Surgery 4802 10th Ave, Brooklyn, NY 11219, USA
b Division of Cardiothoracic Surgery, Department of Surgery, State University of New York-Health Science Center (SUNY-HSC) at Brooklyn Brooklyn, NY, USA

* Corresponding author: Tel.: +1-718-283-7686; fax: +1-718-283-7392. E-mail address: mishavayn{at}aol.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims: The purpose of this study was to determine that the administration of an angiotensin converting enzyme (ACE) inhibitor enalapril would confer protection against doxorubicin-induced experimental heart failure, and attenuate the development of left ventricular dysfunction.

Methods: Seventeen dogs were chronically instrumented with an intracoronary catheter and received doxorubicin weekly for 4 weeks. Animals were assigned to two groups: group 1: untreated heart failure; and group 2: simultaneous enalapril administration (5 mg twice a week). Hemodynamic data were obtained at week 0 and 12. Echocardiography was performed weekly.

Results: Survival improved with simultaneous enalapril administration (36% in group 1 vs. 100% in group 2, P=0.04). The increase in the left ventricular end-diastolic pressure was significantly reduced at week 12 (17±1 mmHg in group 1 vs. 9±1 mmHg in group 2, P=0.0042). The fall in left ventricular stroke work index was significantly prevented (52% in group 1 vs. 21% in group 2, P=0.006). The increase in right ventricular end-diastolic diameter was significantly reduced by enalapril prophylaxis.

Conclusion: Simultaneous treatment with enalapril was beneficial in the prevention of doxorubicin-induced cardiomyopathy.

Key Words: Heart failure • Cardiomyopathy • Dog • ACE inhibitors • Ventricular function

Received March 29, 2001; Revised February 7, 2002; Accepted April 25, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Angiotensin converting enzyme (ACE) inhibitors are beneficial in patients with left ventricular dysfunction and congestive heart failure [1]. Clinical trials support the use of ACE inhibitors as cornerstone in the treatment of symptomatic heart failure patients [2]. Patients in all New York Heart Association functional classes benefit from these agents [1]. Significant clinical advantage is obtained with the administration of ACE inhibitors [3,4] in asymptotic patients with depressed left ventricular function (ejection fraction <40%). The progression of left ventricular dysfunction and the incidence of frank congestive heart are reduced.

Doxorubicin has a broad spectrum of anti-neoplastic activity that includes: hematologic tumors; breast; gastric; lung; gynecologic, urologic and hepatocellular cancers; and bone and soft tissue sarcomas. A total administered dose of doxorubin of 500 mgxm2 body surface area is rarely exceeded due to cardiotoxicity [5]. Doxorubicin-induced cardiomyopathy is clinically relevant since several patients develop lethal heart failure after anti-neoplastic therapy thus compromising its clinical effectiveness. If anti-neoplastic therapy is successful, some patients with left ventricular dysfunction will progress to intractable heart failure and require heart transplantation. From 1990 to 1996 the United Network for Organ sharing (UNOS) recorded 89 cases of heart transplantation in patients with doxorubicin-induced cardiomyopathy (UNOS Research Division, unpublished data, 1997).

In the present study, we hypothesized that the administration of enalapril would confer protection from doxorubicin-induced experimental heart failure and attenuate the development of left ventricular dysfunction.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
Seventeen male mongrel dogs weighing 20–34 (26±1) kg were used in this experiment. The investigation conforms with the ‘Guide for the Care and Use of Laboratory Animal’ published by the US national Institute of Health (NIH publication No. 85-23, revised 1996). Animals were assigned to two groups: group 1: a total of 11 dogs with untreated heart failure; and group 2: a total of six dogs that underwent simultaneous enalapril treatment (5 mg orally twice daily starting 1 week prior to doxorubicin treatment and continued until being killing or death).

All dogs underwent a left thoracotomy to place a 4 French silastic catheter (V-A-PTM Access port Model CPV; Access Technologies, Skokie, IL) into the diagonal coronary artery [6,7]. All animals received a total dose of 1 mg1xkg (31 mgxm2) of intracoronary doxorubicin (Adria Laboratories, Columbus, OH) in four divided weekly doses. The doxorubicin solution was prepared by dissolving the weekly dose of doxorubicin in 60 ml of 0.9% saline solution. This solution was infused over 1 h using a Harvard pump (model 901; Harvard Apparatus Co., Millis, MA). The initial infusion was given 1 week after the intracoronary catheter placement and it was repeated weekly for a total of 4 weeks.

Data from each animal were obtained by left and right heart catherisation at week 0 and 12. Right heart pressures and thermodilution cardiac output (model 9520A, American Edwards Laboratories, Irvine, CA) were obtained with Swan–Ganz catheter (Arrow International, Inc., Reading, PA) which was placed through the right external jugular vein. Left ventricular pressure was obtained by direct puncture using an 18 G needle at week 0 and 12. Arterial and mixed venous blood gases were obtained at each catherisation. All animals received butorphanol tartrate (0.4 mgxkg1, Aveco Co., Inc., Fort Dodge Laboratories, Inc., Fort Dodge, IA) intramuscularly for analgesia. The animals were killed after the final catheterization at week 12.

Two-dimensional echographic studies were performed using 1500 echographic system (Hewlett–Packard, Andover, MA) with a 2.5-MHz transducer. Long and short axis views were obtained at the apex, left sternal border and subcostal margin. Three sets of repeated measures were made in each echographic view at week 0 and weekly for 12 weeks in all animals. The calculated parameters include: left and right ventricular end-diastolic diameter; length; endocardial area and volume; and ejection fraction. Left ventricular volumes were calculated using Simpson's rule [8]. All studies were analyzed by the same echocardiographer.

Time-related events were analyzed by Kaplan–Meier actuarial estimate and were compared by Breslow–Gehan–Wilcoxon test. Repeated measures analysis of variance was used to test hemodynamic and echocardiographic parameters. Data were expressed as mean±standard error of the mean (S.E.M.). Multiple comparisons were performed by the Scheffe test. A probability value of 0.05 or less was considered to represent statistical significance.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Survival at 12 weeks was 36% in the untreated heart failure group and 100% in the Enalapril group (P=0.04, Fig. 1). The left ventricular end-diastolic pressure increased significantly at week 12 (17±1 mmHg in group 1 vs. 11±1 mmHg in group 2, P=0.0042). The left ventricular stroke work index decreased by 52% in group 1 and by 21% in group 2 at week 12 (P=0.006). The right ventricular end-diastolic diameter increased by 19% in group 1 and by 3% in group 2 at week 12 (P=0.034). The cardiac index decreased by 37% in group 1 and by 10% in group 2 at week 12 but was not statistically significant. The ejection fraction decreased by 25% in group 1 and by 19% in group 2 (Fig. 2). Differences in heart rate, mean arterial pressure and systemic vascular resistance did not reach statistical significance.


Figure 1
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  		Fig. 1 Survival curve (Kaplan–Meier actuarial estimate) in 11 dogs from group 1 and six dogs from group 2 for 12 weeks. Sacrificed dogs were censored alive at 12 weeks.

 


Figure 2
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  		Fig. 2 Ejection fraction (EF) decreases gradually over the 12 weeks for both groups. The difference from week 0 reaches statistical significance at week 5 (Scheffe test) (circle=enalapril treated group and square=control).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Cardiac dysfunction following anti-neoplastic therapy with doxorubicin is a lethal side effect which limits its therapeutic potential. Doxorubicin cardiotoxicity is associated with a reduction of left ventricular ejection fraction as determined by radionuclide angiography [9]. Myocardial damage is irreversible [10] and progresses to congestive heart failure often unresponsive to any supportive therapy. This has been shown to occur through the metabolic breakdown of doxurubicin to a free radical state that interacts with molecular oxygen to generate superoxides [11]. These highly toxic reactive oxygen species react with cellular molecules including nucleic acids, protein and lipids, causing cell damage [12]. An effective modality for the prevention of cardiac dysfunction is clinically not available. Cardiac transplantation is the only therapeutic option.

Angiotensin-converting enzyme (ACE) inhibition is the first line of intervention in heart failure therapy [2]. The beneficial effects of ACE inhibitors include: reduction of mortality; decrease in left ventricular end-diastolic pressure [13]; end-diastolic volume [14]; total blood volume [14]; mean circulatory filling pressure [13]; and systemic vascular resistance [11]; as well as an increase in venous compliance [14]. ACE inhibitors are also known to act as free radical scavengers in vitro studies [15] and to decrease myocardial oxygen consumption [16].

Several clinical investigations demonstrated a significant reduction in heart failure mortality following ACE inhibition. In the Prevention Trial from the SOLVD study, patients with reduced left ventricular ejection fraction showed an 8% reduction in mortality [17]. The CONSENSUS Trial investigated the effects of enalapril in severe congestive heart failure and reported a reduction in mortality by 31% [18] and the Treatment Trial from the SOLVD study reported a reduction in mortality by 16% [19]. Enalapril improved left ventricular ejection fraction in patients receiving cyclophosphamide induction therapy before bone marrow transplantation [20]. In our canine model of doxorubicin-induced cardiomyopathy, enalapril treatment reduced mortality by 64%. The survival benefit obtained in the present study appears to be greater than the advantage demonstrated in clinical trials. The difference may be attributed to the direct scavenging effect of ACE inhibitors on the free radical production induced by doxorubicin. In addition both aldosterone and angiotensin II may be associated with progressive collagen accumulation in the cardiac interstitium [21]. ACE inhibitors thus may have an antifibrotic effect, thereby impeding adverse architectural damage and myocyte destruction after doxorubicin therapy [21].

ACE inhibitors are known to improve cardiac function by reducing afterload and preload. In the present study the increase in left ventricular end-diastolic pressure and in the right ventricular end-diastolic diameter are attenuated. Cardiac index decreased more in the untreated group than in the enalapril group. The difference, however, did not reach statistical significance. No histopathological studies were performed, but in future studies this would further enhance these findings. Enalapril administration is usually well tolerated and has been advocated in asymptotic patients with left ventricular dysfunction. Therefore, cardiac protection with ACE inhibition may be considered as an adjunct therapy in all patients receiving doxorubicin.

This study suggests simultaneous ACE inhibition may confer protection and reduce the development of heart failure following doxorubicin administration. Further experimental studies are required to assess the effects of ACE inhibition on the therapeutic index of doxorubicin.


   Acknowledgements
 
The Foundation for Surgical Education and Investigation, State University of New York Health Science Center at Brooklyn and the Maimonides Research and Development Foundation supported this research. We thank the Adria Laboratories of Columbus, OH, for graciously providing our laboratory with doxorubicin.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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  3. The SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. New Engl J Med (1992) 327:669–677.[Abstract]
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  7. Shah H.R., Vaynblat M., Ramdev G., Cunningham J.N. Jr. Chiavarelli M. Experimental cardiomyopathy as a model of chronic heart failure. J Invest Surg (1997) 10:387–396.[Web of Science][Medline]
  8. Wyatt H., Heng M.K., Meerbaum S., et al. Cross-sectional echocardiography 1. Analysis of mathematic models for quantifying mass of the left ventricle in dogs. Circulation (1979) 60:1104.[Abstract/Free Full Text]
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  11. Singal P.K., Deally C.M.R., Weinberg L.E. Subcellular effects of adriamycin in the heart: a concise review. J Mol Cell Cardiol (1987) 19:817–828.[Web of Science][Medline]
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