Doxorubicin‐induced cardiomyopathy: Prevention and treatment by a coronary specific vasodilator
Authors: Gyulkhasyan Tigran , Hakobyan Tatevik , Parikh Ankur , Peketi Punita , Enrick Molly , Shockling Lindsay , Kolz Christopher L. , Chilian William , Ohanyan Vahagn 
Published: June 2021

Doxorubicin is an anthracycline class chemotherapeutic agent that is used alone or in conjunction with other medications to treat different types of cancer. Doxorubicin works by slowing or stopping the growth of cancer cells due to its toxic effects mediated through redox cycling that produces oxidative stress. One of the side effects of doxorubicin treatment, that restricts its use and efficacy is a form of cardiomyopathy, termed doxorubicin‐induced cardiomyopathy (DiC). DiC typically has morphological and functional abnormalities of dilated cardiomyopathy with all four cardiac chambers being dilated. This dilation occurs as a result of a reduction in ventricular ejection fraction and contractile function, resulting in diastolic and systolic dysfunction. Eventually, congestive heart failure can result, which carries a 50% mortality rate. Currently, there is no treatment or prevention for DiC. The goal of this proposal is to test the hypothesis that cardiomyopathy induced by doxorubicin is caused by insufficient blood flow to the heart, leading to the cardiomyopathy. Accordingly, we proposed that the coronary specific dilator, chromonar, will prevent and treat DiC. Previously, we have shown that chromonar has a beneficial effect on the treatment of dilated cardiomyopathy caused by coronary microvascular insufficiency, i.e., inadequate blood flow to the heart. We, also observed that chromonar has a beneficial effect for treating heart failure with non‐obstructive coronary artery disease. Thus, if our speculation that DiC is caused by insufficient blood flow to the heart is correct, then chromonar will be an effective treatment for this condition. Our goal is to determine if the improvement of myocardial blood flow will prevent and treat doxorubicin‐induced cardiomyopathy.

Methods

C57Bl6 mice (Male N=10) were treated with doxorubicin (5mg/kg/) once a week for 6 weeks period. After doxorubicin treatment, chromonar treatment started (3mg/kg/day) for 4 weeks. Cardiac function was measured by using a high‐frequency ultrasound system (Vevo 2100).

Results and Conclusion

Six weeks after doxorubicin treatment, all mice developed heart failure. Ejection fraction was below 40% (figure). Chromonar treatment significantly improved cardiac function (EF increased from 39±5%to 62±4%). In untreated mice, cardiac function continued to deteriorate, even after cessation of doxorubicin treatment. Based on these findings, we propose that a cause of doxorubicin‐induced cardiomyopathy is inadequate myocardial blood flow. Pharmacological coronary vasodilation with chromonar increases myocardial blood flow, which can stop and reverse the functional decline associated with doxorubicin‐treatment, as well as improve cardiac function. Taken together, our results indicate that doxorubicin‐induced cardiotoxicity, which leads to cardiomyopathy may be related to inadequate myocardial perfusion. Correction of the insufficient perfusion produced by doxorubicin reverses the functional decline of the heart.

Support or Funding Information

R01 HL135024;RO1HL132240; AHA 10POST4360030

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.