Is chemotherapy-induced cardiomyopathy caused by myocardial ischemia?

Title

Is chemotherapy-induced cardiomyopathy caused by myocardial ischemia?

Creator

Davidian A;Mistry M;Pucci T;Kolz C;Shockling L;Enrick M;Yin L;Chilian W;Ohanyan V

Publisher

Faseb Journal

Date

2020
2020-04

Description

Over the last 50 years progress has been made in treating childhood and adult solid and hematological tumors. One commonly used chemotherapeutic agent is doxorubicin (DOX), an anthracycline antitumor antibiotic, which was discovered in early 1960s. Anthracycline (ANT) chemotherapy alone or in combination with other chemotherapeutic agents markedly improves the survival rate of cancer patients, particularly among children, where survival rates have more than doubled over 5 decades. However, the use of ANT chemotherapy is a double‐edged sword in that it can produce chemotherapy induced cardiac dysfunction (CRCD), which can cause death in 50% of the patients with who present with the cardiomyopathy. We hypothesized, that one of the causes for CRGD is a reduction in myocardial blood flow (MBF) that leads to cardiac myocyte hypoxia, producing small areas of ischemia and myocyte damage. We also hypothesize that increasing MBF by the coronary vasodilator chromonar prevents cardiomyocytes from hypoxic damage. To test these hypotheses, we treated mice genetically engineered to show cardiac myocyte fluorescence if the cells are hypoxic (hypoxia fate mapping [HFM]) with DOX for 6 weeks (group 1, N=8) and Dox + Chromonar for 6 weeks (group 2 N=8). Five weeks after treatment we started tamoxifen for 5 days to activate the HFM protocol. Tamoxifen induces Cre in cardiac myocytes and hypoxia activates a program that results in the expression of td‐tomato only in hypoxic cardiac myocytes. In tissue sections, hypoxic cardiac myocytes are visualized by fluorescence microscopy. Cardiac function was measured by ultrasound and MBF was measured with contrast echocardiography. Six weeks after DOX treatment many hypoxic myocytes were observed in the myocardium. Cardiac function was significantly decreased at the end of DOX treatment (% ejection fraction EF=39±3) compared to baseline (62±5.8%). Simultaneous administration of chromonar prevents the cardiomyocytes from hypoxic damage and prevents cardiac dysfunction development. %EF was 58±6 at the end of the chemotherapy. Chromonar also significantly increased MBF in group 2 mice compared to group 1 (P<0.05). Based on these data CRCD may be a type of ischemic heart disease where the treatment reduces MBF, which leads cardiomyocyte hypoxia, and causes progressive, accumulative cardiac injury. Moreover, increasing myocardial blood flow by chromonar prevents the cardiomyocytes from hypoxic damage and development of CRCD.

Rights

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Format

journalArticle

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Issue

1

Volume

34

ISSN

0892-6638

NEOMED College

NEOMED College of Medicine

NEOMED Department

NEOMED Student Publications
Department of Integrative Medical Sciences

Update Year & Number

September 2020 List

Citation

Davidian A;Mistry M;Pucci T;Kolz C;Shockling L;Enrick M;Yin L;Chilian W;Ohanyan V, “Is chemotherapy-induced cardiomyopathy caused by myocardial ischemia?,” NEOMED Bibliography Database, accessed November 24, 2020, https://neomed.omeka.net/items/show/11302.

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