Cardiotoxicity is a well-known complication following treatment with anthracyclines. However, they are still widely used in chemotherapy for breast cancer, lymphoma, leukemia, and sarcoma, among others. Patient clinical characteristics, such as age, sex, comorbidities, anthracycline dose and infusion schedule, and the combined anti-cancer agents used, are diverse among cancer types. It is difficult to recommend guidelines for the prevention or management of anthracycline-induced cardiotoxicity applicable to all cancer types. Therefore, anthracycline-induced cardiotoxicity remains a major limitation in the proper management of cancer patients treated with an anthracycline-combined regimen. Efforts have been extensive to determine the mechanism and treatment of anthracycline-induced cardiotoxicity. Because cardiotoxicity causes irreversible damage to the myocardium, prevention is a more effective approach than treatment of cardiotoxicity after symptomatic or asymptomatic cardiac dysfunction develops. This article will review the pathophysiological mechanisms of anthracycline-induced cardiotoxicity and strategies for protecting the myocardium from anthracycline.

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Pathophysiology and preventive strategies of anthracycline-induced cardiotoxicity

BACKGROUND There is no proven primary preventive strategy for doxorubicin-induced subclinical cardiotoxicity (DISC), especially among patients without a cardiovascular (CV) risk. We investigated the primary preventive effect on DISC of the concomitant use of angiotensin receptor blockers (ARBs) or beta-blockers (BBs), especially among breast cancer patients without a CV risk. METHODS A total of 385 patients who were scheduled for doxorubicin chemotherapy were screened. Among them, 195 patients of the study populations were included and were randomly divided into two groups [candesartan 4 mg q.d. vs. carvedilol 3.125 mg q.d.] and patients who were unwilling to take one of the medications were evaluated as controls. The primary outcomes were the incidence of early DISC (DISC developing within 6 months after chemotherapy), and late DISC (DISC developing only at least 12 months after chemotherapy). RESULT Compared with the control group (8 out of 43 patients (18.6%)), only the candesartan group (4 out of 82 patients (4.9%)) showed a significantly lower incidence of early DISC (p = 0.022). Compared with the control group, the candesartan group demonstrated a significantly reduced decrease in left ventricular ejection fraction (LVEF) throughout the study period [-1.0% vs. -3.00 (p < 0.001) at the first follow-up, -1.10% vs. -3.40(p = 0.009) at the second follow-up]. CONCLUSIONS Among breast cancer patients without a CV risk treated with doxorubicin-containing chemotherapy, subclinical cardiotoxicity is prevalent and concomitant administration of low-dose candesartan might be effective to prevent an early decrease in LVEF. Further large-scale, randomized controlled trials will be needed to confirm our findings.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.3956

Candesartan and carvedilol for primary prevention of subclinical cardiotoxicity in breast cancer patients without a cardiovascular risk treated with doxorubicin.

Vildagliptin improves vascular smooth muscle relaxation and decreases cellular senescence in the aorta of doxorubicin-treated rats

Many novel anti-cancer therapies have dramatically improved outcomes of various cancer patients. However, it also poses a risk for cardiovascular complications as well. For the novel anti-cancer agent with which physicians does not have enough clinical experiences to determine the characteristics of cardiovascular complications, it is important to assess risk factors for cardiotoxicity before starting anti-cancer therapy. High-risk patient should be consulted to cardiologist before initiating anti-cancer therapy and pre-emptive cardiac function monitoring plan might be prepared in advance. The biomarkers, electrocardiography and echocardiography are useful tools for the detection of subclinical cardiotoxicity during anti-cancer therapy. This review article tried to suggest the cardiac function monitoring strategies for newly encountered potential cardiotoxic anti-cancer agents and to summarize the cardiovascular complications of novel anti-cancer immunotherapies including immune checkpoint inhibitor (ICI) and chimeric antigen receptor (CAR) T-cell therapy. ICIs can cause fatal myocarditis, which usually occurs early after initiation, and prompt treatment with high-dose corticosteroid is necessary. CAR T-cell therapy can cause cytokine release syndrome, which may result in circulatory collapse. Supportive treatment as well as tocilizumab, an anti-interleukin-6 receptor antibody are cornerstones of treatment.

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Cardiovascular Complications of Novel Anti-Cancer Immunotherapy: Old Problems from New Agents?

It has been reported that the chemotherapeutic agent, adriamycin, not only has an effect on the myocardium but also on the arteries. The aim of this study is to elucidate effects of adriamycin and an angiotensin receptor blocker, candesartan, on collagen and elastin of the aorta in rats. Twenty four male 8-week-old Wistar-Kyoto rats were divided into four groups: control (C) group, adriamycin-treated (AD) group, candesartan-treated (CA) group, and adriamycin- and candesartan-treated (AD + CA) group. Adriamycin of 2.5 mg/kg/wk was administered intraperitoneally one time per week for 6 weeks, and candesartan of 10 mg/kg/day was administered orally everyday for 6 weeks. After 6 weeks, the rats were sacrificed and the aortas were harvested. Hematoxylin-eosin staining, Verhoff’s elastic, and Goldner’s trichrome staining were performed for histopathologic analyses. Tunica media thickness, collagen, and elastic area fractions were measured quantitatively with a computerized digital image analyzer. Tunica media thickness in the CA and AD + CA groups was significantly lesser than that in the C and AD groups, respectively. The AD and AD + CA groups had a tendency of lower elastin area fraction than the C and CA groups, respectively. Collagen area fraction in the AD + CA group was significantly lower than that in the AD group. There were no significant differences of collagen/elastin ratio between groups. These findings suggest that adriamycin has a tendency of decreasing the quantity of elastin fibers and candesartan cannot mitigate the effects of adriamycin on elastin fibers.

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Effects of adriamycin and candesartan on the collagen and elastin of the aorta in rats

After publication of the article [1] it was discovered that a citation error had occurred, resulting in different citation numbers in the PDF and HTML files. The correct citation of 20:8 has now been updated in all versions of the manuscript. We apologise for any inconvenience caused by this error.

/pdf/erratum-to-effects-of-adriamycin-and-candesartan-on-the-1d6tqwa33m.pdf

Jung-Sook Yoon

Papers

Effects of adriamycin and candesartan on the collagen and elastin of the aorta in rats

Erratum to: Effects of adriamycin and candesartan on the collagen and elastin of the aorta in rats