Coronary microcirculation damage in anthracycline cardiotoxicity

Abstract

Aims The aim of this study was to study changes in coronary microcirculation status during and after several cycles of anthracycline treatment. Methods and Results Large-White male pigs (n = 40) were included in different experimental protocols (ExPr.) according to anthracycline cumulative exposure (0.45 mg/kg intracoronary (IC) doxorubicin per injection) and follow-up: Control (no doxorubicin); Single injection and sacrifice either at 48 hours (ExPr. 1) or 2 weeks (ExPr. 2); Three injections two weeks apart (low cumulative dose) and sacrifice either 2 weeks (ExPr. 3) or 12 weeks (ExPr. 4) after third injection; Five injections two weeks apart (high cumulative dose) and sacrifice 8 weeks after fifth injection (ExPr. 5). All groups were assessed by serial cardiac magnetic resonance (CMR) to quantify perfusion and invasive measurement of coronary flow reserve (CFR). At the end of each protocol, animals were sacrificed for ex vivo analyses. Vascular function was further evaluated by myography in explanted coronary arteries of pigs undergoing ExPr. 3 and controls. A single doxorubicin injection had no impact on microcirculation status, excluding a direct chemical toxicity. A series of five fortnightly doxorubicin injections (high cumulative dose) triggered a progressive decline in microcirculation status, evidenced by reduced CMR-based myocardial perfusion and CFR-measured impaired functional microcirculation. In the high cumulative dose regime (ExPr. 5), microcirculation changes appeared long before any contractile defect became apparent. Low cumulative doxorubicin dose (3 biweekly injections) was not associated with any contractile defect across long-term follow-up, but provoked persistent microcirculation damage, evident soon after third dose injection. Histological and myograph evaluations confirmed structural damage to arteries of all calibers even in animals undergoing low cumulative dose regimes. Conversely, arteriole damage and capillary bed alteration occurred only after high cumulative dose regime. Conclusion Serial in vivo evaluations of microcirculation status using state-of-the-art CMR and invasive CFR show that anthracyclines treatment is associated with progressive and irreversible damage to the microcirculation. This long-persisting damage is present even in low cumulative dose regimes, which are not associated with cardiac contractile deficits. Microcirculation damage might explain some of the increased incidence of cardiovascular events in cancer survivors who received anthracyclines without showing cardiac contractile defects.

Oxymatrine Synergistically Enhances Doxorubicin Anticancer Effects in Colorectal Cancer

“…Doxorubicin (DOX), an anthracycline antibiotic, is commonly used in different types of neoplastic diseases, such as lymphomas, stomach cancer, endocrine cancer, and CRC. However, a notable incidence of cardiovascular side effects including tachycardia, hypotension, arrhythmias, and sequentially induced heart toxicity are frequently observed when used clinically ( Liu et al, 2020 ; Galán-Arriola et al, 2021 ). Combination with other active drugs, especially natural products which possesses low toxicity characteristics, has become a promising strategy to alleviate DOX cardiotoxicity.…”

New Insights in Early Detection of Anticancer Drug-Related Cardiotoxicity Using Perfusion and Metabolic Imaging

“…These properties suggest that, in addition to its known direct effect on deoxyribonucleic acid through topoisomerase II beta inhibition (29), endothelial cells injury could be one cause of anthracycline cardiotoxicity. Although anthracyclines cardiotoxicity is usually detected at a stage of altered ejection (21), studies suggest that anthracyclines cardiotoxicity occurs in a continuum, challenging the hypothesis of irreversible cardiac injury (30,31). Current guidelines suggest monitoring of patients with cancer undergoing chemotherapy by echocardiography since most definitions of cardiotoxicity are based on LVEF decline (2), but the literature reports microcirculation changes long before any LVEF or contraction alterations occur (31,32).…”

“…Although anthracyclines cardiotoxicity is usually detected at a stage of altered ejection (21), studies suggest that anthracyclines cardiotoxicity occurs in a continuum, challenging the hypothesis of irreversible cardiac injury (30,31). Current guidelines suggest monitoring of patients with cancer undergoing chemotherapy by echocardiography since most definitions of cardiotoxicity are based on LVEF decline (2), but the literature reports microcirculation changes long before any LVEF or contraction alterations occur (31,32). This myocardial perfusion alteration could be the result of increased arterial walls thickening, which can occur early and even after a single DOX injection (31,33), but is more overt with repeated injections (33).…”

“…Current guidelines suggest monitoring of patients with cancer undergoing chemotherapy by echocardiography since most definitions of cardiotoxicity are based on LVEF decline (2), but the literature reports microcirculation changes long before any LVEF or contraction alterations occur (31,32). This myocardial perfusion alteration could be the result of increased arterial walls thickening, which can occur early and even after a single DOX injection (31,33), but is more overt with repeated injections (33). The increase in intima-media thickness under anthracyclines (34) is in part secondary to oxidative inflammation.…”

“…Since 1997, Hasdai et al reported that coronary endothelial dysfunction may be associated with myocardial perfusion defects (72). Both radiotherapy and chemotherapy have shown to be associated with microvascular dysfunction (2), although the effect of non-radiation therapies on the latter is less well-described (31). Knowing the effects of anticancer drugs on myocardial microcirculation, myocardial perfusion imaging appears to be an attractive modality to detect anticancer drugrelated myocardial toxicity.…”