Coronary Artery Vasospasm Induced by 5-fluorouracil: Proposed Mechanisms, Existing Management Options and Future Directions

Abstract

Cardiovascular disease and cancer are leading contributors to the global disease burden. As a result of cancer therapy-related cardiotoxicities, cardiovascular disease results in significant morbidity and mortality in cancer survivors and patients with active cancer. There is an unmet need for management of cardio-oncology conditions, which is predicted to reach epidemic proportions, and better understanding of their pathophysiology and treatment is urgently required. The proposed mechanisms underlying cardiotoxicity induced by 5-fluorouracil (5-FU) are vascular endothelial damage followed by thrombus formation, ischaemia secondary to coronary artery vasospasm, direct toxicity on myocardium and thrombogenicity. In patients with angina and electrocardiographic evidence of myocardial ischaemia due to chemotherapy-related coronary artery vasospasm, termination of chemotherapy and administration of calcium channel blockers or nitrates can improve ischaemic symptoms. However, coronary artery vasospasm can reoccur with 5-FU re-administration with limited effectiveness of vasodilator prophylaxis observed. While pre-existing coronary artery disease may increase the ischaemic potential of 5-FU, cardiovascular risk factors do not appear to completely predict the development of cardiac complications. Pharmacogenomic studies and genetic profiling may help predict the occurrence and streamline the treatment of 5-FU-induced coronary artery vasospasm. Echocardiographic measures such as the Tei index may help detect subclinical 5-FU cardiotoxicity. Further research is required to explore the cardioprotective effect of agents such as coenzyme complex, GLP-1 analogues and degradation inhibitors on 5-FU-induced coronary artery vasospasm.

5-Fluorouracil Rechallenge After Cardiotoxicity

“…A study demonstrated that 50% of patients developed vasospasm of the brachial artery after administration of 5-FU, while patients who received non-5-FU chemotherapy did not experience vasospasm [ 15 ]. Drug-induced coronary vasospasm has also been demonstrated in coronary angiography [ 16 ]. 5-FU may also act on the kallikreinthrombin pathway, which leads to increased concentrations of micro-thrombi.…”

A Case of 5-Fluorouracil-Induced Coronary Artery Vasospasm in a Patient With Salivary Gland Cancer

“…It is recommended to discontinue 5-FU application or if not possible, rechallenge carefully the treatment with administration of CCB, long-acting nitrates, and close cardiac monitoring [2]. Experimental treatments exploring the protective effect of coenzyme complex or glucagon-like peptide-1 analogues may reveal new options in the management of 5-FU-induced cardiotoxicity [4].…”

“…Possible factors increasing 5-FU cardiotoxicity are: underlying cardiovascular diseases, traditional risk factors like hypertension, hyperlipidemia, smoking; continuous vs bolus regimen of application; concomitant or previous radiation therapy; and simultaneous administration of another cardiotoxic drug [2,4]. Further investigations on risk stratification are needed because of the lack of definitive data and the controversial results of previous studies.…”

MicroRNAs in Cancer Treatment-Induced Cardiotoxicity

“…Taxane-mediated cardiotoxicity could be associated with myocardial damage via effects on subcellular organelles [64] or to massive histamine release, resulting in conduction disturbances and arrhythmias [65]. Antimetabolites mainly induce vascular endothelial damage [66], while proteasome inhibitors have dangerous effects mainly on cardiomyocytes but also on ECs by altering the protein synthesis-degradation balance [67]. Taxanes, antimetabolites and proteasome inhibitors, as anti-ErbB2 inhibitors, enhance cardiotoxicity in combination with ANTs by inducing the formation of toxic ANT metabolites [68][69][70].…”