1. Symptoms of Fluoropyrimidine Cardiotoxicity

The clinical presentation of fluoropyrimidine cardiotoxicity includes a wide variety of symptoms, including angina pectoris, myocardial infarction, cardiogenic shock, arrhythmias (atrial fibrillation, ventricular arrhythmias, atrioventricular block,), coronary vasospasm, and heart failure ^{[1][2][3][4][5][6]}[4,10,36,51,52,53] The ESC described 5-FU as a drug that may lead to arrhythmias including bradycardia, atrioventricular block, atrial fibrillation, supraventricular tachycardias, ventricular tachycardia/fibrillation, or sudden cardiac death. Furthermore, 5-fluorouracil is also associated with peripheral arterial toxicity (including Raynaud’s phenomenon), and ischemic stroke diseases ^[7][22]. Table 1 presents the most significant adverse reactions after administration of 5-FU. Landmark studies on 5-FU cardiotoxicity were considered, with most indicating the numerous consequences of coronary vasospasm, such as ischemic changes or dysrhythmias, as the most crucial adverse reactions. The mechanism of 5-FU explains clinically manifested chest pain and heart palpitations. Some adverse reactions, such as myocardial infarction, heart failure, or hypotension, could be life-threatening. Some articles also provide divergent information about the mortality rate after the administration of 5-FU, which may be explained by different schedules, routes of administration, populations of patients, health professionals’ awareness, and patient knowledge.

Studies presented an increased duration of QT in patients after fluoropyrimidine treatment, which persists for up to 6 months after administration ^[12][13][16][30,33,54]. Fluoropyrimidine treatment leads to both tachycardia and bradycardia ^[17][18][19][29,34,55]. Rezkalla et al. reported that the frequency of asymptomatic ST changes during 5-FU infusion is up to 68% of patients ^[9][24]. On the other hand, the multicenter study conducted by Płońska–Gościniak et al. (2017) showed that chemotherapy with 5-FU or capecitabine in colorectal cancer patients did not affect the conduction system, LV structural parameters, and systolic function as measured by LVEF. However, chemotherapy with 5-FU or capecitabine in colorectal cancer patients may trigger subtle changes in myocardial performance, which are solely detectable by tissue Doppler echocardiography after 12 months ^[16][54]. Some case repots described a 5-FU induced myocarditis with a set of symptoms typical for myocarditis after the first course of 5-FU treatment ^[20][21][56,57]. Many studies described Takotsubo cardiomyopathy that developed after 5-FU chemotherapy ^[22][23][24][58,59,60]. Takotsubo cardiomyopathy, also known as apical ballooning syndrome (ABS), is primarily induced by stress and the release of catecholamines, resulting in transient myocardial abnormalities and hyperkinesis. The disease may be easily confused with coronary artery disease; however, it does not have a long-lasting impact on ventricular walls ^[24][60]. Moriyama et al. (2019) described the case of a 69-year-old patient with frequent paroxysms of atrial fibrillation (AF) during combination chemotherapy with 5-FU, which was sensitive to antianginal agents. Coronary angiography performed within the chemotherapeutic period demonstrated moderate stenosis in the right coronary artery (RCA). Severe spasm at the proximal portion of the atrial branch of the RCA was induced by the acetylcholine provocation test, suggesting that 5-FU might have predisposed vasospasm in the RCA, and the subsequent atrial ischemia could have led to AF ^[25][61]. Ray et al. (2020) presented a case of simultaneous cardiotoxicity and stroke-like neurotoxicity in a patient treated with the FOLFOX regimen. This study suggests that 5-FU-induced vasospasm in coronary arteries and cerebral vasculature is likely to cause simultaneous cardiac and neurological events. Similar observations were not reported previously in the medical literature ^[26][62].

Capecitabine may also lead to a cardiotoxicity similar to 5-FU-induced cardiotoxicity, including angina pectoris, arrhythmias, and dyspnea ^{[12][8][13][27]}[30,31,33,63]. Saunders et al. described a patient who developed capecitabine-induced acute myopericarditis ^[28][64]. Another example is a rare case of Takotsubo cardiomyopathy after the administration of capecitabine described by Qasem et al. ^[29][65].

In summary, the average mortality rate due to fluoropyrimidines cardiotoxicity oscillates from 1.6% to 10.2%. Although oral capecitabine may also pose a risk of cardiovascular complications, its administration is sometimes more convenient for patients ^[30][2][31][9,10,11].

2. Mechanisms of Fluoropyrimidines Cardiotoxicity

Using 5-FU treatment may lead to myocardial ischemia and coronary artery disease, including Prinzmetal’s angina, heart failure, and arrhythmic changes ^[32][81], yet detailed mechanisms of cardiotoxicity induced by fluoropyrimidines remain unclear and uncertain, but are definitely multifactorial ^{[33][34][35][36]}[7,82,83,84]. The European Society of Cardiology identified coronary vasospasm and endothelial injury as key pathophysiologic processes ^[7][22]. An endothelial-dependent vasospasm is related to direct endothelial dysfunction, whereas an endothelial-independent vasospasm refers to primary smooth muscle dysfunction ^[33][7]. Based on preclinical studies, endothelial dysfunction should activate apoptosis and autophagy pathways in both endothelial cells and myocytes ^[37][38][85,86]. Another consequence of endothelial damage is an increased blood level of vasoconstrictors, such as endothelin-1 and urotensin-2, which was observed in 5-FU treated patients ^[39][40][87,88]. Severe endothelial damage, together with platelet accumulation and fibrin formation, was also observed in 5-FU-treated rabbits in scanning electron microscopy studies ^[41][89]. Thus, after vessel injury, a thrombogenic effect may also be triggered. The pro-coagulant effect is further enhanced due to the primary cause of the patients’ treatment, i.e., tumors ^[42][43][90,91]. Moreover, due to endothelial dysfunction, or eNOS abnormalities, acetylcholine can cause paradoxical vasoconstriction instead of vasodilation ^[44][45][92,93]. In this way, chronic vasoconstriction related to 5-FU treatment might have cardiotoxic consequences. Primary smooth muscle dysfunction should result in vasoconstriction in the presence of a functionally intact endothelium. Such contraction of vascular smooth muscles was proven in vitro when aortic rings of white rabbits were exposed to increasing doses of 5-FU. This endothelium-independent vasoconstriction was mediated by the activation of kinase C (PK-C) in vitro ^[4][46][51,94]. It is worth mentioning that Salepci et al. demonstrated that 5-FU-induced coronary vasospasm was independent of angiotensin II levels in 31 patients treated with 5-FU/leucovorin ^[47][95].

Using 5-FU treatment is also associated with enhanced oxidative stress due to the formation of reactive oxygen species, lipid peroxidation, and the decrease in glutathione level, with cardiomyocytes being especially vulnerable to reactive oxygen species damage because of their numerous mitochondria ^{[33][34][35][36][48]}[7,82,83,84,96]. For example, Durak et al. demonstrated that the administration of 5-FU to guinea pigs reduced the activity of superoxide dismutase and glutathione peroxidase with a concomitant increase in catalase activity and concentration of malondialdehyde ^[49][97]. Similarly, an increase of the oxidative stress was observed in vitro in 5-FU treated cardiomyocytes ^[38][86]. Moreover, animal studies revealed the significant role of 5-FU degradation to highly toxic metabolites, which could interfere with the Krebs cycle ^[50][51][98,99]. In a single case report, an increased serum level of alpha-fluoro-beta-alanine, a precursor of fluoroacetate, was reported in a patient who received a continuous intravenous infusion of 5-FU and experienced precordial pain with right bundle branch block ^[52][100].

Furthermore, 5-FU-induced cardiotoxicity could be related to the disruption of the energetic metabolism of erythrocytes, which was observed in both in vivo and in vitro studies ^[53][54][101,102]. A rapid increase in O2 consumption leads to severe changes in the metabolism of phosphate compounds in erythrocytes, while a drastic decrease in ATP levels causes disruptions in their structure and functioning, such as irreversible echinocytosis or increased membrane fluidity, diminishing their ability to deliver oxygen. As a result, it makes oxygen transport or delivery more difficult, leaving metabolically active organs like the heart with insufficient oxygen supply, and inevitably resulting in ischemic damage ^[53][54][101,102].

Figure 1 summarizes the possible mechanisms of 5-FU-induced cardiotoxicity, which are mostly based on preclinical studies only. We have yet to discover the mechanistic relationships that would let us predict the chances of serious adverse cardiac reactions in patients treated with fluoropyrimidines, and we have also yet to learn to react effectively enough to avoid those complications.

Figure 1. Mechanisms leading to cardiotoxicity.

3. Management of Fluoropyrimidine Cardiotoxicity

Saif et al. described that even though 92% of patients with an episode of 5-FU-related cardiotoxicity survived and recovered, the noted mortality rates were still high ^[55][69]. Thalambedu et al. summarized that in case of any signs of 5-FU cardiotoxicity, therapy should be discontinued and replaced by anti-anginal agents. Some studies suggested that this intervention could bring about the disappearance of cardiac symptoms in as much as 69% of patients ^[56][130].

First, in patients with acute chest pain, which is the most common manifestation of 5-FU cardiotoxicity, a precise anamnesis needs to be taken and a cardio-pulmonary physical examination conducted, including an assessment of cardiac risk factors and details of the chemotherapy protocol such as dosage, routes of administration, and the date of the last cycle before the onset of symptoms. Moreover, non-invasive tests, including ECG, need to be conducted to check for any signs of ischemic ST changes or arrhythmias. Echocardiographic examination, cardiac troponins, BNP levels, and CT coronary angiography should be performed to establish the diagnosis. The necessity of constant monitoring of cardiac biomarker levels among patients who undergo 5-FU-based chemotherapy remains undetermined. However, the 2012 Clinical Practice Guidelines of the European Society of Medical Oncology recommend it in the case of patients with a history of cardiovascular diseases as a class III/IV recommendation ^[57][58][131,132]. The results of non-invasive tests may indicate the need for invasive tests, such as a coronary angiogram, which are generally dedicated for patients with known risk factors for cardiovascular disease ^[33][7]. The American College of Cardiology/American Heart Association suggests that urgent coronary angiography should be performed in ACS (acute coronary syndrome) or the need to exclude ACS. Invasive pharmacologic provocation during coronary angiography seems to be a practical test to diagnose functional coronary abnormalities. Nonetheless, this method is not widely available, and its usefulness in risk-stratification in the case of 5-FU cardiotoxicity remains unclear, necessitating further studies ^[59][133].

The next step in managing patients with clinical manifestation of anginal chest pain should be nitrates, beta-blockers, and calcium channel blockers. These medications are standard initial therapy despite the debate on their efficacy ^{[60][12][8][11][61]}[25,30,31,67,134]. Steger et al. stated that even though some studies could not confirm the effect of calcium channel blockers or nitrates in reducing the risk of cardiotoxicity, prophylactic administration is widespread ^[62][135]. It is also worth mentioning that the direct toxic effect of 5-FU on the vascular endothelium may cause severe thrombogenic disorders. This problem was addressed by Kinhult et al., and their in vivo experiment on rabbits suggested a protective dalteparin treatment. However, no such clinical trials have ever been performed ^[41][89]. Sara et al. (2018) summarized that management of patients with cardiac adverse effects after treatment with 5-FU should be focused on determining whether 5-FU can be attributed to the cardiotoxicity and identifying and treating other coexisting coronary disease. Moreover, it is crucial to determine whether further 5-FU is required, or if any acceptable alternative treatment can be safely considered. When further doses of 5-FU are required, clinicians should continue cautiously, consider using prophylactic antianginal therapy, and monitor patients closely with a low threshold to terminating therapy. However, to clarify the optimal strategy, randomized clinical trials comparing different approaches to manage these patients will be essential ^[33][7].

To conclude, different ways of management in the case of 5-FU induced cardiotoxicity are proposed, but most of them depend on the individual state of the patient. The general rule worth remembering is discontinuing chemotherapy and replacing it with anti-anginal drugs after any symptom of cardiotoxicity. A precise anamnesis and a cardio-pulmonary physical examination need to be taken, including assessing cardiac risk factors and the details of the chemotherapy such as dosage, routes of administration, and the date of the last course before symptoms occurred. Moreover, non-invasive tests, including ECG, need to be conducted to check for any signs of ischemic ST changes or arrhythmias. Finally, despite the debate about its efficacy, standard initial therapy with nitrates and calcium channel blockers should be initiated. Any further clinical decisions should be based on the patient’s clinical state and other possible therapeutic options.