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Jurczyk, M. Cardiotoxicity of Fluoropyrimidines. Encyclopedia. Available online: (accessed on 22 June 2024).
Jurczyk M. Cardiotoxicity of Fluoropyrimidines. Encyclopedia. Available at: Accessed June 22, 2024.
Jurczyk, Michał. "Cardiotoxicity of Fluoropyrimidines" Encyclopedia, (accessed June 22, 2024).
Jurczyk, M. (2021, October 19). Cardiotoxicity of Fluoropyrimidines. In Encyclopedia.
Jurczyk, Michał. "Cardiotoxicity of Fluoropyrimidines." Encyclopedia. Web. 19 October, 2021.
Cardiotoxicity of Fluoropyrimidines

The definition of cardiotoxicity includes not only clinical symptoms but also changes in left ventricular ejection fraction or histopathological changes in cardiomyocytes. Cardiotoxicity is a rare but serious complication of cytostatic agents, defined as a negative impact on heart function or cardiac cells. Fluoropyrimidine cardiotoxicity was first described in 1969, and since then, many studies have confirmed these findings, but many details such as incidence, mechanisms, and treatment are unclear and remain disputed.

cancer treatment chemotherapy fluoropyrimidines 5-fluorouracil capecitabine side effects cardiotoxicity heart failure arrhythmias vasospasm

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] 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]. 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.

Table 1. Frequency of signs and symptoms after the administration of 5-FU. *—retrospective study; #—prospective study.
Article Frequency of Sings and Symptoms
Jensen et al. (2006) * [8] Angina: 3.9%
Arrhythmias 0.4%
Rezkalla et al. (1989) # [9] ECG changes: 68%
De Forni et al. (1992) # [10] Angina pectoris: 4.9%
Hypotension: 0.3%
Tsavaris et al. (2002) # [11] ECG changes: 4%
Arrhythmias: 2.3%
Chest pain: 2.1%
Myocardial infarction: 1.6%
Palpitation: 1.4%
Conductive abnormalities: 0.9%
Malaise: 0.5%
Loss of consciousness: 0.5%
Kosmas et al. (2008) # [12] ECG changes: 4%
Chest pain: 1.7%
Palpitation: 1.1%
Malaise: 0.6%
Koca et al. (2011) # [13] ECG changes: 30.8%
Palpitation: 23%
Angina: 9.6%
Dyspnea 7.6%
Tachycardia: 5.6%
Hypotension: 3.8%
Hypertension: 1.9%
Peng et al. (2018) # [14] Ischemic change: 19.9%
Arrhythmia: 16.8%
Heart failure: 2.6%
Myocardial infraction: 1.0%
Dyhl-Polk et al. (2020) # [15] Acute coronary syndrome: 4%
Chest pain: 0.7%

Studies presented an increased duration of QT in patients after fluoropyrimidine treatment, which persists for up to 6 months after administration [12][13][16]. Fluoropyrimidine treatment leads to both tachycardia and bradycardia [17][18][19]. Rezkalla et al. reported that the frequency of asymptomatic ST changes during 5-FU infusion is up to 68% of patients [9]. 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]. 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]. Many studies described Takotsubo cardiomyopathy that developed after 5-FU chemotherapy [22][23][24]. 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]. 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]. 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].

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

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].

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], yet detailed mechanisms of cardiotoxicity induced by fluoropyrimidines remain unclear and uncertain, but are definitely multifactorial [33][34][35][36]. The European Society of Cardiology identified coronary vasospasm and endothelial injury as key pathophysiologic processes [7]. An endothelial-dependent vasospasm is related to direct endothelial dysfunction, whereas an endothelial-independent vasospasm refers to primary smooth muscle dysfunction [33]. Based on preclinical studies, endothelial dysfunction should activate apoptosis and autophagy pathways in both endothelial cells and myocytes [37][38]. 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]. Severe endothelial damage, together with platelet accumulation and fibrin formation, was also observed in 5-FU-treated rabbits in scanning electron microscopy studies [41]. 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]. Moreover, due to endothelial dysfunction, or eNOS abnormalities, acetylcholine can cause paradoxical vasoconstriction instead of vasodilation [44][45]. 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]. 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].

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]. 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]. Similarly, an increase of the oxidative stress was observed in vitro in 5-FU treated cardiomyocytes [38]. Moreover, animal studies revealed the significant role of 5-FU degradation to highly toxic metabolites, which could interfere with the Krebs cycle [50][51]. 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].

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]. 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].

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]. 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].

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]. 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]. 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].

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]. 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]. 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]. 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].

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.

4. Reintroduction of 5-FU

The reintroduction of 5-FU in patients with a previous history of cardiotoxic events after 5-FU administration is not currently recommended. It was documented that repeated exposure to 5-FU can cause a recurrence of cardiotoxicity in 82–100% of patients, with a death rate in these cases approaching 18% [63][55]. After the resolution of cardiotoxic symptoms, rechallenge may be considered if it is the only therapeutic option to improve the patient’s chances for survival. It should be preceded by a multidisciplinary discussion between oncologists and cardiologists. In addition, risk stratification, coronary evaluation, and treatment following ACA/AHA guidelines need to be performed. Patients with antecedent CAD (coronary artery disease) are recommended to reduce other risk factors, including smoking, hypertension, or uncontrolled diabetes [64].
Moreover, a reduction in the dosage of 5-FU seems to be a viable option, and even though we still have no confirmation of the efficacy of the pharmacologic prophylaxis, a prolonged course of pretreatment with nitrates and calcium channel blockers and its continuation during drug infusion has been proposed. To mitigate the risk, patients should also be provided with careful cardiac monitoring, and the suggested method for drug administration is a bolus regimen that has been proven to be safer than a continuous infusion of 5-FU [12][61][65][66]. The study performed by Jensen et al. showed that a combination of prophylaxis with dose-reduced 5-FU decreased the risk of cardiotoxicity in 9 out of 12 patients [8]. Some authors tried to find indications for other prophylaxis agents. For example, Salepci et al. performed a study to assess the prophylactic use of ACEI. They measured the level of angiotensin II among the patients treated with 5-FU bolus administration. However, no changes were observed compared to the control group, and their theory was disproven [47].
Some case reports described successful conversion from 5-FU to capecitabine without a recurrence of cardiac symptoms. They show that capecitabine may be an option for patients who develop 5-FU-induced chest pain. Nevertheless, these patients should be very closely monitored for the recurrence of symptoms [67][68]. The European Society of Cardiology prepared dedicated guidelines about the cardiotoxicity of oncology treatment. The authors emphasized that the final decision about treatment continuation or cessation has to be made by responsible physicians based on the individual characteristics of the patient [7].
Nevertheless, when the completion of the fluoropyrimidine-based regimens is limited, alternative strategies should be considered. An example of a safe therapeutic option in patients who experienced FIC after prior 5-FU infusion seems to be raltitrexed [69][70].
Another possible alternative is TAS-102 (trifluridine/tipiracil). This is a combination of substances that contain DPD inhibitors. As a result, less FBAL (α-fluoro-β-alanine) metabolite is concentrated, and lower rates of cardiac complications may be observed [71][72]. TAS-102 is an oral fluoropyrimidine, and its use was proposed in the recent review written by Petrelli et al. They analyzed the incidence of cardiotoxic effects in phase I, phase II, and phase III trials. The observations included three cases of cardiac events. Based on these data and different pharmacokinetics of TAS-102, they suggested this drug as an alternative, especially among patients at increased cardiovascular risk [73].
All in all, the reintroduction of 5-FU after an adverse cardiac reaction is not recommended. Instead, rechallenge may be considered only after resolving cardiotoxic symptoms and if it is the only therapeutic option to improve the patient’s chances for survival. This decision requires aggressive inpatient supportive care, constant cardiac monitoring, and preventative strategies, including decreasing the 5-FU dose and vasodilator therapy. However, when the completion of the fluoropyrimidine-based regimen is limited, clinicians should consider other, less cardiotoxic alternatives and ways of management. For the time being, the therapeutic options that seem safe enough include raltitrexed and TAS-102.


  1. Madeddu, C.; Deidda, M.; Piras, A.; Cadeddu, C.; Demurtas, L.; Puzzoni, M.; Piscopo, G.; Scartozzi, M.; Mercuro, G. Pathophysiology of cardiotoxicity induced by nonanthracycline chemotherapy. J. Cardiovasc. Med. 2016, 17, S12–S18.
  2. Labianca, R.; Beretta, G.; Clerici, M.; Fraschini, P.; Luporini, G. Cardiac Toxicity of 5-Fluorouracil: A Study on 1083 Patients. Tumori 1982, 68, 505–510.
  3. Jin, X.; Bai, Y.; Gao, L.; Wu, S. Incidence of and risk factors for cardiotoxicity after fluorouracil-based chemotherapy in locally advanced or metastatic gastric cancer patients. Cancer Chemother. Pharmacol. 2019, 84, 599–607.
  4. Burger, A.; Mannino, S. 5-fluorouracil-induced coronary vasospasm. Am. Heart J. 1987, 114, 433–436.
  5. Karakulak, U.N.U.N.; Aladaǧ, E.; Maharjan, N.; Övünç, K. Capecitabine-induced coronary artery vasospasm in a patient who previously experienced a similar episode with fluorouracil therapy. Turk. Kardiyol. Dern. Ars. 2016, 44, 71–74.
  6. Akhtar, S.S.; Salim, K.P.; Bano, Z.A. Symptomatic cardiotoxicity with high-dose 5-fluorouracil infusion: A prospective study. Oncology 1993, 50, 441–444.
  7. Zamorano, J.L.; Lancellotti, P.; Rodriguez Muñoz, D.; Aboyans, V.; Asteggiano, R.; Galderisi, M.; Habib, G.; Lenihan, D.J.; Lip, G.Y.H.; Lyon, A.R.; et al. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC committee for practice guidelines. Euro. Heart J. 2016, 37, 2768–2801.
  8. Jensen, S.A.; Sørensen, J.B. Risk Factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine. Cancer Chemother. Pharmacol. 2006, 58, 487–493.
  9. Rezkalla, S.; Kloner, R.A.; Ensley, J.; Al-Sarraf, M.; Revels, S.; Olivenstein, A.; Bhasin, S.; Kerpel-Fronious, S.; Turi, Z.G. Continuous ambulatory ECG monitoring during fluorouracil therapy: A prospective study. J. Clin. Oncol. 1989, 7, 509–514.
  10. de Forni, M.; Malet-Martino, M.C.; Jaillais, P.; Shubinski, R.E.; Bachaud, J.M.; Lemaire, L.; Canal, P.; Chevreau, C.; Carrié, D.; Soulié, P. Cardiotoxicity of high-dose continuous infusion fluorouracil: A prospective clinical study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 1992, 10, 1795–1801.
  11. Tsavaris, N.; Kosmas, C.; Vadiaka, M.; Zinelis, A.; Beldecos, D.; Sakelariou, D.; Koufos, C.; Stamatelos, G. Cardiotoxicity following different doses and schedules of 5-fluorouracil administration for malignancy—A survey of 427 patients. Med. Sci. Monit. 2002, 8, 51–57.
  12. Kosmas, C.; Kallistratos, M.S.; Kopterides, P.; Syrios, J.; Skopelitis, H.; Mylonakis, N.; Karabelis, A.; Tsavaris, N. Cardiotoxicity of fluoropyrimidines in different schedules of administration: A prospective study. J. Cancer Res. Clin. Oncol. 2008, 134, 75–82.
  13. Koca, D.; Salman, T.; Unek, I.T.; Oztop, I.; Ellidokuz, H.; Eren, M.; Yilmaz, U. Clinical and electrocardiography changes in patients treated with capecitabine. Chemotherapy 2012, 57, 381–387.
  14. Peng, J.; Dong, C.; Wang, C.; Li, W.; Yu, H.; Zhang, M.; Zhao, Q.; Zhu, B.; Zhang, J.; Li, W.; et al. Cardiotoxicity of 5-fluorouracil and capecitabine in chinese patients: A prospective study. Cancer Commun. 2018, 38, 22.
  15. Dyhl-Polk, A.; Vaage-Nilsen, M.; Schou, M.; Vistisen, K.K.; Lund, C.M.; Kümler, T.; Appel, J.M.; Nielsen, D.L. Incidence and risk markers of 5-fluorouracil and capecitabine cardiotoxicity in patients with colorectal cancer. Acta Oncol. 2020, 59, 475–483.
  16. Płońska-Gościniak, E.; Różewicz, M.; Kasprzak, J.; Wojtarowicz, A.; Mizia-Stec, K.; Hryniewiecki, T.; Pysz, P.; Kułach, A.; Bodys, A.; Sulżyc, V.; et al. Tissue doppler echocardiography detects subclinical left ventricular dysfunction in patients undergoing chemotherapy for colon cancer: Insights from ONCOECHO multicentre study. Kardiol. Pol. 2017, 75, 150–156.
  17. Wacker, A.; Lersch, C.; Scherpinski, U.; Reindl, L.; Seyfarth, M. High incidence of angina pectoris in patients treated with 5-fluorouracil: A planned surveillance study with 102 patients. Oncology 2003, 65, 108–112.
  18. Khan, M.A.; Masood, N.; Husain, N.; Ahmad, B.; Aziz, T.; Naccm, A. A retrospective study of cardiotoxicities induced by 5-fluouracil (5-FU) And5-FU based chemotherapy regimens in pakistani adult cancer patientsat shaukat khanum memorial cancer hospital & research center. J. Pak. Med. Assoc. 2012, 62, 430–434.
  19. Yilmaz, U.; Oztop, I.; Ciloglu, A.; Okan, T.; Tekin, U.; Yaren, A.; Somali, I.; Alacacioglu, A.; Kirimli, O. 5-fluorouracil increases the number and complexity of premature complexes in the heart: A prospective study using ambulatory ECG monitoring. Int. J. Clin. Pract. 2007, 61, 795–801.
  20. Amraotkar, A.R.; Pachika, A.; Grubb, K.J.; DeFilippis, A.P. Rapid extracorporeal membrane oxygenation overcomes fulminant myocarditis induced by 5-fluorouracil. Tex. Heart Inst. J. 2016, 43, 178–182.
  21. Çalik, A.N.; Çeliker, E.; Velibey, Y.; Çaǧdaş, M.; Güzelburç, Ö. Initial dose effect of 5-fluorouracil: Rapidly improving severe, acute toxic myopericarditis. Am. J. Emerg. Med. 2012, 30, 257.e1–257.e3.
  22. Sundaravel, S.; Alrifai, A.; Kabach, M.; Ghumman, W. FOLFOX induced takotsubo cardiomyopathy treated with impella assist device. Case Rep. Cardiol. 2017, 2017, 1–4.
  23. Joy, G.; Eissa, H.; Al Karoudi, R.; White, S.K. Fluorouracil-induced takotsubo cardiomyopathy causing cardiogenic shock: A case report of clinical and acute cardiac magnetic resonance imaging features. Euro. Heart J. Case Rep. 2019, 3, 1–6.
  24. Gianni, M.; Dentali, F.; Lonn, E. 5 flourouracil-induced apical ballooning syndrome: A case report. Blood Coagul. Fibrinolysis 2009, 20, 306–308.
  25. Moriyama, S.; Yokoyama, T.; Irie, K.; Ito, M.; Tsuchihashi, K.; Fukata, M.; Kusaba, H.; Maruyama, T.; Akashi, K. Atrial fibrillation observed in a patient with esophageal cancer treated with fluorouracil. J. Cardiol. Cases 2019, 20, 183–186.
  26. Ray, J.; Mahmood, A.; Dogar, M.; Guo, J.; Nwamaghinna, F.; Salciccioli, L.; Mcfarlane, S.I. Simultaneous cardiotoxicity and neurotoxicity associated with 5-fluorouracil containing chemotherapy: A case report and literature review. Am. J. Med. Case Rep. 2020, 8, 73–75.
  27. Polk, A.; Shahmarvand, N.; Vistisen, K.; Vaage-Nilsen, M.; Ole Larsen, F.; Schou, M.; Lisbeth Nielsen, D. Incidence and risk factors for capecitabine-induced symptomatic cardiotoxicity: A retrospective study of 452 consecutive patients with metastatic breast cancer. BMJ Open 2016, 6, e012798.
  28. Saunders, S.; Anwar, M. Capecitabine-induced myopericarditis-a case report and review of literature. J. Oncol. Pharm. Prac. Off. Publ. Int. Soc. Oncol. Pharm. Pract. 2019, 25, 1006–1010.
  29. Qasem, A.; bin Abdulhak, A.A.; Aly, A.; Moormeier, J. Capecitabine-induced takotsubo cardiomyopathy: A case report and literature review. Am. J. Ther. 2014, 23, 1–5.
  30. Gradishar, W.J.; Vokes, E.E. Review 5-Fluorouracil Cardiotoxicity: A Critical Review. Ann. Oncol. 1990, 1, 409–414.
  31. Kikuchi, K.; Majima, S.; Murakami, M. Clinical survey on cardiotoxicity of tegafur (FT-207)—Compilation of a nationwide survey. Gan To Kagaku Ryoho. Cancer Chemother. 1982, 9, 1482–1488.
  32. Ben-Yakov, M.; Mattu, A.; Brady, W.J.; Dubbs, S.B. Prinzmetal angina (coronary vasospasm) associated with 5-fluorouracil chemotherapy. Am. J. Emerg. Med. 2017, 35, 1038.e3–1038.e5.
  33. Sara, J.D.; Kaur, J.; Khodadadi, R.; Rehman, M.; Lobo, R.; Chakrabarti, S.; Herrmann, J.; Lerman, A.; Grothey, A. 5-Fluorouracil and Cardiotoxicity: A Review. Ther. Adv. Med. Oncol. 2018, 10, 1–18.
  34. Depetris, I.; Marino, D.; Bonzano, A.; Cagnazzo, C.; Filippi, R.; Aglietta, M.; Leone, F. Fluoropyrimidine-induced cardiotoxicity. Crit. Rev. Oncol. Hematol. 2018, 124, 1–10.
  35. Polk, A.; Vistisen, K.; Vaage-Nilsen, M.; Nielsen, D.L. A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity. BMC Pharmacol. Toxicol. 2014, 15, 47.
  36. Chong, J.H.; Ghosh, A.K. Coronary artery vasospasm induced by 5-fluorouracil: Proposed mechanisms, existing management options and future directions. Interv. Cardiol. Rev. 2019, 14, 89.
  37. Focaccetti, C.; Bruno, A.; Magnani, E.; Bartolini, D.; Principi, E.; Dallaglio, K.; Bucci, E.O.; Finzi, G.; Sessa, F.; Noonan, D.M.; et al. Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ros production in endothelial cells and cardiomyocytes. PLoS ONE 2015, 10, e0115686.
  38. Lamberti, M.; Porto, S.; Zappavigna, S.; Addeo, E.; Marra, M.; Miraglia, N.; Sannolo, N.; Vanacore, D.; Stiuso, P.; Caraglia, M. A Mechanistic study on the cardiotoxicity of 5-fluorouracil in vitro and clinical and occupational perspectives. Toxicol. Lett. 2014, 227, 151–156.
  39. Thyss, A.; Gaspard, M.H.; Marsault, R.; Milano, G.; Frelin, C.; Schneider, M. Very high endothelin plasma levels in patients with 5-FU cardiotoxicity. Ann. Oncol. 1992, 3, 88.
  40. Seker, M.; Isen, H.C.; Çevirme, N.; Aydln, S.; Bilici, A.; Bulut, H.; Yasin, A.I.; Coban, E.; Demir, T.; Aliyev, A.; et al. Role of urotensin-2 in 5-fluorouracil-related arterial vasoconstriction in cancer patients. Oncol. Res. Treat. 2018, 41, 545–549.
  41. Kinhult, S.; Albertsson, M.; Eskilsson, J.; Cwikiel, M. Antithrombotic treatment in protection against thrombogenic effects of 5-fluorouracil on vascular endothelium: A scanning microscopy evaluation. Scanning 2001, 23, 1–8.
  42. Prandoni, P.; Falanga, A.; Piccioli, A. Cancer and venous thromboembolism. Lancet Oncol. 2005, 6, 401–410.
  43. Jensen, S.A.; Sørensen, J.B. 5-fluorouracil-based therapy induces endovascular injury having potential significance to development of clinically overt cardiotoxicity. Cancer Chemother. Pharmacol. 2012, 69, 57–64.
  44. Vita, J.A.; Treasure, C.B.; Nabel, E.G.; McLenachan, J.M.; Fish, R.D.; Yeung, A.C.; Vekshtein, V.I.; Selwyn, A.P.; Ganz, P. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation 1990, 81, 491–497.
  45. Hasdai, D.; Gibbons, R.J.; Holmes, D.R.; Higano, S.T.; Lerman, A. Coronary endothelial dysfunction in humans is associated with myocardial perfusion defects background coronary endothelial dysfunction may occur in patients with minimally. Circulation 1997, 96, 3390–3395.
  46. Mosseri, M.; Fingert, H.J.; Varticovski, L.; Chokshi, S.; Isner2, J.M. In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle1. Cancer Res. 1993, 53, 30–33.
  47. Salepci, T.; Seker, M.; Uyarel, H.; Gumus, M.; Bilici, A.; Ustaalioğlu, B.B.O.; Öztürk, A.; Sonmez, B.; Orcun, A.; Ozates, M.; et al. 5-fluorouracil induces arterial vasoconstrictions but does not increase angiotensin II levels. Med. Oncol. 2010, 27, 416–420.
  48. Zhao, Q.; Sun, Q.; Zhou, L.; Liu, K.; Jiao, K. Complex regulation of mitochondrial function during cardiac development. J. Am. Heart Assoc. 2019, 8, e012731.
  49. Durak, I.; Karaayvaz, M.; Kavutcu, M.; Cimen, M.Y.; Kaçmaz, M.; Büyükkoçak, S.; Oztürk, H.S. reduced antioxidant defense capacity in myocardial tissue from guinea pigs treated with 5-fluorouracil. J. Toxicol. Environ. Health. Part A 2000, 59, 585–589.
  50. Arellanol, M.; Malet-Martino’, M.; Martino1, R.; Gires2, P. The Anti-Cancer Drug 5-Fluorouracil Is Metabolized by the Isolated Perfused Rat Liver and in Rats into Highly Toxic Fluoroacetate. Br. J. Cancer 1998, 77, 79–86.
  51. Koenig, H.; Patel, A. Biochemical basis for fluorouracil neurotoxicity the role of krebs cycle inhibition by fluoroacetate. Arch. Neurol. 1970, 23, 155–160.
  52. Muneoka, K.; Shirai, Y.; Yokoyama, N.; Wakai, T.; Hatakeyama, K. 5-fluorouracil cardiotoxicity induced by α-fluoro-β-alanine. Int. J. Clin. Oncol. 2005, 10, 441–443.
  53. Spasojević, I.; Maksimović, V.; Zakrzewska, J.; Bacić, G. Effects of 5-fluorouracil on erythrocytes in relation to its cardiotoxicity: Membrane structure and functioning. J. Chem. Inf. Modeling 2005, 45, 1680–1685.
  54. Spasojević, I.; Jelić, S.; Zakrzewska, J.; Bačić, G. Decreased oxygen transfer capacity of erythrocytes as a cause of 5-fluorouracil related ischemia. Molecules 2009, 14, 53–67.
  55. Saif, M.W.; Shah, M.M.; Shah, A.R. Fluoropyrimidine-associated cardiotoxicity: Revisited. Exp. Opin. Drug Safety 2009, 8, 191–202.
  56. Thalambedu, N.; Khan, Y. Fluorouracil (5-FU)-Induced Cardiomyopathy. Cureus 2019, 11, e5162.
  57. Bovelli, D.; Plataniotis, G.; Roila, F. Cardiotoxicity of chemotherapeutic agents and radiotherapy-related heart disease: ESMO clinical practice guidelines. Ann. Oncol. 2010, 21, v277–v282.
  58. Curigliano, G.; Cardinale, D.; Suter, T.; Plataniotis, G.; de Azambuja, E.; Sandri, M.T.; Criscitiello, C.; Goldhirsch, A.; Cipolla, C.; Roila, F. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: Esmo clinical practice guidelines. Ann. Oncol. 2012, 23, vii155–vii166.
  59. Anderson, J.L.; Adams, C.D.; Antman, E.M.; Bridges, C.R.; Califf, R.M.; Casey, D.E.; Chavey, W.E.; Fesmire, F.M.; Hochman, J.S.; Levin, T.N.; et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-st-elevation myocardial infarction: A report of the american college of cardiology foundation/american heart association task force on practice guidelines. J. Am. Coll. Cardiol. 2013, 61, 179–347.
  60. Kanduri, J.; More, L.A.; Godishala, A.; Asnani, A. Fluoropyrimidine-associated cardiotoxicity. Cardiol. Clin. 2019, 37, 399–405.
  61. Perrino, C.; Schiattarella, G.G.; Magliulo, F.; Ilardi, F.; Carotenuto, G.; Gargiulo, G.; Serino, F.; Ferrone, M.; Scudiero, F.; Carbone, A.; et al. Cardiac side effects of chemotherapy: State of art and strategies for a correct management. Curr. Vasc. Pharmacol. 2014, 12, 106–116.
  62. Steger, F.; Hautmann, M.G.; Kölbl, O. 5-FU-induced cardiac toxicity--an underestimated problem in radiooncology? Radiat. Oncol. 2012, 7, 212.
  63. Becker, K.; Erckenbrecht, J.F.; Häussinger, D.; Frieling, T. Cardiotoxicity of the antiproliferative compound fluorouracil. Drugs 1999, 57, 475–484.
  64. Layoun, M.E.; Wickramasinghe, C.D.; Peralta, M.V.; Yang, E.H. Fluoropyrimidine-induced cardiotoxicity: Manifestations, mechanisms, and management. Curr. Oncol. Rep. 2016, 18, 35.
  65. Lestuzzi, C.; Crivellari, D.; Rigo, F.; Viel, E.; Meneguzzo, N. Capecitabine cardiac toxicity presenting as effort angina: A case report. J. Cardiovasc. Med. 2010, 11, 700–703.
  66. Sorrentino, M.F.; Kim, J.; Foderaro, A.E.; Truesdell, A.G. 5-fluorouracil induced cardiotoxicity: Review of the literature. Cardiol. J. 2012, 19, 453–458.
  67. Saneeymehri, S.S.; Markey, K.R.; Mahipal, A. Paradoxical effect of capecitabine in 5-fluorouracil-induced cardiotoxicity: A case vignette and literature review. J. Oncol. Pharm. Pract. Off. Publ. Int. Soc. Oncol. Pharm. Pract. 2016, 22, 552–555.
  68. Bathina, J.D.; Yusuf, S.W. 5-Fluorouracil-induced coronary vasospasm. J. Cardiovasc. Med. 2010, 11, 281–284.
  69. Kohne’, C.-H.; Thuss-Patience’, P.; Friedrich2, M.; Daniel’, P.T.; Kretzschmarl, A.; Benterl, T.; Bauer1, B.; Dietz2, R.; Dorken1, B. Raltitrexed (tomudex): An alternative drug for patients with colorectal cancer and 5-fluorouracil associated cardiotoxicity. Br. J. Cancer 1998, 6, 973–977.
  70. Kelly, C.; Bhuva, N.; Harrison, M.; Buckley, A.; Saunders, M. Use of raltitrexed as an alternative to 5-fluorouracil and capecitabine in cancer patients with cardiac history. Euro. J. Cancer 2013, 49, 2303–2310.
  71. Franck, C.; Malfertheiner, P.; Venerito, M. Safe Administration of S-1 after 5-fluorouracil-induced cardiotoxicity in a patient with colorectal cancer. BMJ Case Rep. 2017, 2017, bcr-2016.
  72. Mayer, R.J.; van Cutsem, E.; Falcone, A.; Yoshino, T.; Garcia-Carbonero, R.; Mizunuma, N.; Yamazaki, K.; Shimada, Y.; Tabernero, J.; Komatsu, Y.; et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N. Engl. J. Med. 2015, 372, 1909–1919.
  73. Petrelli, F.; Barni, S.; Bertocchi, P.; Zaniboni, A. TAS-102, the first “cardio-gentle” fluoropyrimidine in the colorectal cancer landscape? BMC Cancer 2016, 16, 1–4.
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