International Journal of Cardiology 177 (2014) e65–e67
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
A case of Takotsubo syndrome following 5-fluorouracil chemotherapy Kristopher Knott a,⁎, Naureen Starling a, Shahnawaz Rasheed a, John Foran b, Catherine Cafferkey a, Stuart Rosen b, Andrew Nicholson b, John Baksi b, Alexander Lyon b a b
The Royal Marsden NHS Foundation Trust, United Kingdom Royal Brompton and Harefield NHS Foundation Trust, United Kingdom
a r t i c l e
i n f o
Article history: Received 17 September 2014 Accepted 27 September 2014 Available online 13 October 2014 Keywords: Takotsubo syndrome Chemotoxicity Cardiomyopathy
A 59 year old gentleman was referred to oncology following the diagnosis of a moderately invasive adenocarcinoma of the sigmoid colon (T3dN2M0). He had no previous cardiac history, was taking no regular medications and was an ex-smoker with a 36 pack year history. He was offered neoadjuvant chemotherapy prior to surgical resection as part of a clinical trial. According to the protocol, he was commenced on oxaliplatin, folinic acid and 5-fluorouracil (5-FU), a 48-hour continuous infusion. After 46 h of the 5-FU infusion he developed severe central chest pain associated with vomiting and sweating and he presented to his local emergency department. The 5-FU infusion was stopped, ECGs were recorded and bloods drawn. Electrocardiogram documented upsloping ST-segment elevation and hyperacute T-wave changes in the septal, inferior and lateral leads (Fig. 1a). Blood tests revealed an initial cardiac troponin I of 0.048 μg/L (normal range b 0.04) which rose to 1.0 μg/L after 14 h. He was admitted to the coronary care unit where transthoracic echocardiography revealed a left ventricular ejection fraction of 40% with global hypokinesia. He was discharged the following day with a presumed diagnosis of 5-FU induced cardiotoxicity. The next day, while undergoing oncology review, he collapsed suddenly, lost cardiac output and was found to be in cardiac arrest with ventricular fibrillation as the underlying rhythm. Cardiopulmonary resuscitation was promptly commenced as per Advanced Life Support protocols [1]. Upon the return of a spontaneous circulation the patient was transferred to the cardiac catheterization laboratory of our tertiary ⁎ Corresponding author at: Department of GI Oncology, The Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, United Kingdom. Tel.: +442073528171. E-mail address: [email protected] (K. Knott).
http://dx.doi.org/10.1016/j.ijcard.2014.09.154 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
cardiac center where he proceeded to urgent diagnostic coronary angiography. This revealed unobstructed coronary arteries with minimal atheroma. Left ventriculography documented severe global dysfunction with an LVEF ~ 10%. In shock with a systolic arterial pressure of 60–70 mm Hg, intraaortic balloon pump counterpulsation was commenced. He was endotracheally intubated, commenced on inotropes and transferred to the intensive care unit. He recovered over a period of thirteen days and was subsequently discharged on carvedilol, enalapril, spironolactone and a reducing regimen of amiodarone. Four weeks later repeat echocardiography revealed left ventricular function had normalized with an LVEF of 68%. Dobutamine stress echocardiography showed excellent contractile reserve with no inducible regional wall motion abnormalities. Cardiovascular magnetic resonance (CMR) imaging showed no evidence of myocardial fibrosis or infarction (Fig. 1b). Transarterial LV endomyocardial biopsy taken at the time of diagnostic cardiac catheterization revealed endocardial contraction bands consistent with high catecholamine exposure and mild interstitial fibrosis, but no necrosis or inflammatory infiltrates (Fig. 2). Thus the cardiovascular diagnosis is consistent with severe 5-FU induced acute myocardial stunning, a Takotsubo syndrome variant secondary to 5-FU, complicated by a VF arrest with post arrest stunning. Ten weeks later, the patient underwent a high anterior resection of his sigmoid cancer without perioperative cardiac complications and was discharged on day 8 post-operatively. Given the small potential benefit of adjuvant chemotherapy and in the context of his serious cardiotoxicity, he was not given adjuvant chemotherapy and will be followed up with a standard surveillance protocol. He continues to do well and has returned to normal function. Takotsubo syndrome [2] is an observed transient regional myocardial dysfunction caused by catecholamine release. The modified Mayo Clinic criteria [3] have been defined as: Transient left ventricular hypokinesia with ECG changes accompanied by an elevation in cardiac enzymes in the absence of an obstructive coronary artery lesion, myocarditis or phaeochromocytoma. Our case fulfills these criteria. The pathophysiology has not been fully elucidated but a potential mechanism includes the negatively inotropic effects of high levels of epinephrine on the myocardium [4]. Of interest, an association between Takotsubo syndrome and malignancy has been observed. In one study [5], 40% of the survivors of Takotsubo syndrome died from cancer. A paraneoplastic phenomenon could be responsible.
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K. Knott et al. / International Journal of Cardiology 177 (2014) e65–e67
Fig. 1. a. Electrocardiogram documenting upsloping ST elevation and hyperacute T waves in the septal, inferior and lateral leads. b. CMR images. The upper panels show SSFP images of the 4-chamber view with normal left ventricular size at end-diastole (A) and end-systole (B). In the lower panels, STIR T2 imaging (C) shows normal myocardial signal not suggestive of myocardial oedema or inflammation and there is no myocardial enhancement on late gadolinium enhancement images (D) to suggest any myocardial fibrosis, infarction, infiltration or potentially persistent oedema.
The incidence of cardiotoxicity with 5-fluorouracil has been reported to be as high as 4.3% [6]. A variety of mechanisms have been proposed, most commonly through provoking coronary vasospasm [7].
Rarer is a 5-FU-induced cardiomyopathy or a Takotsubo syndrome reported in small numbers of case reports [8]. Possible causes include a direct toxic effect on the myocardium or myocarditis. Unlike all
K. Knott et al. / International Journal of Cardiology 177 (2014) e65–e67
e67
ischaemic 5-FU induced cardiotoxity and illustrates the dramatic potential reversibility and recovery. Oncology patients receiving 5-fluorouracil chemotherapy should be closely monitored and referred for investigation if they develop cardiac symptoms. Prompt acute clinical assessment coupled with ECG recordings and cardiac enzyme analysis should be followed by specialist cardiology review with a view to further invasive and non-invasive cardiac investigations if cardiotoxicity is suspected. Further research is required to investigate the mechanism(s) underlying 5-FU induced cardiotoxicity and to identify any predictive factors for its development. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References Fig. 2. An endomyocardial biopsy shows mild interstitial fibrosis and scattered contraction bands (arrows). H&E: ×200 magnification.
other reports, in our case a myocardial biopsy was taken, revealing no evidence of myocarditis. Risk factors for developing cardiotoxicity may include pre-existing cardiac disease [6], previous treatment with other cardiotoxic drugs and previous chest irradiation [9]. Our patient possessed none of these risk factors. Following 5-FU induced cardiotoxicity the balance of evidence appears to be in favor of not re-treating post recovery of cardiac function although the risk: benefit must be tailored to each individual case. A literature review [10] found eighteen out of twenty one patients retreated with 5-FU experiencing cardiac complications including three myocardial infarctions and two deaths. This case highlights a rare diagnosis of severe 5-FU induced cardiac stunning (Takotsubo variant) complicated by VF arrest. It is unique in the extent to which it has been characterized with immediate coronary angiography, cardiac magnetic resonance (CMR) evaluation and endomyocardial biopsy. Our report sheds light onto the cause of non-
[1] Resuscitation Council UK. Resuscitation guidelines; 2010. [2] Sato H, Tateishi H, Uchida T. Takotsubo-type cardiomyopathy due to multivessel spasm. In: Kodama K, Haze K, Hon M, editors. Clinical aspect of myocardial injury: from ischemia to heart failure. Tokyo, Japan: Kagakuhyouronsha; 1990. p. 56–64. [3] Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155: 408–17. [4] Lyon AR, Rees PS, Prasad S, Poole-Wilson PA, Harding SE. Stress (Takotsubo) cardiomyopathy: a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med 2008;5:22–9. [5] Song BG, Hahn JY, Cho SJ, Park YH, Choi SM, Park JH, et al. Clinical characteristics, ballooning pattern, and long-term prognosis of transient left ventricular ballooning syndrome. Heart Lung 2010;39(3):188–95. [6] Jensen SA, Sørensen JB. Risk factors and prevention of cardiotoxicity induced by 5fluorouracil or capecitabine. Cancer Chemother Pharmacol 2006;58(4):487–93. [7] Südhoff T, Enderle MD, Pahlke M, Petz C, Teschendorf C, Graeven U, et al. 5Fluorouracil induces arterial vasocontractions. Ann Oncol 2004;15(4):661–4. [8] Ozturk MA, Ozveren O, Cinar V, Erdik B, Oyan B. Takotsubo syndrome: an underdiagnosed complication of 5-fluorouracil mimicking acute myocardial infarction. Blood Coagul Fibrinolysis 2013;24(1):90–4. [9] Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf 2000;22(4):263–302. [10] Segalini G, Labianca R, Beretta GD, Borsotti E, Calasso F, Carini L, et al. Cardiotoxicity of 5-fluorouracil. Personal cases and review of the literature. G Ital Cardiol 1987; 17(9):781–5.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
A case of Takotsubo syndrome following 5-fluorouracil chemotherapy Kristopher Knott a,⁎, Naureen Starling a, Shahnawaz Rasheed a, John Foran b, Catherine Cafferkey a, Stuart Rosen b, Andrew Nicholson b, John Baksi b, Alexander Lyon b a b
The Royal Marsden NHS Foundation Trust, United Kingdom Royal Brompton and Harefield NHS Foundation Trust, United Kingdom
a r t i c l e
i n f o
Article history: Received 17 September 2014 Accepted 27 September 2014 Available online 13 October 2014 Keywords: Takotsubo syndrome Chemotoxicity Cardiomyopathy
A 59 year old gentleman was referred to oncology following the diagnosis of a moderately invasive adenocarcinoma of the sigmoid colon (T3dN2M0). He had no previous cardiac history, was taking no regular medications and was an ex-smoker with a 36 pack year history. He was offered neoadjuvant chemotherapy prior to surgical resection as part of a clinical trial. According to the protocol, he was commenced on oxaliplatin, folinic acid and 5-fluorouracil (5-FU), a 48-hour continuous infusion. After 46 h of the 5-FU infusion he developed severe central chest pain associated with vomiting and sweating and he presented to his local emergency department. The 5-FU infusion was stopped, ECGs were recorded and bloods drawn. Electrocardiogram documented upsloping ST-segment elevation and hyperacute T-wave changes in the septal, inferior and lateral leads (Fig. 1a). Blood tests revealed an initial cardiac troponin I of 0.048 μg/L (normal range b 0.04) which rose to 1.0 μg/L after 14 h. He was admitted to the coronary care unit where transthoracic echocardiography revealed a left ventricular ejection fraction of 40% with global hypokinesia. He was discharged the following day with a presumed diagnosis of 5-FU induced cardiotoxicity. The next day, while undergoing oncology review, he collapsed suddenly, lost cardiac output and was found to be in cardiac arrest with ventricular fibrillation as the underlying rhythm. Cardiopulmonary resuscitation was promptly commenced as per Advanced Life Support protocols [1]. Upon the return of a spontaneous circulation the patient was transferred to the cardiac catheterization laboratory of our tertiary ⁎ Corresponding author at: Department of GI Oncology, The Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, United Kingdom. Tel.: +442073528171. E-mail address: [email protected] (K. Knott).
http://dx.doi.org/10.1016/j.ijcard.2014.09.154 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
cardiac center where he proceeded to urgent diagnostic coronary angiography. This revealed unobstructed coronary arteries with minimal atheroma. Left ventriculography documented severe global dysfunction with an LVEF ~ 10%. In shock with a systolic arterial pressure of 60–70 mm Hg, intraaortic balloon pump counterpulsation was commenced. He was endotracheally intubated, commenced on inotropes and transferred to the intensive care unit. He recovered over a period of thirteen days and was subsequently discharged on carvedilol, enalapril, spironolactone and a reducing regimen of amiodarone. Four weeks later repeat echocardiography revealed left ventricular function had normalized with an LVEF of 68%. Dobutamine stress echocardiography showed excellent contractile reserve with no inducible regional wall motion abnormalities. Cardiovascular magnetic resonance (CMR) imaging showed no evidence of myocardial fibrosis or infarction (Fig. 1b). Transarterial LV endomyocardial biopsy taken at the time of diagnostic cardiac catheterization revealed endocardial contraction bands consistent with high catecholamine exposure and mild interstitial fibrosis, but no necrosis or inflammatory infiltrates (Fig. 2). Thus the cardiovascular diagnosis is consistent with severe 5-FU induced acute myocardial stunning, a Takotsubo syndrome variant secondary to 5-FU, complicated by a VF arrest with post arrest stunning. Ten weeks later, the patient underwent a high anterior resection of his sigmoid cancer without perioperative cardiac complications and was discharged on day 8 post-operatively. Given the small potential benefit of adjuvant chemotherapy and in the context of his serious cardiotoxicity, he was not given adjuvant chemotherapy and will be followed up with a standard surveillance protocol. He continues to do well and has returned to normal function. Takotsubo syndrome [2] is an observed transient regional myocardial dysfunction caused by catecholamine release. The modified Mayo Clinic criteria [3] have been defined as: Transient left ventricular hypokinesia with ECG changes accompanied by an elevation in cardiac enzymes in the absence of an obstructive coronary artery lesion, myocarditis or phaeochromocytoma. Our case fulfills these criteria. The pathophysiology has not been fully elucidated but a potential mechanism includes the negatively inotropic effects of high levels of epinephrine on the myocardium [4]. Of interest, an association between Takotsubo syndrome and malignancy has been observed. In one study [5], 40% of the survivors of Takotsubo syndrome died from cancer. A paraneoplastic phenomenon could be responsible.
e66
K. Knott et al. / International Journal of Cardiology 177 (2014) e65–e67
Fig. 1. a. Electrocardiogram documenting upsloping ST elevation and hyperacute T waves in the septal, inferior and lateral leads. b. CMR images. The upper panels show SSFP images of the 4-chamber view with normal left ventricular size at end-diastole (A) and end-systole (B). In the lower panels, STIR T2 imaging (C) shows normal myocardial signal not suggestive of myocardial oedema or inflammation and there is no myocardial enhancement on late gadolinium enhancement images (D) to suggest any myocardial fibrosis, infarction, infiltration or potentially persistent oedema.
The incidence of cardiotoxicity with 5-fluorouracil has been reported to be as high as 4.3% [6]. A variety of mechanisms have been proposed, most commonly through provoking coronary vasospasm [7].
Rarer is a 5-FU-induced cardiomyopathy or a Takotsubo syndrome reported in small numbers of case reports [8]. Possible causes include a direct toxic effect on the myocardium or myocarditis. Unlike all
K. Knott et al. / International Journal of Cardiology 177 (2014) e65–e67
e67
ischaemic 5-FU induced cardiotoxity and illustrates the dramatic potential reversibility and recovery. Oncology patients receiving 5-fluorouracil chemotherapy should be closely monitored and referred for investigation if they develop cardiac symptoms. Prompt acute clinical assessment coupled with ECG recordings and cardiac enzyme analysis should be followed by specialist cardiology review with a view to further invasive and non-invasive cardiac investigations if cardiotoxicity is suspected. Further research is required to investigate the mechanism(s) underlying 5-FU induced cardiotoxicity and to identify any predictive factors for its development. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References Fig. 2. An endomyocardial biopsy shows mild interstitial fibrosis and scattered contraction bands (arrows). H&E: ×200 magnification.
other reports, in our case a myocardial biopsy was taken, revealing no evidence of myocarditis. Risk factors for developing cardiotoxicity may include pre-existing cardiac disease [6], previous treatment with other cardiotoxic drugs and previous chest irradiation [9]. Our patient possessed none of these risk factors. Following 5-FU induced cardiotoxicity the balance of evidence appears to be in favor of not re-treating post recovery of cardiac function although the risk: benefit must be tailored to each individual case. A literature review [10] found eighteen out of twenty one patients retreated with 5-FU experiencing cardiac complications including three myocardial infarctions and two deaths. This case highlights a rare diagnosis of severe 5-FU induced cardiac stunning (Takotsubo variant) complicated by VF arrest. It is unique in the extent to which it has been characterized with immediate coronary angiography, cardiac magnetic resonance (CMR) evaluation and endomyocardial biopsy. Our report sheds light onto the cause of non-
[1] Resuscitation Council UK. Resuscitation guidelines; 2010. [2] Sato H, Tateishi H, Uchida T. Takotsubo-type cardiomyopathy due to multivessel spasm. In: Kodama K, Haze K, Hon M, editors. Clinical aspect of myocardial injury: from ischemia to heart failure. Tokyo, Japan: Kagakuhyouronsha; 1990. p. 56–64. [3] Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155: 408–17. [4] Lyon AR, Rees PS, Prasad S, Poole-Wilson PA, Harding SE. Stress (Takotsubo) cardiomyopathy: a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med 2008;5:22–9. [5] Song BG, Hahn JY, Cho SJ, Park YH, Choi SM, Park JH, et al. Clinical characteristics, ballooning pattern, and long-term prognosis of transient left ventricular ballooning syndrome. Heart Lung 2010;39(3):188–95. [6] Jensen SA, Sørensen JB. Risk factors and prevention of cardiotoxicity induced by 5fluorouracil or capecitabine. Cancer Chemother Pharmacol 2006;58(4):487–93. [7] Südhoff T, Enderle MD, Pahlke M, Petz C, Teschendorf C, Graeven U, et al. 5Fluorouracil induces arterial vasocontractions. Ann Oncol 2004;15(4):661–4. [8] Ozturk MA, Ozveren O, Cinar V, Erdik B, Oyan B. Takotsubo syndrome: an underdiagnosed complication of 5-fluorouracil mimicking acute myocardial infarction. Blood Coagul Fibrinolysis 2013;24(1):90–4. [9] Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf 2000;22(4):263–302. [10] Segalini G, Labianca R, Beretta GD, Borsotti E, Calasso F, Carini L, et al. Cardiotoxicity of 5-fluorouracil. Personal cases and review of the literature. G Ital Cardiol 1987; 17(9):781–5.
