Article

Clinical Features and Outcomes of Patients with Chemotherapy-induced Takotsubo Syndrome

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Abstract

Chemotherapy treatment of malignancy accounts for 1–2% of takotsubo syndrome (TS) triggers. Women comprise 60–70% of patients with chemotherapy-associated TS, a distinctly lower prevalence than the 90% female prevalence in TS overall. Fluorouracil is the most commonly reported TS-triggering chemotherapeutic agent, although this must be interpreted in the context of the frequency of worldwide use of this agent. The onset of TS relative to chemotherapy initiation is quite variable, ranging from the initial administration to subsequent chemotherapy cycles several weeks beyond initiation. Limited information suggests chemotherapy can be safely reinitiated once the patient has recovered from the initial TS event. Having a TS event in the setting of chemotherapy treatment for malignancy is associated with substantial mortality.

Disclosure:Funding: Minneapolis Heart Institute Foundation, Minneapolis, MN, US.

Received:

Accepted:

Correspondence Details:Scott W Sharkey, MD, Minneapolis Heart Institute Foundation, 920 East 28th St., Suite 620, Minneapolis, MN 55407. E: scott.sharkey@allina.com

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

During the past 25 years, takotsubo syndrome (TS) has emerged as an important form of acute myocardial injury characterized by a distinctive regional left ventricular (LV) contraction abnormality, often with marked reduction of the LV ejection fraction, and typically completely reversible. At presentation, TS is often indistinguishable from acute coronary syndrome, yet its occurrence is independent of epicardial coronary artery obstruction.1–4 Other features include a predilection for older women and an association with antecedent stressful event acting as the TS trigger. During the early experience with this condition, these triggering events were largely related to emotional trauma.5–10 As experience has expanded, a greater association with physical stressors has emerged.3,4,11–13 The increased association with a physical trigger likely reflects greater awareness of secondary TS complicating acute illness. Within the realm of physical triggers, a number of reports have documented pharmacological agents as TS triggers, including cocaine, nortriptyline, venlafaxine, albuterol, flecainide, epinephrine, duloxetine, and a number of chemotherapeutic agents.14 In this article, we examine the association of chemotherapeutic agents with TS.

Takotsubo Syndrome and Malignancy

Surprisingly little information is available regarding the association of chemotherapy with TS triggering. The most commonly used chemotherapeutic agents for malignancy among Medicare recipients in the US are listed in Table 1. A 2015 international systematic review of 1,109 TS patients reported malignancy as a comorbid condition in 10%, although malignancy itself was not necessarily the TS trigger and no information was provided regarding chemotherapy use.15 A 2010–2014 analysis of 1,067,977 adult chemotherapy-related admissions from the US National Inpatient Sample database noted 562 patients (average age 63 ± 12 years, 69% female) with a TS diagnosis, representing an incidence of 37.0 (female) and 16.6 (male) per 100,000 chemotherapy-related hospitalizations.16 The annual incidence of chemotherapy-associated TS is increasing by an estimated 8.6 per 100,000 patients.16

A 2008–2014 analysis from a tertiary cancer center noted 30 patients (average age 65 ± 9 years, 73% female) with cancer and TS. Among these patients, cancer treatment was identified as the TS trigger in 17 (57%), dominated by surgical procedures in 10 (33%), with chemotherapy as the apparent trigger in only 5 (17%) patients.17

The International Takotsubo Registry (1,750 patients) noted malignancy in only 1.3% of 630 patients (8 individuals) with physical TS triggers, although details regarding use of chemotherapy were not provided.12 Therefore, examining the association of chemotherapy with TS is limited by the relatively small number of patients and the lack of detail surrounding these events.

Methods

A computer-assisted search of the electronic database MEDLINE (1996–January 2019) was conducted. References were also examined for relevant articles, including review papers. The main search terms were: “takotsubo cardiomyopathy”, “takotsubo syndrome”, “chemotherapy”, “stress cardiomyopathy”, “apical ballooning syndrome”, and “cancer”. Published case reports of TS and chemotherapy were chosen. We excluded studies in which cancer itself (not chemotherapy) was reported as the primary physical stressor.

US Medicare Claims Chemotherapy Drugs 2016

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Results

From 2007 to 2018, we identified 36 unique patients with chemotherapy-associated TS (female patients 19 [61%], average age 64 ± 13 years, range 24–85 years; Table 2). ST-elevation was the most frequent initial ECG finding, present in 56% of reports providing this detail, and the average initial ejection fraction was 28 ± 12%. The onset of TS relative to initiation of chemotherapy was highly variable, ranging from the initial administration to subsequent chemotherapy cycles several weeks beyond initiation. In some cases, the temporal delay between chemotherapy administration and TS onset was lengthy, raising the question of whether the chemotherapeutic agent was actually the TS trigger.

The antimetabolite class of drugs (5-fluorouracil, capecitabine and cytarabine) represented the agents most commonly reported as TS triggers (Table 2). A variety of other chemotherapeutic classes were also represented, including tyrosine kinase inhibitors (sunitinib, axitinib, and pazopanib), HER2 monoclonal antibodies (trastuzumab and pertuzamab), angiogenesis inhibitors (bevacizumab), CD20 monoclonal antibodies (rituximab), microtubule-targeting drugs (paclitaxel and combretastatin), and anthracyclines (doxorubicin and daunorubicin). The TS event was associated with the use of a single chemotherapeutic agent in 69% of patients. Among patients with chemotherapy-associated TS, the most frequent malignancies were colorectal (n=10, 28%), leukemia (n=4, 11%), lymphoma (n=3, 8%), and renal (n=3, 8%).

Additional Considerations

Chemotherapeutic agents have a long-established reputation for cardiotoxicity, including left ventricular dysfunction and heart failure, acute myocardial ischemia and infarction, thromboembolism, hypertension, and arrhythmia.47 Several of these drugs (e.g., fluorouracil, capecitabine, paclitaxel, docetaxel, bevacizumab, erlotinib, and sorafenib) have been associated with an acute MI-like syndrome that may be difficult to distinguish from a TS event.

Acute Myocarditis Mimicking Takotsubo Syndrome

Recently, immune checkpoint inhibitors have been associated with acute myocarditis characterized by onset of new cardiovascular symptoms, troponin elevation, and abnormal ECG, typically within days to weeks of treatment initiation.48 Acute myocarditis and TS share clinical features, including presentation, ischemic ECG changes, troponin release, and absent acute coronary artery obstruction. In rare circumstances, acute myocarditis may result in a TS-like regional LV contraction abnormality, in which case it may be challenging to distinguish the two conditions.49 In this setting, cardiac MRI may be useful because TS is characterized by myocardial edema in a transmural distribution (T2-weighted imaging) without late gadolinium enhancement.50,51

Acute Coronary Syndrome Mimicking Takotsubo Syndrome

The apical LV ballooning phenotype is not pathognomonic of TS and urgent coronary angiography is necessary to exclude an unstable coronary obstruction that would require revascularization.3,4 In particular, TS-like apical ballooning may be the consequence of acute myocardial ischemia in the setting of proximal stenosis involving the left anterior descending (LAD) coronary artery, which extends beyond the LV apex to supply the inferior wall (‘wrap around’ LAD).52 In uncertain situations, such as late presentation, suspected coronary embolism, or when coronary angiographic findings are equivocal, CMR is useful because late gadolinium enhancement is rarely evident in TS, but frequently present in a vascular distribution in patients with ischemic injury from coronary artery obstruction.3,4,53

Outcomes

In the largest study to date, all-cause in-hospital mortality was substantially greater among chemotherapy-treated patients with versus without a TS event (18.3% versus 3.2% respectively; p<0.001).16 Advanced age (>85 years), sepsis, fluid–electrolyte disorders, respiratory failure, and cardiogenic shock were univariate predictors of in-hospital mortality in patients with chemotherapy-associated TS. Metastatic cancer was present in only 17%.16 There is limited information regarding the safety of continuing or reinitiating chemotherapy after a TS event. A study involving a small number of patients (n=30) noted the majority of patients were able to resume chemotherapy cancer treatment after normalization of LV ejection fraction (generally within 3 weeks of the TS event), without TS recurrence.54

Discussion

The current body of information regarding chemotherapy-triggered TS reveals a patient profile that differs from that of the larger TS experience. In particular, women account for only 60–70% of patients with chemotherapy-associated TS, yet comprise > 90% of all TS cases,3 an anomaly without an obvious explanation. In women, the five most common malignancies are breast, lung, colorectal, uterine, and thyroid, versus prostate, lung, colorectal, bladder, and melanoma in men.55 Although publication bias may explain some of these findings, it is possible that men have a particular TS vulnerability in the setting of malignancy and chemotherapy. In fact, physical TS triggers are more common in men, and men have a higher 1-year TS-related mortality than women.56

The frequency of reports noting 5-fluorouracil as a TS trigger is curious. This drug is on the WHO’s list of essential medicines for cancer; therefore, fluorouracil likely represents one of the most commonly used chemotherapy agents worldwide.57 Consequently, the frequency of fluorouracil-associated TS may be driven by exposure of a greater number of patients to this agent (Table 1). Alternatively, fluorouracil may have pharmacological properties that can trigger a TS event. For example, there is evidence that fluorouracil is an arterial vasoconstrictor,40 and coronary microvascular vasoconstriction is proposed as a mechanism in TS pathophysiology.58

Conclusion

Chemotherapy treatment of malignancy is a relatively uncommon TS trigger, with a significantly greater proportion of men than is typically observed with TS. Fluorouracil is the most commonly reported chemotherapeutic agent, although this must be interpreted in the context of the frequency of worldwide use of this agent.

Whether certain chemotherapeutic agents are more likely to trigger TS is unresolved. Based on limited information, chemotherapy can be safely reinitiated, with careful observation, once the patient has recovered from the initial TS event. A TS event in the setting of chemotherapy treatment of malignancy is associated with substantial mortality.

To view table 2, please download the PDF of this article.

References

  1. Sharkey SW, Windenburg DC, Lesser JR, et al. Natural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy. J Am Coll Cardiol 2010;55:333–41.
    Crossref | PubMed
  2. Bossone E, Erbel R. The “takotsubo syndrome”: from legend to science. Heart Fail Clin 2013;9: xiii–xv.
    Crossref | PubMed
  3. Sharkey SW, Maron BJ. Epidemiology and clinical profile of Takotsubo cardiomyopathy. Circ J 2014;78:2119–28.
    Crossref | PubMed
  4. Ghadri JR, Wittstein IS, Prasad A, et al. International expert consensus document on takotsubo syndrome (part I): clinical characteristics, diagnostic criteria, and pathophysiology. Eur Heart J 2018;39:2032–46.
    Crossref | PubMed
  5. Sharkey SW, Lesser JR, Zenovich AG, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation 2005;111:472–9.
    Crossref | PubMed
  6. Tsuchihashi K, Ueshima K, Uchida T, et al. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. J Am Coll Cardiol 2001;38:11–18.
    PubMed
  7. Kurisu S, Sato H, Kawagoe T, et al. Tako-tsubo-like left ventricular dysfunction with ST-segment elevation: a novel cardiac syndrome mimicking acute myocardial infarction. Am Heart J 2002;143:448–55.
    PubMed
  8. Abe Y, Kondo M, Matsuoka R, et al. Assessment of clinical features in transient left ventricular apical ballooning. J Am Coll Cardiol 2003;41:737–42.
    PubMed
  9. Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005;352:539–48.
    Crossref | PubMed
  10. Bybee KA, Prasad A. Stress-related cardiomyopathy syndromes. Circulation 2008;118:397–409.
    Crossref | PubMed
  11. Sharkey SW, Pink VR, Lesser JR, et al. Clinical profile of patients with high-risk tako-tsubo cardiomyopathy. Am J Cardiol 2015;116:765–72.
    Crossref | PubMed
  12. Templin C, Ghadri JR, Diekmann J, et al. Clinical features and outcomes of Takotsubo (stress) cardiomyopathy. N Engl J Med 2015;373:929–38.
    Crossref | PubMed
  13. Kurisu S, Kihara Y. Tako-tsubo cardiomyopathy: clinical presentation and underlying mechanism. J Cardiol 2012;60:429–37.
    Crossref | PubMed
  14. Summers MR, Prasad A. Takotsubo cardiomyopathy: definition and clinical profile. Heart Fail Clin 2013;9:111–22.
    Crossref | PubMed
  15. Pelliccia F, Parodi G, Greco C, et al. Comorbidities frequency in Takotsubo syndrome: an international collaborative systematic review including 1109 patients. Am J Med 2015;128:654.e11–19.
    Crossref | PubMed
  16. Desai R, Abbas SA, Goyal H, et al. Frequency of takotsubo cardiomyopathy in adult patients receiving chemotherapy (from a 5-year nationwide inpatient study). Am J Cardiol 2019;123:667–73.
    Crossref | PubMed
  17. Munoz E, Iliescu G, Vejpongsa P, et al. Takotsubo stress cardiomyopathy: “good news” in cancer patients? J Am Coll Cardiol 2016;68:1143–4.
    Crossref | PubMed
  18. Voit J, Tibrewala A, Akhter N. Heart of the matter: reverse takotsubo syndrome in an anthracycline-exposed oncology patient. BMJ Case Rep 2018 Oct 3.
    Crossref
  19. Grunwald MR, Howie L, Diaz LA Jr. Takotsubo cardiomyopathy and fluorouracil: case report and review of the literature. J Clin Oncol 2011;30:e11–14.
    Crossref
  20. Goel S, Sharma A, Garg A, et al. Chemotherapy induced Takotsubo cardiomyopathy. World J Clin Cases 2014;2:565.
    Crossref | PubMed
  21. Franco TH, Khan A, Joshi V, et al. Takotsubo cardiomyopathy in two men receiving bevacizumab for metastatic cancer. Ther Clin Risk Manag 2008;4:1367–70.
    PubMed
  22. Damodaran S, Mrozek E, Liebner D, et al. Focal takotsubo cardiomyopathy with high-dose interleukin-2 therapy for malignant melanoma. J Ntl Compr Canc Netw 2014;12:1666–70.
    Crossref | PubMed
  23. Basselin C, Fontanges T, Descotes J, et al. 5-fluorouracil-induced tako-tsubo-like syndrome. Pharmacotherapy 2011;31:226.
    Crossref | PubMed
  24. Malley T, Watson E. A case of takotsubo cardiomyopathy after chemotherapy. Oxf Med Case Reports 2016;2016:55-58.
    Crossref | PubMed
  25. Coen M, Rigamonti F, Roth A, et al. Chemotherapy-induced Takotsubo cardiomyopathy: a case report and review of the literature. BMC Cancer 2017;17:394.
    Crossref | PubMed
  26. Baumann S, Huseynov A, Goranova D, et al. Takotsubo cardiomyopathy after systemic consolidation therapy with high-dose intravenous cytarabine in a patient with acute myeloid leukemia. Oncol Res Treat 2014;37:487–90.
    Crossref | PubMed
  27. Coli S, Pigazzani F, Gaibazzi N. Midventricular takotsubo cardiomyopathy after oxaliplatin infusion: an unreported side effect. J Cardiovasc Med 2015;16:646–9.
    Crossref | PubMed
  28. Lees C, Yazdan‐Ashoori P, Jerzak KJ, et al. Takotsubo cardiomyopathy during anti‐HER2 therapy for metastatic breast cancer. Oncologist 2019;24:e80-e82.
    Crossref | PubMed
  29. Giza DE, Lopez-Mattei J, Vejpongsa P, et al. Stress-induced cardiomyopathy in cancer patients. Am J Cardiol 2017;120:2284–8.
    Crossref | PubMed
  30. Kobayashi N, Hata N, Yokoyama S, et al. A case of takotsubo cardiomyopathy during 5-fluorouracil treatment for rectal adenocarcinoma. J Nippon Med Sch 2009;76:27–33.
    Crossref | PubMed
  31. Geisler BP, Raad RA, Esaian D, et al. Apical ballooning and cardiomyopathy in a melanoma patient treated with ipilimumab: a case of takotsubo-like syndrome. J Immunother Cancer 2015;3:4.
    Crossref | PubMed
  32. Lim SH, Wilson SM, Hunter A, Hill J, et al. Takotsubo cardiomyopathy and 5-fluorouracil: getting to the heart of the matter. Case Rep Oncol Med 2013;2013:206765.
    Crossref | PubMed
  33. Van de Donk NW, America YG, Zelissen PM, et al. Takotsubo cardiomyopathy following radioiodine therapy for toxic multinodular goitre. Neth J Med 2009;67:350–2.
    PubMed
  34. Numico G, Sicuro M, Silvestris N, et al. Takotsubo syndrome in a patient treated with sunitinib for renal cancer. J Clin Oncol 2012;30:e218–20.
    Crossref | PubMed
  35. Ovadia D, Esquenazi Y, Bucay M, et al. Association between takotsubo cardiomyopathy and axitinib: case report and review of the literature. J Clin Oncol 2014;33:e1–3.
    Crossref | PubMed
  36. Shams Y, Tornvall P, Törnerud M, et al. Capecitabine caused cardiogenic shock through induction of global Takotsubo syndrome. Cardiovasc Revasc Med 2013;14:57–61.
    Crossref | PubMed
  37. Gianni M, Dentali F, Lonn E. 5 flourouracil-induced apical ballooning syndrome: a case report. Blood Coagul Fibrinolysis 2009;20:306–8.
    Crossref | PubMed
  38. White AJ, LaGerche A, Toner GC, et al. Apical ballooning syndrome during treatment with a vascular endothelial growth factor receptor antagonist. Int J Cardiol 2009;131:e92–4.
    Crossref | PubMed
  39. Khanji M, Nolan S, Gwynne S, et al. Tako-Tsubo syndrome after trastuzumab: an unusual complication of chemotherapy for breast cancer. Clin Oncol 2013;25:329.
    Crossref | PubMed
  40. Smith SA, Auseon AJ. Chemotherapy-induced takotsubo cardiomyopathy. Heart Fail Clin 2013;9:233–42.
    Crossref | PubMed
  41. Stewart T, Pavlakis N, Ward M. Cardiotoxicity with 5‐fluorouracil and capecitabine: more than just vasospastic angina. Intern Med J 2010;40:303–7.
    Crossref | PubMed
  42. Bhakta S, Flick SM, Cooney MM, et al. Myocardial stunning following combined modality combretastatin‐based chemotherapy: two case reports and review of the literature. Clin Cardiol 2009;32:E80–4.
    Crossref | PubMed
  43. Ng KH, Dearden C, Gruber P. Rituximab-induced takotsubo syndrome: more cardiotoxic than it appears? BMJ Case Rep 2015;2015.
    Crossref | PubMed
  44. Ozturk MA, Ozveren O, Cinar V, et al. Takotsubo syndrome: an underdiagnosed complication of 5-fluorouracil mimicking acute myocardial infarction. Blood Coagul Fibrinolysis 2013;24:90–4.
    Crossref | PubMed
  45. Kim L, Karas M, Wong SC. Chemotherapy-induced takotsubo cardiomyopathy. J Invasive Cardiol 2008;20:E338–40.
    PubMed
  46. Fernandez SF, Basra M, Canty JM. Takotsubo cardiomyopathy following initial chemotherapy presenting with syncope and cardiogenic shock-a case report and literature review. J Clin Exp Cardiol 2011;2:124.
    Crossref
  47. Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 2009;53:2231–47.
    Crossref | PubMed
  48. Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol 2018;71:1755–64.
    Crossref | PubMed
  49. Caforio AL, Tona F, Vinci A, et al. Acute biopsy-proven lymphocytic myocarditis mimicking Takotsubo cardiomyopathy. Eur J Heart Fail 2009;11:428–31.
    Crossref | PubMed
  50. Eitel I, Schuler G, Thiele H. Myocarditis mimicking Takotsubo cardiomyopathy or Takotsubo cardiomyopathy with secondary inflammation? Eur J Heart Fail2009;11:809, author reply 810.
    Crossref | PubMed
  51. Ghadri JR, Wittstein IS, Prasad A, et al. International expert consensus document on Takotsubo syndrome (part II): diagnostic workup, outcome, and management. Eur Heart J 2018;39:2047–62.
    Crossref | PubMed
  52. Chao T, Lindsay J, Collins S, et al. Can acute occlusion of the left anterior descending coronary artery produce a typical ‘takotsubo’ left ventricular contraction pattern? Am J Cardiol 2009;104:202–4.
    Crossref | PubMed
  53. Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, et al. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA 2011;306:277–86.
    Crossref | PubMed
  54. Giza DE, Lopez-Mattei J, Vejpongsa P, et al. Stress-induced cardiomyopathy in cancer patients. Am J Cardiol 2017;120:2284–8.
    Crossref | PubMed
  55. Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat databases [research data 1973–2015]. DCCPS, Surveillance Research Program, released April 2018, based on the November 2017 submission. Bethesda, MD: National Cancer Institute. Available at:https://seer.cancer.gov/data-software/documentation/seerstat(accessed 9 July 2019).
  56. Murugiah K, Wang Y, Desai NR, et al. Trends in short-and long-term outcomes for takotsubo cardiomyopathy among medicare fee-for-service beneficiaries, 2007 to 2012. JACC Heart Fail 2016;4:197–205.
    Crossref | PubMed
  57. Robertson J, Barr R, Shulman LN, et al. Essential medicines for cancer: WHO recommendations and national priorities. Bull World Health Organ 2016;94:735.
    Crossref | PubMed
  58. Sharkey SW, Maron BJ, Kloner RA. The case for takotsubo cardiomyopathy (syndrome) as a variant of acute myocardial infarction. Circulation 2018;138:855–7.
    Crossref | PubMed