What's Behind the Mysterious Chest Pain in Bladder Cancer Patient?

An obese female patient, age 62, presents to the invasive cardiology department at a hospital in Białystok, Poland. She has been transferred from the district hospital after 3 days of angina, which referring clinicians suspect is due to an acute coronary event.

Upon admission, the patient reports having chest pain at rest that lasts for around 1 hour. She is a smoker. Previous diagnoses include chronic pulmonary arterial hypertension, hypothyroid disease, and inflammatory arthritis.

The patient's history also reveals that 6 months prior, she was diagnosed with a high-grade urothelial bladder cancer. After the transurethral electroresection of the tumor 5 months before admission and then chemotherapy with gemcitabine and cisplatin, the patient was qualified for her next cancer surgery.

When the patient is admitted to the clinic, she denies any chest pain. Examination shows that she is hemodynamically stable; her blood pressure is 110/80 mm Hg. An ECG reveals a normal sinus rhythm of 96 bpm with singular ventricular and supraventricular beats, as well as inverted T waves in the leads from above the anterior and lateral wall.

Clinicians perform cardiac catheterization, which reveals evidence of minor atherosclerotic changes in the coronary arteries. The left ventriculography conducted at the same time shows akinesis of the apex and the apical and mid-segment of the anterior wall, and the patient's ejection fraction is 38%.

Clinicians make a provisional diagnosis of Takotsubo syndrome, for which the patient is qualified for conservative coronary disease treatment.

Laboratory tests show low levels of red blood cells, with a hemoglobin of 9.3 g/dL, and markedly elevated concentration of several cardiac markers, including:

• High sensitivity troponin I – 9,552 ng/L (lab standard: 0.00-15.60 ng/L)
• B-type natriuretic peptide (BNP) – 175 pg/mL (lab standard: 0.00-100.00 pg/mL)
• N-terminal pro-B-type natriuretic peptide (NT-proBNP) – 2,691 pg/mL (lab standard: 0.00-125.00 pg/mL)

The patient has no complications during her hospitalization and does not experience further retrosternal pain. Subsequent ECGs reveal deeply inverted T waves and numerous ventricular premature beats, with the QTc interval increased to 528 ms.

An echocardiogram shows normal functioning of all valves. Also, the patient's left ventricular function has improved, with a 47% ejection fraction, confirming their diagnosis of Takotsubo syndrome.

On day 4 of hospitalization, the patient is discharged with a referral for further surgical and oncological treatment. Clinicians also recommend that she take the following medical treatments: acetylsalicylic acid 75 mg/day, bisoprolol 2.5 mg/day, ramipril 1.25 mg/day, atorvastatin 20 mg/day, pantoprazole 20 mg/day, supplementation with iron and thyroid hormones, and continuation of the ongoing analgesic chronic therapy.

Four months later, the patient dies from cancer.

Discussion

Clinicians presenting this case of Takotsubo syndrome -- also known as broken heart syndrome or stress-induced cardiomyopathy -- in a woman with bladder cancer noted in their American Journal of Case Reports paper that the condition is extremely rare in the general population. But while accounting for only 0.02% of hospitalizations and approximately 1% to 2% of acute coronary events, Takotsubo syndrome's incidence in cancer patients is approximately 10%, the authors pointed out.

Indeed, the International Takotsubo Registry showed that malignancy was observed in almost 17% of the 1,604 patients with Takotsubo syndrome.

The most frequent type of malignancy was breast cancer (26.2%, n=70), followed by tumors affecting the GI system (16.1%, n=43), respiratory tract (15.4%, n=41), internal sex organs (14.6%, n=39), and skin (13.1%, n=35). Interestingly, that analysis found that patients with malignancy were older and more likely to have physical triggers, but they were less likely to have emotional triggers compared with those without malignancy.

Case authors suggested that, given the small number of cancer patients who present to their clinic with Takotsubo syndrome, some cases may go undiagnosed. This may be because heart problems due to underlying disease and cardiotoxic effects of therapy may be similar to the symptoms of Takotsubo syndrome. The authors added that diagnosis may be complicated by the various causes of myocardial damage in cancer patients -- as in this patient, whose coronary atherosclerosis made differential diagnosis very difficult.

In cancer patients, authors wrote, the main causes for Takotsubo syndrome include the stress of receiving a cancer diagnosis, as well as the stress associated with its treatment, disease-related pain, and complications of surgical or medical treatment, as well as paraneoplastic syndromes.

In this patient's case, they suggested that her Takotsubo syndrome was most likely caused by the stress associated with the subsequent stages of oncological therapy, chemotherapy, and another scheduled surgical intervention.

Research has identified several chemotherapeutic agents as risk factors for Takotsubo syndrome, including 5-fluorouracil, capecitabine, cisplatin/docetaxel, cytarabine, and cytarabine/daunorubicin. A 2020 report of atypical Takotsubo cardiomyopathy secondary to combination of carboplatin and pemetrexed chemo-immunotherapy in a patient with non-small cell lung cancer noted that this favored first-line regimen for that cancer is not yet known to be associated with Takotsubo syndrome.

Case authors noted that ECG, troponin and BNP concentrations, echocardiography, and cardiac catheterization with ventriculography are central to diagnosis of Takotsubo syndrome in cancer patients: ECG findings are characterized by ischemic changes such as ST elevation, negative T, or QT prolongation.

The ST-segment elevations and negative T waves reported early in Takotsubo syndrome are thought to be related to abnormal repolarization resulting from high catecholamine levels, they wrote, while negative T, QT prolongation, or ventricular arrhythmias that develop later are probably due to cardiomyocyte ischemia.

Differential diagnosis is best informed by the evidence of contractility disorders, noted on echocardiography, ventriculography, CT, and magnetic resonance assessments, authors noted. While the cardiotoxic effect of chemotherapy drugs leads to global defect of left ventricular contractility, Takotsubo syndrome is characterized by segmental disorders of the systolic function, primarily in the apex area and apical segments of the left ventricle.

Takotsubo syndrome related to neoplastic disorders is primarily a secondary form of Takotsubo, the authors observed, and is characterized by a more severe clinical course and a more frequent occurrence of severe complications. They added that cases reported in oncological patients have generally involved severe heart failure with very low left ventricular ejection fraction (10%-20%), cardiogenic shock, sudden cardiac arrest secondary to ventricular tachycardia or asystole, or rupture of the left ventricular wall. Takotsubo syndrome complications were more likely to be severe during chemotherapy and were frequently observed during or shortly after the patient received the infusion or shortly after the procedure.

In this woman's case, they noted that diagnosis was made more challenging by findings of the coronary angiography, which identified a borderline stenosis in the middle segment of the left anterior descending artery. The change, estimated at 60%, was ultimately determined to be insignificant and not to be the cause of her left ventricular contractility disorders. As well, they noted that the image of the left ventricle was characteristic of Takotsubo syndrome, which was probably a primary, stress-induced form of the condition in this patient, they added, citing its benign and relatively uncomplicated course, aside from the minor rhythm abnormalities.

This patient died after 4 months due to the nature and advancement of her bladder cancer. However, case authors noted that generally, treatment of cancer, particularly during chemotherapy, is more challenging in the patients with Takotsubo syndrome. It can delay delivery of further stages of oncological treatment, thus worsening patients' prognosis.

Takotsubo syndrome that occurs in the patient during the administration of the chemotherapy drug should be noted by clinicians and considered for treatment with ACE inhibitors to avoid further recurrence of the myopathy. Chemotherapy may be resumed after left ventricular contractility function is restored, they noted, which is typically after 2 to 3 weeks.

In patients with cancer, chest pain can have many various etiologies, including Takotsubo syndrome, which makes diagnosis difficult – especially in patients with evidence of coronary atherosclerosis, they wrote, concluding that delays in planned cancer treatments can worsen the prognosis of these patients.

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