Takotsubo cardiomyopathy (TC) is a form of acute heart failure, characterized by regional dysfunction of the left and/or right ventricle, usually reversible, caused in most cases by acute physical or emotional stress in the absence of obstructive coronary artery disease. In 2006, the American Heart Association classified it in the group of acquired cardiomyopathies, under the name of stress-induced cardiomyopathy.
The main manifestations of TC are chest pain, dyspnea, electrocardiographic changes of ischemia, slight increase in cardiac enzymes and segmental ventricular dysfunction.
Cancer patients have many stressors and pathophysiological factors in common with patients with TC. This relationship has recently been described in the medical literature, and patients who develop TC with a previous history of cancer or active disease have a poorer prognosis.
Nowadays, TC has been considered as an epiphenomenon of cardiotoxicity in patients with cancer.
The objective of this article is to review the association between cancer and TC and to propose a rational clinical follow-up for cancer patients regarding the prevention and treatment of TC.
TC incidence in cancer patients is equivalent in men and women, while there is an apparent predisposition for women in the general population.
Recent evidence shows that the prevalence of neoplasms is boosted in patients with TC compared to people of the same age and sex without the syndrome ranging around 4-29%, both at the time of diagnosis and during follow-up.
TC can simulate an acute coronary syndrome (ACS) initially, with very similar constellation of signs and symptoms, and similar changes in electrocardiogram and cardiac enzymes, representing a challenging diagnosis. In fact, up to 6% of patients with an initial diagnosis of ACS in the emergency room have a final diagnosis of TC.
Takotsubo cardiomyopathy clinical presentation model
Primary
Acute cardiac symptoms are the primary cause of seeking medical care
Secondary
Occurs in patients already hospitalized for reasons other than cardiac. It is a complication of the primary condition or its treatment. It is the most frequent model in cancer patients.
The secondary TC model has epidemiological aspects that differ from the primary model: a higher prevalence in men, reaching 50% in some studies, with the most comprehensive age group, generally above 40 years. It usually develops after a few days of hospitalization.
TC: Takotsubo cardiomyopathy; ACS: acute coronary syndrome.
Primary TC
Secondary TC
Presentation
On emergency admission
Mostly hospitalized, during postoperative or intensive care
Diagnosis
Rapid, based on the history of chest pain and dyspnea, abnormal electrocardiogram and/or elevated troponin and echocardiogram with typical alteration. Urgent catheterization almost always confirms the diagnosis by excluding ACS
Usually made after the patient presents clinical worsening, hemodynamic instability, arrhythmia, signs of heart failure. Catheterization is performed in a much smaller portion
Gender
90% women
50% women
Age
> 60 years
> 40 years
Complications
Few, mild and transient
High incidence of shock, mechanical ventilation, use of vasoactive amines and mechanical circulatory support
In-Hospital mortality
Low: around 5%
High: can reach 30%
TC in cancer patients usually has the secondary type of presentation, as a cardiac complication in patients submitted to multi-drug treatments for cancer during hospitalizations.
It has been shown that patients with solid tumors are more likely to TC than those with hematologic malignancies. Breast cancer, followed by tumors of the gastrointestinal system and respiratory track the most common malignancy associated with TC.
In a large US cohort study that analyzed more than four million inpatients with active cancer, the prevalence of TC in these patients was 12%. The investigators also examined the association between primary tumor type and the risk for TC. They found that only breast and lung cancer were associated with a significant chance of TC.
The first Brazilian TC registry, REMUTA (Takotsubo multicenter registry), has included 169 patients admitted with primary or secondary TC. An incidence of 14.7% of patients with a previous or current cancer diagnosis was observed.
There are several proposed pathophysiological mechanisms responsible for TC, with activation of the sympathetic nervous system and coronary vasospasm as the main ones.
The triggers of TC in cancer are various. Cancer patients are constantly under stressors that increase the risk of developing TC. First, the emotional stress that a cancer diagnosis and its treatment impose to patients can increase the adrenergic load. Additionally, patients are frequently submitted to the physical stress of surgeries and diagnostic procedures, and to pain, and some physical complications of chemotherapy such as anemia, and dehydration that may lead to hyperkinesia.
These causative and predisposing factors explain the “multi-hit hypothesis” for TC in cancer patients.
Chest pain or dyspnea during or after anticancer treatment is the typical clinical presentation of TC, however in 26.8% of patients, cardiogenic shock may be the first and potentially fatal manifestation.
Further complications comprise respiratory failure, pulmonary edema, arrhythmias, cardiac thrombus, or cardiac arrest.
The median time of TC onset is two days (1–150) after the beginning of treatment,
Investigations in a patient with cancer with presumed TC should include clinical examination, ECG, transthoracic echocardiography, cardiac biomarkers, and cardiac magnetic resonance as show in
The diagnostic criteria for TC are shown in
TC: Takotsubo cardiomyopathy; ECG: electrocardiogram; CK: creatine kinase; BNP: B-type natriuretic peptide.
1
Presence of transient left ventricular dysfunction. Associated right ventricular dysfunction may occur. Contractility abnormality extends beyond the territory of an epicardial coronary artery. In rare cases of focal TC, it may be restricted to one territory.
2
Physical or emotional stress often precedes the event but is not mandatory
3
Acute neurological disease and pheochromocytoma can be a trigger for TC
4
Acute electrocardiographic changes are almost always present, but in rare cases the electrocardiogram may be normal
5
Levels of cardiac biomarkers (CK or troponin) are often moderately elevated, as well as BNP
6
Significant coronary artery disease can coexist with TC
7
There can be no evidence of acute myocarditis
Most patients need invasive coronary angiography to exclude acute myocardial infarction. In patients with advanced malignancy or significant thrombocytopenia where invasive coronary angiography is contraindicated, a coronary computed tomography angiography is advised. Cardiac imaging studies should be conducted as early as feasible when the diagnosis is presumed, as left ventricular dysfunction (LVD) can be transient. If substantial LVD is seen, repeat imaging is recommended to confirm recovery.
Nuclear magnetic resonance is an important diagnostic tool, especially in cases where myocarditis needs to be ruled out as a differential diagnosis or in cases of focal TC, with respect to the coronary territory, to assess whether the pattern of delayed enhancement is typical of ischemic disease or not. Enhancement may be present in a minority of patients – fragmented and not typical for coronary artery disease but absent in most cases. In addition, it accurately quantifies left ventricular and right ventricular function, and detects complications (thrombi, pleural and pericardial effusion).
In addition, interruption of the anticancer drug treatment in patients with Takotsubo syndrome is suggested, and QT-prolonging drugs should be avoided.
In cases of ICI-associated TC, the role of immunosuppression is unknown; if myocardial inflammation is present in a TC pattern on cardiac magnetic resonance, then intravenous methylprednisolone is recommended given the overlap between ICI-induced TC and ICI-induced myocarditis. Limited information exists regarding the feasibility of ICI rechallenge following TC and after recovery of left ventricular function.
A multidisciplinary team discussion is recommended after recovery from the acute phase of TC and, if restarting the cancer drug is necessary from an oncology point of view, cardiac follow-up is recommended.
TC usually occurs during oncologic treatment, and it is commonly attributed to the acute cardiotoxicity of the treatment mainly by free radicals-induced cardiac myocyte damage. The primary chemotherapeutic agents associated with TC are 5-fluorouracil, capecitabine, cytarabine, hydroxyurea, daunorubicin, cisplatin, docetaxel, paclitaxel.
Among cancer patients exposed to these drugs, those with risk factors such as female sex, age more than 45 years, hypertension, dyslipidemia, anemia, lung and neurologic disease were more predisposed to develop TC.
It is possible that an interconnection between different cancer stressors, inflammation, and cytokine synthesis in response to catecholamines, may explain the differences in the manifestations of TC in patients with cancer. Other oncologic treatments have also been linked to TC.
Bevacizumab is associated with specific cardiovascular side effects, in particular arterial thromboembolism.
Rituximab has also been shown to induce adverse cardiac events, including arrhythmia and less frequently, myocardial infarction. Recently, it was documented acute ventricular dysfunction after infusion of rituximab, indicating that changes in the growth factor-β levels may have led to the formation of reticulin fiber (diffusely present in cardiac muscles), generating a reduction in myocardial contractility and conduction.
Cancer patients who develop TC have a poorer prognosis;
The RETAKO, a registry on TC, developed between 2002 and 2019 in 38 hospitals, included patients with history of any malignancy or tumor, even benign, that received chemotherapy, radiotherapy or specific surgery, current or in the past. Any type of neoplasm was described in 129 (11.8%) in a cohort of 1097 patients with TC. The results showed that, during hospital stay, cancer patients suffered more complications, highlighting heart failure/shock, acute renal failure and a trend towards combined infections. On follow-up, they presented higher mortality and more combined MACE events, with a non-significant trend in cardiovascular recurrences or readmissions.
TC in cancer patients can lead to interruptions in chemotherapy, which may adversely affect oncologic outcome. Additionally, cancer patients are at increased risk for developing TC while they are on active oncologic treatment with surgery, radiation and chemotherapy.
Cancer patients should be carefully and closely monitored to identify those patients at greater risk of developing TC in order to make early diagnosis and efficient care.
Cancer patients at higher risk for developing takotsubo should have more rigorous clinical follow-up. The Brazilian cardio-oncology guideline recommends, ideally, a consultation with a cardiologist, and baseline tests such as ECG, laboratory tests (complete blood count, thyroid function tests, type B natriuretic peptide, kidney and liver function tests and cardiac troponin) and Echocardiogram and if possible, at three, six and 12 months. In addition to these general recommendations for cardiac follow-up of cancer patients, additional evaluations could be considered whenever the cancer patient is submitted to new diagnostic or therapeutic procedures during the oncologic treatment once they can trigger the appearance of TC.