A Decidedly Darker Prognosis for Takotsubo Syndrome

Patrice Wendling

January 08, 2019

Takotsubo syndrome (TS) has been considered a transient benign disorder, but mounting evidence of a darker long-term prognosis is reshaping that belief.

A systematic review of 54 studies involving 4679 patients showed relatively high rates of life-threatening complications such as acute heart failure (HF) with shock (19%) and malignant arrhythmias (10%), with in-hospital death occurring in 1.8% of cases.

Among survivors, 1% had a recurrent episode of TS and 3.5% died per year over a median follow-up of 28 months (range, 6-99 months).

"We now know that Takotsubo syndrome is not a benign disease and is associated with important in-hospital and, more importantly, long-term mortality rates," study author Francesco Pelliccia, MD, PhD, Department of Cardiovascular Sciences, La Sapienza University, Rome, told theheart.org | Medscape Cardiology.

Although the review included only original studies and excluded multicenter international registries to avoid overlap between cohorts, the results are comparable with registry findings, he said.

"The advantage is that it really represents a real-world experience much more than other international registries, which have data only from Takotsubo syndrome centers," Pelliccia said.

The study was published January 3 in the Journal of the American College of Cardiology: Heart Failure.

"Basically it confirms what we published three years ago," said Thomas Lüscher, MD, FRCP, from the Royal Brompton & Harefield Hospital Trust and Imperial College, London, and the University of Zurich, Switzerland.

They published in-hospital and long-term mortality rates of 4.1% and 5.6%, respectively, among 1750 patients in the International Takotsubo Registry (InterTAK), a consortium of 26 centers in Europe and the US.

Last year, similarly high short- and long-term mortality rates were reported in 711 patients in Spain's National Registry on Takotsubo Syndrome (RETAKO) (2.4% and 4.6%/yr) and in a study of 826 TS patients with and without diabetes in the German Italian Stress Cardiomyopathy (GEIST) registry (6.4% vs 5.7%; 31.4% vs 16.5%).

"It's quite clear that the mortality currently and acute cardiogenic shock rate is the same as in patients with infarction treated according to current possibilities, so I think it has to be taken seriously," said Lüscher, who is among those proposing TS as a microvascular acute coronary syndrome.

Nevertheless, change comes slowly, he said. Takotsubo syndrome, often called broken heart syndrome or stress cardiomyopathy, continues to be underdiagnosed and the risk for adverse events underappreciated.

"Most physicians still believe it is a benign condition," Lüscher said. "I just did a case this morning in an elderly, postmenopausal lady who came in with pulmonary edema who couldn't lie flat, had water on the lungs, and had blood pressure that was low, and they didn't even dare to do an angiogram and today we proved she had Takotsubo."

Along with current uncertainty about the natural history of TS, Pelliccia and colleagues note that it remains unclear whether presenting characteristics in the acute phase are associated with long-term prognosis.

Of the 4679 patients analyzed, the average ages ranged from 53 to 75 years and 87% were women. TS was preceded in two thirds of patients by an emotional (36%) or physical (36%) stressor.

Two thirds of patients presented with chest pain (64%) and roughly half had signs of acute heart failure (26% dyspnea, 19% shock). Moderate functional left ventricular (LV) dysfunction was present in most patients, with a mean LV ejection fraction ranging from 28% to 54% (mean, 40%). The typical pattern of TS characterized by apical ballooning was found in 72%.

Cardiovascular risk factors including hypertension (59%) and diabetes (34%) were common, while a few studies also reported concurrent neurologic (15%) and psychological diseases (18%) and cancer (17%).

Most of the deaths (78%) were due to noncardiac causes, suggesting that concomitant conditions play a major, long-term prognostic role, the authors note.

Meta-regression analysis showed that long-term mortality was significantly associated with older age (P = .05; coefficient, 0.002), physical stressor (P = .0001; coefficient, 0.001), and an atypical ballooning pattern (P = .009; coefficient, 0.001). HF at presentation, however, was not a significant determinant of TS recurrence or long-term mortality.

"We now have indicators that might constitute red flags to us that signal there might be an increased risk after an acute episode," Pelliccia said. "We have to pay particular attention to whether or not our patients are vulnerable, as defined by their relative function, age, presence of comorbidities, and evidence of more extensive damage at time of the acute phase."

Limitations of the study include the lack of control groups and the inability to investigate the cause of death or assess the effects of medication on long-term outcomes, he said. Although most patients were discharged on an angiotensin-converting enzyme inhibitor (ACE)/angiotensin receptor blocker (ARB) (92%) or beta-blocker (54%), there was "extreme heterogeneity" in medications during follow-up.

"We noticed that patients were treated differently in different countries, in different centers," Pelliccia said. "There were those who received beta blockers but not ACE inhibitors during follow-up and we now have preliminary data showing that ACE inhibitors are effective in this, whereas beta blockers are not."

"There's no really good treatment yet," said Lüscher, who coauthored a new expert international consensus document on Takotsubo, published in 2018. "In fact, if you give catecholamines, this may actually be detrimental in these patients because they contract at the base of the heart, and if you stimulate at only the base of the heart you get a gradient across the left ventricular outflow tract, and blood pressure may actually go down rather than up. So it is a tricky thing."

He noted that a large trial is being planned in the United Kingdom, but would not reveal details other than to say efforts need to focus on interfering with microvascular and endothelial dysfunction, which continue to exist in TS outside the acute event.

In the acute setting, research is needed to assess devices like extracorporeal membrane oxygenation (ECMO) that unload the heart until it recovers in severe cases that develop hypotension.

"I haven't used the Impella but conceptually it's a good device because it takes the blood from the apical ballooning up the aorta," he said. "We've done quite a few cases with ECMO, which is quite invasive, but saved quite a few patients with this intervention. But this is all evidence-based; this has not been tested in a trial."

In a related editorial, L. Christian Napp, MD, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany, writes: "We can conclude that TS carries considerable risk, especially if a physical trigger is present, and it is not a 'self-healing syndrome.' "

However, some "big black holes" remain that still make it difficult to treat and consult patients with TS, he notes, including the true pathogenesis of TS; how patients should be treated during the acute phase, especially when shock develops; whether patients need long-term medical therapy; and the allegedly transient nature of TS.

"To answer the open questions, we should aim for prospective studies with comprehensive data acquisition in the acute phase and systematic follow-up including the cause of death," Napp concludes. "Given the existing recurrence rate and the still huge amount of beta-blockers prescribed without data, studies aiming to test medical therapies are needed."

Senior author Paolo G. Camici has been a consultant for Servier; all other authors have disclosed no relevant financial relationships. Lüscher has disclosed no relevant financial relationships. Napp reported receiving modest, personal fees for lectures, proctorship, consulting, or travel support from Abiomed, Maquet, Cytosorbents, Bayer, Zoll, Amgen, Biotronik, Merit Medical, Servier, and Terumo.

J Am Coll Cardiol HF. Published online January 3, 2019. Abstract, Editorial


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