Novel Insights on Takotsubo Could Lead to New Therapies

New mechanisms underlying Takotsubo syndrome, often dubbed “broken heart syndrome,” are suggested from hemodynamic studies, which could lead to new treatment strategies for the condition.

Takotsubo syndrome is a form of acute heart failure that mimics acute coronary syndromes, with troponin elevation and symptoms including chest pain and dyspnea, but without a culprit lesion on coronary angiography.

However, echocardiography shows the heart to be massively enlarged. The condition was named by Japanese researchers as the shape of the left ventricle resembles the Takotsubo fishing pot used to trap octopi.

The condition affects mainly older women and accounts for about 6% of female patients presenting with acute coronary syndrome symptoms. In around two thirds of cases there is a triggering stress event which can be physical, such as an acute disease, or emotional, such as an argument or the sudden death of someone close, hence the term “broken heart syndrome.” The emotional stress triggering the syndrome can also be positive such as a birthday party or the birth of a grandchild.

“The mechanisms involved in Takotsubo syndrome are unknown. Because there is often a stress trigger it is believed that sympathetic activation causes a surge of catecholamine release, but that is not fully understood,” lead author of the current study, Thomas Stiermaier, MD, University Heart Center Lübeck, Lübeck, Germany, explained to | Medscape Cardiology.

“We wanted to look more closely at the hemodynamic effects in the hearts of patients with Takotsubo syndrome to see if we could identify novel mechanisms contributing to the condition,” he added.

The aptly named Optimized Characterization of Takotsubo Syndrome by Obtaining Pressure Volume Loops (OCTOPUS) study was published online in the Journal of the American College of Cardiology (JACC) on May 15, 2023.

For the study, the researchers used a conductance catheter inserted into the left ventricle of the heart to analyze pressure-volume relationships in 24 consecutive patients with Takotsubo syndrome and a control population of 20 participants without cardiovascular disease.

These pressure-volume loops are “the gold standard for direct, real-time assessment of systolic and diastolic cardiac function independent of loading conditions,” and “provide in-depth information regarding ventricular–arterial coupling and cardiac energetics and efficiency,” the authors say.

“These parameters comprise a considerable amount of information on cardiac performance and help to advance our understanding of cardiac physiology and its pathophysiological role in various conditions,” they note, adding that this is believed to be the first comprehensive hemodynamic analysis in patients with Takotsubo syndrome using such invasive tracing of pressure-volume loops.

Results showed that Takotsubo syndrome is associated with a severely impaired cardiac contractility and a shortened systolic period. In response, the heart compensates by increasing left ventricular end diastolic volume to preserve the stroke volume.

Diastolic function is characterized by prolonged active relaxation but unaltered passive elastic properties. The analysis of myocardial energetics revealed an inefficient system with increased potential and decreased kinetic energy (stroke work).

“These are new and important findings,” Stiermaier said, adding that these hemodynamic changes give clues as to the underlying mechanisms at play in Takotsubo syndrome, as well as possible treatment strategies that could be investigated.  

“Taking all this information together, we believe that it is likely that decreased phosphorylation of myofilament proteins — which may be caused by some kind of disturbance in calcium metabolism — may partially account for the impaired contractility and shortened systolic period seen in Takotsubo syndrome,” he commented.  

The researchers suggest that Takotsubo syndrome may therefore be treated with medications such as omecamtiv (a drug that increases systolic duration) or the calcium sensitizer levosimendan, which improves contractility, possibly in combination with beta-blockers to protect against the intense adrenergic activation.  

They note that several studies have reported the use of levosimendan in Takotsubo syndrome and have suggested positive effects by accelerating recovery of ventricular function. But they add that prospective data are lacking, and, to their knowledge, omecamtiv has not been tested in Takotsubo syndrome.

“We need to clearly identify the mechanism involved in these changes at the cellular level, and then test these medications to see if they can help prevent or reverse the hemodynamic changes seen in Takotsubo syndrome,” Stiermaier said.   

He explained that the contractile abnormalities in Takotsubo syndrome are transient and generally normalize after a few weeks or months, but while systolic function may appear normal in the long term there are other more subtle changes that can persist, and these patients have an increased rate of cardiovascular events compared with the healthy population over the long term.

However, because Takotsubo syndrome patients generally have a high rate of other comorbidities, it is not known whether their increased event rate is due to the syndrome or to these other comorbidities.

While some patients with Takotsubo syndrome have a mild disease course and a good prognosis, others have more complications, with around 10% to 15% going on to develop severe disease with cardiogenic shock or pleural effusion, Stiermaier noted.

“These patients have a bad prognosis. Our aim is to try to identify the patients who are at high risk of these complications and treat them early to prevent cardiogenic shock and pleural effusion from developing,” he said. 

“We are hopeful that by identifying the hemodynamic changes occurring in Takotsubo syndrome we can figure out the mechanisms involved and give medications in the acute setting to prevent the complications that can arise down the road,” he added.

Mechanisms ‘Appealing but Speculative’

In an editorial accompanying the paper in JACC, Jorge Salamanca, MD, and Fernando Alfonso, MD, Hospital Universitario de La Princesa, Madrid, Spain, describe this new study as “an important piece of research, providing a careful, systematic, and comprehensive set of sophisticated invasive hemodynamic data that shed new light on our understanding of this unique clinical entity.”

They say the researchers have provided “robust data on the acute hemodynamic behavior of the left ventricle in patients with Takotsubo syndrome that clearly advance the field but also raise new questions.”

But the editorialists caution that the hypotheses of the potential mechanisms linking a molecular basis for the metabolic dysregulation, resulting in increased potential energy coupled with a decreased kinetic energy, “are appealing but largely speculative.”

“Whether these hemodynamic findings could be the foundation and would support the use of novel and attractive drugs in Takotsubo syndrome, remains unsettled and can only be considered as hypothesis generating,” they say.

“Further studies are required to elucidate factors associated with a more severe hemodynamic derangement and to devise therapeutic strategies helping to rapidly restore an efficient left ventricular function in these challenging patients,” they conclude. 

The study authors and the editorialists report no relevant financial relationships.

J Am Coll Cardiol. Published online May 15, 2023. Abstract; editorial.

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