Takotsubo Snapshot Reveals Some Surprises: InterTAK Registry

About one in 10 patients who present with Takotsubo cardiomyopathy are no more than 50 years old, with individuals in this cohort more likely to be men and to present with coexisting acute neurological or psychiatric disorders, atypical symptoms, and cardiogenic shock, according to a new analysis.

The findings are notable because Takotsubo is most commonly thought by physicians to affect postmenopausal women, despite studies showing the syndrome’s differing presentations.

“Giving the increased awareness of the disease, it could be hypothesized that younger and male patients were diagnosed more frequently in more recent years,” write Victoria L. Cammann, MD (University Hospital Zurich, Switzerland), and colleagues. “However, when analyzing age and sex distribution over the entire study period, we could not confirm this assumption. Interestingly, the prevalence of male patients increased with decreasing age and was highest in younger patients.”

Of the 2,098 Takotsubo patients from the 11-country InterTAK Registry analyzed in the study, published in the April 28, 2020, issue of the Journal of the American College of Cardiology, 11.5% were 50 years old or younger. Compared with those aged 51 to 74 years (56.9%) or 75 years and older (31.6%), the youngest cohort more often presented with cardiogenic shock (15.3% vs 9.1% vs 8.1%; P = 0.004) and had a numerically higher in-hospital mortality (6.6% vs 3.6% vs 5.1%; P = 0.07). Patients were enrolled between 2011 and 2017.

“Given the substantially worse in-hospital course, younger [Takotsubo] patients present as a particularly vulnerable patient subset in need for close monitoring and intensive care,” the authors suggest.

Additionally, the younger patients were more often men (12.4% vs 10.9% vs 6.3%; P = 0.002) and had increased prevalence of acute neurological disorders (16.3% vs 8.4% vs 8.8%; P = 0.001)—seizures, intracranial hemorrhages, and migraine attacks or headache disorders—and psychiatric disorders (14.1% vs 10.3% vs 5.6%; P < 0.001)— particularly affective and adjustment disorders—compared with middle-aged and older patients.

Interestingly, the prevalence of typical Takotsubo syndrome was lowest in younger patients (66.5% vs 67.9% vs 79.3%; P < 0.001), and compared with older patients, they presented with higher troponin (P = 0.017) and creatinine levels (P = 0.049) as well as higher heart rate (P = 0.009) and lower systolic BP (P = 0.012) at admission.

“It may therefore be speculated that myocardial susceptibility to triggering factors as well as protective defense mechanisms may vary according to age, and these alterations in turn may result in distinct and age-related variants of wall motion abnormalities and disease severity in [Takotsubo] patients,” the authors write. “Alternatively, the activation of midbrain structures and in turn the topical activation of specific nerve fibers may differ with age. Whether and to what extent age- and sex-related changes in sympathetic activity of the left ventricular apex determine the course of the disease remains to be elucidated.”

On multivariate analysis, younger age (OR 1.60; 95% CI 0.86-3.01) and older age (OR 1.09; 95% CI 0.66-1.80) were not independently associated with in-hospital mortality when using the middle-aged group as a reference. There were also no differences in 60-day mortality rates among cohorts.

‘A Particularly Concerning Population’

In an associated editorial, Ilan Wittstein, MD (Johns Hopkins University School of Medicine, Baltimore, MD), says that while previous smaller studies have observed a similar incidence of younger Takotsubo patients, this finding is “now well validated by this much larger study.”

“It may seem counterintuitive that young patients with fewer cardiovascular risk factors would have a higher prevalence of acute neurologic disorders and cardiogenic shock, but several of the observations made in this study can be explained by considering the proposed pathophysiology of [Takotsubo syndrome],” he writes. “The risk of developing [Takotsubo syndrome] may depend on the delicate balance between resting sympathetic tone and microvascular function. Individuals with elevated resting sympathetic tone and microvascular dysfunction (eg, older postmenopausal women) are at high risk for developing [Takotsubo]. In contrast, the risk is low in young healthy patients with normal sympathetic and vasomotor tone.”

The relationship between risk and age is also affected by how “young” is defined, Wittstein explains, as some patients younger than 50 can have cardiovascular risk factors and endothelial dysfunction and many women in their mid to late 40s are perimenopausal. “It is probable that a significant number of the younger patients in this study were actually physiologically at moderate risk for [Takotsubo syndrome], and had the definition of ‘young’ been 40 years or less, the prevalence of [Takotsubo syndrome] in this group would likely have been extremely low,” he comments.

As for the increased presence of atypical presentation in younger patients, Wittstein says “there are data to suggest that the left ventricular apex may have both age- and sex-specific susceptibility to sympathetic stimulation, but this seems to be an unlikely explanation in [Takotsubo] where up to 20% of individuals with recurrent episodes over a relatively short time period present with different ballooning variants. An alternative explanation is that young patients in the current study had a higher prevalence of acute neurologic disorders.”

Finally, the lack of difference observed by age in in-hospital mortality is in contrast to what has been seen before, he writes. “Not surprisingly, what did emerge as a predictor of in-hospital mortality was acute neurologic injury, reinforcing what has been previously shown from InterTAK that among the most important determinants of both short- and long-term survival in [Takotsubo syndrome] is the type of trigger that precipitates the syndrome in the first place.”

As for what this all means for clinical practice, Wittstein said while the study emphasizes that Takotsubo is primarily a syndrome of middle-aged or elderly women, “the fact that 11% of the patients were below the age of 50 years reinforces that [it] should be in the differential diagnosis for patients of any age with suspected acute coronary syndrome, including healthy young adults and children. Because young patients are likely the least susceptible to [Takotsubo], they may require the greatest amount of sympathetic stimulation to precipitate the syndrome.

“Clinicians need to be aware that this may make young patients with [Takotsubo] a particularly concerning population that will frequently require the most aggressive hemodynamic support and vigilant monitoring during the initial presentation,” he concludes.