Introduction

Takotsubo syndrome (TTS) is a condition characterized by acute heart failure and transient ventricular contractile dysfunction that is frequently precipitated by acute emotional or physical stress. Although the precise pathophysiologic mechanism underlying this syndrome remains unknown, enhanced sympathetic stimulation resulting in microvascular dysfunction and/or direct myocyte injury is believed to be central to the syndrome’s pathogenesis.¹ Since its original description in the early 1990s, a consistent observation in all series of TTS has been the marked preponderance of older postmenopausal women. Women comprise approximately 90% of the cases reported in the literature with a mean age of 65-75 years in most series, and the risk of developing TTS increases 5-fold in women after the age of 55 years.² The precise reason that older women are so disproportionately affected remains unknown, but it is believed that the declining beneficial effects of estrogen on cardiac microvascular function as women age make postmenopausal women particularly susceptible to microvascular ischemia and TTS during episodes of excessive sympathetic stimulation. Given the marked female predisposition to TTS, it is not surprising that most of the literature over the past 20 years has focused primarily on women with this disorder, and far less has been written about the clinical features and outcomes of men with TTS. Although men clearly make up the minority of reported cases, the available literature suggests that males with TTS may represent a particularly vulnerable population with increased rates of arrhythmia, cardiogenic shock, and mortality compared with females with the syndrome.^3-5

In this issue of the Journal of the American College of Cardiology, Arcari et al⁶ provide much needed insight into the influence of sex on TTS by presenting a large population of both men and women with TTS enrolled in the GEIST (GErman Italian Spanish Takotsubo) registry. The investigators looked at 2,492 patients enrolled in this registry and compared the clinical features and short- and long-term outcomes between men and women with TTS. After examining sex differences in this large population, they then performed a propensity score analysis by matching men and women 1:1 based on several variables that included age, presence of diabetes, current smoking status, history of malignancy, and the type of trigger precipitating the syndrome (emotional vs physical). Several important observations were made in this study: 1) men comprised 11% of the total TTS population, a prevalence similar to what has been reported in other studies and registries; 2) physical triggers were more frequently reported in male patients, whereas emotional triggers were more common in female patients; 3) men were significantly sicker at the time of initial presentation and were more likely to have cardiogenic shock, to require catecholamine administration, and to require intubation both in the total population and after propensity score matching; 4) in-hospital mortality was significantly higher in men, both in the overall and matched cohorts; and 5) long-term mortality was higher in men in the overall population but was not different between men and women in the matched cohort. Some of these observations can be readily explained by looking at the demographics of the overall GEIST population. Men had a significantly higher prevalence of diabetes mellitus, tobacco use, pulmonary disease, malignancies, and coronary artery disease, comorbidities that one would expect to have an impact on in-hospital complications as well as short- and long-term survival. Men in the overall population were also more likely to develop TTS following physical triggers, which has been previously shown to be associated with worse outcomes compared with emotional triggers.⁷ Men were also less likely to be discharged from the hospital on beta-blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, which may have also had an impact on long-term outcomes. Although there were significant demographic differences between men and women in the overall population, the study by Arcari et al⁶ is novel in that the relatively large size of the GEIST registry made it possible for the investigators to account for many of these confounding variables by performing a propensity score matching analysis. Interestingly, even after matching for age, comorbidities, and type of precipitating trigger, men with TTS remained much sicker than women with a higher incidence of cardiogenic shock, in-hospital death, and death at 60 days. Men also had a lower ejection fraction and a higher prevalence of the apical ballooning variant compared with women, echocardiographic features known to be associated with worse short-term outcomes.⁸ By contrast, long-term mortality was not affected by sex in the matched cohort. This last observation suggests that once left ventricular systolic function recovers, which typically occurs within days to weeks of initial presentation, long-term mortality in TTS is driven primarily by non-cardiac comorbidities and events.

The study by Arcari et al⁶ shows convincingly that although men are far less likely to develop TTS than women, they have more serious complications and are more likely to die than women presenting with the syndrome. Although these observations may seem paradoxical at first, they may actually provide important clues about the pathophysiologic mechanisms of this disorder. There is increasing evidence that the transient myocardial dysfunction observed in TTS is the result of sympathetically mediated microvascular ischemia.¹Figure 1 illustrates how TTS susceptibility may be dependent on the delicate balance between resting sympathetic tone and microvascular function. In this paradigm, individuals with normal basal sympathetic tone and normal microvascular function may be at low risk for developing TTS, whereas individuals with elevated resting sympathetic tone and significant microvascular dysfunction may be highly vulnerable. This paradigm helps to explain why older women are particularly susceptible to TTS. Resting sympathetic tone appears to be particularly elevated in older women,⁹ and as women age, there are significant decreases in cardiac vagal tone and baroreflex sensitivity with an associated increase in sympathetic activation.¹⁰ Estrogen is also an important regulator of endothelial function and vasomotor tone, and can attenuate catecholamine-mediated vasoconstriction, making older postmenopausal women potentially more susceptible than men to stress-related microvascular ischemia.¹¹Figure 1 further illustrates that the sympathetic stimulus required to precipitate TTS is inversely related to susceptibility. Only mild sympathetic stimulation may be needed to precipitate TTS in highly susceptible individuals such as older women, and whereas older women may be more likely to develop the syndrome following acute stress, the smaller sympathetic stimulus may result in less myocardial injury and fewer cardiac complications. By contrast, significant noradrenergic stimulation may be necessary to precipitate TTS in men who have lower resting sympathetic tone and less microvascular dysfunction, thus resulting in more myocardial injury (eg, higher troponin, more contraction band necrosis, lower ejection fraction) and a higher incidence of cardiovascular complications and death in the acute period.

The proposed paradigm in Figure 1 helps to explain an interesting and recurrent theme that has emerged in the Takotsubo literature, and that is that groups with the lowest prevalence of TTS appear to be the sickest at the time of presentation. African Americans made up <10% of the reported cases of TTS in one series but had a greater number of in-hospital complications compared with Caucasians.¹² Young individuals (aged <50 years) comprised only 11% of the InterTAK (International Takotsubo) registry but were more likely to have cardiogenic shock and to require inotrope and ventilator support than older patients.^13,14 Once again in the current study, men accounted for only 11% of the total GEIST registry but were significantly sicker than their female counterparts. These observations not only shed light on possible pathophysiologic mechanisms of this disorder, but also serve as an important reminder to clinicians that the patients least likely to get TTS are perhaps the most likely to die from it.