"Happy Heart" Versus "Broken Heart" Syndrome

The 2 Faces of Takotsubo Syndrome: Similarities and Differences

Joseph Adu-Amankwaah, MLS, PHD


JACC Heart Fail. 2022;10(7):467-469. 

The recognition of takotsubo syndrome (TTS) as a significant cause of abrupt heart failure associated with a specific pattern of transient left ventricular contraction anomalies has risen dramatically in recent decades. TTS, discovered in 1990 and classified as acquired primary cardiomyopathy in 2006,[1] has been the subject of an increasing number of clinical and research papers, revealing some distinctive features of this intriguing but multifaceted clinical disease. The initiation of this clinical condition has been linked with various emotional and physical stressors. Notably, the implication of negative emotions such as grief, anger, or fear with TTS during its discovery resulted in the common moniker "broken heart" syndrome, which has well-studied diagnostic and prognostic features. Recently, emerging evidence reveals that TTS can also be triggered by pleasant emotional life events in some patients, hence referring to it as "happy heart" syndrome,[2,3] with under-reported characteristics and prognostic implications. Emotions, both positive and negative, are an inescapable part of everyday life that can negatively affect overall cardiac health. Therefore, it is crucial to highlight the similarities and differences among akin multifaceted cardiac diseases resulting from emotional events, particularly the 2 faces of TTS, to improve their diagnosis and prognosis effectively. Additionally, the awareness of these similarities and differences will provide an avenue for the pathophysiological exploration of TTS, which is key in understanding the underlying disease mechanisms to provide effective treatment, as there are currently no standard treatments for this condition.

In this issue of JACC: Heart Failure, Stiermaier et al[2] present an in-depth description of "happy heart" syndrome's frequency, characteristics, and prognostic implications using retrospective and prospective clinical data of 2017 onwards from the Multicenter GEIST (GErman-Italian-Spanish Takotsubo) Registry. Of 2,482 TTS patients in the registry, 910 (36.7%) had an emotional trigger, with 873 "broken hearts" (95.9%) and 37 "happy hearts" (4.1%). The prevalence of "happy heart" syndrome was 1.5% of all the TTS cases.[2] In summary, the findings from this clinical study support the existing evidence that joyful triggers can also provoke TTS. According to the investigators, the clinical presentation, including chest pain, dyspnea, electrocardiographic changes, and left ventricular ejection fraction, were similar between the 2 faces of TTS. In addition, despite statistically reduced event rates in patients with "happy heart" syndrome, the study found that in-hospital complications such as death, pulmonary edema, cardiogenic shock, or stroke and long-term mortality rates are similar in cases of positive and negative emotional events. The authors concluded that "happy heart" syndrome is a rare type of TTS characterized by a higher prevalence in male patients, with transient wall abnormalities such as atypical and nonapical ballooning features, specifically mid-ventricular ballooning, compared with cases of "broken heart" syndrome (Figure 1). This study is interesting and an excellent starting point for updating the field's current state. The authors should be commended for using such a large clinical registry to provide a comprehensive description of "happy heart" syndrome. Although Ghadri et al[3] reported similar findings from the InterTAK (International Takotsubo) Registry, this current study is the most extensive. It adds to the body of knowledge about "happy heart" syndrome by including systemic data on acute complications and long-term prognosis in patients with "happy heart" syndrome.

Figure 1.

A Schematic Diagram Summarizing the Clinical Similarities and Differences Between "Happy Heart" and "Broken Heart" Syndrome From the Findings of Stiermaier et al2
ECG = electrocardiographic; LV = left ventricular; TTS = takotsubo syndrome.

Ignoring the fact that this is the largest cohort study of patients with "happy heart" condition to date, the sample size was most likely insufficient to guarantee high accuracy. Furthermore, this study excluded the recurrence rates and vital laboratory results from patients, such as catecholamine levels, myonecrosis markers, and natriuretic peptides, which could shed more light on the similarities and differences in the clinical manifestations between these 2 faces of TTS. The investigators explained that the previously mentioned limitations were caused by missing values or unmeasured confounders, the use of different assays by participating centers to determine cardiac biomarker levels, and the significant variations in the length of clinical follow-up between patients and participating centers; hence, these aspects will need to be addressed in future clinical studies to yield more accurate findings.

It is natural to expect parallels between "happy heart" and "broken heart" syndrome as they result in the same clinical condition: TTS. Although "happy heart" syndrome is rare, clinicians should be aware that its occurrence should merit the same clinical attention as "broken heart" syndrome since they share similar prognostic implications, as revealed by Steimer et al.[2] According to the authors, one possible explanation for the rarity of "happy heart" syndrome is that intense positive emotions in life are less common than negative or, more justifiably, because some central modulators are involved in better emotional management of good rather than bad news.[2] Although research suggests that women are more prone to intense negative and positive emotions compared with men,[4] the association of "happy heart" and "broken heart" syndrome with men and post-menopausal women, respectively, may be consistent with the fact that both respond differently to specific emotional stress due to the sex differences in brain structure. However, both share a unique feature: lower estrogen levels, which predispose them to TTS, as studies have demonstrated that estrogen, via its receptors, plays a cardioprotective role under acute emotional stress.[5]

To date, the specific pathophysiological mechanism associated with TTS regarding negative emotions is still a puzzle yet to be solved. But, a growing body of evidence reveals that a brain-heart interaction with sympathetic overdrive and catecholamine excess triggered by acute emotional or physical stress is strongly associated with the pathogenesis of this condition.[1,6] By examining the brain parts that are activated during the experience of specific emotions, researchers have concluded that the amygdala, a roughly almond-shaped mass of gray matter inside each cerebral hemisphere, is associated with the processing of both pleasant and negative emotions. Hence, it is not astonishing to see the implication of positive emotions in TTS. During an acute emotional event, the amygdala's hyperactivity has been linked to a catecholamine surge, and several studies have shown that excess catecholamines play a crucial role in TTS occurrence.[1,6] For instance, in 2008, Akashi et al[6] reported that the histological alterations in the human myocardium during TTS triggered by negative emotions are comparable to those found in catecholamine-induced cardiotoxicity. In the presence of excess catecholamines, the manifestation of nonapical or apical ballooning patterns in TTS patients could be attributed to the disparities in sympathetic innervation of the heart, such as an apical-basal gradient of sympathetic nerve endings, variability of regional ß1/ß2-adrenoceptor distribution, and a switch from the positive inotropic Gαs to the negative inotropic Gαi pathway.[1,2]

Despite the limitations of this current study by Stiermaier et al,[2] there are several novel findings that raise the following critical research questions: Do you believe the pathophysiology of "happy heart" and "broken heart" syndrome may be the same due to their clinical similarities? If this is the case, why then do they exhibit some differences in their clinical manifestations? Thus, the pathophysiological mechanisms of TTS regarding negative and positive emotional triggers remain a mystery. Hence, more research is needed to clarify the questions mentioned in the previous text, which will go a long way to improve the diagnosis and prognosis of TTS in general and illuminate its pathophysiological mechanisms, thereby providing effective treatment strategies.