Understanding the pathophysiology of apical ballooning syndrome: a step closer

Abstract

Although it has been almost 20 years since the first case of Takotsubo cardiomyopathy was described in Japan, its pathophysiology remains an enigma. While several hypotheses have been proposed to explain the pathophysiology, the exact mechanism of the syndrome is unknown. This editorial reviews the literature published on various theories on the pathophysiology of Takotsubo cardiomyopathy.

Keywords:

• apical ballooning syndrome
• pathophysiology
• tako-tsubo cardiomyopathy

Takotsubo cardiomyopathy (TCM) (aka, stress-induced cardiomyopathy, apical ballooning syndrome) is characterized by transient hypokinesis of the left ventricular apex mimicking acute myocardial infarction without angiographic evidence of obstructive coronary artery disease [1]. It is often preceded by significant emotional stress or trauma and has a predilection for postmenopausal women. It usually involves the apex (classic), however, variant forms that include isolated basal (reverse), mid-ventricular, and localized have been identified. The most common presentation is chest pain and less commonly dyspnea, cough and syncope. While there have been several hypotheses regarding pathogenesis, catecholamine-induced cardiotoxicity is perhaps the most widely supported. Here we review the literature and provide commentary on the pathophysiology of TCM.

The catecholamine theory

It has been noted that many patients with TCM have suffered an emotional loss or trauma immediately preceding their diagnosis, thus earning the colloquial name ‘broken heart syndrome’ [1]. In light of this, it has been hypothesized that an excess of catecholamine release precipitated by this stressful event led to left ventricular dysfunction. Several findings help to support this theory. TCM patient has been noted to have 7–34 times higher levels of circulating catecholamines compared to normal values in the days following their diagnosis. [2]. However, there could be reverse causality whereby the TCM caused the elevated catecholamine levels. In support of catecholamines causing the TCM, contraction band necrosis, a hallmark of myocardial catecholamine toxicity, has been seen on myocardial biopsy of TCM patients [3]. More indirectly, a significant number of intensive care unit (ICU) patients develop transient LV dysfunction at the time of peak illness. In one series, nearly 30% of ICU patients admitted with a non-cardiac diagnoses developed left ventricular (LV) dysfunction (average ejection fraction 33%), the majority of which resolved by 7 days [4].

Several proposed mechanisms linking TCM to catecholamine excess are discussed below (Figure 1).

Figure 1. Catecholamine theory.

Stimulus trafficking

The theory of ‘stimulus trafficking’ has shed light on the mechanism behind the catecholamine theory. In essence, high levels of catecholamines are negatively inotropic because β-2 adrenoreceptor mediated Gs protein signaling (positively inotropic) is converted to Gi protein signaling (negatively inotropic). With a greater β adrenoreceptor concentration at the ventricular apex compared to the base, left ventricular dysfunction would be expected to localize to the apical segment as is often seen in this disorder in the classic presentation [5]. The reason behind the disparate apical and basal distribution of these receptors is unclear, and the alternative reverse and mid-ventricular presentations are not explained by this receptor distribution.

Microvascular dysfunction

Given that microvascular dysfunction has been linked to an increase in cardiovascular death, unstable angina, myocardial infarction, and stroke, its role in TCM has been evaluated by several invasive and noninvasive studies [6]. Consistent with the proposed link between them, myocardial contrast echocardiography and myocardial single photon emission computed tomography imaging have demonstrated myocardial perfusion defects indicative of microvascular dysfunction in TCM patients who resolved with reversal of the myopathy [7,8]. The association of TCM with migraines and Raynaud phenomenon further supports the role of vasomotor dysfunction of the endothelium [9]. Further, the presence of abnormal Thrombolysis in Myocardial Infarction frame counts involving multiple coronary vessels on angiography further supports the hypothesis [8]. While LV asynergy localized to the apical region could not be explained by this study, it has subsequently been demonstrated that Thrombolysis in Myocardial Infarction frame counts in TCM patients compared to controls were significantly higher in the left anterior descending (LAD) when compared to other vessels when matched to age, gender, and risk factors, potentially explaining the link between microvascular dysfunction and localization to the apical region [10].

With regards to its link to catecholamines, there is evidence of microvascular hypoperfusion from alterations in erythrocyte and endothelial membranes induced by catecholamine storm, expressed by a marked increase in von willibrand factor and plasminogen activator inhibitor 1 in TCM [11]. Catecholamine induction of TNF-α and IL-6 with its resulting oxidative stress likely plays a role in the development of this microvascular dysfunction. Myocardial edema was demonstrated on cardiac magnetic resonance imaging in TCM patients, and animal studies reported a significant increase in heme oxygenase-1, which is considered a major oxidative marker for atherosclerosis [12].

Left ventricular outflow tract obstruction

A small observational series demonstrated that the presence of a mid-cavity gradient with left ventricular outflow tract (LVOT obstruction) can lead to TCM. After the recovery of wall motion, a similar apical dyskinesis was induced with dobutamine stress-echocardiography with a provoked LV mid-cavity gradient at peak dose, similar to what would be expected in a high catecholamine state [13]. In theory, the development of severe, transient LV mid-cavity obstruction effectively divides the LV into two cavities resulting in increasing wall stress and high pressures in the distal apical chamber. This subsequently can induce widespread ischemia and a pattern of apical ballooning. However, a large cohort published in 2008 showed that only 25% of the patients with TCM have LVOT obstruction, which does not support this hypothesis completely, possibly lending to the conclusion that LVOT obstruction is a consequence rather than a cause of TCM [14].

Mulivessel vasospasm

Multivessel vasospasm has been observed on several occasions in cases of TCM. In a case series, 3 of 30 TCM patients had spontaneous vasospasm on angiography and 43% of patients as a result of provocation with acetylcholine or ergonovine [15]. However, other studies have demonstrated only 10% provocation of vasospasm and the vasospasm did not necessarily correlate with the area of hypokinesis, leading to disagreement in its role in TCM pathogenesis [16]. It is possible that stress-induced release of catecholamines makes coronary arteries more prone to vasospasm, consistent with the provocation of spasm in the above studies. However, the inconsistency in the data calls into question how significant a role this mechanism may have.

Non-catecholamine mechanisms

Aborted MI or plaque rupture

One alternative to the catecholamine theory is the possibility of an aborted MI with spontaneous recanalization, a variant of acute coronary syndrome. It has been hypothesized that plaque rupture occurs in the apical segment of a large wrap-around LAD leading to ischemia and induced wall motion abnormalities. Rapid autolysis of the clot leads to normal coronary anatomy on angiography. However, not all TCM patients have this wrap-around coronary anatomy. Further, there is conflicting intravascular ultrasound data with only one intravascular ultrasound study demonstrating destabilized plaque leading to a transient ischemic occlusion [17]. The majority of studies have shown no arterial lesions, thus refuting the plaque rupture theory [18,19].

Myocardial bridging

Recent evidence suggests that myocardial bridging of the mid LAD is a frequent finding in typical TCM patients as revealed by both conventional coronary angiography and cardiac CT, suggesting a role of myocardial bridging in the pathogenesis of apical ballooning syndrome [20]. The presence of reversible myocardial edema by cardiac magnetic resonance at the apical segments associated with bridging segment of the LAD supports this theory further.

The genetic theory

A genetic link to TCM has been suggested recently with familial cases having been reported, one in two sisters and the other is a mother and daughter [21,22]. Several studies were published in the last decade on polymorphism affecting adrenergic receptors on the myocardial cell membrane which could explain the genetic predisposition of this syndrome. An association between TCM and the fragile X FMR1 mutation which predisposes to early cardiovascular disease has also been noted [23].

The hormonal theory

Approximately 90% of TCM patients are women and post-menopausal. This has led to further interest in the role of hormones in TCM. Reduced estrogen stimulation at the level of the myocyte, as seen during menopause, may contribute to this association. Animal studies have demonstrated a greater reduction in ejection fraction in ovariectomized rats when compared to rats on estrogen replacement [24]. Similarly, a retrospective review of 290 studies revealed that many post-menopausal women who developed TCM were not on hormone replacement therapy [25]. The role of estrogen in pathogenesis is unclear and complex, and although it may partly explain the gender disparity, many of the described findings are simply observational.

Conclusion & perspective

We believe that TCM pathophysiology is not a homogenous process. Even though catecholamine toxicity is the widely accepted theory, in isolation it has limitations and remains quite simplistic. It should be considered an end result of a potential myriad of preceding steps, inciting events, and predisposing factors, only some of which are described above and many of which are likely yet to be described. Although likely playing a large role, not all cases of TCM have preceding stressors or elevated catecholamines, and rarely do patients with pheochromocytoma have TCM, implicating more complicated mechanisms to explain the pathophysiology of this syndrome. The role of genetics and hormones, perhaps in combination with catecholamines excess remains interesting but speculative. Given its growing incidence, either due to increased occurrence or increased recognition, further studies need to be done from a clinical as well as a basic science perspective to better delineate the pathophysiology of this syndrome and provide targets for treatment and prevention.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Notes