Takotsubo Cardiomyopathy

Abstract

Takotsubo cardiomyopathy Takotsubo cardiomyopathy occurs worldwide. The condition is thought to be responsible for 2% of all acute coronary syndromes’ cases presenting to hospitals. Although it has generally been considered a self-limiting disease, spontaneously resolving over the course of days to weeks, a subset of patients may present with symptoms arising from its complications, e.g., heart failure, pulmonary oedema, stroke, cardiogenic shock, or cardiac arrest. It occurs more commonly in postmenopausal women.

1. Introduction

Takotsubo syndrome (TTS), also known as stress cardiomyopathy or ‘broken heart syndrome’, has been described for the first time in Japan in 1990. It is an acute cardiac condition characterized by systolic and diastolic left ventricular (LV) dysfunction with apical hypokinesis that is typically transient. Approximately 90% of patients are postmenopausal women with a mean presentation between 62 and 75 years of age. It has been described in medical literature across the globe, spanning virtually every major ethnic group. Historic evidence suggests that patients with TTS have less traditional risk factors for coronary artery disease [1].

2. Pathophysiology

Despite increasing diagnosis and awareness of TTS, the exact mechanism remains unknown. The most accepted etiologic theory of Takotsubo syndrome is one of excess catecholaminergic-induced myocardial stunning. The association between stressful emotional states and development of TTS has been well-documented. Studies have measured the plasma concentration of catecholamines (dopamine, epinephrine, norepinephrine) present in patients with TTS, finding them higher (two to threefold) than both the general population and patients with ACS [2]. The mechanism by which supraphysiologic catecholaminergic state causes myocardial injury is a continued debate. Multivessel coronary artery spasm, cardiac microvascular dysfunction, and direct cardiomyocyte injury are proposed mechanisms [3].

Direct myocyte injury is thought to occur via beta-2 inhibitory effects of G-protein [guanine nucleotide-binding protein] coupled receptors resulting in negative inotropy with resultant LV dysfunction. Normal circulating levels of catecholamines bind to Beta-2 adrenergic receptors of ventricular cardiomyocytes resulting in stimulation of Gs protein-adenylyl cyclase-protein kinase A pathway and thus a positive inotropic effect. The inhibitory effect happens with supraphysiologic levels of catecholamines, though to take place to protect myocytes from apoptosis occurring with strong stimulation of Gs, a phenomenon known as ‘stimulus trafficking’ [4].

The gender disparity in disease presentation remains a point of ambiguity. Men have higher basal levels of sympathetic hormone than women, they produce higher amounts of catecholamines when presented with stressors and have a higher degree of catecholamine-mediated vasoconstriction. Yet, women seem to have a higher susceptibility to adrenergic myocardial stunning as exampled in LV dysfunction after subarachnoid hemorrhage. The cardioprotective effects of estrogen including protection against atherosclerosis and endothelial dysfunction is well known. There is the additional proposed benefit that estrogen downregulates beta-adrenergic receptors. Studies performed on ovariectomized rats subjected to stress demonstrated a higher deleterious cardiovascular response compared to groups provided with estrogen supplementation [5]. The overwhelming majority of patients with TTS are post-menopausal, further correlating that estrogen deficiency may predispose women to developing TTS. This may be the rationale behind the higher mortality of TTS seen in men. Men with TTS have an approximate mortality rate of 4.4%, comparable to the mortality rate of men with ST elevation myocardial infarction treated with primary percutaneous coronary intervention [6].

A hallmark feature of TTS is underlying inflammatory injury and edema of myocardial cells. In TTS, edema is generally diffuse and transmural in nature but worsened in areas with regional wall motion abnormalities and not limited to a vascular territory. Endomyocardial biopsies show mononuclear infiltrates, contraction-band necrosis, and myocardial inflammation-mediated edema.

Recent studies have demonstrated that elevated neutrophil/lymphocyte ratios, inflammatory markers, and even elevated neoplastic markers as a surrogate for systemic inflammation are independent risk factors for increased in-hospital complications, long-term adverse events, and death [7].

3. Diagnosis

The Mayo Clinic diagnostic criteria for stress cardiomyopathy must include all four of the following for diagnosis:

1. Transient LV systolic dysfunction with wall motion abnormalities extending beyond a single epicardial coronary artery distribution. (Excepts include rare focal and global subtypes).

2. Absence of obstructive coronary artery disease (CAD) or angiographic evidence of acute plaque rupture. If CAD is found, diagnosis of stress cardiomyopathy can still be made if the wall motion abnormalities are not in the distribution of the coronary artery.

3. New electrocardiographic abnormalities (ST elevation, ST depression, T wave inversions) or moderate elevation in cardiac troponin.

4. Absence of pheochromocytoma or myocarditis [8]

Presentation often mimics acute coronary syndrome (ACS): chest pain, ST elevations on electrocardiography, and elevated cardiac biomarkers. Diagnostic coronary angiography is typically performed revealing normal or nonobstructive coronary artery disease in the vast majority of patients. It is estimated that approximately 2% of all patients undergoing emergent coronary angiography for presumed ACS have TTS [3]. Though ACS and TTS may share similar features, theorized pathogenesis, management, and prognosis of TTS is unique.

4. Diagnostic modalities

Traditionally, transthoracic echocardiography is one of the first non-invasive diagnostic tools utilized in patients with suspected Takotsubo syndrome. Transthoracic echocardiography depicts LV geometry, LV function and anatomic variants. In recent years, assessing global longitudinal strain (GLS) using speckle-tracking echocardiography, has become a sensitive marker for myocardial dysfunction with increasing prognostic utility (Figure 1). GLS is a simple parameter that expresses longitudinal shortening as a percentage (change in length as a proportion to baseline length) [7]. Not only does strain pattern help differentiate acute TTS from ACS, but it can help identify persistent LV dysfunction even after recovery of ejection fraction (EF) [9].There is an increasing population of patients that have continued abnormal GLS even after complete LVEF recovery. The clinical implications of persistently abnormal GLS with association to recurrence of TTS has yet to be investigated.

Figure 1.

Global longitudinal strain plot on transthoracic echocardiography with ‘evil eye’ pattern seen in Takotsubo syndrome.

Cardiac Magnetic Resonance (CMR) has become an increasingly utilized imaging tool in patients with TTS. Like echocardiography, CMR can visualize wall motion abnormalities and identify areas of LV dysfunction. More significantly, CMR can identify the presence of reversible (edema) and irreversible myocardial damage (scarring). CMR can also identify potential complications of TTS, such as LV outflow tract (LVOT) obstruction, valve disease, pericardial effusion, and LV thrombus. In TTS, the hallmark features of inflammatory injury and edema are visualized on CMR as signal hyperintensity in the T2- weighted sequences. Not only can the extent of edema be quantified with more diagnostic accuracy, CMR has the capability to identify potential areas of irreversibility. To assess for the presence/absence of scarring tissue, short and long axis acquisitions are performed after contrast injection using an inversion-recovery gradient echo sequence to help identify late gadolinium enhancement (LGE) (Figure 2). Though not common in TTS, LGE can identify areas of contraction-band necrosis often seen in endomyocardial biopsies in TTS patients [10].

Figure 2.

Late gadolinium enhancement of apical and lateral wall segments in apical-type Takotsubo syndrome.

Cardiac imaging advances not only assist in monitoring recovery and identifying persistent injury; they can also aid in elucidating pathogenesis of Takotsubo syndrome. Microcirculatory dysfunction as a pathologic mechanism of TTS has been previously underrecognized due to lack of imaging modalities. New studies involving single-photon emission computed tomography perfusion have shown a decrease in tracer uptake during the acute phase of TTS and a return to normal at follow-up, suggesting a role for coronary microvascular dysfunction as a trigger of myocardial ischemia in this condition. Additionally, perfusion CMR has corroborated disruptions in coronary microcirculation in the absence of obstructive epicardial disease in patients with TTS.

5. Treatment

The treatment for Takotsubo syndrome is largely empiric and supportive. Angiotensin-converting enzyme inhibitors (ACE-i), angiotensin II receptor blockers (ARB), and/or beta-blockers are often utilized in stable patients. Beta-blockade initiated in the acute phase of TTS has been associated with a statistically significant higher long-term survival with a greater benefit seen in hypertensive patients or those who developed cardiogenic shock [11]. Neither beta-blockers nor ACE-i/ARB were shown to reduce the recurrence of TTS [12]. There exists a plethora of evidence regarding optimized medical treatment for patients with reduced LV function due to other etiologies. Again, few data exist regarding optimum regimen for patients with TTS.

6. Outcomes

Historically, Takotsubo syndrome was often thought to portend a more benign course with favorable outcomes compared to ACS. More recent, larger-scale analyses are revealing that up to 50% of patients suffer from acute complications and acute mortality rates similar to ACS. In most patients, recovery of LV function can be seen within 1–6 months. The risk factors that influence rate of LV recovery process are unknown. Concerningly, factors that lead to delayed resolution of wall motion abnormalities also remain unknown. The nebulous nature of this disease course has significant clinical implications. Patients without early LV recovery have higher prevalence of in-hospital complications and higher mortality and should be monitored closely. Patients with persistent wall motion abnormalities also require close monitoring with repeat cardiac imaging. Recurrence rates of TTS average between 2 and 10% [12]. A variable TTS pattern at recurrence is common in up to 20% of recurrence cases (see Figure 3 for variant patterns of TTS). Despite these findings, few data exist regarding treatment, long-term prognosis, and risk stratification.

Figure 3.

Variants of Takotsubo cardiomyopathy.

7. Future implications

Though Takotsubo syndrome remains an enigma in many aspects, new capabilities of cardiac imaging are emerging that can assist with clarifying pathogenesis, tracking injury patterns, and preventing recurrence. With the utilization of global longitudinal strain on transthoracic echocardiography, persistent LV dysfunction can be detected even when ejection fraction has recovered, a feature that can potentially be used to identify which patients are at a higher risk of recurrence. CMR affords clinicians the opportunity to identify pathogenic features not previously recognized as large contributors to TTS etiology, ultimately enhancing treatment options. Further studies are being conducted investigating both genetic predispositions and biomarkers to better assess disease course. It is our hope that with each new discovery, we become closer to deciphering the complexities of Takotsubo syndrome.

Conflict of interest

The authors declare no conflict of interest.

Abbreviations

TTS	Takotsubo syndrome
LV	left ventricular
CAD	coronary artery disease
ACS	acute coronary syndrome
ACE-i	Angiotensin-converting enzyme inhibitors
ARB	angiotensin II receptor blockers