Stress cardiomyopathies beyond Takotsubo: does a common catecholaminergic pathophysiology fit all?

Abstract

Diagnostic criteria for Takotsubo cardiomyopathy (TTC) still remains a matter of debate. The similarities between cardiac dysfunction which complicates cerebrovascular events and ‘typical’ TTC let us hypothesize that the current diagnostic criteria of TTC need to be widened. Moreover, clinical, histological and scintigraphic similarities have been robustly reported between TTC and other Takotsubo-like syndromes, and we agree that central to this unifying hypothesis is a catecholamine surge which triggers the abnormality in left ventricular contraction. Given these overlapping features, we propose that the terms ‘acute ballooning cardiomyopathy’ or ‘catecholamine-induced stress cardiomyopathy’ could be used to refer to these conditions in the future.

Keywords::

• acute coronary syndromes
• apical ballooning syndrome
• catecholamines
• cerebrovascular events
• Takotsubo cardiomyopathy

Takotsubo cardiomyopathy (TTC) is an increasingly reported acute cardiac syndrome, precipitated by intense emotional stress occurring predominantly in postmenopausal women. Definitely accepted diagnostic criteria for TTC are not available and the general consensus is that early coronary angiography is mandatory, since the main differential diagnosis is unstable coronary artery disease (CAD). Acute brain injury was initially considered an exclusion criterion from the mainstay of TTC; yet, the features of left ventricular (LV) dysfunction complicating subarachnoid hemorrhage (SAH) have dropped several hints of discussion about the similarities with the ‘typical’ TTC [1].

A great body of literature about the cardiac complications of SAH actually exists. Evolving ECG changes, apparently consistent with myocardial ischemia, were classically reported several decades ago; however, autopsy-based studies showed that SAH-related ECG changes did not correlate with CAD or with gross myocardial damage. Release of cardiac biomarkers consistent with such damage and reversible LV wall motion abnormalities were later reported in patients with both cerebrovascular events and other forms of brain injury. Coronary angiography in SAH patients, however, constantly demonstrated that LV dysfunction usually occurs in the absence of CAD [2]. Despite this phenomenon, known as neurogenic stunned myocardium [2], being reported in about half of SAH patients [3], the pathogenesis had remained controversial. Nonetheless, more recent experimental data [4] indicate that SAH results in catecholamine-mediated cardiotoxicity and clinical [3] and genetic [5] human studies have suggested that such cardiac dysfunction is due to a catecholamine surge.

Accordingly, cardiac dysfunction after SAH can be considered a catecholamine-mediated event. Briefly, SAH-related damage to discrete sites within cerebral cortex, hypothalamus and brainstem promotes a neuroendocrine and autonomic disequilibrium that leads, in turn, to cardiac dysfunction [6]. Not differently than in TTC, in neurogenic stunned myocardium after SAH, the LV dysfunctional region frequently centers around the apex and the wall motion normalizes within few weeks [2]. Isolated TTC generally carries a favorable prognosis, whereas increased morbidity has been reported when SAH is complicated by transient cardiac dysfunction; in such cases, neurological damage is the key factor in determining the outcome [3]. In general, the substantial clinical differences between TTC and Takotsubo-like syndromes complicating neurological disorders are, in the latter cases, the need of additional care and a more unfavorable outcome related to the severe underlying extracardiac conditions [7].

Even the pathophysiological debate about mechanisms leading to TTC is still open. Intravascular imaging offers an extraordinary contribution to rule out unstable CAD. Sustained multivessel coronary spasm is generally considered an uncommon finding [8], although we have recently demonstrated that extreme spasticity elicited at the level of myocardial bridging and involving a territory beyond a single coronary branch may subtend the Takotsubo-shaped dysfunction of the left ventricle [9]. Coronary microvascular dysfunction is invariably present [10], although it remains not totally understood whether such impairment is the cause or an epiphenomenon of myocardial contractile dysfunction. A combination of both myocardial and coronary vascular responses to excessive catecholamine release associated with emotional or physical stress and the consequent direct myocyte injury have been advocated as the most plausible pathophysiological mechanisms [11,12].

This theory was initially supported by the association of TTC with excessive catecholamine release, as in the endocrine crisis of pheochromocytoma. In addition, data from nuclear medicine studies demonstrate that all stress-induced cardiomyopathies share specific scintigraphic features: indeed, the association of severe ¹²³I-metaiodobenzylguanidine and ¹⁸FDG defects contrasting with normal ^99mTc-tetrofosmin perfusion has been reported in a large variety of clinical settings, including the classical stress-induced TTC, catecholamine stunning because of epinephrine treatment or overdosing, trauma, acute medical or surgical illness including shock, intracranial bleeding, and ultimately, pheochromocytoma [13].

There is an ongoing controversy about whether transient LV dysfunction syndromes associated with these catecholamine excess states, both endogenous and exogenous, should be considered or not a form of TTC. The Japanese authors exclude the possibility of diagnosing TTC in the presence of cerebrovascular disease or pheochromocytoma [14], thus keeping the stressing trigger, either emotional or physical, as the mainstay of TTC, and naming other conditions as Takotsubo-like syndrome. At the time of the formulation of their diagnostic criteria, the Mayo Clinic authors as well suggested to rule out TTC in those patients with head trauma or intracranial bleeding, mainly because the distribution of wall-motion abnormalities in consecutive patients with different forms of brain injury varied significantly in the literature.

The updated Mayo Clinic criteria [15], on the contrary, do not rule out intracranial bleeding as a potential cause of TTC: the most common example of this condition is cardiac dysfunction associated with SAH [1]. In addition, the coeval review by the same authors [16] underlined common pathophysiological mechanisms in all forms of stress cardiomyopathies, consistently with our own clinical experience [17].

After the preliminary reports of TTC in the Japanese population, new variants of ventricular ballooning have been described: the ballooning may spare the cardiac apex and affect different segments of the left ventricle and the right ventricle as well. Actually, the ‘typical’ apical wall motion abnormality is seen in about two-thirds of the patients [18]. Therefore, we suggest that TTC should no longer be regarded as an exclusively ‘apical’ disease. Rather, it should be identified as a transient syndrome of cardiac dysfunction with a wall motion abnormality consisting of a ventricular ballooning that peculiarly extends beyond the distribution of a single epicardial coronary artery. Importantly, the term Takotsubo would be then used misleadingly, since the LV shape in systole would not necessarily look like the typical Japanese octopus-trapping pot.

In light of the experimental [4], clinical [19] and histological [20] similarities and, especially, of the reversibility [2], it seems reasonable to consider SAH, due to its inherent catecholamines surge, as one of the possible stressors that typically precipitates TTC and, in turn, to consider TTC merely as one of the possible manifestations of the neurogenic stunned myocardium. Moreover, all forms of reversible cardiac dysfunction mediated by the CNS and triggered by acute brain injury, both physical, like intracranial bleeding or head traumas, and psychical, like sudden emotional stress (even if due to a concurrent medical condition) had to be summarized into a unifying definition. Such definition should include both specific features and pathophysiologic issues that, to the best of our knowledge, are still unresolved, such as the prevalence in postmenopausal women, the spatial distribution of β-adrenergic receptors and the potential involvement of microvascular dysfunction [1].

Cardiologists should always consider stress cardiomyopathy in the differential diagnosis of ECG changes and troponin leaks in patients with intracranial bleeding. Importantly, it seems unnecessary to refer a patient with acute cerebrovascular events for urgent coronary angiography, provided that the intracranial event is the only precipitating ‘stressor’. Yet, unstable CAD must be ruled out because of its different management and prognostic implications. Making this differential diagnosis, especially outside the cardiologists’ environment, would benefit all physicians for a more suitable clinical approach to patients with multidisciplinary problems. A pragmatic implication, moreover, is that LV systolic dysfunction is common in potential cardiac allograft donors and the reversibility of such process is poorly recognized. A sense of security that LV function will return to normal, at least in case of SAH, may be key to expanding a pitifully insufficient organ donor pool. Therefore, it is appropriate to propose an early echocardiographic evaluation in all patients with acute cerebrovascular events for the appropriate risk stratification and the adequate hemodynamic management. Yet, first of all, increased awareness of this intriguing clinical entity is mandatory.

Besides the matter of definitions, clinical histological and scintigraphic similarities have been robustly reported between TTC and other Takotsubo-like syndromes, and we agree that central to this unifying hypothesis is the catecholamine surge that triggers the abnormality in LV contraction. Given these points of pathophysiological similarity, we propose that the terms acute ballooning cardiomyopathy [1] or catecholamine-induced stress cardiomyopathy could be used in the future to refer to these conditions.

Financial & competing interests disclosure

The authors are institutionally funded by the University of Messina. The authors have no other 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 apart from those disclosed.

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