Characterization of priMary And sEcondary STress Related takOtsubo: the MAESTRO Pilot Study

Background and rationale Takotsubo syndrome (TTS) is an acute and reversible form of myocardial injury often preceded by a physical or emotional trigger. Although TTS was generally considered a benign disease for its reversible nature, it is now clear that hemodynamic and electrical instability during the acute phase exposes patients to frequent serious adverse in-hospital complications. However, the pathophysiology of TTS is far from being completely understood. Consistent evidence demonstrated that the environmental events experienced by most of these patients and perceived as stressful (both physical or emotional) induce a brain activation and a stress-related response, with increasing bioavailability of local and circulating stress mediators, such as catecholamine and cortisol, which showed to play a major role in the etiology of to the "neurogenic stunning myocardium" responsible for this clinical condition. Recent studies strengthened the hypothesis of an outstanding link between the brain stress response system and heart in TTS patients using neuroimaging approach. The fundamental anatomic structures involved in the stress response are the neocortex, limbic system, reticular formation, brainstem, and spinal cord along with the hypothalamic-pituitary-adrenal axis which finally leads to cortisol secretion. In this regard, substantial structural differences in the neocortex and the limbic network (insula, amygdala, cingulate cortex, and hippocampus), have been shown among TTS patients compared to healthy controls using brain functional magnetic resonance imaging (fMRI), along with a hypoconnectivity of the central brain regions holding a regulatory function of the autonomic and limbic system. Moreover, a recent PET/TC study demonstrated that heightened limbic activity precedes the development of TTS and that patients with the highest activity of the amygdala develop the syndrome earliest, supporting the hypothesis that a neurobiological substrate may predispose them to this clinical syndrome.

Of interest, since TTS has been identified in an increasing number of hospitalized patients, an important clinical heterogeneity emerged among those affected, and clinical characteristics such as physical triggers along with acute neurologic or psychiatric disease, high troponin levels, and low ejection fraction showed to identify a specific category of individuals with TTS at higher risk of mortality and in-hospital complications. Therefore, it is recently emerging that so far two different categories of TTS patients were described, with different clinical features and risk profiles: primary TTS, which mainly affects patients after an emotional stressor, in the absence of epicardial coronary disease, with minor troponin release, slightly reduced and rapidly reversed left ventricular (LV) dysfunction and benign prognosis; the second one of secondary TTS, occurring after a physical stressor, in the presence of epicardial coronary artery disease (CAD), with major troponin release, with more severe or persistent LV dysfunction and associated with worse prognosis. An interesting hypothesis, that remains to be tested, is that only primary TTS might result from reversible left ventricular dysfunction of neurogenic origin through activation of neurons originating in the limbic system which may cause reversible vasoconstriction of coronary microvasculature, while secondary TTS may be due to a direct catecholamine-induced myocardial damage provoked by a physical trigger in patients with concomitant CAD. However, the pathophysiological determinants of primary and secondary TTS respectively have never been investigated so far as well as a different brain-heart axis activation in these two categories of TTS patients has never been demonstrated.

Myocardial dysfunction following a physical stressor has been also described in sepsis-induced cardiomyopathy, a well-known systemic complication of the cytokine storm following the host immune response to infection, which can significantly affect the prognosis of these patients. Both left ventricular systolic dysfunction (LVSD) and LV diastolic dysfunction (LVDD) have been described in the first period of severe septic shock as in secondary TTS, but except for the reversible nature of the myocardial dysfunction, clinical and echocardiographic characteristics (e.g. typical left ventricular kinetic abnormalities, electrocardiographic features, and possible detrimental effects of vasopressors use) seemed to distinguish secondary TTS from sepsis-induced cardiomyopathy, thus suggesting a different host systemic response to the same "stressors" and different pathophysiological mechanisms underlying these clinical conditions.

Biochemical profiles of primary vs. secondary TTS patients are still largely unidentified, and whether a different profile exists associated with these two categories of patients remains unknown. The known mechanisms associated with the development of TTS include elevated levels of circulating plasma catecholamines and their metabolites. TTS has been reported to be characterized by a myocardial macrophage inflammatory infiltrate and an increase in systemic proinflammatory cytokines. Indeed, recent studies reported that patients with acute TTS had elevated levels of the pro-inflammatory cytokines IL-6, IL-8 and CXCL1 in the blood, however, to the best of our knowledge no study before ever investigated the inflammatory burden on primary and secondary TTS.

A pro-inflammatory response is also known as a key pathogenetic mechanism of sepsis-induced cardiomyopathy. Indeed, pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β) and chemokines activated by pathogen-associated molecular patterns (PAMPs) have been implicated in the pathogenesis of the myocardial dysfunction following sepsis, as well as endothelial dysfunction and impaired endothelium-derived NO release which can alter the physiological regulation of blood flow distribution. Of note, in sepsis-induced cardiomyopathy, the altered immune response to pathogens leads to a down-regulation of β-adrenergic receptors, and to the attenuation of the adrenergic response at the cardiomyocyte level, as the opposite of what has been demonstrated in TTS. However, if different biological responses to the same stressors may underly the different clinical features of secondary TTS, sepsis-induced cardiomyopathy, and patients with sepsis/septic shock without myocardial dysfunction have never been investigated so far.