**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 *supra*physiologic 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].
