Pivotal role of early coronary microvascular dysfunction in Takotsubo Syndrome

Background Takotsubo Syndrome (TTS) generally presents like a form of acute coronary syndrome, with variable extents of coronary flow retardation and concomitant release of markers from damaged endothelial glycocalyx (eGC). Whilst systemic hypotension often develops early, there is also rapid emergence and slow resolution of left ventricular (LV) dysfunction. It remains uncertain whether these hypotensive and LV functional complications reflect severity of early coronary vasculitis. Methods 284 patients admitted to 3 South Australian hospitals from May 2008 to May 2021 with a diagnosis of TTS were evaluated. Coronary flow velocity was measured using the corrected TIMI frame count. Putative correlations between extent of acute coronary flow retardation and that of acute impairment of LV systolic function, as measured on global longitudinal strain (GLS: primary hypothesis), were determined. Other parameters of acute disturbance of homeostasis, including extent of eGC shedding and of myocardial edema, and residual impairment in GLS and quality of life at 3-months’ follow-up, were correlated with extent of flow retardation. We also evaluated correlates of extent of acute systemic hypotension. Results were analysed via univariate followed by multivariate analyses. Results The patients studied exhibited mild coronary flow retardation relative to previously described norms at early angiography. On univariate analyses, corrected TIMI frame count correlated with extent of acute impairment of GLS (r=0.31, p=0.003) and this association persisted on backwards stepwise multiple logistic regression (β=0.52, p=0.03). Flow retardation also correlated with preservation of renal function (β=0.50, p=0.02), but tended to vary inversely with C-reactive protein (CRP) concentrations (β=-0.44, p=0.06). There were no significant associations between acute TIMI frame count and other acute or 3-months’ parameters. Neither TIMI frame count nor acute GLS predicted minimal systolic blood pressure. Conclusions The data demonstrated a strong association between extent of early coronary flow reduction in TTS and that of LV functional impairment, thus establishing some commonality of causation of the coronary and acute myocardial manifestations of TTS. However, neither extent of coronary vasculitis nor that of acute LV systolic dysfunction predict acute hypotensive changes in TTS. Clinical Perspective What is new? We have shown for the first time, that the extent of acute coronary flow retardation in Takotsubo Syndrome (TTS) predicts that of early impairment in left ventricular (LV) systolic function. However, severity of acute hypotension is independent of both coronary flow reduction and LV functional impairment. What are the clinical implications? These results confirm that the initial pathophysiology of TTS is that of coronary vasculitis, and that the severity of this vasculitis predicts the extent of LV dysfunction. Therefore, future therapeutic investigations in TTS should focus on early intervention to limit coronary vasculitis. Hypotension/shock in acute TTS appear to have little to do with extents of acute coronary vasculitis or of LV systolic dysfunction, and therefore theoretically, neither coronary vasodilatation nor positive inotropic therapy is likely to ameliorate this problem.