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. What is new? What are the clinical implications? ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial N/A ### Funding Statement GJO was partly supported by an Australian Postgraduate Scholarship from the University of Adelaide. FJ was supported by a short-term research scholarship from the Faculty of Medicine, University of Adelaide. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Central Adelaide Local Health Network Human Research Ethics Committee I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are available from the corresponding author upon reasonable request.