The Vascular Basis of Takotsubo Syndrome

Takotsubo Syndrome (TTS) is an unmet medical need as there is no "standard of care" with an in-hospital mortality rate equivalent to patients with an acute myocardial infarction. Characteristic of TTS is systolic ballooning of the left ventricular (LV) apex, simultaneous with contraction of the base. The mechanism(s) underlying this disassociation of mechanical activities in the LV is(are) unknown, however, a murine model may provide insights into this clinical conundrum. Previously, we found that mice null for Kv1.5 channels (KO), a model of inadequate coronary metabolic dilation, exhibit TTS (KOTTC) when stressed by transaortic constriction (TAC). Because of the microvascular link to inadequate dilation, we hypothesized that coronary vessels in the base and the apex of the left ventricle have different phenotypes as shown by variations in gene expression. To address this, we dissected small coronary arteries from the LV apex and base of KO control mice (KOC) and following TAC when the mice exhibited profound TTS. Ventricular function (fractional shortening [FS]) was calculated from echocardiographic (Echo) imaging. The Echo measurements revealed FS of 39±3% and 34±6% in LV base and apex, respectively, in KOC (P=NS). In contrast, FS was significantly changed in KOTTC with FS of -9±4% in LV apex and 25±11% in the base (P<0.05, with the negative FS representing systolic ballooning). After the Echo measurements, hearts were removed, placed in a chilled dish, and vessels immediately isolated from the LV apex and base (using a dissecting microscope) were placed in Trizol and flash frozen. Total RNA was extracted and used for RNAseq to profile the transcriptomes of small arteries from the apex and base of KOC and KOTTC groups. RNAseq revealed expression of 197 genes significantly changed in the LV apex versus base of KOTTC mice (P<0.05). The 197 genes represented 24 distinct pathways with some of the most significant comprising neuroactive-receptor ligand interactions, miRs in cancer, and complement and coagulation cascades. The endothelin pathway was significantly upregulated in small arteries of the LV apex compared to base in KOTTC. Moreover, 460 genes were differentially expressed between the apex of KOTTC versus KOC (P<0.05) representing 37 pathways, including miR's in cancer and cytokine signaling. The changes in miR expression in cancer may also denote changes associated with cell differentiation and apoptosis. These changes support our concept that regional, apex vs base, differences in vascular gene expression may underlie the basis of Takotsubo Syndrome.