Functional and Histological Assessment of an Experimental Model of Takotsubo's Cardiomyopathy

Abstract

BackgroundOur objectives were to characterize functional and structural features of an experimental model of Takotsubo cardiomyopathy, and its response to beta‐blockers.Methods and ResultsIn protocol 1, a dose‐finding study: 69 rats received various doses of isoproterenol (ISO) and echocardiographic and histologic parameters were measured on days 2 to 3 or day 8. There were no dose‐dependent effects and, out of 69 ISO‐treated rats, 40 (58.0%) survived and 29 (42.0%) died within 24 hours. Of survivors, 30 had apical akinesis averaging 12.1±1.6% of the long axis LV circumference. Out of the 40 survivors, 32.5% showed apical akinesis ≥10%, 42.5% showed akinesis<10% and 25% showed no apical akinesis. The basal portion of the LV was always preserved. At 24 hours, histology and ultrastructure showed necrosis, vacuolization, lipid droplets, mononuclear cell infiltration, damaged mitochondria, and edema. On day 8, apical akinesis fully resolved but histologic abnormalities were still present. In protocol 2, rats were randomized to Control; ISO100 mg/kg; propranolol+ISO; and metoprolol+ISO groups. Pretreatment with propranolol and metoprolol improved survival to 90% and 100% respectively, compared with 60% in the ISO group, but did not reduce the incidence and extent of akinesis or the structural damage.ConclusionTC can be mimicked in a rat model of ISO exposure that demonstrates apical akinesis on days 2 to 3 with full recovery of systolic regional wall motion abnormality despite the presence of persistent foci of necrosis and fibrosis on day 8. Pretreatment with beta‐blockers improved survival but did not affect structural and functional alterations.

Acute Catecholamine Exposure Causes Reversible Myocyte Injury Without Cardiac Regeneration

“…EBD uptake is further associated with loss of membrane integrity and loss of mitochondrial membrane potential 33, 34 . Myocardial necrosis after ISO administration has been reported in several animal models 5, 10, 23, 24, 35, 36 , but we did not find global functional defects or cardiac fibrosis. Therefore, we questioned if EBD + myocytes were indeed all destined for necrosis.…”

“…In an earlier 2007 study in rats, Ellison et al 23 reported that a single subcutaneous ISO (5mg/kg) injection induced acute LV failure at 1 day with full recovery by 6 days. Sachdeva et al 24 described a “takotsubo-like” cardiomyopathy in rats after a single subcutaneous injection that used a 20-fold higher concentration than used by Ellison et al 23 . In mice, Shao et al 25 demonstrated LV systolic dysfunction 1 day after intraperitoneal injection of 400 mg/kg ISO.…”

“…It seems clear that chronic ISO administration can induce myocardial injury with subsequent functional impairment, myocardial necrosis, fibrosis, and hypertrophy in rats and cats 5, 24, 28-30 . Studies in mice have shown that serial subcutaneous ISO administration induces hypertrophy, diastolic dysfunction and increased myocardial fibrosis, but does not affect systolic function 26, 27 .…”

An Endomyocardial Biopsy of the Left Ventricle in an Anorexia Nervosa Patient with Sinus Bradycardia and Left Ventricular Systolic Dysfunction

“…Specifically, this case study indicated a decline in the apex LV wall motion that mimics Takotsubo cardiomyopathy. Sachdeva et al showed that an experimental model of Takotsubo cardiomyopathy presents persistent foci of necrosis and fibrosis [4]. Izgi et al reported myocardial edema as one of the characteristic features in the pathogenesis of Takotsubo syndrome [5].…”

Takotsubo Syndrome Therapy: Current Status and Future Directions

“…These findings have also been observed in the animal models of TTS where histological abnormalities persist despite normalization of the LV ejection fraction. 52 Furthermore, there is a clear association between the ongoing symptoms in patients with TTS at 3 months and chemical and imaging myocardial abnormalities. 24 At the moment, there is no evidence-based therapy for chronic management of patients with TTS.…”