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.

AimsInfiltration of macrophages and apoptosis of vascular smooth muscle cells (VSMCs) promote the development of abdominal aortic aneurysm (AAA). Previously, we demonstrated that global Notch1 deficiency prevents the formation of AAA in a mouse model. Herein, we sought to explore the cell-specific roles of Notch1 in AAA development.Methods and resultsCell-specific Notch1 haploinsufficient mice, generated on Apoe-/- background using Cre-lox technology, were infused with angiotensin II (1000 ng/min/kg) for 28 days. Notch1 haploinsufficiency in myeloid cells (n = 9) prevented the formation of AAA attributed to decreased inflammation. Haploinsufficiency of Notch1 in SMCs (n = 14) per se did not prevent AAA formation, but histoarchitectural traits of AAA including elastin degradation and aortic remodeling, were minimal in SMC-Notch1+/-;Apoe-/- mice compared to Apoe-/- mice (n = 33). Increased immunostaining of the contractile SMC-phenotype markers and concomitant decreased expression of synthetic SMC-phenotype markers were observed in the aortae of SMC-Notch1+/-;Apoe-/- mice. Expression of connective tissue growth factor (CTGF), a matrix-associated protein that modulates the synthetic VSMC phenotype, increased in the abdominal aorta of Apoe-/- mice and in the adventitial region of the abdominal aorta in human AAA. Notch1 haploinsufficiency decreased the expression of Ctgf in the aorta and in vitro cell culture system. In vitro studies on SMCs using the Notch1 intracellular domain (NICD) plasmid, dominant negative mastermind-like (dnMAML), or specific siRNA suggest that Notch1, not Notch3, directly modulates the expression of CTGF.ConclusionsOur data suggest that lack of Notch1 in SMCs limits dilation of the abdominal aorta by maintaining contractile SMC-phenotype and preventing matrix-remodeling.

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This investigation examines the role of heat shock protein (Hsp) 27 and its modulation by curcumin in isoproterenol-induced myocardial ischemic injury in rats. Evidence from hemodynamic functions and oxidative stress parameters were also included in the study. The animals were divided into control, isoproterenol, and curcumin 100, 200, and 400 mg/kg treatment groups. Curcumin was administered orally for 15 days to all the treated groups. On 13th and 14th day, isoproterenol (85 mg/kg, s.c.) was injected to curcumintreated and isoproterenol group. On day 15, hemodynamic parameters were recorded. Thereafter, animals were sacrificed and hearts were kept for biochemical and Western blot analysis. We found dosedependent increase in the expression of Hsp27 with drastic fall at highest dose. Hemodynamically, the lower 2 doses also restored the cardiac function as evident by improved contractile functions, decreased left ventricular end-diastolic pressure, restored arterial pressures, and heart rate. In addition, there was an increase in then level of superoxide dismutase, catalase, reduced glutathione, and decreased production of thiobarbituric acid reactive substances and leakage of cardiac necroenzyme creatine kinase-MB isoenzyme and lactate dehydrogenase in curcumin 100 and 200 mg/kg group as compared with isoproterenol. However, at a dose of 400 mg/kg, there was ineffectual protection against isoproterenol-induced myocardial damage. Our results suggested 200 mg/mg as the most optimum therapeutic dose showing improved cardiac function due to stabilization of cytoskeleton structure which in turn is attributed to Hsp27 expression along with fortified antioxidant defense system.