Effects of metoprolol on epinephrine-induced takotsubo-like left ventricular dysfunction in non-human primates.
Takotsubo cardiomyopathy, alternatively known as stress cardiomyopathy, is an increasingly recognized clinical syndrome characterized by acute reversible apical ventricular dysfunction. To elucidate the mechanism, we tried to make a new model of takotsubo-like cardiomyopathy in non-human primates. Echocardiography revealed that repeated intravenous infusion of epinephrine overdose in cynomolgus monkeys induced takotsubo-like cardiomyopathy, which is characterized by progressive left ventricle and depressed systolic function with severe hypokinesis in apical regions and hyperkinesis in the basal region. Although this cardiac dysfunction almost normalized after a month even without any treatment, metoprolol, a beta-blocker, improved the decreased ejection fraction earlier than in the control. Luxol fast blue staining, which is useful for estimating myocytolysis, showed that increased myocytolysis was observed in the apical ventricle of the epinephrine-infused heart. Metoprolol diminished epinephrine-induced cardiomyocytolysis. To explain the mechanism of takotsubo myopathy and the effect of metoprolol, gene expressions in apical or basal ventricle were compared. Heart failure-related genes, such as brain natriuretic peptide, connective tissue growth factor and osteopontin; calcium signaling-related genes, such as ryanodine receptor 2, sarcoendoplasmic reticulum Ca(2+)-ATPase 2A2 and adenylate cyclase 7; renin-angiotensin system-related genes, such as angiotensinogen, angiotensin II receptor, type 1 and type 2; and mitochondria-related genes, such as peroxisome proliferator-activated receptor-gamma co-activator-1alpha, cytochrome c and transcription factor A mitochondrial, were significantly changed at the apical ventricle rather than at the basal ventricle. The changes of some genes improved with metoprolol treatment. These results indicate that this model is valuable in understanding the pathogenesis of takotsubo cardiomyopathy and the effectivity of beta-blockers.
Izumi
Yasukatsu
Y
Department of Pharmacology, Osaka City University Medical School, Osaka, Japan. izumi@msic.med.osaka-cu.ac.jp
Okatani
Hideaki
H
Shiota
Masayuki
M
Nakao
Takafumi
T
Ise
Ryota
R
Kito
Go
G
Miura
Katsuyuki
K
Iwao
Hiroshi
H
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004837:Epinephrine / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008252:Macaca fascicularis; D008790:Metoprolol / Q000627:therapeutic use*; D054549:Takotsubo Cardiomyopathy / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
D000319:Adrenergic beta-Antagonists; D008790:Metoprolol; D004837:Epinephrine