たこつぼ心筋症と,そのモデル動物を用いた実験的解析  [in Japanese] Takotsubo Cardiomyopathy and Experimental Analysis using an Animal Model  [in Japanese]

たこつぼ心筋症は,"たこつぼ"状に心尖部の収縮不全を呈する急性心疾患であり,高齢女性が強い情動的ストレスを受けた際に発症する.症状は急性心筋梗塞に似ているが,冠動脈造影では異常を認めない.突然死を起こすこともあるが,多くの症例では数週間で回復する.血中カテコラミンの増加と心収縮不全を起こす.ラットの不動化ストレス負荷によって,たこつぼ心筋症に特徴的な心電図変化,左心室の収縮不全が再現でき,αβ遮断薬の前投与で完全に抑制でき,エストロゲンの投与によりこの収縮不全が抑制できる.エストロゲン受容体は脳でも発現し,中枢神経機能,自律神経機能を修飾している.エストロゲンの投与により外側中隔核,扁桃体内側核,視床下部室傍核,視床下部背内側核,外側中脳水道周囲灰白質,外側背側被蓋核,青斑核でストレス負荷によるc-Fos発現が抑制された.これら領域は,交感神経の高次中枢領域と重なり,エストロゲン受容体陽性神経細胞が存在した.またエストロゲンの投与により,副腎,左心室でのc-Fos発現も抑制された.これはエストロゲン補充により,辺縁系→視床下部→副腎→心臓の各レベルでストレス応答が低下することを示唆している.一方,エストロゲンの投与により,心臓でのANP,HSP70の発現は増加した.これらの結果は,閉経によるエストロゲンの低下が,神経系への間接的作用,心臓への直接作用により,たこつぼ心筋症発症の要因になることを示唆している.

The term, takotsubo cardiomyopathy, refers to a relatively recently described form of acute, reversible cardiomyopathy, in which apical akinesia gives the heart the shape of a takotsubo, a Japanese fishing pot for trapping octopus. Takotsubo cardiomyopathy seems to occur mainly in elderly women soon after exposure to severe emotional distress. Symptoms mimic acute myocardial infarction; however, coronary angiography fails to demonstrate coronary occlusion. The condition can trigger sudden cardiac failure or death, yet in survivors cardiac function typically normalizes within a few weeks. Takotsubo cardiomyopathy features remarkably elevated plasma catecholamine levels and depressed cardiac contractile function. Immobilization stress (IMO) of rats can reproduce the ECG and LVG changes that occur in takotsubo cardiomyopathy, both of which are prevented by combined blockade of α- and β-adrenoceptors. Increase of serum estrogen partially attenuates these cardiac changes. Estrogen receptors are expressed in the brain, where estrogen modulates central nervous function and autonomic nervous function. Estrogen attenuated the IMO stress-induced c-Fos expression in the lateral septum, medial amygdaloid nucleus, paraventricular hypothalamic nucleus, dorsomedial hypothalamic nucleus, laterodorsal tegmental nucleus and locus coeruleus; these same regions contain central sympathetic neurons and neurons with immunoreactive estrogen receptors. It also down-regulated c-fos mRNA expression in the adrenal gland and the heart, suggesting an increase of estrogen attenuated the stress-induced hypothalamo-sympathoadrenal outflow from the central nervous system to the target organs. Estrogen treatment also up-regulated the levels of cardio-protective substances such as ANP and HSP70 in the heart. These data suggest that reduction of estrogen levels following menopause might be involved in the primary cause of takotsubo cardiomyopathy both by indirect action on the nervous system and by direct action on the heart.