心不全における心筋の興奮収縮連関とカルシウム

The Roles of Calcium and Phosphorus in Cardiovascular Diseases. Excitation-Contraction coupling and intracellular calcium cycling in failing hearts.

　心筋の興奮収縮連関においてカルシウム（Ca2＋）は必要不可欠であり，心筋の収縮・弛緩をつかさどる重要なイオンである。心不全は心筋の収縮・弛緩の障害を基盤とする症候群であり，心筋の興奮収縮連関および心筋細胞内Ca2＋動態の異常が密接に関わっている。つまり，心筋細胞内のCa2＋貯蔵庫である心筋筋小胞体（SR）におけるCa2＋制御蛋白の構造的および機能的変化により，SR内のCa2＋濃度が減少し，細胞内Ca2＋過負荷をきたした結果，心筋障害をきたす。なかでもSR のCa2＋放出チャネルであるリアノジン受容体（RyR2）の機能異常は心不全のみならず不整脈誘発の直接の原因となり，RyR2を安定化させることによる細胞内Ca2＋動態の改善は心不全，不整脈の治療にもつながることが判明しつつある。

　Alterations in Excitation-Contraction coupling have recently been shown to play a crucial role in the pathogenesis of heart failure（HF）. In failing hearts, abnormalities of neurohormonal mechanisms, which were included chronic activation of the sympathetic nervous system or of the renin-angiotensin system result in structural and functional changes in the calcium（Ca2＋）regulatory proteins. These changes include the decreased sarcoplasmic reticulum（SR）load, which could be caused by reduced SR Ca2＋-ATPase（SERCA2A）function and increased SR Ca2＋ leak via cardiac ryanodine receptor（RyR2），a functional defect in L-type Ca2＋ channel and activation of the reversal mode of Na＋/Ca2＋ exchanger. The abnormal regulation of intracellular Ca2＋ affects troponin C binding and actin-myosin cross bridging and modulates post signaling pathway, which in turn contributes to the contractile dysfunction of hearts and hence to the progression of HF. Moreover, diastolic Ca2＋ leak may develop delayed after depolarization and triggered activity as a substrate for lethal arrhythmia and sudden cardiac death. In this review, we focus on the underlying mechanism of defective Ca2＋ regulation in HF and on the possibility of proceeding to clinical application as a new treatment for HF by targeting Ca2＋ regulatory proteins.