Zannad Faiez, Radauceanu Anca
Department of Cardiology, Division of Heart Failure, Hypertension and Preventive Cardiolgy, and Centre d'Investigation Clinique CIC INSERM-CHU, University Henri Poincaré, Nancy, France.
Heart Fail Rev. 2005 Jan;10(1):71-8. doi: 10.1007/s10741-005-2351-3.
Collagen is the major extracellular matrix protein in the heart and represents a crucial target for anti-remodeling and cardioprotective therapy. Collagen quantity and quality have been shown to be regulated under various physiological and pathologic conditions. Excessive deposition of collagen, leading to cardiac fibrosis, is a major determinant of cardiac dysfunction and arrhythmogenecity associated with sudden death. Serological markers of collagen turnover were proven as a noninvasive reliable tool for monitoring from a distance cardiac tissue repair and fibrosis, both in experimental and clinical conditions. Some markers of collagen synthesis and degradation were shown to have a prognostic significance in myocardial infarction, cardiomyopathy and heart failure, and were reported as independent predictors of mortality. Aldosterone represents the end-product of the renin angiotensin aldosterone system and may play a role in cardiac collagen deposition independent of its effect on blood pressure. Production of aldosterone is mainly regulated by angiotensin II and is activated in the failing human ventricle in proportion to heart failure severity. Circulating or locally produced aldosterone stimulates fibrillar collagen accumulation in the heart directly via mineralocorticoid receptors or, indirectly, modifying angiotensine II receptors number and/or function. The use of mineralocorticoid receptor antagonists counters collagen deposition, even when used on top of classical RAAS inhibitors, such as ACE inhibitors and angiotensine II receptor blockers. There is now accumulating evidence from experimental and clinical studies showing antifibrotic and cardioprotective effect for aldosterone antagonists, spironolactone and eplerenone. In chronic heart failure and post myocardial infarction patients, aldosterone receptor blockade benefit was associated with decreased serum levels of collagen synthesis marker PIIINP (procollagen type III amino-terminal peptide), without affecting collagen degradation. Understanding various autocrine/paracrine mechanisms involved in extracellular matrix remodeling in heart failure represents a major challenge, essential for developing new cardioreparative and cardioprotective strategies.
胶原蛋白是心脏主要的细胞外基质蛋白，是抗重塑和心脏保护治疗的关键靶点。研究表明，在各种生理和病理条件下，胶原蛋白的数量和质量都会受到调控。胶原蛋白过度沉积会导致心脏纤维化，这是心脏功能障碍和与猝死相关的心律失常的主要决定因素。在实验和临床条件下，胶原蛋白周转的血清学标志物已被证明是一种用于远距离监测心脏组织修复和纤维化的非侵入性可靠工具。一些胶原蛋白合成和降解的标志物在心肌梗死、心肌病和心力衰竭中具有预后意义，并被报道为死亡率的独立预测因子。醛固酮是肾素-血管紧张素-醛固酮系统的终产物，可能在心脏胶原蛋白沉积中发挥作用，而与其对血压的影响无关。醛固酮的产生主要受血管紧张素II调节，并在衰竭的人体心室中随着心力衰竭严重程度的增加而被激活。循环或局部产生的醛固酮通过盐皮质激素受体直接刺激心脏中纤维状胶原蛋白的积累，或间接改变血管紧张素II受体的数量和/或功能。即使在使用经典的肾素-血管紧张素-醛固酮系统抑制剂（如ACE抑制剂和血管紧张素II受体阻滞剂）的基础上，使用盐皮质激素受体拮抗剂也能对抗胶原蛋白沉积。目前，实验和临床研究积累的证据表明，醛固酮拮抗剂螺内酯和依普利酮具有抗纤维化和心脏保护作用。在慢性心力衰竭和心肌梗死后患者中，醛固酮受体阻断的益处与血清胶原蛋白合成标志物PIIINP（III型前胶原氨基末端肽）水平降低有关，而不影响胶原蛋白降解。了解心力衰竭中细胞外基质重塑所涉及的各种自分泌/旁分泌机制是一项重大挑战，这对于开发新的心脏修复和心脏保护策略至关重要。
