CARDIAC FUNCTION AND PROTECTION IN CARDIOGENIC SHOCK

总体目标是开发药理学和代谢策略， 改善急性缺血性衰竭（致龋性）期间心脏功能 休克），而不增加缺血性损伤，以维持功能， 可以进行血管重建。 致龋性休克的左心室 由严重缺血的大区域（40%）组成， 梗塞的和非收缩的区域，以及 急性超负荷，并经历渐进性收缩衰竭， 全身性低血压 伴有低血压冠状动脉灌注压 降低，并且该非闭塞区域变为中度缺血。 的 局部缺血加速了衰竭，形成"恶性循环"， 死亡率90%。 拟议的研究将制定战略， 维持过度负荷的中度缺血的收缩功能 心肌，其将用作心肌的非闭塞区域的模型。 致龋性休克心室在其已经发展成急性超负荷之后， 进行性缺血和衰竭。 孤立的等容（球囊在 LV）血液灌注的兔心脏制备物将用于模拟 致龋性休克时心肌灌注和负荷情况。 离体心脏将进行左主干结扎 冠状动脉或全球低流量缺血（全球减少50%， 冠状动脉血流）。 将通过测量来评估心脏功能和损伤 收缩和舒张功能，冠状动脉血管运动，磁化 转移，ATP，磷酸肌酸和糖原含量和损失 心肌肌酸激酶活性 研究将在非 肥大的心脏和心脏肥大继发于慢性 心肌梗死，因为龋源性休克经常发生在患者 之前有过梗死和继发性肥大 干预措施将 评估其在逆转或抑制以下方面的疗效 缺血性病理生理学的组成部分：收缩（收缩）减少 功能，舒张功能障碍增加，高能磷酸盐 供应/需求不匹配和冠状血管舒张不足。 目标 将最大化主动收缩张力的产生，同时最小化 任何增加肌丝对钙的敏感性， 无机磷酸盐降低缺血时主动张力的作用。 心脏血管紧张素转换酶及其蛋白的抑制 激酶C系统将被研究作为干预措施，以减少缺血 舒张功能障碍 将增加选定底物的水平 提供测试的假设，超载心肌可能成为 在持续低流量缺血期间底物受限，并试图 改善高能磷酸盐供需不匹配;它们的功效 将通过31-P NMR磁化转移测量ATP 周转 对低血压的内源性冠状动脉舒张反应受损， 血流缺血将用冠状血管扩张剂逆转。 整体 一种假设是心肌缺血的各个组成部分 功能抑制和损伤需要联合纠正。 改善缺血心肌功能可降低高死亡率 致龋性休克率。

The overall goal is to develop pharmacologic and metabolic strategies to improve cardiac function during acute ischemic failure (cariogenic shock), without increasing ischemic injury, to maintain function until revascularization can be done. The left ventricle in cariogenic shock is composed of a large region (40%) which is severely ischemic, infarcting, and non-contractile, and a non-occluded region which is acutely overloaded and undergoes progressive contractile failure leading to systemic hypotension. With hypotension coronary perfusion pressure decreases and this non-occluded region becomes moderately ischemic. The ischemia accelerates the failure creating a "vicious cycle," and a mortality rate 90%. The proposed research will develop strategies to maintain contractile function of over-loaded moderately ischemic myocardium which will serve as a model of the non-occluded region of the cariogenic shock ventricle after it has developed acute overload, progressive ischemia and failure. The isolated isovolumic (balloon in LV) blood perfused rabbit heart preparation will be used to model the myocardial perfusion and loading conditions in cariogenic shock. Isolated hearts will be subjected to either a ligation of the left main coronary artery or to global low flow ischemia (50% decrease in global coronary flow). Cardiac function and injury will be assessed by measures of systolic and diastolic function, coronary vasomotion, magnetization transfer, ATP, creatine phosphate and glycogen contents and loss of myocardial creatine kinase activity. Studies will be done in non- hypertrophied hearts and in hearts with hypertrophy secondary to chronic myocardial infarction since cariogenic shock often occurs in patients with a previous infarct and secondary hypertrophy. Interventions will be assessed for their efficacy in reversing or inhibiting the following components of ischemic pathophysiology: decreased contractile (systolic) function, increased diastolic dysfunction, high energy phosphate supple/demand mismatch, and inadequate coronary vasodilation. The goal will be to maximize active systolic tension generation while minimizing any increase myofilament sensitivity to calcium, and which block inorganic phosphate's effect to decrease active tension during ischemia. Inhibition of cardiac angiotensin converting enzyme and the protein kinase C system will be studied as interventions to reduce ischemic diastolic dysfunction. Increased levels of selected substrates will be provided to test the hypothesis that overloaded myocardium may become substrate limited during sustained low-flow ischemia and to attempt to improve the high energy phosphate supply/demand mismatch; their efficacy will be measured by 31-P NMR magnetization transfer to measure ATP turnover. The impaired intrinsic coronary vasodilator response to low- flow ischemia will be reversed with coronary vasodilator. The overall hypothesis is that the separate components of myocardial ischemic depression of function and injury need to be corrected in combination. Improved function of ischemic myocardium should reduce the high mortality rate of cariogenic shock.