In Vivo Myocardial Microcirculatory Function

我们的建议将一种在猪身上开发的基于CT的微创方法转化为临床研究领域。 这项建议的总体目标是解决临床上检测心肌微循环功能受损的问题，例如在动脉粥样硬化、由于心外膜冠状动脉狭窄或由于某些心肌病的心肌衰竭而出现症状之前。 我们提出的方法的假设是，心肌微循环在这些疾病过程的早期受到影响，可以通过血管舒缩张力的微血管障碍、内皮通透性增加和/或零星的微观心肌灌注缺陷的发展来检测。 我们的方法是通过使用基于FAST-CT的方法(我们实验室使用这些疾病过程的猪模型开发的)来量化这些微血管变化，以证明我们可以检测和量化那些动脉粥样硬化风险因素增加或左心功能受损但没有心外膜冠状动脉疾病临床证据的患者的微血管变化。 目前的拨款建议基本上是一项可行性试验，以确定我们基于CT的方法是否具有在未来临床试验中使用所需的敏感性。这一新方法以我们以前的研究结果为基础，并将这一方法应用于以下几组受试者： 使用电子束CT(但最近使用多层、双源CT)扫描猪模型的心肌内微血管障碍的图像分析进展表明： (A)心肌灌注(F)和心肌内血容量(BV)可以通过静脉注射造影剂来定量； (B)心肌血容量与流量的关系表征了心肌微循环的管道(即小动脉)和交换(即毛细血管)成分； (C)心肌对比剂稀释曲线的延迟洗脱成分提供微循环内皮细胞通透性指数(PS乘积)； (D)微灌注性缺陷(即反映微动脉功能障碍的微动脉灌注区)的大小和数量可以量化； (E)左心功能不全的严重程度与这些灌注缺损区的累积表面积成正比，而不是与非灌注区心肌的累积体积成正比。 因此，我们的具体目标是： 目的：正常受试者(24例)。 目的II无冠脉钙化的高脂血症患者动脉粥样硬化风险增加(24例)。 目的：特发性心肌病但无心外膜冠状动脉狭窄或钙化患者24例。 每组受试者年龄在40-55岁之间，12名绝经前女性和12名年龄范围匹配的男性。所有选定的受试者都将接受冠状动脉钙化扫描(如果尚未临床获得)以及心肌灌注扫描。 这种方法的意义在于，如果基于CT的方法能够识别疾病过程的早期微血管发作，医疗干预更有可能在不可逆转的损害发生之前阻止甚至逆转疾病过程。

Our proposal translates a minimally invasive CT-based approach, developed in pigs, to the clinical research arena. The overall goal of this proposal is to address the clinical problem of detecting impairment of myocardial microcirculatory function, such as occurs in atherosclerosis, prior to symptoms due to narrowing of epicardial coronary arteries or due to myocardial failure in some cardiomyopathies. The hypothesis driving our proposed approach is that the myocardial microcirculation is affected early in these disease processes and can be detected by virtue of development of microvascular disturbances of vasomotor tone, increased endothelial permeability and/or development of scattered microscopic myocardial perfusion defects. Our approach is to quantitate such microvascular changes by the use of a fast-CT-based methodology (developed in our laboratory using pig models of these disease processes) to demonstrate that we can detect and quantitate those microvascular changes in patients who have increased risk factors for atherosclerosis, or have impaired LV function, but without clinical evidence of epicardial coronary artery disease. This current grant proposal is basically a feasibility trial to establish whether our CT-based methodology has the sensitivity needed to be of use in future clinical trials. This new methodology is based on our previous findings and to apply this methodology to these groups of subjects: Image analysis developments using Electron Beam CT (but recently using multislice, dual-source CT) scans of a pig model of various aspects of microvascular disturbance within the myocardium, have shown that: (a) myocardial perfusion (F) and intramyocardial blood volume (Bv) can be quantitated using an intravenous bolus injection of contrast medium; (b) the myocardial blood volume-to-flow relationship characterizes the conduit (i.e., arterioles) and exchange (i.e., capillaries) components of the myocardial microcirculation; (c) the delayed washout components of the myocardial contrast dilution curve provide an index of microcirculatory endothelial permeability (PS product); (d) the size and number of micro-perfusion defects (i.e., arteriolar perfusion territories reflecting the arteriolar dysfunction) can be quantitated and (e) the severity of LV dysfunction is proportional to the cumulative surface area of those perfusion defects more so than to the cumulative volume of non-perfused myocardium. Our Specific Aims are therefore: AIM I Normal subjects (24). AIM II Patients with elevated risk for atherosclerosis due to hyperlipidemia without coronary calcium (24). AIM III Patients with idiopathic cardiomyopathy but no epicardial coronary artery stenosis or calcification (24). Subjects in each group would be 40-55 years old, twelve pre-menopausal women and twelve age-range-matched men. All selected subjects will have a coronary calcium scan (if not already obtained clinically) as well as a myocardial perfusion scan. The Significance of this approach is that if the CT-based method can identify the early microvascular onset of the disease processes, medical intervention is more likely to arrest or even reverse the disease process before irreversible damage occurs.