In Vivo Myocardial Microcirculatory Function

我们的建议将在猪身上开发的基于CT的微创方法转化为临床研究竞技场。 该提案的总体目标是解决在心外膜冠状动脉狭窄或某些心肌病中的心肌衰竭引起的症状之前检测心肌微循环功能受损的临床问题，例如动脉粥样硬化中发生的心肌微循环功能受损。 驱动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，并且可以通过血管紧张素的微血管紊乱、内皮通透性增加和/或分散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快速CT的方法（在我们的实验室中使用这些疾病过程的猪模型开发）来定量这种微血管变化，以证明我们可以检测和定量动脉粥样硬化风险因素增加或LV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个可行性试验，以确定我们的CT为基础的方法是否具有在未来的临床试验中使用所需的灵敏度。这种新方法是基于我们以前的研究结果，并将这种方法应用于这些受试者群体： 使用心肌内微血管紊乱的各个方面的猪模型的电子束CT（但最近使用多层、双源CT）扫描的图像分析发展已经表明： (a)心肌灌注（F）和心肌内血容量（Bv）可以使用造影剂的静脉内团注来定量; (b)心肌血容量-流量关系表征导管（即，小动脉）和交换（即，毛细血管）心肌微循环的组分; (c)心肌造影剂稀释曲线的延迟洗脱成分提供了微循环内皮渗透性指数（PS产品）; (d)微灌注缺陷的大小和数量（即，反映小动脉功能障碍的小动脉灌注区域）可以被定量， (e)LV功能障碍的严重程度与这些灌注缺陷的累积表面积成比例，比与未灌注心肌的累积体积成比例更大。 因此，我们的具体目标是： AIM I正常受试者（24）。 无冠状动脉钙化的高脂血症导致动脉粥样硬化风险升高的患者（24）。 无心外膜冠状动脉狭窄或钙化的特发性心肌病患者（24）。 每组中的受试者将为40-55岁，12名绝经前女性和12名年龄范围匹配的男性。所有选定的受试者将接受冠状动脉钙扫描（如果尚未在临床上获得）以及心肌灌注扫描。 这种方法的意义在于，如果基于CT的方法可以识别疾病过程的早期微血管发作，则医疗干预更有可能在不可逆损伤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.