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.
This study will test the feasibility of a computed tomography-based method to detect early changes of the heart wall's microcirculation before chest pain, heart attacks, and/or heart failure develop. This method is minimally invasive and has greater potential for treatments to arrest, and perhaps reverse, the disease process than do current treatments directed at diseased large arteries. This new approach should be particularly applicable to people who have a high level of risk factors for developing arterial disease, but do not yet have symptoms.
