DESCRIPTION (provided by applicant): Peripheral arterial disease (PAD) affects about 8 million Americans. The disease is typically caused by atherosclerosis and thus is systemic in nature. PAD's clinical manifestations are caused by stenosing of the major arteries supplying the lower extremities (iliac, femoral and popliteal arteries). The condition has further been recognized as an independent risk factor for future cardiovascular events, in particular myocardial infarction and stroke. The initial test for diagnosing PAD is measurement of the ankle-brachial index (ABI), a simple inexpensive test typically performed in a physician's office. However, while being highly specific, the test's sensitivity is low. Thus, while low ABI is a strong indicator of elevated cardiovascular risk, a normal ABI does not rule out high risk due to the test's high false negative rate. The ABI is therefore of limited utility as a screening tool for the general population. It is well known that more subtle functional deficits precede the build-up of atherosclerotic lesions (which at a later stage cause obstructions or vulnerable plaques that can trigger a vascular event). It would therefore be particularly beneficial, both to the patient and also from a healthcare cost containment point of view, if the onset of the disease could be determined well before it becomes symptomatic, so as to allow for lifestyle changes or preventive drug intervention. Among the early manifestations of PAD is decreased vascular compliance and impaired microvascular reactivity, which has been suggested to provide better prognostic assessment in the general population. Microvascular reactivity is typically evaluated on the basis of a measurement of reactive hyperemic indices by ultrasound, performed in the brachial artery, which, however, is not a common site of PAD. Compliance is often inferred from a measurement of pulse wave velocity (PWV), which is proportional to vessel wall stiffness, and thus is inversely related to compliance. PWV is usually quantified from the time lag of the systolic pressure wave between a location in the carotid artery and a point in the femoral artery using tonometry, an approach that is problematic since the path length the blood travels can only be estimated. Thus, the current approaches have limitations and there is no single modality that allows noninvasive quantification of the various physiological parameters that may predispose a subject to develop PAD and, by association, augment a person's cardiovascular risk in general. We have, in preliminary work in support of this proposal, conceived and reduced to practice, new MRI- based techniques for measuring multiple parameters as part of a single examination, including (1) a measurement of microvascular reactivity based on monitoring the temporal changes in venous oxygen saturation serving as an endogenous label in the femoral artery and vein during reactive hyperemia, (2) a high- speed, ungated, projection-based technique for measuring time-resolved arterial blood flow, (3) a method for deriving aortic pulse-wave velocity and compliance (which accounts for 60-70% of systemic arterial compliance), by combining #2 with an image-based measurement of aortic path length. We hypothesize that the measured parameters vary characteristically with age and degree of peripheral vascular disease. We will evaluate the above hypotheses by addressing the following specific aims: 1. Fully implement, and evaluate, a high-speed projection technique for measurement of time-resolved aortic blood flow in a single heart beat simultaneously in the ascending and descending aorta for quantifying pulse-wave velocity and compliance. 2. Integrate the method of aim #1 with the previously developed oximetric technique for quantifying microvascular reactivity into a single protocol. 3. Apply the protocol of aim #2 to subjects, ages 25-65 years, without significant cardiovascular risk factors, characterized further by ABIe0.9, and subjects in the age range of 46-65 years who have PAD based on ABI<0.9 to address the question whether in healthy subjects (i) the metrics derived with the protocol of aim #2 vary in an age-dependent manner including the hypothesized decrease in overall systemic compliance and decreased microvascular reactivity; (ii) subjects with PAD, age-matched to healthy controls, have lower systemic compliance and microvascular reactivity than their healthy peers. Public Health Relevance: The expected outcome of this research is that the results will provide new insight into the early manifestations of PAD and the age-related changes in micro- and macrovascular competence of the arterial system through an entirely noninvasive procedure. Since the methodology to be used in the proposed project is largely in place the investigators have confidence that the project can be completed within the allotted time frame. Lastly, the project ensures retention of personnel in compliance with the stimulus initiative. There is currently no sensitive noninvasive for diagnosing preclinical peripheral arterial disease (PAD), which affects 8 million Americans. In this project we propose to implement and evaluate a new noninvasive MRI-based method in healthy subjects and patients with PAD to address the hypothesis that the measured parameters vary characteristically with age and degree of peripheral vascular disease.

There is currently no sensitive noninvasive for diagnosing preclinical peripheral arterial disease (PAD), which affects 8 million Americans. In this project we propose to implement and evaluate a new noninvasive MRI-based method in healthy subjects and patients with PAD to address the hypothesis that the measured parameters vary characteristically with age and degree of peripheral vascular disease.