Patients with elastin insufficiency describe a range of symptoms that can be ascribed to their arteriopathy: dyspnea, chest pain, headache, cognitive changes, hypertension and abdominal pain. In order to produce a viable treatment for this condition, its pathophysiology must be understood. Using a translational approach consisting of animal models and human studies, we have sought to 1) examine the impact of elastin arteriopathy on end organs, 2) investigate the cause of sudden death in this population, and 3) test potential therapies to treat elastin mediated vasculopathy. The effect of elastin insufficiency on large conducting vessels has been well described, consisting of reduced elastin content and a reciprocal increase in arterial smooth muscle cell number. This change in the cell to matrix ratio produces vessels with narrow luminal diameter and thickened, poorly compliant walls. Work to date has shown that mice and humans with decreased elastin have increased resting blood pressure, higher pulse wave velocity (a marker for arterial stiffness) and reduced blood flow through the major conducting arteries. Subsequent investigation in Eln+/- mice using blood flow imaging has shown globally reduced brain perfusion relative to wild types. Recently, we opened a new protocol at the NIH clinical center which allows us to evaluate blood flow to multiple end organs in patients with elastin insufficiency. To date, 55 individuals have undergone evaluation. Knowledge gained from this study will impact patients with WBS/SVAS, it will be important as we consider potential new therapies to balance a drugs impact on blood pressure and arterial stiffness to its impact on blood flow. It will also have an impact for understanding the changes to blood flow that occur with normal aging, a process that involves gradual loss of elastin over the lifetime. Information gained to date confirms increased vascular stiffness in patients with both WS and SVAS as well as new findings related to cardiac function, end organ blood flow and arterial reactivity. Individuals with elastin insufficiency are reported to have a 25-100X increased risk of sudden death. A recent study of anesthesia use in 649 affected individuals and 1872 procedures showed a need for CPR in 2.1% of cases. Of those, 97.5% reported the presence of supravalvar aortic or pulmonary stenosis and 75% of events were associated with a cardiovascular surgery or imaging procedure, suggesting more severe cardiovascular disease. However, the precise cardiovascular features that predict disease are unknown, making risk stratification difficult. Moreover, 47.5% of these events were found to occur in the hours to days after the surgery rather than during the procedure itself, suggesting a more complex relationship between elastin insufficiency and sudden death than a simple case of acute hypoperfusion and ischemia. Current work by our group includes in vivo and ex vivo animal work to quantify changes to arterial beds not easily imaged in human clinical studies. MicroCT studies of Eln+/- mouse hearts revealed abnormal branching patterns and tortuosity to the coronaries with electrical studies showing abnormal currents, while electrophysiology studies have clarified the precise current changes and mechanisms by which elastin insufficiency produces these phenotypes. Taken together, our work suggests a mechanism by which at risk tissue may be become hypoperfused at times of rapid drops in systemic vascular resistance, such as in induction of anesthesia. Elastin is deposited in the extracellular matrix of developing vessels in late pregnancy and early neonatal life and attempts to increase elastin deposition outside of this period have been largely unsuccessful. Previous work by our group showed that individuals with elastin insufficiency have increased pulse wave velocity, a finding that is mitigated by treatment with anti-hypertensive medications. These same medications, however, by reducing the distending pressure of the vessel, lead to a further reduction in arterial diameter and lower blood flow. Consequently, our more recent studies have focused on a KATP channel opener, minoxidil. In animal models, this drug remodels large arteries (aorta, carotid, and pulmonary arteries) as well as smaller ones (coronary). RNAseq analysis shows that the drug works initially by inducing vasodilation that, when persistent, leads to matrix remodeling. Once completed, the vascular remodeling remains stable for some time after the drug is removed. The end result is lower blood pressure, increased luminal diameter, and increased arterial flow. A manuscript containing this data was published this year. Subsequent investigation focusing on the pulmonary vasculature is underway as well as assessment of endpoints in our baseline population to be used in clinical trials.
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