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. Studies are ongoing in human patients with elastin insufficiency to determine whether they also possess impaired intracranial blood flow. Such knowledge will impact patient care as it will be important to balance a drug's impact on blood pressure and arterial stiffness to its impact on blood flow. Future work will also investigate the long term impact of elastin arteriopathy on end organ function with increasing age. 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 covering 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 can be accounted for by acute hypoperfusion and ischemia. A manuscript reporting this data is in preparation. 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 (coronaries and more distal pulmonary branches) as well as collaboration with imagers in the DIR to optimize human imaging protocols for this population. Combined with our developing understanding of the pathophysiology of elastic fiber disease, we expect work in this area to identify features that predispose to acute life threatening events so that risk quantification can be optimized and appropriate interventions in and out of the or can be established. 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 and increases elastin in the extracellular matrix leading to lower blood pressure, increased luminal diameter, and increased arterial flow. A manuscript containing this data is under development. Subsequent investigation will center on using minoxidil in patients with elastic fiber disease and in understanding the mechanism by which KATP channel openers lead to long term arterial remodeling and elastin deposition. Finally, because risk of arterial stenosis had previously been linked to early hypercalcemia in elastin insufficiency patients, we investigated the rate of hypercalcemia in the Williams syndrome (elastin deletion) population. We found that affected individuals have higher calcium levels than controls at all time points but that only 6% of individuals had medically actionable hypercalcemia. That hypercalcemia however was not associated with the presence of stenosis. It was inversely correlated in real time, however, with QTc interval suggesting the need for telemetry monitoring individuals with WS and acute actionable hypercalcemia. The manuscript describing this data was recently published in the Journal of Pediatrics.
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