Williams syndrome: A Translational Approach to Mechanism and Treatment

National Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

Using a translational approach consisting of animal models and human studies, we have sought to 1) examine the impact of elastin insufficiency on end organs, and 2) investigate the cause of sudden death in this population. Impact of elastin insufficiency on end organs: The effect of elastin insufficiency on 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. 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. To investigate these findings in humans, we developed a human protocol to allow us to broadly evaluate the impact of elastin insufficiency on end organs. To date, 148 individuals have completed evaluation at the NIH. In the last year, we have published two papers in this area. One study, outlining differences in heart rate variability (HRV) in people with WS and another using the NIH tool kit to study executive function in this population. The HRV study showed increased heart rate (both awake and asleep) in people with WS and strong evidence for decreased variability and decreased parasympathetic markers. Taken together, these findings suggest that differences in autonomic responses that may impact health outcomes including sudden death, anxiety, and GI features of the condition. We are following that up with studies of pulse rate variability using wearable devices so that our work can be readily translated to home environments. Work continues in the areas of gastrointestinal outcomes, cardiac dysfunction and strain abnormalities, flow mediated dilation and retinal vascular tortuositywe expect manuscripts in several of these areas in the coming year. Knowledge gained from these studies will impact patients with WBS/SVAS, as 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 tissue perfusion and end organ impact. 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. Sudden death in Williams Beuren syndrome: Individuals with elastin insufficiency are reported to have a 25-100X increased risk of sudden death; this risk is enhanced during anesthesia. We questioned whether features of the heart itself may contribute to sudden death risk in this population. Evaluation of coronaries in both the WBS patients and Eln+/- mouse found increased tortuosity for the vessels and studies designed to recapitulate anesthesia hemodynamic changes in mice resulted in hemodynamic collapse and ventricular fibrillation in study animals but not controls. Further investigation of dissociated Eln+/- mouse and control cardiomyocytes showed: 1. Increased inward calcium current 2. Abnormal calcium current kinetics 3. Diminished potassium currents 4. Prolonged action potential duration (APD) and 5. Early after-depolarizations (EADs) which are a cellular correlate for increased arrhythmia in the Eln+/- mice. We conceptualize a two-hit type mechanism where coronary abnormalities underlie substrate abnormalities and cardiomyocyte abnormalities result in increased trigger formation. Together, these abnormalities give rise to increased arrhythmia, likely ventricular fibrillation (VF), or cardiac collapse, both of which we have demonstrated in animal model testing. Studies this year focused on development of novel imaging modalities to visualize the impact of elastin mediated disease at the capillary level in the heartour finding suggest although elastin insufficiency is expected to be a large vessel disease, small vessel disease is also apparent. Together with our heart rate variability work, we believe that our findings represent a critical sudden death biomarker and mechanistic insight that may be useful for both assessing risk as well as effectiveness of interventions designed to mitigate this risk.