Williams syndrome: A Translational Approach to Mechanism and Treatment

National Heart, Lung, And Blood Institute

Investigators

Linked publications, trials & patents

Abstract

Patients with elastin insufficiency present with a range of symptoms that may be associated with 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 insufficiency on end organs, 2) investigate the cause of sudden death in this population, and 3) test potential therapies to treat elastin mediated vasculopathy. Impact of elastin insufficiency on end organs: 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. 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, 122 individuals have undergone complete evaluation at the NIH for a total of 271 separate patient visits. Our work to date has led to 4 submitted manuscripts and two in preparation. The previously submitted work includes: 1) an analysis of heart rate variability in people with WSfinding reduced variability for this cohort (see below for additional detail); 2) a study of lung function in this population--elastin also impacts the mechanical function of the lung and adults with WS experience increased air trapping and obstruction, 3) a collaborative study utilizing the NIH tool kit, to study executive function in people with intellectual disability, and 4) a descriptive study looking at ocular findings in people with WS. Of particular note are findings of retinal vascular tortuosity and nanophthalmos, two conditions potentially linked to aspects of the patients vascular disease, but ultimately not shown in 5 individuals with isolated ELN-related SVAS. In addition, two additional manuscripts are in preparation: one demonstrating abnormal diastolic function in people with WS using echocardiographic doppler measures and a second study showing both abnormal diastolic and systolic function in the same cohort using echocardiographic strain imaging. 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. A survey performed by our group in 649 affected individuals and 1872 procedures confirmed the previously reported finding that shows increased risk of negative outcomes with anesthesia in our cohort and bilateral outflow track obstruction in this population. However, this finding does not account for all of the anesthesia risk. 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, or cardiac collapse, both of which we have demonstrated in animal model testing. We are currently repeating previous experiments to confirm results and extending studies into conditionally deleted KATP mice to further test our hypothesis. We anticipate submitting the resulting manuscript at the conclusion of the related experiments. Together with our heart rate variability work, alluded to above, we believe that our findings represent new variables that may impact risk of severe outcomes in people with WS who undergo anesthesia. In particular, HRV provides a means of quantifying autonomic system abnormalities using ambulatory ECG data from human subjects and controls. Similar studies in post-myocardial infarction, stroke, and diabetes mellitus have shown that diminished HRV provides reliable means for risk-stratifying these latter patients, correlating increased morbidity and mortality with diminished HRV. Our data confirms the presence of HRV abnormalities in people with WS using time and frequency domain, as well as non-linear analyses. Each show multiple biomarkers consistent with decreased HRV and decreased parasympathetic activity. Increased sympathetic activity was inferred from increased heart rate. Additional analyses on subjects receiving chronic beta blockade suggest this medication might prove useful to mitigate risk conferred by autonomic abnormalities and a clinical trial might be pursued to test this. These data not only provide an important mechanistic insight into factors contributing sudden death, but also provide a means for risk stratifying patients at risk of sudden death. Therapies for elastin mediated disease: As stated above, individuals with elastin insufficiency have stiff blood vessels with narrow caliber. Previous work by our lab showed that this combination of findings contributed to decreased cerebral perfusion in Eln+/- mice. Previous analyses showed that treatment with minoxidil, at KATP channel opener, normalized blood pressure, reduced apparent stiffness and improved brain perfusion. Once completed, the vascular remodeling remains stable for some time after the drug is removed. Recent investigations focused on the pulmonary vascular tree, an area of particular concern for patients with elastin insufficiency because the disease their tends to affect multiple vessels, leading to challenges for surgical intervention. In our mouse model, vessels are also narrow and pressure is higher. When evaluated by latex injection, we also find that the vascular tree is longer, a finding that continues to increase over time. When treated with minoxidil, the caliber of the vessels improves as does the arterial resistance. However, the increased branching an arcade length remain fixed. Our in-person studies were slowed due to COVID limitations for in-laboratory investigation, but we are currently focusing on efforts to understand the mechanism behind the increase in pulmonary vasculature arcade length and branching.