Mechanisms of premature vascular aging in children with Hutchinson-Gilford progeria syndrome

Abstract

Hutchinson-Gilford progeria syndrome is a rare, segmental premature aging syndrome of accelerated atherosclerosis and early death from myocardial infarction or stroke. This study sought to establish comprehensive characterization of the fatal vasculopathy in Hutchinson-Gilford progeria syndrome and its relevance to normal aging. We performed cardiovascular assessments at a single clinical site on the largest prospectively studied cohort to date. Carotid-femoral pulse wave velocity was dramatically elevated (mean: 13.00±3.83 m/s). Carotid duplex ultrasound echobrightness, assessed in predefined tissue sites as a measure of arterial wall density, was significantly greater than age- and sex-matched controls in the intima-media (P<0.02), near adventitia (P<0.003), and deep adventitia (P<0.01), as was internal carotid artery mean flow velocity (P<0.0001). Ankle-brachial indices were abnormal in 78% of patients. Effective disease treatments may be heralded by normalizing trends of these noninvasive cardiovascular measures. The data demonstrate that, along with peripheral vascular occlusive disease, accelerated vascular stiffening is an early and pervasive mechanism of vascular disease in Hutchinson-Gilford progeria syndrome. There is considerable overlap with cardiovascular changes of normal aging, which reinforces the view that defining mechanisms of cardiovascular disease in Hutchinson-Gilford progeria syndrome provides a unique opportunity to isolate a subset of factors influencing cardiovascular disease in the general aging population.

Trial registration: ClinicalTrials.gov NCT00425607.

Figure 1

PWV_cf is elevated in HGPS. PWV_cf for each of 21 children with HGPS. Published pediatric normal range (mean±SD) is plotted as diagonal lines for comparison.

Figure 2

ICA flow velocity is elevated in HGPS. Mean (± standard error) distal ICA flow velocity in m/s for left and right sides in control cohort (n=53), white bars and HGPS cohort (n=24), black bars. **P<0.0001 between control and HGPS groups on both left and right sides.

Figure 3

Increased carotid artery echodensity in HGPS. A, Longitudinal image of the CCA. L indicates lumen; IJV indicates the internal jugular vein. Area of interest indicated by large dashed rectangle; B., Enlargement of the area of interest seen in panel A, showing echodensity assessed in pre-specified areas indicated by the dashed boxes in the distal CCA far wall. White dashed box indicates intima-media area, and black dashed boxes indicated superficial and deep adventitial areas of measurement; C, Posterior CCA wall in control subject demonstrating normal echodensity of the intima (I), media (M) and adventitia (A), compared with D, increased echodensity noted in the HGPS posterior CCA wall; E–G, Sample histogram plots showing pixel intensity (X axis) versus pixel count (Y axis) derived from the deep adventitia site in E, a control child, F and G, children with HGPS. Solid vertical line represents 50^th percentile and dashed vertical line represents 10^th percentile for each plot; H, Mean (± standard error) values for intima-media density, superficial adventitia density, and deep adventitia density at the 10^th percentile in the control (white bar) (n=53) and HGPS (black bar) (n=23) groups. P values for HGPS versus controls were *P<0.05 and **P<0.001.