Abstract 11518: Diastolic Left Ventricular Dysfunction is a Common and Early Cardiac Abnormality in Hutchinson-Gilford Progeria Syndrome

Abstract

Introduction: Hutchinson-Gilford progeria syndrome (HGPS) is associated with premature death due to cardiovascular events. However, little is known about the natural history of cardiac disease in this population. We prospectively evaluated children with HGPS to identify echocardiographic abnormalities in ventricular and valve function and to assess the effect of treatment on these abnormalities. Methods and Results: Transthoracic echocardiography was used to evaluate 51 children with HGPS (45 with classic type, 6 with non-classic type; 55% males) at a median age of 10.7 (2.4-19.8) years. Among the study population, 19 were evaluated prior to entry into an open label drug trial of the farnesyltransferase inhibitor lonafarnib while the other 32 were receiving combination therapy with lonafarnib, pravastatin and zoledronic acid (triple therapy) at the time of evaluation. As seen in the Table, diastolic dysfunction diagnosed using pulsed wave tissue Doppler was the most common cardiac abnormality at all ages, developing early and present universally beyond 12.1 years of age. Other cardiac abnormalities including left ventricular hypertrophy (LVH), LV systolic dysfunction, and mitral or aortic valve disease were less common and appeared later. Using multiple linear regression to control for age and gender, patients receiving triple therapy demonstrated less severe LV diastolic dysfunction evidenced by higher lateral E’ velocities (p=0.01) and lower mitral inflow E velocity/lateral E’ velocity ratio (p=0.006). Other cardiac abnormalities were not associated with triple therapy. Conclusions: In patients with Hutchinson-Gilford progeria syndrome, LV diastolic dysfunction is common and appears early. Other cardiac abnormalities are less common and appear at a later age. Triple therapy is associated with less severe diastolic dysfunction. Echocardiographic parameters of LV diastolic dysfunction may be useful endpoints in future clinical trials.