Intervention for Critical Aortic Stenosis in Hutchinson-Gilford Progeria Syndrome

Abstract

Background Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare genetic premature aging disease that is historically fatal in teenage years, secondary to severe accelerated atherosclerosis. The only approved treatment is the farnesyltransferase inhibitor lonafarnib, which improves vascular structure and function, extending lifespan by several years. With this longer lifespan, calcific aortic stenosis (AS) was identified as an emerging critical risk factor for cardiac death in older patients. Intervention to relieve critical AS in those with HGPS has the potential for immediate improvement in healthspan and lifespan. However, in the face of cardiovascular pathology that is seen almost exclusively in aging adults, HGPS patient-device size mismatch, pervasive peripheral arterial disease, skin and bone abnormalities, and lifelong failure to thrive present unique challenges to intervention. Main Body: An international group of HGPS experts and leaders in pediatric and adult cardiology, cardiac surgery, and pediatric critical care convened to discuss pivotal features of AS progression in HGPS, identifying challenges to and strategies for successful treatment. Candidate procedures were evaluated by in-depth examination of 4 cases of end stage classic HGPS with critical calcific AS that typify the pathology that necessitates individualized surgical risk/benefit assessments. Modified transcatheter aortic valve replacement (TAVR) and left ventricular Apico-Aortic Conduit (AAC) placement were deemed high risk but viable options. Two cases received TAVR and 2 received AAC post-summit. Three were successful and 1 patient died perioperatively due to cardiovascular disease severity, highlighting the importance of intervention timing and comparative risk stratification. Conclusions Modified TAVR and AAC breakthrough interventions for treatment of critical aortic stenosis in HGPS patients could rewrite the current clinical perspective on disease course by greatly improving late-stage quality of life and increasing average lifespan. Expanding worldwide medical and surgical competency for this ultra-rare disease through expert information-sharing could have a high impact on treatment success.