Abstract 34: Myh11 R247C is a Modifier Allele for Aortic Disease

Abstract

Thoracic aortic aneurysms and dissections (TAAD) affect more than 30,000 Americans annually. TAAD can be inherited due to mutations in a number of genes, including MYH11, which encodes the smooth muscle myosin heavy chain. In non-familial TAAD patients, hypertension is the most common risk factor, but genetic contributors have not been explored. Exome sequencing has identified non-synonymous variants of unknown significance in MYH11 in the population, and these variants are enriched in TAAD patients without a family history. The goal of this study was to determine if rare MYH11 variants contribute to TAAD. A knock-in mouse model of one recurrent rare variant, Myh11 R247C, shows no structural or pathologic abnormalities of the aorta, but does have decreased aortic contractility. We sought to determine if the Myh11 R247C allele could modify aortic disease due to another gene mutation. The Myh11R247C allele was bred into Acta2-/- mice, which develop aortic aneurysms, and into Acta2+/- mice, which do not. In both cases, the R247C allele significantly increases aortic diameter and accelerates elastin fragmentation and proteoglycan deposition; however the aneurysms do not progress to aortic dissection. Treatment of Myh11R247C/R247C mice with a combination of L-NAME and high salt diet induced a sustained increase in systolic blood pressure from 130mmHg to 180mmHg. Approximately 25% of Myh11R247C/R247C mice on treatment died spontaneously with evidence of aortic dissections at necropsy, but without aortic dilation. The surviving mice also show no aneurysm formation. Aortic pathology shows significant fragmentation and thinning of elastin fibers, medial thickening, and a unique pattern of proteoglycan deposition along the elastin layers in the hypertensive Myh11R247C/R247C mice. These data indicate that the Myh11R247C allele in mice increases severity of Acta2-/- associated aortic aneurysms and induces aortic disease when added to a known risk factor for TAAD, hypertension. Therefore, patients with the Myh11R247C rare variant and a disease-causing mutation may have earlier disease onset and increased severity; co-occurrence of the Myh11R247C allele in individuals with other benign genetic variants or risk factors like hypertension may induce TAAD.