The vascular smooth muscle cell (SMC)-specific isoform of alpha-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD. Sequencing of DNA from patients with nonfamilial TAAD and from premature-onset CAD patients independently identified ACTA2 mutations in these patients and premature onset strokes in family members with ACTA2 mutations. Vascular pathology and analysis of explanted SMCs and myofibroblasts from patients harboring ACTA2 suggested that increased proliferation of SMCs contributed to occlusive diseases. These results indicate that heterozygous ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, including TAAD, premature CAD, ischemic strokes, and MMD. These data demonstrate that diffuse vascular diseases resulting from either occluded or enlarged arteries can be caused by mutations in a single gene and have direct implications for clinical management and research on familial vascular diseases.

Background-Arterial tortuosity is described as a common and distinctive feature of Loeys-Dietz syndrome (LDS), yet reports on arterial tortuosity are based on qualitative observations and none have investigated an association between tortuosity and cardiovascular outcomes in LDS or other connective tissue disorders. Methods and Results-We performed a retrospective analysis of 90 patients Յ50 years of age with Marfan syndrome, LDS, Ehlers-Danlos syndrome, or nonspecific connective tissue disorder who underwent thoracic contrast-enhanced magnetic resonance angiography. Controls (nϭ30) underwent magnetic resonance imaging to exclude arrhythmogenic right ventricular dysplasia. Using a volume-rendered angiogram, vertebral arteries were measured along the curvature of the vessel (actual length) and linearly (straight length), and distance factor was calculated: [(actual/straight lengthϪ1)ϫ100]. Each subject's maximum distance factor was designated the Vertebral Tortuosity Index (VTI). The VTI was compared among diagnostic groups and among patients with cardiac surgery, dissection, and death. Median age at magnetic resonance imaging was 19.6 years (range 0.2 to 50.1). VTI interrater reliability was excellent (intraclass correlation coefficient ϭ0.987). The VTI was higher in Marfan syndrome (nϭ57, median 26; interquartile range 10 to 49) and LDS (nϭ13, median 58; interquartile range 18 to 92) compared with controls (median 4.5; interquartile range 3 to 6; PϽ0.001 for both). Higher VTI was associated with younger age at surgery even when controlling for root size (adjusted Pϭ0.002). Vertebral tortuosity index Ն50 was associated with earlier age at dissection and death compared with VTI Ͻ50 (Pϭ0.001 versus PϽ0.001). We found no difference in age at surgery, dissection, or death in Marfan syndrome compared with LDS. Conclusion-Arterial tortuosity measured by magnetic resonance angiography is a reproducible marker of adverse cardiovascular outcomes in connective tissue disorders. (Circulation. 2011;124:388-396.)

Fontan patients with a higher MELD-XI score have shorter freedom from sudden cardiac death, death from congestive heart failure and cardiac transplantation.