Aggressive cardiovascular phenotype of aneurysms-osteoarthritis syndrome caused by pathogenic SMAD3 variants

J Am Coll Cardiol. 2012 Jul 31;60(5):397-403. doi: 10.1016/j.jacc.2011.12.052. Epub 2012 May 23.

Abstract

Objectives: The purpose of this study was describe the cardiovascular phenotype of the aneurysms-osteoarthritis syndrome (AOS) and to provide clinical recommendations.

Background: AOS, caused by pathogenic SMAD3 variants, is a recently described autosomal dominant syndrome characterized by aneurysms and arterial tortuosity in combination with osteoarthritis.

Methods: AOS patients in participating centers underwent extensive cardiovascular evaluation, including imaging, arterial stiffness measurements, and biochemical studies.

Results: We included 44 AOS patients from 7 families with pathogenic SMAD3 variants (mean age: 42 ± 17 years). In 71%, an aortic root aneurysm was found. In 33%, aneurysms in other arteries in the thorax and abdomen were diagnosed, and in 48%, arterial tortuosity was diagnosed. In 16 patients, cerebrovascular imaging was performed, and cerebrovascular abnormalities were detected in 56% of them. Fifteen deaths occurred at a mean age of 54 ± 15 years. The main cause of death was aortic dissection (9 of 15; 60%), which occurred at mildly increased aortic diameters (range: 40 to 63 mm). Furthermore, cardiac abnormalities were diagnosed, such as congenital heart defects (6%), mitral valve abnormalities (51%), left ventricular hypertrophy (19%), and atrial fibrillation (22%). N-terminal brain natriuretic peptide (NT-proBNP) was significantly higher in AOS patients compared with matched controls (p < 0.001). Aortic pulse wave velocity was high-normal (9.2 ± 2.2 m/s), indicating increased aortic stiffness, which strongly correlated with NT-proBNP (r = 0.731, p = 0.005).

Conclusions: AOS predisposes patients to aggressive and widespread cardiovascular disease and is associated with high mortality. Dissections can occur at relatively mildly increased aortic diameters; therefore, early elective repair of the ascending aorta should be considered. Moreover, cerebrovascular abnormalities were encountered in most patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aneurysm / diagnostic imaging
  • Aneurysm / genetics*
  • Aneurysm / mortality
  • Aneurysm, Dissecting / diagnostic imaging
  • Aneurysm, Dissecting / genetics
  • Aneurysm, Dissecting / mortality
  • Aortic Aneurysm, Thoracic / diagnostic imaging
  • Aortic Aneurysm, Thoracic / genetics
  • Aortic Aneurysm, Thoracic / mortality
  • Aortography
  • Cardiovascular Diseases / diagnostic imaging
  • Cardiovascular Diseases / genetics*
  • Cardiovascular Diseases / mortality
  • Cause of Death
  • Cerebrovascular Disorders / diagnostic imaging
  • Cerebrovascular Disorders / genetics
  • Cerebrovascular Disorders / mortality
  • Chromosome Aberrations
  • Cohort Studies
  • Female
  • Genes, Dominant / genetics
  • Genomic Structural Variation / genetics*
  • Humans
  • Image Interpretation, Computer-Assisted
  • Imaging, Three-Dimensional
  • Male
  • Middle Aged
  • Natriuretic Peptide, Brain / genetics
  • Osteoarthritis / diagnostic imaging
  • Osteoarthritis / genetics*
  • Osteoarthritis / mortality
  • Peptide Fragments / genetics
  • Phenotype*
  • Pregnancy
  • Smad3 Protein / genetics*
  • Survival Analysis
  • Syndrome
  • Vascular Stiffness / genetics
  • Young Adult

Substances

  • Peptide Fragments
  • SMAD3 protein, human
  • Smad3 Protein
  • pro-brain natriuretic peptide (1-76)
  • Natriuretic Peptide, Brain