Aggressive cardiovascular phenotype of aneurysms-osteoarthritis syndrome caused by pathogenic SMAD3 variants.
OBJECTIVE
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.
Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands.
Denise
D
van der Linde
Ingrid M B H
IM
van de Laar
Aida M
AM
Bertoli-Avella
Rogier A
RA
Oldenburg
Jos A
JA
Bekkers
Francesco U S
FU
Mattace-Raso
Anton H
AH
van den Meiracker
Adriaan
A
Moelker
Fop
F
van Kooten
Ingrid M E
IM
Frohn-Mulder
Janneke
J
Timmermans
Els
E
Moltzer
Jan M
JM
Cobben
Lut
L
van Laer
Bart
B
Loeys
Julie
J
De Backer
Paul J
PJ
Coucke
Anne
A
De Paepe
Yvonne
Y
Hilhorst-Hofstee
Marja W
MW
Wessels
Jolien W
JW
Roos-Hesselink
D000293:Adolescent; D000328:Adult; D000368:Aged; D000783:Aneurysm / Q000000981:diagnostic imaging / Q000235:genetics* / Q000401:mortality; D000784:Aortic Dissection / Q000000981:diagnostic imaging / Q000235:genetics / Q000401:mortality; D017545:Aortic Aneurysm, Thoracic / Q000000981:diagnostic imaging / Q000235:genetics / Q000401:mortality; D001027:Aortography; D002318:Cardiovascular Diseases / Q000000981:diagnostic imaging / Q000235:genetics* / Q000401:mortality; D002423:Cause of Death; D002561:Cerebrovascular Disorders / Q000000981:diagnostic imaging / Q000235:genetics / Q000401:mortality; D002869:Chromosome Aberrations; D015331:Cohort Studies; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D056914:Genomic Structural Variation / Q000235:genetics*; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D021621:Imaging, Three-Dimensional; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D010003:Osteoarthritis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000401:mortality; D010446:Peptide Fragments / Q000235:genetics; D010641:Phenotype; D011247:Pregnancy; D051900:Smad3 Protein / Q000235:genetics*; D016019:Survival Analysis; D013577:Syndrome; D059289:Vascular Stiffness / Q000235:genetics; D055815:Young Adult
D010446:Peptide Fragments; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain