Familial Clustering of Aortic Aneurysms and Dissections
- Greater aortic size clusters in families, as demonstrated by data from the Framingham Heart Study.
- Aortic aneurysm or dissection in a first-degree family member confers a substantial increase in risk for these conditions (absolute event rate approaching 1 per 1,000 person-years), even in the absence of well-defined connective tissue disorders.
What are the risks of increased aortic size, aortic aneurysm, and dissection among first-degree relatives of persons with these conditions?
Data from the Framingham Heart Study (FHS), including the original cohort, offspring study, and third-generation cohort, were used to assess familial clustering of greater aortic size. Subjects were included if both parents were enrolled in FHS and if both parents and children had transthoracic echocardiograms or computed tomography (CT) of the thorax and abdomen. Logistic regression models were used to estimate odds ratios (ORs) of belonging to the upper quartile of an imaging-derived measurement of aortic size, indexed to body surface area and age- and sex-standardized, if one parent belonged to the upper quartile of the same variable.
Data from Danish nationwide administrative registries were used to assess risk of aortic aneurysm and aortic dissection in first-degree relatives of patients with these conditions, as compared with age- and sex-matched controls. Individuals with a first diagnosis of aortic dissection or aneurysm between 1997 and 2017 were identified, excluding individuals who did not have both parents registered. For each first-degree relative with the specific aortic condition, 10 controls were matched for aneurysm and 100 for dissection. A Cox regression model was used to estimate hazard ratios (HRs) for aortic aneurysm and dissection among first-degree relatives of subjects with those conditions.
The FHS cohort included 2,089 subjects with echocardiograms (52% women) and 235 subjects with CT scans (38% women). For subjects with ≥1 parent with aortic size in the upper quartile, a two- to three-fold increase in risk of increased aortic size was seen, persisting after multivariable adjustment for hypertension and smoking status (adjusted OR for aortic root size on echocardiography, 2.17; 95% confidence interval [CI], 1.75-2.70; adjusted OR for ascending aorta on CT, 3.13; 95% CI, 1.57-6.24; adjusted OR for abdominal aorta on CT, 2.57; 95% CI, 1.38-4.76). Having a parent with aortic size in the upper quartile was not significantly associated with major adverse cardiovascular events (MACE; including nonfatal stroke, myocardial infarction, or cardiovascular death) (n = 41 events, multivariable adjusted HR, 1.07; 95% CI, 0.58-1.20).
The Danish cohort included 68,939 and 7,209 first-degree relatives of patients with aortic aneurysm and dissection, respectively. Prevalence of Marfan and Ehlers-Danlos syndromes was <0.5%. Over a median follow-up of 7.1 years, 1,307 individuals (0.17%) developed aortic aneurysm, and 188 (0.03%) were diagnosed with aortic dissection. In an age- and sex-adjusted model, having a first-degree relative with aortic aneurysm was associated with approximately a seven-fold increase in aneurysm risk (HR, 6.70; 95% CI, 5.96-7.52); for aortic dissection, findings were similar (HR, 9.24; 95% CI, 5.53-15.44). Among individuals with incident aortic aneurysm, the prevalence of bicuspid aortic valve was lower in those with a first-degree relative with aortic aneurysm than in those without such a family history (0.7% vs. 3.9%, p < 0.0001). Having any first-degree relative with aortic dissection was not significantly associated with MACE (multivariable adjusted HR, 1.11; 95% CI, 0.97-1.26), although in cases with proband 50 years old or younger, MACE risk was increased (multivariable adjusted HR, 2.02; 95% HR, 1.43-2.86). Risk of MACE was somewhat increased in first-degree relatives of patients with aortic aneurysm (multivariable adjusted HR for MACE with any first-degree relative, 1.09; 95% CI, 1.05-1.14; for proband 50 years or younger, HR, 1.38; 95% CI, 1.05-1.18).
Greater aortic size clusters in families. First-degree family members of patients with aortic dissection and aneurysm are at considerably increased risk for developing these conditions, especially when aortic disease is diagnosed at younger ages in probands. Monogenic heritable connective tissue diseases likely account for only a small portion of the burden of aortic aneurysm and dissection seen in the general population.
The FHS cohort presented in this study was small, and the clinical significance of an upper-normal or mildly increased aortic diameter remains ill-defined. Large, prospective studies will be needed to define best practices for management of patients with such findings. Family history is critical in risk stratification for aortic disease, and with increasingly broad dissemination of imaging technology and electronic medical records, it will likely become easier over time for providers to obtain details of family history to inform clinical judgment.
Clinical Topics: Cardiac Surgery, Congenital Heart Disease and Pediatric Cardiology, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Valvular Heart Disease, Vascular Medicine, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and CHD and Pediatrics, Cardiac Surgery and VHD, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Imaging, CHD and Pediatrics and Interventions, CHD and Pediatrics and Quality Improvement, Interventions and Imaging, Interventions and Structural Heart Disease, Interventions and Vascular Medicine, Computed Tomography, Echocardiography/Ultrasound, Nuclear Imaging
Keywords: Aorta, Abdominal, Aortic Aneurysm, Body Surface Area, Cardiac Surgical Procedures, Diagnostic Imaging, Dissection, Echocardiography, Electronic Health Records, Heart Valve Diseases, Marfan Syndrome, Myocardial Infarction, Risk, Secondary Prevention, Stroke, Tomography, X-Ray Computed, Vascular Diseases
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