Yagubyan, Marineh

Background: Bicuspid aortic valve disease (BAV), the most common congenital cardiovascular malformation, has an incidence of 0.5–1.0% of live births. While most cases of BAV appear to be sporadic, familial inheritance patterns have been observed consistent with autosomal dominant inheritance with variable penetrance. However, little is known about specific genetic loci responsible for familial BAV. Here, we performed linkage analysis on a large multi-generational pedigree affected with BAV. Methods: We identified a large, five-generation pedigree (136 family members) with 10 individuals having BAV. Two-dimensional echocardiography was used to assign aortic valve phenotype. Genome-wide linkage analysis using 430 microsatellite markers (Marshfield Clinic) and fine mapping using 100 single nucleotide polymorphisms (Affymetrix) on chromosome 9 was performed on genomic DNA from all available family members. Logarithm of odds (LOD) scores of >2.0 were considered suggestive of linkage. Comprehensive splice site/open reading frame mutational analysis of candidate genes residing in the putative locus is underway using PCR, DHPLC, and DNA sequencing. A candidate gene, KLF9, Krüppel-like factor 9 was analyzed for mutations because of its role in cardiogenesis. Results: Multi-point genome-wide linkage analysis demonstrated a 7 cM region on chromosome 9q21 that was suggestive of linkage for familial BAV with a maximum multipoint LOD score of 2.8 flanked by the microsatellite markers GATA7D12 and D9S1834. This region contains several candidate genes with biological plausibility for BAV phenotype. KLF9- encoded Krüppel-like factor 9, localized to chromosome 9q21, was targeted as a prime candidate gene for familial BAV. However, no mutations involving the translated exons of KLF9 were detected. Further fine mapping studies and candidate gene analysis are currently underway. Conclusions: We report a novel susceptibility locus on chromosome 9q21 for BAV in a large multi-generational family. Although coding region mutations in KLF9 are not responsible for BAV in this pedigree, several candidate genes with biological plausibility for the development of congenital BAV lie within this region and warrant further scrutiny.

OBJECTIVE A bileaflet aortic valve (BAV) occurs in 1–2% of the population, making it the most common cardiovascular malformation. Patients with BAV have increased risk of thoracic ascending aortic aneurysm (TAA) and dissection compared to those with trileaflet aortic valves (TAV). We have evaluated the gene expression profile of the aorta of patients with BAV and TAV with TAA. METHODS Segment of aneurysmal tissue was collected from 12 patients with BAV (age 43–68) and 19 patients with TAV (age 37–79). RNA was extracted using the Invitrogen RNA extraction Kit. RNA that was of adequate quality by the Agilent Bioanalyzer was used in the Affymetrix protocol for the U133A gene chips probing for over 16,000 genes on each chip. Real‐time RT‐PCR was used to confirm the microarray results for a subset of genes. RESULTS Data filtering (using two different statistical methods) identified significant differences in gene expression between the BAV and TAV groups. The real time RT‐PCR independently confirmed that the expression levels of osteopontin and tenascin were consistently increased in TAA with TAV. CONCLUSIONS The results indicate that many genes are involved in a complicated manner in the pathogenesis of TAA. This study also demonstrates two basic gene expression profiles in the TAA, one characteristic of patients with BAV and the other of those with TAV. Variations in the molecular mechanisms underlying different types of TAA warrant further investigation. (This work was supported by an SS‐50 award to Dr. Thoralf Sundt from the Department of Surgery, Mayo Clinic)

Axillary artery injury from blunt trauma to the shoulder is uncommon. Fracture of the neck of the humerus is a rare cause of injury to the axillary artery. Four cases of axillary artery thrombosis from humeral neck fracture are reported. Each of the first 2 patients presented with a pulseless and acutely ischemic limb after a trivial fall. A repair of the axillary artery with saphenous vein interposition graft was performed in the first patient. The extremity was salvaged, but a residual radial and ulnar neurologic deficit persisted. The second patient presented with a pulseless insensate upper extremity accompanied by motor loss. He underwent primary axillary artery repair. Still early in his postoperative course, he has had global brachial plexopathy and is undergoing intensive physical therapy. The third patient had a delayed presentation of brachial plexopathy and sympathetic reflex dystrophy. Arterial reconstruction was not required owing to excellent collateralization. The fourth patient presented with a cool pulseless extremity. His recovery is nearly complete after bypass of the axillary artery with a reversed saphenous vein graft. In addition, a review of the literature revealed 24 cases of axillary artery injury associated with humeral neck fracture. The mean age was 66.6 years. The most common mechanism of injury was a fall (79%). Thirteen patients (46%) presented with a neurologic deficit. Acute ischemia was present in 68%. Physical examination predicted the arterial injury in all but 1 patient. The injured axillary artery was repaired in 26 cases. Revascularization by an interposition graft was the most common procedure. All grafts and reanastomoses were patent and led to limb salvage. Of 9 primary repairs, 3 amputations were performed. Although limb salvage rate was 89%, a good functional outcome was obtained in only half of the patients. A high index of suspicion is required for early diagnosis of axillary artery injury. Despite excellent results of vascular reconstruction, the outcome remains determined by the excessive neurologic morbidity. Recognition of the associated brachial plexus injury is essential to improve the functional outcome of this unusual arterial injury.