Carotid-femoral pulse wave velocity is negatively correlated with aortic diameter.

Cardiovascular events pose significant morbidity and mortality burden to abdominal aortic aneurysm (AAA) patients. Arterial stiffness as measured by pulse wave velocity (PWV) is an independent predictor of cardiovascular risk. We investigated the relationship between aortic diameter and PWV. Consecutive patients with AAA were invited to participate. Patients completed a health questionnaire, received aortic ultrasound and carotid-femoral PWV (cfPWV) recordings with a Vicorder. Thirty patients were used for reproducibility assessment. A linear regression model was used to identify significant predictors of cfPWV. Observer variation was assessed using Bland and Altman analysis and the intraclass correlation coefficient. Three hundred and nine patients were included-148 with AAA and 161 controls. The mean difference for repeated cfPWV between observers was 0.11 ms(-1). cfPWV was positively correlated with age (r=0.24, P<0.001) and systolic blood pressure (r=0.29, P<0.001) and negatively correlated with aortic diameter (r=-0.15, P=0.008). There was no difference in cfPWV between AAA and control groups (9.75±2.3 ms(-1) vs. 9.55±2.3 ms(-1), P=0.43). Aortic diameter (P=0.003) and systolic blood pressure (P<0.001) were significant predictors of cfPWV independent of age, aspirin usage and a history of myocardial infarction. Patients with large AAA (>5 cm) had decreased cfPWV compared with patients with small AAA (P=0.02) or normal diameter aorta (P=0.02). Vicorder measurements of cfPWV are repeatable. cfPWV is negatively associated with infra-renal aortic diameter and reduced in large AAA. cfPWV is likely invalid for accurate arterial stiffness assessment in patients with AAA owing to the apparent confounding effect of aortic size.

Plasma thrombin-antithrombin complex, prothrombin fragments 1 and 2, and D-dimer levels are elevated after endovascular but not open repair of infrarenal abdominal aortic aneurysm.

INTRODUCTION: Abdominal aortic aneurysm (AAA) is associated with hypercoagulability, evidenced by increased markers of coagulation activation, including thrombin-antithrombin complex (TAT), prothrombin fragments 1 and 2 (F1+2), and D-dimer. Our aim was to compare the effect of endovascular aneurysm repair (EVAR) and open aneurysm repair (OAR) on changes in coagulation activation markers after intervention. METHODS: Consecutive patients with AAAs reaching their intervention threshold in a tertiary vascular referral unit in the United Kingdom were invited to participate. The coagulation markers TAT, F1+2, and D-dimer were measured in venous blood collected at baseline and at 5 months after intervention. A forward stepwise multiple linear regression model was used to identify whether treatment by OAR or EVAR had an effect on changes in coagulation factors, independent of significant covariates. RESULTS: The study included 47 patients (14 EVAR, 33 OAR; 85% men) who were a median age of 76 years (range, 69.5-80 years). Aortic diameter at intervention was 5.9 cm (range, 5.5-6.8 cm). There were no significant differences in clinical, anthropometric, or hematologic parameters between groups. At baseline, TAT (P = .13), F1+2 (P = .08), and D-dimer (P = .11) were similar in EVAR and OAR patients. Postintervention, there was a significant increase in TAT (3.0 [2.1-6.0] vs 7.2 [6.3-8.4] ng/mL; P = .03), F1+2 (242 [189-323] vs 392 [312-494] ng/mL; P = .003), and D-dimer (457 [336-615] vs 1197 [840-1509] ng/mL; P = .002) in the EVAR group. No significant changes were observed after intervention in the OAR group. CONCLUSIONS: AAA-related hypercoagulability persists after intervention, with increased TAT, F1+2, and D-dimer levels after EVAR. These findings suggest a potential period of increased cardiovascular risk in the postoperative period after EVAR.

Modeling the Growth of Infrarenal Abdominal Aortic Aneurysms.

BACKGROUND: Abdominal aortic aneurysm (AAA) growth is a complex process that is incompletely understood. Significant heterogeneity in growth trajectories between patients has led to difficulties in accurately modeling aneurysm growth across cohorts of patients. We set out to compare four models of aneurysm growth commonly used in the literature and confirm which best fits the patient data of our AAA cohort. METHODS: Patients with AAA were included in the study if they had two or more abdominal ultrasound scans greater than 3 months apart. Patients were censored from analysis once their AAA exceeded 5.5 cm. Four models were applied using the R environment for statistical computing. Growth estimates and goodness of fit (using the Akaike Information Criterion, AIC) were compared, with p-values based on likelihood ratio testing. RESULTS: Of 510 enrolled patients, 264 met the inclusion criteria, yielding a total of 1861 imaging studies during 932 cumulative years of surveillance. Overall, growth rates were: (1) 0.35 (0.31,0.39) cm/yr in the growth/time calculation, (2) 0.056 (0.042,0.068) cm/yr in the linear regression model, (3) 0.19 (0.17,0.21) cm/yr in the linear multilevel model, and (4) 0.21 (0.18,0.24) cm/yr in the quadratic multilevel model at time 0, slowing to 0.15 (0.12,0.17) cm/yr at 10 years. AIC was lowest in the quadratic multilevel model (1508) compared to other models (P < 0.0001). CONCLUSION: AAA growth was heterogeneous between patients; the nested nature of the data is most appropriately modeled by multilevel modeling techniques.

Calcium channel blockers enhance sac shrinkage after endovascular aneurysm repair.

OBJECTIVE: Sac shrinkage is a surrogate marker of success after endovascular aneurysm repair (EVAR). We set out to determine if any common cardioprotective medications had a beneficial effect on sac shrinkage. METHODS: This retrospective observational study took place at Leeds Vascular Institute, a tertiary vascular unit in the Northern United Kingdom. The cohort comprised 149 patients undergoing EVAR between January 1, 2005, and December 31, 2008. Medication use was recorded at intervention (verified at study completion in 33 patients), and patients were monitored for 2 years. The main outcome measures were the effect of medication on sac shrinkage as determined by percentage change in maximal idealized cross-sectional area of the aneurysm at 1 month, 6 months, 1 year, and 2 years by linear regression model, in addition to 2-year endoleak and death rates determined by a binary logistic regression model. RESULTS: After exclusions, 112 patients, who were a median age of 78 years (interquartile range, 78-83 years), remained for analysis. The median Glasgow Aneurysm Score was 85 (interquartile range, 79-92). At 2 years, mortality was 13.4%, endoleak developed in 37.5%, and significant endoleak developed in 14.3%. Patients taking a calcium channel blocker had enhanced sac shrinkage, compared with those not taking a calcium channel blocker, by 6.6% at 6 months (-3.0% to 16.3%, P = .09), 12.3% at 1 year (2.9% to 21.7%, P = .008), and 13.1% at 2 years (0.005% to 26.2%, P = .007) independent of other medication use, graft type, endoleak development, or death. CONCLUSIONS: Enhanced sac shrinkage occurred after EVAR in patients taking calcium channel blockers. This warrants further study in other centers and at the molecular level.

Propensity for paternal inheritance of de novo mutations in Alexander disease.

De novo dominant mutations in the GFAP gene have recently been associated with nearly all cases of Alexander disease, a rare but devastating neurological disorder. These heterozygous mutations must occur very early in development and be present in nearly all cells in order to be detected by the sequencing methods used. To investigate whether the mutations may have arisen in the parental germ lines, we determined the parental chromosome bearing the mutations for 28 independent Alexander disease cases. These cases included 17 different missense mutations and one insertion mutation. To enable assignment of the chromosomal origin of the mutations, six new single nucleotide polymorphisms in the GFAP gene were identified, bringing the known total to 26. In 24 of the 28 cases analyzed, the paternal chromosome carried the GFAP mutation (P < 0.001), suggesting that they predominantly arose in the parental germ line, with most occurring during spermatogenesis. No effect of paternal age was observed. There has been considerable debate about the magnitude of the male to female germ line mutation rate; our ratio of 6:1 is consistent with indirect estimates based on the rate of evolution of the sex chromosome relative to the autosomic chromosomes.

Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease.

Alexander disease is a progressive, usually fatal neurological disorder defined by the widespread and abundant presence in astrocytes of protein aggregates called Rosenthal fibers. The disease most often occurs in infants younger than 2 years and has been labeled a leukodystrophy because of an accompanying severe myelin deficit in the frontal lobes. Later onset forms have also been recognized based on the presence of abundant Rosenthal fibers. In these cases, clinical signs and pathology can be quite different from the infantile form, raising the question whether they share the same underlying cause. Recently, we and others have found pathogenic, de novo missense mutations in the glial fibrillary acidic protein gene in most infantile patients examined and in a few later onset patients. To obtain further information about the role of glial fibrillary acidic protein mutations in Alexander disease, we analyzed 41 new patients and another 3 previously described clinically, including 18 later onset patients. Our results show that dominant missense glial fibrillary acidic protein mutations account for nearly all forms of this disorder. They also significantly expand the catalog of responsible mutations, verify the value of magnetic resonance imaging diagnosis, indicate an unexpected male predominance for the juvenile form, and provide insights into phenotype-genotype relations.

Alexander disease: a leukodystrophy caused by a mutation in GFAP.

Alexander disease, a rare fatal disorder of the central nervous system, causes progressive loss of motor and mental function. Until recently it was of unknown etiology, almost all cases were sporadic, and there was no effective treatment. It was most common in an infantile form, somewhat less so in a juvenile form, and was rarely seen in an adult-onset form. A number of investigators have now shown that almost all cases of Alexander disease have a dominant mutation in one allele of the gene for glial fibrillary acidic protein (GFAP) that causes replacement of one amino acid for another. Only in very rare cases of the adult-onset form is the mutation present in either parent. Thus, in almost all cases, the mutation arises as a spontaneous event, possibly in the germ cell of one parent.

Alexander's disease: clinical, pathologic, and genetic features.

Alexander's disease, a rare and fatal disorder of the central nervous system, most commonly affects infants and young children but can also occur in older children and sometimes adults. In infants and young children, it causes developmental delay, psychomotor retardation, paraparesis, feeding problems, usually megalencephaly, often seizures, and sometimes hydrocephalus. Juvenile cases often do not have megalencephaly and tend to have predominant pseudobulbar and bulbar signs. In both groups, characteristic magnetic resonance imaging findings have been described. In adult cases, the signs are variable, can resemble multiple sclerosis, and might include palatal myoclonus. In all cases, the examination of brain tissue shows the presence of widely distributed Rosenthal fibers. Almost all cases have recently been found to have a heterozygous, missense, point mutation in the gene for glial fibrillary acidic protein, which provides a new diagnostic tool. In most cases, the mutation appears to occur de novo, not being present in either parent, but some adult cases are familial.

Microtubule reduction in Alzheimer's disease and aging is independent of tau filament formation.

Biochemical studies show that phosphorylated tau, like that found in paired helical filaments (PHFs), does not promote microtubule assembly leading to the view that PHF formation leads to microtubule deficiency in Alzheimer's disease (AD). However, although this issue is one of the most important aspects to further understanding the cell biology of AD, no quantitative examination of microtubule diminution in AD and its relationship with PHFs has been performed. To examine this issue directly, we undertook a morphometric study of brain biopsy specimens from AD and control cases. Ultrastructural analysis of neurons was performed to compare the microtubule assembly state in neurons of diseased and control cases and to examine the effect of PHF accumulation. We found that both number and total length of microtubules were significantly and selectively reduced in pyramidal neurons from AD in comparison to control cases (P = 0.000004) but that this decrement in microtubule density was surprisingly unrelated to PHFs (P = 0.8). Further, we found a significant age-dependent decrease in microtubule density with aging in the control cases (P = 0.016). These findings suggest that reduction in microtubule assembly is not dependent on tau abnormalities of AD and aging.

Alexander disease: a review and the gene.

This review presents historical and clinical information on the rare human brain disorder known as Alexander disease (ALX), and reports on the recent discovery of the gene that appears to be causative. The disease is a fatal, white matter disorder (leukodystrophy) of childhood. Adult onset cases also have been described, but it has not been clear whether they represent the same disease. Until recently the diagnosis was made by the pathological examination of brain tissue, in which abundant Rosenthal fibers were found. These abnormal structures occurred within astrocytes, but their composition was unclear. In 1985, a child underwent a diagnostic brain biopsy at this institution, which established the diagnosis of ALX. Ultrastructural immunocytochemistry revealed that the Rosenthal fibers contained abundant amounts of glial fibrillary acidic protein (GFAP), a normal component of astocytic intermediate filaments. Thus, the gene for this filament protein was considered a candidate gene for the cause of ALX, and DNA samples from children presumed or proven to have this disorder were banked for future study. Other work on the same brain biopsy showed that Rosenthal fibers also contained abundant alphaB-crystallin, a heat shock protein, but no defect was found in its gene. A decade after the biopsy, a transgenic mouse with an extra copy of the gene for GFAP was produced. These mice died early and their brains contained Rosenthal fibers. Although not an exact model for ALX, this also suggested that the gene for GFAP should be considered a candidate gene for ALX. Subsequent research has demonstrated that the great majority of childhood ALX cases contain mutations in the gene for GFAP. This work is now being extended as a diagnostic test, as well as to seek understanding of the pathogenesis of ALX and possible approaches for treatment.