Intermittent claudication: a plea for guidelines for medical management.
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Antihypertensive Agents↗
Biomedical subjects
J T Powell
Publications and source records attributed to J T Powell.
How much evidence is needed for the introduction of new technologies into clinical practice in vascular surgery?
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Aortic Aneurysm, Abdominal↗
Genes predisposing to rapid aneurysm growth.
The aim of the study was to investigate the effect of functional polymorphisms in promoters of the MMP-2 (-1306 C > T), MMP-3 (-1171 5A > 6A), MMP-9 (-1562 C > T), MMP-12 (-82 A > G), TIMP-1 (-372 C > T), and PAI-1 (-675 4G > 5G and -847 A > G) genes on the growth rate of small abdominal aortic aneurysms. The patients with small aneurysms were recruited from the surveillance arm of the U.K. Small Aneurysm Trial and monitored for aneurysm growth, mean follow-up 2.6 years. Mean linear aneurysm growth rates were calculated by flexible modeling. For MMP-2, MMP-3, MMP-9, MMP-12, and TIMP-1 polymorphisms there were no clear associations with aneurysm growth. The increased growth rates for patients of 5G5G PAI-1 genotype were of borderline significance (P = 0.06). However, PAI-1 haplotype analysis showed that 5G5G/GG patients had significantly faster aneurysm growth (mean 0.46 mm/year faster). There was no evidence that any specific MMP polymorphism had a clinically significant effect on aneurysm growth. However the plasminogen system (via PAI-1) appears to have a small, but clinically significant, role in aneurysm growth.
Aortic Aneurysm, Abdominal↗
Genotype-phenotype relationships in an investigation of the role of proteases in abdominal aortic aneurysm expansion.
BACKGROUND: The aim of the study was to investigate the effect of functional polymorphisms in promoters of matrix metalloproteinase (MMP) 2, MMP-3, MMP-9, MMP-12 and plasminogen activator inhibitor (PAI) 1 genes on the growth rate of small abdominal aortic aneurysms (AAA). METHODS: Some 455 individuals with a small AAA (4.0-5.5 cm) were monitored for aneurysm growth by ultrasonography (mean follow-up 2.6 years). They also provided a DNA sample for analysis of the -1306 C > T, -1171 5A > 6A, -1562 C > T, -82 A > G and -675 4G > 5G alleles of MMP-2, MMP-3, MMP-9, MMP-12 and PAI-1, respectively. Mean linear AAA growth rates were calculated by flexible modelling; the sample size was sufficient to detect variants that influenced the growth rate by 25 per cent. RESULTS: For MMP-2, MMP-9 and MMP-12 genotypes, growth rates were similar to the mean linear growth rate of 3.08 mm per year. For MMP-3, growth rates were 3.05 (for 5A5A), 3.19 (for 5A6A) and 2.90 (for 6A6A) mm per year. For PAI-1, patients with 4G4G, 4G5G and 5G5G genotypes had growth rates of 3.18, 2.92 and 3.47 mm per year, respectively, for aneurysms with a baseline diameter of 45.1, 44.6 and 46.2 mm. The increased growth rate for patients with PAI-1 5G5G genotype was not statistically significant (P = 0.061), although these patients had the lowest plasma PAI-1 concentrations (P = 0.018). CONCLUSION: There was no evidence that any specific MMP polymorphism had a clinically significant effect on AAA expansion. The plasminogen system may have a small but clinically significant role in AAA development. Much larger studies would be needed to evaluate genes of smaller effect.
Aged↗
Perioperative beta-blockade (POBBLE) for patients undergoing infrarenal vascular surgery: results of a randomized double-blind controlled trial.
OBJECTIVE: To assess whether a pragmatic policy of perioperative beta-blockade, with metoprolol, reduced the 30-day cardiovascular morbidity and mortality and reduced the length of hospital stay in average patients undergoing infrarenal vascular surgery. METHODS: This was a double-blind randomized placebo-controlled trial that occurred in vascular surgical units in four UK hospitals. Participants were 103 patients without previous myocardial infarction who had infrarenal vascular surgery between July 2001 and March 2004. Interventions were oral metoprolol (50 mg twice daily, supplemented by intravenous doses when necessary) or placebo from admission until 7 days after surgery. Holter monitors were kept in place for 72 hours after surgery. RESULTS: Eighty men and 23 women (median age, 73 years) were randomized, 55 to metoprolol and 48 to placebo, and 97 (94%) underwent surgery during the trial. The most common operations were aortic aneurysm repair (38%) and distal bypass (29%). Intraoperative inotropic support was required in 64% and 92% of patients in the placebo and metoprolol groups, respectively. Within 30 days, cardiovascular events occurred in 32 patients, including myocardial infarction (8%), unstable angina (9%), ventricular tachycardia (19%), and stroke (1%). Four (4%) deaths were reported. Cardiovascular events occurred in 15 (34%) and 17 (32%) patients in the placebo and metoprolol groups, respectively (unadjusted relative risk, 0.94; 95% confidence interval, 0.53-1.66; adjusted [for age, sex, statin use, and aortic cross-clamping] relative risk, 0.87; 95% confidence interval, 0.48-1.55). Time from operation to discharge was reduced from a median of 12 days (95% confidence interval, 9-19 days) in the placebo group to 10 days (95% confidence interval, 8-12 days) in the metoprolol group (adjusted hazard ratio, 1.71; 95% confidence interval, 1.09-2.66; P < .02). CONCLUSIONS: Myocardial ischemia was evident in a high proportion (one third) of the patients after surgery. A pragmatic regimen of perioperative beta-blockade with metoprolol did not seem to reduce 30-day cardiovascular events, but it did decrease the time from surgery to discharge.
Adrenergic beta-Antagonists↗
Influence of fibrillin-1 genotype on the aortic stiffness in men.
Aortic stiffness is a predictor of cardiovascular mortality. The mechanical properties of the arterial wall depend on the connective tissue framework, with variation in fibrillin-1 and collagen I genes being associated with aortic stiffness and/or pulse pressure elevation. The aim of this study was to investigate whether variation in fibrillin-1 genotype was associated with aortic stiffness in men. The mechanical properties of the abdominal aorta of 79 healthy men (range 28-81 yr) were investigated by ultrasonographic phase-locked echo tracking. Fibrillin-1 genotype, characterized by the variable tandem repeat in intron 28, and collagen type I alpha 1 genotype characterized by the 2,064 G>T polymorphism, were determined by using DNA from peripheral blood cells. Three common fibrillin-1 genotypes, 2-2, 2-3, and 2-4, were observed in 50 (64%), 10 (13%), and 11 (14%) of the men, respectively. Those of 2-3 genotype had higher pressure strain elastic modulus and aortic stiffness compared with men of 2-2 or 2-4 genotype (P = 0.005). Pulse pressure also was increased in the 2-3 genotype (P = 0.04). There was no significant association between type 1 collagen genotype and aortic stiffness in this cohort. In conclusion, the fibrillin-1 2-3 genotype in men was associated with increased aortic stiffness and pulse pressure, indicative of an increased risk for cardiovascular disease.
Adult↗
Vitamin D, shedding light on the development of disease in peripheral arteries.
Vitamin D is generally associated with calcium metabolism, especially in the context of uptake in the intestine and the formation and maintenance of bone. However, vitamin D influences a wide range of metabolic systems through both genomic and nongenomic pathways that have an impact on the properties of peripheral arteries. The genomic effects have wide importance for angiogenesis, elastogenesis, and immunomodulation; the nongenomic effects have mainly been observed in the presence of hypertension. Although some vitamin D is essential for cardiovascular health, excess may have detrimental effects, particularly on elastogenesis and inflammation of the arterial wall. Vitamin D is likely to have a role in the paradoxical association between arterial calcification and osteoporosis. This review explores the relationship between vitamin D and a range of physiological and pathological processes relevant to peripheral arteries.
Animals↗
Genetic approach to the role of cysteine proteases in the expansion of abdominal aortic aneurysms.
BACKGROUND: The elastinolytic cysteine proteases, including cathepsins S and K, are overexpressed at sites of arterial elastin damage. Cystatin C, an inhibitor of these enzymes, is expressed in arterial smooth muscle cells; an imbalance in cystatin C has been implicated in the aortic wall degeneration observed in abdominal aortic aneurysms (AAAs). The aim of the study was to investigate the impact of a polymorphism in the signal peptide of the cystatin C gene on the growth of small AAAs. METHODS: Some 424 patients with a small AAA (4.0-5.5 cm) were monitored for AAA growth by ultrasonography and provided a DNA sample for analysis of the + 148 G > A polymorphism in the cystatin C signal peptide and the-82 G > C polymorphism in the gene promoter. The median length of follow-up was 2.8 years and AAA growth rates were calculated by linear regression analysis. RESULTS: For patients of + 148 GG (n = 263), GA (n = 147) and AA (n = 20) genotypes, the mean(s.d.) AAA growth rates were 0.37(0.29), 0.37(0.23) and 0.30(0.26) cm, and initial diameters were 4.58(0.35), 4.58(0.35) and 4.62(0.36) cm, respectively. Patients of + 148 AA genotype had a slower aneurysm growth rate (unadjusted P = 0.058; after adjustment for age, sex, initial AAA diameter and smoking, P = 0.027). There also was a trend for the rare homozygotes of the-82 C allele to have slower AAA growth (adjusted P = 0.055). Smoking history had a stronger association with aneurysm growth (P = 0.003). CONCLUSION: There was a weak association between variation in the cystatin C gene and AAA growth. Medical strategies to limit AAA growth might include the inhibition of cysteine proteases.
Aged↗
The UK Endovascular Aneurysm Repair (EVAR) trials: design, methodology and progress.
OBJECTIVES: The endovascular aneurysm repair (EVAR) trials aim to assess the efficacy of EVAR in the treatment of AAA in terms of mortality, quality of life, durability and cost-effectiveness. DESIGN: Male and female patients aged at least 60 years with an AAA diameter measuring at least 5.5 cm on a computed tomography (CT) scan are assessed for anatomical suitability for EVAR. Suitable patients are offered entry either into EVAR Trial 1 if they are considered fit for conventional open repair or EVAR Trial 2 if they are considered unfit. EVAR 1 randomly allocates patients to EVAR or open repair and EVAR 2 randomly allocates patients to EVAR with best medical treatment or best medical treatment alone. Target recruitment for EVAR Trials 1 and 2 is 900 and 280 patients, respectively. PROGRESS: Recruitment began in September 1999 and there are currently 40 UK centres participating in the trials. Monthly targets are being exceeded in EVAR Trial 1 with 1037 patients randomised by October 2003. EVAR Trial 2 is also meeting monthly targets with a total of 319 patients randomised. When recruitment closes in December 2003 patients will need to be followed for at least 1 year from their operation. Publication of full results for both trials is expected in mid 2005.
Aortic Aneurysm, Abdominal↗
Familial clustering of abdominal aortic aneurysm--smoke signals, but no culprit genes.
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Aortic Aneurysm, Abdominal↗
Prostaglandin E2 receptors in abdominal aortic aneurysm and human aortic smooth muscle cells.
BACKGROUND: Prostaglandin (PG) E(2) (PGE(2)) appears to have a role in stimulating production of interleukin-6 (IL-6) and apoptosis of smooth muscle cells in diseased aortic tissue. These actions are mediated by cellular receptors for PGE(2) EP receptors. OBJECTIVE: This study was undertaken to identify EP receptors associated with production of IL-6 by aortic explants. METHODS: Biopsy specimens of abdominal aortic aneurysm were used for explant culture and preparation of messenger RNA. The presence of EP1, EP2, EP3, and EP4 receptors in tissue and cells was investigated with reverse-transcriptase polymerase chain reaction. IL-6 and cyclic adenosine monophosphate were measured with an enzyme-linked immunosorbent assay. RESULTS: PGE(2) or 11-deoxy-PGE(1) (EP 2/3/4 agonist) reversed partially the indomethacin suppression of IL-6 secretion from explant cultures, whereas butaprost (EP2 receptor agonist) and sulprostone (EP 1/3 receptor agonist) had no effect. Aortic biopsy specimens expressed EP2, EP3-III, and EP4 receptors. Aortic smooth muscle cells expressed EP2 receptor and four variants of EP3 receptor, ie, EP3-Ib, EP3-II, EP3-III, and EP3-IV, but PGE(2) did not stimulate secretion of IL-6. In contrast, PGE(2) or 11-deoxy-PGE(1) stimulated secretion of IL-6 from aortic macrophages. CONCLUSIONS: In aortic explants, PGE(2) stimulates IL-6 secretion by activation of EP4 receptors, present in macrophages.
Aorta↗
Long-term outcomes of immediate repair compared with surveillance of small abdominal aortic aneurysms.
BACKGROUND: Two clinical trials, one British and one American, have shown that early, prophylactic elective surgery does not improve five-year survival among patients with small abdominal aortic aneurysms. We report long-term outcomes in the United Kingdom Small Aneurysm Trial. METHODS: We randomly assigned 1090 patients, 60 to 76 years of age, with small abdominal aortic aneurysms (diameter, 4.0 to 5.5 cm) to one of two groups: 563 were assigned to undergo early elective surgery, and 527 were assigned to undergo surveillance by ultrasonography. Patients were followed in the trial until June 1998 and thereafter until August 2001; the mean duration of follow-up was 8 years (range, 6 to 10). RESULTS: The mean duration of survival was 6.5 years among patients in the surveillance group, as compared with 6.7 years among patients in the early-surgery group (P=0.29). The adjusted hazard ratio for death from any cause in the early-surgery group as compared with the surveillance group was 0.83 (95 percent confidence interval, 0.69 to 1.00; P=0.05). The 30-day operative mortality in the early-surgery group (5.5 percent) led to an early disadvantage in terms of survival. The survival curves crossed at three years, and at eight years, mortality in the early-surgery group was 7.2 percentage points lower than that in the surveillance group (P=0.03). There was no evidence that age, sex, or the initial size of the aneurysm modified the hazard ratio or that delayed surgery in the surveillance group increased 30-day postoperative mortality. Death was attributable to a ruptured aneurysm in 19 of the 411 men who died (5 percent) and in 12 of the 85 women who died (14 percent) (P=0.001). The rate of early cessation of smoking was higher in the early-surgery group than in the surveillance group. CONCLUSIONS: Among patients with a small abdominal aortic aneurysm, we found no long-term difference in mean survival between the early-surgery and surveillance groups, although after eight years, total mortality was lower in the early-surgery group. This difference may be attributed in part to beneficial changes in lifestyle adopted by members of the early-surgery group.
Age Factors↗
Interleukin-6 (IL-6) and the prognosis of abdominal aortic aneurysms.
BACKGROUND: Abdominal aortic aneurysm is a multifactorial disorder in which inflammation is an important pathophysiological feature. In explant culture, aneurysm biopsies secrete large amounts of interleukin-6 (IL-6), and among aneurysm patients, the circulating concentration of IL-6 appears to be increased. METHODS AND RESULTS: We investigated, in 19 patients, whether aneurysm wall was an important source of circulating IL-6. We also tested the hypotheses, in 466 patients with a small aneurysm, that (1) high concentrations of circulating IL-6 signaled rapid aneurysm growth and (2) the -174 G-->C polymorphism in the IL-6 promoter predicted survival. For 19 patients with large or inflammatory aneurysms, the concentration of IL-6 was higher in the iliac arteries than the brachial arteries (median difference 26.5 pg/mL, this difference increasing with aneurysm diameter, P=0.01). In 466 patients with small aneurysms, the frequency of the -174 C allele (0.40) was similar to that in a normal healthy population. Patients of GG genotype had lower plasma concentrations of IL-6 than patients of GC and CC genotypes (medians 1.9, 4.8, and 15.6 pg/mL, respectively, Kruskal-Wallis P=0.047). Cardiovascular and all-cause mortalities were lower for patients of GG genotype than for patients of GC and CC genotype: hazard ratios 0.32 (95% CI 0.12 to 0.93), P=0.036, and 0.51 (95% CI 0.25 to 1.00), P=0.05, respectively. There was no association between plasma IL-6 or IL-6 genotype and aneurysm growth. CONCLUSIONS: Aortic aneurysms appear to be an important source of circulating IL-6, the concentration being influenced by genotype. For patients with small aneurysms, the -174 G-->C IL-6 genotype predicts future cardiovascular mortality.
Aged↗
Provocation of experimental aortic inflammation and dilatation by inflammatory mediators and Chlamydia pneumoniae.
BACKGROUND: The macrophage appears to have a key role in the inflammation and proteolysis associated with the growth and development of abdominal aortic aneurysms. The role of inflammatory mediators and Chlamydia pneumoniae in stimulating the influx of macrophages and dilatation of the abdominal aorta was investigated in an experimental model. METHODS: Periaortic application of calcium chloride solution (and monocyte chemoattractant protein (MCP) 1, a cocktail of cytokines or C. pneumoniae) to the abdominal aorta of New Zealand White rabbits was performed at laparotomy. Some animals were fed a cholesterol-rich diet. The diameter of the aorta was measured by ultrasonography and after perfusion fixation, 3 weeks after laparotomy. Aortic sections were stained with RAM-11 to identify macrophages for counting. The presence of C. pneumoniae DNA was confirmed using the polymerase chain reaction. RESULTS: Aortic macrophage influx in response to MCP-1, thioglycollate or C. pneumoniae was more than doubled in the cholesterol-fed animals. In response to human recombinant MCP-1 (1 microg) the mean(s.d.) macrophage count increased from 79(19) to 340(215) per unit area (P < 0.02). Even in cholesterol-fed animals, application of MCP-1 (recombinant human or rabbit form) was not associated with aortic dilatation. Application of thioglycollate 0.1 mol/l, or live or formalin-inactivated C. pneumoniae (0.5 x 108 organisms), was associated with a similar increase in macrophages to that caused by MCP-1 and a significant (approximately twofold) increase in aortic diameter after 3 weeks. CONCLUSION: Macrophage influx into rabbit abdominal aorta, without macrophage activation, is insufficient to cause experimental aortic dilatation. C. pneumoniae antigens appeared to stimulate aortic dilatation, probably by specific activation of macrophages.
Animals↗
Are we ignoring the importance of ankle pressures in patients with abdominal aortic aneurysm?
BACKGROUND AND PURPOSE: the ankle/brachial pressure index (ABPI) has been shown to be a reliable marker of cardiovascular risk in population studies. We investigated whether the ABPI was a useful prognostic index for patients with abdominal aortic aneurysm. METHODS: patients entered into the U.K. Small Aneurysm Trial and Study had their ABPI measured in both legs at baseline (mean ABPI reported) and were followed up until 30 June 1998, with information about cause of death being obtained from the Office of National Statistics. This study focussed on cardiovascular and all-cause mortality. RESULTS: a total of 1827 men and 478 women, mean age 69 years, median aneurysm diameter 4.4 cm, were followed up for a median of 5.7 years. A total of 829 deaths were reported (rate 8.1 per 100 person-years), 546 (66%) from cardiovascular causes. The all-cause mortality risk increased as the ABPI decreased, hazard ratio 1.25 per 0.2 unit decrease in ABPI (95% CI 1.17 to 1.34, p<0.001). For patients in the lowest tertile group (ABPI <0.87) there were 11.6 deaths per 100 person-years. This increased risk persisted after adjustment for age, sex, evidence of ischaemia on resting ECG and initial aneurysm diameter, adjusted hazard ratio 1.17 per 0.2 unit decrease in ABPI (95% CI 1.07 to 1.28, p<0.001). CONCLUSION: the ankle/brachial pressure index is an important prognostic indicator for patients with abdominal aortic aneurysm. Patients with an ABPI below 0.87 (limit of lowest tertile) have the highest mortality risk and best clinical practice demands that attention is focussed on active treatment to minimise their cardiovascular risk factors.
Aged↗
Fibrin monomer and fibrinopeptide B act additively to increase DNA synthesis in smooth muscle cells cultured from human saphenous vein.
PURPOSE: We investigated the hypothesis that fibrinogen increased DNA synthesis (and cell proliferation) of smooth muscle cells (SMCs) cultured from human saphenous vein and that the increased DNA synthesis was attenuated when cells were cultured on polymeric collagen. METHODS: SMCs were cultured from human saphenous vein on plastic, fibronectin, monomeric, and polymeric collagen. Fibrinogen products were prepared by proteolytic digestion. DNA synthesis was measured by bromodeoxyuridine incorporation into DNA, cell proliferation by cell counting, cyclic adenosine monophosphate by enzyme-linked immunosorbent assay, and fibrinopeptide B labeled with iodine 125 used for binding studies. RESULTS: Fibrin monomer (0.003-0.1 micromol/L) stimulated a concentration-dependent increase in DNA synthesis of up to 10-fold, which could be inhibited by the peptide Bbeta15-42. The stimulation of DNA synthesis was highest for cells cultured on plastic and lowest for cells cultured on type I collagen polymer. Much higher concentrations of fibrinogen (0.3-1 micromol/L) were required to effect similar increases in DNA synthesis. Fibrinogen had a particular effect to augment DNA synthesis, up to 14-fold, when cells were cultured on monomeric type I collagen. This augmented DNA synthesis was inhibited by a neutralizing antibody to urokinase-type plasminogen activator. Incubation of cells cultured on collagen monomer with fibrinogen resulted in production of fibrinopeptide B. Fibrinopeptide B (5 micromol/L) increased DNA synthesis by fourfold and had additive effects with fibrin monomer to increase DNA synthesis. Iodinated tyrosine fibrinopeptide B bound to SMCs (dissociation constant 0.6 micromol/L). CONCLUSION: Cultured human saphenous vein SMCs appear to have high-affinity receptors for fibrin monomer and fibrinopeptide B, the engagement of which stimulates DNA synthesis. These mechanisms may be pertinent to the association between fibrinogen and vein graft stenosis in vivo.
Bromodeoxyuridine↗
Cadmium accumulation in aortas of smokers.
Abdominal aortic aneurysm is a smoking-related disorder. Cadmium, inhaled from cigarettes, may accumulate in the aorta and facilitate weakening of the aorta through adverse effects on smooth muscle cell metabolism. Cadmium was measured by atomic absorption spectrometry in infrarenal aortas from 13 patients with abdominal aortic aneurysm and from 17 age- and sex-matched patients with normal-diameter abdominal aorta. Total cadmium content was associated with smoking, assessed as pack-years (r=0.54, P=0.004), but was similar in aneurysmal and undilated aortas. The cadmium content (mean+/-SE) was higher in the media (3.25+/-0.53 ng/mg dry wt, 7+/-1.2 micromol/L) than in the intima or adventitia (1.14+/-0.24 and 1.87+/-0.38 ng/mg dry wt, respectively; ANOVA, P<0.005). There was a strong correlation between medial cadmium content and pack-years of smoking (r=0.87, P<0.001). In aortic smooth muscle cells cultured on fibrillar collagen, cadmium inhibited DNA synthesis and collagen synthesis and diminished cell numbers (IC(50) 2 micromol/L, 6 micromol/L, and 6 micromol/L, respectively), but higher concentrations of cadmium were required for upregulation of metallothionein (EC(50) 23 micromol/L). The cadmium content of the aorta increases in direct proportion to the pack-years of cigarettes smoked, with selective accumulation in the medial layer. However, the cadmium content of aneurysmal aortas was not higher than that of nondilated aortas for patients with matched smoking history. In smokers, the level of cadmium accumulation is probably sufficient to impair the viability of cultured smooth muscle cells. Similar mechanisms could underlie the development of degenerative aortic disease in smokers.
Aged↗
Aortic aneurysm diameter and risk of cardiovascular mortality.
After successful surgical repair of an abdominal aortic aneurysm, patients have for many years an increased risk of death from cardiovascular causes. We have tested the hypothesis that for patients with abdominal aortic aneurysms, the risk of nonaneurysm cardiovascular mortality before and after surgery increased with aneurysm diameter. Records of aneurysm repair or rupture and mortality were available from 2305 patients entered into the UK Small Aneurysm Trial and Study. Two hundred fifty-nine deaths occurred before aneurysm repair or rupture (mean follow-up 1.7 years), and 325 occurred after surgical repair (mean follow-up 3.6 years). The risk of nonaneurysm-related mortality and cardiovascular death before and after surgery increased with aneurysm diameter at baseline, even after adjustment for other known risk factors. The adjusted hazard ratios for cardiovascular mortality, per standard deviation (0.8-cm) increase in aneurysm diameter, were 1.34 (95% CI 1.01 to 1.79) and 1.31 (95% CI 1.06 to 1.63) in the periods before aneurysm repair or rupture and after aneurysm repair, respectively. The significant association between aortic diameter and cardiovascular mortality, excluding aneurysm-related deaths, suggests that aneurysm diameter is an independent marker of cardiovascular disease risk.
Aged↗