Impact of gender on the outcome of endovascular aortic aneurysm repair using the Zenith stent-graft: midterm results.

PURPOSE: To analyze the 2-year outcomes of female patients after endovascular aortic aneurysm repair (EVAR) with the Zenith AAA Endovascular Graft. METHODS: A retrospective analysis was conducted of data from the US Zenith multicenter trial and the Zenith female registry on 40 women (10.9%, study group) and 326 men (89.1%, control group) enrolled. All patients had completed their 2-year follow-up. Primary study endpoints were survival, aneurysm rupture, and conversion rate. Significance was assumed if p<0.05. RESULTS: Overall rates of mortality (12.5% for women versus 13.2% for men, p = 0.94) and aneurysm rupture (2.5% for women versus 0% for men, p = 0.11) were comparable between groups. Conversion to open repair within 2 years was significantly more frequent in women compared to men (7.5% versus 0.6%, p = 0.01). The incidence of endoleaks of any type was equivalent between groups at 2 years (13.3% for women versus 6.9% for men, p = 0.30). No difference was observed in the need for secondary interventions (15% for women versus 13.5% for men, p = 0.81) or aneurysm dilatation >5 mm (10.5% for women versus 2.3% for men, p = 0.10). None of the patients developed device migration >10 mm or required intervention for migration. CONCLUSION: While women underwent conversion to open repair more frequently compared to men at 2 years post EVAR, there was no difference in survival, freedom from aneurysm rupture, or need for secondary interventions between groups. As in men, the Zenith AAA Endovascular Graft provides reliable protection from aneurysm rupture and aneurysm-related death in women in a midterm follow-up.

Endovascular aortic aneurysm repair with the Zenith endograft in patients with ectatic iliac arteries.

Endovascular aortic aneurysm repair (EVAR) in patients with ectatic iliac arteries is feasible; however, most studies have reported experience from single institutions where distal flare techniques with endograft components were used on an "off-label basis." The Zenith endovascular graft allows adequate seal in ectatic common iliac arteries (CIAs) with diameters up to 20 mm. To determine whether large or ectatic CIAs are a risk factor for early and late endograft failure, we analyzed data from the Zenith U.S. multicenter trial. Among 352 patients receiving the endograft in the Zenith u.s. clinical study, 156 patients (44%) had at least one ectatic iliac artery (maximum diameter between 14 and 20 mm), whereas 22 (6.3%) had bilateral CIAs of normal diameter (< 14 mm). Variables analyzed included those defined by the reporting standards for EVAR (SVS/AAVS) as well as iliac-related outcome and indications for secondary iliac interventions. Univariate (Kaplan-Meier [KM] receiver operating characteristics curve, and Cox regression analyses were used to determine the association between CIA diameter and iliac-related complications. The median follow-up period was 24 months. Technical success was similar (>99%) for patients with ectatic and normal CIAs. Only one late type I distal endoleak was reported and was attributed to failure of distal iliac seal in a patient with ectatic CIAs. Freedom from iliac-related secondary intervention (IRSI) was not significantly different between the groups (KM, log-rank test, p = 0.98) with rates at 1, 12, and 24 months of 98%, 97%, and 95% for patients with ectatic CIAs, and 100%, 95%, and 95% for patients with normal iliac arteries, respectively. Moreover, Cox regression analysis revealed that the maximum CIA diameter was not a significant predictor of freedom from IRSI (hazard ratio, 0.98; 95% confidence interval, 0.7-1.4; p = 0.98). In patients with large CIAs, indications for IRSI included distal type I endoleak (1, 0.6%), type III endoleak (1, 0.6%), graft limb occlusion (4, 2.6%), and device stenosis (1, 0.6%). The only IRSI in a patient with normal CIAs was performed for device stenosis (4.6%). In conclusion, the Zenith endograft is effective for EVAR in patients with ectatic CIAs. Moreover, the presence of large CIAs was not associated with an increased risk of adverse iliac-related outcome or subsequent IRSI. Long-term surveillance, however, is mandatory, as IRSIs may be necessary.

UCP-mediated energy depletion in skeletal muscle increases glucose transport despite lipid accumulation and mitochondrial dysfunction.

To address the potential role of lipotoxicity and mitochondrial function in insulin resistance, we studied mice with high-level expression of uncoupling protein-1 in skeletal muscle (UCP-H mice). Body weight, body length, and bone mineral density were decreased in UCP-H mice compared with wild-type littermates. Forelimb grip strength and muscle mass were strikingly decreased, whereas muscle triglyceride content was increased fivefold in UCP-H mice. Electron microscopy demonstrated lipid accumulation and large mitochondria with abnormal architecture in UCP-H skeletal muscle. ATP content and key mitochondrial proteins were decreased in UCP-H muscle. Despite mitochondrial dysfunction and increased intramyocellular fat, fasting serum glucose was 22% lower and insulin-stimulated glucose transport 80% higher in UCP-H animals. These beneficial effects on glucose metabolism were associated with increased AMP kinase and hexokinase activities, as well as elevated levels of GLUT4 and myocyte enhancer factor-2 proteins A and D in skeletal muscle. These results suggest that UCP-H mice have a mitochondrial myopathy due to depleted energy stores sufficient to compromise growth and impair muscle function. Enhanced skeletal muscle glucose transport in this setting suggests that excess intramyocellular lipid and mitochondrial dysfunction are not sufficient to cause insulin resistance in mice.

Skeletal muscle overexpression of nuclear respiratory factor 1 increases glucose transport capacity.

Nuclear respiratory factor 1 (NRF-1) is a transcriptional activator of nuclear genes that encode a range of mitochondrial proteins including cytochrome c, various other respiratory chain subunits, and delta-aminolevulinate synthase. Activation of NRF-1 in fibroblasts has been shown to induce increases in cytochrome c expression and mitochondrial respiratory capacity. To further evaluate the role of NRF-1 in the regulation of mitochondrial biogenesis and respiratory capacity, we generated transgenic mice overexpressing NRF-1 in skeletal muscle. Cytochrome c expression was increased approximately twofold and delta-aminolevulinate synthase was increased approximately 50% in NRF-1 transgenic muscle. The levels of some mitochondrial proteins were increased 50-60%, while others were unchanged. Muscle respiratory capacity was not increased in the NRF-1 transgenic mice. A finding that provides new insight regarding the role of NRF-1 was that expression of MEF2A and GLUT4 was increased in NRF-1 transgenic muscle. The increase in GLUT4 was associated with a proportional increase in insulin-stimulated glucose transport. These results show that an isolated increase in NRF-1 is not sufficient to bring about a coordinated increase in expression of all of the proteins necessary for assembly of functional mitochondria. They also provide the new information that NRF-1 overexpression results in increased expression of GLUT4.

A peroxovanadium compound stimulates muscle glucose transport as powerfully as insulin and contractions combined.

Stimulation of glucose transport by insulin involves tyrosine phosphorylation of the insulin receptor (IR) and IR substrates (IRSs). Peroxovanadates inhibit tyrosine phosphatases, also resulting in tyrosine phosphorylation of the IRSs. Muscle contractions stimulate glucose transport by a mechanism independent of the insulin-signaling pathway. We found that the peroxovanadate compound bis-peroxovanadium,1,10-phenanthrolene [bpV(phen)] stimulates glucose transport to the same extent as the additive effects of maximal insulin and contraction stimuli. Translocation of GLUT4 to the cell surface mediates stimulation of glucose transport. There is evidence suggesting there are separate insulin- and contraction-stimulated pools of GLUT4-containing vesicles. We tested the hypothesis that bpV(phen) stimulates both the insulin- and the contraction-activated pathways. Stimulation of glucose transport and GLUT4 translocation by bpV(phen) was completely blocked by the phosphatidylinositol 3-kinase (PI 3-K) inhibitors wortmannin and LY294002. The combined effect of bpV(phen) and contractions was no greater than that of bpV(phen) alone. Activation of the IRS-PI 3-K signaling pathway was much greater with bpV(phen) than with insulin. Our results suggest that the GLUT4 vesicles that are normally translocated in response to contractions but not insulin can respond to the signal generated via the IRS-PI 3-K pathway if it is sufficiently powerful.

Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1.

Endurance exercise induces increases in mitochondria and the GLUT4 isoform of the glucose transporter in muscle. Although little is known about the mechanisms underlying these adaptations, new information has accumulated regarding how mitochondrial biogenesis and GLUT4 expression are regulated. This includes the findings that the transcriptional coactivator PGC-1 promotes mitochondrial biogenesis and that NRF-1 and NRF-2 act as transcriptional activators of genes encoding mitochondrial enzymes. We tested the hypothesis that increases in PGC-1, NRF-1, and NRF-2 are involved in the initial adaptive response of muscle to exercise. Five daily bouts of swimming induced increases in mitochondrial enzymes and GLUT4 in skeletal muscle in rats. One exercise bout resulted in approximately twofold increases in full-length muscle PGC-1 mRNA and PGC-1 protein, which were evident 18 h after exercise. A smaller form of PGC-1 increased after exercise. The exercise induced increases in muscle NRF-1 and NRF-2 that were evident 12 to 18 h after one exercise bout. These findings suggest that increases in PGC-1, NRF-1, and NRF-2 represent key regulatory components of the stimulation of mitochondrial biogenesis by exercise and that PGC-1 mediates the coordinated increases in GLUT4 and mitochondria.

Respiratory uncoupling lowers blood pressure through a leptin-dependent mechanism in genetically obese mice.

Insulin resistance is commonly associated with hypertension, a condition that causes vascular disease in people with obesity and type 2 diabetes. The mechanisms linking hypertension and insulin resistance are poorly understood. To determine whether respiratory uncoupling can prevent insulin resistance-related hypertension, we crossed transgenic mice expressing uncoupling protein 1 (UCP1) in skeletal muscle with lethal yellow (A(y)/a) mice, genetically obese animals known to have elevated blood pressure. Despite increased food intake, UCP-A(y)/a mice weighed less than their A(y)/a littermates. The metabolic rate was higher in UCP-A(y)/a mice than in A(y)/a mice and did not impair their ability to alter oxygen consumption in response to temperature changes, an adaptation involving sympathetic nervous system activity. Compared with their nontransgenic littermates, UCP-A(y)/a mice had lower fasting insulin, glucose, triglyceride, and cholesterol levels and were more insulin sensitive. Blood pressure, serum leptin, and urinary catecholamine levels were also lower in uncoupled mice. Independent of sympathetic nervous system activity, low-dose peripheral leptin infusion increased blood pressure in UCP-A(y)/a mice but not in their A(y)/a littermates. These data indicate that skeletal muscle respiratory uncoupling reverses insulin resistance and lowers blood pressure in genetic obesity without affecting thermoregulation. The data also suggest that uncoupling could decrease the risk of atherosclerosis in type 2 diabetes.

Glucose transport rate and glycogen synthase activity both limit skeletal muscle glycogen accumulation.

We varied rates of glucose transport and glycogen synthase I (GS-I) activity (%GS-I) in isolated rat epitrochlearis muscle to examine the role of each process in determining the rate of glycogen accumulation. %GS-I was maintained at or above the fasting basal range during 3 h of incubation with 36 mM glucose and 60 microU/ml insulin. Lithium (2 mM LiCl) added to insulin increased glucose transport rate and muscle glycogen content compared with insulin alone. The glycogen synthase kinase-3beta inhibitor GF-109203 x (GF; 10 microM) maintained %GS-I about twofold higher than insulin with or without lithium but did not increase glycogen accumulation. When %GS-I was lowered below the fasting range by prolonged incubation with 36 mM glucose and 2 mU/ml insulin, raising rates of glucose transport with bpV(phen) or of %GS-I with GF produced additive increases in glycogen concentration. Phosphorylase activity was unaffected by GF or bpV(phen). In muscles of fed animals, %GS-I was approximately 30% lower than in those of fasted rats, and insulin-stimulated glycogen accumulation did not occur unless %GS-I was raised with GF. We conclude that the rate of glucose transport is rate limiting for glycogen accumulation unless %GS-I is below the fasting range, in which case both glucose transport rate and GS activity can limit glycogen accumulation.

Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca(2+).

There is evidence suggesting that adaptive increases in GLUT4 and mitochondria in skeletal muscle occur in parallel. It has been reported that raising cytosolic Ca(2+) in myocytes induces increases in mitochondrial enzymes. In this study, we tested the hypothesis that an increase in cytosolic Ca(2+) induces an increase in GLUT4. We found that raising cytosolic Ca(2+) by exposing L6 myotubes to 5 mM caffeine for 3 h/day for 5 days induced increases in GLUT4 protein and in myocyte enhancer factor (MEF)2A and MEF2D, which are transcription factors involved in regulating GLUT4 expression. The caffeine-induced increases in GLUT4 and MEF2A and MEF2D were partially blocked by dantrolene, an inhibitor of sarcoplasmic reticulum Ca(2+) release, and completely blocked by KN93, an inhibitor of Ca(2+)-calmodulin-dependent protein kinase (CAMK). Caffeine also induced increases in MEF2A, MEF2D, and GLUT4 in rat epitrochlearis muscles incubated with caffeine in culture medium. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR), which activates AMP-activated protein kinase (AMPK), also induced approximately twofold increases in GLUT4, MEF2A, and MEF2D in L6 myocytes. Our results provide evidence that increases in cytosolic Ca(2+) and activation of AMPK, both of which occur in exercising muscle, increase GLUT4 protein in myocytes and skeletal muscle. The data suggest that this effect of Ca(2+) is mediated by activation of CAMK and indicate that MEF2A and MEF2D are involved in this adaptive response.

Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin.

Evidence has accumulated that activation of AMP kinase (AMPK) mediates the acute increase in glucose transport induced by exercise. As the exercise-induced, insulin-independent increase in glucose transport wears off, it is followed by an increase in muscle insulin sensitivity. The major purpose of this study was to determine whether hypoxia and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), which also activate AMPK and stimulate glucose transport, also induce an increase in insulin sensitivity. We found that the increase in glucose transport in response to 30 microU/ml insulin was about twofold greater in rat epitrochlearis muscles that had been made hypoxic or treated with AICAR 3.5 h previously than in untreated control muscles. This increase in insulin sensitivity was similar to that induced by a 2-h bout of swimming or 10 min of in vitro electrically stimulated contractions. Neither phosphatidylinositol 3-kinase activity nor protein kinase B (PKB) phosphorylation in response to 30 microU/ml insulin was enhanced by prior exercise or AICAR treatment that increased insulin sensitivity of glucose transport. Inhibition of protein synthesis by inclusion of cycloheximide in the incubation medium for 3.5 h after exercise did not prevent the increase in insulin sensitivity. Contractions, hypoxia, and treatment with AICAR all caused a two- to three-fold increase in AMPK activity over the resting level. These results provide evidence that the increase in insulin sensitivity of muscle glucose transport that follows exercise is mediated by activation of AMPK and involves a step beyond PKB in the pathway by which insulin stimulates glucose transport.