Influence and interaction of diabetes and lipoprotein (a) serum levels on mortality of patients with peripheral artery disease.

BACKGROUND: Diabetes mellitus is a risk factor for early complications and mortality in patients with peripheral artery disease. Lipoprotein (a) [Lp(a)] is also suggested to be a marker of increased cardiovascular risk. We investigated the association and interaction between diabetes mellitus, lipoprotein(a) and mortality in high risk patients with peripheral artery disease (PAD). METHODS: We studied 700 consecutive patients [median age 73 years, interquartile range (IQR) 62-80, 393 male (56%)] with PAD from a registry database. Atherothrombotic risk factors (diabetes, smoking, hyperlipidaemia, arterial hypertension) and Lp(a) serum levels were recorded. We used stratified multivariate Cox proportional hazard analyses to assess the mortality risk at a given patient's age with respect to the presence of diabetes and Lp(a) serum levels (in tertiles). RESULTS: Patients with Lp(a) levels above 36 mg dL(-1) (highest tertile) and insulin-dependent type II diabetes had a 3.01-fold increased adjusted risk for death (95% confidence interval 1.28-6.64, P = 0.011) compared to patients without diabetes or patients with non-insulin-dependent type II diabetes. In patients with Lp(a) serum levels below 36 mg dL(-1) (lower and middle tertile), diabetes mellitus was not associated with an increased risk for death. CONCLUSION: Insulin-dependent type II diabetes mellitus seems to be associated with an increased risk for mortality in PAD patients with Lp(a) serum levels above 36 mg dL(-1). PAD patients with non-insulin-dependent type II diabetes, and patients with diabetes and Lp(a) levels below 36 mg dL(-1) showed survival rates comparable to PAD patients without diabetes.

Low level laser therapy for treatment of primary and secondary Raynaud's phenomenon.

BACKGROUND: We recently performed a pilot study which suggested that clinical and thermographic improvements occurred in patients with primary and secondary Raynaud's phenomenon (RP) following treatment with low level laser irradiation (LLLI). In view of these findings, we have proceeded with a double blind, placebo-controlled study. METHODS: Forty seven patients suffering from primary or secondary RP were randomly assigned in a double-blind manner to receive either 10 sessions of distant LLLI (16 f, 8 m, median age 45 years) or placebo irradiation (21 f, 2 m, median age 46 years) during winter months. The attack frequency of RP was measured by a diary count; its severity was assessed by means of visual analogue scale. Response to cold challenge test before and after LLL or placebo treatment was assessed by infrared thermography. RESULT: Overall a significant reduction of the frequency as well as the severity of RP in patients with either LLLI (frequency p < 0.0001, severity p < 0.0001) or placebo treatment (frequency p < 0.0001, severity p = 0.02) was found, but patients in the LLLI group exhibited a statistically more significant improvement of the frequency at 6 weeks p = 0.007 and 3 months p = 0.02 and the severity p = 0.02, p = 0.04 of RP. Thermographic response to cold challenge improved only in patients treated with LLL but not in those treated with placebo. CONCLUSION: LLLI significantly lowers the frequency and severity of Raynaud's attacks in patients with primary and secondary RP. Since this therapeutic modality is a safe, and non-invasive treatment, it might be considered as an alternative to existing therapeutic regimes.

Fibrinogen predicts mortality in high risk patients with peripheral artery disease.

OBJECTIVE: Fibrinogen plays a key role in the pathogenesis of atherosclerosis and complications of atherothrombotic disease. We investigated the prognostic impact of fibrinogen levels on mortality of high risk patients with peripheral artery disease (PAD). METHODS: We studied 486 patients with PAD and several cardiovascular comorbidities. Atherosclerotic risk factors and fibrinogen levels were determined at initial presentation and patients were followed for median 7 years (IQR 6-10) for all-cause and cardiovascular mortality. Multivariate Cox regression analysis was applied to assess the predictive value of fibrinogen levels (in quartiles) on patients' outcome. RESULTS: Cumulative survival rates at 1, 3, 5 and 10 years were 96, 91, 83 and 67%, respectively. Overall, 138 patients (28%) died, 70% of these patients died of cardiovascular complications (n=96). Patients with fibrinogen levels 10.2-12.2 micromol/l (third quartile) and patients with fibrinogen levels above 12.2 micromol/l (fourth quartile) had a significantly increased adjusted risk for all-cause mortality (hazard ratios [HR] 1.87 and 1.90, p=0.025 and p=0.020, respectively) compared to patients in the lowest quartile (fibrinogen below 8.6 micromol/l). A consistent effect was observed for cardiovascular causes of death. Diabetes mellitus and critical limb ischemia were the only other independent predictor variables (HR 2.08, p<0.001 and 1.88, p=0.001, respectively). CONCLUSION: Elevated fibrinogen levels in high risk patients with PAD indicate an increased risk for poor outcome, particularly for fatal cardiovascular complications.

Predictors of long-term results after treatment of iliac artery obliteration by transluminal angioplasty and stent deployment.

PURPOSE: To investigate initial and long-term success rate after percutaneous treatment of iliac artery occlusion with angioplasty and stent deployment. To investigate the influence of vascular comorbidity, lesion length, stent placement and lesion coverage as possible predictors of outcome. METHODS: Between January 1994 and December 1999, 80 iliac recanalizations were performed on 78 patients, median age 61.1 +/- 11.5 (SD) years. All patients were followed up by clinical examinations, duplex ultrasound and intravenous digital subtraction angiography. Mean follow-up time was 2.0 +/- 1.53 (SD) years. Multivariate Cox regression analysis was used to determine the influence of cofactors on patency. RESULTS: One, 2 and 4 years after recanalization, primary patency was 78.1%, 74.5% and 64.0%; secondary patency was 88.8%, 88.8% and 77.9%, respectively. Patients with shorter occlusions, complete lesion coverage and patent ipsilateral femoral arteries had significantly longer patency rates. Complications included inguinal hematoma (n=1), technical failure (n=3) aortic dissection (n=1), embolic occlusions (n=7), gluteal claudication (n=1) and genital necrosis after subsequent urethral surgery in one patient with contralateral occlusion and ipsilateral overstenting of the internal iliac artery with subsequent stenosis. Complications were of permanent clinical significance in seven of 78 (9%) of the patients. In 17 (22%) cases, percutaneous reintervention was performed with angioplasty in the stent (n=16) or deployment of a new stent (n=1). CONCLUSION: Endoluminal stent placement has its place in an interdisciplinary therapeutic approach as a viable therapeutic alternative to major transabdominal bypass surgery and can be performed with comparable complication rates. Patients with short occlusions, patent femoral arteries, and stents covering the entire occlusion have significant longer patency.

Clinical outcome and prognostic factors for ischaemic ulcers treated with PTA in lower limbs.

OBJECTIVE: To analyse the clinical outcome of patients with ischaemic ulcers (Fontaine stage IV) undergoing percutaneous transluminal angioplasty (PTA). METHODS AND DESIGN: Retrospective cohort study of 40 patients (21 males) treated between January 1998 and December 1998. Cardiovascular risk factors, co-morbid, baseline laboratory, angiographic data and technical success were recorded. Patients were followed for a median of 20 (inter quartile range (IQR) 8-26) months. RESULTS: Cumulative ulcer healing rates at 3, 6, 12, and 24 months were 15, 40, 54 and 81%, respectively. The median time to healing was 5 (IQR 2-7) months. Cumulative restenosis at 1, 3, 6 and 12 months was 3, 10, 29 and 52%, respectively. Nine patients (22%) suffered ulcer reappearance. Lipoprotein (a) serum levels > 30 mg/dl (HR 0.2, 95% CI 0.05-1.0, p = 0.05) and diabetes mellitus (HR 0.2, 95% CI 0.5-0.7, p = 0.01) were associated with delayed ulcer healing. CONCLUSION: PTA leads to ulcer healing in the majority of patients. Elevated lipoprotein (a) levels > 30 mg/dl and diabetes mellitus are independently associated with ulcer persistence.

Low level laser treatment of primary and secondary Raynaud's phenomenon.

BACKGROUND: Patients who had been treated with low level laser (LLL) for their digital ulcers reported an impressive improvement of their symptoms of episodic digital ischaemia. Therefore this pilot study was performed to evaluate the efficacy of LLL as a new non-drug non-invasive treatment for patients with primary and secondary Raynaud's phenomenon (RP). PATIENTS AND METHODS: Forty patients (29 female, 11 male, mean age 51 years) with active primary (28%) and secondary (72%) Raynaud's phenomenon received 10 sessions of LLL distant irradiation during winter months. Assessment of subjective and objective parameters was performed at baseline, one week after the last session and three months later. Variations of subjective parameters as number of daily acute episodes and severity of discomfort were assessed by a coloured visual analogue scale. A standardised cold challenge test using computed thermography of continuous temperature recordings by means of infrared telethermography was used to assess the digital blood flow. RESULTS: A significant improvement was noticed clinically and thermographically after 6 weeks and 3 months, respectively (p < 0.0001). CONCLUSIONS: These data suggest that LLL treatment has a good short and medium term effectiveness in patients with Raynaud's phenomenon.

Intraarterial (192)Ir high-dose-rate brachytherapy for prophylaxis of restenosis after femoropopliteal percutaneous transluminal angioplasty: the prospective randomized Vienna-2-trial radiotherapy parameters and risk factors analysis.

PURPOSE: The aim of the Vienna-2-trial was to compare the restenosis rate of femoropopliteal arteries after percutaneous transluminal angioplasty (PTA) with or without intraarterial high-dose-rate (HDR) brachytherapy (BT) using an (192)Ir source. MATERIALS AND METHODS: A prospective, randomized trial was conducted from 11/96 to 8/98. A total of 113 patients (63 men, 50 women), with a mean age of 71 years (range, 43-89 years) were included. Inclusion criteria were (1) claudication or critical limb ischemia, (2) de-novo stenosis of 5 cm or more, (3) restenosis after former PTA of any length, and (4) no stent implantation. Patients were randomized after successful PTA for BT vs. no further treatment. A well-balanced patient distribution was achieved for the criteria used for stratification, as there were "de-novo stenosis vs. restenosis after former PTA," "stenosis vs. occlusion," "claudication vs. critical limb ischemia" and above these for "diabetes vs. nondiabetes." PTA length was not well balanced between the treatment arms: a PTA length of 4-10 cm was seen in 19 patients in the PTA alone group and in 11 patients in the PTA+BT group, whereas a PTA length of greater than 10 cm was seen in 35 patients and 42 patients, respectively. A dose of 12 Gy was prescribed in 3-mm distance from the source axis. According to AAPM recommendations, the dose was 6.8 Gy in 5-mm distance (vessel radius + 2 mm). Primary endpoint of the study was femoropopliteal patency after 6 months. RESULTS: PTA and additional BT were feasible and well tolerated by all 57 pts in this treatment arm. No acute, subacute, and late adverse side effects related to BT were seen after a mean follow up of 12 months (6-24 months) in 107 patients (PTA n = 54; PTA+ BT n = 53). Crude restenosis rate at 6 months was in the PTA arm 54% vs. 28% in the PTA + BT arm (chi(2) test; p < 0.013). Actuarial estimate of the patency rate was at 6 months 45% vs. 72% (p < 0.004). Comparison of restenosis rates for the different subgroups with risk factors (restenosis after former PTA, occlusion and PTA length >10 cm) showed significant decrease of the restenosis rate, if BT was added. Significant reduction was not achieved in diabetes patients. CONCLUSION: BT after femoropopliteal PTA is feasible and a safe therapeutic option. No BT related morbidity was observed. A significant reduction of the restenosis rate was obtained in the PTA+BT arm. Subgroup analysis showed significant decrease of restenosis rate in the subgroups with restenosis after former PTA, occlusion and PTA length of greater than 10 cm. With dose escalation and reduction of dose variation by a centering device a further significant decrease of restenosis rate can be expected.

Endovascular brachytherapy for prophylaxis of restenosis after femoropopliteal angioplasty : results of a prospective randomized study.

BACKGROUND: Inasmuch as endovascular brachytherapy (BT) has gained recent interest because of its inhibitory effect on mechanisms leading to restenosis after percutaneous transluminal angioplasty (PTA), we performed this randomized study to determine its efficacy for prophylaxis of restenosis after femoropopliteal PTA. METHODS AND RESULTS: One hundred thirteen patients (63 men, 50 women; mean age 71 years) with de novo or recurrent femoropopliteal lesions were included in this randomized trial comparing the restenosis rate after PTA plus BT (57 patients, PTA+BT group) versus PTA (56 patients, PTA group) without stent implantation. The mean treated length was 16.7 cm (PTA+BT group) versus 14.8 cm (PTA group). In patients randomized to PTA plus BT, a dose of 12 Gy was applied by an (192)Ir source 3 mm from the source axis. Follow-up examinations included measurement of the ankle-brachial index, color-flow duplex sonography, and angiography. The primary end point of the study was patency after 6 months. The overall recurrence rate after 6 months was 15 (28.3%) of 53 in the PTA+BT group versus 29 (53.7%) of 54 in the PTA group (chi(2) test, P<0.05). The cumulative patency rates at 12 months of follow-up were 63.6% in the PTA+BT group and 35.3% in the PTA group (log-rank test, P<0.005). CONCLUSIONS: This is the first randomized study to demonstrate the efficacy of endovascular BT for prophylaxis of restenosis after femoropopliteal PTA. The value of this approach should now be improved by modification of the BT procedure and by combination with stent implantation.

Serum nitrate concentrations in patients with peripheral arterial occlusive disease.

BACKGROUND: Nitric oxide (NO), an endogenous product of L-arginine oxidation, seems to account for the vasodilatatory effect of the endothelium-derived relaxing factor. It was the aim of the present study to measure serum nitrate concentrations, the degradation product of nitric oxide in patients with peripheral arterial occlusive disease (PAOD). PATIENTS AND METHODS: 20 patients with PAOD in Fontaine stage IIb, 10 patients in stage III and IV respectively were included in the study. Serum samples for determination of nitrate were taken at admission after fasting overnight. Nitrate concentrations were determined using a recently developed high performance liquid chromatography which allows direct measurement of nitrate. The control group comprised 14 age and risk factor matched volunteers. RESULTS: We found significantly increased nitrate concentrations in patients with PAOD compared to the control group [stage IIb: 6.65 +/- 1.58 mumol/l; stage III: 6.94 +/- 1.85 mumol/l, stage IV: 7.05 +/- 1.16 mumol/l; control: 4.41 +/- 1.24 mumol/l], however no significance was calculated within the different PAOD groups. There was no association of either diabetes mellitus, hypertension and smoking behaviour with increased nitrate levels. CONCLUSION: These data might indicate that NO might be involved in adaptive vasodilatation already in the early phase of the disease. The source of nitrate in PAOD patients, however, remains unclear.

Brachytherapy for prophylaxis of restenosis after long-segment femoropopliteal angioplasty: pilot study.

PURPOSE: To evaluate in a pilot study the feasibility and efficacy of endovascular brachytherapy for prophylaxis of restenosis after femoropopliteal percutaneous transluminal angioplasty (PTA) without stent implantation in a group of patients with a high risk of restenosis. MATERIALS AND METHODS: Ten patients (six women, four men; mean age, 68 years) with long-segment (mean length, 16 cm; range, 9-22 cm) restenosis underwent PTA followed by endovascular irradiation with high-dose-rate afterloading of an iridium-192 rod. A dose of 12 Gy was targeted to the inner intimal layer of the vessel. Follow-up examinations until 12 months after PTA included measurement of the ankle-brachial index, color duplex ultrasonography (US) with calculation of the peak velocity ratio, and intraarterial angiography when recurrence was suspected. RESULTS: Irradiation was technically feasible in all patients without complications. In six patients, the dilated and irradiated segment remained widely patent at color US, with corresponding excellent hemodynamic and clinical results after 12 months. In four patients, clinical and laboratory findings indicated recurrence and arteriography demonstrated restenosis with a diameter reduction of 60%, 70%, 80%, or 90%. CONCLUSION: Considering the negative selection of patients with a high risk of restenosis, the results of our pilot study are promising concerning the possibility of reduction of restenosis by means of endovascular brachytherapy after long-segment femoropopliteal PTA without stent implantation. The value of this approach should now be determined definitively in randomized trials.

Association between Helicobacter pylori infection and pancreatic cancer.

PURPOSE: In order to determine whether infection with Helicobacter pylori might be associated with pancreatic adenocarcinoma, we performed a study to compare the H. pylori seroprevalence rate between patients with pancreatic carcinoma and matched control subjects. PATIENTS AND METHODS: Blood samples from 92 patients with histologically confirmed diagnosis of pancreatic adenocarcinoma admitted to our hospital between January 1994 and July 1995 were analyzed for the presence of IgG antibodies against H. pylori by a commercially available enzyme-linked immunosorbent assay. Thirty patients with gastric cancer, 35 patients with colorectal cancer, and 27 healthy volunteers served as controls. In addition to these serological analyses, tumor specimens from 20 patients with pancreatic adenocarcinoma were microscopically investigated for the presence of H. pylori. RESULTS: 65% of pancreatic cancer patients and 69% of those with gastric cancer were found to be seropositive, while only 45% of the other controls tested positive. Statistical analysis revealed no difference in seropositivity between the cohort of patients suffering from pancreatic and gastric cancer. The rate of seropositivity was more prominent, however, in pancreatic cancer patients when compared with those suffering from colorectal cancer combined with normal controls (p = 0.035), with an odds ratio of 2.1 (1.1-4.1). Microscopic evaluation of human pancreatic cancer specimens showed no evidence for the presence of H. pylori. CONCLUSION: Our data suggest an association between H. pylori infection and pancreatic cancer. Despite demonstration of a positive relationship and its physiological plausibility, larger prospective studies are needed to confirm our preliminary findings and to assess H. pylori as a potential carcinogenic risk factor.

Elevated lipoprotein(a) and increased incidence of restenosis after femoropopliteal PTA. Rationale for the higher risk of recurrence in females?

It has been shown that the incidence of recurrent stenosis following successful percutaneous transluminal coronary angioplasty (PTCA) is correlated with serum Lipoprotein(a) [Lp(a)] levels. The aim of the present study was to examine the influence of Lp(a) on restenosis after primary successful femoropopliteal PTA. One hundred and thirty nine consecutive patients with peripheral arterial occlusive disease (PAOD) and successful femoropopliteal PTA were studied. Follow-up included clinical examination and non-invasive laboratory testing (pulse volume recordings, ankle-brachial arterial pressure measurement) in every patient before and after 1, 3, 6 and 12 months following intervention. Duplex sonography was performed 1 year after PTA. Suspicion of restenosis (> or = 50% diameter reduction) was verified by angiography. Lp(a) was determined using ELISA technique (mg/dl). Twelve months after successful PTA no restenosis was found in 82 patients (59%: group A). The one-year recurrence rate of 41% (group B) was due to significant restenosis in 35 patients (25%) and reocclusion in 22 patients (16%). The corresponding mean values +/- S.E.M. for Lp(a) were as follows: group A, 28 +/- 5.3; group B 59 +/- 11 (P < 0.01). Women showed a higher frequency of recurrences (55%) versus men (30%, P < 0.01) also corresponding with a high Lp(a) level (51.8 +/- 8 versus 32.7 +/- 5; P < 0.05). Furthermore Lp(a) aggravated the well known increased risk for recurrence in multiple stenoses or occlusions of > or = 5 cm in length. There were no significant differences between groups A and B with respect to age, diabetes, hyperlipidaemia, obesity and cigarette smoking. The results support the view that Lp(a) is an independent risk factor for recurrence after PTA in the femoropopliteal area. It might also be a causal basis for the higher incidence of recurrences in female PAOD patients.

Tissue concentration of clindamycin and gentamicin near ischaemic ulcers with transvenous injection in Bier's arterial arrest.

BACKGROUND: In the treatment of patients with inflamed ischaemic ulcers in peripheral arterial occlusive disease, high tissue concentrations of antibiotics (TCA) are important. With local transvenous pressure injection in Biers' arterial arrest (TVA-Bier) higher TCAs are assumed to be obtained but they have not been measured. METHODS: Two groups of 16 patients each with ischaemic foot ulcers were studied. In one group, patients received a mean of 284 (SD 116) mg gentamicin and in the other, 1200 mg clindamycin. The antibiotics were given intravenously, intra-arterially, and by TVA-Bier in a randomised order at intervals of 48 hours. Biopsy samples were taken from the edge of the ulcers 20 minutes and 3 hours after TVA-Bier, and 1 hour and 3 hours after intravenous and intra-arterial injection. At the same times blood samples were taken. FINDINGS: TCAs of gentamicin and clindamycin with TVA-Bier were significantly higher compared with intravenous or intra-arterial injection. Median TCA-enhancing factor of clindamycin achieved by TVA-Bier at 20 min 1 hour was 18.3 and 14.1 versus intravenous and intra-arterial infusion, respectively, and at 3 hours 7.3 and 5.6, respectively. The median TCA-enhancing factor for gentamicin by TVA-Bier versus intravenous and intra-arterial application was, at 1 hour 20 min, 9.4 and 9.7, respectively, and at 3 hours 1.2 and 1.7, respectively. INTERPRETATION: Higher TCAs could be achieved with TVA-Bier than with intravenous or intra-arterial infusion. TCAs were lower when using gentamicin and higher with clindamycin.

Increased serum laminin and angiogenin concentrations in patients with peripheral arterial occlusive disease.

AIM: To measure serum laminin and angiogenin concentrations in patients with peripheral arterial occlusive disease (PAOD) Fontaine stages IIb, III, and IV. METHODS: The study population comprised 38 patients (20 men and 18 women) with stage IV PAOD, 11 patients (six men and five women) with stage III PAOD, 18 patients (10 men and eight women) with stage IIb PAOD, and 23 patients (10 men and 13 women) with deep vein thrombosis. Fifteen normal subjects (matched for risk factors) and 10 patients (five men and five women) without PAOD served as controls. Serum samples were obtained at admission and serum laminin and angiogenin concentrations were measured using an enzyme linked immunosorbent assay. RESULTS: Patients with stage IV PAOD had higher serum laminin (mean +/- SEM; 826 +/- 97 ng/ml) and angiogenin concentrations (467 +/- 26 pg/ml) than normal subjects (laminin: 379 +/- 21 ng/ml; angiogenin: 358 +/- 16 pg/ml) and patients without PAOD (laminin: 277 +/- 34 ng/ml; angiogenin: 406 +/- 25 pg/ml). A significant correlation was found between angiogenin and laminin and between serum laminin and fibrinogen concentrations in patients with stage IV disease. CONCLUSIONS: Raised laminin and angiogenin concentrations may be indicators of endothelial damage caused by reduced vascular perfusion or compensatory revascularisation, or both.

[Secondary prevention of diabetic retinopathy in type I diabetes mellitus. Dependence on retinopathy status before the intervention]. / Sekundärprävention der diabetischen Retinopathie bei Diabetes mellitus Type I. Abhängigkeit vom Retinopathiestatus vor der Intervention.

OBJECTIVE: To assess prospectively the effect of improving the metabolic state on the course of diabetic retinopathy in relation to the extent of retinal changes before intervention. PATIENTS AND METHODS: 140 patients with type I (insulin-dependent) diabetes mellitus (IDDM) (55 men, 85 women; mean age 30 +/- 11 years; mean duration of illness 11 +/- 8 years), underwent intensified insulin treatment and were then followed for 4 years. At the beginning of the trial fundoscopy was unremarkable in 68 patients (stage 0), a few microaneurysms and (or) punctate bleeding (stage 1) in 21, nonproliferative retinopathy (stage 2) in 27, preproliferative retinopathy (stage 3) in six, proliferative retinopathy (stage 4) in 14, and proliferative retinopathy with complications (stage 5) in four. The average retinopathy stage was 1.2 +/- 1.0, mean HbA1c value 7.0 +/- 1.3%). RESULTS: The retinopathy remained unchanged in 94 patients (group A), it improved in 16 (group B), and deteriorated in 30 (group C). There was no significant change in mean HbA1c value in any of the groups (A: 6.2 +/- 0.9%; B: 6.4 +/- 1.0%; C: 6.3 +/- 6.0%). There were also no differences with respect to blood glucose, M-value according to Schlichtkrull, frequency of hypoglycaemia, serum lipids, blood pressure and renal biopsy parameters. However, significant differences (P < 0.001 C vs. A and B) were found in relation to duration of diabetes (A: 9.3 +/- 7.2 years; B: 8.8 +/- 8.6 years; C: 16.9 +/- 7.8 years) and mean retinopathy stage at beginning of the study (A: 0.8 +/- 0.8; B: 1.2 +/- 0.7; C: 2.4 +/- 1.6). CONCLUSION: Decisive for the course of retinopathy in patients with IDDM of long duration and secondarily optimised metabolic state is the duration of illness and especially the degree of fundal changes when intensified insulin treatment is undertaken.