Haemodilution in patients with peripheral arterial occlusive disease.

Haemodilution is an efficient conservative therapy of peripheral arterial occlusive disease. Already a single isovolaemic haemodilution (replacement of 500 ml blood for Haes* 0.5, 10%) increases the pain-free walking distance by 85%. These effects can be maintained by a constant therapy over six weeks and following haemodilution once or twice per month. The haematocrit values should be between 38 and 42%. The haemodilution should be done hyper- or isovolaemically. Not more than 250 ml blood and 500 ml Haes should be infused during one session in order to avoid hypovolaemia. This means an infusion of 250 ml Haes, venesection of 250 ml blood via the same access and then infusion of the remaining 250 ml. The whole procedure should not last more than one hour. Blood pressure, heart rate, lung auscultation and percussion as well as creatinine values has to be controlled during an intensive therapy. If the hydroxyethyl starch concentration exceeds 150 g per week pruritus may occur in singular cases, if the concentration exceeds 700 g per week it is observed in 50% of the cases. Provided the preventive measures are observed haemodilution is an efficient and good therapy which also increases the compliance to practice vascular exercise.     

Angiotensin-converting enzyme gene insertion/deletion polymorphism and carotid artery wall thickness in patients with peripheral arterial occlusive disease.

BACKGROUND: It has been suggested that the deletion polymorphism of the angiotensin converting enzyme (ACE) gene is linked to a high risk of cardiovascular disease. The relationship between the insertion/deletion (I/D) polymorphism of the ACE gene and the carotid intima-media thickness in patients with peripheral arterial occlusive disease is unknown. We tested the hypothesis that the early progression of atherosclerosis in the extracranial carotid arteries in patients with peripheral arterial disease is associated with a genetic predisposition. METHODS: This prospective trial included 98 patients who only had manifestations of arteriosclerotic disease in peripheral arterial vascular regions of the lower extremities (stable stage II PAOD). Maximal common carotid intima-media thickness (mIMT) was measured using high resolution B-mode ultrasonography. Determinations of ACE gene polymorphism were made using a polymerase chain reaction technique. Multivariate regression analysis was performed to assess the influence of ACE genotypes, ACE activity and vascular risk factors on intima-media thickness. RESULTS: There was no significant association between intima-media thickness and ACE gene polymorphism. History of symptomatic peripheral arterial disease without local or systemic progression exists in subjects with the II-genotype significantly longer than in subjects with the DD genotype (p=0.01). With the presence of an II-genotype, there was also a tendency towards a thinner intima-media thickness. We found significant correlations between intima-media thickness and age (p<0.0001), fasting serum insulin (p=0.001), and lipoprotein (a) (p=0.008). CONCLUSIONS: In the present study involving patients with stage II peripheral arterial occlusive disease, ACE gene polymorphism could not be identified as a determining marker for the development of intima-media thickening in the common carotid artery. However, it can be assumed that there is a reduced risk for the systemic progression of atherosclerosis in patients with the II genotype.     

Determinants of peak V(O2) in peripheral arterial occlusive disease patients

Peripheral arterial occlusive disease (PAOD) patients with intermittent claudication are functionally limited and deconditioned. This study examined whether peak aerobic capacity (V(O2) peak) was associated with PAOD severity, muscle mass, and comorbidities in 109 PAOD patients (93 men and 16 women) aged 48-86 years. The V(O2) peak (1.12+/-0.34 L/min), percentage body fat (30.6+/-8.3%), lean tissue mass of the total body (51.4+/-8.4 kg), lean tissue mass of the legs (16.6+/-3.0 kg), and appendicular skeletal mass (22.8+/-4.2 kg) were determined. The lean tissue mass of the total body (r = .44), lean tissue of the legs (r = .43) and resting ankle/brachial systolic pressure index (ABI; r = .41) correlated with peak V(O2) (all p < .001). None of the comorbidity variables (obesity, arthritis, coronary artery disease, hypertension, diabetes, and smoking history) were significantly associated with peak V(O2) except smoking status. The final model for the prediction of peak V(O2) included lean tissue mass of the legs, resting ABI, smoking status, and ABI x smoking status (r2 = .37,p < .001). In older patients with intermittent claudication, lean tissue mass is an important determinant of physical performance independent of PAOD severity and smoking status. Prevention of muscle atrophy may preserve ambulatory function and peak exercise capacity in older PAOD patients.     

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.     

Increasing prevalence of peripheral artery occlusive disease in hemodialysis patients: a 2-year follow-up

IntroductionPeripheral artery occlusive disease (PAOD) has been reported to be prevalent in hemodialysis patients and influence their mortality. Ankle-brachial index (ABI) < 0.9 is a reliable marker for PAOD. The aims of the 2-year longitudinal study were to assess whether there was a progression in PAOD and to find out the determinants of ABI progression in hemodialysis patients.MethodsThis study enrolled 237 routine hemodialysis patients and 154 patients completed the 2-year follow-up. The ABI was measured by an ABI-form device at baseline and at the first and second year follow-up. The change in ABI (ΔABI) was defined as ABI measured at the second year followup minus ABI measured at baseline.ResultsThe prevalence of ABI < 0.9 increased yearly (10.4%, 22.7% and 27.9%, respectively; P < 0.001) and the values of ABI decreased yearly (1.11 ± 0.16, 0.97 ± 0.17 and 0.96 ± 0.19, respectively; P < 0.001) in the 154 follow-up patients. Multiple stepwise analysis identified fasting glucose level, calcium-phosphorous product, high-sensitivity C-reactive protein and homocysteine level as independent determinants of ΔABI.ConclusionsOur results demonstrated the prevalence of PAOD increased and the values of ABI decreased yearly in hemodialysis patients. The ABI progression was associated with high fasting glucose level, high calcium-phosphorous product, high-sensitivity C-reactive protein and low homocysteine levels.     

Haptoglobin polymorphism and peripheral arterial occlusive disease.

Haptoglobin (Hp) 2-2 phenotype is a genetic risk factor in coronary atherosclerosis. In this study, haptoglobin phenotypes were determined in 141 patients with peripheral arterial occlusive disease (PAOD) and compared to a reference population (n = 1000). The relative Hp1 allele frequency was decreased among PAOD patients (0.294 vs. 0.403 for the reference population, P < 0.01) due to an overrepresentation of the Hp 2-2 phenotype (50%, odds ratio 1.82 (95% C.I. 1.28-2.60), P < 0.001). This finding was even more pronounced in non-diabetic and in non-smoking PAOD patients (Hp1 allele frequencies: 0.265 and 0.228, respectively). Serum lipids, inflammatory parameters, and blood pressure levels were comparable among the Hp phenotypes, but serum levels of the antioxidant vitamin C were lower in Hp 2-2 patients than in patients with another phenotype (P < 0.05). In PAOD patients with severe atherosclerotic lesions, maximal walking distance of patients carrying a Hp 2-2 phenotype (225-525 m) exceeded that of other Hp phenotypes (50-242 m) (interquartile ranges) (P < 0.05). The findings demonstrate that, despite an increased risk for developing PAOD, the Hp 2-2 phenotype is associated with a longer maximal walking distance which might be attributed to the earlier reported in vitro angiogenic properties of the Hp 2-2 molecule.     

Dyslipoproteinemia and peripheral arterial occlusive disease

Peripheral arterial occlusive disease (PAOD) is common in older age. PAOD is associated with an increased risk of vascular events (eg, myocardial infarction or stroke). Therefore, the prevention and treatment of PAOD is important, especially at a time when the elderly population is increasing. There is an association between lipid abnormalities and the risk of developing PAOD. However, it is not yet definitively established that early intervention with lipid-lowering drugs prevents the development of PAOD. There is evidence that vascular events in patients with PAOD can be significantly reduced by statins and that the symptoms associated with PAOD are improved by this treatment. There is an urgent need for appropriately designed lipid-lowering trials in patients with PAOD.     

Thrombophilias and peripheral arterial occlusive disease

Peripheral arterial occlusive disease is a frequent disease due to the classical vascular risk factors such as smoking, diabetes mellitus, dyslipidemia, and hypertension. Despite these risk factors, many thrombophilias (physiological inhibitors defects, Factor V Leiden and 20210A prothrombin gene variant, antiphospholipid antibodies, mild hyperhomocysteinemia 15-30micromol/l) can be evoked in some clinical forms of peripheral arterial occlusive disease. This paper provides a synthesis of the published data about this topic. Screening for these thrombophilias is justified in patients with venous thromboembolic disease, or signs of antiphospholipid syndrome and possibly in different situations such as premature atheroma of lower limbs, chronic ischaemia, evolutive disease despite adapted treatment and revascularisation failures without evident technical explanation. Except for the antiphospholipid syndrome, there is currently no consensus for systematic screening of thrombophilia and treatment in patients with peripheral arterial occlusive disease.     

Ankle-brachial index as an indicator of arterial stiffness in patients without peripheral artery disease

We tested the hypothesis that the Ankle-Brachial Index (ABI) in patients without peripheral arterial disease ([PAD] ABI > 1.0) is an indicator of arterial stiffness. Fifty-five patients had measurement of carotid pulse wave contour, pulse wave velocity (PWV), and ABI. Vascular stiffness as assessed by augmentation index (AIx) showed a significant (P = .002) inverse correlation with ABI. Dichotomizing ABI into groups above and below the median showed that persons with a lower ABI, >1.0 to 1.5 (n = 27) had a significantly (P < .01) higher AIx than those with a higher ABI > 1.5 (n = 28). In contrast, vascular stiffness assessed by brachial-ankle or carotid femoral PWV did not correlate with ABI. In summary, ABI is an indicator of arterial stiffness assessed by AIx. Vascular changes detected by AIx are not the same as those detected by PWV. Assessment of ABI may have utility in cardiovascular risk assessment in patients without PAD.     

Serum hepatocyte growth factor in patients with peripheral arterial occlusive disease.

Hepatocyte growth factor (HGF) is a multifunctional protein implicated in tissue regeneration, wound healing, and angiogenesis. We measured serum HGF concentrations in 37 patients with peripheral arterial occlusive disease (PAOD). Among them, 36 patients underwent arteriography. Serum HGF concentrations were also measured in 40 control subjects who remained free of vascular, liver, kidney, or lung disease. Patients with PAOD showed elevated serum HGF concentrations compared with control subjects (0.40+/-0.02 vs. 0.19+/-0.01 ng/mL; P<0.001). Serum HGF concentrations were significantly higher in smokers compared with nonsmokers (0.45+/-0.03 vs. 0.35+/-0.02 ng/mL; P = 0.003). The serum HGF concentrations in patients with collaterals tended to be higher than those in patients without collaterals (0.43+/-0.03 vs. 0.35+/-0.02 ng/mL; P = 0.06). Moreover, in patients who underwent bypass surgery or angioplasty, serum HGF concentrations decreased from 0.41+/-0.03 to 0.21+/-0.04 ng/mL after treatment (P<0.001). Serum HGF may be an useful marker for the diagnosis of PAOD. HGF may play an important role in angiogenesis and collateral vessel growth in PAOD.     

Haemostatic derangement in advanced peripheral occlusive arterial disease.

BACKGROUND: Dysbalance of the coagulation and fibrinolysis system was suspected to be a further risk factor for the progression of peripheral occlusive arterial disease (POAD). Reports on disturbed platelet function in advanced disease, however, were contradictory. Therefore, we studied haemostasis parameters and platelet function in symptomatic patients with peripheral arterial disease. METHODS: 60 peripheral arterial disease patients hospitalised for invasive diagnostic procedures were included into this comparative study. Patients were clinically stratified according to the criteria for chronic limb ischemia (grade I: n=36; grade II: n=11; grade III: n=13). Plasma fibrinogen, antithrombin III, von Willebrand factor, tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) prothrombin time, and activated partial thromboplastin time were determined using standard methods. We measured flow cytometrically, the platelet activation marker P-selectin on nonstimulated, ADP- and TRAP-6-stimulated platelets. Angiographic data were assessed using the Bollinger score. RESULTS: Plasma levels of the procoagulant proteins fibrinogen (grade I: 3.7/grade II: 3.9/grade m: 4.0 g/l) and vWF (158/156/178%) increased and of antithrombin III (109/103/102%) and the PAI-1/tPA ratio (5.2/5.0/4.1) decreased with progressive disease. Highest platelet activation levels were observed in the CLI grade II subgroup. A significant correlation of disease severity was seen with the ankle-brachial pressure index (p=0.006; r=0.39) and with the Bollinger score (p=0.002; r=-0.41). CONCLUSIONS: Progressive peripheral obstructive arterial disease was associated with platelet hyper-reactivity, haemostatic dysbalance of pro- and anticoagulant proteins, and a counterregulatory increase of fibrinolytic activity. Therapeutic concepts should include these pathogenetic mechanisms.     

Alteration of the fibrinolytic system in patients with peripheral arterial occlusive disease.

BACKGROUND: The fibrinolytic system may play an important role in the development and progression of peripheral arterial occlusive disease. PATIENTS AND METHODS: The fibrinolytic system of the whole blood and a diseased leg was investigated in twenty men with chronic peripheral atherosclerotic occlusive arterial disease (PAOD, clinical stage II according to Fontaine), aged from 46 to 66 years (x = 55.3) [symbol: see text]. The diagnosis of PAOD was established by clinical examination and segmental systolic blood pressure measurements using a Doppler ultrasound detector. Twenty age-matched (x = 53.4) male volunteers with normal arterial circulation of the lower limbs and without risk factors of atherosclerosis, served as controls. In both groups fibrinolytic system was investigated in basal conditions and during provocation. Release of tissue-type plasminogen activator (t-PA) was provoked by 20 min venous occlusion of the arm and the leg and by infusion of DDAVP (1-desamino-8-D-arginine-vasopressin, 0.4 ug/kg of body weight). Blood samples were obtained from the arm and the leg before and after each stimulus. The fibrinolytic parameters: euglobulin clot lysis time, t-PA activity (amidolytic assay) and antigen (ELISA) and t-PA inhibitor (PAI) activity (amidolytic assay) were determined. RESULTS: With the exception of a boderline increase in PAI activity in patients, no other differences between the two groups were observed in basal conditions. The most prominent deterioration of the fibrinolytic system detected in male PAOD patients was a significantly higher residual PAI activity registered during venous occlusion of the arm and two minutes after combined stimulation. Two minutes after combined stimulation (DDAVP and venous occlusion of the arm) significantly lower t-PA activity was observed in patients. In patients t-PA antigen response to venous occlusion and DDAVP was not significantly different from the response observed in healthy volunteers. The fibrinolytic response of the leg to venous occlusion was poor and after DDAVP application it was comparable to the arm. The fibrinolytic response of the diseased leg in men was not significantly different from the healthy leg. CONCLUSION: The results of our study indicate that alteration of the fibrinolytic system in atherosclerotic disease is predominantly a generalised phenomenon and is not directly related to a local atherosclerotic process.     

Doppler diagnosis in peripheral arterial occlusive disease

PHYSICAL AND TECHNICAL FUNDAMENTALS OF DOPPLER ULTRASONOGRAPHIC METHODS: In addition to units recording both velocity and direction of blood flow, mostly using two ultrasonic frequencies and phase-out technique, there are small non-directional units available which provide useful diagnostic information from the acoustic Doppler signal derived. Doppler ultrasonic techniques utilize two physical phenomena: a) High-frequency ultrasonic energy penetrates biologic tissue and is partially reflected at borders between tissues of differing density. b) If the border area is in motion, due to the Doppler effect, there is a change in the reflected ultrasonic frequency with respect to the frequency emitted. In blood vessels the ultrasonic beam is primarily reflected from the flowing red blood cells where the change in frequency is a function of the velocity of flow (Doppler effect). From the Doppler transducer, the continuously-emitted ultrasonic beam is also received after being reflected. The frequency of the reflected beam is directly proportional to the velocity of the flowing blood. If flow is directed toward the transducer, the frequency of the reflected beam increases and if the flow is away from the transducer, the converse is true. The best Doppler signals can be received when the angle beta of the transducer to the studied vessel is about 45 degrees. The unprocessed Doppler signal represents a frequency spectrum corresponding to the various velocities of the individual lamina of the blood stream from which the prevailing velocity is integrated and registered. The penetration depth is dependent on the frequency emitted. Doppler units are preferred with working frequencies of 8 to 10 MHz and 3 to 5 MHz. With 8 MHz, the maximal depth of penetration is 3.5 cm, with 4 MHz, 8 cm. The lowest detectable velocity is also dependent on the frequency emitted: with 8 MHz, minimum is 3 cm/s. Since flow toward the transducer results in a positive Doppler shift and flow away in a negative shift, with the Doppler signal, the direction of flow can also be determined. The recorded Doppler curves enable a qualitative and, to some degree, quantitative assessment. Phase-out and frequency analysis systems enable differentiation of forward and backward flow components. From separate forward and backward flow curves, the instantaneous summation curve (integrated instantaneous hemotachygram) as well as a trend curve over 5 to 7 seconds can be constructed and the mean flow velocity displayed.     

Use of abciximab and tirofiban in patients with peripheral arterial occlusive disease and arterial thrombosis

Acute peripheral arterial occlusive disease is an important factor affecting the mobility and mortality rate of elderly patients. Catheter-guided arterial thrombolysis in these patients has its limitations: long lysis times, early occlusions, and high restenosis rates. The study investigated whether the use of tirofiban has the same favorable effect as the glycoprotein (GP) IIb/IIIa receptor antagonist abciximab and whether lysis times can be shortened and the disease course positively influenced by these substances. Sixty patients were randomly assigned to 2 groups. Each group received 5 mg recombinant tissue-type (rt-PA) plasminogen activator by slow intra-arterial injection for 10 minutes followed by 5 mg rt-PA per hour and 500 IU heparin per hour IV. After randomization 1 group received a bolus of 0.25 mg abciximab per kg body weight followed by 10 mg per minute IV for 12 hours (heparin was reduced to 250 IU/hr). The other group received a bolus of 0.4 microg tirofiban per kg body weight as well as postinterventional medication with 0.1 microg tirofiban per minute and kg body weight for 24 hours. During medication with GP IIb/IIIa inhibitor, the patients received a reduced heparin dosage for 24 hours. After 24 hours both groups received 200 mg aspirin orally and full heparinization controlled on the basis of the partial thromboplastin time. The following efficacy criteria were analyzed: rehospitalization events, reintervention events, and amputations within 6 months. Secondary endpoints were changes in the Fontaine stage, the crurobrachial index, the distance to claudication, and the duration of local arterial lysis. No significant differences were found between the abciximab and tirofiban groups in terms of the rehospitalization, reintervention, or amputation rates, nor were there any group differences in the total number of events. The secondary parameters, such as the crurobrachial index, distance to claudication, and Fontaine stage, also showed no significant differences between the 2 groups within 6 months. The duration of lysis was significantly shorter in the abciximab group. Major bleeding events did not occur in either group. With regard to the adverse effect rate, there were no significant differences between the 2 groups. Both abciximab and tirofiban can be used successfully in patients with peripheral arterial occlusive disease and arterial thrombosis.     

Long-term oil therapy in elderly patients with peripheral arterial occlusive disease

3-years dietetic application of polyenic fatty acids in 41 patients with peripheral arterial occlusion disease evoked significantly alterations of total and LDL-cholesterol level and of the serum fatty acid spectrum. These alterations must be valued as "antiatherogenic" although the HDL-cholesterol was not influenced. Linolenic acid enriched linseed oil seems to be more efficient than linolenic acid enriched sun flowers oil.