A.J. Kroese

Markers of vascular inflammation are associated with the extent of atherosclerosis assessed as angiographic score and treadmill walking distances in patients with peripheral arterial occlusive disease

The importance of inflammation in atherosclerosis is well established in cardiovascular disease. However, limited data exist on the relationship between vascular inflammation and the severity of peripheral arterial occlusive disease (PAD). We investigated the relationship between biochemical markers of vascular inflammation and the diagnostic measures of PAD: ankle-brachial pressure index (ABI), maximum treadmill walking distance and angiographic score. In 127 patients (mean age 66 years; 64% males) with angiographically verified PAD, fasting blood samples were drawn for determination of selected soluble cell adhesion molecules, cytokines and chemokines. Tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and CD40 ligand (CD40L) were all significantly correlated with the angiographic score (p < 0.05 for all). After adjustment for relevant co-variates, MCP-1 and CD40L remained statistically significant (p < 0.01 for both). IL-6 was, independent of other risk factors, inversely correlated with the maximum treadmill walking distance (p < 0.01). Our cross-sectional study in PAD patients showed that the vascular inflammatory markers MCP-1, CD40L and IL-6 were significantly associated with the extent of atherosclerosis, assessed by angiographic score and maximum treadmill walking distance. These findings indicate that vascular inflammation is implicated in PAD, which might be of importance in future diagnosis and treatment of the disease.

Laser Doppler flowmetry in evaluation of lower limb resting skin circulation. A study in healthy controls and atherosclerotic patients

Laser Doppler flowmetry (LDF) was used to evaluate lower limb resting skin perfusion in sixty subjects divided into four groups: healthy young and elderly controls, and patients with intermittent claudication or critical ischaemia. Measurements were performed in pulp skin containing microvascular AV anastomoses and in the skin of leg and thigh where these shunts are absent. In toe pulp controls and claudicators had higher perfusion values than in leg and thigh skin (p less than 0.01), indicating that the LDF method evaluates flow both in nutritional capillaries, AV anastomoses and in dermal vascular plexa. Elderly controls had higher flux values in the pulp than claudicators (p less than 0.01), and claudicators had higher values than patients with critical ischaemia (p less than 0.01), showing that LDF could differentiate between the clinical groups. Study of reproducibility confirmed that values were reproducible on a given population. Day to day variation was considerable in individual subjects, probably because of changes in sympathetic vascular tone and because of different vascular architecture in the measuring volumes which are only some few mm3. The fact that LDF measures total skin blood flow explains why several papers have found a poor correlation between LDF and methods which mainly evaluate nutritional blood flow. The method is non-invasive, continuous and easy to perform. Laser Doppler flowmetry may have several clinical applications, like evaluating progress of atherosclerotic disease or therapeutic effects of drugs or operations. To increase the reproducibility of resting skin flux measurements local heating of the skin is recommended and the measurements should be performed with an integrating probe, which averages the readings obtained at several positions simultaneously.

Venous Valve Reconstruction in Patients with Secondary Chronic Venous Insufficiency

OBJECTIVES To evaluate the durability of venous valve reconstruction (VVR) and its benefits in terms of symptom improvement, ulcer healing and symptom/ulcer recurrence among patients with secondary chronic venous insufficiency (SCVI) in whom superficial venous surgery and compression treatment had failed. METHODS During a ten year period (1993-2004) 1800 patients with chronic venous insufficiency (CVI) were evaluated by colour duplex ultrasound (CDU) and ambulatory venous pressure measurement (AVP). Approximately two thirds of patients had SCVI. Initial treatment consisted of compression therapy for a 6 month period. In addition, superficial vein and perforator surgery was performed in those presenting with reflux in these venous systems. 121 patients who did not improve with this treatment were investigated by ascending venography, descending video venography, air plethysmography and measurement of post-ischaemic venous pressure gradient. Thirty two cases having venous reflux without obstruction were selected for VVR. RESULTS The ulcer healing rate within three months was 68% (13/19 patients). VVR resulted in valvular competence and a clinical success rate of 47% and 40% after 3 and 7 years respectively. In 8/13 (54%) of patients with a healed leg ulcer, a median post-operative AVP reduction of 33 mm Hg (range 20-38) was recorded. The durability of clinical success was numerically longer in patients with haemodynamic improvement (n=10) median 24 months (12-108), when compared with that in those without haemodynamic improvement (n=22) median 18 months (6-108). Popliteal vein reconstruction was part of the VVR procedure in all patients with haemodynamic improvement (post-op. AVP reduction >or=20 mm Hg). VVR at the popliteal level alone or combined with inguinal reconstruction seemed to be the one significant factor associated with haemodynamic improvement (P=0.014, Chi squared). CONCLUSION VVR may lead to ulcer healing, but when performed at the popliteal level, haemodynamic improvement can be obtained along with a longer recurrence-free period (durability). VVR should be considered in the treatment of patients with SCVI who do not respond to superficial venous surgery and compression treatment.

Blood pressure response to isometric exercise in patients with peripheral atherosclerotic disease

Background  The purpose of this study was to compare the circulatory responses to isometric exercise in patients with peripheral atherosclerotic disease (PAD) with healthy controls.

Ketanserin in intermittent claudication: effect on walking distance, blood pressure, and cardiovascular complications.

In a 7-center Scandinavian double-blind placebo-controlled study of 179 patients with intermittent claudication, the effect of the serotonin antagonist ketanserin was evaluated on walking distance, brachial and ankle blood pressure, and symptoms. For all centers together, pain-free walking distance was significantly in-creased after 6 months with both ketanserin (+ 65%; 71 patients) and placebo (+ 42%; 78 patients), with no significant difference. However, there was large variability among centers. Classification of “responders” (doubling of walking distance) and patients who deteriorated (decrease of walking distance or dropout for inefficacy) showed significantly more patients responding and significantly fewer patients deteriorating with ketanserin than with placebo. Systemic blood pressure was significantly decreased by ketanserin in hypertensive, but not normotensive, patients, while ankle pressure was unaffected. The incidence and nature of side effects were equal with ketanserin and placebo, but there were more side effects causing dropout in the ketanserin group. An unexpected and possibly important observation was the occurrence of six serious cardiovascular events (myocardial infarction, cerebrovascular complications, and development of rest pain) in the placebo group but none in ketanserintreated patients. Moreover, there were four additional similar complications in the placebo run-in period. Ketanserin appears to be beneficial in a subgroup of patients with intermittent claudication. A fortuitous finding of this study is that ketanserin might possess a protective effect against thrombovascular complications in patients with intermittent claudication.

The distribution of oedema in the lower limb of patients with chronic critical limb ischaemia: a study with computed tomography.

Background: A substantial number of patients with chronic critical limb ischaemia (CLI) have considerable oedema at the distal leg and foot of non deep venous thrombosis origin. The primary aim of the pre-sent study was to quantify the distribution of oedema in the different tissues of the leg and foot by applying computed tomography and planimetry. The interstitial fluid hydrostatic pressure (Pif) in the subcutaneous tissue was measured to evaluate the effect of oedema on local tissue pressure. Patients and methods: Six men and 12 women with unilateral CLI and peripheral pitting oedema were included. Cross sectional areas (CSA) of subcutaneous tissue, muscle and bone were measured by computer tomography combined with planimetry to assess the distribution of oedema within the soft tissues. Pif was measured by “wick-in-needle” technique. Results: The median total CSA of soft tissue, subcutaneous and muscle tissues at the foot level were respectively 17%, 34% and 9% greater in the limbs with CLI compared to...

Beneficial effects of 1-year optimal medical treatment with and without additional PTA on inflammatory markers of atherosclerosis in patients with PAD. Results from the Oslo Balloon Angioplasty versus Conservative Treatment (OBACT) study

The influence of optimal medical treatment (OMT) with or without additional percutaneous transluminal angioplasty (PTA) on vascular inflammation in peripheral arterial occlusive disease (PAD) patients was investigated. Patients with intermittent claudication (IC) and angiographically verified PAD were randomized to OMT (n = 28) or OMT + PTA (n = 28) and followed for 12 months. Ankle—brachial index (ABI), treadmill walking distances (WD), visual analogue scale (VAS), and blood sampling for the determination of selected soluble biomarkers were undertaken at baseline and after 3 and 12 months. After both 3 and 12 months, ABI, WD and VAS were highly significantly improved in favour of OMT + PTA (p < 0.05 for all). Significant improvements were recorded in both groups in serum lipids (p < 0.01 for all), except for triglycerides, and in the inflammatory markers P-selectin, interleukin-6, interleukin-10, monocyte chemoattractant protein-1 and fibrinogen (p < 0.05 for all). There were, however, no differences in the changes from baseline between the groups in any variable. Intervention with OMT alone or in combination with PTA did not differ with regard to the effects on serum lipids and markers of inflammation in our population of PAD patients. The combined treatment was, however, better for the treadmill walking distance.

Prothrombotic activity is associated with the anatomical as well as the functional severity of peripheral arterial occlusive disease

The importance of prothrombotic activity in cardiovascular disease has been well established. However, limited data exist on the relationship between prothrombotic activity and the severity of peripheral arterial occlusive disease (PAD). The objective of the present study was to investigate the relationship between markers of haemostasis and the diagnostic measures of PAD: ankle-brachial-index (ABI), maximum treadmill walking distance and angiographic score. In a cross-sectional study of 127 patients (mean age 66 years; 64% males) with angiographically verified PAD, fasting blood samples were drawn, and citrated plasma was obtained for determination of selected haemostatic variables: von Willebrand factor (vWF), thrombomodulin (sTM), thrombin-antithrombin complex (TAT), soluble tissue factor (sTF), tPA antigen (tPAag) and D-dimer were all significantly correlated with the angiographic score (p < 0.05 for all). D-dimer, tPAag and fibrinogen were inversely correlated with the maximum treadmill walking distance, (p < 0.0001, p < 0.04 and p < 0.05, respectively), whereas fibrinogen was the only variable correlating to ABI (r = -0.223, p < 0.05). After adjustment for relevant covariates, D-dimer and TAT remained statistically significantly associated with the angiographic score (p < 0.001), and fibrinogen was, independent of other risk factors, inversely related with both the maximum treadmill walking distance and the ABI (p < 0.01 for both). This rather large study in patients with PAD showed that plasma levels of D-dimer, TAT and fibrinogen significantly predicted the extent of atherosclerosis, evaluated by angiographic score, maximum treadmill walking distance and ABI, respectively. These findings demonstrate a prothrombotic state in PAD patients, which might be of importance in future diagnosis and treatment of the disease.

Alterations in capillary permeability in the lower limb of patients with chronic critical limb ischaemia and oedema.

Background: Oedema formation in lower limbs of patients with chronic critical limb ischaemia (CLI) is a common clinical feature. The rate of fluid filtration through the capillary wall depends on the capillary permeability, i.e. capillary filtration coefficient (CFC). In order to elucidate the pathogenesis of this ischaemic oedema, CFC was measured in the limbs with CLI and oedema and was compared with CFC measurements both in the contralateral sides and in the lower limbs of a control group. Patients and methods: Eleven women and 4 men, with a mean age of 75 ± 8.8 years, with unilateral CLI and leg and foot oedema were included. Leg and foot volume was measured with water displacement volumetry (WDV). CFC was measured in both limbs by strain-gauge plethysmography using a double-stranded mercury in silicone strain gauge around the middle portion of the foot. As a control group, 8 patients, 5 women and 3 men, with a mean age of 77 ± 7.6 years with a proximal femur fracture were included and the CFC in this...BACKGROUND Oedema formation in lower limbs of patients with chronic critical limb ischaemia (CLI) is a common clinical feature. The rate of fluid filtration through the capillary wall depends on the capillary permeability, i.e. capillary filtration coefficient (CFC). In order to elucidate the pathogenesis of this ischaemic oedema, CFC was measured in the limbs with CLI and oedema and was compared with CFC measurements both in the contralateral sides and in the lower limbs of a control group. PATIENTS AND METHODS Eleven women and 4 men, with a mean age of 75 +/- 8.8 years, with unilateral CLI and leg and foot oedema were included. Leg and foot volume was measured with water displacement volumetry (WDV). CFC was measured in both limbs by strain-gauge plethysmography using a double-stranded mercury in silicone strain gauge around the middle portion of the foot. As a control group, 8 patients, 5 women and 3 men, with a mean age of 77 +/- 7.6 years with a proximal femur fracture were included and the CFC in this group was measured in the foot of the non-fractured limb. RESULTS Mean CFC in the limbs with CLI and oedema was 0.0036 +/- 0.001 ml/min.100 ml.mmHg, significantly greater than both the contralateral limbs (0.0019 +/- 0.0003 ml/min.100 ml.mmHg, p < 0.01) and mean CFC in the control limbs (0.0017 +/- 0.0002 ml/min.100 ml.mmHg, p < 0.003). There was a mean volume difference of 13 +/- 9% between limbs with CLI and contralateral sides measured by WDV. There was no significant correlation between total leg-foot volume and CFC (p > 0.05). CONCLUSION CFC in the ischaemic limb was twice as great as both the contralateral side and the limbs of the control group. It is therefore concluded that an increased CFC is probably one of the important factors in the development of this ischaemic oedema.

Postischemic transcutaneous oxygen tension response in assessment of peripheral atherosclerosis

The applicability of transcutaneous oxygen tension measurements (TCpO2) at rest and after a postischemic response test was investigated in a control group and in patients with peripheral atherosclerosis. Three parameters were evalu ated : oxygen reappearance time (ORT), oxygen recovery index (ORI), and rest ing oxygen tension (ROT). ORT distinguished controls and patients, as well as patient groups. An ORT ≥ twenty seconds is indicative of peripheral circulatory insufficiency and seemed to be dependent on the postischemic reappearance of blood flow. ORI did not separate the groups as well as ORT and was signifi cantly reduced only in patients with critical ischemia. It is concluded that mea surement of ORT, ORI, and ROT are easily performed, assessing oxygenation of the skin. ORT probably indicates the function of supplying arteries. ORI is related to compensatory mechanisms and changes in the microcirculation.