Coronary plaque volume and predictors for fast plaque progression assessed by serial coronary CT angiography-A single-center observational study.

PURPOSE: The rationale of this study was to identify patients with fast progression of coronary plaque volume PV and characterize changes in PV and plaque components over time. METHOD: Total PV (TPV) was measured in 350 patients undergoing serial coronary computed tomography angiography (median scan interval 3.6 years) using semi-automated software. Plaque morphology was assessed based on attenuation values and stratified into calcified, fibrous, fibrous-fatty and low-attenuation PV for volumetric measurements. Every plaque was additionally classified as either calcified, partially calcified or non-calcified. RESULTS: In total, 812 and 955 plaques were detected in the first and second scan. Mean TPV increase was 20 % on a per-patient base (51.3 mm³ [interquartile range (IQR): 14.4, 126.7] vs. 61.6 mm³ [IQR: 16.7, 170.0]). TPV increase was driven by calcified PV (first scan: 7.6 mm³ [IQR: 0.2, 33.6] vs. second scan: 16.6 mm³ [IQR: 1.8, 62.1], p < 0.01). Forty-two patients showed fast progression of TPV, defined as >1.3 mm3 increase of TPV per month. Male sex (odds ratio 3.1, p = 0.02) and typical angina (odds ratio 3.95, p = 0.03) were identified as risk factors for fast TPV progression, while high-density lipoprotein cholesterol had a protective effect (odds ratio per 10 mg/dl increase of HDL cholesterol: 0.72, p < 0.01). Progression to >50 % stenosis at follow-up was observed in 34 of 327 (10.4 %) calcified plaques, in 13 of 401 (3.2 %) partially calcified plaques and 2 of 221 (0.9 %) non-calcified plaques (p < 0.01). CONCLUSION: Fast plaque progression was observed in male patients and patients with typical angina. High HDL cholesterol showed a protective effect.

Gastroenterological aspects of primary aorto-enteric fistulae (PAEF).

BACKGROUND: Gastrointestinal haemorrhage associated with a primary aorto-enteric fistula (PAEF) is potentially lethal. The aims of this study were to discuss the gastrointestinal characteristics of PAEF, to identify associated laboratory findings and to discuss pitfalls in pre-operative diagnostics. METHODS: Medical and surgical charts of patients with PAEF. RESULTS: Individuals with PAEF (n = 7, 68 +/- 5 years) presented with multiple episodes of haematemesis (n = 5) and/or melaena (n = 6), all in the presence of aneurysmatic aortas (5.4 +/- 1.0 cm). Laboratory testing reflected a state of acute (C-reactive protein, CRP, 94 +/- 12 mg/ml; leucocyte counts, 12.0 +/- 1.0.10(9)/L) and chronic inflammation (erythrocyte sedimentation rate, ESR 52 +/- 5 mm/hr). Prior to operation, a gastroduodenoscopy correctly diagnosed only one PAEF patient and CT scans identified 3. Two patients exsanguinated in a two-week waiting period prior to corrective surgery. CONCLUSIONS: Recurrent gastrointestinal blood loss in the presence of an aneurysm requires urgent gastroduodenoscopic evaluation. Computer tomography is sensitive in providing direct or circumstantial evidence of a fistula. A combined acute and chronic inflammatory state associated with PAEF is reflected by elevations of CRP and ESR. A PAEF is a unique form of ruptured aneurysm, and this entity mandates imminent radiological and surgical consultation aimed at instituting aggressive treatment within hours.

Usefulness and applicability of femorofemoral crossover bypass grafting.

We examined the usefulness of femorofemoral crossover bypass grafting (FFC) and factors influencing its outcome by retrospectively analyzing all FFCs performed in our hospital over a 5-year period, focusing on both patency rates and clinical efficacy. For 95 patients Kaplan-Meier patency rates were calculated (follow-up 40.4 +/- 3.0 months). Clinical outcome was defined according to Rutherford's standardized categories. The influence of cardiovascular risk factors and technical characteristics on outcome was determined. Clinical status of the limb remained improved in 89%. One- and 5-year primary, primary assisted, and secondary patency rates were 88.2% and 57.3%, 90.6% and 62.4%, and 92.6% and 68.1%, respectively. Clinical outcome of the limb was better in patients with <50% stenosis in the femoral arteries preoperatively (p = 0.033). No predictors for patency rates were identified. FFCs are effective in the medium long term for patients in all age categories independently of cardiovascular risk factors. The best predictor of clinical outcome is the preoperative degree of stenosis, with a better outcome for patients affected by <50% stenosis. Success of FFC cannot be reliably measured by graft patency alone but should be assessed by combining patency rates and clinical outcome according to standardized categories.

Quantification of coronary low-attenuation plaque volume for long-term prediction of cardiac events and reclassification of patients.

BACKGROUND: To investigate the incremental prognostic value of low-attenuation plaque volume (LAPV) from coronary CT angiography datasets. METHODS: Quantification of LAPV was performed using dedicated software equipped with an adaptive plaque tissue algorithm in 1577 patients with suspected CAD. A combination of death and acute coronary syndrome was defined as primary endpoint. To assess the incremental prognostic value of LAPV, parameters were added to a baseline model including clinical risk and obstructive coronary artery disease (CAD), a baseline model including clinical risk and calcium scoring (CACS) and a baseline model including clinical risk and segment involvement score (SIS). RESULTS: Patients were followed for 5.5 years either by telephone contact, mail or clinical visits. The primary endpoint occurred in 30 patients. Quantified LAPV provided incremental prognostic information beyond clinical risk and obstructive CAD (c-index 0.701 vs. 0.767, p < .001), clinical risk and CACS (c-index 0.722 vs. 0.771, p < .01) and clinical risk and SIS (c-index 0.735 vs. 0.771, p < .01. A combined approach using quantified LAPV and clinical risk significantly improved the stratification of patients into different risk categories compared to clinical risk alone (categorical net reclassification index 0.69 with 95% CI 0.27 and 0.96, p < .001). The combined approach classified 846 (53.6%) patients as low risk (annual event rate 0.04%), 439 (27.8%) patients as intermediate risk (annual event rate 0.5%) and 292 (18.5%) patients as high risk (annual event rate 0.99%). CONCLUSION: Quantification of LAPV provides incremental prognostic information beyond established CT risk patterns and permits improved stratification of patients into different risk categories.

First experiences with model based iterative reconstructions influence on quantitative plaque volume and intensity measurements in coronary computed tomography angiography.

PURPOSE: Investigate the influence of adaptive statistical iterative reconstruction (ASIR) and the model-based IR (Veo) reconstruction algorithm in coronary computed tomography angiography (CCTA) images on quantitative measurements in coronary arteries for plaque volumes and intensities. METHODS: Three patients had three independent dose reduced CCTA performed and reconstructed with 30% ASIR (CTDIvol at 6.7 mGy), 60% ASIR (CTDIvol 4.3 mGy) and Veo (CTDIvol at 1.9 mGy). Coronary plaque analysis was performed for each measured CCTA volumes, plaque burden and intensities. RESULTS: Plaque volume and plaque burden show a decreasing tendency from ASIR to Veo as median volume for ASIR is 314 mm3 and 337 mm3-252 mm3 for Veo and plaque burden is 42% and 44% for ASIR to 39% for Veo. The lumen and vessel volume decrease slightly from 30% ASIR to 60% ASIR with 498 mm3-391 mm3 for lumen volume and vessel volume from 939 mm3 to 830 mm3. The intensities did not change overall between the different reconstructions for either lumen or plaque. CONCLUSION: We found a tendency of decreasing plaque volumes and plaque burden but no change in intensities with the use of low dose Veo CCTA (1.9 mGy) compared to dose reduced ASIR CCTA (6.7 mGy & 4.3 mGy), although more studies are warranted.

Chlamydia pneumoniae infections augment atherosclerotic lesion formation: a role for serum amyloid P.

Multiple reports have demonstrated an association between Chlamydia pneumoniae (Cpn) and cardiovascular disease. In this study we evaluated the effect of Cpn infections on early lesion progression in C57BL/6J mice. Since plaque formation in these mice does not develop past the initial stage, we thought these mice might be a better model for unravelling the effect of Cpn infection on early lesion type progression. C57BL/6J mice were fed an atherogenic diet and injected 10 times with 5 x 10(7) IFU Cpn or mock. At sacrifice, lesion number, size and type were analysed. To study the role of Cpn in inflammation, serum amyloid P (SAP) in plasma was determined as well as T-cells, macrophages and SAP in the lesions. In the aortic sinus of both groups, type 2 lesions were found. Cpn infection resulted in a 2.2-fold increase in total lesion size (Cpn: 10821+/-2429 microm(2)vs mock: 5022+/-1348 microm(2); p=0.04). No difference in lesion number was observed. Also, Cpn infection increased SAP in the lesions from 1.10(-4)+/-0.1.10(-4) SAP-positive cells/lesion area to 10.10(-4)+/-1.10(-4) SAP-positive cells/lesion area (p=0.05). The influx of T-lymphocytes and macrophages in the lesions as well as SAP plasma levels were not different between groups. Multiple Cpn infections resulted in a significant increase in total lesion size of C57BL/6J mice. Increase in total SAP-positive area in infected mice suggests a role for this acute-phase protein in lesion enlargement.

Identification of genes potentially involved in rupture of human atherosclerotic plaques.

Although rupture of an atherosclerotic plaque is the major cause of acute vascular occlusion, the exact molecular mechanisms underlying this process are still poorly understood. In this study, we used suppression subtractive hybridization to make an inventory of genes that are differentially expressed in whole-mount human stable and ruptured plaques. Two libraries were generated, one containing 3000 clones upregulated and one containing 2000 clones downregulated in ruptured plaques. Macroarray analysis of 500 randomly chosen clones showed differential expression of 45 clones. Among the 25 clones that showed at least a 2-fold difference in expression was the gene of perilipin, upregulated in ruptured plaques, and the genes coding for fibronectin and immunoglobulin lambda chain, which were downregulated in ruptured plaques. Reverse transcriptase-polymerase chain reaction analysis on 10 individual ruptured and 10 individual stable plaques showed a striking consistency of expression for the clones SSH6, present in 8 ruptured and 2 stable plaques, and perilipin, expressed in 8 ruptured plaques and completely absent in stable plaques. Localization studies of both perilipin mRNA and protein revealed expression in cells surrounding the cholesterol clefts and in foam cells of ruptured atherosclerotic plaques. No expression was observed in nondiseased artery, and only a few cells in the shoulder region of stable plaques tested positive for perilipin. In conclusion, this study shows that it is possible to identify genes that are differentially expressed in whole-mount stable or ruptured atherosclerotic plaques. This approach may yield several potential regulators of plaque destabilization.

Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging.

BACKGROUND: One of the features of high-risk atherosclerotic plaques is a preponderance of macrophages. Experimental studies with hyperlipidemic rabbits have shown that ultrasmall superparamagnetic particles of iron oxide (USPIOs) accumulate in plaques with a high macrophage content and that this induces magnetic resonance (MR) signal changes. The purpose of our study was to investigate whether USPIO-enhanced MRI can also be used for in vivo detection of macrophages in human plaques. METHODS AND RESULTS: MRI was performed on 11 symptomatic patients scheduled for carotid endarterectomy before and 24 (n=11) and 72 (n=5) hours after administration of USPIOs (Sinerem) at a dose of 2.6 mg Fe/kg. Histological and electron microscopical analyses of the plaques showed USPIOs primarily in macrophages within the plaques in 10 of 11 patients. Histological analysis showed USPIOs in 27 of 36 (75%) of the ruptured and rupture-prone lesions and 1 of 14 (7%) of the stable lesions. Of the patients with USPIO uptake, signal changes in the post-USPIO MRI were observed by 2 observers in the vessel wall in 67 of 123 (54%) and 19 of 55 (35%) quadrants of the T2*-weighted MR images acquired after 24 and 72 hours, respectively. For those quadrants with changes, there was a significant signal decrease of 24% (95% CI, 33% to 15%) in regions of interest in the images acquired after 24 hours, whereas no significant signal change was found after 72 hours. CONCLUSIONS: Accumulation of USPIOs in macrophages in predominantly ruptured and rupture-prone human atherosclerotic lesions caused signal decreases in the in vivo MR images.

Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques.

In the present study, we examined the expression of regulators of bone formation and osteoclastogenesis in human atherosclerosis because accumulating evidence suggests that atherosclerotic calcification shares features with bone calcification. The most striking finding of this study was the constitutive immunoreactivity of matrix Gla protein, osteocalcin, and bone sialoprotein in nondiseased aortas and the absence of bone morphogenetic protein (BMP)-2, BMP-4, osteopontin, and osteonectin in nondiseased aortas and early atherosclerotic lesions. When atherosclerotic plaques demonstrated calcification or bone formation, BMP-2, BMP-4, osteopontin, and osteonectin were upregulated. Interestingly, this upregulation was associated with a sustained immunoreactivity of matrix Gla protein, osteocalcin, and bone sialoprotein. The 2 modulators of osteoclastogenesis (osteoprotegerin [OPG] and its ligand, OPGL) were present in the nondiseased vessel wall and in early atherosclerotic lesions. In advanced calcified lesions, OPG was present in bone structures, whereas OPGL was only present in the extracellular matrix surrounding calcium deposits. The observed expression patterns suggest a tight regulation of the expression of bone matrix regulatory proteins during human atherogenesis. The expression pattern of both OPG and OPGL during atherogenesis might suggest a regulatory role of these proteins not only in osteoclastogenesis but also in atherosclerotic calcification.

Biphasic pattern of cell turnover characterizes the progression from fatty streaks to ruptured human atherosclerotic plaques.

OBJECTIVE: To study the amount and phenotype of DNA-synthesizing and apoptotic cells during atherogenesis. METHODS: Atherosclerotic lesions (n = 76), obtained at autopsy (N = 6) or during vascular surgery (N = 8), were classified [type I-VI; American Heart Association (AHA) classification], immunolabeled with MIB 1 or the TUNEL technique and double stained with cell-type-specific antibodies. Subsequently, the labeled fractions were quantified. RESULTS: In type II-VI lesions, intimal DNA synthesis was increased compared to that of the non-diseased (ND) arterial wall. DNA synthesis peaked in early type II lesions (2.7 +/- 0.5 vs. 0.02 +/- 0.02% in ND; p < 0.05), and declined to 0.7 +/- 0.2% in type V lesions (p < 0.05). Interestingly, a second peak of DNA synthesis of 1.7 +/- 0.1%, was observed in type VI (ruptured plaque) lesions. Double staining revealed that DNA synthesis was mostly confined to the macrophage-derived foam cell (51.9%). In type II lesions, 100.0% of all DNA-synthesizing cells were present in the intimal foam cell-rich area, while in advanced type III, IV and V lesions, DNA synthesis had shifted to the shoulder region (74.8, 78.5 and 68.1%, respectively). In type VI lesions, DNA synthesis was present in the area underlying the plaque rupture (52.7%). Apoptosis was only elevated in advanced type IV, V and VI lesions (0.8 +/- 0.1, 0.8 +/- 0.1 and 1.1 +/- 0.1%, respectively, vs. 0.0 +/- 0.0% in ND) and was predominant in the lipid core (90.5% in type IV lesions; 54.2% in type V lesions) or equally divided between the lipid core and the region underlying the plaque rupture (31.8 and 34.6% in type VI lesions). In type III-VI lesions, 50.0, 38.9, 42.6 and 42.8% of the TUNEL-positive cells were macrophages. CONCLUSIONS: In stable atherosclerotic lesions, DNA synthesis is an early event, while apoptosis is a late event. Ruptured plaques show a second peak of cell turnover. Lastly, cell turnover is mostly confined to the macrophage-derived foam cell.

Wall shear stress in the human common carotid artery as function of age and gender.

OBJECTIVES: It has been postulated that in the arterial system mean wall shear stress is maintained at a constant value. The present study was performed to investigate the level of wall shear stress in the common carotid artery (CCA) as function of age and possible interactions between diameter and storage capacity, defined as the absolute area change per heart beat, with mean wall shear stress. METHODS: Wall shear stress (wall shear rate multiplied by whole blood viscosity) was assessed in the right CCA of 111 presumed healthy male (n = 56) and female (n = 55) volunteers, varying in age between 10 and 60 years. Wall shear rate was measured with a high resolution ultrasound system. Simultaneously, arterial diameter and storage capacity were determined. Whole blood viscosity was calculated from haematocrit, plasma viscosity and shear rate. RESULTS: From the second to the sixth age decade peak wall shear stress was significantly higher in males than in females and decreased from 4.3 Pa to 2.6 Pa (r = -0.56, p < 0.001) in males and from 3.3 Pa to 2.5 Pa (r = -0.54, p < 0.001) in females. Mean wall shear stress tended to decrease from 1.5 Pa to 1.2 Pa (r = -0.26, p = 0.057) in males and decreased significantly from 1.3 Pa to 1.1 Pa (r = -0.30, p = 0.021) in females. No significant difference in mean wall shear stress was found between males and females in any age decade. The diameter of the CCA increased significantly in both males (r = 0.26, p < 0.05) and females (r = 0.40, p < 0.003). Storage capacity decreased significantly in both sexes (males: r = -0.63, p < 0.001; females: r = -0.68, p < 0.001). CONCLUSIONS: These observations suggest that the reduction in mean wall shear stress with age results from the concomitant increase in diameter in an attempt of the arterial system to limit the reduction in storage capacity of the arterial system with increasing age.

Chlamydophila pneumoniae (Chlamydia pneumoniae) accelerates the formation of complex atherosclerotic lesions in Apo E3-Leiden mice.

OBJECTIVE: Atherosclerosis is an inflammatory process and is characterised by the presence of T-lymphocytes in the lesions. To study the role of Chlamydophila pneumoniae (C. pneumoniae) in this process and the effect of infection on T-cell influx, we infected Apo E3-Leiden mice with C. pneumoniae and investigated the effect on lesion development and T-cell influx in atherosclerotic lesions at different time points post infection (pi). METHODS: Nine week old mice, fed an atherogenic diet, were either mock-infected or infected with C. pneumoniae and sacrificed at 1, 6 and 9 months pi. Longitudinal sections of the aortic arches of the mice were stained with hematoxylin-eosin for atherosclerotic lesion type and lesion area analysis, or with rabbit-anti-CD3(+) to detect the presence of T-cells in the atherosclerotic lesions. T-cell influx was expressed as number of T-lymphocytes/lesion area. RESULTS: At 1 month pi, type 1, 2 and 3 lesions were present. At other time points pi, more complex lesion types 4, 5a and 5b were also present. Although infection did not influence the total lesion number or area, we observed an effect of C. pneumoniae infection on lesion type. Infection resulted in a significant shift in lesion formation from type 3 to type 4 (P=0.022) at 6 months pi, and from type 4 to type 5a (P=0.002) at 9 months pi. T-cells were observed at every time point pi. At 1 month pi, a significant increase in T-cell influx in the C. pneumoniae-infected atherosclerotic lesions was observed (P=0.0005). CONCLUSION: This study shows that C. pneumoniae infection enhances the inflammatory process by increasing T-lymphocytes in the plaque and accelerates the formation of complex lesions.

The spinal component to skin blood flow abnormalities in reflex sympathetic dystrophy.

OBJECTIVE: To determine whether the mechanisms of reflex sympathetic dystrophy, a neuropathic pain syndrome characterized by skin blood flow abnormalities associated with sympathetic vasoconstrictor and antidromic vasodilator mechanisms, are solely of peripheral origin or have an additional spinal component and act exclusively through neural or also involve humoral pathways. PATIENTS: The 54 patients with unilateral reflex sympathetic dystrophy were divided into the following three stages according to their perception of skin temperature in the clinically affected hand: stage I, stationary warmth sensation; stage II, intermittent warmth and cold sensation; and stage III, stationary cold sensation. METHODS: Investigation of basal skin blood flow and vasoconstrictive response to dependency of skin microvessels in the clinically unaffected hand and the clinically affected hand of patients with reflex sympathetic dystrophy and the left hand of 16 control subjects. Microcirculation was investigated at the predominantly neurally controlled thermoregulatory level (Doppler laser flowmetry) and at the predominantly humorally controlled nutritive level (capillary microscopy). RESULTS: In the clinically unaffected hand, at the thermoregulatory level of the microcirculation: (1) basal skin blood flow was increased at stage I compared with the control subjects, whereas no differences could be observed at this stage compared with the clinically affected hand; (2) the vasoconstrictive response to dependency (defined as skin blood flow at heart level divided by skin blood flow in the dependent position) was attenuated at stage I compared with the control subjects, whereas no differences could be observed at this stage compared with the clinically affected hand; and (3) basal skin blood flow and the vasoconstrictive response to dependency did not differ from the control subjects at stages II and III. In the clinically unaffected hand, at the nutritive level, no differences could be observed at any stage of the syndrome compared with the control subjects. CONCLUSIONS: This study indicates that there is a spinal component to microcirculatory abnormalities at stage I of the reflex sympathetic dystrophy syndrome that most likely acts through neural (antidromic vasodilator) mechanisms and that may be initiated by traumatic excitation of a peripheral nerve on the clinically affected side.

Reflex sympathetic dystrophy: evolution of microcirculatory disturbances in time.

Reflex sympathetic dystrophy (RSD) is a pain syndrome that is characterised by autonomic, motor and sensory disturbances. The syndrome has often been associated with sympathetic dysfunction. Therefore, we investigated whether there are disturbances in the sympathetic function of skin microcirculation in the various clinical stages of RSD. Laser Doppler flowmetry (LDF) was used to obtain information about total (mainly thermoregulatory) skin blood flow (TSBF), since blood flow in arteriovenous anastomoses and subpapillary plexus, which are richly innervated by sympathetic nerve endings, contributes predominantly to the flow signal as obtained by LDF. Capillary microscopy was used to appraise whether the trophic changes, as observed in RSD, result from an impaired nutritive skin blood flow (NSBF). Transcutaneous oximetry (TCPO2) was employed as a measure of the oxygenation of superficial skin layers. Skin temperature (ST) was also determined. Patients were divided into 3 clinical stages: stage I in case of a chronic warmth sensation, stage II in case of an intermittent warmth and cold sensation, and stage III in case of a chronic cold sensation. As compared to controls: (1) TSBF was increased (P < 0.05) at stage I and decreased at stages II (P < 0.05) and III (P < 0.001), (2) NSBF was decreased at stages II (P < 0.05) and III (P < 0.001), (3) TCPO2 was not impaired at any stage, (4) ST was increased (P < 0.01) at stage I and decreased (P < 0.05) at stage III. The present study is the first to report an increase of TSBF at stage I of RSD, which may be caused by a decrease in efferent sympathetic nerve impulses. At stages II and III both TSBF and NSBF were decreased which may reflect increased sensitivity of skin microvessels to (circulating) catecholamines.

Skin blood flow disturbances in the contralateral limb in a peripheral mononeuropathy in the rat.

Electrical excitation of nociceptive afferents in an extremity has been demonstrated to increase skin blood flow in the contralateral extremity. Hence, one would expect that loose sciatic nerve ligation, which induces an experimental painful peripheral neuropathy, may also provoke a vasodilator response in the contralateral hindpaw. On the non-ligated side, such a response may involve inhibited skin vasoconstrictor activity as well as neurogenically mediated active vasodilation. We studied skin blood flow changes in the rat hindpaw consequent to contralateral loose sciatic nerve ligation. After ligation, we also investigated whether blockade of afferent input from the ligated sciatic nerve to the spinal cord, by means of lidocaine, overrules the vasodilator response in the non-ligated paw. On the non-ligated side, we assessed the vasoconstrictor response of skin microvessels to cooling of the rat abdomen as a measure of skin vasoconstrictor activity in this paw. In order to investigate the involvement of sensory and/or non-sensory nerve fibers in the non-ligated sciatic nerve on skin blood flow abnormalities in the non-ligated paw, we studied the influence of blockade of these fibers through successive capsaicin and lidocaine application. We show that loose ligation of the sciatic nerve induces a vasodilator response in the contralateral hindpaw, which is completely abolished by blockade of afferent input from the ligated sciatic nerve. From day 1 after ligation, skin vasoconstrictor activity in the non-ligated paw was reduced, as indicated by an impaired vasoconstrictor response to cooling of the rat abdomen. Besides, blockade of sensory but not of non-sensory nerve fibers on the non-ligated side attenuated the vasodilator response in this paw. The data presented here indicate that loose ligation of the rat sciatic nerve induces a vasodilator response in the contralateral hindpaw. On the non-ligated side, this vasodilator response may involve inhibition of skin vasoconstrictor activity, as well as antidromically acting sensory nerve fibers.

The diagnostic value of the measurement of the ankle-brachial systolic pressure index in primary health care.

We investigated the value of the ankle-brachial systolic pressure index (ABPI) as a test for the diagnosis of peripheral arterial occlusive disease (PAOD) in general practice. ABPI measurements on 231 legs of 117 subjects performed in three general practice centers (GPC) were compared with the diagnostic conclusions of a Vascular Laboratory. The optimum cutoff value for the ABPI, its accuracy and diagnostic value were estimated. In a subpopulation of 51 subjects for whom repeated measurements were available, we checked whether taking the mean of three consecutive ABPIs for test outcome would enhance diagnostic performance. Receiver Operating Characteristic analysis showed that overall performance of the GPC ABPI was good (area under the curve approximately 0.9). Performing repeated ABPI measurements was superior to performing a single measurement. The optimum cutoff value for the ABPI was 0.97, associated with a diagnostic odds ratio (OR) of 17 and an accuracy of 81%. In a somewhat more selected subpopulation, the optimum cutoff value was 0.92 (OR 70, accuracy 90%). On the basis of our results, we suggest the following rule of thumb: if the ABPI < 0.8 or if the mean of three ABPIs < 0.9, it is highly probable that PAOD is present (PV+ > or = 95%); if the ABPI > 1.1 or if the mean of three ABPIs > 1.0, PAOD can be ruled out (PV- > or = 99%). In conclusion, in primary health care, the ABPI measurement can be a useful supplementary test in ambiguous diagnostic situations with regard to PAOD.

Reflex sympathetic dystrophy: does sympathetic dysfunction originate from peripheral neuropathy?

BACKGROUND: Sympathetic dysfunction in reflex sympathetic dystrophy (RSD) has been purported to consist of an afferently-induced increase in efferent sympathetic nerve impulses (somato-sympathetic reflex) and/or denervation-induced supersensitivity to catecholamines. In addition, both the central and peripheral nervous systems have been claimed to be involved. It was the aim of this study to obtain more insights into these underlying mechanisms. METHODS: In the affected extremeties of 42 patients with RSD we investigated as indirect measures of sympathetic (dys)function: (1) skin blood flow and the vasoconstrictive response to dependency of skin microvessels by means of laser Doppler flowmetry (distal to the site of trauma), (2) relative distention of the brachial artery and changes in relative distention consequent to a cold pressor test by means of ultrasonic vessel wall tracking (proximal to the site of trauma), and (3) arterial blood pressures by means of the Finapres technique. Both provocation tests induce a sympathetically mediated response. Patients were divided into three categories according to their perception of skin temperature in their injured limb (stage I, stationary warmth sensation; stage II, intermittent warmth and cold sensation; or stage III, stationary cold sensation). RESULTS: Distal to the site of trauma, when compared with controls, skin blood flow was increased at stage I and decreased at stages II and III, whereas the vasoconstrictive response to dependency was impaired at all three stages. Proximally, when compared with controls, relative distention of the brachial artery and its response to the cold pressor test were decreased at all three stages. No differences were observed in pulse pressure between patient groups and controls. CONCLUSIONS: These results suggest that sympathetic dysfunction in extremities of patients with RSD distal to the site of trauma consists of hypersensitivity to catecholamines at stages II and III as a result of autonomic denervation at stage I, whereas proximal to the site of trauma sympathetic nerve impulses may be increased at all three stages.

Motor denervation induces altered muscle fibre type densities and atrophy in a rat model of neuropathic pain.

Loose ligation of a sciatic nerve in rats (chronic constriction injury; CCI) provokes sensory, autonomic, and motor disturbances like those observed in humans with partial peripheral nerve injury. So far, it is unknown whether these motor disturbances result from (mechanical) allodynia or from damage to the motor neuron. These considerations prompted us to assess, in CCI rats, the density of motor axons in both the ligated sciatic nerve and the ipsilateral femoral nerve. To this end, we determined the number of cholinesterase positive fibres. It has been demonstrated previously that muscle fibre type density may be used as a measure of motor denervation and/or hypokinesia. Therefore, the myofibrillar ATPase reaction was employed to assess fibre type density in biopsies obtained from the lateral gastrocnemius muscle (innervated by sciatic nerve) and rectus femoris muscle (innervated by femoral nerve). We observed axonal degeneration of motor fibres within the loosely ligated sciatic nerve, both at an intermediate (day 21) and at a late stage (day 90) after nerve injury. The reduction in the number of motor nerve fibres was more pronounced distal to the site of the ligatures than proximal. A (less pronounced) reduction of motor fibres was observed in the ipsilateral (non-ligated) femoral nerve. In line with these findings, we observed altered fibre type densities in muscle tissue innervated by the ligated sciatic nerve as well as the non-ligated femoral nerve indicative of motor denervation rather than hypokinesia. The findings of this study suggest that the motor disorder induced by partial nerve injury involves degeneration of motor nerve fibres not only within the primarily affected nerve but also within adjacent large peripheral nerves. This spread outside the territory of the primarily affected nerve suggests degeneration of motor neurons at the level of the central nervous system.

Randomized trial of stripping versus high ligation combined with sclerotherapy in the treatment of the incompetent greater saphenous vein.

This prospective randomized study compared the treatment of greater saphenous vein insufficiency by stripping and local avulsions of varicose veins with high ligation of the saphenofemoral junction (crossectomy) combined with sclerocompression therapy. Of 156 consecutive patients, 89 legs were randomly allocated to stripping and 92 to high ligation. At follow-up of 3 months and 1, 2, and 3 years after treatment, clinical and Doppler ultrasound results, and complaints and cosmetic results, as judged by the patient and the surgeon, were scored. At 3 years, 69 limbs in the stripping group (78%) and 73 limbs in the ligation group (79%) were available to follow-up. The cosmetic results, both judged by the patient and the surgeon, were significantly better (P < 0.05) in the stripped limbs than in the limbs with high ligation and sclerotherapy. Clinical and Doppler ultrasound evidence of reverse flow in the saphenous vein was significantly less (P < 0.001) after the stripping operation. The results of treatment of isolated saphenous vein insufficiency by stripping operation, therefore, were superior to those obtained by high ligation combined with sclerotherapy.

Neurogenic inflammation in an animal model of neuropathic pain.

Loose ligation of a rat sciatic nerve (chronic constriction injury (CCI) model) provokes signs and symptoms like those observed in reflex sympathetic dystrophy (RSD) patients. Primary afferent nociceptive C-fibers seem to be involved in an afferent orthodromic as well as in an efferent antidromic manner. In this study we hypothesize that consequent to development of antidromic impulses in C-nociceptive afferents, neuropeptides released from peripheral endings of these fibers, increase skin blood flow (SBF), vascular permeability, and tissue accumulation of polymorphonuclear leukocytes (PMNs). Collectively, these phenomena have been referred to as neurogenic inflammation. To investigate the presence of neurogenic inflammation in the CCI-model, we assessed skin blood flow (SBF) as well as the level of edema and accumulation of PMNs in muscle tissue obtained from the affected hindpaw. SBF was measured, by means of laser Doppler flowmetry, before ligation as well as at day 4 after ligation. At day 4, SBF measurements were performed before and after abolition of the capability of C-fibers to mediate a vasodilator response. To this end, capsaicin was applied perineurally. Increased vascular permeability was inferred from the level of edema of muscle tissue as determined by assessment of wet/dry weight ratios of muscle biopsies. PMN accumulation was investigated by enzymatic detection of myeloperoxidase (MPO) activity in muscle biopsies. Compared with preligation values, at day 4 SBF was increased more than twofold (p < 0.05). The latter response was annihilated by capsaicin application. Compared with sham operated controls, wet/dry ratios were higher in the ligated animals (1.104 vs. 1.068; p < 0.05). Likewise, when compared with sham operated controls, MPO activity was found to be increased in the ligated hindpaw (Optic Density 0.15 vs. 0.89; p < 0.001). In conclusion, the findings of this study indicate that loose ligation of a sciatic nerve induces an inflammatory response in the ipsilateral hindpaw, which most likely is mediated by release of neuropeptides from the peripheral endings of antidromically acting nociceptive C-fibres.