Einar Stranden

Remission is the goal for cardiovascular risk management in patients with rheumatoid arthritis: a cross-sectional comparative study

Objectives To compare markers of cardiovascular disease (CVD) risk between patients with rheumatoid arthritis (RA) in an active disease state and those with RA in remission, and to compare both groups with community controls. Methods 113 patients with RA and 86 community controls were assessed across a panel of biomarkers for CVD. RA in remission was defined as Clinical Disease Activity Index ≤2.8. Community controls were selected at random by Statistics Norway, and controls were matched with patients in the cohorts in strata using details of age, sex and residential area. A panel of biomarkers (N-terminal pro-brain natriuretic peptide (NT-proBNP), total cholesterol, reactive hyperaemia index (RHI), pressure measurements, measures of arterial stiffness and intima-media thickness) were compared between patients with active RA and those with RA in remission. Both groups were compared with controls. In addition, biomarker levels were compared across subgroups based on anticyclic citrullinated peptide status, level of joint destruction and presence of extra-articular manifestations. Results Patients with active RA had significantly higher levels of NT-proBNP, brachial systolic pressure, augmentation index and central systolic pressure but lower cholesterol than patients in remission and controls. In addition, patients with active RA had significantly higher levels of pulse wave velocity and worse RHI than patients in remission. Comparison across other subgroups gave less consistent differentiations in levels of CVD risk markers. Conclusion Patients with active RA, but not those in remission, had significantly increased levels of CVD risk markers. These results link inflammatory activity to markers of CVD risk in patients with RA and may indirectly support the notion that remission in RA confers diminished cardiovascular morbidity.

Carotid plaque characteristics and disease activity in rheumatoid arthritis.

Objective. Carotid plaques (CP) are predictive of acute coronary syndrome in patients with rheumatoid arthritis (RA), suggesting that atherosclerotic plaques in these patients are vulnerable. The objective of our study was to characterize vulnerability of CP in patients with RA compared to a control population, and between RA patients with different levels of disease activity. Methods. Ultrasound examination of carotid arteries was performed in 152 patients with RA and 89 controls. CP echolucency was evaluated by the Gray-Scale Median (GSM) technique. Lower GSM values indicate higher vulnerability of plaques. CP characteristics were compared between RA patients with active disease and in remission, and between patients and controls. All analyses were performed with adjustment for confounding factors (sex, age, smoking, and blood pressure). Poisson regression analysis was used for count data, mixed modeling for GSM and area per plaque, and analysis of covariance for minimum GSM value per patient. Results. Patients with RA more frequently had CP (median 2, range 0, 4) compared with controls (median 1, range 0, 3; p < 0.001), after adjustment for age and sex. Patients with active RA disease according to the Clinical Disease Activity Index (CDAI) had lower median GSM (p = 0.03), minimum GSM (p = 0.03), and a larger CP area (although the latter finding was not significant; p = 0.27), compared with patients with RA in remission. These findings were not confirmed for other disease measures (Simplified Disease Activity Index, Disease Activity Score-28, C-reactive protein, erythrocyte sedimentation rate). Conclusion. Patients with RA had more CP compared with controls and patients in CDAI remission, and controls had more stable CP than patients with active disease; these findings point to the importance of achieving remission in RA.

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.

Impaired endothelial function in persons with obstructive sleep apnoea: impact of obesity

Objective Obstructive sleep apnoea (OSA) and obesity are both associated with endothelial dysfunction, which precedes the development of atherosclerosis. As obesity is highly prevalent in OSA, we wanted to test the hypothesis that OSA is associated with endothelial dysfunction independently of obesity. Design Cross-sectional, population-based study. Setting Norwegian university hospital. Patients Seventy-one subjects (median age 44 years, 35% female) were recruited from a population-based study in Norway. Participants were categorised as obese (body mass index (BMI) ≥30 kg/m2), non-obese (BMI<30 kg/m2) with OSA (apnoea–hypopnoea index (AHI)≥10), or non-obese without OSA (AHI<5). Interventions None. Main outcome measures Endothelial function measured by brachial artery ultrasound and expressed as percentage of flow-mediated dilation (FMD%). Results When non-obese subjects without OSA were used as the reference (FMD% (mean±SD) 10.1±6.3), endothelial function was found to be impaired in subjects with OSA (FMD% 6.4±3.2) (p=0.003). FMD% did not differ between obese (6.0±3.4) and non-obese (6.7±3.1) OSA subjects (p=0.3). By univariate linear regression analysis, AHI, BMI, gender and baseline brachial artery diameter were significantly associated with FMD%. When these variables were entered into a multivariate model, only AHI was significantly associated with FMD%. Conclusions OSA is associated with endothelial dysfunction independently of obesity and conventional risk factors.

Supervised Exercise Training Reduces Plasma Levels of the Endothelial Inflammatory Markers E-Selectin and ICAM-1 in Patients With Peripheral Arterial Disease

Elevated plasma levels of vascular inflammatory markers have been reported in patients with peripheral arterial disease (PAD). We assessed the effect of supervised exercise training (ET) on vascular inflammation, hypothesizing that ET reduces plasma levels of the endothelial adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Twenty-nine patients with PAD underwent a supervised ET program for 8 weeks. Before and after ET, walking distances (pain-free, PWD; maximal, MWD) were determined by a standard treadmill test. Plasma levels of E-selectin and ICAM-1 were significantly reduced (E-selectin: 45.5-40.4 ng/mL, P = .013); ICAM-1: 342.0-298.0 ng/mL, P = .016). VCAM-1 levels were unchanged. Walking distances increased significantly (PWD: median 77-150 m, P < .001; MWD: median 306-535 m, P < .001). In conclusion, 8 weeks of ET in patients with PAD reduces plasma levels of the specific endothelium-derived inflammatory markers E-selectin and ICAM-1.

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.

Reduced preload elicits increased LV twist in healthy humans: an echocardiographic speckle-tracking study during lower body negative pressure.

Background:  In normal left ventricles (LV), counterclockwise rotation (CCR) and net twist angle (NTA) have shown important roles during ejection. We investigated the effect of reduced preload by lower body negative pressure (LBNP) on CCR and NTA.