Carotid and femoral ultrasound morphology screening and cardiovascular events in low risk subjects: a 10-year follow-up study (the CAFES-CAVE study(1)).

BACKGROUND: Subclinical arteriosclerotic lesions at the carotid and femoral bifurcations may be related to the occurrence of future cardiovascular events and of occult arteriosclerotic coronary disease. B-mode ultrasound of carotid and femoral arteriosclerotic bifurcation lesions may provide a simple screening method to select asymptomatic subjects at risk of future events. METHODS AND RESULTS: 13221 low-risk, healthy, asymptomatic individuals were included in a 10-year, prospective, follow-up based on carotid and femoral bifurcation morphology defined by B-mode ultrasound. Four classes were considered at inclusion (I: normal wall, II: wall thickening, III: non-stenosing plaques, IV: stenosing plaques). When 10000 subjects (75.6% of included subjects; 6055 males, 3945 females) completed the 10-year follow-up the study was concluded. At 10 years there were 10 events (out of 7989 subjects) in class I and 81 events in II (930 subjects; incidence=8.6%); 239 events were observed in class III (611 subjects; 39.28%) and 381 events (470 subjects; 81.06%) in IV; 61 deaths occurred in classes III+IV (1081 subjects) producing a death rate within these two classes of 5.5% (51 out of 61=81.5% in class IV). The increased event rates in classes III and IV were significant (log rank; P<0.02) in comparison with I and II. CONCLUSIONS: Carotid and femoral morphology identified 2011 subjects (20.1% of the population) in classes II,III,IV including 98.6% of cardiovascular events and deaths in the following 10 years. A higher (P<0.05) rate of progression in classes III and IV in comparison with I and II was also observed. The ultrasound carotid and femoral classification was useful in selecting subjects at very low risk of cardiovascular events (class I), those at limited risk (class II) and a group at moderate risk (class III). A subpopulation at high risk of cardiovascular events (IV) was identified.

Vascular screening in andropause: non-invasive investigations in vascular disease screening.

Erectile dysfunction (ED) can be associated with atherosclerotic disease. It is therefore important to be able to evaluate the extent of arterial disease. This includes subclinical arterial disease. We have developed a score based on high-resolution-B-mode ultrasound scanning of the carotid-femoral bifurcations. This is a cost-effective screening procedure that correlates well with the risk of cardiovascular events. The penile circulation can also be investigated to assess local circulation and the level of fibrosis. During this investigation it is worthwhile evaluating the carotid-femoral arteries because the risk factors that predict ED are the same as those for atherosclerosis. Penile fibrosis contributes to the pathogenesis of ED. Whether this change is associated with hypertension needs to be established by further studies.

Skin blood flux and the venoarteriolar response in the perimalleolar area in patients with venous hypertension.

In patients with venous hypertension due to postphlebitic syndrome or varicose veins skin changes, liposclerosis and ulcerations are associated with increased skin blood flux at rest, a decreased venoarteriolar response and increased capillary filtration. Using laser-Doppler flowmetry we studied skin flux and the venoarteriolar response in the perimalleolar region in 100 normal limbs, 100 limb with varicose veins and 100 postphlebitic limbs with edema, skin changes and liposclerosis. The venoarteriolar response was studied with the leg on dependency, the foot being 50 cm below heart level. Flux at rest and on dependency were increased and the venoarteriolar response decreased in both groups of patients at a significantly greater extent in postphlebitic limbs. In conclusion laser-Doppler flowmetry measurements differentiate between normal limbs and those with venous hypertension and between postphlebitic limbs and limbs with venous hypertension due to varicose veins. The increase in skin flux and decrease in venoarteriolar response may be useful to define and quantify the degree of microangiopathy and the effects of treatments in venous hypertension.

Laser-Doppler flux in the normal and atherosclerotic carotid artery wall in normotensive and hypertensive subjects.

UNLABELLED: The aim of this study was to evaluate in vivo the perfusion of the arterial wall in normal sections of the carotid artery, in sections with fibrotic plaques and in sections with plaques and heavy calcifications using laser-Doppler flowmetry. Patients with carotid plaques undergoing carotid endarterectomy were studied. Using intraoperative ultrasound three different levels of atherosclerosis involvement of the arterial wall were defined: normal arterial wall where all components (intima, media and adventitia) were clearly separated and intact; wall with intima-media thickening and fibrotic plaques (no calcification); sections with diffusely calcified plaques. In 20 patients 20 normal sections, 20 sections with fibrotic plaques and 20 sections with large plaques and heavy calcifications were studied. Diabetic patients were excluded. Also the carotid wall of 10 patients with essential hypertension were evaluated. Wall flux was measured on the external surface of the common carotid artery before endarterectomy. Measurements were recorded when at least 3/4 of the adventitia was intact for a lenght of at least 4 cm. RESULTS: The average flux in normal sections was higher (p < 0.05) than in sections with fibrotic plaques and in sections with calcified plaques. A significant difference in flux (p < 0.05) between fibrotic (decreased flux) and calcified areas (very low flux). In hypertensive subjects flux measurements were significantly lower than in non-hypertensive patients (p < 0.05). In conclusions a higher wall perfusion was observed in normal arterial sections in comparison with sections with plaques. Sections with calcifications and large plaques had a markedly low flux. In hypertensive subjects all sections had a significantly lower flux.

Acute effects of TTFCA on capillary filtration in severe venous hypertension.

The acute variation in capillary filtration [CF] was evaluated with strain-gauge plethysmography in patients with severe venous hypertension due to deep venous disease. Two groups were selected and randomly treated with a single oral dose or TTFCA (60 mg or 120 mg). CF was assessed again after 5 and 10 hours. Eleven patients were randomised in the 60 mg group and 9 in the 120 mg group. Also 5 normal subjects were studied with the same procedure to act as controls. No variations in CF were observed in normal limbs. In both groups of patients there was a significant decrease in CF after 5 and 10 hours. The percent decrease in CF after 10 hours was higher in the high dose group. These results indicate that TTFCA is acutely effective in reducing CF and oedema in subjects with venous hypertensive microangiopathy. The effects of TTFCA on CF appear to be dose related.

Skin flux and the venoarteriolar response in essential hypertension.

Vasoconstriction is considered an important factor in patients with hypertension. The presence of skin flow reduction and the decrease in the venoarteriolar response (the skin flow decrease due to postural changes such as standing of lowering the leg below heart level) were studied in normal subjects and in patients with essential hypertension with laser-Doppler flowmetry. Measurements were repeated after a period of four weeks treatment with nifedipine. Laser-Doppler skin flux when the patient was resting supine and with the foot 50 cm below heart level was significantly lower than in normals. Also the venoarteriolar response was significantly reduced in hypertensives. After nifedipine treatment a significant increase in skin flux and improvement of the venoarteriolar response were observed. In conclusion laser-Doppler flowmetry can be used in hypertensives to quantify skin flow reduction, the altered venoarteriolar response and possibly the effects of drugs on the microcirculation.

Treatment of intermittent claudication with defibrotide or mesoglycan. A double blind study.

Forty-four patients with intermittent claudication were included and randomised in two groups respectively treated with oral defibrotide (one 400 mg tablet bid) or oral mesoglycan (one 24 mg tablet bid) for 6 months. Twenty-two subjects completed the study in the defibrotide group and 20 in the mesoglycan group. The two treatments were well tolerated and the two drop outs in the mesoglycan group were not due to medical causes. In the defibrotide group, after 1 month the pain-free walking distance (PFWD) increased from 473 +/- 96 m to 586 +/- 84 (p < 0.05). The walking distance (WD) increased from 767 +/- 125 m to 898 +/- 109 (p < 0.05). After 6 months the posterior tibial pressure (PTP) at the end of the treadmill exercise test also increased from 40 +/- 19 to 63 +/- 12 (p < 0.05). No variations in PFWD, WD and PTP were observed in the mesoglycan group. The improvement in walking was possibly due to the action of defibrotide increasing local fibrinolysis and decreasing the distal vasospasm present in subjects with peripheral vascular disease and intermittent claudication.

Inter/intra-observer variability of carotid and femoral bifurcation intima-media thickness measurements.

Arterial wall thickening may be quantitatively assessed by measuring the intima-media thickness (IMT) with high resolution ultrasound. Previous studies have shown a good inter/intraobserver variability of IMT measurements in the common carotid. In this study we evaluated the inter/intraobserver variability of IMT measurements in 10 randomly selected asymptomatic subjects (age 55.4 +/- 6). Two carotids and two femorals were studied in each subject. IMT for each patient was the average of five IMT measurements at the artery bifurcation. Three observers repeated the scanning and the measurements twice with no knowledge of the previous readings. The between observer coefficient of variation (CV) was 8.45%; the intraobserver CV (mean of carotids and femorals) varied from 4.4 to 5.1% for the three observers who measured IMT three times. The mean absolute difference between the first and the third measurement was 0.0738 mm. In conclusion IMT measurement variability is mostly due to differences between observers. The intraobserver variability is very small. IMT measurements at the carotid and femoral bifurcations have a low variability and are a good expression of atherosclerosis as they consider early lesions at the bifurcation level which may not be observed in the common carotid.

The edema tester in the evaluation of swollen limbs in venous and lymphatic disease.

BACKGROUND: Edema is a common condition in most venous and lymphatic diseases. The ACI edema testers (ET) have been developed to objectively evaluate the presence of edema. Two types of testers have been developed. ET1 is a soft plastic plate (5 x 2 cm) characterised by two parallel protrusions while the ET2 is characterised by two lines of 7 holes. METHODS: The ETs are applied onto the internal perimalleolar region with the protrusions/holes in contact with the skin. A blood pressure cuff is applied over the area (pressure maintained at 50 mmHg for a period between 1-3 minutes). When the cuff is removed, with the ET1 skin marks are usually just visible in normal limbs (they disappear in a few minutes). We studied 22 normal limbs, 19 with varicose veins, 22 with chronic venous insufficiency, 5 with primary lymphedema and 8 with severe chronic lymphedema. RESULTS: In limbs with severe edema the whole length of the protrusions is visible; with moderate edema only a part of the protrusions is visible. With the ET2 skin marks are just visible in normal limbs (only the larger holes). Marks disappear in a few minutes in normal limbs while in limbs with edema the number of visible holes is increased (in severe edema all holes are visible). There were significant differences between normals and patients (considering skin mark length, number of visible holes and disappearance times). CONCLUSIONS: The two testers separated patients with different severity of edema due to chronic venous or lymphatic problems. In severe lymphatic problems all parameters were different (p < 0.02) from those observed in venous disease. A reproducibility study indicated that the ET tests have minimal variations in mark visibility or length or hole numbers (for the ET2).

Methods of evaluation and quantification of microangiopathy in high perfusion microangiopathy (chronic venous insufficiency and diabetic microangiopathy).

Noninvasive macro- and microcirculatory tests provide quantitative information that offers answers to most questions posed in venous diseases. Duplex scanning is used to assess the macrocirculation, and microcirculatory methods are used to assess and quantify venous microangiopathy. Laser Doppler flowmetry is used to assess perfusion. Transcutaneous Po(2) and Pco(2) measurements are used to study venous hypertension, and strain-gauge plethysmography is used to assess capillary filtration. In venous hypertension, fluid filtration into the extracapillary compartment is increased. The increase in filtration is associated with a decreased venoarteriolar response. To quantify capillary filtration, two methods have been developed: venous occlusion plethysmography and rate of ankle swelling. These methods quantify filtration into the extracapillary compartment and, therefore, are an indication of the formation of edema, the most frequent sign in venous hypertension. Other methods, such as the vacuum suction chamber and the edema tester, can be used to assess changes due to treatments in venous hypertension. The techniques described in this article should be used in controlled environmental conditions

Treatment of diabetic microangiopathy and edema with HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides): a prospective, placebo-controlled, randomized study.

UNLABELLED: This study was planned to demonstrate in a prospective, placebo-controlled, randomized study, whether HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides), is effective in improving the microcirculation in subjects with diabetic microangiopathy and neuropathy. Patients with severe diabetic microangiopathy, neuropathy and edema, patients with microangiopathy, without neuropathy, and 20 healthy subjects were included. Microangiopathy was defined by laser Doppler flowmetry and capillary filtration (rate of ankle swelling (RAS)). Inclusion criteria were: increase in resting flux (RF) and RAS, a decrease in venoarteriolar response (VAR), and alterations in flux increase with temperature. The 2 groups of patients and the control group were randomized in a treatment sub-group which received HR (1 g, twice daily for 6 months); those in the placebo group received similar treatment. RESULTS: Groups were comparable; there were no drop-outs. There were no differences in the treatment and placebo groups at inclusion. Treatment was well tolerated; no adverse effects were reported. No variations were observed in healthy subjects at 6 months. In both groups of patients, significant decreases (P < 0.05) in RF and RAS were observed in the active treatment groups. The decrease in RAS was associated with a decrease in edema (P < 0.05) in both treatment groups. The decrease in RF and the increase in VAR were associated with a proportional decrease in RAS (P < 0.05). In patients without neuropathy, the variations in RF, VAR, and RAS were larger (P < 0.05) at 6 months. The variations in healthy subjects were limited and not significant. CONCLUSION: The decrease in capillary filtration and edema with HR is associated with symptomatic improvement. The action on edema is beneficial for the evolution of neuropathy. The effects of HR on flux, RAS, and edema are important in early stages of microangiopathy to avoid progression to clinical stages.

Treatment of edema and increased capillary filtration in venous hypertension with HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides): a clinical, prospective, placebo-controlled, randomized, dose-ranging trial.

UNLABELLED: The variation of capillary filtration rate (CFR) and ankle edema (AE) were evaluated in three groups of patients with venous hypertension with ambulatory venous pressure > 42 mmHg and in healthy subjects before and after treatment for four weeks with HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides), a venoactive drug acting on the microcirculation and on capillary permeability. Group A (30 patients) was treated with HR 500 mg tid; group B (30 patients) was treated with 1 g tid; group C (30 patients) was treated with placebo; group D (10 healthy subjects) was treated with HR 1 g/day in a randomised study. CFR was assessed by venous occlusion plethysmography. Subjective symptoms of venous hypertension were assessed by an analogue scale line considering four symptoms: swelling sensation, restless lower extremity, pain and cramps, and tiredness. RESULTS: There were no significant differences for sex and age distribution among the groups; no significant differences were found for ambulatory venous pressure and refilling time and parameters of venous hypertension among groups. There was a significant difference between normal subjects and patients. There were no drop-outs and observed intolerance. In group A, there was a significant decrease of CFR (P < 0.01) after treatment. In group B (2 g/day), the decrease was greater than that in group A (P < 0.05). In group C (placebo) there was no significant difference before or after treatment. The variations in analogue score was higher with the higher dosage. The score of group A fell from 7.8 (SD 1.3) to 4 (1). Group B's score fell from 7.9 (2) to 3.1 (1.2). In group C (placebo) there was no change. The decrease in the score in the groups of patients was correlated with the variation in edema and CFR. CONCLUSION: HR is effective in venous edema and hypertension. Its effects are dose-related.

Variations in plasma free radicals in patients with venous hypertension with HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides): a clinical, prospective, placebo-controlled, randomized trial.

The aim of this study was to demonstrate whether HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides), was effective in improving levels of plasma free radicals (PFRs) in patients with chronic venous insufficiency (CVI) and venous microangiopathy. Patients were randomized into the treatment group, which received oral HR (1g sachets, twice daily, for 4 weeks), and a placebo group, which received comparable placebo. Below-knee Sigvaris stockings were used during the study. PFRs were measured with the D-Rom test at the finger and at a vein of the leg in an area of CVI. The mean age of included subjects was 46 years (SD 11) in the treatment group (20 patients; 6 females) and 46.4 (SD 8) in the placebo group (20 patients; 7 females). There were no differences between placebo and treatment groups at inclusion in age and sex distribution and in parameters indicating venous hypertension. The decrease of PFRs levels in the treatment group was significant, both at the finger and in the distal blood taken in areas of CVI. There there were no significant changes in the control group. In areas of venous hypertension, PFRs values were on average higher than at the finger (systemic) level (P < 0.05). In parallel with the progressive decrease in PFRs associated with treatment, the analogue score was significantly decreased at 2 (P < 0.05) and 4 weeks (P < 0.02) in the HR group. No changes were observed in the placebo group. No adverse effects were observed. In conclusion, HR treatment is effective in decreasing both the systemic and local values of PFRs and therefore may have a positive effect on the evolution of CVI.

Flight microangiopathy in medium-to-long distance flights: prevention of edema and microcirculation alterations with HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides): a prospective, randomized, controlled trial.

This study evaluated the effects of HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides) on the prevention and control of flight microangiopathy, and particularly on edema, in subjects with varicose veins flying for more than 7 hours. Forty patients with varicose veins, edema, and initial skin alterations due to chronic venous hypertension were included. Measurements of skin laser Doppler flowmetry resting flux, Po(2) and rate of ankle swelling, were made before and after the flights (within 4 hours before the flights and within 2 hours after the flights). The length of the flights was between 7 and 9 hours; all seats were in coach class. The 2 groups were comparable for distribution. The variation of Po(2) was significant in both groups. However, in subjects treated with HR, the decrease in Po(2) was smaller (P < 0.05). The decrease in laser Doppler flowmetry resting flux was also significant in both groups, with a higher flux at the end of the control period in the treated subjects (P < 0.05). The venoarteriolar response progressively decreased at 7 and 9 hours. The decrease was less evident in the treatment group (P < 0.05). The rate of ankle swelling was progressively increased in the control group; the increase was not significant in the HR group. In long-haul flights, HR is useful for reducing the increased capillary filtration and in controlling edema in patients with venous hypertension and is effective in controlling perfusion disorders and microangiopathy, particularly swelling and edema, due to flights.

HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides) in venous hypertensive microangiopathy: a prospective, placebo-controlled, randomized trial.

UNLABELLED: The aim of this study was to demonstrate whether HR (Paroven-Venoruton; 0-(beta-hydroxyethyl)-rutosides), was effective in improving the microcirculation in venous hypertension and microangiopathy. Sixty patients with severe venous hypertension due to chronic venous insufficiency, ankle swelling, and lipodermatosclerosis were included. After informed consent, patients were randomized into a treatment group and a placebo group. Patients in the treatment group received oral HR (2 g/day for 8 weeks); those in the placebo group received a comparable placebo. RESULTS: The two groups were comparable for age and sex distribution. The mean age was 45 years (SD 9) in the treatment group (31 patients) and 45.5 (SD 10) in the placebo group (29 patients). There were no differences between the placebo and treatment groups at inclusion. There was no change between inclusion and measurements at 8 weeks in the placebo group. A significant decrease (P < 0.05) in flux at rest and rate of ankle swelling was observed in the treatment group. The decrease in capillary filtration was associated with improvement in signs and symptoms (P < 0.05). The difference in flux, sign and symptoms, and filtration was clinically important at 8 weeks in the treatment group when compared with the placebo group. No adverse effects were observed. CONCLUSION: Venous microangiopathy was improved by HR treatment.

Laser Doppler skin perfusion pressure in normal and vascular subjects with rest pain: an universal measurement?

Laser-Doppler (LDF) skin perfusion pressure was measured and compared with Doppler ankle pressure measurements in 40 normal subjects and 20 patients with rest pain and ankle/foot Doppler pressure lower than 70 mmHg. Six different, commercially available LDF instruments were used. To obtain perfusion pressure a standard blood pressure cuff was used measuring the pressure at which the skin flux reading reached the biological zero level when inflating the cuff (P1) and the pressure at which the LDF tracing reappeared after deflating the cuff from sovrasistolic pressure level (P2). Perfusion pressure (PP) was considered to be the average [P1 + P2]/2. No differences in PP amongst the 6 instruments both in normal and vascular subjects were observed. These results indicate that PP is an universal LDF measurement which can be easily obtained with different LDF instruments.

Microcirculation in high perfusion microangiopathy.

Using laser-Doppler flowmetry in association with other noninvasive microcirculatory techniques such as transcutaneous PO2 and PCO2 and capillary filtration measurements it is possible to define two major types of microangiopathy. Low perfusion microangiopathy (LPM) is observed in peripheral vascular disease, essential hypertension, Raynaud's disease etc. High perfusion microangiopathy (HPM) is observed in venous hypertensive microangiopathy and diabetic microangiopathy. In both these conditions there is an increased skin flux, decreased venoarteriolar response and increased capillary filtration leading to edema formation. In HPM elastic compression and drugs acting on capillary filtration effectively reduce skin flux and the increased capillary leakage and edema formation.

Delayed arteriosclerosis progression in high risk subjects treated with mesoglycan. Evaluation of intima-media thickness.

Noninvasive ultrasonic biopsy (UB) can be used to classify arteriosclerotic lesions and their progression in the carotid and femoral bifurcation. Also the evaluation of intima-media thickness (IMT) is useful to quantify the progression of early arteriosclerosis. Two randomly selected groups of asymptomatic subjects were included in a 18 month, open study. One group was treated with oral mesoglycan (200 mg/day) and one group was followed-up as control. The two groups were comparable for age and sex distribution. The average UB score was 14.4 +/- 5 in the treatment group and 14.3 +/- 8 in the control group. After 18 months the UB score was 15.7 +/- 4 in the treatment and 16.2 +/- 6 in the control group. These differences were not significant. However the average increase in IMT in 18 months in the treatment group was 0.016 mm equivalent to 0.0106 mm per year. In the control group the average increase was 0.119 equivalent to 0.0793 per year. Therefore the increase in IMT was 7.48 times greater in the control group. These differences were significant (p < 0.05). Two drop-outs were recorded in the treatment group and 1 in the control group. In conclusion IMT measurements showed a decreased level of IMT progression in subjects under mesoglycan treatment. These results need to be confirmed by a larger randomised study.

Microcirculatory effects of elastic stockings in diabetic microangiopathy: a 24-week study.

Patients with diabetic microangiopathy were studied by laser-Doppler flowmetry--measuring skin blood flux at rest (RF) and the venoarteriolar response (VAR) and evaluating the rate of ankle swelling (RAS) to study capillary filtration. After randomisation, 38 patients were treated for 24 weeks with below-knee elastic stockings, and 36--acting as controls--were left without elastic compression. After 12 and 24 weeks, there were no significant changes in the control group, while there was a significant improvement of the microcirculatory parameters in patients using stockings. RF (increased at the beginning of the study) was significantly decreased, the VAR (impaired at the beginning of the study) improved significantly and the abnormally increased capillary filtration decreased. Elastic stockings seem to be useful in diabetic microangiopathy improving microcirculatory parameters and decreasing capillary filtration and oedema. These effects may improve diabetic microangiopathy and possibly slow down its rate of progression.

Subclinical arteriosclerosis screening. The PAP/PEA study. Prevalenza dell'Arteriosclerosi Precoce (Prevalence of Early Arteriosclerosis).

Noninvasive screening of subclinical atherosclerosis is possible with ultrasonic biopsy (UB) performed with high resolution ultrasound scanning. Five UB classes have been identified, each class corresponding to a different incidence of cardiovascular events (CVE) in 4 years and silent coronary ischemia (SCI). In a study including 2230 asymptomatic subjects 3 risk groups were defined. In the low risk group (class I and II; 82.01% of the population sample) the incidence of CVE and SCI was zero. These subjects may be seen again after 3 years. In the moderate risk group (class II and IV; 13.3%) monitoring and early intervention may be needed. In the high risk group (class V; 4.6%) prophylaxis or treatment may be necessary. The screening is effective, simple and may be organised at very low cost--i.e. 30.000 asymptomatic subjects may be scanned at the cost of 100.000 ECU. Each scan, including carotid and femoral bifurcations, may be performed in 15 minutes. In our communities this cost is equivalent to the average cost of a single major stroke or major coronary ischemic event in a working adult aging between 45 and 60. Organization problems and the fragmentation of competences has prevented the evolution of atherosclerosis screening. The problem can be solved organising a network including epidemiologists, angiologists and cardiovascular surgical centres where all phases of atherosclerosis may be studied and detected, progression prevented and complications treated with a global vision of the disease.