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.

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.

Non-invasive ultrasonic biopsy in the classification of early arterial lesions and in the evaluation of the rate of progression of arteriosclerosis.

The evaluation of early arterial lesions and the follow-up of the progression of arteriosclerotic wall changes is possible with high resolution ultrasound. While dynamic (duplex scanning) data are suitable for the follow-up of advanced stenosis and plaques, the morphological evaluation performed using the technique of non-invasive ultrasonic biopsy may be used to follow-up early lesions and their progression. The data obtained by ultrasonic biopsy are related to the incidence of occult coronary ischemia and to the occurrence of cardiovascular events in 4 years. The rate of progression (ROP) to the next, more advanced UB class can be also evaluated by ultrasonic biopsy. It has been shown that in diabetic and hyperlipidemic subjects the ROP is higher. Also in interventional studies using lipid lowering agents (with a four-year follow-up) a reduction in ROP in treated asymptomatic hyperlipidemic subjects in comparison with controls has been documented. The combination of dynamic data and morphological data gives us a complete evaluation of the vascular system both for the assessment of single individuals and for large population studies.

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).

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.

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.

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.

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.

Ultrasonic classification of carotid plaques causing less than 60% stenosis according to ultrasound morphology and events.

Carotid plaque morphology studied by ultrasound has been used to classify 3 types of bifurcation plaques, producing less than 60% stenosis on duplex scanning: Type A, the homogeneous, highly echogenic plaque; Type B, the heterogeneous (mainly echogenic, B-1 or mainly echolucent, B-2) plaque; Type C, the complex plaque with irregular surface, echogenic and/or echolucent with calcifications. One hundred asymptomatic subjects in each plaque group were included in a prospective 4-year follow-up study to evaluate clinical events and brain damage by yearly cerebral CT and MR scans. After four years 96 subjects with type A plaque, 89 with type B-1 and 67 with type C plaques completed the study. While there were no clinical events or positive cerebral scans in subjects with type A plaques there was a significantly increasing number of cerebral and vascular events in subjects with plaque B and C type with a zero mortality in the plaque A group, a 2.24% mortality in type B plaques and a significantly higher (p > 0.05) mortality (13.4%) in type C plaques. CT and MR scans revealed brain damage which had been totally asymptomatic with MR detecting a larger number of lesions. Also the number of cerebral lesions observed by CT/MR were significantly greater than the number of recorded clinical episodes. ECG stress test revealed a larger number of asymptomatic coronary disease in the C type plaques. In conclusion ultrasound plaque morphology is linked to different incidences of cerebral and cardiac events, brain damage and asymptomatic coronary disease. Also CT and MR may reveal lesions which do not cause signs or symptoms.

Ocular and orbital blood flow velocity in patients with peripheral vascular disease and diabetes treated with intravenous prostaglandin E1.

The purpose of this study was to evaluate the effect of intravenous prostaglandin E1 (PGE1) on the flow velocity of the ophthalmic artery and the central retinal artery in patients with peripheral vascular disease manifested by intermittent claudication. The flow velocity of these vessels is frequently decreased in vascular patients. Since these patients were already being treated with PGE1 for their intermittent claudication, the authors wanted to evaluate the effect on the flow velocity of the ocular vessels as well. A randomized 21-week study of two groups of vascular patients was performed. The first group had intermittent claudication. The second group had intermittent claudication and were also diabetics. Both groups were treated with intravenous PGE1 for their intermittent claudication. Using the color Doppler, the flow velocities of the ophthalmic artery and central retinal artery were measured before and after the intravenous treatment. Before treatment, the flow velocity of the ophthalmic artery and the central retinal artery was decreased when compared to that in the normals. After treatment, there was a significant increase in the systolic and diastolic phases of the flow velocity in both arteries. The systolic flow velocity increased by as much as 40%, and the diastolic flow velocity increased by as much as 80%. The flow velocities of the ophthalmic artery and the central retinal artery are frequently decreased in certain ocular diseases, and this decreased flow may contribute to the ocular pathology. If intravenous PGE1 is able to increase the flow velocity of these vessels in patients with peripheral vascular disease, it is possible that it is also able to increase the flow velocity of these vessels in patients with ocular disease as well. Intravenous PGE1 may prove to be a useful adjunct therapy in eyes when ischemia is part of the pathology.

Ocular and retrobulbar blood flow in ocular hypertensives treated with topical timolol, betaxolol and carteolol.

The purpose of this study was to evaluate the effect of topical timolol 0.5%, betaxolol 0.5% and carteolol 2% on the blood flow velocity of the central retinal artery (CRA), the posterior ciliary artery (PCA) and the ophthalmic artery (OA) in patients with ocular hypertension. A group of 14 patients with ocular hypertension and a group of 11 normals were studied. The color Doppler was used to measure the peak systolic flow velocity (PSFV) and the end diastolic flow velocity (EDFV) of the CRA, the PCA and the OA in the normals and in the patients. The normals were under no treatment, while the patients were studied before and after treatment with topical timolol 0.5%, betaxolol 0.5% and carteolol 2%. In the systolic phase, there was a significant increase in the flow velocity of the CRA with all three drugs. In the diastolic phase of the CRA, the increase was significant for timolol 0.5% and carteolol 2% but not for betaxolol 0.5%. The flow velocity of the PCA and OA remained unchanged. In this study of 14 patients with ocular hypertension, topical timolol 0.5%, betaxolol 0.5% and carteolol 2% led to a significant increase in the flow velocity of the CRA without creating a steal or decrease in the flow velocity of the PCA.

A simple test to monitor oxidative stress.

BACKGROUND: The role of oxygen free radicals is considered important in the development of cardiovascular disease. However, until recently determination of free radicals plasma levels and the effect of antioxidant therapy on these levels has been difficult. The aim of the study was to determine the oxidative stress and the effect of the antioxidant compound AR(D) Stenovit on this stress in normal subjects and patients with intermittent claudication after oral administration for one week. METHODS: A portable, free radicals (FRs) determination system (D-Roms test, Diacron, Grosseto, Italy) was used. This test is based on the ability of transition metals to catalyse in the presence of peroxides with formation of FRs which are trapped by an alchilamine. The alchilamine reacts forming a coloured radical detectable at 505 nm. The reagents utilised are the cromogen (R1, an alchilamine) and a pH 4.8 buffer (R2). Ten microl of hemolysis-free serum are to 1 ml of R2 and to 10 microl of R1. The sample is mixed, incubated (1 min; 37 degrees C) and read for optical density. After another minute, the sample is read again. The average delta A/min is multiplied by a K factor and calculated using serum with defined value. RESULTS: In normal subjects the mean (+/-SD) levels of free radicals were 312+/-49 U.CARR (Carratelli units) before treatment and 218+/-33 U.CARR after treatment (p<0.05). A decrease of at least 10% was detected in every subject. In patients with peripheral vascular disease the mean (+/-SD) levels of free radicals were 404+/-42 U.CARR before treatment and 278+/-33 U.CARR after treatment (p<0.02). A decrease of at least 15% was detected in every patient (medium value 31%). CONCLUSIONS: The D-Roms test provides a simple, inexpensive and practical method to identify subjects with a high level of oxidative stress and to demonstrate the effect of treatment. The compound AR(D) Stenovit is effective in reducing circulating free radicals. Its action on the progression of atherosclerotic disease should be assessed in future studies.

Doppler ultrasonography in giant cell arteritis.

A patient with biopsy negative giant cell arteritis was examined and treated by our group. Since in some cases the visual loss in this disease is due to a central retinal artery occlusion, a technique to evaluate the blood flow velocity in this artery would be useful. The Duplex scanner was utilized by us in this patient to study the blood flow velocity of the central retinal artery. The flow velocity was reduced. The patient was treated with systemic steroids which lead to clinical and symptomatic improvement. After the treatment with steroids the Duplex scanner was again used to study the flow velocity of the central retinal artery. The blood flow velocity improved. We think that Doppler ultrasonography may be useful in the diagnosis of and in monitoring the treatment of some cases of giant cell arteritis.

Oxygen-free radical decrease in hypertensive patients treated with lercanidipine.

BACKGROUND: The relationship between oxidative stress, lipoproteins, cardiovascular risk factors and vascular disease progression has recently attracted fresh attention due to the possibility of measuring free radicals (FRs). The aim of this study was to evaluate blood plasma variations in oxygen FRs in hypertensive patients treated with lercanidipine, a drug acting on blood pressure and microcirculation. METHODS: Twenty-two patients with moderate hypertension (M:F=12:10; age=52) and no vascular disease (evaluated by high-resolution ultrasound) were treated for 24 weeks with Lercanidipine (10 mg/day or 20 mg/day if BP values did not decrease at least 15 percent after four weeks of treatment). BP was measured at inclusion and after 4, 8, 12 and 24 weeks of treatment. FRs measurements (using the D-Roms test) were made at inclusion, at the 8th, 12th and 24th week. RESULTS: All patients completed the treatment which was well tolerated and without side effects. Systolic and diastolic BP decreased after 8, 12 (p<0.05) and 24 weeks (at 24 weeks systolic pressure was decreased by 21.1 percent, and diastolic by 11.1 percent; p<0.02). FRs levels progressively decreased from 541 Carr Units (SD 54) at inclusion to 411 (SD 56) at eight weeks (p<0.05), to 401 (SD 35) (p<0.05) at 12 weeks and finally to 398 (SD 33), (p<0.02) at 24 weeks of treatment (72.2 percent of the initial value). CONCLUSIONS: The possibility of measuring FRs in vivo with a simple, inexpensive test allows the identification of subjects with a high level of oxidative stress, and the monitoring of the effects of treatments. Lercanidipine, acting on blood pressure, on the microcirculation and decreasing oxidative stress and Frs plasma levels may effectively decrease the rate of progression of cardiovascular diseases offering the advantage of an increased level of protection in patients with high levels of oxidative stress.

Topical treatment of venous microangiopathy in patients with venous ulceration with Essaven gel--a placebo-controlled, randomized study.

The involvement of the microcirculation in chronic venous insufficiency (CVI), due to venous hypertension, causes venous hypertensive microangiopathy (VHM) and ulceration. VHM is characterized by enlarged, convoluted capillaries; microvascular thrombosis; obliteration of some capillaries; increase in flux, permeability, and edema and altered microlymphatics. PO2 is decreased and CO2 increased. Capillary exchanges are altered and nutritional alterations eventually lead to venous ulcers. Edema is associated with increased capillary pressure, reduced clearance, and increased exchange surface of capillaries, which become tortuous and glomerular-like. The aim of this randomized, placebo-controlled study was to evaluate local treatment with Essaven gel (EG) in subjects with venous microangiopathy and ulcers. Measurements of laser Doppler flux, PO2, and PCO2 in standardized conditions showed positive changes (a significant decrease of the abnormally increased flux and CO2 while PO2 increased) in the EG treatment group. Changes in the placebo and control group were more limited (changes in the placebo group were mainly associated with skin manipulation when placebo-EG was applied). In conclusion, Essaven gel, in comparison with placebo, acutely improves the microcirculation in VHM even with a single acute application.