Veno-active drugs in the management of chronic venous disease. An international consensus statement: current medical position, prospective views and final resolution.

BACKGROUND: Veno-active drugs (VAD) have effects on edema and symptoms related to chronic venous disease (CVD), especially so-called venous pain. VAD's effectiveness, although well established, is regularly debated. OBJECTIVE: Our purpose was to select all randomized controlled trials (RCTs) and meta-analyses devoted to VAD and symptoms in CVD, to submit them to a group of international experts in CVD and to vote with secrete ballot to determine the level of efficacy of each drug, according to EBM (Evidence-Based Medicine) rules and critical analysis. METHODS: Publications in any language devoted to VAD and venous symptoms were searched for in different databanks and submitted to the experts prior to the meeting. RESULTS: 83 papers were analyzed, including 72 RCTs or meta-analyses. Experts determined the level of EBM of each drug, according to the literature and personal experience, using 3 levels of recommendation, A, B and C (from large RCTs to non-randomized trials). CONCLUSIONS: VAD are effective and may be applied in CVD when symptomatic, from C0s to C6s. However, etiological treatment of venous reflux and venous hypertension has always priority. In some cases VAD may replace compression and/or complement its effects. If respecting these prerequisites, VAD are safe and effective.

Primary and secondary blood hyperviscosity syndromes, and syndromes associated with blood hyperviscosity.

Despite the methodological difficulties of evaluating the role of a single rheological component, some clinical situations characterised by an increase of blood viscosity can be identified. These are classified as 'blood hyperviscosity syndromes' and can be divided into 2 groups. The first includes pathophysiological conditions in which a primary blood abnormality causes a decrease of blood flow, as occurs in polycythaemic, sclerocythaemic and seric hyperviscosity syndromes, and may be referred to as 'primary blood hyperviscosity syndromes'. The second group includes pathological conditions in which a primary reduction of blood supply to tissue provokes tissue ischaemia, and an impairment of rheological properties of blood can be observed at microcirculatory level. Thus, these situations have been described as 'secondary blood hyperviscosity syndromes'. Patients with peripheral obliterative arterial disease, ischaemic cardiopathies and cerebrovascular insufficiencies show a diminution in blood fluidity during spontaneous or provoked ischaemic conditions which disappears after reperfusion of the tissue. The pathogenesis of this rheological damage is unclear, but may arise from the complex relationship among blood cells (red cells, leucocytes, platelets), endothelium and plasma components. In addition to these 2 groups of blood hyperviscosity syndromes, several pathological states such as diabetes, shock, surgery, and rheumatic disease have been described in which an increase of blood viscosity can be observed. For these situations, which require much further investigation, the term 'syndromes associated with blood hyperviscosity' could be proposed.

Arterial blood gas analysis and alveolar-arterial oxygen gradient in diagnosis and prognosis of elderly patients with suspected pulmonary embolism.

BACKGROUND: Arterial blood gas analysis (BGA) remains a first-step diagnostic approach in patients with suspected pulmonary embolism (PE). The aim of this study was to evaluate BGA parameters in elderly patients with suspected pulmonary embolism for diagnosis and 14-day prognosis. METHODS: We performed a retrospective cohort observational study of 6 years (1994-1999) in a 60-bed acute geriatric ward of University Hospital in Siena, Italy. Room air arterial oxygen partial pressure (pO2), arterial carbon dioxide partial pressure (pCO2), pH, arterial oxyhemoglobin saturation (SO2), and alveolar-arterial oxygen gradient [D(A-a)O2] were performed on hospital admission of 75 patients with confirmed PE (CPE) and were compared with data from 43 patients with unconfirmed PE (UCPE). The same parameters of 54 CPE surviving patients were compared with 21 CPE nonsurviving patients. RESULTS: Significantly lower PO2 and SO2, and higher DA-aO2 were found in CPE patients. Respiratory alkalosis was found in one third of the patients in both groups (no significant difference). In the CPE group, there was a significantly lower SO2 in nonsurviving patients, without significant differences for the other parameters. Metabolic acidosis was significantly more frequent in nonsurviving patients. CONCLUSION: More severe hypoxemia, oxyhemoglobin hyposaturation, and higher D(A-a)O2 are associated with the diagnosis of PE in elderly patients. Respiratory alkalosis is less frequent than in younger patients, and metabolic disorders are negative prognostic indicators.

Effect of contralateral internal carotid stenosis on the accuracy of continuous wave Doppler spectral analysis results.

In order to determine the effect of a hemodynamically significant contralateral stenosis on the results of a carotid Doppler study, 333 continuous wave Doppler spectral analysis studies were compared to angiography. For most grades of stenoses, both the peak frequency and the spectral broadening index were increased in the group of patients with contralateral carotid arterial stenoses greater than 50% by comparison with the group with less severe stenoses. Using receiver operating characteristic curves, the diagnostic accuracy was found to be slightly reduced by the presence of significant contralateral disease. Hence, when interpreting the results of carotid Doppler examinations, the presence or absence of a hemodynamically significant contralateral stenosis should be considered in determining the likelihood that an ipsilateral stenosis is present and in evaluating its severity.

Arterial and venous blood viscosity in ischemic lower limbs in patients affected by peripheral obliterative arterial disease.

Blood, plasma and serum viscosity, packed red cell volume, and plasma fibrinogen concentration was measured in a group of 13 subjects, suffering from peripheral obliterative arterial disease of the lower limbs (stage III or IV), awaiting surgery, and in 9 control subjects, none of whom showed signs of circulatory disease of the lower limbs either by clinical examination or by instrumental measurements. The blood samples were taken from the: (a) antecubital vein; (b) femoral vein; (c) femoral artery. In the patients venous blood viscosity was significantly higher than arterial blood viscosity. No significant differences have been found between the femoral and the antecubital vein, but in the femoral vein blood viscosity was slightly higher. Packed red cell volume and plasma viscosity were slightly but significantly higher in venous blood, while no difference was seen in serum viscosity and in plasma fibrinogen concentration. In the control subjects blood viscosity values were decidedly lower than in patients and no statistically significant differences were to be found between artery and vein, even if viscosity values were lower in artery. These results support the hypothesis that an interrelation exists between hyperivscosity syndrome and vascular ischaemia-inducing diseases.

Efficacy of O-(beta-hydroxyethyl)-rutosides at high dosage in counteracting the unwanted activity of oral contraceptives on venous function.

In a double-blind study the effect of a high dosage of O-(beta-hydroxyethyl)-rutosides (HR) was tested in women taking oral contraceptives and suffering from venous insufficiency of the lower limbs. Ten patients were treated for 28 days with HR (3 g/day) and ten with a placebo. In basal conditions and after therapy, the symptoms of venous disorders and the venous function, by means of strain gauge plethysmography, was evaluated in both groups. The results showed an increase of venous capacitance and a reduction of venous tone in the subjects treated including those without symptoms in the lower limbs. The HR treatment resulted in a significant improvement of the venous function parameters and of the symptoms in lower limbs.

PIP: Venous insufficiency of the lower limbs in oral contraceptive users was treated with Venoruton 1000 (o-(beta-hydroxyethyl)-rutoside) at a high dose of 3 g/day in a double-blind, placebo controlled trial. 20 women aged 19-42, who had taken pills 3 months to 7 years (mean 30.2 months) were randomly assigned to treatment vs. placebo. The soluble powder was prepared in sachets indistinguishable from placebos. Venous function was assessed by strain gauge plethysmography (Periflow, Janssen Scientific, Beerse, Belgium), and the following parameters were determined: maximal venous incremental volume, maximal venous incremental volume time, maximal venous outflow, time of total emptying, index of venous distensibility, index of venous tone, and venous pressure. Subjective symptoms were evaluated on a scale of 0-5: pain, swelling, nocturnal cramps, tingling, heaviness and restless legs. Basal measurements showed high values of venous capacity, distensibility, and reduced venous tone. After 28 days of treatment, several venous parameters were significantly improved in the test group vs. placebo: maximal venous incremental volume at 40 and 60 mm Hg (venous capacity), index of venous distensibility and index of venous tone. There was significant improvement in subjective reports of pain, swelling, heavy legs and restless legs in the treated over placebo group. No side effects or changes in laboratory findings were observed.

Triflusal in the treatment of patients with chronic peripheral arteriopathy: multicentre double-blind clinical study vs placebo.

Many clinical trials have shown the effectiveness of platelet-antiaggregant drugs in the treatment of obliterative peripheral arteriopathy, both locally and in the system, by improving the claudication symptoms and by preventing major cardiovascular events. In this study we evaluated the effectiveness of a 24-week treatment with triflusal, a comparatively new inhibitor of platelet aggregation, in patients affected by chronic peripheral arteriopathy, comparing twice-daily oral doses of 300 mg triflusal with twice-daily placebo doses. The percentages of successes (defined as a 40% increase of total walking distance over the basal control) were 63.6% in the triflusal group (35/55 patients) and 22.5% in the placebo group (14/62 patients). Patients treated with triflusal showed a more important increase in total walking distance and in pain-free walking distance over the basal values than those treated with placebo, together with an improvement of the symptomatology correlated with claudication. Moreover, in the triflusal group there was an increase in the peak-flow recorded through strain-gauge plethysmography. In conclusion, triflusal significantly increased both the distance which could be walked and the clinical symptoms, presumably by improving microperfusion.

Treatment of critical limb ischemia in the elderly.

Acute critical limb ischemia (CLI) is a rather frequent clinical event in elderly patients. Atherosclerotic plaques or cardiopathies (atrial enlargement and fibrillation, ventricular thrombosis) are the most frequent clinical situations related to peripheral embolization. Rapid diagnosis followed by suitable treatment allows us to obtain good results even in elderly patients. The decision about the treatment of acute CLI is related to the clinical and functional condition of the patient. Anamnesis must inquire about recent ischemic or hemorrhagic events in the cardiovascular, gastro-intestinal and urinary apparatuses, or the presence of disorders of coagulation and fibrinolysis. An objective clinical examination and a multidimensional assessment must evaluate the degree of functional impairment and provide the basis of a therapeutic strategy (cost/benefit ratio). Diagnostic examination in the frail elderly patient (FP) involves only the ultrasonographic method, to localize the level of thromboembolic occlusion, which is followed by angiography in the non-frail patient (NFP). In the case of proximal occlusion (of the iliac or femoro-popliteal arteries), the elective treatment in both groups of patients is thromboendarterectomy, plus transcutaneous angioplastics or by-pass in NFP, followed by prostacyclin or heparin infusions. Distal occlusion (below the popliteal artery) in FP is treated only with prostacyclin or heparin, whereas in NFP, fibrinolysis is the elective treatment, followed by prostacyclin or heparin. In the cases of distal gangrene, before amputation is performed, a "limb salvage" operation must be considered. After the acute phase of medical or surgical treatment, vasoactive or antiplatelet drugs are employed in FP, whereas in NFP the use of coumadin is the preferred treatment to counteract the rethrombosis and prevent new embolizations. Antiplatelet therapy could be selected when coumadin is contra-indicated.

The association of serum lipoprotein(a) levels with myocardial infarction and ictus cerebri in the elderly.

This study was aimed at revealing the relationship between the serum concentrations of lipoprotein(a) [Lp(a)], the coronary atherosclerotic disease (CAD) and the cerebral vasculopathies (CVP) in elderly patients. A group of 117 patients (66 women and 51 men, mean age 83 +/- 5.8 years) was investigated. Of them, 58 suffered from acute myocardial infarct (AMI) and 59 from ictus cerebri (IC). The parameters were compared with those obtained from a control-group of 88 old people without any recent clinical history of cerebrovasculopathy or atherosclerotic coronariopathy. In the patients with AMI, the average serum value of Lp(a) was 40.8 +/- 18.5 mg%, and in those suffering from IC, it was 46.7 +/- 13.2 mg%; the differences of these averages against the mean found in the control patients (23.2 +/- 11.5 mg%) were statistically significant (p < 0.01). One can conclude that an increased Lp(a) is of diagnostic value for the presence of both IC and AMI, and represents a risk factor for cerebrovasculopathies, too.

Influence of non-selective and selective beta adrenoceptor blockade on isoxsuprine-dependent hemodynamic and rheologic changes.

The infusion of isoxsuprine was followed by an increase of heart rate and calf blood flow and by a decrease of arterial diastolic pressure and blood viscosity both in normal controls and patients with peripheral obstructive arterial disease. The pre-treatment with a non-selective beta adrenoceptor blocker (propranolol) canceled all the isoxsuprine-dependent changes, while the pre-treatment with a selective beta adrenoceptor blocker (metoprolol) abolished only tachycardia and did not influence the increase of calf blood flow and the decrease of blood viscosity. These findings indicate the different role of vascular beta receptors in the regulation of muscular blood flow and suggest the pharmacologic possibility to unmask the beta2-dependent vasodilation.

Behavior of circulating endothelin-1 in a group of patients with acute myocardial infarction.

The aim of this study was to investigate the behavior of plasma endothelin-1 (ET-1) in 23 patients with acute myocardial infarction, complicated and uncomplicated by left ventricular failure, and treated with and without thrombolytic agents. ET-1 was measured on admission; on days 2, 3, and 5; and again on discharge. In addition, on discharge, ET-1 was correlated with left ventricular systolic function. Left ventricular failure was present, on admission, in 14 patients, whereas the other nine did not have any hemodynamic impairment. On discharge, no patients had left ventricular failure, but 11 had moderate to severe left ventricular systolic dysfunction, defined as left ventricular ejection fraction (LVEF) < 40%. Fourteen subjects, matched for age and sex, served as a control group. Compared with the control range, ET-1 was highly elevated on the first day, in both uncomplicated (p < 0.01) and complicated patients (p < 0.001). Then it decreased rapidly in the uncomplicated group, reaching the control range within day 5, whereas in the complicated group it remained significantly elevated in comparison with both the control subjects and the uncomplicated patients, until discharge. ET-1 was not correlated with the peak of creatine-kinase MB isoenzyme in any group. In seven patients submitted to thrombolytic treatment ET-1 was always significantly lower than in the nonthrombolyzed patients (p < 0.05), but the pattern of variation across time was no different. On discharge, the difference in plasma ET-1 between patients with LVEF < 40% and the control group was significant (p < 0.001), as was the difference between patients with and without moderate to severe systolic dysfunction (p < 0.01). ET-1 was closely and inversely correlated with LVEF when patients were considered as a whole (p < 0.001). These results suggest that the ET-1 increase in the early phase of myocardial infarction could be due to an ischemic process, to stress reaction, and to cardiac hemodynamic impairment, and therefore, ET-1 may be a good marker of disease. In the following phase the ET-1, being correlated with LVEF, could be a reliable index of systolic function.

Effect of felodipine on arterial blood flow and venous function at rest in patients with mild essential hypertension.

Felodipine is a second-generation dihydropyridine calcium antagonist used to treat mild to moderate arterial hypertension. The authors used venous occlusion plethysmography to study the effect of this drug on lower limb arterial inflow and venous outflow in 10 at rest patients with mild essential hypertension. They also sought correlations between changes in district blood flow and blood pressure. Plethysmography was carried out at 8 AM and 4, 8, and 24 hours later at baseline (after washout), on the first day of treatment with a single daily administration of 10 mg felodipine ER, and after 7 and 30 days of treatment. The drug was given after the 8 AM evaluation. The authors determined rest flow, maximal venous incremental volume (MVIV) at 40 mmHg and 60 mmHg, and gradient of venous volume between 60 and 40 mmHg divided by the pressure difference (DV/DP) as index of venous distensibility. On the days of plethysmographic evaluation, arterial blood pressure and heart rate were measured continuously over 24 hours by the ABPM (Ambulatory Blood Pressure Monitoring). The results were analyzed by ANOVA. Rest flow, MVIV, and DV/DP were stable at the baseline evaluation. On days 1, 7, and 30 of treatment the rest flow after 4 and 8 hours was significantly greater than at 8 AM but had always returned to normal after 24 hours. No other plethysmographic parameters changed significantly; in particular venous outflow remained unchanged. Mean arterial, systolic, and diastolic blood pressure were significantly reduced, compared with baseline, following treatment on the first day and after 7 and 30 days' treatment. There was no effect on heart rate. The authors conclude that felodipine is useful for the treatment of mild essential hypertension, since it reduces arterial resistance without altering venous capacitance or distensibility.

Action of cinnarizine on the hyperviscosity of blood in patients with peripheral obliterative arterial disease.

Cinnarizine, a drug capable of improving blood flow, was studied for its action on blood viscosity and its main components in patients affected by peripheral obliterative arterial diseases (POAD). Both acute and chronic administration of the drug diminished the increased whole-blood viscosity in patients, without affecting plasma and serum viscosity, hematocrit, plasma fibrinogen concentration, and plasma osmolality. Since cinnarizine also led to a significant increase of peripheral muscular blood flow, it was hypothesized that this action may be due to an increased deformability of the red cells, and may play a considerable role in the therapeutic approach to POAD.

Evaluation of hemorheological parameters and red cell morphology in hypertension.

The aim of our study was to evaluate hemorheological parameters in two groups of patients both suffering from essential hypertension compared with an homologous group of subjects not suffering from hypertension; the 1st group was composed of 16 patients (8 females and 8 males, mean age 65.6 +/- 16.5) suffering from essential hypertension; the 2nd one of 26 patients (8 females and 18 males, mean age 74.3 +/- 11.7) suffering from essential hypertension and cerebral or cardiac ischemia in a chronic phase. The group of controls was composed of 20 subjects (mean age 50.5 +/- 11.5). In all these subjects we evaluated: blood viscosity, hematocrit, plasmatic fibrinogen, red cell morphology according to Zipursky-Forconi method and blood pressure. Our results show that blood viscosity and fibrinogen were statistically increased relative to controls. Comparison between these groups leads us to observe that blood viscosity and fibrinogen are slightly higher in the first group in a statistically significant way (7.5 +/- 1.1 cPs 10 s(-1) 1st group, 7.9 +/- 1.05 cPs 10 s(-1) 2nd group; 362.2 +/- 167.3 mg% 1st group, 384.6 +/- 106.9 mg% 2nd group). Blood pressure was higher in the second group. The study of red cell morphology in all the patients showed a prevalence in the percentage of discocytes, cells which have less deformability compared to bowls. The study demonstrated EMI (Erythrocyte Morphology Index) decreased in a statistically significant way compared to controls (0.70 +/- 0.03 1st group; 0.65 +/- 0.02 2nd group; 1.2 +/- 0.09 control group). In subjects suffering from essential hypertension with end-organ damage EMI further decreases. So we observed that hypertension is also delineated by the increase in the discocytes percentage which results in reduction of the red cell deformability. In conclusion, when hypertension causes end-organ damage, the hemorheological alterations, which implicate a worsening in microcirculation, are more evident.

Blood viscosity and red cell morphology in subjects suffering from cirrhosis before and after treatment with S-adenosyl-L-methionine (SAM).

Alterations of fluidity of the hepatocytic membrane and of the transport related systems are the basis of the cholesteatic syndrome and favour the tissue accumulation of cytotoxic metabolites. S-Adenosyl-L-Methionine (SAM) is a natural molecule which acts as a giver of methylic groups and as an enzymatic activator in several enzymatic actions of transmethylase and of transulphuration and plays a key role in biochemical processes of hepatic cell. The aim of our study was to evaluate the effects of SAM on the restoration of the membrane fluidity and on the hepatic function in general. In studying the fluidity of the cell membrane we evaluated some hemorheological parameters (total blood viscosity and red cell morphology). Fluidity of the red cell membrane is one of the most important elements of red cell rheology. We studied 15 patients (Group A) suffering from micro- and macro-nodular cirrhosis verified through hepatic biopsy, with alcoholic or post-viral causes. We evaluated the values of: blood viscosity (with a cone-plate rheometer by Carri-med), haematocrit, plasma fibrinogen and the erythrocytic morphology at the optical microscope with the Zipursky-Forconi method before and after 7 days of therapy with SAM i.v.. Data were compared with those of a similar group (Group B) treated with traditional therapy only (hyposodic and hypoprotein diet supplemented with multivitamin preparations, vitamin K in particular, if necessary, and potassium sparing diuretics). We also measured biliary salts, alkaline phosphatase, transaminase and gamma-GT. In the first group we observed a statistically significant reduction of blood viscosity, haematocrit didn't change significantly; biliary salts reduced in a statistically significant way. Evaluation of red cell morphology showed in all cases a pathological percentage (>15%) of echinocytes and knizocytes which reduced to a mean of 5% after SAM therapy. We observed no further modifications of the other hemorheological parameters. Results demonstrate that SAM has a positive action on the fluidity of the membrane, as indicated by the improvement of haemorheological parameters and by the significant decrease of biliary salts, indicating the presence of cholesteasis.

Determination of plasma concentrations of cyclandelate and mandelic acid in patients with generalized atherosclerotic vasculopathy treated with oral cyclandelate.

Cyclandelate, a vasoactive substance consisting of the mandelic acid ester of 3,3,5-trimethylcyclohexanol, was administered to 10 patients with cerebrovascular and/or peripheral vascular disease. Blood specimens were collected at 1-6 h after oral administration of 1600 mg cyclandelate, and the ester and acid were extracted from plasma in acid medium using n-hexane/isopropyl alcohol. The concentrations were determined by a high-performance liquid chromatography isocratic system. The highest plasma cyclandelate concentrations were detected at the third hour, whereas plasma mandelic acid concentrations were still increasing 6 h after administration.

Fibrinolytic activity of oral cyclandelate in patients with generalized atherosclerotic vasculopathy: a double-blind study.

In a double-blind study, a single dose of 1600 mg cyclandelate or placebo was administered to 10 patients with cerebrovascular and/or peripheral vascular disease, and fibrinolytic activity was evaluated before and 1, 2, 4 and 6 h after treatment. Cyclandelate induced a reduction in euglobulin lysis time, an increase in tissue plasminogen activator concentration and a reduction in plasminogen activator inhibitor, alpha 2-antiplasmin and immunological fibrinogen concentrations, but no changes in antithrombin III and plasminogen concentrations were observed. After placebo administration no significant changes were observed. After treating two patients with 800 mg cyclandelate twice daily for 14 days, 1600 mg cyclandelate stimulated fibrinolysis for 8 h. It is concluded that the fibrinolytic activity of cyclandelate has implications for the treatment of cardiovascular complications of atherosclerosis.

Evaluation of erythrocyte morphology as deformability index in patients suffering from vascular diseases, with or without diabetes mellitus: correlation with blood viscosity and intra-erythrocytic calcium.

The aim of our study was to evaluate the erythrocytic morphology in vascular patients, with or without diabetes, showing cell alterations correlated to blood viscosity and intra-erythrocytic calcium. We studied 108 subjects: 20 normal subjects, 58 vascular patients (25 suffering from CHD, 19 from CVD, 14 from POAD) and 30 non-insulin-dependent diabetes patients with vascular disease in metabolic compensation (13 CHD, 9 CVD, 8 POAD). Erythrocytic morphology, blood viscosity and intra-erythrocytic calcium were evaluated. Our results show that bowls, the most deformable red cells, decreased significantly in vascular patients and in POAD diabetics, while the discocytes, having a stiffer form, greatly increased in subjects suffering from ischemic disease and in POAD diabetics. The altered red cells (echinocytes and knizocytes) reached a statistical significance in CVD and POAD diabetics. Comparing the percentage of discocytes to intraerythrocytic calcium content in vasculopathic subjects, we obtained a significant correlation. No evidence of a relationship between discocytes and blood viscosity was found, even if blood viscosity significantly increased in patients affected by ischemic disease. These results suggest that ischemia decreases the deformability of red cells which is supported by the study of red cells morphology, by the erythrocytic morphology index (EMI), which becomes < 1, and by the evaluation of cytosolic calcium content.

Variations of erythrocyte morphology in different pathologies.

In our study we evaluated erythrocytic morphology in different pathologies which can modify flowing red cells. We followed the methodology proposed by Zipursky which allows a three-dimensional evaluation of the red cell and a classification according to the shapes observed through the optical microscope. We studied 150 subjects: 20 normal subjects, 58 patients suffering from vascular diseases, 40 affected by diabetes (type II) (10 without and 30 with vascular diseases), 22 patients with liver disease, 5 patients with monoclonal gammopathies and 5 dehydrated patients. Results show that in normal subjects bowls, which is the shape of the most deformable red cells, are more (55%) than discocytes (44%); the altered forms are only 1%. In vascular patients we noted a statistically significant increase of discocytes (60%). There are no significant differences between subjects affected by diabetes without vascular disease and normal subjects. In diabetics with vascular diseases there are more discocytes (57%) and some altered forms (3%). In patients suffering from chronic hepatitis a great increase (13%) in echinocytes and knizocytes was noticed, which suggests an alteration in the fluidity of the membrane. Our observations testify the importance of this simple methodology in focusing the morphological alterations which can be accounted for both by pathologies of the red cells and by changes in their metabolism.

Haemorheological and endothelial-dependent alterations in heart failure after ACE inhibitor, calcium antagonist and beta blocker.

The aim of our study was to evaluate endothelium-dependent dilatation induced by an ACE-inhibitor, calcium antagonist and beta blocker in patients suffering from heart failure (NYHA class II and III). We studied 34 patients (19M, 15F, mean age 76.96+/-8.82) in pharmacological wash-out for at least one week, divided into 3 groups: Group A (15 patients, 9M and 6F) taking ramipril (5 mg/die); Group B (10 patients, 6M and 4F) taking amlodipine (10 mg/die), Group C: (9 patients, 4M and 5F) taking carvedilole (25 mg/die). The groups were homologous for NYHA class and instrumental echographic parameters (mean EF=22.5+/-6.7 and mean sAPP 38.4+/-8.7). At the beginning and after 3 weeks of therapy, we performed a clinical and instrumental assessment; we studied endothelial function by determination of L-arginine and L-citrulline (amino acids of the nitric oxide metabolic pathway), the L-citrulline/L-arginine ratio (an index of NOS activity) and VCAM-1 (endothelial dysfunction index); haemorheological parameters (blood viscosity, plasma fibrinogen and erythrocyte morphology); coagulative/fibrinolytic parameters (PT, aPTT, fibrinogen and PAI-1). The results show that L-citrulline and L-arginine increase, while VCAM-1 decreases. The L-citrulline/L-arginine ratio increases in a statistically significant way. This trend is maintained in each group. These results demonstrate that the drugs used induce an improvement of endothelium-dependent dilatation. In addition, there is progressive haemorheological and fibrinolytic improvement, with a reduction of PAI-1 and blood viscosity.