Moderate red wine consumption improves hemorheological parameters in healthy volunteers.

Pieces of epidemiological evidence have supported that moderate red wine consumption reduces the risk of cardiovascular diseases (French-paradox). Our previous in vitro experiment has demonstrated favourable hemorheological effects of red wine, alcohol-free red wine extract and ethanol. Thirty-nine healthy, non-smoking male volunteers between 18-40 years were assigned into two groups: control group had drunk water, while red wine group had consumed 2 dl of red wine each day at dinner for 3 weeks. No alcohol had been drunk for one week prior to the study. Blood was obtained in the morning of the first and last day. Hematocrit (Hct), plasma (PV) and whole blood viscosity (WBV) (Hevimet 40 capillary viscometer), red blood cell (RBC) aggregation (Myrenne and LORCA aggregometer) and deformability (LORCA ektacytometer) were measured and Hct/WBV ratio was calculated to determine oxygen carrying capacity. Hct was adjusted to 40%. Hct and PV were not affected. WBV remained unchanged in controls, but it considerably decreased in the red wine group compared to the 3-week control group, while Hct/WBV ratio became significantly higher in the red wine group compared to the control (p < 0.05). RBC aggregation significantly decreased in the red wine group and became significantly lower compared to the 3-week controls (p < 0.05). Red wine significantly increased RBC deformability (p < 0.05) at high shear stress. Our results show that moderate red wine consumption has beneficial effects on hemorheological parameters which may contribute to the French-paradox.

Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease.

Several beneficial effects of resveratrol (RES), a natural antioxidant present in red wine have already been described. The aim of our study was to investigate if RES had a clinically measurable cardioprotective effect in patients after myocardial infarction. In this double-blind, placebo controlled trial 40 post-infarction Caucasian patients were randomized into two groups. One group received 10 mg RES capsule daily for 3 months. Systolic and diastolic left ventricular function, flow-mediated vasodilation (FMD), several laboratory and hemorheological parameters were measured before and after the treatment. Left ventricular ejection fraction showed an increasing tendency (ns) by RES treatment. However, left ventricular diastolic function was improved significantly (p < 0.01) by RES. A significant improvement in endothelial function measured by FMD was also observed (p < 0.05). Low-density lipoprotein (LDL) level significantly decreased (p < 0.05) in the RES treated group. Red blood cell deformability decreased and platelet aggregation increased significantly in the placebo group (p < 0.05), while resveratrol treatment has prevented these unfavourable changes. Concerning other measured parameters no significant changes were observed neither in placebo nor in RES group. Our results show that resveratrol improved left ventricle diastolic function, endothelial function, lowered LDL-cholesterol level and protected against unfavourable hemorheological changes measured in patients with coronary artery disease (CAD).

In vitro hemorheological effects of red wine and alcohol-free red wine extract.

The French paradox is based on epidemiological evidence which supports that moderate red wine consumption reduces the risk of cardiovascular diseases. A number of experimental animal studies reported favourable cardiovascular effects of alcohol-free red wine extract (AFRW). Our study was designed to determine red wine and AFRW induced changes in various hemorheological parameters. These effects may play a role in the pathophysiology of the French paradox regarding the cardiovascular protective impacts of red wine. Blood samples of healthy volunteers were mixed with red wine to achieve alcohol concentrations of 1 per thousand, 3 per thousand and 10 per thousand, respectively, with equivalent amount of AFRW or physiological saline. Blood samples were pretreated with red wine or AFRW in order to prove the protective effects on erythrocytes from impairment of deformability caused by the free radical generator phenazine methosulfate (PMS). Erythrocyte aggregation (Myrenne and LORCA), deformability (LORCA) and platelet aggregation (Carat TX4) were measured. Erythrocyte aggregation using Myrenne aggregometer was inhibited by red wine and AFRW compared to the saline treated samples. The difference reached already significance at 1 per thousand concentration at the AFRW samples (p < 0.05). Furthermore, red wine caused stronger inhibition than AFRW. The difference between the two agents became significant at 10 per thousand concentration (p < 0.05). LORCA aggregation index and threshold shear rate supported these results at the highest concentration. Erythrocyte deformability of healthy volunteers did not change significantly for any concentrations of red wine and AFRW. On the other hand AFRW at 3 per thousand concentration significantly prevented erythrocytes from impairment of deformability caused by PMS (p < 0.05). Platelet aggregation was significantly inhibited by the highest concentration of AFRW (p < 0.05). Our results show that red wine and AFRW have some beneficial effects on hemorheological parameters that may contribute to the French paradox.

Follow-up of hemorheological parameters and platelet aggregation in patients with acute coronary syndromes.

Pathologic hemorheological parameters and increased platelet aggregation in association with other risk factors significantly increase the possibility of the development of myocardial ischemia. Hemorheological parameters and platelet aggregation were investigated in 157 patients (mean age: 65+/-12 years) with acute coronary syndromes and in 68 healthy subjects (mean age: 36+/-6 years). Plasma fibrinogen, plasma and whole blood viscosity, red blood cell aggregation and filterability and platelet aggregation were measured in the hospital phase (after admission, on 2nd and 6th days) and monitored after discharge (at 1, 6 and 12 months). After admission all these parameters were significantly higher in patients than in control subjects (p<0.01) and almost all of them remained in the pathologic range at discharge. Some of the rheologic parameters showed a slight improvement after 1 month, but hematocrit and whole blood viscosity were higher than those after admission and of control subjects (p<0.05). After 6 and 12 months these parameters showed a small, but significant increase. Pathologically altered hemorheological parameters could be observed in patients with classical cardiovascular risk factors and significant improvement was found after elimination of them. Antiplatelet therapy was efficient in about half of the treated patients after admission; and despite a significant improvement, the proportion of ineffectively treated patients was still considerable during the follow-up. Our results support the role of abnormal hemorheological parameters in the development of myocardial ischemia and draw attention to the rheologic risk of these patients. The results of platelet aggregation measurements show the insufficiency of antiplatelet therapy at some cases and confirm the importance of guided secondary prevention.

QRS Score: a composite index of exercise-induced changes in the Q, R, and S waves during exercise stress testing in patients with ischemic heart disease.

BACKGROUND: To detect ischemic heart disease, the exercise-induced ST-segment displacement is the most frequently used ECG parameter. However, the value of this marker was proven to be limited with varying sensitivity and specificity. A new parameter, called QRS score, emerged to improve the efficacy of exercise testing. METHODS: Our study aimed at evaluating the diagnostic value of QRS score in ischemic heart disease, investigating males and females separately, and examining the effects of heart rate and antiischemic medication. QRS score and cumulative ST depression were calculated in 212 patients and correlated to the findings of the stress myocardial perfusion SPECT (197 subjects) or coronary angiography (54 subjects). RESULTS: An inverse correlation could be found between the QRS score and the results of myocardial SPECT and coronary angiography in the whole population, especially in males; females did not show a significant relationship. In patients with conclusive tests (achieving 85% of the maximal predicted heart rate) QRS score correlated significantly with the results of the stress myocardial perfusion SPECT and coronary angiography. The sensitivity, specificity, and validity of the QRS score surpassed those of the cumulative ST depression in the entire population as well as in patients with conclusive tests. The antiischemic medication did not affect correlation values. CONCLUSION: QRS score was significantly related to the extent of myocardial ischemia and the severity of coronary heart disease, thus along with the analysis of ST-segment displacement may contribute to the more precise evaluation of exercise testing.

Effects of doxazosin on hemorheological, hemodynamic and lipid parameters in patients with essential hypertension.

It is known from previous studies that hemorheological parameters are altered in patients with essential hypertension. The hemorheological and hemodynamical effects of doxazosin, a selective alpha-1-adrenoreceptor blocker agent, was examined in twenty patients (mean age: 54+/-10 years) with essential hypertension. Hemorheologic (hematocrit, fibrinogen, plasma and whole blood viscosity) and hemodynamic (cardiac output and index, total peripheral resistance) parameters and plasma lipids were determined. The measurements were carried out before the beginning of the treatment, after 1 week and after 12 weeks treatment periods. Besides significant reduction of blood pressure and total peripheral resistance (p < 0.001), a decrease in cholesterol (p < 0.001) and triglyceride (p < 0.01) levels and a beneficial effect on hemorheological parameters was detected. Fibrinogen and plasma viscosity decreased significantly (p < 0.01). Hematocrit value was also lower after one week (p < 0.001), then an increase could be seen. Whole blood viscosity showed similar changes as hematocrit, but the degree of its final increase was slighter, which was supported by the significantly lower value of corrected blood viscosity (p < 0.05).

Hemorheological and hemodynamic parameters in patients with essential hypertension and their modification by alpha-1 inhibitor drug treatment.

Hemorheological factors play an important role in the pathogenesis of different cardiovascular diseases. The hemorheological and hemodynamic parameters in essential hypertension and their possible modification by antihypertensive treatment were examined in the following two studies. In the first study the fundus appearance and hemorheological parameters (plasma and whole blood viscosity (WBV), fibrinogen level) of 33 hypertensive patients (mean age: 55 years) were examined. The fundus appearance showed retinopathy in all the cases between stages I-III. All the measured hemorheological parameters of the examined patients were in the pathological range (WBV at 90 s(-1): 5.18 mPa s) and were significantly (p < 0.01) higher than in healthy controls (WBV at 90 s(-1): 4.18 mPa s). The hemorheological factors showed a parallel deterioration with the fundus appearance, namely their values were significantly (p < 0.01) higher in patients with a fundus appearance stage III (WBV at 90 s(-1): 6.02 mPa s) than stage I (WBV at 90 s(-1): 4.51 mPa s). These results show that there is a correlation between hemorheological parameters and fundus appearance in hypertensives, and this suggests that hemorheological factors may play a role in the development of hypertensive retinopathy. In the second study the hemorheological and hemodynamical effects of Doxazosin, a selective alpha-1-adrenoreceptor blocker agent, was examined in twenty patients (mean age: 54 years) with essential hypertension. Hemorheologic (hematocrit, fibrinogen, plasma and whole blood viscosity) and hemodynamic (cardiac output and index, total peripheral resistance) parameters and plasma lipids were determined. The measurements were carried out before the beginning of the treatment, after 1 week and after 12 weeks treatment periods. Besides significant reduction of blood pressure and total peripheral resistance (p < 0.001), a decrease in cholesterol (p < 0.001) and triglycerides (p < 0.01) levels and a beneficial effect on hemorheological parameters was detected. Fibrinogen and plasma viscosity decreased significantly (p < 0.01). Hematocrit value was also lower after one week (p < 0.001), then an increase could be seen. Whole blood viscosity showed similar changes as hematocrit, but the degree of its final increase was slighter, which was supported by the significantly lower value of corrected blood viscosity (p < 0.05). All these findings indicate that hemorheological factors may play a role in the pathogenesis and in the development of organ damages in hypertension.

[Comparative study of verapamil and bisoprolol in the secondary prevention of myocardial infarction]. / A verapamil és bisoprolol összehasonlító vizsgálata szívinfarktuson átesett betegek szekunder prevenciójában.

The effect of Ca-antagonist, long-acting verapamil and the selective beta-1 blocking bisoprolol were investigated and compared in the secondary prevention after myocardial infarction. Eighty-seven patients were enrolled, 27 patients were not included because of the exclusion criteria, 30 patients were treated with verapamil and 30 patients with bisoprolol. During the 540 days of follow up period treadmill ergometry and dobutamine stress-test with SPECT investigation were performed two times. Both clinically and the data of our investigations the effect of the two drugs in the secondary prevention was good, and even at the 540th day the protective effect was still excellent.

The values of detection of free radical mediated reactions in patients.

The peroxidative processes and individual antioxidant protection were measured in patients with different cardiovascular diseases. We concluded that monitoring of this system we were able to detect not only the actual changes of lipid peroxidation and antioxidant defence mechanisms, but additionally the therapeutic efficacy of the treatment.

Monitoring of plasma total antioxidant status in different diseases.

The pathological increase of oxygen free radical generation has already been recognised in more than one hundred diseases. To gain information about the consequences of oxidative stress the investigation of plasma antioxidants seems to be plausible. In our study we used a new kit (RANDOX, England) for measurement of total antioxidant status (TAS) to determine whether it has diagnostic value in comparison with our earlier results of measuring other parameters of oxidative stress in the following diseases: i./In the group of patients with ischemic heart disease (n = 19) the TAS elevated from 1.08 +/- 0.13 to 1.16 +/- 0.11 mM after 2 weeks of cardioprotective drug administration showing the beneficial effect of drug treatment. ii./In the group of patients with essential hypertension (n = 47) its values were below the normal range (1.11 +/- 0.15 mM) at the time of the first investigation and increased gradually following antihypertensive treatment. iii./The changes of TAS values of patients who underwent open (n = 21) or laparoscopic (n = 21) cholecystectomy indicated the less surgical trauma following laparoscopic procedures. Our results suggest that determination of TAS is a valuable and reproducible method to detect the actual antioxidant status in patients.

Quantitation of the alveolar distribution of surfactant mixtures in normal and injured lungs.

The uptake and distribution of two surfactant mixtures, Exosurf and Infasurf, instilled into the lungs of normal and hyperoxia-exposed (100% O2, 60 h) rabbits, were quantified at the alveolar level using flow cytometry and fluorescence microscopy. The surfactants were labeled with the fluorescent phospholipid analog NBD-C12-PC (1-palmitoyl-2-[12-[(7-nitro-2-1, 3-benzoxadiazol-4-yl)amino]dodecanoyl]-sn-glycero-3-phosphocholine ) in 100:1 molar ratio. Rabbits were killed 2 h after the instillation of either surfactant (80 mg phospholipid [PL]/kg), and alveolar macrophages (AM) and alveolar type II (ATII) cells were isolated and examined for the presence of NBD fluorescence. The fractions of cells, with NBD fluorescence values higher than autofluorescence, isolated from the lungs of air-breathing rabbits instilled with either Infasurf or Exosurf, were 84% and 63% for AM, and 55% and 45% for ATII cells. Exposure of rabbits to hyperoxia decreased the fraction of NBD-positive AM following Infasurf instillation, and the mean increase in NBD-associated fluorescence in ATII cells following Exosurf instillation. Our results suggest that sublethal hyperoxia decreases the short-term uptake but not the distribution of intratracheally instilled Exosurf.

Regulation of fluid-phase endocytosis in alveolar macrophages.

We investigated whether fluid-phase endocytosis in rabbit alveolar macrophages (AM) was regulated by alterations in intracellular adenosine 3',5'-cyclic monophosphate (cAMP). Suspensions of freshly isolated AM were incubated with anionic dextrans (mol mass = 10 kDa), coupled to fluorescein isothiocyanate (FITC), at either 37 or 4 degrees C. There was a rapid increase in AM-associated fluorescence, quantified by laser flow-cytometry and video microscopy during the first hour of incubation at 37 degrees C, which was directly proportional to the amount of tracer present in the medium. In contrast, at 4 degrees C, AM fluorescence was similar to autofluorescence. Incubation of AM with forskolin (50 microM) or 3-isobutyl-1-methyl xanthine (IBMX; 0.1 mM) increased their cAMP content by 67 +/- 2 and 52 +/- 5% (mean +/- SE; n = 4) and decreased FITC-dextran uptake by 29 +/- 4 and 31 +/- 4% (n = 3). On the other hand, incubation of AM with 0.5 mM IBMX inhibited FITC-dextran uptake by 62 +/- 4% (n = 3), without any further increase in cAMP. Incubation of AM with 0.4 mM 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (CPT-cAMP), a cell-permeable analogue of cAMP, decreased FITC-dextran uptake by 48 +/- 5% (n = 6). Pulse-chase experiments showed that the rate of FITC-dextran exocytosis was not affected by cAMP. We concluded that fluid-phase endocytosis in rabbit AM is regulated by cAMP and by an additional, cAMP-independent mechanism of IBMX.

Quantitation of alveolar distribution of liposome-entrapped antioxidant enzymes.

Liposome-encapsulated Cu,Zn superoxide dismutase (Cu,Zn SOD) and catalase (CAT) were instilled intratracheally in rabbits, and the temporal and spatial distribution of Cu,Zn SOD and CAT within the lung was assessed at the organ and cellular levels. Specific activities of Cu,Zn SOD and CAT were increased in both lung homogenates and isolated alveolar type II pneumocytes. Peak Cu,Zn SOD activities in lung homogenates and alveolar type II cells were observed 4 h after liposome instillation and returned to control levels by 24 h, whereas CAT activities remained significantly above controls. There were no significant differences in liposome distribution or antioxidant enzyme uptake among lung lobes. The distribution of fluorescently labeled Cu,Zn SOD and CAT was assessed with the use of epifluorescence microscopy and digital image processing to determine patterns of cellular incorporation of liposome-entrapped Cu,Zn SOD and CAT within the lung. Although the mean fluorescence intensity of alveoli from rabbits instilled with liposomes containing labeled Cu,Zn SOD and CAT was greater than autofluorescence observed with either no liposome or empty liposome instillation, fluorescence intensity varied between adjacent alveoli. Both fluorescently labeled Cu,Zn SOD and CAT were located cytosolically, and uptake was not limited to alveolar type II pneumocytes. These results demonstrate that a single intratracheal instillation of liposomes can effect increases in Cu,Zn SOD and CAT activities in distal lung cells, including alveolar type I and type II cells and macrophages.