Human clinical hemorheological studies in healthy subjects...

Human clinical hemorheological studies in healthy subjects and in

patients with coronary artery disease

PhD dissertation

Author: Andras Toth MD

Interdisciplinary Medical Sciences Doctoral School

Molecular and cellular biochemistry Doctoral Program

Doctoral School and Program leader: Prof. Balazs Sumegi PhD, ScD

Project leaders:

Istvan Battyani MD, PhD Gabor Kesmarky MD, PhD

University of Pecs, Medical School Pecs, Hungary

2014

1

Table of contents

TABLE OF CONTENTS ................................................................................................ 1

ABBREVIATIONS AND SYMBOLS ............................................................................... 4

INTRODUCTION ........................................................................................................ 6

THE BURDEN OF CARDIOVASCULAR DISEASES ............................................................................ 6

THE FRENCH PARADOX ........................................................................................................ 6

HEMORHEOLOGICAL PARAMETERS AS CARDIOVASCULAR RISK FACTORS ........................................ 10

CLINICAL IMPORTANCE OF HEMORHEOLOGICAL PARAMETERS IN CARDIOVASCULAR DISEASES ........... 11

Hematocrit ....................................................................................................................................... 12

Plasma and whole blood viscosity .................................................................................................... 12

Red blood cell aggregation ............................................................................................................... 12

Red blood cell deformability ............................................................................................................. 13

AIMS ...................................................................................................................... 14

HEMORHEOLOGICAL EFFECTS OF MODERATE RED WINE CONSUMPTION ........................................... 14

HEMORHEOLOGICAL PARAMETERS IN CT-DETECTED CORONARY ARTERY DISEASE ........................... 14

HEMORHEOLOGICAL EFFECTS OF MODERATE RED WINE CONSUMPTION ................ 16

METHODS ...................................................................................................................... 16

Subjects ............................................................................................................................................ 16

Blood sampling ................................................................................................................................. 17

Hemorheological measurements ..................................................................................................... 17

Hematocrit ................................................................................................................................................... 17

Plasma and whole blood viscosity ................................................................................................................ 17

Hematocrit per whole blood viscosity ratio ................................................................................................. 18

Red blood cell aggregation ........................................................................................................................... 18

Red blood cell deformability ........................................................................................................................ 20

Statistical analysis ............................................................................................................................ 21

RESULTS ......................................................................................................................... 21

Subjects ............................................................................................................................................ 21

Hematocrit ....................................................................................................................................... 22

Viscosity ............................................................................................................................................ 22

Hematocrit per whole blood viscosity ratio ...................................................................................... 23

2



DISCUSSION .................................................................................................................... 25

Hematocrit ....................................................................................................................................... 25


Hematocrit per whole blood viscosity ratio ...................................................................................... 26



CONCLUSIONS ................................................................................................................. 27

HEMORHEOLOGICAL PARAMETERS IN CT-DETECTED CORONARY ARTERY DISEASE.. 28

METHODS ...................................................................................................................... 28

Patients ............................................................................................................................................ 28

Blood sampling ................................................................................................................................. 28

Coronary computed tomography angiography ................................................................................ 29

Hemorheological measurements ..................................................................................................... 29

Central laboratory measurements ................................................................................................... 30

Classification of patients .................................................................................................................. 30

Statistical analysis ............................................................................................................................ 30

RESULTS ......................................................................................................................... 31

Subject characteristics ...................................................................................................................... 31

Hemorheological parameters ........................................................................................................... 32

Hematocrit ................................................................................................................................................... 32

Plasma and whole blood viscosity ................................................................................................................ 32

Red blood cell aggregation ........................................................................................................................... 34

Red blood cell deformability ........................................................................................................................ 34

Central laboratory parameters ......................................................................................................... 35

DISCUSSION .................................................................................................................... 36

Subject characteristics ...................................................................................................................... 36

Hematocrit ....................................................................................................................................... 36




Other laboratory parameters ........................................................................................................... 39

Study limitations ............................................................................................................................... 40

CONCLUSIONS ................................................................................................................. 41

SUMMARY OF NEW SCIENTIFIC RESULTS ................................................................ 42

3

HEMORHEOLOGICAL EFFECTS OF MODERATE RED WINE CONSUMPTION ........................................... 42

HEMORHEOLOGICAL PARAMETERS IN CT-DETECTED CORONARY ARTERY DISEASE ........................... 42

ACKNOWLEDGEMENTS .......................................................................................... 43

REFERENCES ........................................................................................................... 44

PUBLICATIONS OF THE AUTHOR ............................................................................. 55

PAPERS FROM THE TOPICS .................................................................................................. 55

OTHER PAPERS ................................................................................................................ 56

PUBLISHED ABSTRACTS ...................................................................................................... 57

4

Abbreviations and symbols

ACEI angiotensin-converting enzyme inhibitor

AFRW alcohol free red wine extract

AI LORCA aggregation index

ARB angiotensin-receptor blocker

ASA acetylsalicylic acid

BMI body mass index

CABG coronary artery bypass grafting

CAD coronary artery disease

CHD coronary heart disease

CLP clopidogrel

CT computed tomography

CV cardiovascular

CVD cardiovascular disease

DM diabetes mellitus

EI elongation index

Hct hematocrit

HDL high density lipoprotein

Hgb hemoglobin

LDL low density lipoprotein

LORCA Laser-assisted Optical Rotational Cell Analyzer

M Myrenne aggregation index (M mode)

M1 Myrenne aggregation index (M1 mode)

MCH mean corpuscular hemoglobin

MCHC mean corpuscular hemoglobin concentration

MCV mean corpuscular volume

NSAID non-steroid anti-inflammatory drug

PCI percutaneous coronary intervention

PTP pre-test probability

5

PV plasma viscosity

RBC red blood cell

SDR standardized death ratio

S.E.M standard error of mean

t½ LORCA aggregation half time

WBV whole blood viscosity

WHO World Health Organization

6

Introduction

The burden of cardiovascular diseases

Cardiovascular diseases (CVDs) are the leading cause of death globally. In 2008, around

17.3 million people died of CVDs, representing 30% of total global deaths, of which an

estimated 7.3 million were due to coronary heart disease (CHD). In the high-income

countries, cardiovascular (CV) mortality is decreasing due to the improving prevention

programs and healthcare system, however in the low- and middle-income countries it

increases in a very fast rate. Contrary to popular opinion, over 80% of CV deaths take

place in the low- and middle-income countries, thus in spite of the decreasing trend in

the high-income countries, the global CV mortality is still expected to rise in the future:

by 2030 it is projected to reach 23.3 million and to remain the number one cause of

death. Most of these events could be prevented, therefore further research of their risk

factors, pathogenesis and prevention is essential. In Hungary – considered as an “upper

middle income” country – CV mortality is decreasing since 1993 [standardized death

ratio (SDR), 1993: 640.48/100,000], but it is still much higher [SDR, 2011:

402.08/100,000] compared to the European Union members before May 2004 [SDR,

2011: 160.11/100,000] (Mathers & Loncar, 2006; World Health Organization, 2008;

World Health Organization, 2011; World Health Organization, 2013; World Health

Organization, 2014).

The French paradox

Series of prospective epidemiological studies, such as the Framingham Study (Gordon &

Kannel, 1984), the British Doctors Study (Doll, et al., 2005), the Nurses Health Study

(Fuchs, et al., 1995; Mukamal, et al., 2005), the Physicians’ Health Study (Gaziano, et al.,

2000), the British Heart Study (Emberson, et al., 2005) and the Copenhagen Heart Study

(Schnohr, et al., 2002) observed a J-shaped relationship between the relative risk of CHD

and alcohol intake. According to these studies, low to moderate consumption of

7

alcoholic beverages is associated with reduced risk of CHD, while on the other hand,

binge or heavy drinking increases the risk of CHD. A meta-analysis reported that light or

moderate alcohol consumption may also be protective against total and ischemic stroke,

while heavy alcohol consumption increased their relative risk (Reynolds, et al., 2003).

According to another meta-analysis, involving 34 studies, consumption of alcohol, up to

2 drinks/day in women and 4 drinks/day in men is inversely associated with total and CV

mortality, while higher doses of alcohol are associated with increased mortality (Di

Castelnuovo, et al., 2006).

Further studies have described that wine is more beneficial than any other forms

of alcohol. According to the Copenhagen City Heart Study, low-to-moderate intake of

wine is associated with lower mortality from CV and cerebrovascular diseases, while

similar intake of spirits increases and beer drinking does not affect mortality (Gronbaek,

et al., 1995). A prospective cohort study, carried out in France, reported that moderate

consumption of either beer or wine lowered the risk of CV deaths, but the effect of wine

was more significant. In case of all-cause mortality only wine was associated with

reduced relative risk (Renaud, et al., 1999). A meta-analysis processing 26 studies found

a significant inverse association between low to moderate wine consumption and

vascular risk. Beer drinking was also associated with reduced risk of vascular events, but

failed to show any significant correlation between different amounts of beer intake and

vascular risk (Di Castelnuovo, et al., 2002). Several papers suggest that the greater

benefit seen in wine drinkers compared to other alcohol consumers can also be

attributed to the wine drinkers’ advantageous lifestyle characteristics (Wannametheem

& Shaper, 1999).

The beneficial effect is likely to depend on the type of wine. In spite of the much

lower cholesterol levels in Alsace, a white wine drinking region in France, higher

mortality rates were observed there, compared to the red wine drinking Mediterranean

regions (Opie & Lecour, 2007). Studies examining alcohol free red wine extract (AFRW)

also support that red wine has additional positive effects beyond alcohol alone. In 1993

Frankel, et al. found that 1000-fold diluted red wine inhibited copper-catalyzed low

density lipoprotein (LDL) oxidation, significantly more than alpha-tocopherol, a known

antioxidant. In another study 113 ml of AFRW, but not white wine increased total plasma

8

antioxidant capacity 50 minutes after its ingestion (Serafini, et al., 1998). In a double-

blind, cross-over study either 250 ml of red wine or AFRW decreased arterial stiffness in

patients with coronary artery disease (CAD) (Karatzi, et al., 2005).

Total mortality is not, but mortality from CVDs is much lower in France than in

other Western-European countries [Fig. 1.1.], although the consumption of saturated

fats [Fig. 1.2.] and blood cholesterol level – considered as major CV risk factors – are

higher in this country. Furthermore, prevalence of other risk factors such as smoking

and hypertension are similar in France as in other developed regions of Europe.

According to epidemiological studies, this phenomenon, called as “French paradox”,

may be caused by the moderate and regular consumption of red wine [Fig. 1.3.] (St

Leger, et al., 1979; Renaud & de Lorgeril, 1992; Renaud, et al., 1999; de Lorgeril, et al.,

2002; Opie & Lecour, 2007; World Health Organization, 2014).

Literature data exist that these epidemiological findings are confounded by

social, cultural, lifestyle and dietary factors. A cross-sectional survey, carried out at the

French MONICA Centers, found that healthy diet and behaviors are more often observed

in wine drinkers than in beer or spirit consumers (Ruidavets, et al., 2004). Another

published confounding factor is called “time lag” hypothesis which states that in the

1960s fat intake was lower in France than nowadays, and it takes about 25-35 years till

dietary changes manifest in mortality data (Law & Wald, 1999).

<= 900

<= 700

<= 500

<= 300

<= 200

<= 125

No data

Min = 100

SDR, diseases of circulatory system, all ages, per 100 000

2009

European Region

384.66

Fig. 1.1. Mortality due to circulatory diseases in Europe, 2009. Source: World Health Organization, HFA-DB. Updated: April 2014.

9

According to several in vitro and in vivo studies, the favorable effect of red wine

may originate from its alcoholic and non-alcoholic components. Moderate intake of

alcohol lowers platelet aggregation and fibrinogen level (Renaud & Ruf, 1996), increases

high density lipoprotein (HDL) level (McConnell, et al., 1997), tissue-type plasminogen

activator level (Ridker, et al., 1994; Aikens, et al., 1998) and production of endothelial

nitrogen monoxide (Abou-Agag, et al., 2005), decreases insulin level and improves

insulin sensitivity (Davies, et al., 2002).

<= 7

<= 6.5

<= 5

<= 3.5

<= 2

<= 0.5

No data

Min = 0

Wine consumed in pure alcohol, litres per capita, age 15+

2009

European Region

2.71

Fig. 1.3. Wine consumption in Europe, 2009. Source: World Health Organization, HFA-DB. Updated: April 2014.

<= 200

<= 160

<= 120

<= 80

No data

Min = 40

Fat available per person per day (g)

2009

European Region

No data

Fig. 1.2. Fat intake in Europe, 2009. Source: World Health Organization, HFA-DB. Updated: April 2014.

10

Non-alcoholic part of red wine contains polyphenols and anthocyanins.

Anthocyanins are responsible for the color of wines, while polyphenols are considered

as the main source of cardiovascular protection. From this group resveratrol, catechin

and quercetin have been extensively studied and their antioxidant properties have been

reported (Frankel, et al., 1993; Rice-Evans, et al., 1996; Kerry & Abbey, 1997; Serafini, et

al., 1998). The resveratrol content of red wine depends on vintage year and variety

(Edelmann, et al., 2001; Casavecchia, et al., 2007), winemaking technology and winery

regions (Goldberg, et al., 1995; Kontkanen, et al., 2005; Avar, et al., 2007). It has been

revealed that polyphenols increase production of nitrogen monoxide (Leikert, et al.,

2002), inhibit platelet aggregation and decrease the production of proinflammatory

eicosanoids (Pace-Asciak, et al., 1995; Soleas, et al., 1997). Polyphenols also decrease

the oxidation of LDL (Frankel, et al., 1993; Teissedre, et al., 1996), Apo B100 production

and increase the expression of LDL receptors (Pal, et al., 2003).

Hemorheological parameters as cardiovascular risk factors

Decades ago prospective epidemiological studies – such as the Framingham Study –

identified the conventional risk factors of CAD: age, male gender, arterial hypertension,

smoking, diabetes mellitus, dyslipidemia, obesity, stress, low physical activity and

positive family history. Reduction of the modifiable risk factors help to considerably

prevent CV events, but not all the CV events can be explained by the presence of the

classical risk factors thus further investigation of new risk factors is necessary. Further

studies have revealed several additional risk factors: abnormal hemorheological

parameters, hyperuricemia, metabolic syndrome, hyperhomocysteinemia, infections

(e.g. Chlamydia pneumoniae), chronic inflammation, microalbuminuria, chronic renal

failure, oxidative stress, air pollution, noise pollution, carotid intima/media thickness

and high resting heart rate.

The alterations of hemorheological parameters in CAD have been described by

several prospective epidemiological studies. Moreover the Framingham Study (Kannel,

11

et al., 1987), the Edinburgh Artery Study (Lowe, et al., 1993; Lee, et al., 1998), the

MONICA-Augsburg Cohort Study (Koenig, et al., 1998), the Physicians' Health Study (Ma,

et al., 1999), the Caerphilly Study and the Speedwell Study (Yarnell, et al., 1991;

Sweetnam, et al., 1997) identified elevated hematocrit (Hct), whole blood viscosity

(WBV), plasma viscosity (PV) and plasma fibrinogen level as primary CV risk factors. In

the Physicians' Health Study elevated plasma fibrinogen level, independently of other

CV risk factors, was associated with increased risk of future myocardial infarct (Ma, et

al., 1999). In the Edinburgh Artery Study WBV, PV and fibrinogen level correlated linearly

with carotid intima/media thickness even on multivariate analysis. After adjusting all

common CV risk factors, elevated WBV and fibrinogen level still significantly correlated

with carotid intima/media thickness. These results suggest that altered hemorheological

parameters are associated not just with CVDs, but also with the early stages of

atherosclerosis (Lee, et al., 1998).

Clinical importance of hemorheological parameters in cardiovascular diseases

In spite of the systemic nature of CV risk factors, atherosclerotic lesions do not occur

randomly in the vascular system. These lesions tend to develop at specific locations – at

the outer wall of vessel bifurcations, the inlet of branches and the inner, distal wall of

arterial curvatures – suggesting the importance of hemodynamic and hemorheological

factors in their pathogenesis (Chien, et al., 1987; Toth & Kesmarky, 2007). The fact that

hemorheological alterations appear prior to the development of vascular lesions

suggests that they could play a role in the pathogenesis of the atherosclerotic process.

(Vaya, et al., 1996; Toth & Kesmarky, 2007).

The coronary vessel system is a unique part of the human vascular structure due

to the periodic change in perfusion pressure and blood flow. Moreover, it has the

narrowest capillaries in the human vascular system, thus hemorheological alterations

might have a more significant impact on myocardial perfusion compared to other

organs. At normal circumstances coronary blood flow is mainly determined by

12

hemodynamic factors, but in certain conditions, such as a pre-existing coronary stenosis,

alteration of hemorheological parameters may early impair myocardial microcirculation

(Dintenfass, 1969; Chien, et al., 1987; Baskurt, et al., 1991; Toth & Kesmarky, 2007).

Hematocrit

Hct and its determinants, such as RBC count and mean corpuscular volume (MCV), affect

most of the other hemorheological parameters. Both low and high Hct can impair tissue

oxygen supply by either lowering the oxygen binding capacity or increasing WBV and

flow resistance. Elevated Hct has been identified as a CV risk factor by several

epidemiological studies. Furthermore, epidemiological data suggest that increased Hct

even within the normal range is a risk factor of acute myocardial infarct (Toth &

Kesmarky, 2007).

Plasma and whole blood viscosity

Due to the axial migration of RBCs, the mechanical influence of blood flow is mediated

through the plasma. PV is an important parameter determining wall shear stress

(Cabrales & Tsai, 2006) and flow resistance in the microcirculation (Meiselman &

Baskurt, 2006). It has also been demonstrated that PV plays a significant role in the

regulation of vascular tone (Tsai, et al., 1998; Cabrales & Tsai, 2006).

WBV is a major determinant of flow resistance. In case of high WBV, flow

resistance increases, while flow rate decreases proportionally. To maintain adequate

flow, elevated blood pressure and cardiac work is required. The increased stress both to

the heart and the vessels promote cardiac and vascular remodeling, leading to heart

failure and accelerated atherosclerosis. Elevated WBV has also been identified as a CV

risk factor by numerous epidemiological studies.

Red blood cell aggregation

At constant Hct and temperature, RBC aggregation is the primary determinant of low

shear blood viscosity (Cokelet & Meiselman, 2007). Enhanced RBC aggregation alters

13

both macro- and microrheological properties of blood, and can either decrease or

increase flow resistance at different sites of the circulation (Baskurt & Meiselman, 2007).

RBC aggregation is determined by several factors: by membrane surface adhesion

molecules, type and concentration of macromolecules in the plasma, such as fibrinogen.

Alteration of any of the mentioned factors alters RBC aggregation and thus blood flow

characteristics (Cokelet & Meiselman, 2007).

Red blood cell deformability

Deformability of RBCs is essential to pass through the coronary capillaries being

narrower than the cell itself. As mentioned earlier, coronary capillaries are the

narrowest in the human body, therefore perfusion insufficiency due to impaired RBC

deformability may firstly manifest in the myocardium. RBC deformability impairment

may seriously reduce myocardial oxygen supply even in case of normal epicardial vessels

by increasing flow resistance in the capillaries (Baskurt & Meiselman, 2007; Toth &

Kesmarky, 2007).

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Aims

Atherosclerosis of the coronary arteries starts in the early childhood and progresses

asymptomatically until a significant stenosis develops or a plaque rupture causes acute

coronary syndrome. Hemorheological parameters have been identified as CV risk factors

and supposed to play a pathophysiological role in the development of atherosclerosis.

Our two studies were designed to investigate the alterations of hemorheological factors

in two distant points of the atherosclerotic process: in healthy subjects, on one side and

in patients with CAD, on the other side.

Hemorheological effects of moderate red wine consumption

Until now only, a limited number of controlled studies have reported the medium term

effects of regular red wine intake on hemorheological parameters in healthy volunteers

(Jensen, et al., 2006; Kaul, et al., 2010). These experiments gave information about PV,

WBV and RBC deformability, but no literature data have been found about RBC

aggregation. Our previous in vitro experiments showed that red wine, AFRW and ethanol

significantly and dose dependently decrease RBC aggregation (Rabai, et al., 2010; Rabai,

et al., 2014). In our current study we aimed to confirm the in vitro findings and examine

the effects of moderate red wine consumption on hemorheological parameters,

including viscosity, RBC aggregation and deformability. Ours is the first prospective,

controlled study which examined a complete hemorheological panel in this field.

Hemorheological parameters in CT-detected coronary artery disease

Previous clinical studies reported significantly elevated Hct, WBV, PV, fibrinogen level

and RBC aggregation in CAD (Lowe, et al., 1980; Rainer, et al., 1987; Lee, et al., 2008),

15

however only a few were able to detect statistically significant differences between the

various stages of CAD (Neumann, et al., 1989; Kesmarky, et al., 1998).

Our previous study showed significantly increased Hct, WBV, PV and fibrinogen

levels in CAD compared to healthy controls, moreover significant differences were found

between CAD subgroups, suggesting a correlation with the severity of CAD (Kesmarky,

et al., 1998).

We aimed to conduct a full scale hemorheological study on patients with CAD,

including the measurement of RBC aggregation and deformability which was not carried

out previously. To the best of our knowledge, all previous studies used invasive coronary

X-ray angiography to evaluate for CAD. In our current study, a new and well established

method, coronary CT angiography was used for the evaluation of the coronary vessel

system. This method is able to measure coronary stenosis precisely and can also

determine the total extent of coronary calcification.

16


Methods

Subjects

The study was approved by the Regional Ethics Committee of the University of Pecs and

written informed consent was signed by all subjects. Forty healthy, non-smoking male

volunteers between the ages of 18-40 were enrolled. None of them had taken any drugs

for one week prior entering the study and during the whole duration of it. In order to

eliminate any possible effect of the previously consumed alcoholic beverages, no alcohol

consumption was allowed in the first 7 days of the study. On the morning of the 8th day

the subjects were assigned into 2 groups:

In the control group, volunteers drunk mostly water for 3 weeks, coffee and soft

drinks were permitted, no alcohol consumption was allowed.

In the red wine group, 2 dl of red wine (2007 Merlot, Polgar Winery, Villany,

Hungary; resveratrol content ≈ 4 mg/l, ethanol content ≈ 13.5 V/V%) was

consumed each day during dinner for 3 weeks, no other forms of alcoholic

beverages were allowed [Fig. 2.1.].

40 healthy young subjects

1st

– 7th

days: no alcohol consumption

Control group No alcohol Mostly tap water Soft drinks and coffee

allowed

Red wine group 2 dl of red wine for dinner No other alcohol Additional fluid intake

similarly to control group

29th

day: 3-week blood samples

8th

day: baseline blood samples

Fig. 2.1. Study protocol.

17

Blood sampling

After fasting for 12 hours, in the mornings of the 8th and 29th days, 17 ml of antecubital

venous blood samples were obtained into Li-heparin coated BD Vacutainer® tubes with

a 21-gauge butterfly needle set with a minimal tourniquet, according to the latest

guideline for hemorheological laboratory techniques (Baskurt, et al., 2009). Blood

samples were stored at ambient temperature until hemorheological measurements.

Hemorheological measurements

Hemorheological measurements were performed within 1 hour from blood sampling at

the Hemorheological Laboratory of the 1st Department of Medicine, University of Pecs

Medical School.

Hematocrit

The anticoagulated blood samples were placed into a native capillary then centrifuged

with Haemofuge microhematocrit centrifuge (Heraeus; Germany) at 12,000 RPM for 3

minutes at room temperature (22±1°C). Hct was determined by the fraction of volume

occupied by RBCs. For further measurements Hct

was adjusted to 40% with autologous plasma.


PV and WBV were measured by Hevimet 40 capillary

viscometer (Hemorex; Budapest, Hungary) [Fig.

2.2.]. Plasma was obtained by centrifugation of

blood samples at 2500 g for 10 minutes at 22°C

(Labofuge 400 R, Heraeus; Germany).

The viscometer is composed of a vertical

glass tube and 40 diodes placed next to it. 620 μl of

fluid is injected into the system and released to flow

out, while the height of the fluid column is registered

in the function of time. The height of each diode

vacuum

light source

glass tube

capillary

height of fluid column

sample

oil bath

Fig. 2.2. Hevimet 40 capillary viscometer.

18

from the baseline of the fluid column is known, thus the flow maintaining hydrostatic

pressure and shear stress at each point can be calculated. For the same points, flow

velocity and shear rate is calculated from the height-time function. From the shear stress

and shear rate data points, viscosity values are determined. Viscosity values

interpolated at 90 s-1 shear rate were used in our study. Measurements were performed

at 37 °C temperature.

Hematocrit per whole blood viscosity ratio

From Hct and WBV data, Hct/WBV ratio

was calculated to determine rheological

oxygen carrying capacity of blood.

Oxygen binding capacity linearly,

viscosity and flow resistance

exponentially increases with Hct. In

healthy subjects Hct/WBV ratio reliably

reflects rheological oxygen carrying

capacity of blood (Bogar, et al., 2005).

Values of Hct/WBV in the function of

Hct results in an inverted U-shaped

curve [Fig. 2.3.] (Kenyeres, 2010). Both

in anemia and polycythemia oxygen

supply is impaired and lower Hct/WBV ratios are calculated. In case of anemia, low

oxygen transport originates from low oxygen binding capacity, while in polycythemia

the decreased flow velocity is responsible for the clinical symptoms. A study from our

research group demonstrated that unfavorable Hct/WBV ratio in patients with CHD is

associated with increased risk of cardiac morbidity and mortality (Kenyeres, et al., 2008).


RBC aggregation was measured by Myrenne (MA-1 Aggregometer, Myrenne GmbH;

Roetgen, Germany) and LORCA (Laser-assisted Optical Rotational Cell Analyzer; R&R

Mechatronics; Hoorn, The Netherlands) aggregometers. Blood samples were taken from

the same tube.

Fig. 2.3. Hct/WBV ratio at different Hct-s and shear rates.

Source: Kenyeres P., PhD dissertation. University of Pecs, Medical School, 2010.

With the Author’s approval.

Hct (%)

Hct

/WB

V (

mP

a-1s-1

)

19

Myrenne aggregometer [Fig. 2.4.]

employs the light transmission method of

Schmid-Schonbein through a transparent

cone-plate shearing instrument (Klose, et

al., 1972). 30 µl of blood is injected between

the glass cone and plate. The sample is

sheared at 600 s-1 to disperse all pre-existing RBC aggregates, then shear rate falls to

zero (in M mode) or to 3 s-1 (in M1 mode). The instrument measures the infrared light

intensity passing through the blood sample: as RBCs aggregate the light intensity

gradually increases. The extent of aggregation was characterized by the aggregation

indices (M, M1) calculated from the surface area under the light intensity curve in a 10

s period of time (Vaya, et al., 2003). Measurements were performed at room

temperature (22±1 °C).

LORCA aggregometer [Fig. 2.5.] detects the laser back-scattering generated by

the RBCs. To increase back-scattering, blood samples were oxygenated by incubation

with 10-times higher volume of air on a rollerbank for 15 minutes. 1 ml of oxygenated

blood was injected into the gap between the static inner glass cylinder and the rotating

outer glass cylinder which creates a simple shear flow. RBCs are first disaggregated at

500 s-1 shear rate, then shear rate falls to zero. During RBC aggregation, the intensity of

back-scattering laser light is drawn in the function of time (syllectogram) [Fig. 2.6.].

Aggregation behavior of blood was characterized by:

detector

infrared light source

blood sample

glass plate (static)

glass cone (rotating)

Fig. 2.4. Myrenne RBC aggregometer.

laser diode

sample

outer cylinder

inner cylinder

diffraction pattern

camera system

photo diodes (for measurement of

RBC aggregation)

Fig. 2.5. LORCA; RBC aggregation and laser diffraction ellipsometry measurements.

20

the aggregation index (AI), calculated from the first 10 seconds of the syllectogram

after the shape recovery period: AI = A/(A+B) [Fig. 2.6.]

and the time that elapses until peak intensity is reduced by half the amplitude (t½)

(Hardeman, et al., 2001; Dobbe, 2003).

During the measurements temperature was kept at 37 °C. Analyses were performed on

LORCA Aggregation Program v2.1.


RBC deformability was measured by LORCA [Fig. 2.5.], using the laser diffraction

ellipsometry technique. 25 μl of blood was suspended in 5 ml of high viscosity (32.6

mPas) polyvinylpyrrolidone (Sigma-Aldrich, 360 kDa) solution dissolved in phosphate

buffered saline (290 mOsm/kg, pH = 7.4). 1 ml of this suspension was injected into the

gap between the two cylinders. RBCs are deformed by various shear stresses, generated

0.0

0.7

0.1

Shear stress (Pa)

Elo

ng

ati

on

in

de

x (

EI)

0.6

0.5

0.4

0.3

0.3

-0.1

A

B

EI = (A-B) / (A+B) 0.30 1.00 10.00 30.00

Time (s)

0.01 0.10 10.00 1.00 120.00 0.0

10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0

100.0

Isc

(au

)

shape recovery aggregation

B

A amplitude

AI = A/(A+B)

Fig. 2.6. LORCA syllectogram.

Fig. 2.7. Diffraction pattern and deformability curve.

21

by the rotation of the outer cylinder, meanwhile a laser diode is projecting through the

sample. The elongated RBCs create a laser diffraction pattern captured by a video

camera and analyzed by LORCA Elongation Program v2.1.

RBC deformability was characterized by the elongation index (EI), calculated

from the two radiuses of the ellipsoid diffraction pattern as (A-B)/(A+B), at shear stresses

from 30 Pa to 0.3 Pa. From these data the deformability curve was drawn [Fig. 2.7.]

(Hardeman, et al., 1994; Dobbe, 2003).

Statistical analysis

Continuous variables are presented as mean values ± S.E.M. Differences were analyzed

using paired (dependent samples between baseline and 3rd week results) and un-paired

(independent samples between the control and the red wine group) Student’s t-test. A

two-tailed p value less than 0.05 was considered statistically significant.

Results

Subjects

There was no significant difference between the control and the red wine group in age,

body mass index (BMI) and average physical activity [Table 2.1.]. One volunteer from

the wine drinking group was withdrawn due to complaints of heartburn.

Table 2.1.

Subject characteristics.

Control group Red wine group

Age (years) 27.5 ± 1.2 26.8 ± 1.0

BMI (kg/m2) 24.9 ± 0.87 23.9 ± 0.64

Physical activity score 3.0 ± 0.2 3.1 ± 0.2 Physical activity score: 1: none, 2: monthly, 3: weekly, 4: daily, 5: professional

22

Hematocrit

Red wine consumption had no effect on Hct and no difference was found between the

two groups neither at baseline, nor after 3 weeks [Table 2.2.].

Table 2.2.

Hemorheological parameters.

Baseline 3 weeks

Control Red wine Control Red wine

Hct (%) 47.8 ± 0.6 46.6 ± 0.5 47.4 ± 0.7 46.4 ± 0.5

PV 1.27 ± 0.02 1.25 ± 0.03 1.26 ± 0.02 1.26 ± 0.02

WBV (mPa·s) 3.9 ± 0.1 3.8 ± 0.1 3.9 ± 0.1 3.7 ± 0.1c

Hct/WBV

(mPa-1s-1)

10.4 ± 0.3 10.7 ± 0.2 10.4 ± 0.3 11.0 ± 0.3c

M 8.6 ± 0.7 9.0 ± 0.4 8.1 ± 0.5 8.1 ± 0.3b

M1 16.0 ± 0.7 15.2 ± 0.7a 14.1 ± 0.6a 12.8 ± 0.4b,c

AI 57.2 ± 2.2 55.4 ± 1.7 54.1 ± 1.9 53.5 ± 1.8b

t½ (s) 2.9 ± 0.3 3.2 ±0.3 3.4 ± 0.3 3.5 ± 0.3b

EI (at 30 Pa) 0.631 ± 0.002 0.630 ± 0.003 0.632 ± 0.002 0.632 ± 0.003b a: significant (p<0.05) difference compared to the control group at baseline b: significant (p<0.05) difference compared to the red wine group at baseline c: significant (p<0.05) difference compared to the control group after 3 weeks

Viscosity

PV did not change during the 3 weeks in either group compared to baseline, and there

was no significant difference between the two groups nor at baseline, neither after 3

weeks [Table 2.2.].

Adjusted WBV remained constant in the control group, while in the red wine

group it decreased, and after 3 weeks WBV in the red wine group became significantly

lower compared to the control group (p<0.05) [Table 2.2.].

23


The Hct/WBV ratio remained steady during the 3 weeks in the control group, while in

the red wine group the parameter tended to increase compared to baseline. After 3

weeks, significantly higher (p<0.05) ratio was calculated in the red wine group compared

to the control group [Table 2.2., Fig. 2.8.].

Fig. 2.8. Change in hematocrit/adjusted whole blood viscosity ratio. Arrow represents significant (p<0.05) difference.


Both Myrenne (M and M1) and LORCA aggregation indices significantly decreased

(p<0.05) in the red wine group [Table 2.2., Fig. 2.9., 2.10.]. LORCA t½ also indicates

significantly (p<0.05) decreased RBC aggregation in the red wine group [Table 2.2.].

Furthermore, after 3 weeks, Myrenne M1 parameter was also significantly lower

(p<0.05) in the red wine group compared to the control group. M1 significantly

decreased (p<0.05) in the control group after 3 weeks, but none of the other RBC

aggregation parameters (M, AI, t½) showed a significant change [Table 2.2., Fig. 2.9.,

2.10.].

90

95

100

105

110

115

Baseline 3 weeks

1/(

Pa·

s)

Hct/WBV ratio (40%)

Control Red wine

24

Fig. 2.9. Red blood cell aggregation in adjusted samples measured by Myrenne. Arrow represents significant (p<0.05) difference.

Fig. 2.10. Red blood cell aggregation in adjusted samples measured by Myrenne.

Arrows represent significant (p<0.05) differences.


At the highest shear stress (30 Pa), the EI significantly increased (p<0.05) in the red wine

group after 3 weeks compared to baseline, while it did not change in the control group

[Table 2.2.].

5.0

6.0

7.0

8.0

9.0

10.0

Baseline 3 weeks

Myrenne M (40%)

Control Red wine

5

7

9

11

13

15

17

19

Baseline 3 weeks

Myrenne M1 (40%)

Control group Red wine group

25

Discussion

Only limited data have been presented on the hemorheological consequences of

medium and long-term red wine consumption. Several studies have demonstrated an

inverse association between red wine or polyphenol intake and cardiovascular events,

but not all sources of this cardioprotective effect are known. Most authors have

emphasized the effect of elevated HDL level, decreased platelet aggregation and

fibrinogen level, thus these were mostly examined. In a randomized crossover study,

five-week red wine consumption significantly decreased collagen-induced platelet

aggregation and increased HDL level (Pikaar, et al., 1987), moreover in another study

collagen-induced platelet aggregation and fibrinogen level were significantly reduced

after 4-week red wine intake (Pellegrini, et al., 1996).

Only a few controlled results are known about other important hemorheological

parameters – such as PV, WBV, RBC aggregation and RBC deformability – in healthy

human subjects consuming red wine. A randomized controlled study reported that

moderate red wine consumption (6 or 12 ounces/day; ≈ 1.77 or 3.55 dl/day), up to 2

weeks, significantly increased HDL level, but it did not change Hct, WBV, RBC

deformability and fibrinogen level (Kaul, et al., 2010). Another controlled experiment

observed significantly reduced PV and fibrinogen level after 3-week moderate red wine

intake (Jensen, et al., 2006). Our prospective, controlled study presents new data about

the in vivo hemorheological effects of moderate red wine consumption.

Hematocrit

Red wine consumption had no significant effect on Hct, confirming the results of Kaul,

et al. (2010). In order to completely eliminate the influence of Hct on the dependent

hemorheological parameters (WBV and RBC aggregation) Hct was standardized to 40%.


PV did not change significantly after 3-week red wine consumption. Although we did not

measure plasma fibrinogen level (the main determinant of PV), Kaul, et al. (2010)

26

reported no significant change after 2 weeks of red wine intake. On the other hand,

lower plasma viscosity and fibrinogen level were measured after 3 weeks in a different

study (Jensen, et al., 2006).

The observed reduction of WBV in the red wine group may result from the

reduction of RBC aggregation and the increased RBC deformability. Red wine

consumption increased WBV of Hct-standardized samples after 3 hours, but no

difference from baseline was observed 13 hours after ingestion (Fehr, et al., 2008). This

suggests that the observed reduction of WBV in our study was not due to the short-term

effect of the red wine, consumed in the previous evening. Kaul, et al. (2010) found no

changes after 2 weeks of red wine consumption, but Jensen, at al. (2006) reported

decreased WBV after 3 weeks. It is assumed that more time is required until the effect

can be detected.


The significantly higher Hct/WBV ratio in the red wine group (due to unaffected Hct and

lowered WBV) means greater oxygen carrying capacity of the blood.


The reduction of RBC aggregation was observed both by Myrenne and LORCA in the red

wine group. These findings confirm our previous in vitro results, where red wine, AFRW

and ethanol inhibited RBC aggregation (Rabai, et al., 2010; Rabai, et al., 2014). The

decrease of RBC aggregation may be a consequence of the modifications of plasma

proteins. It is known that polyphenols, such as resveratrol, are bounded to plasma

proteins due to their poor water solubility. The phenol-protein interactions may change

the properties of plasma proteins and RBC surface molecules, therefore reducing the

capability to form cross links between cellular components and decreasing RBC

aggregation. It has been reported that resveratrol binding to albumin or hemoglobin

changes their secondary structures (Lu, et al., 2007). The absorption of resveratrol in

humans is about 70%, but due to the extensive metabolism, resveratrol is mostly

present in sulphate and glucuronide conjugated forms and only minimal amounts of

27

unchanged resveratrol can be detected in the plasma (Walle, et al., 2004). The reported

fibrinogen lowering effect of red wine (Jensen, et al., 2006) may also be a reason of the

observed decrease in RBC aggregation.


RBC deformability was enhanced at the highest shear stress in the red wine group. EI at

30 Pa approximates the maximal deformability of RBCs. In our earlier in vitro study, no

significant changes were observed after direct addition of red wine or AFRW to the blood

samples (Rabai, et al., 2010). It was assumed that under no significant oxidative stress,

RBC of healthy humans has optimal deformability; therefore no further improvement

could be expected. On the other hand, RBC deformability even of healthy volunteers

could be improved with moderate red wine consumption. Contrarily, another study

reported no significant changes in RBC deformability after 2 weeks of red wine

consumption (Kaul, et al., 2010). It is possible again, that more time is required till the

changes become significant.

Conclusions

This in vivo study confirmed our previous in vitro findings about the beneficial

hemorheological effects of ethanol, AFRW and red wine on RBC aggregation. Decreased

WBV, RBC aggregation, higher calculated oxygen carrying capacity and increased RBC

deformability may positively affect microcirculation. These findings may take part in the

cardiovascular protection of moderate red wine consumption.

28


Methods

Patients

The study was approved by the Regional Ethics Committee of the University of Pecs. 130

patients, admitted to coronary CT angiography at the Department of Radiology,

University of Pecs Medical School, participated in the study. Informed consent was

signed by all subjects prior to enrollment. Patients were questioned regarding previous

medical history and existing medications. Patients with autoimmune disorders or

malignancies were not enrolled.

Blood sampling

Blood samplings were performed according to the latest guideline for hemorheological

laboratory techniques (Baskurt, et al., 2009). Samples were obtained via an antecubital

vein just before the coronary CT examination, using a 21-gauge butterfly needle set with

minimal tourniquet into the following BD Vacutainer® tubes:

2x6 ml Li-heparin anticoagulated (for hemorheological measurements)

3 ml K2EDTA anticoagulated (for qualitative and quantitative blood cell analyses)

2.7 ml Na-citrate anticoagulated (for fibrinogen level)

5 ml SST native (for lipid profile)

Blood samples were stored at ambient temperature until hemorheological

measurements.

29

Coronary computed tomography angiography

Coronary CT angiography examinations were performed at the Department of

Radiology, University of Pecs Medical School with a first generation 64-slice, dual source

Siemens Somatom Definition CT device. The instrument has two X-ray tubes and dual

detector system in perpendicular position: during coronary CT measurements the two

systems work simultaneously, providing better temporal resolution, which reduces the

presence of motion artefacts (Dérczy & Battyány, 2008).

Prior to the examinations no food or caffeine containing fluid consumption was

allowed for 4 hours. Sublingual nitrate was given to all patients and depending on the

resting heart rate, intravenous beta-blocker was administered. First a native scan was

carried out to estimate total coronary calcification. After that a contrast enhanced scan

was performed to evaluate coronary system. Coronary calcification was characterized

by Agatson-score; lesions were defined as area stenosis. Data processing and image

evaluation was done with Siemens syngo software on Siemens Multimodality

workstation (Dérczy & Battyány, 2008).

Hemorheological measurements

Hemorheological measurements were performed within 2 hours from blood sampling

at the Hemorheological Laboratory of the 1st Department of Medicine, University of Pecs

Medical School. The instruments and measurement protocols used in this study are

identical to the ones in the previous work, therefore only the differences will be detailed

here:

Hct, PV and WBV were measured with the same settings.

RBC aggregation was determined only by Myrenne aggregometer. Both native

samples and suspensions of RBCs, adjusted to 40% Hct with autologous plasma

were measured. Instrument settings were identical.

For RBC deformability measurements, blood was suspended in 29.43 mPas

viscosity polyvinylpyrrolidone solution. Other conditions remained unchanged.

30

Central laboratory measurements

Central laboratory measurements were carried out at the Department of Laboratory

Medicine, University of Pecs Medical School. The following parameters were measured:

Hct, Hgb concentration, RBC count, MCV, MCH, MCHC, LDL, HDL and fibrinogen level.

Classification of patients

Patients were classified into four groups based on their coronary vessel state, according

to Table 3.1.

Table 3.1.

Classification of patients.

Negative

(Neg)

no coronary stenosis or atherosclerotic lesion and

zero calcium-score

Non-significant

(NS)

below 40% area stenosis on one or more coronary vessels and

no PCI or CABG

Single-vessel

(SV)

1. over 40% area stenosis on one coronary vessel or

2. history of PCI or CABG on one coronary vessel

Multi-vessel

(MV)

1. over 40% area stenosis on multiple coronary vessels or

2. over 40% area stenosis on one coronary vessel and history of

PCI or CABG on one coronary vessel or

3. history of PCI or CABG on multiple coronary vessels

Statistical analysis

Continuous variables are presented as mean ± S.E.M. Discrete variables are described

through relative or absolute frequencies. Continuous variables were analyzed with one-

way ANOVA; in case of dichotomous variables χ2 test was used. A two-tailed p value less

than 0.05 was considered statistically significant.

31

Results

Nine patients were excluded from the study due to classification-limiting CT image

quality.

Subject characteristics

There is an increasing trend in average age, BMI and proportion of males in

Negative<Non-significant<Single-vessel<Multi-vessel rank order. The average age in the

Multi-vessel group is significantly higher compared to the Negative group. The

proportion of males is greatly higher in the CAD (Non-significant, Single-vessel and Multi-

vessel) groups compared to the Negative group, and continues to increase in a smaller

extent in the CAD subgroups [Table 2.2.].

The prevalence of hypertension, diabetes mellitus (DM) and smoking has a

similar rank order: Negative<Non-significant<Single-vessel<Multi-vessel. In the Single-

vessel and Multi-vessel groups all of them are significantly higher compared to the

Negative group. PCI and CABG are only present in the Single-vessel and Multi-vessel

groups, being highest in the Multi-vessel group. Ca-score also has the previously

described trend [Table 2.2.].

Table 2.2.

Demographic data, Ca-score, risk factors and revascularization procedures.

Neg NS SV MV

N 32 27 32 30

Age (years) 56.8 ± 2.0 59.2 ± 11.4 58.8 ± 1.5 62.1 ± 1.5a

Males 22 % 70 %a 75 %a 90 %a

BMI (kg/m2) 27.6 ± 0.9 29.3 ± 0.9 29.5 ± 0.8 29.7± 1.0

Ca-score 0 145.7a 264.9a 425.8a,b

Hypertension 66 % 70 % 87 %a 90 %a

DM 6 % 22 % 35 %a 35 %a

Smoking 19 % 33 % 43 %a 45 %a

PCI 0 % 0 % 19 %a,b 33 %a,b

CABG 0 % 0 % 6 % 30 %a,b,c a: significant (p<0.05) difference compared to the Negative group

b: significant (p<0.05) difference compared to the Non-significant group

c: significant (p<0.05) difference compared to the Single-vessel group

32

The use of antiplatelet, statin, angiotensin-converting enzyme inhibitor (ACEI),

angiotensin-receptor blocker (ARB) and beta-blocker medication is already considerable

in the Negative group and follows an increasing trend. The prevalence of acetylsalicylic

acid (ASA), clopidogrel (CLP), statin and beta-blocker medication in the Multi-vessel

group is significantly higher compared to the Negative group. Statin use is significantly

higher in all CAD subgroups compared to the Negative group. Dual anti-platelet therapy

is only used in the Single-vessel and the Multi-vessel groups.

Table 2.3.

Medications.

Neg NS SV MV

Antiplatelet agents:

Mono antiplatelet therapy 41 % 62 % 55 % 57 %

Dual antiplatelet therapy 0 % 0 % 6 % 21 %a,b

ASA 38 % 46 % 58 % 68 %a

CLP 3 % 15 % 10 % 32 %a,c

Statin 31 % 62 %a 58 %a 64 %a

ACEI/ARB 59 % 62 % 68 % 79 %

Beta-blocker 47 % 63 % 61 % 75 %a a: significant (p<0.05) difference compared to the Negative group



Hemorheological parameters

Hematocrit

Hct increases in a Negative<Non-significant<Single-vessel<Multi-vessel manner. In the

Non-significant, Single-vessel and Multi-vessel groups it is significantly higher compared

to the Negative group [Table 2.4., Fig. 3.1.].


No significant difference was found in PV [Table 2.4.]. WBV shows the following rank

order: Negative<Non-significant<Single-vessel<Multi-vessel. WBV in the Multi-vessel

group is significantly higher compared to the Negative group [Table 2.4., Fig. 3.2].

33

Table 2.4.

Hemorheological parameters.

Neg NS SV MV

Hct (%) 42.7 ± 0.4 44.1 ± 0.7a 44.3 ± 0.6a 44.9 ± 0.6a

PV (mPa·s) 1.31 ± 0.2 1.28 ± 0.2 1.29 ± 0.2 1.27 ± 0.2

WBV (mPa·s) 4.3 ± 0.1 4.4 ± 0.1 4.4 ± 0.1 4.5 ± 0.1a

M 5.5 ± 0.3 5.7 ± 0.3 6.1 ± 0.3 6.4 ± 0.3a

M (40 %) 5.9 ± 0.3 6.1 ± 0.4 6.6 ± 0.3 7.0 ± 0.4a, b

M1 12.3 ± 0.3 12.6 ± 0.5 12.8 ± 0.4 13.0 ± 0.4

M1 (40 %) 12.8 ± 0.4 12.9 ± 0.6 13.5 ± 0.4 14.0 ± 0.5a

EI (at 30 Pa) 0.624 ± 0.002 0.620 ± 0.001a 0.622 ± 0.001 0.621 ± 0.002

EI (at 16.8 Pa) 0.594 ± 0.002 0.590 ± 0.001a 0.592 ± 0.002 0.591 ± 0.003 a: significant (p<0.05) difference compared to the Negative group



Fig. 3.1. Hematocrit. Arrows represent significant (p<0.05) differences.

Fig. 3.2. Whole blood viscosity at 90 s-1 shear rate. Arrow represents significant (p<0.05) difference.

38

39

40

41

42

43

44

45

46

Neg NS SV MV

%

Hematocrit

3.9

4.0

4.1

4.2

4.3

4.4

4.5

4.6

4.7

Neg NS SV MV

mP

a·s

Whole blood viscosity (90 s-1)

34


In native samples, both M and M1 parameters increase in Negative<Non-

significant<Single-vessel<Multi-vessel manner. The M parameter is significantly higher

in the Multi-vessel group compared to the Negative group [Table 2.4., Fig. 3.3.].

In case of adjusted samples, the M and M1 parameters show similar

Negative<Non-significant<Single-vessel<Multi-vessel trend. Both indices are

significantly higher in the Multi-vessel group compared to the Negative group, moreover

the M parameter is significantly higher in the Multi-vessel group compared to the Non-

significant group [Table 2.4., Fig. 3.4.].


RBC deformability shows a decreasing trend at all shear stresses. EI at 30 and 16.87 Pa

was significantly lower in the Non-significant group compared to the Negative group

[Table 2.4.].

Fig. 3.3. Red blood cell aggregation in native and adjusted (Hct=40%) samples measured by Myrenne. Arrows represent significant (p<0.05) differences.

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

Neg NS SV MV

Myrenne M

native

adjusted

35

Fig. 3.4. Red blood cell aggregation in native and adjusted (Hct=40%) samples measured by Myrenne. Arrow represents significant (p<0.05) difference.

Central laboratory parameters

RBC count, Hbg concentration, MCV, MCH, and MCHC have the same rank order:

Negative<Non-significant<Single-vessel<Multi-vessel. In the Multi-vessel group all

parameters are significantly higher compared to the Negative group. LDL levels are

similar in all groups. HDL has a decreasing trend and it is significantly lower in the Multi-

vessel group compared to all the other ones. Fibrinogen level has an increasing tendency

in the CAD subgroups, although no significant difference was found [Table 2.5.].

Table 2.5.

Central laboratory parameters.

Neg NS SV MV

RBC count (G/l) 4.5 ± 0.1 4.6 ± 0.1 4.6 ± 0.1 4.7 ± 0.1a

Hbg concentration (g/l) 134.7 ± 1.5 140.6 ± 2.2a 140.5 ± 2.3a 145.3 ± 2.1a

MCV (fl) 90.5 ± 0.7 91.0 ± 1.0 91.7 ± 1.2 92.2 ± 0.6a

MCH (pg) 30.0 ± 0.3 30.5 ± 0.4 30.7 ± 0.5 31.0 ± 0.3a

MCHC (g/l) 331.0 ± 1.4 334.7 ± 2.2 334.8 ± 2.4 336.6 ± 2.1a

LDL (mmol/l) 3.1 ± 0.2 2.7 ± 0.2 3.1 ± 0.3 3.1 ± 0.2

HDL (mmol/l) 1.5 ± 0.1 1.4 ± 0.1 1.3 ± 0.1 1.2 ± 0.1a,b,c

fibrinogen (g/l) 3.06 ± 0.10 2.97 ± 0.20 3.04 ± 0.11 3.28 ± 0.16 a: significant (p<0.05) difference compared to the Negative group



11.0

11.5

12.0

12.5

13.0

13.5

14.0

14.5

Neg NS SV MV

Myrenne M1

native

adjusted

36

Discussion

Subject characteristics

Age, male gender, obesity, hypertension, DM and smoking are major CV risk factors,

thus the Negative<Non-significant<Single-vessel<Multi-vessel trend was expected. The

high prevalence of hypertension in the Negative group can be explained by the relatively

high average age of this cluster. The same increasing trend was observed in the

prevalence of PCI and CABG procedures. These procedures are indicated in

hemodynamically significant coronary stenosis, therefore they are only present in the

most severe CAD subgroups.

Generally, the amount of applied medication increases with the deteriorating

coronary status. The use of anti-platelet, statin, ACEI/ARB and beta-blocker is already

notable in the Negative group and increases in the CAD subgroups. According to the

latest guideline for the management of CAD, prescription of these drugs is indicated in

all cases, if contraindications are not present (The Task Force on the management of

stable coronary artery disease of the European Society of Cardiology, 2013).

Unfortunately, in the CAD subgroups not all patients receive proper medication. These

drugs are also present in the Negative group. It is likely that these patients receive these

drugs due to existing hypertension (ACEI/ARB, beta-blocker) or dyslipidemia (statin).

Dual antiplatelet therapy is only present in the Single-vessel and Multi-vessel groups,

where PCIs were performed and dual therapy is routinely used.

Hematocrit

Hct was significantly higher in the CAD subgroups compared to the patients with no

vessel disease which result is similar to the findings of our earlier study (Kesmarky, et

al., 1998). However, we were not able to detect significant differences between CAD

subgroups, although the increasing tendency is well visible. Elevated Hct has also been

reported by Lowe, et al. (1980) and Rainer, et al. (1987). On the other hand Pfafferott,

et al. (1999) did not find significant difference between healthy controls, patients with

37

stable/unstable angina and acute myocardial infarct, but the epidemiological studies

strongly support our findings.

It has been demonstrated, that vascular mechanisms can reduce flow resistance

increment, caused by increased Hct in isolated dog hind limb (Whittaker & Winton,

1933). Baskurt, et al. (1991) reported, that 57% increase of Hct elevated coronary flow

resistance only by 8% in healthy dogs, demonstrating the substantial coronary

autoregulatory reserve. However, after exhausting the coronary reserve by inducing

critical stenosis, coronary flow resistance increased by 22%. This result suggests that in

case of an existing stenosis – e.g. in severe CAD, where hemorheological alteration are

greater – altered hemorheological parameters have more impact on the coronary

circulation.


Our study found similar PV levels in all groups, supporting the findings of Lowe, et al.

(1980). On the other hand, our earlier study (Kesmarky, et al., 1998), Rainer, et al.

(1987), Pfafferott, et al. (1999) and Lee, et al. (2008) found significantly elevated PV in

CAD.

No significant difference was found in fibrinogen level, although an increasing

trend is evident in CAD subgroups. Lowe, et al. (1980) reported similar plasma fibrinogen

levels in CAD compared to healthy controls, while Kesmarky, et al. (1998) and Rainer, et

al. (1987) observed a significant increase. The dissimilar findings in PV and fibrinogen

levels may originate from the nowadays widely used statin medication. Ten years ago in

the same region Marton, et al. (2003) reported only 13% statin medication in patients

admitted to hospital due to acute coronary syndrome. This is two times lower compared

to our Negative group and four times lower compared to the CAD subgroups.

WBV was significantly elevated in the most severe vessel state, confirming our

previous result (Kesmarky, et al., 1998). This result is supported by the findings of Lowe,

et al. (1980), Rainer, et al. (1987) and Lee, et al. (2008). Kesmarky, et al. (1998) and Lee,

et al. (2008) reported statistically significant differences between CAD subgroups, while

Vosseler, et al. (2012) found no significant difference between CAD and healthy controls.

38

Increased WBV has also been observed in hypertension and diabetes mellitus, therefore

the elevated WBV in the Multi-vessel group may be a consequence of the increased

prevalence of these comorbidities.


RBC aggregation was significantly increased in CAD and significant difference was found

between the subgroups. Rainer, et al. (1987), Pfafferott, et al. (1999) and Lee, et al.

(2008) confirm our results.

RBC aggregation alters both macro- and microrheological properties of blood

and can either decrease or increase flow resistance. These effects depend on several

factors: vessel diameter, geometry, orientation or flow rate. On one hand, enhanced

RBC aggregation reduces flow resistance by increasing axial migration of RBCs,

promoting Fahraeus effect and plasma skimming (Baskurt & Meiselman, 2007).

On the other hand, elevated RBC aggregation increases low shear viscosity which

may affect flow resistance in large blood vessels when shear forces are sufficiently low.

RBC aggregation also has impact at the microcirculatory level: aggregates must be

dispersed in order to enter the microcirculation. In case of elevated RBC aggregation,

higher force is required which increases microvascular flow resistance (Baskurt &

Meiselman, 2007). Studies have also demonstrated in vivo, that RBC clumps may

become entrapped at the entrance to the capillaries (Lipowsky, 2007).

In isolated in situ guinea pig hind limb preparation, elevated RBC aggregation had

no significant effect on flow resistance with intact vascular control mechanisms.

However, after inhibition of smooth muscle tone, perfusion with a series of increasing

aggregating RBC suspensions, flow resistance first increased, then returned to control

and finally increased again (Yalcin, et al., 2004). These results also support the complex

effect of RBC aggregation on hemodynamics and the effect of exhausted vascular

compensation (which is present in CHD).

39


RBC deformability has a decreasing trend, being significantly lower in non-significant

vessel disease compared to patients with no vessel disease. Pfafferott, et al. (1999)

reported no significant difference of RBC filterability.

RBC deformability is the primary determinant of flow resistance in blood vessels

with dimensions similar to the RBC size. Lower RBC deformability negatively affects

microcirculation by increasing the flow resistance in the capillaries. Again, the

magnitude of this effect depends on the available vascular compensatory mechanisms.

Baskurt, et al. (2004) reported that if RBCs were minimally hardened with

glutaraldehyde, EI decreased by 16% and flow resistance increased by 78% in isolated-

perfused rat hind limb. However, after the pharmacological elimination of vascular tone,

the flow resistance increased by 250% for the same amount of deformability

impairment. This suggest that in case of CHD, where the vascular compensatory

mechanisms are limited, even a slight change in RBC deformability might have a great

effect on myocardial microcirculation.

Other laboratory parameters

RBC count, Hgb concentration, MCV, MCH and MCHC were significantly increased in

severe CAD. Increase of RBC count and MCV explains the same elevating trend of Hct.

Increased Hgb concentration may be a counter mechanism against stenosis-caused low

flow rate, in order to maintain oxygen delivery. In case of increased MCV, RBCs may

require higher force to enter and to pass thought the capillaries. Elevated MCH and

MCHC may increase intracellular viscosity, which can decrease RBC deformability (Cooke

& Lim, 2007).

LDL levels were similar in each group. Though LDL is a CV risk factor and expected

to be elevated in CAD patients, the much higher use of statins in CAD groups

counteracts. The decreasing HDL levels were also expected in CAD.

40

Study limitations

This is a cross-sectional study; therefore inference on the relationship between the

measured variables may be speculative. According to the latest American

(ACCF/AHA/ACP/AATS/PCNA/SCAI/STS, 2012) and European guidelines (The Task Force

on the management of stable coronary artery disease of the European Society of

Cardiology, 2013), coronary CT is indicated in medium pre-test probability of CAD [Fig.

3.5.], while coronary X-ray angiography is performed on high risk patients. In our study

this resulted in a lower number of patients with severe CAD compared to our previous

study where 65% of patient had multi-vessel disease. Due to these guidelines, much

fewer multi-vessel CAD cases were expected therefore 40% area stenosis was chosen as

a cut-off-point. Another important difference between our studies is the “distance”

between control and severely ill groups. We did not have healthy controls, and the most

severe cases are likely to be less severe compared to our earlier study. As a

consequence, the differences in severity of CAD between the groups are lesser and

significant differences are harder to be observed. Another possible reason for the

scarcity of significant differences between CAD subgroups is the relatively poor

discriminatory power of CT: this method is good at excluding CAD, but not as good in

distinguishing high-grade from non-high grade stenosis.

Pre-test probability (PTP) for the presence of coronary stenosis

Low PTP (<15%) Intermediate PTP (15-85%) High PTP (>85%)

Coronary CT angiography in patients at low intermediate

PTP (15% - 50%)

Stress testing for ischemia

Investigate other causes

Consider functional coronary disease

Diagnosis of stable CAD

established

Risk stratification Guideline-directed medical

therapy Invasive coronary angiography

Fig. 3.5. Non-invasive testing in patients with suspected stable CAD. Based on: 2013 ESC guidelines on the management of stable coronary artery disease.

41

Conclusions

Our results indicate that both macro- and microrheological parameters are altered in

CAD, therefore myocardial oxygen supply may be reduced at both macro- and

microcirculatory levels, and may play a pathophysiological role in the deterioration of

this disease.

42

Summary of new scientific results


Our controlled study demonstrated beneficial effects of 3-week moderate red wine

consumption on hemorheological parameters in healthy volunteers:

1. Three-week red wine intake decreases whole blood viscosity in healthy subject.

2. As a consequence, red wine consumption improves hematocrit per whole blood

viscosity ratio, suggesting improved oxygen transport efficiency of blood even in

healthy volunteers.

3. Moderate drinking of red wine lowers red blood cell aggregation.

4. Moderate consumption of red wine improves red blood cell deformability.


Our study revealed that hemorheological parameters are altered in CT-detected

coronary artery disease:

1. Hematocrit is higher in patients with coronary artery disease. The increase was

already significant in the least severe group.

2. Whole blood viscosity is elevated in patients with severe coronary artery disease.

3. Red blood cell aggregation is increased in severe coronary artery disease.

4. Red blood cell deformability is lower in patients with coronary artery disease.

5. These findings support that in CT-detected coronary artery disease beyond the

impaired hemodynamic factors (stenosis), hemorheological parameters are also

negatively affected.

43

Acknowledgements

I would like to express my greatest gratitude to my program leader, Professor Balazs

Sumegi for his great support throughout my PhD studies. I am grateful for the

continuous help and ideas of my project leaders, Dr. Istvan Battyani and Dr. Gabor

Kesmarky.

I am thankful to Prof. Dr. Kalman Toth, Dr. Istvan Juricskay, Dr. Laszlo Czopf, Dr.

Zsolt Marton and Dr. Peter Kenyeres for assisting my work with useful ideas. I would like

to express my special thanks to the present and former Ph.D. students, Dr. Barbara

Sandor, Dr. Miklos Rabai and to our technician Kornelia Tapasztone Fazekas for the

evening shifts. Moreover, I thank Dr. Judit Papp, Dr. Katalin Biro, Dr. Kinga Totsimon and

to the student researchers and the other colleagues for their support and for the friendly

lab community.

I am greatly thankful to Dr. Sandor Szukits, Dr. Edit Varady and the assistants and

technicians at the Department of Radiology for the friendly atmosphere and for the

continuous assistance.

The first study was supported by SROP-4.2.1.B-10/2/KONV-2010-0002 (TAMOP 4.2.1.B).

44

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Graded alterations of RBC aggregation influence in vivo blood flow resistance.

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55

Publications of the Author

Papers from the topics

1. RÁBAI M., TÓTH A., KENYERES P., MÁRK L., MÁRTON Z., JURICSKAY I., SÜMEGI B.,

TÓTH K. Vörösbor és alkoholmentes vörösborkivonat kedvező in vitro

haemorheologiai hatásai. Érbetegségek, 2 (2009), 45-52.

2. RABAI M., TOTH A., KENYERES P., MARK L., MARTON Z., JURICSKAY I., TOTH K.,

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

extract. Clin Hemorheol Microcirc, 44 (2010), 227-236.

3. TOTH A., SANDOR B., PAPP J., RABAI M., BOTOR D., HORVATH Z., KENYERES P.,

JURICSKAY I., TOTH K., CZOPF L. Moderate red wine consumption improves

hemorheological parameters in healthy volunteers. Clin Hemorheol Microcirc, 56

(2014), 13-23.

4. TOTH A., PAPP J., RABAI M., KENYERES P., MARTON Z., KESMARKY G., JURICSKAY

I., MEISELMAN H.J., TOTH K. The role of hemorheological factors in cardiovascular

medicine. Clin Hemorheol Microcirc, 56 (2014), 197-204.

5. TOTH A., SZUKITS S., VARADY E., SANDOR B., RABAI M., PAPP J., JURICSKAY I.,

KESMARKY G., TOTH K., SUMEGI B., BATTYANI I. Hemorheological parameters in

coronary artery disease detected by multi-slice CT. Korea-Aust Rheol J, 26 (2014),

229-235.

56

Other papers

6. VEKASI J., KOLTAI K., GAAL V., TOTH A., JURICSKAY I., KESMARKY G. The effect of

aspirin on hemorheological parameters of patients with diabetic retinopathy. Clin

Hemorheol Microcirc, 39 (2008), 385-389.

7. KENYERES P., RABAI M., TOTH A., KESMARKY G., MARTON Z., TOTH K. Reviewing

data reduction methods for ektacytometry. Clin Hemorheol Microcirc, 47 (2011),

143-150.

8. PAPP J., TOTH A., SANDOR B., KISS R., RABAI M., KENYERES P., JURICSKAY I.,

KESMARKY G., SZABADOS S., TOTH K. The influence of on-pump and off-pump

coronary artery bypass grafting on hemorheological parameters. Clin Hemorheol

Microcirc, 49 (2011), 331–346.

9. PAPP J., BÓTOR D., SÁNDOR B., TÓTH A., BIRÓ K., CSERNUS Z., TÓTH K., KÉSMÁRKY

G. A Raynaud-jelenség hemoreológiai vonatkozásai. Érbetegségek, 20 (2013), 33-

39.

10. PAPP J., SANDOR B., VAMOS Z., BOTOR D., TOTH A., RABAI M., KENYERES P.,

CSEPLO P., JURICSKAY I., MEZOSI E., KOLLER A., TOTH K. Antiplatelet effect of

acetylsalicylic acid, metamizole and their combination - in vitro and in vivo

comparisons. Clin Hemorheol Microcirc, 65 (2014), 1-12.

11. BIRO K., SANDOR B., TOTH A., KOLTAI K., PAPP J., RABAI M., TOTH K., KESMARKY

G. In vitro hemorheological effects of parenteral agents used in peripheral arterial

diseases. Korea-Aust Rheol J, 26 (2014), 243-247.

12. SANDOR B., VARGA A., RABAI M., TOTH A., PAPP J., TOTH K., SZAKAY P. Aspirin

resistance as cardiovascular risk after kidney transplantation. Korea-Aust Rheol J,

26 (2014), 237-241.

57

Published abstracts

1. RÁBAI M., KENYERES P., TÓTH A., KÉSMÁRKY G., MÁRTON Z., TÓTH K. Lehetőségek

ektacitometriás eredmények egyszerűsítésére, korrekciójára és

összehasonlítására. A Magyar Haemorheologiai Társaság XVII., a Magyar

Mikrocirkulációs és Vaszkuláris Biológiai Társaság, illetve a Magyar

Szabadgyökkutató Társaság I. Közös Kongresszusa, 2008. március 18-19.,

Balatonkenese. Érbetegségek, 15 (2008), 21.

2. RÁBAI M., TÓTH A. Lehetőségek ektacitometriás eredmények egyszerűsítésére,

korrekciójára és összehasonlítására. PTE ÁOK Tudományos Diákköri Konferencia

2008, 2008. április 3-5., Pécs. Absztraktok, 155.

3. KENYERES P., RABAI M., TOTH A., KESMARKY G., MARTON Z., TOTH K. Methods to

simplify, correct and compare ektacytometric results. 13th International Congress

of Biorheology and 6th International Conference on Clinical Hemorheology, 9-13

July 2008, State College, USA. Biorheol, 45 (2008), 138.

4. RABAI M., TOTH A., KENYERES P., MARTON Z., KESMARKY G., TOTH K. Rheological

benefit of red wine and its alcohol free extract. 13th International Congress of

Biorheology and 6th International Conference on Clinical Hemorheology, 9-13 July

2008, State College, USA. Biorheol, 45 (2008), 147.

5. TOTH K., KESMARKY G., MARTON Z., JURICSKAY I., TOTH A., ALEXY T., MEISELMAN

H.J. Hemorheological parameters in acute and stable forms of coronary heart

disease. 13th International Congress of Biorheology and 6th International

Conference on Clinical Hemorheology, 9-13 July 2008, State College, USA. Biorheol,

45 (2008), 47.

6. KENYERES P., RABAI M., TOTH A., KESMARKY G., TOTH K. The impact of in vitro

aging on erythrocyte aggregation. 25th Conference of the European Society for

Microcirculation, 26-29 August 2008, Budapest, Hungary. J Vasc Res, 45 (2008),

105.

58

7. KENYERES P., RÁBAI M., TÓTH A., KÉSMÁRKY G., BOGÁR L., TÓTH K. Egy új

megközelítés az optimális hematokrit értelmezésében akut koronária szindrómás

betegek adatai alapján. A Magyar Kardiológusok Társasága 2009. évi Tudományos

Kongresszusa, 2009. május 6-9., Balatonfüred. Card Hung, 39 Suppl. A (2009), A66.

8. RÁBAI M., PÁLFI A., BARTHA É., KENYERES P., TÓTH A., MAGYAR K., SÜMEGI B.,

TÓTH K. Vörösbor és alkoholmentes vörösborkivonat protektív hatásai

állatkísérletes és in vitro hemoreológiai modellekben. A Magyar Kardiológusok

Társasága 2009. évi Tudományos Kongresszusa, 2009. május 6-9., Balatonfüred.

Card Hung, 39 Suppl. A (2009), A74.

9. KENYERES P., RÁBAI M., TÓTH A., TÓTH K. Új módszer a hematokrit - vérviszkozitás

arány, és a virtuális optimális hematokrit meghatározására. 6. Magyar

Mikrokeringés Kongresszus, 2009. május 22-23, Balatonkenese. Érbetegségek, 2

(2009), 59.

10. KENYERES P., RABAI M., TOTH A., TOTH K. New method to determine hematocrit

to blood viscosity ratio and virtual optimal hematocrit. 15th Conference of the

European Society for Clinical Hemorheology and Microcirculation, 28 June - 1 July

2009, Pontresina/St. Moritz, Switzerland. Clin Hemorheol Microcirc, 42 (2009),

191.

11. RABAI M., KENYERES P., TOTH A., PALFI A., BARTHA E., MAGYAR K., SUMEGI B.,

TOTH K. In vitro hemorheological and cardioprotective effects of red wine and

alcohol free red wine extract. 15th Conference of the European Society for Clinical

Hemorheology and Microcirculation, 28 June - 1 July 2009, Pontresina/St. Moritz,

Switzerland. Clin Hemorheol Microcirc, 42 (2009), 191-192.

12. SÁNDOR B., TÓTH A. A hiperhomociszteinémia hatása a vér reológiai

paramétereire. XVII. Tudományos Diákköri Konferencia, 2010. március 18-21.,

Marosvásárhely. Orvosi és Gyógyszerészeti Szemle, 56 Suppl. 1 (2010), 12.

13. SÁNDOR B., TÓTH A. Hemoreológiai vizsgálatok hiperhomociszteinémiás patkány

modellen. PTE ÁOK Tudományos Diákköri Konferencia 2010, 2010. április 15-17.,

Pécs. Absztraktok, 166.

59

14. TÓTH A. A vörösbor és alkoholmentes vörösbor kivonat hatásának vizsgálata in

vitro hemoreológiai modellen. PTE ÁOK Tudományos Diákköri Konferencia 2010,

2010. április 15-17., Pécs. Absztraktok, 194.

15. SÁNDOR B., TÓTH A. A hemoreológia és a hyperhomociszteinémia

összefüggéseinek vizsgálata. XV. Korányi Frigyes Tudományos Fórum, 2010. április

29-30., Budapest. Absztraktok, 118.

16. PAPP J., SANDOR B., TOTH A., RABAI M., VAMOS Z., KENYERES P., KOLLER A., TOTH

K. Effects of Hyperhomocysteinemia on Various Hemorheological Parameters. 2nd

International Symposium on Hypertension, 18-21 November 2010, Osijek, Croatia.

Kidney Blood Press Res, 35 (2010), 428.

17. PAPP J., TÓTH A., SÁNDOR B., KISS R., RÁBAI M., KENYERES P., SZABADOS S., TÓTH

K. On-pump és off-pump technikával végzett koszorúér bypass műtétek (CABG)

hemoreológiai összehasonlítása. A Magyar Kardiológusok Társasága 2010. évi

Tudományos Kongresszusa, 2010. május 5-8., Balatonfüred. Card Hung, 40 Suppl.

G (2010), G89.

18. SÁNDOR B., PAPP J., TÓTH A., RÁBAI M., KENYERES P., KOLLER Á., TÓTH K.

Hiperhomociszteinémia hatása a vér reológiai paramétereire. A Magyar

Kardiológusok Társasága 2010. évi Tudományos Kongresszusa, 2010. május 5-8.,

Balatonfüred. Card Hung, 40 Suppl. G (2010), G69.

19. PAPP J., TÓTH A., SÁNDOR B., KISS R., RÁBAI M., KENYERES P., SZABADOS S., TÓTH

K. Különböző technikákkal végzett koszorúér bypass műtétek (CABG)

hemoreológiai összehasonlítása. XVII. Magyar Klinikai Hemoreológiai

Kongresszus, a Magyar Haemorheologiai Társaság, a Magyar Mikorcirkulációs és

Vaszkuláris Biológiai Társaság és a Magyar Szabadgyökkutató Társaság II. közös

kongresszusa, 2010. június 25-26. Pécs. Absztraktok, 25.

60

20. SÁNDOR B., PAPP J., TÓTH A., RÁBAI M., KENYERES P., KOLLER Á., TÓTH K.

Hemoreológiai vizsgálatok hiperhomociszteinémiás patkány modellen. XVII.

Magyar Klinikai Hemoreológiai Kongresszus, a Magyar Haemorheologiai

Társaság, a Magyar Mikorcirkulációs és Vaszkuláris Biológiai Társaság és a

Magyar Szabadgyökkutató Társaság II. közös kongresszusa, 2010. június 25-26.

Pécs. Absztraktok, 18.

21. PAPP J., TOTH A., SANDOR B., KISS R., RABAI M., KENYERES P., SZABADOS S., TOTH

K. The influence of on-pump and off-pump coronary artery bypass grafting (CABG)

on hemorheological parameters. 18th International Meeting of the Alpe-Adria

Association of Cardiology, 16-18 September 2010, Vienna, Austria. J Kardiol, 17

Suppl. A (2010), 19-20.

22. TÓTH A., SÁNDOR B. On-pump és off-pump technikákkal végzett koszorúér bypass

műtétek (CABG) hatása a hemoreológiai paraméterekre. PTE ÁOK Tudományos

Diákköri Konferencia 2011, 2011. február 17-18., Pécs. Absztraktok, 144.

23. KENYERES P., PAPP J., TÓTH A., RÁBAI M., FEHÉR G., KOLTAI K., KÉSMÁRKY G.,

TÓTH K. Szinergizmus és kereszthatás az acetilszalicilsavval és tienopiridin

származékokkal elérhető thrombocyta aggregáció gátlás esetében. 7. Magyar

Mikrokeringés Kongresszus, 2011. április 1-2., Dobogókő. Érbetegségek, 18 Suppl.

1 (2011), 13.

24. PAPP J., TÓTH A., SÁNDOR B., RÁBAI M., KENYERES P., KISS R., SZABADOS S., TÓTH

K. On-pump és off-pump technikával végzett koszorúér bypass műtétek (CABG)

hatása a hemoreológiai és vérzési-transzfúziós paraméterekre. 7. Magyar

Mikrokeringés Kongresszus, 2011. április 1-2., Dobogókő. Érbetegségek, 18 Suppl.

1 (2011), 20-21.

25. KENYERES P., TÓTH A., KOLTAI K., FEHÉR G., PAPP J., RÁBAI M., TÓTH K.

Acetilszalicilsav és tienopiridinek trombocitaaggregáció gátlásának szinergizmusa.

A Magyar Kardiológusok Társasága 2011. évi Tudományos Kongresszusa, 2011.

május 1-14., Balatonfüred. Card Hung, 41 Suppl. F (2011), F33.

61

26. PAPP J., TÓTH A., KISS R., SÁNDOR B., RÁBAI M., KENYERES P., SZABADOS S., TÓTH

K. Különböző technikákkal végzett koszorúér bypass műtétek (CABG) hatása a

hemoreológiai és vérzési-transzfúziós paraméterekre. A Magyar Kardiológusok


Card Hung, 41 Suppl. F (2011), F47-F48.

27. PAPP J., VÁMOS Z., SÁNDOR B., TÓTH A., RÁBAI M., KENYERES P., CSÉPLŐ P.,

KOLLER Á., TÓTH K. Acetilszalicilsav és metamizol trombocita aggregáció gátló

hatásának in vitro összehasonlítása egészséges önkéntesek vérmintáin. FAMÉ,

2011. június 8-11., Pécs. Acta Phys, 202 Suppl. 684 (2011), 91-92.

28. PAPP J., TOTH A., SANDOR B., RABAI M., KISS R., TOTH K. The influence of various

coronary artery bypass grafting (CABG) methods on hemorheological parameters.

16th Conference of the European Society for Clinical Hemorheology and

Microcirculation, 18-21 June 2011, Munich, Germany. Abstract book, 96.

29. TOTH A., RABAI M., KENYERES P., MEISELMAN H.J., TOTH K. In vitro

hemorheological effects of red wine, alcohol free red wine extract and alcohol.

16th World Congress on Heart Disease, 23-26 July 2011, Vancouver, BC, Canada. J

Heart Dis, 8 (2011), 10.

30. KENYERES P., PAPP J., TOTH A., RABAI M., FEHER G., KOLTAI K., TOTH K. Synergic

antiplatelet effect of acetylsalicylic acid and thienopyridines. 19th International

Meeting of the Alpe-Adria Association of Cardiology, 15-17 September 2011,

Budapest, Hungary. Interventional Medicine & Applied Sciences, 3 (2011), 148.

31. TÓTH A. Vörösbor, alkohol és alkoholmentes vörösbor kivonat in vitro

hemoreológiai hatásának vizsgálata. PTE ÁOK TDK Miniszimpózium, 2011

november 24., Pécs. Absztraktok, 7.

32. TÓTH A., BÓTOR D., HORVÁTH Z. A vörösbor fogyasztás hatása a hemoreológiai

paraméterekre egészséges önkénteseken. PTE ÁOK Tudományos Diákköri

Konferencia 2012, 2012. április 17-18., Pécs. Absztraktok, 118.

62

33. BÓTOR D., PAPP J., HORVÁTH Z., TÓTH A, SÁNDOR B, RÁBAI M, CSERNUS Z, SZABÓ

Z, TÓTH K, KÉRMÁRKY G. Raynaud-kór: Az életet megkeserítő betegség

hemoreológia vonatkozásai. A Magyar Haemorheologiai Társaság, a Magyar

Mikorcirkulációs és Vaszkuláris Biológiai Társaság és a Magyar Szabadgyökkutató

Társaság III. közös kongresszusa, 2012. április 27-28., Balatonkenese.

Programfüzet, 29.

34. PAPP J., SANDOR B., TOTH A., HORVATH Z., BOTOR D., RABAI M., KENYERES P.,

JURICSKAY I., VAMOS Z., CSEPLO P., KOLLER A., TOTH K. In vitro and vivo

comparison of platelet aggregation inhibitory effect of acetylsalicic acid,

metamizole and their combination. A Magyar Haemorheologiai Társaság, a

Magyar Mikorcirkulációs és Vaszkuláris Biológiai Társaság és a Magyar

Szabadgyökkutató Társaság III. közös kongresszusa, 2012. április 27-28.,

Balatonkenese. Programfüzet, 19.

35. TOTH A., SANDOR B., PAPP J., BOTOR D., HORVATH Z., RABAI M., KENYERES P.,

JURICSKAY I., TOTH K. Red wine and hemorheology: complex results of in vivo and

in vitro studies in healthy volunteers. A Magyar Haemorheologiai Társaság, a

Magyar Mikorcirkulációs és Vaszkuláris Biológiai Társaság és a Magyar

Szabadgyökkutató Társaság III. közös kongresszusa, 2012. április 27-28.,

Balatonkenese. Programfüzet, 22.

36. PAPP J., KOLTAI K., TÓTH A., BÓTOR D., SÁNDOR B., RÁBAI M., CSERNUS Z., TÓTH

K., KÉSMÁRKY G. Hemoreológiai tényezők szerepe perifériás vazospasztikus

kórképekben. A Magyar Kardiológusok Társasága 2012. évi Tudományos

Kongresszusa, 2012. május 9-12., Balatonfüred. Card Hung, 42 Suppl. A (2012), A2.

37. TOTH A., SANDOR B., PAPP J., BOTOR D., HORVATH Z., RABAI M., KENYERES P.,

JURICSKAY I., TOTH K. Red wine and hemorheology: complex results of in vitro and

in vivo studies in healthy volunteers. 14th International Congress of Biorheology

and 7th International Conference of Clinical Hemorheology, 4-7 July 2012, Koc

University, Istanbul, Turkey. Biorheol, 49 (2012), 109.

63

38. PAPP J., SANDOR B., TOTH A., HORVATH Z., BOTOR D., RABAI M., KENYERES P.,

JURICSKAY I., VAMOS Z., CSEPLO P., KOLLER A., TOTH K. In vitro and in vivo

comparison of platelet aggregation inhibitory effect of acetylsalicylic acid,

metamizole and their combination. 14th International Congress of Biorheology and

7th International Conference of Clinical Hemorheology, 4-7 July 2012, Koc

University, Istanbul, Turkey. Biorheol, 49 (2012), 110.

39. KESMARKY G., PAPP J., KOLTAI K., TOTH A., BOTOR D., SANDOR B., RABAI M.,

CSERNUS Z., TOTH K. Raynaud’s disease: haemorheological characteristics. 14th

International Congress of Biorheology and 7th International Conference of Clinical

Hemorheology, 4-7 July 2012, Koc University, Istanbul, Turkey. Biorheol, 49 (2012),

131.

40. KÉRMÁRKY G., BÍRÓ K., SÁNDOR B., PAPP J., TÓTH A., KOLTAI K. A perifériás

ütőérbetegség ellátása a bizonyítékok fényében. A Magyar Haemorheologiai

Társaság 20. Kongresszusa. 2013. július 8., Pécs. Érbetegségek, 20 (2013), 31-32.

41. TÓTH A., SANDOR B., PAPP J., BÓTOR D., RÁBAI M., KENYERES P., JURICSKAY I.,

TÓTH K. A vörösbor fogyasztás hatása a hemoreológiai paraméterekre egészséges

önkénteseken. A Magyar Kardiológusok Társasága 2013. évi Tudományos

Kongresszusa, 2013. május 8-11., Balatonfüred. Card Hung, 43 Suppl. B (2012),

B46.

42. PAPP J., SÁNDOR B., TÓTH A., BÓTOR D., RÁBAI M., KENYERES P., VÁMOS Z.,

KOLLER Á., TÓTH K. Trombocitaaggregáció-gátlás metamizollal, acetilszalicilsavval

és kombinációjukkal: in vitro és in vivo összehasonlítás. A Magyar Kardiológusok


Card Hung, 43 Suppl. B (2012), B115.

43. SÁNDOR B., TÓTH A., PAPP J., RÁBAI M., JURICSKAY I., MEZEY B., TÓTH K.,

SZABADOS E. Fizikai tréning hatása a hemoreológia paraméterekre ambuláns

kardiológiai rehabilitációban résztvevő iszkémiás szívbetegeknél. A Magyar

Kardiológusok Társasága 2013. évi Tudományos Kongresszusa, 2013. május 8-11.,

Balatonfüred. Card Hung, 43 Suppl. B (2012), B52.

64

44. SÁNDOR B., TÓTH A., MEZEY B., PAPP J., RÁBAI M., JURICSKAY I., TÓTH K.,

SZABADOS E. Fizikai tréning hatása az ambuláns kardiológiai rehabilitációban

résztvevő iszkémiás szívbetegekben. A Magyar Élettani, Farmakológiai és

Mikrocirkulációs Társaságok 2013. évi közös Tudományos Kongresszusa. 2013.

június 5-6., Budapest, Absztraktok, A-0013.

45. TOTH A., TOTSIMON K., SZUKITS S., VARADY E., SANDOR B., BOTOR D., VRYZAS N.,

PAPP J., RABAI M., KENYERES P., JURICSKAY I., KESMARKY G., BATTYANI I., SUMEGI

B., TOTH K. Hemorheological parameters in ischemic heart disease. 17th

Conference of the European Society for Clinical Hemorheology and

Microcirculation, 6-9 July 2013, Pecs, Hungary. Clin Hemorheol Microcirc, 52

(2013), 178.

46. SANDOR B., TOTH A., MEZEY B., RABAI M., PAPP J., JURICSKAY I., TOTH K.,

SZABADOS E. Effect of physical activity in ischemic heart disease patients

participating in a cardiological ambulatory rehabilitation program. 17th Conference

of the European Society for Clinical Hemorheology and Microcirculation, 6-9 July

2013, Pecs, Hungary. Clin Hemorheol Microcirc, 52 (2013), 178-179.

47. SANDOR B., BIRO K., TOTH A., JURICSKAY I., VARGA A., RABAI M., PAPP J., TOTH K.,

SZAKAY P. Aspirin resistance after kidney transplantation. 17th Conference of the

European Society for Clinical Hemorheology and Microcirculation, 6-9 July 2013,

Pecs, Hungary. Clin Hemorheol Microcirc, 52 (2013), 139.

48. KESMARKY G., SANDOR B., TOTH A., BIRO K., KOLTAI K., PAPP J., RABAI M., TOTH

K. Peripheral vascular diseases: Role of hemorheological factors. 17th Conference

of the European Society for Clinical Hemorheology and Microcirculation, 6-9 July

2013, Pecs, Hungary. Clin Hemorheol Microcirc, 52 (2013), 180.

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66

MTMT közlemény és idéző összefoglaló táblázat

Tóth András adatai (2014.06.23.)

Közlemény típusok Száma Hivatkozások1

Teljes tudományos közlemények2 Összesen Részletezve Független Összes

I. Tudományos folyóiratcikk 12 --- --- ---

nemzetközi szakfolyóiratban --- 10 17 22

hazai kiadású szakfolyóiratban idegen nyelven --- 0 0 0

hazai kiadású szakfolyóiratban magyar nyelven --- 2 0 0

II. Könyvek 0 --- --- ---

a) Könyv, szerzőként 0 --- --- ---

idegen nyelvű --- 0 0 0

magyar nyelvű --- 0 0 0

b) Könyv, szerkesztőként 0 --- --- ---

idegen nyelvű --- 0 3--- ---

magyar nyelvű --- 0 --- ---

III. Könyvrészlet 0 --- --- ---

idegen nyelvű --- 0 0 0

magyar nyelvű --- 0 0 0

IV. Konferenciaközlemény folyóiratban vagy konferenciakötetben

0 --- --- ---

Idegen nyelvű --- 0 0 0

Magyar nyelvű --- 0 0 0

Tudományos közlemények összesen (I.-IV.) 12 --- 17 22

További tudományos művek4 --- 4 0 0

Összesített impakt faktor 14,5 --- --- ---

Idézetek száma5 --- --- 17 22

Hirsch index5 3 --- --- ---

Oktatási művek

Felsőoktatási tankönyv 0 --- --- ---

Idegen nyelvű --- 0 0 0

Magyar nyelvű --- 0 0 0

Felsőoktatási tankönyv része idegen nyelven --- 0 0 0

Felsőoktatási tankönyv része magyar nyelven --- 0 0 0

További oktatási művek 0 --- 0 0

Oltalmi formák 0 --- 0 0

Alkotás 0 --- 0 0

Ismeretterjesztő művek

Könyvek 0 --- 0 0

További művek 0 --- 0 0

67

Közérdekű és nem besorolt művek 0 --- 0 0

Absztrakt 51 --- 0 0

Egyéb szerzőség 0 --- 0 0

Idézők disszertációban, egyéb típusban 0 --- 1 8

Megjegyzések:

--- : Nem kitölthető cella

1 A hivatkozások a disszertáció és egyéb típusú idézők nélkül számolva. A disszertáció és egyéb típusú idézők összesítve a táblázat végén találhatók.

2 Teljes tudományos közlemény ebben az adatbázisban:

Folyóiratcikk: szakcikk/tanulmány, összefoglaló cikk, rövid közlemény, sokszerzős vagy csoportos szerzőségű közlemény, forráskiadás, recenzió/kritika, műkritika, esszé

Könyv: szakkönyv, monográfia, kézikönyv, tanulmánykötet, forráskiadás, kritikai kiadás, műhelytanulmány, atlasz

Könyvrészlet: szaktanulmány, fejezet, esszé, forráskiadás, recenzió/kritika, műkritika, műtárgyleírás, térkép, műhelytanulmány része

Konferenciaközlemény: folyóiratban, könyvben, egyéb konferenciakötetben megjelent legalább 3 oldal terjedelemben

Oltalmi formák: szabadalmak, mintaoltalmak (részletek) 3 Szerkesztőként nem részesedik a könyv idézéséből 4 Ide értve a teljes közlemények listájában nem szereplő publikációkat, a nem ismert lektoráltságú folyóiratokban megjelent műveket és minden olyan tudományos művet, ami a I.-IV. sorokban nem került összeszámlálásra. 5 A disszertációk és egyéb típusú idézők nélkül számolva (részletek)

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