34th ANNUAL MEETING — AMERICAN COLLEGE OF ANGIOLOGY PARADISE ISLAND, BAHAMAS — OCTOBER, 1987 SYMPOSIUM PROCEEDINGS

Blood Rheology Associated with Cardiovascular Risk Factors and Chronic Cardiovascular Diseases: Results

of

an

Epidemiologic

Cross-sectional

Wolfgang Koenig, From the Division of

Study

M.D.*

Cardiology,

of Internal Medicine,

Department University of Ulm, Ulm, West Germany

Edzard Ernst, M.D.† and

Arpad Matrai, M.D.† ULM and MUNICH, WEST GERMANY

Abstract As part of an epidemiologic crosssectional study to determine cardiovascular (CV) risk factors in the

population (total serum cholesterol, smoking, blood pressure, and body weight) hemoglobin (Hb) and plasma viscosity (PV) were measured. A twostage cluster sample of 5,312 persons, aged twenty-five to sixty-four (available 5,069) was selected from a mixed urban-rural target population of

282,279 inhabitants, from which 4,022 (79.3%) participated in the study. Patients with chronic myocardial infarction (MI), cerebral infarction (CI), angina pectoris (AP), and peripheral arterial disease (PAD) were identified by questionnaire. The results show that there is no age or sex dependency of PV in healthy participants, while hemoglobin shows the well-known sex differ-

t From the Hemorheology Research Laboratory, Clinic for Physical Medicine, University of Munich, Munich, West

Germany *

Nicholas A. Gabriele Presented at the 34th Annual Meeting of the American

’

Photograph by

’

&dquo; .

College of Angiology, 986

Paradise Island, Bahamas, October, 1987

987 In contrast, PV increases continuously with age in the total population. In men, increased PV is found in untreated hypertension, in hypercholesterolemia, and in smokers. In women, it is raised in hypercholesterolemia and in gross obesity. Male MI patients and patients of both sexes after CI in particular show statistically significantly elevated PV. Finally, in male patients with chronic AP or patients of both sexes with PAD, PV is elevated and a tendency ence.

Hb values is seen. These results confirm smaller clinical trials suggesting that blood fluidity is pathologically altered in patients with CV risk factors or diseases. Since impaired blood fluidity may worsen the hemodynamic situation, in particular in patients with limited vasomotor reserve, hemorheologic parameters may be of prognostic relevance. Therapeutic implications of these findings should be considered. to

higher

Introduction Several epidemiologic studies have shown that hematocrit, erythrocyte sedimentation rate, and fibrinogen, allowing an indirect assessment of the rheology of blood, are independent risk factors of cardiovascular morbidity and mortality.’-’ In other investigations, this relation disap8 peared after adjustment for the correlated risk variables6’’ or no association was found/ We included direct measurements of hemorheology in a cross-sectional study of a random sample of the population designed to determine cardiovascular (CV) risk factors. In this report we present preliminary data on plasma viscosity (PV) and hemoglobin (Hb) in relation to cardiovascular risk factors such as hypercholesterolemia, hypertension, smoking, obesity, and overt cardiovascular diseases like myocardial infarction, stroke, angina pectoris, and peripheral arterial occlusive disease. Materials and Methods

of the Study The MONICA project is

Design

WHO-coordinated epidemiologic long-term study conducted presently in forty centers in twenty-seven countries. Its main objective is the evaluation of trends in cardiovascular morbidity, mortality, and case fatality over ten years in defined populations. Furthermore, it investigates the determinants of cardiovascular diseases, which is achieved by multiple cross-sectional studies in five-year intervals recording the cardiovascular risk profile of the population.9,lo For the first survey (conducted from October, 1984, until May, 1985) 5,312 individuals aged twenty-five to sixty-four were sampled from a target population of 282,279 inhabitants by applying a two-stage age- and sex-stratified cluster sampling.&dquo; A net response rate of 79.3% was achieved (4,022 persons from 5,069 available). Subjects Studied All participants were interviewed by trained personnel using a standardized questionnaire concerning medical history, attitude toward and knowledge of health, use of medical care, lifea

988

FIG. 1. Plasma viscosity (mPa.s) by age in men; hatched bars=healthy participants; dark bars=all participants ; number in bars indicates group size. Mean t SEM.

viscosity (mPa.s) by age in women; Figure 1.

FIG. 2. Plasma

explanations,

see

for

socioeconomic variables, and a detailed drug history of the seven days preceding the examination. The following subgroups were selected for the present analysis: 1. Healthy subjects: 274 men and 293 women; no acute inflammatory disease, no cardiovascular or other chronic diseases, no malignancies; nonsmokers; no rheologically active medication ; blood pressure (BP) below 160/95 mm/Hg; and normal total cholesterol, uric acid, body mass index (BMI), and 12-lead resting ECG. 2. Persons with hypercholesterolemia: 75 men, 58 women; total serum cholesterol higher than 260 mg/dL (6.72 mmol/L). 3. Untreated hypertensives: 29 men and 10 women; no antihypertensive medication and BP of 160/95 mmHg or greater. 4. Smokers: 103 men and 32 women; inhalation of more than twenty cigarettes per day on the average (&dquo;Do you smoke presently?&dquo;). 5. Obese persons: 30 men and 26 women; body mass index

style,

body weight (kg) body weight(m)) (kg) 2 of 30 kg/m2 or greater. 12 ((height Patients with chronic myocardial infarction (MI): 48 men and 9 women; diagnosed by a physician. Patients after stroke: 15 men and 7 women; diagnosed by a physician. Patients with chronic angina pectoris (AP): 41 men and 46 women; identified by ROSE(BMI

6. 7. 8.

=

°

&dquo;

questionnaire. &dquo; 9. Patients with peripheral arterial occlusive disease (PAD) : 49

men

and 67 women; identified

by questionnaire. ...; .. : : In groups 2 through 5, only one risk factor was present and the inclusion and exclusion criteria of group 1 were applied. In groups 6 through 10, patients with acute or chronic inflammatory disorders or malignancies were excluded. In groups 8 and 9, in addition, patients with concomitant MI or stroke were not considered. ..... :. Blood Sampling Venous blood was sampled with a 19 G cannula according to the recommendations of the International Committee for Standardization in Haematology and anticoagulated with 1.5 mg &dquo;

’

989

FIG. 3. Hemoglobin (g/dL) in men with a single cardiovascular risk factor; bars from left to right: healthy participants, patients with hypocholesterolemia, untreated hypertensives, smokers, obese; number in bars indicates group size. Mean t SEM.

EDTA/mL.’4 Only short-term

Fic. 4. Hemoglobin (g/dL) in women with a diovascular risk factor. For further explanations, 3.

single carsee Figure

occlusion and minimal suction were applied. Each volunteer had been sitting for at least thirty minutes prior to venipuncture. In a subsample of 1,047 persons the venous occlusion time was recorded, but not statistically significant correlations with hemorheologic variables were found. Experimental Methods Hemoglobin was measured by cyanate method. Blood was centrifuged at 3,000 g for fifteen minutes to obtain plasma. For the measurement of plasma viscosity a capillary viscometer adjusted to 37°C was used.&dquo; The measurement procedure and sample preparation met the criteria of the International Committee for Standardization in Haematology.’6 Hemoglobin (g/dL) measurements were performed in duplicate, plasma viscosity (mPa.s) in triplicate. For quality control, hemoglobin and plasma viscosity measurements were compared daily to standard solutions. There was no baseline shift during the eight months’ trial period for either variable. The variation coefficient for plasma viscosity in our laboratory has been shown to be 0. 3 % with an intraindividual variation of 1.3 % .&dquo; At irregular intervals, duplicates were measured in a single-blind fashion. BP measurements were done under the standardized conditions of the AHA. IS All BP data reported here are based on the first and fifth phases of the Korotkoff sounds and on the . calculation of the mean of the second and third BP measurements on each occasion. Total serum cholesterol was determined by enzymatic method. Internal and external quality control procedures were carried out. A 12-lead resting ECG was also recorded. Statistical Analysis Data are presented as the mean and one standard error of the mean (SEM). Groups were compared by two-tailed unpaired t-test. The null hypothesis was rejected when p was less than 0.05. venous

Results

Hemoglobin levels were similar in different age groups in either sex.

.

There was,

however,

990

FIG. 5. Plasma viscosity (mPa.s) in men with a single cardiovascular risk factor. For explanations, see Figure 3.

the well-known

sex

difference. This

FIG. 6. Plasma viscosity (mPa.s) in women with a single cardiovascular risk factor. For explanations, see Figure

3.

applied to both the group of healthy subjects and the total

study population. healthy subjects was 1.23 ±0.003 mPa. s for both sexes. nor in women was a significant change with age seen. In the total a population, however, continuous increase of plasma viscosity with age in both sexes was found (Figures 1 and 2). In relating hemoglobin to cardiovascular risk factors, only in smoking women was a statistically significant increase found. In all other subgroups a trend for elevation was seen that failed to reach statistical significance (Figures 3 and 4). In several subgroups, however, numbers were rather small. In men, plasma viscosity was statistically significantly elevated in hypercholesterolemia, untreated hypertension, and smoking but not in obesity. In women, a significant increase was found in hypercholesterolemia and obesity, while untreated hypertension and smoking were not associated with significant differences from control values (Figures 5 and 6). Again, numbers in these groups were small. Plasma viscosity was significantly increased in men after MI and stroke (p < 0.001) whereas this difference was smaller for women and did not reach statistical significance in those who had suffered MI (Figure 7). In patients with chronic MI there was a tendency to increased hemoglobin levels in both sexes. In men who had suffered from stroke a statistically significant increase in hemoglobin was found, whereas for women no difference was seen (Figure 8). Tables I and II show selected patient characteristics and the distribution of cardiovascular risk factors in patients after MI and stroke. Finally, similar findings could be demonstrated in patients with AP and PAD. In these groups plasma viscosity was statistically significantly elevated in both sexes, except in women with angina (Figure 9), and hemoglobin again showed a tendency to increased values (Figure 10). The

value for Neither in men mean

plasma viscosity

in

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Discussion

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Our results show that plasma viscosity is not dependent on sex and does not vary with age in a subgroup of participants defined as healthy. In the total study population a continuous increase of plasma viscosity with age is seen, possibly reflecting the increasing prevalence of chronic degenerative disorders with higher age, including cardiovascular risk factors and diseases. Hemoglobin, on the other hand, does not vary significantly with age in healthy persons

991

FIG. 7. Plasma viscosity (mPa.s) in patients after MI and stroke. Empty bars=men; dark bars=women. Mean

FIG. 8. stroke. For

Hemoglobin (g/dL) in patients explanations, see Figure 7.

after MI and

t SEM.

and in the total male population. In women, a trend to higher values is seen after the menopause. For the purpose of rheologic studies, hemoglobin is interchangeable with hematocrit, both being the most important determinants of blood viscosity. There is evidence that classical cardiovascular risk factors like smoking, 19-21 hypertension,22’23 hypercholesterolemia,24,25 and to a certain extent obesityz6 are associated with impaired blood fluidity. This includes an increase of blood and plasma viscosity, hemoglobin (or hematocrit), and red cell aggregation, as well as a decrease in red cell deformability. However, not all parameters of blood rheology have been found by different investigators to be pathologically altered. In our study, there were only trends for an increase of hemoglobin in most subgroups of participants with risk factors for cardiovascular diseases. The discrepancy of our and previous data needs to be investigated in further detail. On the other hand, plasma viscosity clearly discriminated participants with risk factors from those without. Only untreated female hypertensives and smoking women showed no statistically significant increase, owing possibly to small numbers in these subgroups and short duration of smoking. It has to be stressed that in our stratified analysis, only a single cardiovascular risk factor was allowed in each subgroup. It is a drawback of these preliminary analyses that the results have not yet been statistically formally controlled for age, although we were able to demonstrate that plasma viscosity does not vary with age in healthy persons. Patients with acute MI27-30 and those after stroke32 were also found to have abnormal blood rheology. Lowe33 was able to correlate blood viscosity with the extent of coronary artery lesions. Since most patients after MI or stroke are still burdened with one or more cardiovascular risk factors, it is difficult to decide whether decreased blood fluidity is due to their presence or must be seen as an indicator of the underlying, ongoing atherosclerotic process itself. In our study, risk factors in patients after MI and stroke were equally distributed (Table II) . Furthermore controlling for the effect of cardiovascular active medication in these patients makes it even more difficult to estimate the real impact of disturbed blood fluidity in post-MI and stroke patients (Table I). There are data in the literature suggesting that the extent of decreased blood fluidity in the acute phase of these diseases may be a marker of subsequent clinical complications like ar-

992

FIG. 9. Plasma viscosity (mPa.s) in patients with chronic angina pectoris (AP) or peripheral arterial disease (PAD). Empty bars=men; dark bars=women. Mean

Fm. 10. Hemoglobin (g/dL) in patients with AP PAD. For explanations, see Figure 9.

or

+SEM.

rhythmias2g and may determine the size of necrosis in the myocardium or the brain.29’3° Patients with angina34’35 and claudicants36-39 are also known to have increased blood viscosity. In our study, where these diseases were identified solely by means of a questionnaire, plasma viscosity in particular was found to be statistically significantly raised, predominantly in men. It is known, however, that these conditions are difficult to assess in females by questionnaire. 40 Clinical studies in angina have shown that the onset of acute symptoms is associated with an increasing tendency toward blood clotting activation . 34,35 Recently published results from epidemiologic studies&dquo;’ suggest that at least some of the effects of cardiovascular risk factors may be mediated through increased plasma fibrinogen levels. Fibrinogen is the mean determinant of plasma viscosity and has been found to contribute independently to the explanation of the incidence of myocardial infarction and stroke in these studies. The mechanisms of impaired blood fluidity in cardiovascular risk factors and chronic disorders have not been fully understood to date. It has been suggested that atherogenesis represents an abnormal form of repair of intimal injuries.4’ There are predilection sites in particular in the coronary artery tree, where local flow conditions may alter endothelial metabolism.42 In areas where coronary arteries are branching off, even periodic changes of flow direction may occur, disturbing the connecting forces of endothelial cells and leading to chronic stimulation of their metabolism as shown by dramatically increased replication rates of these cells. 43,44 A recent study45 showed that oscillating shear forces lead endothelial cells to increased production of histamine, opening of intercellular spaces, and dissociation of actin filaments. Thus, a disorganized endothelium would no longer be an active barrier for plasma proteins. Protein adsorption also takes place on the surface of blood cells. Thus, it represents a common phenomenon in both-blood cells and endothelial surface. Plasmatic depositions or adsorptions and their interactions on the endothelium may play a key role in the early development of atherosclerotic lesions. Such adsorptions taking place on blood cells are undoubtedly a major determinant of hemorheologic variables. Hence, a link between initial endothelial changes in early atherosclerosis and alteration of hemorheologic parameters is conceivable.

993 TABLE I Selected characteristics of patients after myocardial infarction (MI) and stroke

TABLE II

Cardiovascular risk factors persisting after infarction (MI) and stroke

*BMI=body

mass

index

myocardial

(kg/m2)

Fibrinogen deposits have been identified in atherosclerotic plaques, where they are thought to play an important role in the early development of atherosclerosis.4’ A possible pathophysiologic pathway by which tissue reactions like atherosclerosis might influence circulating fibrinogen levels has been reported.46 The local production of fibrinogen degradation products (particularly fragment D) stimulates macrophages to release a regulator protein (hepatocytestimulating factor) that increases hepatic synthesis of fibrinogen and other acute phase proteins. Moreover, there are data suggesting that decreased fibrinolysis might play a role in this 47

process. It is possible,

therefore, that atherosclerosis and its complications provoke this acute phase

These changes in fibrinogen levels may precede the clinical manifestations of cardiovascular disorders; most of the presently available data are consistent with this hypothesis. Raised levels of plasma fibrinogen may, however, be more than merely a marker for an underlying degenerative process of the vascular system. Plasma proteins, in interaction with the endothelium, could play a causal role in the pathogenesis of atherosclerosis. Hemorheologic parameters could therefore serve as an easily assessible indicator of the individual’s cardiovascular risk. Therapeutic consequences drawn from these insights should first imply reduction of cardiovascular risk factors. Experimental data support the view that abstention from smoking , 20 reduction of body weight,48 treatment of hypertension,49 and lowering of total serum cholesterol50 are associated with normalization of blood rheology. Lowering plasma fibrinogen and thereby improving blood viscosity by thrombolysis in acute MI has been shown to be clinically effective.5’ Similar findings emerged from applying rheologic therapy in acute stroke,52 in unstable (spontaneous) angina 51’ and in peripheral arterial occlusive disease.37.55

reaction, constituting

a

secondary phenomenon.

Conclusion

Hemorheologic considerations should, therefore, be given more thought in the management of clinical complications of premature atherosclerosis. They may be relevant for the

994

therapy of these widespread diseases and might even offer a causal approach to atherosclerotic vascular damage. .. , .. , ,’ Acknowledgment ,

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The authors would like to thank Mr. H. Schneller for his excellent

graphic

work.

Wolfgang Koenig, M. D. Division of Cardiology Dept. of Internal Medicine University Hospital Steinhoevelstr. 9 D-7900 Ulm/West

Germany

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