Relationship between blood viscosity and existence and severity of carotid artery plaque

Abstract

BACKGROUND:

Accumulating evidence shows that the increase in blood viscosity (BV) is an independent risk factor for atherosclerosis and its related diseases, but as far as we know, there are few studies on the relationship between blood viscosity and carotid plaque severity. Therefore, we aimed to investigate the relationship between blood viscosity and the presence of carotid plaques, and further explore its relationship with the severity of carotid plaques.

METHODS:

We retrospectively analyzed the data of consecutive subjects in the physical examination center of the Affiliated Hospital of Ningbo University Medical College from January 2022 to May 2022.

The parameters of blood viscosity include the whole blood viscosity (WBV) at high, middle, and low shear rate, plasma viscosity (PV), hematocrit (HCT), rigidity “k”, rigidity index (RI), aggregation index (AI) and electrophoresis rate (ER), and standardized BV calculated by Quemada’s equation were included in the study. Carotid plaque score (CPS) was used to measure the severity of carotid artery disease, and participants were divided into mild, moderate, and severe groups according to the quartile of the score. Independent samples t-test and one-way ANOVA were used to compare normally distributed continuous variables between two or more independent groups, respectively. Binary logistic regression was used to evaluate the risk factors of carotid plaque.

RESULTS:

314 men were enrolled in the study, of which 165 participants were diagnosed with Carotid artery plaque (CAP) (66.9%). Compared with the CAP- group, the WBV and PV of the CAP+group decreased, but the difference only existed in the PV (p = 0.001). However, standardized BV values (HCT set at 0.45) were higher in the CAP+group than in the CAP- group (3.8643±0.35431vs 3.9542±0.64871, p = 0.188). Regarding the rigidity and aggregation of RBC, the parameters including rigidity “k”, RI, AI and ER increased in the CAP+group compared with the CAP- group. The difference was statistically significant in k and ER (p = 0.04, p = 0.009). To assess the severity of carotid plaque, we divided the participants into mild, moderate, and severe groups by using the tertile of CPS value. The mild group was defined as CPS≤0.5 (n = 108), the moderate group as 0.5 < CPS≤1.7 (n = 105), and the severe group as CPS > 1.7 (n = 101). It was found that WBV and PV decreased with the increase of plaque severity, but the difference among the three groups was significant in PV (F = 8.073, p < 0.0001). In addition, with the severity of plaque from mild to severe, standardized BV gradually increased, which were 3.8611±0.34845, 3.8757±0.36637, 3.9007±0.38353 respectively. The difference between the groups was close to statistically significant (F = 2.438, p = 0.089). The values of parameters describing erythrocyte aggregation and rigidity increased among the mild, moderate, and severe groups. The difference was statistically significant in RBC rigidity “k” and ER of RBC (F = 3.863, p = 0.022; F = 5.897, p = 0.003, respectively).

CONCLUSION:

Increased blood viscosity is a risk factor for carotid plaque, but its increase may be hidden by decreased hematocrit. Therefore, it is necessary to comprehensively analyze various parameters of blood viscosity, such as the standardized BV calculated by Quemada’s equation, which may provide more useful reference value.

Keywords

Carotid plaque blood viscosity hematocrit Quemada’s equation

1 Introduction

Blood health seriously affects the best physiological function, so the abnormality of blood physical characteristics is related to the pathogenesis of various diseases [1]. Shear stress is particularly important in the circulatory system because of its profound influence on blood cells and blood vessel walls. It is generally believed that low shear stress induces atherosclerosis [2 –4]. Blood viscosity (BV) is derived from the shear rate-shear stress relationship [5]. Compared with the fluid with lower viscosity, the fluid with higher viscosity exhibits smaller deformation and slower flow and requires higher external force to maintain the flow.

Hence, increased blood viscosity is associated with atherogenesis. In addition, numerous clinical evidence also supports this point [6 –8]. As atherosclerosis is a generalized disease that affects many arterial beds at the same time, carotid artery assessment creates a unique opportunity to reflect and track atherosclerotic diseases because it is cheap, non-invasive and easy to obtain [9]. In this study, we investigated the relationship between blood viscosity and the presence of carotid artery plaque (CAP), and further explored its relationship with the severity of carotid plaques.

2 Material and methods

2.1 Study population

From January 2022 to May 2022, a total of 328 continuous participants completed physical examination, including carotid artery ultrasound examination, at the physical examination center of the Affiliated Hospital of Ningbo University Medical College. In women’s physical examination package, ultrasound examination focuses more on gynecology or breast than carotid artery. Due to under-representation of the female sex in this cohort (only 14 women), women were excluded from the analysis, rendering a final sample size of 314 male participants. This study was approved by the Medical Ethics Committee of the Affiliated Hospital of Medical College of Ningbo University. The need for informed consent was waived by the Medical Ethics Committee of the Affiliated Hospital of Medical College of Ningbo University due to the study’s retrospective nature. The formulation of this study scheme was in accordance with the requirements of the Declaration of Helsinki of the World Medical Association.

2.2 Methods

Weight and height were measured using a standardized approach, followed by the calculation of body mass index (BMI) in kg/m2. Blood pressure was obtained as the mean of 3 consecutive measurements with an OMRON M10-IT automatic oscillometric sphygmomanometer (OMRON Healthcare Co. Ltd., Kyoto, Japan), with the individuals resting in a seated position for 5 min between readings. Pulse pressure (PP) difference was defined as the difference between systolic blood pressure and diastolic blood pressure [10]. Venous blood for creatinine, lipid, and viscosity analyses was collected after overnight fasting (>8 h). Whole blood was measured using an automated blood rheology analyzer (ZONCI Technology Co., Ltd., Beijing, China). BV levels at 5 s ^–1 are reported as low-shear viscosity, BV measurements at 30 s ^–1 are reported as middle-shear viscosity and BV measurements at 200 s ^–1 are reported as high-shear viscosity. For plasma viscosity (PV) the average of measurements at shear rates of 200 s^–1 was calculated. The coefficient of variation of this method ranges between 2.69and 3.2% (Within the range of CV value (4.29%) set by the manufacturer). The deformation ability of red blood cells under applied shear stress is expressed by the red blood cell (RBC) rigidity index (RI), which is calculated by the following formula [11]: $RI = \frac{{WBV}_{, 200 s^{- 1}} - PV}{PV} * \frac{1}{HCT}$

Apparently, an increase in the RBC RI would lead to a reduction in the RBC deformability.

In addition, the RBC aggregation index (AI) and electrophoresis rate (ER) were introduced to measure the aggregation degree of RBC. RBC AI is calculated from low shear viscosity ratio (1s^–1) to high shear viscosity (200s^–1) [11]. It reflects the objective index of the degree of erythrocyte aggregation, and higher indicates enhanced aggregation. RBC ER represents the aggregation degree of RBC per unit HCT (1%), and is calculated by the following formula: $ER = \frac{AI}{HCT} * 100 %$ ’

Standardize BV for hematocrit 45% was calculated according to Quemada’s Equation [12]. $BV = PV * {(1 - 0.5 k φ)}^{- 2}$ –where φ is the hematocrit, at this time, a fixed value of 0.45 would be taken.

–k is a shear-dependent parameter quantifying the contribution of erythrocyte rheological properties to whole blood viscosity, which can be calculated by the transformation equation of Quemada’s equation. $k = 2 * [1 - {(\frac{{WBV}_{, 200 s^{- 1}}}{PV})}^{- 0.5}] {* φ}^{- 1}$

–At the high shear rate used here k is representative of red cell rigidity

Plaque was defined using the Mannheim criteria as a focal structure that protruded into the arterial lumen by 50% of the surrounding intima-media thickness or that was≥1.5 mm in thickness from the media-adventitia border to the intima-lumen border [13]. The carotid plaque score (CPS) was used to measure the severity of carotid atherosclerosis. The maximum thickness sum of plaques on the common and internal carotid artery, a total of three segments, was calculated. Segment 1 was the region of the internal carotid arteries (ICA) that was < 15 mm distal to its bifurcation from common carotid artery. Segment 2 was the region of the ICA and the common carotid artery (CCA) that was < 15 mm proximal to the bifurcation. Segment 3 was the region of the CCA that was > 15 mm and < 30 mm proximal to the bifurcation. The length of individual plaques was not considered in determining the CPS. The opposite side was calculated in the same way, and the values on both sides was added to the final score.

2.3 Statistical analysis

All statistical analyses were performed using SPSS 26.0 for Mac (IBM Corp., Armonk, New York, USA) and GraphPad Prism version 9.0 for Mac (GraphPad Software, San Diego, California, USA). The normality of the data was visually checked by Q–Q diagram. Independent samples t-test and one-way ANOVA were used to compare normally distributed continuous variables between two or more independent groups, respectively. Homogeneity of variance was evaluated by Levene’s test. Post-hoc testing with Bonferroni correction (equal variance) or the Tamhane’s test (unequal variance) was used for multiple comparisons. Binary logistic regression was used to evaluate the risk factors of carotid plaque. Level of significance was set at p < 0.05.

3 Results

Overall, 314 participants were enrolled in this study. Table 1 shows the characteristics of the examined population, divided according to the presence or absence of arterial plaque. Carotid plaque was diagnosed in 165 patients (66.9%). Subjects with carotid plaques tend to be older, have greater pulse pressure differences, and have higher creatinine (p < 0.001, p < 0.001, p = 0.011, respectively). Compared with the negative group, patients in the CAP positive group had slightly higher BMI and more dyslipidemia, but the difference was not statistically significant (p = 0.68, 0.199, respectively). It shows that values of hematocrit and RBC count are significantly higher in CAP- group compared to that in CAP+group (p = 0.001, 0.034, respectively), and there was no difference in mean cell volume (MCV) between the two groups (p = 0.378). It is worth noting that the glycated hemoglobin in CAP+group was significantly higher than that in CAP- (p = 0.002).

Table 1
Characteristics of the study participants

Total (n = 314) CP –(n = 104) CP + (n = 210) p

Age (year) 69.05±10.391 63.38±11.68 71.86±8.401 <0.0001

BMI (kg/m²) 24.57±2.91 24.47±2.70 24.62±3.0 0.68

PP (mmHg) 63.53±18.55 56.09±13.84 67.21±19.487 <0.0001

HCT (%) 0.44375±0.48403 0.45269±0.030409 0.43932±0.04047 0.001

HbA1 (%) 7.392±0.9899 7.172±0.7407 7.501±1.0775 0.002

NRBC (10⁶/μL) 4.7868±0.48403 4.8595±0.36216 4.7507±0.53131 0.034

MCV (FL) 92.862±4.7295 93.161±3.6402 92.714±5.1867 0.378

Creatinine (μmol/L) 86.508±22.6078 82.757±12.7935 88.366±25.9676 0.011

Dyslipidemia, n (%) 314 (100%) 104 (33.12%) 210 (66.88%) 0.199

WBV at LSR (mPa·s) 8.7908±0.9103 8.899±0.83281 8.7372±0.94364 0.138

WBV at MSR (mPa·s) 5.0819±0.51131 5.1578±0.46437 5.0444±0.53007 0.064

WBV at HSR (mPa·s) 3.819±0.39975 3.8818±0.36497 3.788±0.41321 0.05

PV (mPa·s) 1.413±0.03522 1.4216±0.02866 1.4088±0.03738 0.001

Standardize BV (mPa·s) 3.9244±0.56931 3.8643±0.35431 3.9542±0.64871 0.188

RBC rigidity

k 1.7638±0.15131 1.7411±0.12213 1.7750±0.16295 0.04

RI 3.8362±0.51059 3.8198±0.46067 3.8444±0.53446 0.689

RBC aggregation

ER (%) 11.8309±1.68176 11.4799±1.47142 12.0047±1.75415 0.009

AI 5.2014±0.48299 5.1648±0.46305 5.2195±0.49264 0.346

CPS 1.446±1.6074 0 2.161±1.5213

	Total (n = 314)	CP –(n = 104)	CP + (n = 210)	p
Age (year)	69.05±10.391	63.38±11.68	71.86±8.401	<0.0001
BMI (kg/m²)	24.57±2.91	24.47±2.70	24.62±3.0	0.68
PP (mmHg)	63.53±18.55	56.09±13.84	67.21±19.487	<0.0001
HCT (%)	0.44375±0.48403	0.45269±0.030409	0.43932±0.04047	0.001
HbA1 (%)	7.392±0.9899	7.172±0.7407	7.501±1.0775	0.002
NRBC (10⁶/μL)	4.7868±0.48403	4.8595±0.36216	4.7507±0.53131	0.034
MCV (FL)	92.862±4.7295	93.161±3.6402	92.714±5.1867	0.378
Creatinine (μmol/L)	86.508±22.6078	82.757±12.7935	88.366±25.9676	0.011
Dyslipidemia, n (%)	314 (100%)	104 (33.12%)	210 (66.88%)	0.199
WBV at LSR (mPa·s)	8.7908±0.9103	8.899±0.83281	8.7372±0.94364	0.138
WBV at MSR (mPa·s)	5.0819±0.51131	5.1578±0.46437	5.0444±0.53007	0.064
WBV at HSR (mPa·s)	3.819±0.39975	3.8818±0.36497	3.788±0.41321	0.05
PV (mPa·s)	1.413±0.03522	1.4216±0.02866	1.4088±0.03738	0.001
Standardize BV (mPa·s)	3.9244±0.56931	3.8643±0.35431	3.9542±0.64871	0.188
RBC rigidity
k	1.7638±0.15131	1.7411±0.12213	1.7750±0.16295	0.04
RI	3.8362±0.51059	3.8198±0.46067	3.8444±0.53446	0.689
RBC aggregation
ER (%)	11.8309±1.68176	11.4799±1.47142	12.0047±1.75415	0.009
AI	5.2014±0.48299	5.1648±0.46305	5.2195±0.49264	0.346
CPS	1.446±1.6074	0	2.161±1.5213

AI: RBC aggregation index; BMI: body mass index; BV: blood viscosity; CPS: carotid plaque score; ER: RBC electrophoresis rate; HCT: hematocrit; HbA1: glycated hemoglobin; HSR: high shear rate; k: rigidity “k”; LSR: low shear rate; MSR: middle shear rate; MCV: mean cell volume; NRBC: RBC count; RI: RBC rigidity index; PV: plasma viscosity; PP: pulse pressure; WBV: whole blood viscosity.

Significantly, the value of plasma viscosity was lower in the CAP+group than that in the CAP- group (p = 0.001) (Table 1). In addition, the whole blood viscosity including low shear, medium shear and high shear was lower in CAP+group than in CAP- group, although the difference was not statistically significant (p = 0.138, p = 0.064, p = 0.05, respectively). In contrast, standardized BV values (HCT set at 0.45) were higher in the CAP+group than in the CAP- group (3.8643±0.35431vs 3.9542±0.64871, p = 0.188) (Table 1). Regarding the rigidity and aggregation of RBC, the parameters including k, RI, AI and ER increased in the CAP+group compared with the CAP- group. The difference was statistically significant in k and ER (p = 0.04, p = 0.009) (Table 1).

Binary logistic regression analysis showed that the whole blood viscosity, including at low, middle, high shear rate and the plasma viscosity were negatively correlated with the existence of CAP (Table 2). This correlation was statistically significant in plasma viscosity (p = 0.003), but the correlation was not significant after adjusting for age (Data not shown in table). On the contrary, standardized BV was positively correlated with CAP, that is, for every 1 increase in standardized BV, CAP risk increased by 1.479 times.

Table 2

Binary univariate regression: effect of blood viscosity on CAP

	odds ratio	95% CI	p		odds ratio	95% CI	p
WBV at LSR	0.821	0.632–1.066	0.139	k	5.063	0.804–31.887	0.084
WBV at MSR	0.645	0.405–1.028	0.065	RI	1.101	0.690–1.757	0.688
WBV at HSR	0.553	0.305–1.003	0.051	ER	1.219	1.048–1.417	0.010
Plasma viscosity	0	0–0.021	0.003	AI	1.267	0.775–2.072	0.345
Standardize BV	1.479	0.772–2.834	0.238

Abbreviations as in Table 1.

The rigidity and aggregation parameters of erythrocytes, namely k, RI, AI, and ER, were positively correlated with the existence of CAP (Table 2). Besides, this correlation was significant in ER (p = 0.01), but after adjustment for age, the correlation was insignificant (Data not shown in table) (Table 2).

To assess the severity of carotid plaque, we divided the participants into mild, moderate, and severe groups by using the tertile of CPS value. The mild group was defined as CPS≤0.5 (n = 108), the moderate group as 0.5 < CPS≤1.7 (n = 105), and the severe group as CPS > 1.7 (n = 101) (Fig. 1). One way ANOVA was used to compare the mean values of the three groups. It was found that there was no significant difference in the high, middle, and low shear of whole blood viscosity among the three groups, but there was significant difference in plasma viscosity (F = 8.073, p < 0.0001) (Fig. 1). Levene test for homogeneity was significant (p = 0.002), as a result Tamhane’s test was used for multiple comparisons, which showed that plasma viscosity was significantly different between two pairs i.e., mild group to moderate group and mild group to severe group (p = 0.046, 0.001, respectively) (Fig. 1). Strikingly, the value of plasma viscosity gradually decreased as the severity of carotid plaque increased. In the mild, moderate, and severe groups, the plasma viscosity was 1.4226±0.02882, 1.4124±0.03221 and 1.4035±0.04151, respectively. With the severity of plaque from mild to severe, standardized BV gradually increased, which were 3.8611±0.34845, 3.8757±0.36637, 3.9007±0.38353 respectively. The difference between the groups was close to statistically significant (F = 2.438, p = 0.089) (Fig. 1).

Fig. 1

Blood viscosity levels grouped by severity of CAP. *p < 0.05; **p < 0.01.

In terms of erythrocyte parameters, hematocrit gradually decreased with the increase of plaque severity, which were 0.4537±0.030558, 0.44311±0.034347 and 0.43376±0.04545, respectively (Fig. 1). In mild group and severe group, the difference was statistically significant (p = 0.001). We found that the values of parameters describing erythrocyte aggregation and rigidity increased among the mild, moderate, and severe groups. The difference was statistically significant in RBC rigidity “k” and ER of RBC (F = 3.863, p = 0.022; F = 5.897, p = 0.003, respectively). Post-hoc multiple comparisons showed that ER in moderate group and severe group was significantly higher than that in mild group (p = 0.046, p = 0.001, respectively), and RBC rigidity “k” in the severe group was significantly higher than that in the mild group (p = 0.027) (Fig. 1).

4 Discussion

In this cross-sectional analysis, we reported that under natural HCT, WBV and presence and severity of CAP tended to be negatively correlated, while under fixed HCT, blood viscosity was positively correlated with the presence and severity of CAP. HCT decreased in the CAP+group. In addition, in the CAP+group, the rigidity and aggregation of RBCs were higher.

It has long been believed that the increase of blood viscosity has a negative impact on tissue perfusion and the occurrence of atherosclerosis [14, 15]. A previous study showed that there was a strong association between blood viscosity and the elasticity index of the common carotid artery [16]. In our study, however, the opposite results emerged. We found that WBV and PV appeared to be negatively correlated with the presence and severity of CAP. In fact, a number of recent studies have also challenged the previous view. Point out that the opposite situation, that is, reducing blood viscosity, such as hemodilution, has not been proven to provide a benefit [17, 18]. Furthermore, a study including 451 patients who underwent selective coronary angiography showed that blood viscosity was not related to the degree of coronary artery and carotid atherosclerosis [19]. So, is blood viscosity factor a foe or a friend of arterial plaque?

To explain the phenomenon, we further analyzed other parameters of blood viscosity, such as hematocrit, Standardize BV at 0.45 HCT, erythrocyte rigidity and aggregation.

AI and RI represent the aggregation and rigidity of RBCs under natural HCT, while ER and rigidity “k” are the corresponding parameters after standardized HCT, which are adopted by us. We found that in the CAP+group or the group with higher plaque severity, RBCs had higher rigidity and aggregation. Especially after the standardized HCT, that is, the rigidity “k” and ER of RBCs increased more significantly in CAP+group. Obviously, erythrocyte deformability (represented by rigidity) and aggregation are important determinants of blood viscosity. When the deformability of red blood cells decreases (that is, the rigidity increases) or the aggregation increases, the blood viscosity value should increase. Then in our result analysis, we found a different result, that is, the RBCs deformability decreased, the aggregation increased, and the measured WBV decreased.

As is known to all, WBV is determined mainly by plasma viscosity, temperature, hematocrit, shear-induced deformation of red cells, and erythrocyte aggregation [20]. This means that although the deformability of RBCs is weakened and their aggregation is enhanced, if there is a decrease in PV and/or HCT, it may occur, and the increase in WBV is hidden. Gordon Law once called it “covertly abnormal blood viscosity” [21].

Therefore, blood viscosity may not be beneficial to carotid plaque, but its increase may be hidden by the decrease of HCT. We further calculated the blood viscosity when the fixed HCT value was 0.45 using Quemada’s Equation. The results showed that the Standardize BV increased in the CAP+group or the group with more severe plaque, which also proved our above analysis.

In addition, another thing to note is why HCT decreases in the CAP+group or the group with higher plaque severity. The HCT is regulated by erythropoietin (EPO). In a review, Dr. Reinhardt proposed that blood viscosity may directly affect EPO and proposed some evidence [22]. For example, sickle cell disease is a disease in which the blood viscosity increases due to the decreased of erythrocyte deformability, and its EPO level is lower than the expected level of anemia [23]. Another strong evidence was that in the exchange transfusion experiment of rats, the extracted blood was replaced by a solution with different viscosity at the same volume. It was found that the EPO reaction strongly depends on the solution viscosity. Therefore, the decrease of HCT in our study population may be the automatic regulation mechanism of blood viscosity, that is, the decrease of HCT is a compensatory regulation of the increase of blood viscosity. Then, this compensatory regulation leads to a decrease in whole blood viscosity.

To our knowledge, this is the first study that explores the relationship between blood viscosity and carotid plaque severity (according to carotid plaque score).

Our study had several limitations. First, it is a cross-sectional study and cannot make a causal analysis. And we point that the increase of WBV is hidden by the decrease of HCT, but how much of the increase is hidden cannot be reached in this study. Second, there may be hidden selection bias due to the single-center study. Furthermore, our sample is composed of men, which limits generalizability of the findings, especially to women.

5 Conclusion

In conclusion, increased blood viscosity is a risk factor for carotid plaque, but its increase may be hidden by decreased hematocrit. Therefore, it is necessary to comprehensively analyze various parameters of blood viscosity, such as the standardized viscosity calculated by Quemada’s equation, which may provide more useful reference value.

Footnotes

Acknowledgments

This work was supported by the Science and Technique Plans of Ningbo City (Grant No. 2019C50080).

Conflict of interest

No potential conflicts of interest relevant to this article were reported.

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