Katarzyna Nabrdalik , Artur Chodkowski , Wojciech Bartman , Andrzej Tomasik , Hanna Kwiendacz , Tomasz Sawczyn , Michał Kukla , Władysław Grzeszczak and Janusz Gumprecht

Pentraxin 3 and atherosclerosis among type 2 diabetic patients

De Gruyter Open | Published online: April 24, 2017

Abstract

Type 2 diabetes is contemporarily a major social and epidemiological problem and among others is a strong risk factor for cardiovascular diseases. Pentraxin 3, a potential early biomarker of atherosclerosis, is an acute-phase reactant produced by the peripheral tissues where the inflammation takes place. In this study we examined a group of patients with type 2 diabetes with and without cardiovascular complications compared to persons with normal glucose tolerance (patients with cardiovascular complications and healthy volunteers). Plasma pentraxin 3 concentration as well as some basic biochemical blood analysis were performed. Moreover, transcranial and carotid Doppler ultrasound examination as well as transthoracic echocardiography were performed. It turned out that there was an association of plasma pentraxin 3 concentration and carotid atherosclerosis found in the control group of patients with cardiovascular complications but with normal glucose tolerance. In the group of patients with type 2 diabetes and cardiovascular complications we have found an association of plasma pentraxin 3 concentration with diastolic left ventricular dysfunction. Additionally, in the group of patients with type 2 diabetes without cardiovascular disease plasma pentraxin 3 concentration was associated with elevated urinary albumin creatinine ratio. Further studies, on a larger group of patients, are required to confirm these observations.

1 Introduction

Nowadays, type 2 diabetes (T2DM) is a major social and epidemiological problem. Today, 415 million people worldwide have diabetes and by the year 2040 this number will rise to 642 million. Currently, due to advances in pharmacotherapy, lifespan of people with diabetes is prolonged but in turn it is indispensably related to accelerated development of atherosclerosis and vascular complications which can lead to disability, compromised quality of life and premature death. It is worthwhile to know that atherosclerosis is not only a result of hyperglycemia but many other factors among others insulin resistance, dyslipidemia, and hypercoagulability. These are cardiovascular diseases (CVD) that still remain leading causes of death worldwide despite tremendous progress in their prevention and treatment [1]. One can assess the cardiovascular risk in patients with diabetes using the risk scores for general population (e.g Systematic COronary Risk Evaluation (SCORE) or less popular scales dedicated for individuals with diabetes (i.e. among others: UKPDS risk engine, Diabetes Audit and Research in Tayside, Scotland (DARTS), Swedish National Diabetes Register (NDR), Atherosclerosis Risk in Communities (ARIC) [2]. Chronic hyperglycemia, among other factors like hypertension, tobacco use, lack of physical activity, unhealthy diet, and hypercholesterolemia, is a strong risk factor for cardiovascular diseases. Moreover, Juutilainen et al., on the basis of an 18-year prospective population-based study in Finnish subjects, suggest T2DM to be coronary heart disease equivalent. In other words, diabetes without prior myocardial infarction and prior myocardial infarction without diabetes indicate similar risk for coronary heart disease death in men and women [3]. Since well-established risk factors for CVD are not sufficient to identify all patients at risk, there is a need for additional tools that help identify individuals at high risk for CVD [4]. Biomarkers are one such tool that can augment clinical risk stratification [5]. Even though there are some cardiovascular biomarkers identified, they have only modest predictive value and therefore there is a need to identify ones from new biological pathways [4]. It is well known that the immune and inflammatory response take part in the development of atherosclerotic plaques from the very beginning (the subclinical injuries of the endothelial cells) up till the acute clinical manifestation of the disease. In accordance with current knowledge, moderate inflammation in the arterial wall can lead to the acceleration of the asymptomatic atherosclerotic changes and a rapid and more intensive inflammation precedes the final lesion of the atherosclerotic plaque. It remains unclear whether the inflammatory factors are the trigger factors in the pathogenesis of cardiovascular diseases or only the indicators of the ongoing inflammation. The elements of the innate immune response, such as e.g. C-reactive protein (CRP) and recently pentraxin 3 (PTX3), have been examined as potential early biomarkers of the atherosclerotic process. PTX3 belongs to the pentraxin protein family, which has been divided into two groups on the basis of the primary structure of the subunit. CRP and serum amyloid P (SAP) belong to the short pentraxins, whereas PTX3 is classified as the long one having pentameric cyclic structure [6]. On the contrary to CRP, mainly produced by hepatocytes, PTX3 is produced by the peripheral tissues (e.g. endothelium, monocytes, macrophages, adipocytes, and smooth muscles cells), where the inflammation takes place. The concentration of PTX3 in the blood rises rapidly about 6-8 hours after episodes like acute myocardial infarction, unstable angina, heart failure or sepsis. An elevated concentration of PTX3 was also found inside atherosclerotic plaques, which suggests that it can be an early biomarker of arteriosclerotic vascular damage. PTX3 initiates the synthesis of tissue factor (TF) and therefore activates the coagulation cascade which can be a proof of its proatherogenic role [6, 7]. Studies by Peri et al. and Latini et al. support the evidence that concentration of PTX3 is not only the early marker of irreversible cardiac damage, but can also predict its future course [8, 9]. Moreover, Hudzik et al. proved that PTX3 may be a potential early marker of cardiovascular risk before the increase of systemic markers like hsCRP [10]. The aim of this study was to evaluate the association of plasma PTX3 concentration with atherosclerosis in the carotid and intracranial arteries as well as systolic and diastolic cardiac function among patients with type 2 diabetes with and without cardiovascular complications. The outcomes were compared to the ones obtained in the group of persons with normal glucose tolerance but with cardiovascular disease and to healthy volunteers.

2 Methods

2.1 Patients

We examined 58 consecutive Caucasian patients visiting the Outpatient Diabetology and Outpatient Neurology Clinics in Zabrze, Poland, and 15 healthy volunteers from February to April 2016. There were 28 patients with T2DM without cardiovascular complications (group I) and 15 patients with type 2 diabetes with cardiovascular complication (group II). The control group consisted of 30 participants with normal glucose tolerance: 15 of them having cardiovascular complications (group III) and 15 healthy volunteers (group IV). The main inclusion criteria for patients from the study groups I and II were type 2 diabetes diagnosis without (group I) and with (group II) macrovascular complications (namely history of myocardial infarction, ischemic heart disease, stroke, atherosclerosis in carotid arteries, or peripheral artery disease). The inclusion criteria for the control group (group III) were as follows: the presence of macroangiopathic complications (namely history of myocardial infarction, ischemic heart disease, stroke, atherosclerosis in carotid arteries, or peripheral artery disease) and normal glucose tolerance. Normal glucose tolerance was assessed based on fasting plasma glucose being in the reference range (70 - 99 mg/dl; 3.9 – 5.5 mmol/l). The volunteers (group IV) were healthy with respect to diabetes and cardiovascular diseases. All subjects with end stage renal disease, heart failure NYHA III and IV, or hepatic cirrhosis were excluded from the study. Moreover, the incidence of myocardial infarction, coronary intervention, or stroke in the last 6 months disqualified patients from participation in the study. Informed consent has been obtained from all individuals included in this study.

Ethical approval: The research related to human use has been complied with all the relevant national regulations, institutional policies and in accordance the tenets of the Helsinki Declaration, and has been approved by the Ethical Committee of Medical University of Silesia

3 TESTS

3.1 Laboratory tests

In order to measure plasma PTX3 concentration and perform basic biochemical blood analysis, 15 ml of venous blood was drawn in a tube containing EDTA. The samples were transported to the laboratory and centrifuged at +4°C and stored at −20°C. Plasma samples of subjects were thawed and analyzed for PTX3 concentrations using a commercially available (Biovendor) enzyme-linked immunosorbent assay (ELISA), according to the manufacturer’s manual and the result was expressed in ng/ml. In addition, we performed basic biochemical blood analysis. Haemoglobin A1c was determined using high-performance liquid chromatography (HPLC) and the outcome was expressed in National Glycohemoglobin Standarization Program/ Diabetes Control and Complications Trial units. Fasting plasma glucose was determined by enzymatic method. Cholesterol and triglycerides were measured using enzymatic methods, with HDL-C (high-density lipoprotein cholesterol) measured after precipitation of VLDL (very low-density lipoprotein). The concentration of LDL-C (low density lipoprotein cholesterol) was calculated using the Friedewald formula. Serum creatinine was measured with Jaffe’s method. The estimated glomerular filtration rate (eGFR) per 1.73m2 was calculated according to MDRD formula. CRP was measured using immunoturbimetry method as well as complete blood count test performed. Urinary albumin creatinine ratio (UACR) was estimated in the first morning urine samples collected during three consecutive days and the general urine analysis was performed in order to detect any infections of the urinary tract.

3.2 Anthropometric and blood pressure measurements

Anthropometric parameters, namely height (m) and weight (kg), were measured by standard methods and the body mass index (BMI) was calculated as weight/height2 (kg/m2). Blood pressure was measured 3 times, each 5 minutes apart in a sitting position by Microlife BP AG1-20 sphygmomanometer. Arterial hypertension was defined as a systolic blood pressure ≥ 140mmHg and/or a diastolic blood pressure ≥ 90 mmHg or treatment with antihypertensive medications.

3.3 Ultrasonography

All the study participants underwent a carotid B-mode ultrasound examination. All the measurements were performed by the same researcher. The carotid arteries were interrogated using a high-resolution ultrasound system Esaote MyLab60 with a linear-array transducer operating at a frequency of 5,6 – 8,0 MHz. Measurement of the carotid intima-media thickness (CIMT) was conducted in accordance with the ultrasound scanning protocol recommended in the Mannheim Intima-Media Thickness Consensus 2006. The transcranial Doppler ultrasound via suboccipital and temporal windows was performed by VIASYS Sonara with a 2MHz ultrasound probe in order to measure mean blood flow velocity (MV), resistance index (RI), and pulsatility index (PI). Transthoracic echocardiography was performed using GE Healthcare Vivid 3 equipment in order to assess the systolic cardiac function by measuring the ejection fraction (EF) by the Simpson method. The assessment of diastolic function was conducted by the measurement of the E/A velocity ratio together with tissue Doppler imaging (TDI). All the measurements were performed by the same researcher.

3.4 Statistical analysis

All statistical calculations were performed using MS Excel 2016 for Windows and SAS v 9.2. The Shapiro-Wilk test for normality was used. Descriptive statistics for continuous parameters of the normal distribution were arithmetic means ± standard deviation (SD) or medians. Categorical variables were absolute value and percentage. The statistical methods applied included Student’s t-test and Kruskal-Wallis analysis for quantitative traits. Multiple regression analysis - the method of least squares - was used. The Wilcoxon rank sum test was used to compare plasma PTX3 concentrations between groups. A p value < 0.05 was considered significant.

4 Results

Basic clinical and anthropometric characteristics of the study population are illustrated in Table 1. Mean PTX3 concentration, ultrasonography measurements of carotid and intracranial arteries, and echocardiographic measurements of systolic and diastolic cardiac function among study participants are presented in Table 2. The difference of mean plasma PTX3 concentration between the four studied groups was not significant (Figure 1). There was a significant association between mean plasma PTX3 concentration and UACR in group I (patients with type 2 diabetes without macrovascular complications). In this group mean plasma PTX3 concentration among the patients with elevated UACR was 0.92 ng/ml (± 0.40) higher when compared to mean plasma PTX3 concentration among patients presenting with albuminuria within a normal range. There was a significant association between mean plasma PTX3 concentration and BMI, eGFR, male gender, and diastolic cardiac function among patients in group II (presenting both with diabetes type 2 and macroangiopathic complications). In this group of patients mean plasma PTX3 among patients with BMI ≥ 30 kg/m2 was 2.22 ng/ml (± 0.70) lower (p=0.0152) compared to people with normal weight and overweight (BMI <30 kg/m2). Additionally, mean plasma PTX3 concentration was 1.42 ng/dl (± 0.36) higher (p=0.0052) among patients with impaired renal function (eGFR 30-60 ml/min/1.73m2) compared to the ones with eGFR > 60 ml/min/1.73m2. Male gender was significantly associated with mean plasma PTX3 concentration, where it was 1.08 ng/ml (± 0.28) higher than in females (p=0.0061). In the analyzed group of patients who had diastolic heart dysfunction, mean plasma PTX3 concentration was 3.2 (± 1.24) lower compared to the ones with normal diastolic cardiac function (p=0.0257). Moreover, higher plasma PTX3 concentration turned out to be almost significantly related to the history of myocardial infarction (p=0.0553) in group II. In group III (patients with cardiovascular diseases and normal glucose tolerance) there was a significant relation between mean plasma PTX3 concentration and the existence of atherosclerosis in the carotid arteries and the difference was of 5.84ng/dl (±0.78) higher in comparison to patients without carotid atherosclerosis (p=0.0049). Among the healthy volunteers (group IV) the relation between smoking habit and PTX3 concentration was analyzed but no differences were found. All findings are summarized in Table 3.

Figure 1 Wilcoxon sum of rank for plasma PTX3 concentration among study groups.Group I - patients with type 2 diabetes without macrovascular complications, Group II - patients with diabetes type 2 and macroangiopathic complications, Group III - patients with macroangiopathic complications but normal glucose metabolism, Group IV - healthy volunteers,

Figure 1

Wilcoxon sum of rank for plasma PTX3 concentration among study groups.

Group I - patients with type 2 diabetes without macrovascular complications, Group II - patients with diabetes type 2 and macroangiopathic complications, Group III - patients with macroangiopathic complications but normal glucose metabolism, Group IV - healthy volunteers,

Table 1

Basic clinical and anthropometric characteristics of the study groups

Group I Group II Group III Group IV
Participants n=100% 28 15 15 15
Female n [%] 16 (57.1%) 4 (26.7%) 10 (66.7%) 8 (53.3%)
Male n [%] 12 (42.9%) 11 (73.3%) 5 (33.3%) 7 (46.7%)
Mean age [years] (± SD) 63.87 (± 1.33) 62.73 (± 1.16) 62.27 (± 1.41) 31.60 (± 0.91)
BMI [kg/m2] (± SD) 27.24 (3.47) 26.45 (1.93) 27.27 (4.34) 23.85 (2.93)
Hypertension n [%] 25 (89.3%) 13 (86.7%) 13 (86.7%) 0
eGFR* [ml/min/ 1.73 m2] (± SD) 83.50 (20.68) 65.85 (13.24) 74.28 (19.69) 97.96 (19.48)
HbA1c (mmol/mol); [%] (± SD) 40; 5.8 (0.60) 51;6.8 (0.82) 31; 5.0 (1.19)
Miocardial infarction n [%] 0 7 (46.7%) 1 (6.7%) 0
Stroke n [%] 0 4 (26.7%) 4 (26.7%) 0
CABG** n [%] 0 4 (26.7%) 1 (6.7%) 0
Cholesterol [mmol/l] (± SD) 5.260 (1.35) 5.751 (1.02) 5.437 (1.28) 5.199 (0.85)
HDL [mmol/l] (± SD) 1.375 (0.36) 1.189 (0.30) 1.483 (0.52) 1.631 (0.37)
LDL [mmol/l] (± SD) 3.063 (1.30) 2.673 (0.54) 3.137 (1.05) 3.197 (0.87)

n - number of patients; ± SD - Standard deviation; BMI - body mass index; eGFR - estimated glomerular filtration rate; CABG - coronary artery bypass grafting; HDL - high density lipoprotein; LDL - low density lipoprotein,

Group I - patients with type 2 diabetes without macrovascular complications

Group II - patients with diabetes type 2 and macroangiopathic complications

Group III - patients with macroangiopathic complications but normal glucose metabolism

Group IV - healthy volunteers

Table 2

Mean PTX3 concentration and ultrasound measurements among study groups

Groups Group I Group II Group III Group IV
n=28 n=15 n=15 n=15
PTX3 [ng/ml] (±SD) 1.09 (0.88) 1.28 (0.69) 1.81 (1.70) 1.31 (1.29)
CCA ITM mean [mm] (±SD) 0.74 (0.15) 0.83 (0.2) 0.73 (0.15) 0.55 (0.10)
CCA ITM max [mm] (±SD) 0.91 (0.16) 1.06 (0.24) 0.89 (0.17) 0.71 (0.14)
ICA MV [cm/s] (±SD) 32.93 (9.3) 35.40 (11.3) 32.61 (11.36) 43.0 (6.09)
MCA PI (±SD) 1.08 (0.34) 1.06 (0.19) 1.03 (0.23) 0.91 (0.20)
MCA RI (±SD) 0.69 (0.29) 0.63 (0.06) 0.61 (0.08) 0.56 (0.05)
EF [%] (Median Q1-Q3) 58 (55-60) 46% (43-53) 54 (50-55) 63 (60-65)
E/A ratio (±SD) 1.11 (0.2) 0.95 (0.22) 0.99 (0.16) 1.31 (0.09)

n - number of patients; SD - standard deviation; PTX3 - pentraxin 3; CCA (ITM) mean - common carotid artery (intima-media thickness) mean; CCA (ITM) max - common carotid artery (intima-media thickness) maximum; ICA (MV) - internal carotid artery (mean velocity); MCA (PI) - medium carotid artery (pulsatility index); MCA (RI) - medium carotid artery (resistance index); E/A ratio - E/A ratio in conventional Doppler echocardiography

Group I - patients with type 2 diabetes without macrovascular complications,

Group II - patients with diabetes type 2 and macroangiopathic complications,

Group III - patients with macroangiopathic complications but normal glucose metabolism,

Group IV - healthy volunteers

Table 3

Linear regression of mean PTX3 and analyzed parameters among study groups

Parameters Group I Group II Group III Group IV
n=28 n=15 n=15 n=15
elevated UACR [mg/g] p=0.0316[1] p=NS p=NS p=NS
BMI [kg/m2] ≥31 p=NS p=0.0152[2] p=NS p=NS
p=NS p=0.0052[3] p=NS p=NS
eGFR [ml/min/1.73m2] male gender p=NS p=0.0061[4] p=NS p=NS
E/A ratio <1 p=NS p=0.0257[5] p=NS p=NS
carotid atherosclerosis p=NS p=NS p=0.0049[6] p=NS

n - number of patients; elevated UACR - Urine Albumin-to-Creatinine Ratio; BMI – body mass index; eGFR - estimated glomerular filtration rate; E/A ratio in conventional Doppler echocardiography; Group I - patients with type 2 diabetes without macrovascular complications; Group II - patients with diabetes type 2 and macroangiopathic complications; Group III - patients with macroangiopathic complications but normal glucose metabolism; Group IV - healthy volunteers

5 Discussion

In this study, there was significantly higher mean plasma PTX3 concentration among patients with carotid atherosclerosis and normal glucose tolerance found when compared to the ones without carotid atherosclerosis, in accordance with other studies performed to date [12-14]. Around 20% of ischemic strokes begin from carotid plaques, which is why appropriate management strategies aimed at effectively minimizing the risk are necessary [11]. Atherosclerosis is the focal expression of a systemic disease affecting medium and large arteries. Scientists are interested in the association between biomarkers of subclinical atherosclerosis, namely carotid intima-media thickness (cIMT), which represents an early stage of the disease, but the association of biomarkers of systemic inflammation with atherosclerosis progression in the carotid artery is not well established [12]. It has been suggested to investigate the predictive value of plasma PTX 3 concentration not in subclinical atherosclerosis but rather in overt cardiovascular disease. One of the studies that support the notion were Bruneck Study and the PLIC Study (more than 2400 subjects) where plasma PTX3 concentration was not an independent predictor of progression of subclinical atherosclerosis in carotid and femoral arteries [13]. Our study is in accordance with this data since there was a trend toward higher mean plasma PTX3 concentration in patients with myocardial infarction history. Unlike Liu et al., who found that plasma PTX3 levels were significantly higher among patients with chronic heart failure than in healthy subjects [14], we did not find systolic heart function to be associated with plasma PTX3 concentration in any of the studied groups. However, in the group of patients with type 2 diabetes and a history of cardiovascular disease, we have found an association of mean plasma PTX3 concentration with diastolic left ventricular dysfunction and to our knowledge this is the first such finding in patients with type 2 diabetes. Similar findings but in the patients without glucose metabolism disturbances come from the study performed by Matsubara et al., who report that plasma PTX3 concentration is an independent inflammatory marker correlated with left ventricular diastolic dysfunction in patients with normal ejection fraction and normal glucose tolerance [15]. Additionally, in the group of diabetic patients without cardiovascular disease, plasma PTX3 concentration was associated with elevated UACR. This finding was also described by Suliman et al., where plasma PTX3 concentration was independently associated with proteinuria, and by Wang et al., who confirmed that plasma PTX3 concentration is associated with diabetic nephropathy [16, 17]. These authors also find a correlation of plasma PTX3 concentration and albuminuria to be independently associated with carotid intima thickness, which was not confirmed in our study. Elevated UACR is one of the earliest clinically detectable abnormalities in diabetic nephropathy and there is also growing evidence that this can be associated with cardiovascular disease [18]. What is also important, we found a significantly higher plasma PTX3 concentration in male than in females. The plasma PTX3 concentration association with gender has been noticed in a study performed on patients from Malaysia; however, the authors found lower concentration of plasma PTX3 in males to be associated with type 2 diabetes and diabetic nephropathy [19]. Since males have a higher prevalence of type 2 diabetes and diabetic nephropathy, an association between plasma PTX3 and gender should be taken into consideration in future studies. Moreover, we have observed that in obese patients with type 2 diabetes mean plasma PTX3 concentration was significantly lower than in the group of people with normal weight and overweight, in accordance with previous studies [19]. We have observed no association with glucose metabolism disturbances although, to our knowledge, there is one study where such a relationship was observed [19]. The present study has a major limitation, which is a low number of patients, that could render some differences insignificant and its findings should be interpreted in light of this.

    Conflicts of interest: authors state no conflict of interest.

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Received: 2016-11-13
Accepted: 2017-2-20
Published Online: 2017-4-24

© 2017 Katarzyna Nabrdalik et al.

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.