PRACA ORYGINALNA

ORIGINAL ARTICLE

DYSLIPIDEMIA AS RISK FACTOR OF ATHEROSCLEROSIS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Tetyana M. Ternushchak, Marianna I. Tovt-Korshynska

Uzhhorod National University, Uzhhorod, Ukraine

ABSTRACT

Introduction: Atherosclerosis is one of the most common co-morbidities observed in chronic obstructive pulmonary disease. A better understanding of mechanisms of atherosclerosis in patients with chronic obstructive pulmonary disease is needed to improve clinical outcomes. 

The aim: to evaluate the plasma levels of lipid parameters, atherogenic indices, systemic inflammatory markers and to assess their relationship with the severity of chronic obstructive pulmonary disease.

Materials and methods: A total of 72 subjects diagnosed with chronic obstructive pulmonary disease and 41 healthy controls, the same gender and age categories, with ≥ 10 pack years smoking history, were followed-up of about 5.8 years. Blood tests with determination of lipid profiles, atherogenic indices and systemic inflammatory markers were conducted in remaining patients who fulfilled inclusion criteria of the study.

Results: Triglyceride, atherogenic index of plasma, cardiogenic risk ratio and atherogenic coefficient values were significantly higher, but high-density lipoprotein cholesterol – significantly lower in patients with chronic obstructive pulmonary disease than in controls. Lipid profiles were similar in lower-risk (stage A and B) and higher-risk (stage C and D) patients with chronic obstructive pulmonary disease. The analysis showed that atherogenic indices and serum high sensitive C-reactive protein were inversely correlated with forced expiratory volume in 1 sec, especially in higher-risk patients with chronic obstructive pulmonary disease (r = – 0.61 p < 0.05; r = – 0.57 p < 0.05; r = – 0.54 p < 0.05 and r = – 0.49 p < 0.05 respectively).

Conclusions: Atherogenic indices and serum high sensitive C-reactive protein can be considered as useful biochemical markers to predict an early stage of atherosclerosis especially in higher-risk patients with chronic obstructive pulmonary disease.

KEY WORDS: atherogenic indices, markers of systemic inflammation, chronic obstructive pulmonary disease

Wiad Lek 2019, 72, 4, 617-621

INTRODUCTION

Chronic Obstructive Pulmonary Disease (COPD) is currently the fourth leading cause of death in the world but is projected to be the third leading cause of death by 2020. More than 3 million people died of COPD in 2012 accounting for 6% of all deaths globally [1].

COPD often co-exists with other co-morbidities that may have a significant impact on prognosis. Cardiovascular disease (CVD) is a major cause of mortality and morbidity in patients with COPD [2].

Several epidemiological studies have also provided strong evidence that people with reduced lung function have an increased risk of CVD. Reduced FEV1 is associated with 2- to 3-fold greater risk of coronary artery disease (CAD), stroke, and sudden cardiac death, independent of cardiovascular risk factors. It has been also shown that COPD patients have increased arterial stiffness defined as increased aortic pulse wave velocity. Therefore, COPD appears to be an important risk factor for CVD [3].

Reduced FEV1 itself is a risk factor for cardiovascular mortality in patients of COPD irrespective of conventional risk factors. Every 10% decrease in FEV1 increases all cause mortality by 14%, cardiovascular mortality by 28%, and nonfatal coronary event by almost 20%, after adjustments for relevant confounders such age, sex, smoking status, and treatment assignment [4].

It should be noted that there are several proposed mechanisms for the association of atherosclerosis with COPD and it remains possible that these mechanisms may co-exist in any individual. Cigarette smoking, and the repetitive injury associated with this, is recognized to lead to abnormal cell repair, increased airway inflammation, oxidative stress and extracellular matrix destruction [5].

Patients with COPD can have sustained (patients with chronic respiratory failure) or intermittent hypoxia (during exercise, exacerbations or during sleep). Hypoxia is known to induce an inflammatory response in immune cells, oxidative stress, foam cell production and upregulation of cellular adhesion molecules in endothelial cells, which may all contribute to progression of atherosclerosis, and thus CVD. Furthermore, it can induce hemodynamic stress by increasing the heart rate and activating the sympathetic nervous system [6].

Another putative mechanism is the effect of increased systemic inflammation, with airflow obstruction as an independent predictor of atherosclerosis; treatment to reduce systemic inflammation in COPD has yet to be successful. There are likely to be direct effects on cardiac function as a consequence of vascular remodeling and that of dynamic hyperinflation [7].

Inflammation has been increasingly recognized to have a role in atherosclerosis particularly in the context of coronary artery disease. Blood borne immune and inflammatory cells are an important component of atheroma [8]. Macrophages and T cells infiltrate atheroma with the production of inflammatory cytokines. Activated immune cells (macrophages and T cells) are abundant at sites of plaque rupture and appear to play an important role in acute thrombosis and coronary syndrome [9].

A better understanding of mechanisms of atherosclerosis in COPD patients is needed to improve clinical outcomes. 

THE AIM

To evaluate the plasma levels of lipid parameters, atherogenic indices and systemic inflammatory markers as a predictor of atherosclerosis in subjects with chronic obstructive pulmonary disease and to investigate the relationship between these serum biomarkers and the severity of chronic obstructive pulmonary disease.

MATERIALS AND METHODS

We conducted a longitudinal study of patients with chronic obstructive pulmonary disease compared with healthy control group. A total of 72 subjects diagnosed with chronic obstructive pulmonary disease and 41 matched controls, the same gender and age categories, with ≥ 10 pack years smoking history, were followed-up of about 5.8 years.

Chronic obstructive pulmonary disease was defined as a post-bronchodilator airflow limitation of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) of < 70%.

According to the Global initiative for chronic obstructive lung disease (GOLD), the severity of chronic obstructive pulmonary disease was divided into 4 grades based on FEV1% predicted: stage I: FEV1 ≥ 80%, stage II: 80% < FEV1 ≥ 50%, stage III: 50% < FEV1 ≥ 30% and stage IV: FEV1 < 30%.

All subjects with chronic obstructive pulmonary disease were categorized into groups A – D according to combined chronic obstructive pulmonary disease risk assessment categories defined by GOLD (by using exacerbation risk [airway obstruction level according to FEV1, exacerbation, and hospitalization status within the previous year] and dyspnea score [Modified Medical Research Council dyspnea score]).

The primary outcome was the development of cardiovascular events. Subjects with exacerbation, with known cardiovascular diseases and other chronic diseases, receiving anti-hyperlipidemic treatment, without sufficient past medical history, and lacking needed laboratory data were excluded.

Statistical analyses were carried out in SPSS 22.0 Statistical Package Program for Windows (SPSS Inc., Chicago, Illinois). Blood tests with determination of different parameters such as lipid profiles, systemic inflammatory markers were conducted in remaining patients who fulfilled inclusion criteria of the study.

Atherogenic indices (atherogenic index of plasma (AIP), cardiogenic risk ratio (CRR) and atherogenic coefficient (AC)) were calculated by using the value of lipid profile parameters according to the following formulas: AIP = log (triglyceride/high-density lipoprotein cholesterol (HDL-C)), where the concentrations of triglyceride and HDL-C are in mmol/L, and calculation of AIP was performed using an online calculator; CRR = total cholesterol (TC) / HDL-C; and AC = (TC – HDL-C) / HDL-C.

Continuous variables were presented as the mean ± standard deviation (SD) and were compared using an independent samples t test.

However, if the data were not accorded with normal distribution, nonparametric test should be used. Categorical variables were expressed as frequencies and percentages and were compared using Chi-square tests. The correlation between the atherogenic indices values and other variables were calculated by Pearson correlation analysis.

The adjusted odds ratio (OR) per 1 SD increase in the corresponding lipid variable and 95% confidence intervals (95% CIs) were calculated. A value of p < 0.05 in a 2-sided test was considered significant.

RESULTS

Triglyceride, AIP, CRR and AC values were significantly higher, but HDL-C – significantly lower in COPD patients than in controls (p < 0.05) (Table I). This might partially explain the increased cardiovascular risk in patients with COPD.

We didn’t find any statistically significant differences between total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels in COPD patients and control subjects.

Lipid profiles were similar in lower-risk (stage A and B) and higher-risk (stage C and D) patients with COPD (Table I).

As AIP is a strong marker to predict the risk of atherosclerosis and coronary heart disease, we assessed the correlation between AIP and other important factors. AIP is calculated according to the formula, log (TG/HDL-C). It has been suggested that an AIP value of under 0.11 is associated with low risk of CVD; the values between 0.11 to 0.21 and upper than 0.21 are associated with intermediate and increased risks, respectively.

In clinical examination, the mean±SD of AIP was 0.42 ± 0.15 and 0.07 ± 0.14 respectively in patients with COPD and controls, according to the AIP category that mentioned before, 4.17 % (n=3) were in low risk group, 13.89 % (n= 10) were in intermediate risk and 81.94 % (n=59) were in increased risk of CVD.

Pearson correlation analyses were performed to investigate the correlation of AIP with FEV1.

Correlation analysis showed that AIP was strongly and negatively correlated with FEV1, especially in higher-risk (stage C and D) patients with COPD (r = – 0.61 p < 0.05) (Fig.1).

In lower-risk (stage A and B) COPD patients AIP was also inversely statistically significantly correlated with FEV1 but mildly (r = – 0.27 p < 0.05).

CRR and AC values were moderately negatively correlated with FEV1 in all patients with COPD, especially in higher-risk COPD subjects (r = – 0.57 p < 0.05; r = – 0.54 p < 0.05 respectively).

In lower-risk (stage A and B) COPD patients CRR and AC values were also inversely correlated with FEV1 but mildly (r = – 0.24 p < 0.05; r = – 0.23 p < 0.05).

As expected, serum high sensitive C-reactive protein (hsCRP) level in patient group was significantly higher than in controls.

The mean ± SD of hsCRP was 3.16 ± 0.45 mg/l in patients with COPD compare to control subjects (1.1 ± 0.13 mg/l).

The hsCRP is the most widely evaluated biomarker in the quest for an ideal biomarker for global CVD risk prediction. The AHA/CDC (American Heart Association/Centers for Disease Control) Working Group on markers of inflammation in CVD has classified serum hsCRP levels < 1 as low, 1-3 – intermediate and > 3 mg/l as high-risk groups for global CVD, respectively. 

According to the serum hsCRP levels 2.78 % (n=2) of COPD patients were in low risk group 9.72 % (n= 7) were in intermediate risk and 87.5 % (n=63) were in high risk group of CVD.

HsCRP was inversely correlated with FEV1 in all patients with COPD, especially in higher-risk subjects with COPD (r = – 0.49 p <0.05) (Fig.2).

In lower-risk (stage A and B) COPD patients hsCRP values were also inversely correlated with FEV1 but mildly (r = – 0.22 p < 0.05).

The mean±SD of fibrinogen was 4.1 ± 0.56 g/L in COPD group and 3.8 ± 0.47 g/L in control group. This difference was not statistically significant (p > 0.05).

Also, correlation analysis showed that fibrinogen was not statistically significant correlated with FEV1 in patients with COPD and control subjects.

DISCUSSION

Overall, these data clearly demonstrated impaired cardiovascular risk markers in COPD, even in lower-risk patients without a history of CVD, and supported its potential usage in clinical practice.

The severity of COPD plays an important role in both systemic inflammation and dyslipidemia. Our study shows that reduction of FEV1 could promote disruption of lipid metabolism and increased hsCRP.

Previous studies have shown a link between atherosclerosis and systemic inflammation in COPD. One study showed that lower FEV1 was associated with higher levels of serum hsCRP and a higher frequency of coronary artery calcification. In another study, Kim et al., it was showed an inverse relationship between FEV1 and hsCRP level [10].

Our study revealed the increased hsCRP levels in COPD patients with increased airway obstruction severity, increased and degree of dyspnea with a significant negative correlation between hsCRP with FEV1. These results clearly confirm the fact that the intensity of the inflammatory process in COPD could be related to the severity of the underlying disease.

The strongest negative associations between FEV1 and hsCRP and higher CRP levels over time were associated with a faster FEV1 decline, indicating that CRP measurements might enable identification of patients at high risk of disease progression and mortality [11].

Hypoxia, cigarette smoking, as well as oxidative stress is possible mechanisms responsible for the development of dyslipidemia in COPD patients [12].

We suspect that the impact of smoking status on systemic inflammation differs according to the type of inflammatory marker analyzed.

Higher levels of hsCRP in current smokers and ex-smokers indicate that in patients with COPD inflammation continues for many years after smoking cessation, which is not true for fibrinogen levels [13].

Corticosteroids are widely used in patients with COPD, especially in those with acute exacerbations, stages C and D. For example, one study reported that 7 weeks of dexamethasone treatment facilitated diet-induced dyslipidemia.

Another population based study showed that low-dose short-term corticosteroids markedly affect plasma lipid levels [14].

However, the impact of corticosteroid use on lipid levels in patients with COPD is still unknown and requires further well-designed studies.

CONCLUSIONS

Atherogenic indices and serum high sensitive C-reactive protein can be considered as useful biochemical markers to predict the early stage of atherosclerosis and cardiovascular diseases especially in higher-risk patients with chronic obstructive pulmonary disease. Nevertheless, further prospective investigations on this issue are required.

REFERENCES

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Authors’ contributions:

According to the order of the Authorship.

Conflict of interest:

The Authors declare no conflict of interest.

CORRESPONDING AUTHOR

Tetyana Ternushchak

Internal Diseases Department,

Medical faculty 2, Uzhhorod National University

Gryboedova str., 20, Uzhhorod, Ukraine

tel: +380501499148

e-mail: tatyana.xs38@gmail.com

Received: 01.02.2019

Accepted: 04.04.2019

Table I. Lipid profile, systemic inflammatory markers and atherogenic indices of lower – higher risk COPD patients and control subjects

Control group

(n=41)

Mean±SD

Group A
(n=18)

Mean±SD

Group B
(n=18)
Mean±SD

Group C
(n=18)
Mean±SD

Group D
(n=18)

Mean±SD

TC, mmol/l

4.9 ± 0.23

5.5 ± 0.25

5.8 ± 0.24

6.3 ± 0.27

6.6 ± 0.21

LDL-C, mmol/l

2.3 ± 0.27

2.8 ± 0.21

3.1 ± 0.22

3.4 ± 0.21

3.7 ± 0.20

HDL-C, mmol/l

1.2 ± 0.12 *

1.0 ± 0.11*

0.8 ± 0.11*

0.7 ± 0.13*

0.6 ± 0.10*

Triglycerides, mmol/l

1.4 ± 0.10 *

1.7 ± 0.12*

1.9 ± 0.13*

2.2 ± 0.10*

2.3 ± 0.11*

hsCRP, mg/l

1.1 ± 0.13 *

2.4 ± 0.15 *

2.6 ± 0.12 *

3.7 ± 0.11*

3.9 ± 0.14 *

Fibrinogen, g/l

3.8 ± 0.47

3.9 ± 0.49

4.1 ± 0.56

4.2 ± 0.70

4.3 ± 0.79

AIP

0.07 ± 0.14 *

0.23±0.15*

0.38±0.14 *

0.50± 0.13 *

0.58±0.12*

CRR

4.08 ± 0.10 *

5.51±0.17 *

7.25±0.11 *

9.01±0.15 *

11.02±0.1*

AC

3.09 ± 0.18 *

4.50±0.15 *

6.26±0.17 *

8.04±0.12 *

10.1±0.13*

*: р < 0.05 compared to the control group

Fig.1. Correlation between AIP and FEV1 in higher-risk (stage C and D) patients with COPD

Fig. 2. Correlation between hsCRP levels and FEV1 in higher-risk (stage C and D) patients with COPD