Streszczenie

Wstęp: Wyniki wielu ostatnio opublikowanych badań ukazują istotne związki między wskaźnikami stanu zapalnego a chorobami układu sercowo-naczyniowego. Stężenie CRP jest uważane za niezależ­ny czynnik ryzyka rozwoju chorób układu krążenia i jest ono zwiększone między innymi u cho­rych na nadciśnienie tętnicze.
Materiał/Metody: Celem badania była ocena wpływu leczenia obniżającego ciśnienie tętnicze (za pomocą perin­doprilu, bisoprololu i leczenia skojarzonego) na stężenie CRP w osoczu chorych na nadciśnie­nie tętnicze łagodne i umiarkowane.
Wyniki: Zaobserwowano korelację między stężeniem CRP a wartościami ciśnienia tętniczego. Terapia przeciwnadciśnieniowa doprowadziła do zmniejszenia stężenia CRP. Leczenie bisoprololem i perindoprilem spowodowało porównywalne zmniejszenie stężenia CRP, co prawdopodobnie odzwierciedla podobny efekt hipotensyjny obu leków. Leczenie skojarzone bardziej niż każda z monoterapii zmniejszało stężenie CRP.
Wnioski: W trakcie stosowania każdej z terapii przeciwnadciśnieniowych stwierdzono zmniejszenie stę­żenia CRP. U chorych na umiarkowane nadciśnienie tętnicze nie uzyskano jednak normalizacji stężenia CRP.

Słowa kluczowe:leczenie nadciśnienia • białko C-reaktywne • perindopril • bisoprolol

Summary

Introduction: There is a growing body of data concerning significant interactions between markers of inflam­mation and cardiovascular diseases such as hypertension accompanied by elevated levels of pla­sma C-reactive protein (CRP). Therefore CRP is thought to be an independent risk factor of car­diovascular diseases.
Material/Methods: The aim of this study was to evaluate the effects of antihypertensive therapy (perindopril, biso­prolol and combined therapy) on plasma CRP concentration in 67 subjects with mild or mode­rate hypertension who have been treatment-naive and otherwise healthy.
Results: The results show a correlation between CRP level and blood pressure values. BP reduction was associated with a decrease in CRP concentration. The CRP-lowering effect of perindopril and bisoprolol was comparable and the degree of reduction might reflect their similar influence on blood pressure. Combined treatment influenced the CRP level to a greater extent than both monotherapies.
Conclusions: Plasma CRP level was lowered by antihypertensive therapy independently of the drug applied. The CRP level did not normalize completely in moderate hypertensive patients.

Key words:antihypertensive therapy • C-reactive protein • perindopril • bisoprolol

Abbreviations:

ACE-I – angiotensin-converting enzyme inhibitor; ACS – acute coronary syndrome; ANOVA – analysis of variance; AT-1 – angiotensin receptor 1; BMI – body mass index; BP – blood pressure; BPM – blood pressure monitor; CRP – C-reactive protein; ELISA – enzyme-linked immunosorbent assay; ESC/ESH – European Society of Cardiology/European Society of Hypertension; ICAM-1 – intercellular adhesion molecule 1; HDL – high-density lipoprotein; IL – interleukin; LDL – low-density lipoprotein; MCP-1 – monocyte chemoattractant protein-1; NF-κB – nuclear factor kappa B; NOS – NO synthase; PAI-1 – plasminogen activator inhibitor 1; RAS – renin-angiotensin system; TG – triglycerides; TNF – tumor necrosis factor; VCAM-1 – vascular cell adhesion molecule 1.

Introduction

There is a growing body of data concerning significant in­teractions between markers of inflammation and cardiova­scular diseases. Diseases linked to atherosclerosis, such as myocardial infarction, stroke or unstable angina, are cha­racterized by an increase in inflammatory markers, inc­luding plasma C-reactive protein (CRP). Hypertension is accompanied by an elevated level of CRP and other pro­inflammatory cytokines together with adhesive molecu­les [2,3,4,31,35].

The Women’s Health Study (WHS), performed on 20,250 women with high-normal blood pressure, confirmed a si­gnificant association between the serum CRP level and the risk of subsequent hypertension development [33]. Convergent results were described by Niskanen et al. [25]. It has been shown that increased CRP level (>3 mg/L) in comparison with lower values (<1 mg/L) was associated with more frequent occurrence of hypertension. In 2004, the results of the ATTICA study (with 3,000 subjects) di­sclosed that patients prone to hypertension had augmented immune system reactivity that was expressed, inter alia, by increased (30%) levels of CRP (3). However, to date, the­re are still only a few studies concerning the influence of modern antihypertensive therapy on CRP level [9,34,41]. A question asked was whether long-lasting cardioselec­tive beta-adrenolytics were able to affect CRP level with effectiveness comparable to ACE-I. Additionally, we so­ught to evaluate the magnitude of the influence of com­bined therapy (with bisoprolol and perindopril) on blood pressure and CRP level in patients with moderate hyper­tension. The uniqueness of our study lies in the strict inc­lusion criteria concerning patients with a normal level of lipids (the mean values of lipids were as follows: total cho­lesterol [TC] 5.11 mmol/L, high density cholesterol [HDL] 1.25 mmol/L, low density cholesterol [LDL] 3.28 mmol/L, triglycerides [TG] 1.5 mmol/L). None of the studies per­formed so far have referred to total cholesterol level, tho­ugh its positive correlation with plasma CRP concentra­tion has been shown.

Unlike in similar studies, the method of 24-hour blood pressure monitoring was used to assess blood pressure. There is only a single study reported to use this kind of BP appraisal [28]. Additionally, to date, there have been no studies considering the influence of long-lasting car­dioselective beta-blockers on CRP level. The studies pu­blished to date have provided an insight into the effects of non-cardioselective beta-blockers such as propranolol and carvedilol [24] or short-acting metoprolol [18]. Our study presents the influence of bisoprolol as a long-lasting, car­dioselective beta-blocker, perindopril as a modern ACE-I, and combined therapy on blood pressure and CRP level.

Material and Methods

Study population

The study was carried out on 67 subjects divided into 3 gro­ups (Table 1). The first group included 22 patients with 2^nd stage (moderate) hypertension, while the second and third covered patients with 1^st stage (mild) arterial hypertension. The control group consisted of 30 normotensive patients.

Table 1. Patients characteristics

Hypertension had been recently diagnosed in all subjects, none of whom had ever been treated with any antihyper­tensive drugs. Patients were considered hypertensive if they presented blood pressure higher than 140/90 mmHg following at least four sets of readings (taken at week in­tervals) and having injuries of retinal arteries correspon­ding to 1^st or 2^nd stage arterial hypertension on fundoscopy. Additionally, 24-hour ambulatory non-invasive blood pres­sure monitoring was performed before and after 1-month therapy in each patient. Control subjects had a supine sy­stolic blood pressure lower than 130 mmHg and a diasto­lic one lower than 85 mmHg. The moderate hypertension group was given combined therapy (perindopril 4 mg daily plus bisoprolol 5 mg daily, both administered once a day in the morning). Patients with mild hypertension were rando­mized into two groups: those taking perindopril (4 mg once a day in the morning) and those taking bisoprolol (5 mg in the morning). All patients signed the informed consent.

Exclusion criteria included alcohol or drug abuse, pre­sence of secondary hypertension, isolated systolic or 3^rd stage hypertension, kidney, heart, liver or gastrointestinal diseases, inflammatory diseases, diabetes mellitus and li­pid disorders. Patients treated with any drugs influencing blood pressure or with an acute or chronic inflammatory state were excluded as well as those with endocrine, neu­rological, haematological and metabolic disturbances or cancer history. The study population was comparable in gender, age, body mass index, lipid level and smoking hi­story. Subjects with acute or chronic inflammation were excluded on the basis of the physical examination and ba­sic laboratory tests (complete blood count, CRP, electro­lytes, transaminases, glucose, creatinine and urinalysis). When it was necessary, additional laboratory tests were conducted (electrophoresis, oral glucose tolerance test) to­gether with the radiographic examination (chest and den­tal x-rays) and the consultation of specialists (such as an otolaryngologist). Each patient underwent Doppler ultra­sound imaging of the renal arteries.

Laboratory assays

A heparin blood sample (5 ml) was collected between 800 and 900 a.m. to avoid circadian fluctuations of the para­meters studied following the Mobil-Graph Units for non­-invasive 24-hour blood pressure monitoring.

The CRP level in plasma was assessed with enzyme-lin­ked immunosorbent assay (ELISA) using MP Biomedicals’ High Sensitivity C-Reactive Protein Enzyme Immunoassay Test Kit according to the manufacturer’s instructions. All of the mentioned parameters were analyzed before and after four weeks of treatment.

Statistics

Results were expressed as the mean +/-SD. The normality of distribution was checked by means of the Kolmogorov-Smirnov test. The statistical evaluation was performed using analysis of variance (ANOVA) and post hoc comparison was conducted by means of the Newman-Keuls test. In the case of non-normally distributed data, statistical eva­luation was performed by Kruskal-Wallis and Dunn’s te­sts. Comparison of parameters before and after therapy in the same group was investigated with the Wilcoxon test. The correlation between CRP level and systolic and dia­stolic blood pressure was calculated using Spearman’s me­thod. All statistical analyses were conducted using Graph Pad Prism 4.0 and Statistica 6.0. A p-value of <0.05 was considered significant.

Institutional Review Board

The Local Review Board (Medical University of Silesia, Katowice, Poland) accepted the study protocol.

Results

Drug therapies were not associated with any serious ad­verse effects. Two patients treated with perindopril (one with mild hypertension, another with moderate hyperten­sion) reported cough at the end of the study period. In the bisoprolol-treated group two patients suffered from fati­gue and one from bradycardia (<50 bpm during the day). All patients, excluding those mentioned above, continued the treatment after the end of the study period.

24 h blood pressure monitoring

The measurements were taken and evaluated according to the ESC-ESH guidelines (2007). In the group with mode­rate hypertension the four-week combined therapy resul­ted in a decrease of all measured blood pressure parame­ters, both systolic and diastolic (Table 2).

Table 2. Values of blood pressure before and after therapy

There was no alteration in the ratio between day and night pressure drop. Blood pressure values in mild hypertensive patients were significantly lower than in the group of mo­derate hypertension, but still met all criteria of ESC-ESH. Beta-blocker therapy resulted in significantly lower mean blood pressures (diastolic and systolic pressure) during a twenty-four-hour period as well as during waking hours. The decrease in night values (diastolic and systolic) was not significant. Corresponding results were noted in an ACE inhibitor treated group. Both hypertension therapies were similarly effective, except for the considerably greater re­duction of mean diastolic pressure during the day period by perindopril (79.8 vs. 82.8 mmHg; p=0.017).

Plasma CRP level

The baseline CRP level correlated with the increase of blood pressure in a linear manner. At the beginning of the study the level of CRP did not statistically differ betwe­en control subjects and patients with mild hypertension. In patients with moderate hypertension the difference re­ached statistical significance in relation to the control gro­up (p<0.001) as well as to the mild hypertension group (p<0.04) (Table 3).

Table 3. The CRP level (mg/L) in the control and study groups

Following the antihypertensive therapy, a progressive re­duction in CRP level was observed. In patients with mo­derate hypertension the decrease reached 28% (p=0.03) but even then it was higher than in control subjects. The bisoprolol treatment was associated with a CRP decrease reaching 35% (p<0.001) while the perindopril therapy de­creased it insignificantly by 22% (Table 3).

The comparison of both groups with mild hypertension did not reveal any differences in initial plasma CRP level (p=0.91). The extent of CRP level reduction in the perin­dopril-treated group was analogous to the bisoprolol-tre­ated group.

Correlation analysis

Correlation analysis revealed an association between ini­tial CRP level and the mean 24-hour systolic blood pres­sure (r=0.32, p=0.02) (Table 4).

Table 4. Correlation coefficients for CRP and systolic pressure

Correlation coefficients for mean day and night systolic pressure with CRP level did not reach statistical significance.

Discussion

The obtained results revealed that hypertension is asso­ciated with the intensified function of the immune system, corresponding to an increased CRP level. Our study com­pared head-to-head effects of monotherapies with perin­dopril and bisoprolol as well as combined therapy. We ob­served similar effects on blood pressure associated with monotherapies and superior efficiency of combined thera­py. The CRP level is thought to be an independent factor of increased mortality. The JUPITER study showed that mortality may be reduced by treatment with agents (statins) reducing the CRP level [29]. We noted that an increase of blood pressure is accompanied by an elevated CRP level. During the treatment significant reductions of CRP level were observed. Nevertheless, the CRP level did not drop after 30 days of therapy to the level seen in healthy subjects.

In the past few years the significant role of CRP in athero­sclerosis has been confirmed. CRP increases the expres­sion of adhesive molecules and chemokines on endothelial cells [27] as well as LDL uptake by macrophages [14,15,42], not to mention the raising of the AT-1 receptor expression on smooth muscle cells [40]. Furthermore, CRP inhibits nitric oxide synthase (NOS), and increases release of en­dothelin-1, resulting in endothelium dysfunction [38,39]. In those cases the CRP acts mainly through a specific Fc-gamma receptor, leading to a decrease in NOS activity and prostacyclin levels and an augmented expression of adhe­sion molecules (e.g. ICAM-1 and VCAM-1) [10].

The increased level of CRP correlates with myocardial in­farction severity and its complications [1] together with en­dothelial cell dysfunction and the risk of acute coronary syndromes (ACS) in patients with stable angina [12,13,16] as well as in patients with ACS without ST-elevation [23]. The assessment of CRP level in patients with stable an­gina is recommended by the American Heart Association guidelines for cardiac risk evaluation. There are three ran­ges (<1.0, 1.0-3.0 and >3.0 mg/L) that correspond to three risk categories: low, moderate and high [26].

The relation has also been confirmed in patients at risk of hypertension. A linear correlation was observed during eight-year follow-up in the WHS study between CRP le­vel and the risk of hypertension development in the fu­ture. The level of CRP was 30% higher in patients with high-normal blood pressure compared to healthy subjects [6]. The level of CRP >=3.0 mg/L increased the risk of hy­pertension development three-fold. Another study showed that a CRP level >=3.0 mg/L increased the risk of hyperten­sion by 79% only when coexisting with an increased body mass index (BMI) [19].

In our study, the level of CRP increased linearly with the BP. Those results appertain to the observations of Sesso et al. [31] along with the findings of Schillaci et al. [33] that revealed a correlation of CRP level with systolic va­lues acquired during 24-hour blood pressure monitoring (r=0.28, p<0.001). No correlation was observed with dia­stolic pressure values.

Following one month of antihypertensive therapy, the pre­viously increased CRP levels in the mild hypertension groups (1.45 mg/L) had normalized. The CRP level in the moderate hypertension group had decreased, but still re­mained 23% higher than in control subjects (1.84 vs. 1.42 mg/L). The normalization of CRP appears to have been related to a decrease in BP.

There are only a few studies assessing the effects of anti­hypertensive therapy with cardioselective beta-blockers on CRP in normolipidemic subjects. Yasunari et al. [41] repor­ted the effect of six-month therapy with propranolol ver­sus carvedilol on CRP level. The former did not lower the CRP level but the latter reduced it by 78%. King et al. [18] demonstrated the CRP-lowering properties of metoprolol in 75 hypertensive patients. The level of CRP was decre­ased after one-month therapy, while another 2 months of therapy brought no further reduction. Recently, two studies have corroborated the reduction in CRP level during tre­atment with drugs affecting the renin-angiotensin system (RAS). Nevertheless, there are also studies that have shown no effects on CRP level by antihypertensive treatment [22].

We did not observe a significant difference in the level of CRP between the bisoprolol group (1.35 mg/L) and the per­indopril group (1.56 mg/L) at the end of the study. However, the magnitude of reduction was significantly greater after beta-blocker treatment. The positive effects of beta-bloc­kers have been observed by others, including in patients with angina pectoris (CRP level =1.8 mg/L in beta-bloc­ker treated group vs. 3.1 mg/L in other therapies) as well as in patients with heart failure (the CRP level was 37% lower in the beta-blocker group) [20].

The proinflammatory properties of angiotensin-2 result from the stimulation of AT-1 receptors that lead to the seconda­ry activation of nuclear factor kappa B (NF-κB) and syn­thesis of cytokines (MCP-1, Il-6, TNF-alpha, Il-1, PAI-1) in inflammatory, endothelial and vascular smooth muscle cells (4, 14, 17, 37-39). The angiotensin-2 augments the phospholipase C activation, leading to a higher intracellu­lar calcium level and endothelin-1 release [5].

Considering all of these facts, the angiotensin-converting enzyme inhibitors are believed to lower the CRP level in hypertension. The study by Mitrovic et al. [22] demonstra­ted a decrease in CRP level after 3-month therapy with ra­mipril in patients with atherosclerosis. Also in the MESA study [26] this beneficial effect was observed, while the Trandolapril Cardiac Evaluation (TRACE) study found no influence on CRP level in patients with myocardial in­farction [7]. Similarly, enalapril did not affect the CRP le­vel in patients with angina pectoris or after an acute coro­nary episode [30,37]. Monotherapy with ramipril reduced the CRP level in diabetic (by 24%) and atherosclerotic (by 32%) patients [22] but no effect in diabetic and hyperten­sive patients was observed after treatment with lisinopril [32]. The prospective multi-center study by Di Napoli and Papa [11] showed that treatment with ACE-I lowered the CRP level 2.6-fold and reduced the risk of recurrent ce­rebral stroke.

One of the limitations of our study was the relatively small sample size due to strict inclusion criteria. However, as a result a high degree of homogeneity in treated groups was obtained.

In conclusion, our results suggest that the level of CRP at least partly depends on blood pressure values. A linear correlation between CRP and blood pressure was revealed. Reduction in blood pressure values after antihypertensive therapy and the lack of statistical differences between per­indopril and bisoprolol treated groups might suggest that the CRP-lowering effect of those medications depends on their influence on blood pressure. The blood pressure nor­malization is followed by a decrease of CRP level, which might in turn be reflected in better cardiovascular outco­me in the future (Table 5).

Table 5. Summary of the study

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The authors have no potential conflicts of interest to declare.

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