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Effects of carvedilol vs bisoprolol on inflammation and oxidative stress in patients with chronic heart failure

Open ArchivePublished:August 21, 2019DOI:https://doi.org/10.1016/j.jjcc.2019.07.011

      Highlights

      • Beta-blockers such as carvedilol and bisoprolol improve morbidity and mortality in chronic heart failure (CHF) patients.
      • Inflammation and oxidative stress are implicated in the pathophysiology of CHF.
      • Bisoprolol may have stronger anti-inflammatory effects than carvedilol.
      • Carvedilol may have stronger anti-oxidant effects than bisoprolol.
      • Proper use of bisoprolol or carvedilol based on individual pathophysiology would be promising.

      Abstract

      Background

      Inflammation and oxidative stress play a role in the pathophysiology of chronic heart failure (CHF). Our previous clinical trial, the Bisoprolol Improvement Group for Chronic Heart Failure Treatment Study in Dokkyo Medical University (BRIGHT-D), reported that bisoprolol is superior to carvedilol for myocardial protection in patients with CHF, as demonstrated by high-sensitivity cardiac troponin T (hsTnT) reduction. The present study was a subanalysis of the BRIGHT-D study that focused on the effects of bisoprolol vs carvedilol on inflammation and oxidative stress in CHF patients.

      Methods

      Of the 87 patients enrolled in the BRIGHT-D trial, the present study included 48 patients (26 in the bisoprolol group and 22 in the carvedilol group) who had baseline and follow-up measurements of derivatives of reactive oxygen metabolites (d-ROMs) as an index of oxidative stress.

      Results

      High-sensitivity C-reactive protein (hsCRP), an inflammatory marker, decreased in both groups; however, the decrease in the bisoprolol group [3.35 ± 0.78 to 2.69 ± 0.44 log (ng/ml), p = 0.001] was more significant than that in the carvedilol group [3.38 ± 0.59 to 2.85 ± 0.76 log (ng/ml), p = 0.047]. The d-ROMs also decreased in both groups; however, the decrease in the bisoprolol group (401 ± 106 to 344 ± 82 U.CARR, p = 0.015) was less significant than that in the carvedilol group (382 ± 84 to 312 ± 76 U.CARR, p = 0.006]. In all 48 patients, the change in hsTnT was correlated with that in hsCRP (R = 0.467, p = 0.003).

      Conclusions

      Bisoprolol may be better than carvedilol for reducing inflammation, but carvedilol may be better than bisoprolol for reducing oxidative stress. Proper use of bisoprolol or carvedilol based on individual pathophysiology could be promising in patients with CHF.

      Keywords

      Introduction

      The effects of beta-blockers on long-term morbidity and mortality have been established in patients with chronic heart failure (CHF) with reduced left ventricular function [
      • CIBIS-II Investigators
      The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II); a randomized trial.
      ,
      • Packer M.
      • Bristow M.R.
      • Cohn J.N.
      • Colucci W.S.
      • Fowler M.B.
      • Gilbert E.M.
      • et al.
      The effect of carvedilol on morbidity and mortality in patients with chronic heart failure.
      ,
      • Packer M.
      • Coats A.J.
      • Fowler M.B.
      • Katus H.A.
      • Krum H.
      • Mohacsi P.
      • et al.
      Effect of carvedilol on survival in severe chronic heart failure.
      ,
      • Tsuda E.
      • Yamada O.
      • Kitano M.
      Improvement of the outcome in patients with infantile dilated cardiomyopathy over three decades — the usefulness of long-term gradually medical supportive care.
      ]. Among various beta-blockers, only carvedilol and bisoprolol are approved by Japanese guidelines for the treatment of patients with CHF [

      The Joint Study Group in 2009 of the Japanese Circulation Society. Guidelines for diagnosis and treatment of cardiovascular diseases; guidelines for treatment of chronic heart failure (JCS 2010). http://www.j-circ.or.jp/guideline/pdf/JCS2010 _matsuzaki_h.pdf (in Japanese).

      ]. Bisoprolol is highly selective for the beta-1 receptor, whereas carvedilol is a non-selective beta-blocker with simultaneous alpha-receptor antagonism [
      • Schnabel P.
      • Maack C.
      • Mies F.
      • Tyroller S.
      • Scheer A.
      • Böhm M.
      Binding properties of beta-blockers at recombinant beta1, beta2 and beta3-adrenoreceptors.
      ]. However, there is no established clinical evidence on how to properly use these two agents. Our previous clinical trial, the Bisoprolol Improvement Group for Chronic Heart Failure Treatment Study in Dokkyo Medical University (BRIGHT-D), reported that bisoprolol is superior to carvedilol for myocardial protection in patients with CHF, as demonstrated by a greater reduction in high-sensitivity cardiac troponin T (hsTnT) [
      • Toyoda S.
      • Haruyama A.
      • Inami S.
      • Amano H.
      • Arikawa T.
      • Sakuma M.
      • et al.
      Protective effects of bisoprolol against myocardial injury and pulmonary dysfunction in patients with chronic heart failure.
      ].
      Inflammation and oxidative stress have been implicated in the pathophysiology of CHF. Inflammatory mediators participate in the pathophysiology of CHF by several different mechanisms. They have a direct impact on cardiac myocytes, fibroblasts, and beta-adrenergic receptors leading to hypertrophy, fibrosis, and impaired cardiac contractility, respectively. In addition, they may induce apoptosis by stimulation of the proper genes [
      • Bouras G.
      • Giannopoulos G.
      • Hatzis G.
      • Alexopoulos D.
      • Leventopoulos G.
      • Deftereos S.
      Inflammation and chronic heart failure: from biomarkers to novel anti-inflammatory therapeutic strategies.
      ]. Oxidative stress is elevated in CHF as a result of increased production of free radical species capable of attacking lipids, proteins, and nucleic acids. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA damage, as well as functional decline, further oxygen radical generation, and myocardial cell injury in CHF [
      • Tsutsui H.
      • Kinugawa S.
      • Matsushima S.
      Oxidative stress and heart failure.
      ].
      However, therapeutic strategies to target inflammation or oxidative stress in CHF have not been established. Although carvedilol is believed to have antioxidant activity in human failing hearts, the clinical significance of this effect in patients with CHF has not been elucidated. In addition, anti-inflammatory therapeutic approaches added to conventional therapies to achieve additional benefits for CHF patients are currently under investigation.
      In the BRIGHT-D study, we measured inflammatory and oxidative stress biomarkers in addition to cardiac biomarkers, such as N-terminal pro-brain-type natriuretic peptide (NT-ProBNP) and hsTnT. In this subanalysis, we compared the effects of two beta-blockers, carvedilol and bisoprolol, on inflammation and oxidative stress in patients with CHF.

      Methods

      Study population

      The study was designed as a prospective, open label, randomized trial and was conducted at Dokkyo Medical University (UMIN000011261). The study protocol was approved by the Institutional Review Committee on Human Research, Dokkyo Medical University, and informed consent was obtained from each patient prior to enrollment.
      Study subjects included hospitalized patients with CHF who were not on beta-blockers and fulfilled the following inclusion criteria: 1) age ≥20 years; 2) left ventricular ejection fraction ≤45% by echocardiography; 3) stability of heart failure symptoms as demonstrated by New York Heart Association (NYHA) functional class, for one month prior to enrollment; and 4) treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Exclusion criteria were as follows: 1) severe heart failure, defined as NYHA class IV; 2) serious arrhythmias such as ventricular tachycardia or sustained bradycardia (<60/min), including second-degree atrioventricular block without pacemaker implantation; 3) acute coronary syndrome within 3 months of enrollment; 4) sustained hypotension (resting systolic blood pressure <90 mmHg); 5) serious hepatic or renal dysfunction (serum alanine aminotransferase level ≥50 IU/L and/or serum creatinine level ≥3.0 mg/dL); 6) a contraindication to beta-blockers, such as bronchial asthma; and 7) the treating physician’s objection to inclusion in the study.

      Study protocol

      Eligible patients were randomly assigned to receive either bisoprolol or carvedilol. Patients in the bisoprolol group received bisoprolol once daily, starting at 0.625 mg/day, and increasing every two weeks as tolerated (1.25, 2.5, and 3.75 mg/day) to a final maximum dose of 5 mg/day. Patients in the carvedilol group received carvedilol twice daily, starting at 2.5 mg/day (1.25 mg per dose) and increasing every two weeks as tolerated (5 and 10 mg/day) to a final maximum dose of 20 mg/day. Patients were assessed at baseline and after 24 weeks of treatment for the following parameters: NYHA functional class, heart rate, blood pressure, cardiothoracic ratio on the chest roentgenogram, blood levels of various biomarkers, and echocardiographic parameters (Fig. 1). In the BRIGHT-D study, we measured estimated glomerular filtration rate (eGFR), blood hemoglobin level, and blood levels of NT-ProBNP and hsTnT. We also measured an inflammatory biomarker, high-sensitivity C-reactive protein (hsCRP), and an oxidative stress marker, derivative of reactive oxygen metabolites (d-ROMs). Patients who discontinued the study drugs for any reason were eliminated from the final data analysis.
      Fig. 1
      Fig. 1Study protocol. After randomization, patients were started on low doses of either bisoprolol or carvedilol. Medication doses were gradually increased every 2 weeks, based on drug tolerance, to a maximum target dose for each medication. Data were acquired at baseline and after 24 weeks of treatment.
      BP, blood pressure; CTR, cardiothoracic ratio; HR, heart rate; NYHA, New York Heart Association.

      Echocardiography

      Transthoracic echocardiography was performed with patients in the left lateral decubitus position. Two-dimensional and M-mode images were obtained using a SONOS 7500 (Philips Ultrasound, Bothell, WA, USA) or Vivid 7 (GE Vingmed Ultrasound AS, Horten, Norway) system. Image acquisition was performed by 2 independent cardiologists who were unaware of the study design. Wall motion was observed in 2-dimensional images. Left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV) were determined in the four- and two-chamber apical views using the modified Simpson’s method, and left ventricular ejection fraction (LVEF) was calculated as [(LVEDV-LVESV)/LVEDV] × 100 (%) from these results. These parameters were determined by recording 3 cardiac cycles under stable conditions, and the mean of the measurements was used for analysis.

      Measurement of specific biomarkers

      Blood samples were immediately centrifuged at 1500×g for 15 min at room temperature. The serum was frozen and stored at −80 °C until analyzed. NT-ProBNP determinations were performed using the Roche Diagnostic NT-ProBNP electrochemiluminescent immunoassay kit on an Elecsys 2010 analyzer (Roche Diagnostics Ltd., Rotkreuz, Switzerland) according to the manufacturer's recommendations [
      • Node K.
      • Inoue T.
      • Boyko V.
      • Goldberg I.
      • Fisman E.Z.
      • Adler Y.
      • et al.
      Long-term effects of peroxisome proliferator-activated receptor ligand bezafibrate on N-terminal pro-B type natriuretic peptide in patients with advanced functional capacity impairment.
      ]. The intra-assay variability of the NT-ProBNP test at our institute is 3.9%. Serum hsTnT was measured by Elecsys Troponin T High Sensitive immunoassay (Roche Diagnostics Ltd.). The measurement of hsTnT in our study conformed to guideline precision requirements for the universal definition of myocardial infarction: an increased value for cardiac troponin was defined as a measurement exceeding the 99th percentile of a normal reference population, and optimal precision (coefficient of variation) at the 99th percentile decision limit was defined as ≤10% [
      • Antman E.
      • Bassand J.
      • Klein W.
      • Ohman M.
      • Sendon J.L.L.
      • Rydén L.
      • et al.
      Myocardial infarction redefined — a consensus document of the Joint European Society of Cardiology/American College of Cardiology committee for the redefinition of myocardial infarction: the Joint European Society of Cardiology/American College of Cardiology Committee.
      ]. The normal range of hsTnT in a healthy adult population is ≤0.014 ng/mL (99th percentile) [
      • Gore M.O.
      • Seliger S.L.
      • Defilippi C.R.
      • Nambi V.
      • Christenson R.H.
      • Hashim I.A.
      • et al.
      Age- and sex-dependent upper reference limits for the high-sensitivity cardiac troponin T assay.
      ]. The limit of detection (i.e. the smallest concentration that can be reliably measured by an analytical procedure) is 0.003 ng/mL [
      • Saunders J.T.
      • Nambi V.
      • de Lemos J.A.
      • Chambless L.E.
      • Virani S.S.
      • Boerwinkle E.
      • et al.
      Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
      ]. The hsCRP was measured by particle-enhanced technology on a Behring BN II nephelometer (Dade Behring Inc., Newark, DE, USA) using monoclonal anti-CRP antibodies and a calibrator that was traceable to WHO Reference Material. Using this method, the run-to-run coefficients of variation at hsCRP concentrations of 0.047, 1.05, and 5.49 mg/dl were 6.4%, 3.7%, and 2.9%, respectively, and the detection limit was 0.001 mg/dL (0.1 ng/mL) [
      • Rifai N.
      • Tracy R.P.
      • Ridker P.M.
      Clinical efficacy of an automated high-sensitivity C-reactive protein assay.
      ]. Finally, we measured d-ROMs, using the d-ROMs test (Diacron, Grosseto, Italy) [
      • Cearone M.R.
      • Belcalo G.
      • Carratelli M.
      • Cornelli U.
      • De Sanctis M.T.
      • Incandela L.
      • et al.
      A simple test to monitor oxidative stress.
      ,
      • Cornelli U.
      • Terranova R.
      • Luca S.
      • Cornelli S.
      • Alberti A.
      Bioavailability and antioxidant activity of some food supplements in men and women using the D-Roms test as a marker of oxidative stress.
      ,
      • Cavalleri A.
      • Colombo C.
      • Venturelli E.
      • Miceli R.
      • Mariani L.
      • Cornelli U.
      • et al.
      Evaluation of reactive oxygen metabolites in frozen serum samples. Effect of storage and repeated thawing.
      ]. The d-ROMs test uses a photometric method based on the radical reaction of Fenton and was described in detail by Haber and Weiss [
      • Kehrer J.P.
      The Haber-Weiss reaction and mechanisms of toxity.
      ]. This test measures the quantity of hydroperoxides in serum. Hydroperoxides, which are derived from free radicals, are closely correlated with quantities of ROMs. In the d-ROMs test, hydroperoxides in the serum sample react with a chromogenic substrate that produces a colored derivative. The reaction temperature is 37 °C. The colored complex is detected and quantified by a photometer (FREE, Diacron) at a wavelength of 505 nm. Results of the d-ROMs test are expressed in arbitrary units, the so-called Caratelli Units (U.CARR), where 1 U.CARR corresponds to 0.08 mg/100 mL H2O2.

      Statistical analysis

      Data are expressed as the mean ± standard deviation for continuous variables or the number (percent) of patients for categorical variables. NYHA class was scored as 1, 2, 3 and 4 for NYHA class I, II, III and IV, respectively. Normality for the distribution of continuous variables was assessed using the Shapiro-Wilk test. Since the values of NT-ProBNP, hsTnT and hsCRP exhibited skewed distributions, they were logarithmically transformed for analysis. Continuous variables were compared using paired and unpaired t-tests for intra-group and inter-group comparisons, respectively. The inter-group comparison of categorical variables was performed using a chi-square test. The correlation between two variables was determined by simple linear regression analysis. All statistical analyses were performed using SAS software, Version 9.4 (SAS Institute, Cary, NC, USA). A p-value <0.05 was considered significant.

      Results

      Patient characteristics

      A total of 87 patients (44 in the bisoprolol group and 43 in the carvedilol group) were enrolled in the BRIGHT-D trial. Of these patients, the present study included 48 patients (26 in the bisoprolol group and 22 in the carvedilol group; ischemic heart failure in 9 patients) who had d-ROMs measured at both baseline and at 24 weeks of follow-up. Baseline characteristics including age, gender, cause of heart failure, and comorbidities were comparable between the two groups. Concomitant medications such as ACE inhibitors or ARBs, aldosterone blockers, loop diuretics, anti-arrhythmic agents, and statins were also comparable between the two groups. However, use of digitalis was higher in the carvedilol group (Table 1). During 24 weeks of follow up, statins were discontinued in each of one bisoprolol group patient and one carvedilol group patient. However, the other drugs were continued in all patients of each group. The final dose of beta-blockers at 24 weeks was 2.5 ± 1.6 mg/day in the bisoprolol group and 6.1 ± 4.0 mg/day in the carvedilol group.
      Table 1Baseline characteristics.
      Bisoprolol groupCarvedilol group
      (n = 26)(n = 22)P value
      Age; yrs58.0 ± 14.258.7 ± 15.00.865
      Male gender; n (%)20 (76.9)17 (77.3)1.000
      Cause of heart failure
       Dilated cardiomyopathy; n (%)11 (42.3)12 (54.5)0.578
       Ischemic heart disease; n (%)5 (19.2)4 (18.2)1.000
       Hypertensive heart disease; n (%)4 (15.4)0 (0)0.162
       Tachycardia induced cardiomyopathy; n (%)0 (0)2 (9.1)0.398
       Dilated phase hypertrophic cardiomyopathy; n (%)1 (3.8)0 (0)1.000
       Cardiac sarcoidosis; n (%)1 (3.8)0 (0)1.000
      Comorbidities
       Hypertension; n (%)7 (26.9)11 (50.0)0.178
       Diabetes; n (%)9 (34.6)6 (27.3)0.815
       Dyslipidemia; n (%)8 (30.8)8 (36.4)0.918
       Atrial fibrillation; n (%)4 (15.4)6 (27.3)0.513
       Ventricular tachycardia; n (%)6 (23.1)2 (9.1)0.364
      Medications
       ACE inhibitors/ARBs; n (%)22 (84.6)22 (100)0.162
       Aldosterone blockers; n (%)19 (73.1)19 (86.4)0.440
       Loop diuretics; n (%)15 (57.7)18 (81.8)0.138
       Digitalis; n (%)0 (0)7 (31.8)0.007
       Anti-arrhythmic agents; n (%)8 (30.8)6 (27.3)1.000
       Statins; n (%)9 (34.6)8 (36.4)1.000
      ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker.

      Changes in measured parameters

      In the 26 patients in the bisoprolol group and 22 patients in the carvedilol group, baseline values of measured parameters were similar. The NYHA class, heart rate, cardiothoracic ratio, LVEDV, LVESV, and LVEF were improved after 24 weeks of treatment in both groups (Table 2). The reduction in heart rate was more prominent in the bisoprolol group, whereas the changes in other parameters were similar between the groups. At 24 weeks, heart rate was significantly lower in the bisoprolol group, and the cardiothoracic ratio was significantly lower in the carvedilol group. Blood pressure, eGFR, and hemoglobin levels did not change 24 weeks after beta-blocker treatment in either group (Table 2).
      Table 2Change in measured parameters.
      Bisoprolol groupCarvedilol group
      (n = 26)(n = 22)P value
      NYHA class
       Baseline2.00 ± 0.322.05 ± 0.380.671
       24 weeks1.19 ± 0.51
      P < 0.001 vs Baseline.
      1.05 ± 0.21
      P < 0.001 vs Baseline.
      0.228
      Heart rate; /min
       Baseline79 ± 1378 ± 130.836
       24 weeks65 ± 11
      P < 0.001 vs Baseline.
      71 ± 11
      P < 0.05.
      0.04
      Systolic blood pressure; mmHg
       Baseline119 ± 17115 ± 170.055
       24 weeks122 ± 17121 ± 180.377
      Diastolic blood pressure; mmHg
       Baseline74 ± 1272 ± 120.408
       24 weeks74 ± 1375 ± 130.678
      Cardiothoracic ratio; %
       Baseline55 ± 653 ± 60.183
       24 weeks50 ± 5
      P < 0.001 vs Baseline.
      47 ± 5
      P < 0.001 vs Baseline.
      0.004
      eGFR; mL/min/1.73 m2
       Baseline71 ± 2263 ± 210.168
       24 weeks71 ± 2263 ± 200.118
      Hemoglobin; g/dL
       Baseline14 ± 214 ± 30.913
       24 weeks14 ± 114 ± 20.835
      LVEDV; mL
       Baseline181 ± 62182 ± 640.924
       24 weeks141 ± 45
      P < 0.001 vs Baseline.
      144 ± 66
      P < 0.001 vs Baseline.
      0.835
      LVESV; mL
       Baseline127 ± 51130 ± 550.825
       24 weeks77 ± 31
      P < 0.001 vs Baseline.
      85 ± 55
      P < 0.001 vs Baseline.
      0.879
      LVEF; %
       Baseline31 ± 831 ± 80.929
       24 weeks46 ± 9
      P < 0.001 vs Baseline.
      44 ± 12
      P < 0.001 vs Baseline.
      0.406
      NYHA, New York Heart Association; eGFR, estimated glomerular filtration rate; LVEDV, left ventricular end diastolic volume; LVESV, left ventricular end systolic volume; LVEF, left ventricular ejection fraction.
      * P < 0.05.
      ** P < 0.001 vs Baseline.

      Change in specific biomarkers

      At baseline, the NT-proBNP level was comparable between the bisoprolol and carvedilol groups [2.99 ± 0.50 vs 2.91 ± 0.44 log (pg/ml), respectively]. At 24 weeks after beta-blocker treatment, the NT-ProBNP level decreased in both groups, but the decrease in the bisoprolol group [to 2.48 ± 0.61 log(pg/ml) p = 0.014] was less significant than that in the carvedilol group [to 2.11 ± 0.68 log (pg/ml), p < 0.001]. The baseline hsTnT level was comparable between the bisoprolol and carvedilol groups [1.28 ± 0.55 vs 1.13 ± 0.53 log (ng/ml), respectively]. At 24 weeks, the hsTnT level decreased to 0.95 ± 0.39 log (ng/ml) (p = 0.010) in the bisoprolol group, whereas it only tended to decrease in the carvedilol group [to 0.91 ± 0.35 log (ng/ml), p = 0.064]. The baseline hsCRP level was comparable between the bisoprolol and carvedilol groups [3.35 ± 0.78 vs 3.38 ± 0.59 log (ng/ml), respectively]. At 24 weeks, the hsCRP level decreased in both groups; however, the decrease in the bisoprolol group [to 2.69 ± 0.44 log (ng/ml), p = 0.001] was more significant than that in the carvedilol group [to 2.85 ± 0.76 log (ng/ml), p = 0.047]. The baseline d-ROMs level was comparable between the bisoprolol and carvedilol groups (401 ± 106 vs 382 ± 84 U.CARR, respectively). At 24 weeks, the d-ROMs level decreased in both groups; however, the decrease in the bisoprolol group (to 344 ± 82 U.CARR, p = 0.015) was less significant than that in the carvedilol group (to 312 ± 76 U.CARR, p = 0.006) (Fig. 2).
      Fig. 2
      Fig. 2Comparison of changes in specific biomarker levels between the bisoprolol and carvedilol groups. The baseline NT-proBNP level was comparable between the bisoprolol and carvedilol groups. At 24 weeks, the level decreased in both groups, but the decrease was more significant in the carvedilol group. The baseline hsTnT level was comparable between both groups. At 24 weeks, the level decreased in the bisoprolol group, whereas it only tended to decrease in the carvedilol group. The baseline hsCRP level was comparable between the two groups. At 24 weeks, the hsCRP level decreased in both groups, but it decreased less significantly in the carvedilol group. The baseline d-ROMs level was comparable between the two groups. At 24 weeks, the level decreased in both groups, but it decreased more significantly in the carvedilol group.
      NT-ProBNP, N-terminal pro-brain-type natriuretic peptide; hsTnT, high-sensitivity cardiac troponin T; hsCRP, high-sensitivity C-reactive protein; d-ROMs, derivative of reactive oxygen metabolites.
      When both groups were combined (n = 48), the relationships among changes (baseline values minus values at 24 weeks) in inflammatory, oxidative stress and cardiac biomarkers were assessed. The change in the levels of d-ROMs and hsCRP were correlated each other (R = 0.444, p = 0.005) (Fig. 3). The change in NT-ProBNP level did not correlate with that in the hsCRP level (R = 0.123, p = 0.549) or with that in the d-ROMs level (R = 0.290, p = 0.107). However, the change in the hsTnT level was correlated with that in the hsCRP level (R = 0.467, p = 0.003), but not with that in the d-ROMs level (R = 0.169, p = 0.268) (Fig. 4).
      Fig. 3
      Fig. 3Relationships between changes (baseline values minus values at 24 weeks) in hsCRP and d-ROMs levels after 24 weeks of beta-blocker treatment in all 48 patients that were combined from the bisoprolol and carvedilol groups. Both levels were correlated with each other.
      hsCRP, high-sensitivity C-reactive protein; d-ROMs, derivative of reactive oxygen metabolites.
      Fig. 4
      Fig. 4Relationships between changes in inflammatory and oxidative stress markers and those in cardiac biomarkers after 24 weeks of beta-blocker treatment in all of 48 patients. The change in NT-ProBNP level was not correlated with either the change in hsCRP level or the change in d-ROMs level. However, the change in hsTnT level was correlated with that in the hsCRP level, whereas it was not correlated with the change in the d-ROMs level.
      NT-ProBNP, N-terminal pro-brain-type natriuretic peptide; hsTnT, high-sensitivity cardiac troponin T; hsCRP, high-sensitivity C-reactive protein; d-ROMs, derivative of reactive oxygen metabolites.

      Discussion

      The novel finding of the present study is that an inflammatory biomarker, hsCRP, and an oxidative stress marker, d-ROMs, were both reduced after 24 weeks of beta-blocker treatment with either bisoprolol or carvedilol. However, the reduction of hsCRP was somewhat stronger in patients receiving bisoprolol, whereas that of d-ROMs was somewhat stronger in patients receiving carvedilol. Interestingly, the reduction of hsTnT was closely correlated with that of hsCRP, but not with d-ROMs, whereas the reduction of NT-ProBNP was not correlated with either the reduction of hsTnT or d-ROMs.
      CHF is strongly associated with inflammation in terms of pathogenesis, progression, severity, and prognosis. Circulating levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 have been shown to increase along with the severity of CHF and to predict its prognosis. These cytokines suppress cardiac function via a direct negative inotropic action, inhibit activation of beta-receptors and reduce inducible nitric oxide synthase-dependent nitric oxide production. In addition, these cytokines cause cardiac cachexia due to skeletal muscle wasting, increase vascular permeability, increase peripheral vascular resistance, and reduce exercise capacity in patients with CHF. Importantly, circulating levels of inflammatory cytokines are associated with the severity and prognosis of heart failure [
      • Levine B.
      • Kalman J.
      • Mayer L.
      • Fillit H.M.
      • Packer M.
      Elevated circulating levels of tumor necrosis factor in severe chronic heart failure.
      ,
      • Ferrari R.
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      • Opasich C.
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      • et al.
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      ,
      • Tsutamoto T.
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      • Wada A.
      • Maeda K.
      • Ohnishi M.
      • Mabuchi N.
      • et al.
      Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure.
      ]. The Valsartan Heart Failure Trial (Val-HeFT) demonstrated that hsCRP was increased in CHF patients and that a higher hsCRP level was associated with more severe heart failure and was independently associated with mortality and morbidity. In addition, treatment with the ARB, valsartan, was associated with a decrease in hsCRP [
      • Anand I.S.
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      • Florea V.G.
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      ]. It has also been reported that treatment with beta-blockers was negatively correlated with circulating levels of inflammatory cytokines in patients with CHF, indicating that inhibiting sympathetic nervous system activation might be associated with suppression of inflammatory reactions in patients with CHF [
      • Tsutamoto T.
      • Hisanaga T.
      • Wada A.
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      • et al.
      Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure.
      ]. Also, in the present study, bisoprolol and carvedilol reduced the hsCRP level, suggesting that there may be anti-inflammatory properties of beta-blockers, although bisoprolol seems to have some advantage over carvedilol for the regulation of inflammatory reactions.
      In the present study, both bisoprolol and carvedilol significantly and similarly decreased NT-proBNP levels. However, bisoprolol but not carvedilol significantly decreased hsTnT levels. These results are compatible with the main study findings of BRIGHT-D, which we previously reported [
      • Toyoda S.
      • Haruyama A.
      • Inami S.
      • Amano H.
      • Arikawa T.
      • Sakuma M.
      • et al.
      Protective effects of bisoprolol against myocardial injury and pulmonary dysfunction in patients with chronic heart failure.
      ]. Although NT-proBNP is released from the ventricular myocardium in response to cardiac pressure and/or volume overload [
      • de Bold A.J.
      • Bruneau B.G.
      • Kuroski de Bold M.L.
      Mechanical and neuroendocrine regulation of the endocrine heart.
      ,
      • Panagopoulou V.
      • Deftereos S.
      • Kossyvakis C.
      • Raisakis K.
      • Giannopoulos G.
      • Bouras G.
      • et al.
      NTproBNP: an important biomarker in cardiac diseases.
      ], cardiac troponin is released by injured myocardial tissues in the failing heart [
      • Sato Y.
      • Fujiwara H.
      • Takatsu Y.
      Cardiac troponin and heart failure in the era of high-sensitivity assays.
      ,
      • Nakamura Y.
      • Yoshihisa A.
      • Takiguchi M.
      • Shimizu T.
      • Yamauchi H.
      • Iwaya S.
      • et al.
      High-sensitivity cardiac troponin T predicts non-cardiac mortality in heart failure.
      ]. Potential mechanisms of troponin release include myocardial cell necrosis, apoptosis, normal myocardial cell turnover, cellular release of proteolytic troponin degradation products, increased cellular wall permeability, and formation and release of membranous blebs [
      • White H.D.
      Pathobiology of troponin elevations: do elevations occur with myocardial ischemia as well as necrosis?.
      ]. Proinflammatory cytokines such as TNF-alpha, IL-1-beta, and IL-6 increase the permeability of myocardial cell membranes, and this can promote cardiac troponin release [
      • Nakamura Y.
      • Yoshihisa A.
      • Takiguchi M.
      • Shimizu T.
      • Yamauchi H.
      • Iwaya S.
      • et al.
      High-sensitivity cardiac troponin T predicts non-cardiac mortality in heart failure.
      ]. Therefore, an inflammatory reaction could cause cardiac troponin release in CHF. In the present study, we demonstrated a relationship between the reduction in hsTnT and that of hsCRP after beta-blocker treatment in all 48 CHF patients. This result supports the association between inflammatory reactions and myocardial injury in CHF. In addition, the reduction of both hsTnT and hsCRP was somewhat stronger after bisoprolol treatment than carvedilol treatment, suggesting bisoprolol might have some advantages over carvedilol in terms of suppression of the link between inflammation and myocardial injury. Nishio et al. [
      • Nishio M.
      • Sakata Y.
      • Mano T.
      • Ohtani T.
      • Takeda Y.
      • Miwa T.
      • et al.
      Beneficial effects of bisoprolol on the survival of hypertensive diastolic heart failure model rats.
      ] demonstrated in hypertensive diastolic heart failure rat models that bisoprolol attenuated expression of IL-1-beta mRNA in myocardium, suggesting direct anti-inflammatory action of bisoprolol, and possibly supporting the result of the present study.
      It has been suggested that oxidative stress, defined as an excess production of reactive oxygen species (ROS) relative to antioxidant defenses, also plays a role in the pathophysiology of CHF [
      • Belch J.J.
      • Bridges A.B.
      • Scott N.
      • Chopra M.
      Oxygen free radicals and congestive heart failure.
      ,
      • Hill M.F.
      • Singal P.K.
      Antioxidant and oxidative stress changes during heart failure subsequent to myocardial infarction in rats.
      ,
      • Mallat Z.
      • Philip I.
      • Lebret M.
      • Chatel D.
      • Maclouf J.
      • Tedgui A.
      Elevated levels of 8-iso-prostaglandin F2α in pericardial fluid of patients with heart failure.
      ]. ROS cause myocardial cell dysfunction, protein and lipid peroxidation, and DNA damage, leading to irreversible myocardial cell damage and death, which have been implicated in CHF. ROS enhance cardiac remodeling responsible for the development and progression of CHF [
      • Takimoto E.
      • Kass D.A.
      Role of oxidative stress in cardiac hypertrophy and remodeling.
      ], and directly impair contractile function by modifying proteins central to excitation-contraction coupling. They also activate hypertrophy signaling kinases and transcription factors, and mediate apoptosis. ROS also stimulate cardiac fibroblast proliferation and activate matrix metalloproteinases, leading to extracellular matrix remodeling. These cellular events are involved in the development and progression of CHF [
      • Tsutsui H.
      • Kinugawa S.
      • Matsushima S.
      Oxidative stress and heart failure.
      ]. Administration of beta-blockers as well as ARBs and statins has been shown to reduce oxidative stress and improve cardiac and vascular function in CHF [
      • Nakamura K.
      • Kusano K.
      • Nakamura Y.
      • Kakishita M.
      • Ohta K.
      • Nagase S.
      • et al.
      Carvedilol decreases elevated oxidative stress in human failing myocardium.
      ,
      • Nickenig G.
      Should angiotensin II receptor blockers and statins be combined?.
      ]. Among various beta-blockers, carvedilol is known to have antioxidant effects. Carvedilol reduces lipid peroxidation in patients with CHF by acting as a free radical scavenger [
      • Nakamura K.
      • Kusano K.
      • Nakamura Y.
      • Kakishita M.
      • Ohta K.
      • Nagase S.
      • et al.
      Carvedilol decreases elevated oxidative stress in human failing myocardium.
      ,
      • Kukin M.L.
      • Kalman J.
      • Charney R.H.
      • Levy D.K.
      • Buchholz-Varley C.
      • Ocampo O.N.
      • et al.
      Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure.
      ]. Kawai et al. [
      • Kawai K.
      • Qin F.
      • Shite J.
      • Mao W.
      • Fukuoka S.
      • Liang C.S.
      Importance of antioxidant and antiapoptotic effects of beta-receptor blockers in heart failure therapy.
      ] demonstrated in rapid pacing-induced rabbit heart failure model that increased myocardial mitochondrial DNA 8-oxo-7,8-dihydro-2′-deoxyguanosine, a sensitive oxidative stress marker, was attenuated by carvedilol, more strongly than by a selective beta-1 blocker, metoprolol. Interestingly, the attenuation by carvedilol was more strongly than that by treatment with propranolol plus doxazocin, an alpha-blocker. The result suggested that the anti-oxidative effect of carvedilol might be independent of its alpha-receptor antagonism. In the present study, an oxidative stress marker, d-ROMs, was reduced after treatment with both bisoprolol and carvedilol, but the reduction of d-ROMs was somewhat stronger in patients receiving carvedilol. This finding supports previous reports of a greater antioxidant effect of carvedilol than beta-1 selective blockers. In the present study, the reduction of hsTnT as well as NT-ProBNP after beta-blocker treatment was not correlated with that of d-ROMs, suggesting that the antioxidant properties of beta-blockers might not have a direct effect on myocardial protection, but may act to ameliorate CHF via more complex mechanisms.
      Inflammation and oxidative stress are closely related pathophysiological processes, and both are found in many pathological conditions including cardiovascular disease. Inflammatory cells liberate a number of ROS at the site of inflammation leading to exaggerated oxidative stress. On the other hand, ROS can initiate an intracellular signaling cascade that enhances proinflammatory gene expression. Thus, inflammation and oxidative stress are closely related pathophysiological events that are tightly linked with one another. One can be easily induced by the other, and thus, which one dominates may depend on each pathophysiological condition [
      • Ito F.
      • Sono Y.
      • Ito T.
      Measurement and clinical significance of lipid peroxidation as a biomarker of oxidative stress: oxidative stress in diabetes, atherosclerosis, and chronic inflammation.
      ,
      • Biswas S.K.
      Does the interdependence between oxidative stress and inflammation explain the antioxidant paradox?.
      ]. Kamezaki et al. [
      • Kamezaki F.
      • Yamashita K.
      • Kubara T.
      • Suzuki Y.
      • Tanaka S.
      • Rkouzuma R.
      • et al.
      Derivatives of reactive oxygen metabolites correlates with high-sensitivity C-reactive protein.
      ] demonstrated that serum level of hsCRP corelated with d-ROMs level in patients with coronary artery disease. Also in the present study, we demonstrated that the reduction in hsCRP level and that of d-ROMs after beta-blocker treatment correlated with each other in all 48 patients with CHF. Although both bisoprolol and carvedilol reduced both levels of hsCRP and d-ROMs, the reduction of hsCRP was somewhat stronger by bisoprolol, while that of d-ROMs was somewhat stronger by carvedilol. The results suggest that both agents have both anti-inflammatory and anti-oxidative stress, bisoprolol might act anti-inflammation-dominantly while carvedilol anti-oxidation-dominantly.
      The results of the present study suggest that a CHF-related inflammatory response might be associated with myocardial injury, and that bisoprolol might have an advantage over carvedilol for reduction of inflammation. However, carvedilol might have an advantage over bisoprolol to reduce oxidative stress for the treatment of CHF. Since both inflammation and oxidative stress are very important factors associated with the severity and prognosis of CHF, the effects of beta-blockers on ameliorating these pathophysiologic states might contribute to their therapeutic efficacy in the treatment of CHF. Although bisoprolol and carvedilol are both effective beta-blockers to improve prognosis in patients with CHF, the proper use of each beta-blocker based on an individual’s pathophysiologic state (e.g. inflammation- or oxidative stress-dominance) may be useful in the future to select optimal CHF treatment.

      Limitations

      The present study has several limitations. The biggest limitation is that the sample size was too small to provide clinically-relevant evidence. Although we measured only hsCRP as an inflammatory marker and d-ROMs as an oxidative stress marker in the present study, simultaneous measurement of other biomarkers might be needed to more precisely assess the pathophysiologic state in CHF. Although the reduction of hsCRP was more prominent after bisoprolol treatment and that of d-ROMs was more prominent after carvedilol treatment, the absolute reduction in the values of both hsCRP and d-ROMs was not significantly different between the two beta-blockers. In addition, it cannot be denied that concomitant medications including statins affected the results for changes in hsCRP and d-ROMs, although their continuation status as well as baseline usage was similar between both beta-blocker groups. In particular, the higher use of digitalis in the carvedilol group cannot be ignored, because it has been shown that digitalis has been shown to affect inflammatory as well as oxidative stress status [
      • Fürst R.
      • Zündorf I.
      • Dingermann T.
      New knowledge about old drugs: the anti-inflammatory properties of cardiac glycosides.
      ,
      • Pratt R.D.
      • Brickman C.R.
      • Cottrill C.L.
      • Shapiro J.I.
      • Liu J.
      The Na/K-ATPase signaling: from specific ligands to general reactive oxygen species.
      ]. Therefore, our contention that bisoprolol has some advantages for reducing inflammation and carvedilol has some advantages for reducing oxidative stress might be exaggerated. To establish the pharmacological actions of these two beta-blockers, further study is needed. Although there are also some other limitations, we believe the present study provides new insight into therapeutic strategies targeting inflammation and oxidative stress that might be promising for the next generation of CHF treatments. However, the ability of therapeutic interventions to reduce inflammation or oxidative stress and the prognostic importance of targeting these pathophysiologic states in CHF require further study.

      Conclusions

      Treatment with both bisoprolol and carvedilol reduced cardiac overload and protected against myocardial injury in patients with CHF. In addition, both beta-blockers have anti-inflammatory and antioxidant effects. The myocardial protective effects of beta- blockers might be associated with anti-inflammatory effects. However, these properties are somewhat different between bisoprolol and carvedilol. Proper use of each beta-blocker based on individual pathophysiology would be promising in the future to achieve further benefits in CHF patients.

      Disclosures

      T.I. has received honoraria from Mochida and Bayer; research grants from Astellas, Abbott Vascular, Boehringer Ingelheim, Bayer, Boston Scientific, Sanwa Kagaku Kenkyusho, Teijin Pharma, Takeda, Mitsubishi Tanabe, and Medtronic. K.N. has received honoraria from Boehringer Ingelheim, Daiichi Sankyo, Astellas, MSD, Takeda, Mitsubishi Tanabe, and Sanofi, as well as research grants from Sanwa Kagaku Kenkyusho, Astellas, Takeda, Boehringer Ingelheim, Bayer, Teijin, and Mitsubishi Tanabe. The other authors have no conflicts of interest to report.

      Funding

      This research received no grant from any funding agency in the public, commercial, or not-for-profit sectors.

      Acknowledgment

      We appreciate Ayumi Matsunuma, Clinical Research Coordinator, and Mikie Ogawa, Research Associate in the Department of Cardiovascular Medicine, Dokkyo Medical University, for their efforts in data acquisition and technical support. We also thank Kiyosoh Yamagata, Kureha Special Laboratory Co., Ltd, for his assistance with statistical analysis.

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