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Serial circulating concentrations of c‐reactive protein, interleukin (il)‐4, and il‐6 in patients with acute left heart decompensation

Serial circulating concentrations of c‐reactive protein, interleukin (il)‐4, and il‐6 in patients... YOSHIK~TAKATSU,M.D.,KAZUAKI KATAOKA,M.D.,TASUKUYAMADA,M.D., RYOJITANIGUCHI, SHlGErAKE M.D., SASAYAMA, M.D.,* A m MAI”I’UMORI, M.D.* Division of Cardiology,Department of Internal Medicine, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Hyogo; *Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan Summary Background:Interleukin (IL)-6has recently been shown to have negative inotropic effects, and several studies have reported increases in circulating concentrations of this cytokine in patients with depressed left ventricularejection fraction and chronic left heart failure. However, most previous clinical studies have measured cytokines in compensated chronic heart failure. Hypothesis: The purpose of this study was to examine the temporal evolution of circulating concentrations of C-reactive protein (CRP) and cytokines in patients with cardiomyopathy and acute cardiac decompensation, free of infection and unstable angina. Methods: The time course of circulatingconcentrationsof CRP, an anti-inflammatory cytokine interleukin (a)-4, and a proinflammatory cytokine L - 6 were studied in eight patients with cardiomyopathyand acute cardiac decompensationin the absence of infection or unstable angina. Control samples were obtained from eight age-matched asymptomaticsubjects. Results: Increasedcirculating concentrationsof CRP (2.6f 0.8 mg/dl), IL-4 (164.6 k 36.5 pg/ml), and IL-6 (17.1 k 5.1 pg/ml) were found in all eight patients during acute cardiac de- compensation; these values decreased significantly with the resolution of symptoms of cardiac decompensation (0.5k 0.1 mg/dl, 77.8 r 23.6 pg/ml, 2.3 k 0.1 pg/ml, respectively, p< 0.05 for both). There was a significant correlation between peak CRP and peak IL-6 (p c 0.05). ConcZusions: In patients with acute left heart decompensation in the absence of infection or coronary events, CRP, IL-4, and IL-6 increased and returned toward normal levels as the symptoms of heart failure resolved. Since the changes in concentrationsof CRP, L-4, and IL-6 in patients with heart failure are dynamic, the distinction between compensated and decompensated state is important when discussing the significance of acutereactive proteins or cytokines in the pathogenesis of heart failure. Key words: C-reactive protein, cytokine, heart failure, cardiomyopathy Introduction Chronic left heart failure is the final common pathway of a variety of cardiac disorders, including ischemic heart disease, idiopathic dilated cardiomyopathy (IDC), valvular disand ease, and is usually progressive. Some cytokines have recently been shown to have negative inotropic effects,’ and several studieshave reported increasesin circulatingconcentrationsof these cytokinesin patients with depressed left ventricularejecHowtion fraction (LVEF) and chronic left heart ever, most previous clinical studies have measured cytokines in compensated chronic heart failure. C-reactiveprotein (CRP),an acute phase reactiveprotein, is synthesized in the liver, and its serum concentration is a reliable index of overall inflammatory activity. Respiratory tract infections may precipitate the decompensation of chronic heart failure and are associated with increased serum concentrations of CW. Likewise,patients with unstable angina, an inflammatory form of atherosclerotic disease, have increased Address for reprints: Yukihito Sato Division of Cardiology Department of Internal Medicine Hyogo Prefectural Amagasaki Hospital 1-1-1 Higashi-daimotsu-cho Hyogo 660-0828, Japan Received: March 15, 1999 Accepted with revision: May 26, 1999 Clin. Cardiol. Vol. 22, December 1999 to test the significanceof changes in variablesover time during treatment of acute heart failure. Correlation between CRP and IL-6 was analyzed by Peason’s correlation coefficient test. A p value < 0.05 was considered significant. serum levels of CRp.6The purpose of this study was to examine the temporal evolution of circulating concentrations of CRP and cytokinesin patients with cardiomyopathyand acute cardiac decompensation,free of infectionand unstable angina. Study Populationsand Methods Patients Five patients with IDC and three patients with ischemic cardiomyopathy (ICM) (seven men and one woman, mean age 70.6 years, range 50-83 years), admitted to the Hyogo Prefectural Amagasaki Hospital for treatment of acute left heart failure between August and October 1997, were studied. The underlying cardiomyopathy was diagnosed on the basis of cardiac catheterization,and the diagnosis of IDC versus ICM was made according to the criteria defined by the World Health OrganizationhtemationalSociety and Federation of Cardiology (WHOASFC) task force.’ The diagnosis of acute left heart decompensationwas based on all of the followingfindings: (1) complaint of dyspnea or presence of orthopnea, (2) moist rales audiblein both lungs, (3) radiographicfindingsconsistentwith pulmonary edema, and (4) depressed LVEF on echocardiography. Heart failure was defined as acute when the onset of decompensation had occurred within 2 weeks. Although al l patients had low LVEFs, they had been clinically stable, without signs or symptomsof pulmonary congestion for at least 2 months before the onset of acute decompensation. Patients with a history of myocardial infarction or angina pectoris within 1 year were excluded, and serial creatine kinase enzyme measurements and electrocardiograms(ECGs) were obtained. Patients with infectious diseases, renal failure, cancer, or autoimmune diseases were also excluded. To avoid the nonspecificimunoreactive induction of CRP and inflammatory cytokines, cardiac catheterizationprocedures, including Swan-Ganzcatheters, were withheld for the first 7 days. Controls ReSUltS Patients Characteristics The mean LVEF on echocardiography was 29.5 k 3.6%. No patient had abnormal serum concentrations of creatine kinase or evolving ECG abnormalities (data not shown) and three patients with ICM had serum concentrationsof cardiac troponin T< 0.02 ng/ml.Absence of infection was verifiedby the collection of blood, sputum, urine, and stool cultures from each patient upon admission to the intensive care unit, and all remained afebrile throughout the study. All patie.nts were treated with intravenous furosemide, six patients received an infusion of the phosphodiesteraseinhibitor olprinone (Eisai, Japan), and one patient was placed on an infusion of dopamine. No patient received antibiotics. The symptoms and radiographic signs ofpulmonary congestion resolved within 10 days in all patients. C-ReactiveProtein and Cytokines Increased circulating concentrations of CRP (2.6~t mg/ 0.8 dl), IL-4 (164.6 36.5 pg/ml), and IL-6 (17.1 rt 5.1 pg/ml) were found in all eight patients during acute cardiac decompensation; these values decreased significantly with the resolution of symptoms of acute left heart failure (0.5 +. 0.1 mg/dl, 77.8 23.6 pg/ml, 2.3 0.1 pg/ml, respectively, p < 0.05 for both) (Fig. 1). There was a significant correlation between peak CRP and peak IL-6 (p <0.05).The peak concentrationof CRP, IL-4, and IL-6 did not correlate with the left ventricular Control blood samples were obtained from eight agematched asymptomatic subjects, five men and three women, (average age 70.0years, range 58-83 years), whose echocardiographic left ventricular systolic functionwas normal. Blood Samples Blood was collected daily for 5 to 7 days after admission of the patient to the hospital. Plasma concentrations of interleukin (IL)-4 and IL-6 were measured with commercially available enzyme-linked immunosorbent assay kits. Serum concentrations of CRP were assayed by automated enzyme immunoassays. StatisticalAnalysis Circulating concentrations of cytokines and C W were expressed as mean value standard error. Paired t-test was used IiL Cardiac decornpensation FIG. Circulating concentrations of C-reactive protein (CRP), 1 IL-4, and L-6. All patients with acute cardiac decompensation had increased serum concentrations of CRP, interleukin (IL)-4, and IL-6, which decreased significantlywith the resolution of symptoms (p < 0.05). Y. Sato et al.: C-reactive protein and cytokines in heart failure echocardiographic ejection fraction measured on admission (data not shown). Corresponding concentrations in control subjects were 0.15 k 0.01 mgldl (CRP), < 20 p g / d (IL-4), and 1.3 & 0.1 pg/ml (IL-6). Conclusion Our findings indicate that patients with acute cardiac decompensation in absence of infection or myocardial ischemia have increased circulating concentrations of CRP, IL-4, and IL-6. Since the changes in these parameters in patients with chronic left heart failure are dynamic, the distinction between compensated and decompensated state is important when discussing the significanceof acute reactive proteins or cytokines in the pathogenesis of heart failure. Discussion Our data indicate that CRP, E-4, and IL-6 were elevated in all patients during the acute phase and decreased as the signs and symptoms of acute heart decompensationresolved. Since the acute phase response is a nonspecific phenomenon induced by nearly all forms of tissue injury and inflammation, concurrent disorders must be excluded when examining the specific association between concentrations of circulating acute-phaseproteins and acute heart failure. In this study,patients with recent myocardial infarction, angina pectoris, and infectionswere systematically excluded. Interleukin-6 is a proinflammatory cytokine that induces a wide variety of functional responses. It is a major inducer of CRP, and our data confirmeda significantcorrelationbetween CRP and L - 6 in patients with decompensated heart failure. Although the origin of the increasein L-6 in patientswith heart failure remains unknown, it is produced in monocytes/macrophages, endothelialcells, vascular smooth muscle cells, and fibroblasts; it has also been recently reported that hypoxic stress induces cardiac myocyte-derived L-6.*Cardiac decompensation itself, and other organ injuries induced by low cardiac output, hypoperfusion,hypoxia, and venous congestionmay each be sources of IL-6 which, in turn,may induce the production of CRP in patients with acute cardiac decompensation. Interleukin-4inhibits the ability of monocytes to produce IL-1p and TNF-aand is considered an anti-inflammatorycytokine. We found high circulating concentrations of IL-4 in all patients with acute cardiac decompensation and it seems to be an acutely induced cytokine in this clinical setting. The pathologic significanceof IL-4 in patients with heart failure has not been described at the present time. The imprecise onset of acute cardiac decompensation among individualpatients is a limitation of this study.In addition, we have recently reported that several drugs used in the treatment of heart failure, including phosphodiesterase inhibitors, decrease the production of cytokine? Since six of our patients received a phosphodiesteraseinhibitor, it may have had an effect on the measured concentrationsof cytokines. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Cardiology Wiley

Serial circulating concentrations of c‐reactive protein, interleukin (il)‐4, and il‐6 in patients with acute left heart decompensation

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References (9)

Publisher
Wiley
Copyright
Copyright © 1999 Wiley Periodicals, Inc.
ISSN
0160-9289
eISSN
1932-8737
DOI
10.1002/clc.4960221211
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Abstract

YOSHIK~TAKATSU,M.D.,KAZUAKI KATAOKA,M.D.,TASUKUYAMADA,M.D., RYOJITANIGUCHI, SHlGErAKE M.D., SASAYAMA, M.D.,* A m MAI”I’UMORI, M.D.* Division of Cardiology,Department of Internal Medicine, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Hyogo; *Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan Summary Background:Interleukin (IL)-6has recently been shown to have negative inotropic effects, and several studies have reported increases in circulating concentrations of this cytokine in patients with depressed left ventricularejection fraction and chronic left heart failure. However, most previous clinical studies have measured cytokines in compensated chronic heart failure. Hypothesis: The purpose of this study was to examine the temporal evolution of circulating concentrations of C-reactive protein (CRP) and cytokines in patients with cardiomyopathy and acute cardiac decompensation, free of infection and unstable angina. Methods: The time course of circulatingconcentrationsof CRP, an anti-inflammatory cytokine interleukin (a)-4, and a proinflammatory cytokine L - 6 were studied in eight patients with cardiomyopathyand acute cardiac decompensationin the absence of infection or unstable angina. Control samples were obtained from eight age-matched asymptomaticsubjects. Results: Increasedcirculating concentrationsof CRP (2.6f 0.8 mg/dl), IL-4 (164.6 k 36.5 pg/ml), and IL-6 (17.1 k 5.1 pg/ml) were found in all eight patients during acute cardiac de- compensation; these values decreased significantly with the resolution of symptoms of cardiac decompensation (0.5k 0.1 mg/dl, 77.8 r 23.6 pg/ml, 2.3 k 0.1 pg/ml, respectively, p< 0.05 for both). There was a significant correlation between peak CRP and peak IL-6 (p c 0.05). ConcZusions: In patients with acute left heart decompensation in the absence of infection or coronary events, CRP, IL-4, and IL-6 increased and returned toward normal levels as the symptoms of heart failure resolved. Since the changes in concentrationsof CRP, L-4, and IL-6 in patients with heart failure are dynamic, the distinction between compensated and decompensated state is important when discussing the significance of acutereactive proteins or cytokines in the pathogenesis of heart failure. Key words: C-reactive protein, cytokine, heart failure, cardiomyopathy Introduction Chronic left heart failure is the final common pathway of a variety of cardiac disorders, including ischemic heart disease, idiopathic dilated cardiomyopathy (IDC), valvular disand ease, and is usually progressive. Some cytokines have recently been shown to have negative inotropic effects,’ and several studieshave reported increasesin circulatingconcentrationsof these cytokinesin patients with depressed left ventricularejecHowtion fraction (LVEF) and chronic left heart ever, most previous clinical studies have measured cytokines in compensated chronic heart failure. C-reactiveprotein (CRP),an acute phase reactiveprotein, is synthesized in the liver, and its serum concentration is a reliable index of overall inflammatory activity. Respiratory tract infections may precipitate the decompensation of chronic heart failure and are associated with increased serum concentrations of CW. Likewise,patients with unstable angina, an inflammatory form of atherosclerotic disease, have increased Address for reprints: Yukihito Sato Division of Cardiology Department of Internal Medicine Hyogo Prefectural Amagasaki Hospital 1-1-1 Higashi-daimotsu-cho Hyogo 660-0828, Japan Received: March 15, 1999 Accepted with revision: May 26, 1999 Clin. Cardiol. Vol. 22, December 1999 to test the significanceof changes in variablesover time during treatment of acute heart failure. Correlation between CRP and IL-6 was analyzed by Peason’s correlation coefficient test. A p value < 0.05 was considered significant. serum levels of CRp.6The purpose of this study was to examine the temporal evolution of circulating concentrations of CRP and cytokinesin patients with cardiomyopathyand acute cardiac decompensation,free of infectionand unstable angina. Study Populationsand Methods Patients Five patients with IDC and three patients with ischemic cardiomyopathy (ICM) (seven men and one woman, mean age 70.6 years, range 50-83 years), admitted to the Hyogo Prefectural Amagasaki Hospital for treatment of acute left heart failure between August and October 1997, were studied. The underlying cardiomyopathy was diagnosed on the basis of cardiac catheterization,and the diagnosis of IDC versus ICM was made according to the criteria defined by the World Health OrganizationhtemationalSociety and Federation of Cardiology (WHOASFC) task force.’ The diagnosis of acute left heart decompensationwas based on all of the followingfindings: (1) complaint of dyspnea or presence of orthopnea, (2) moist rales audiblein both lungs, (3) radiographicfindingsconsistentwith pulmonary edema, and (4) depressed LVEF on echocardiography. Heart failure was defined as acute when the onset of decompensation had occurred within 2 weeks. Although al l patients had low LVEFs, they had been clinically stable, without signs or symptomsof pulmonary congestion for at least 2 months before the onset of acute decompensation. Patients with a history of myocardial infarction or angina pectoris within 1 year were excluded, and serial creatine kinase enzyme measurements and electrocardiograms(ECGs) were obtained. Patients with infectious diseases, renal failure, cancer, or autoimmune diseases were also excluded. To avoid the nonspecificimunoreactive induction of CRP and inflammatory cytokines, cardiac catheterizationprocedures, including Swan-Ganzcatheters, were withheld for the first 7 days. Controls ReSUltS Patients Characteristics The mean LVEF on echocardiography was 29.5 k 3.6%. No patient had abnormal serum concentrations of creatine kinase or evolving ECG abnormalities (data not shown) and three patients with ICM had serum concentrationsof cardiac troponin T< 0.02 ng/ml.Absence of infection was verifiedby the collection of blood, sputum, urine, and stool cultures from each patient upon admission to the intensive care unit, and all remained afebrile throughout the study. All patie.nts were treated with intravenous furosemide, six patients received an infusion of the phosphodiesteraseinhibitor olprinone (Eisai, Japan), and one patient was placed on an infusion of dopamine. No patient received antibiotics. The symptoms and radiographic signs ofpulmonary congestion resolved within 10 days in all patients. C-ReactiveProtein and Cytokines Increased circulating concentrations of CRP (2.6~t mg/ 0.8 dl), IL-4 (164.6 36.5 pg/ml), and IL-6 (17.1 rt 5.1 pg/ml) were found in all eight patients during acute cardiac decompensation; these values decreased significantly with the resolution of symptoms of acute left heart failure (0.5 +. 0.1 mg/dl, 77.8 23.6 pg/ml, 2.3 0.1 pg/ml, respectively, p < 0.05 for both) (Fig. 1). There was a significant correlation between peak CRP and peak IL-6 (p <0.05).The peak concentrationof CRP, IL-4, and IL-6 did not correlate with the left ventricular Control blood samples were obtained from eight agematched asymptomatic subjects, five men and three women, (average age 70.0years, range 58-83 years), whose echocardiographic left ventricular systolic functionwas normal. Blood Samples Blood was collected daily for 5 to 7 days after admission of the patient to the hospital. Plasma concentrations of interleukin (IL)-4 and IL-6 were measured with commercially available enzyme-linked immunosorbent assay kits. Serum concentrations of CRP were assayed by automated enzyme immunoassays. StatisticalAnalysis Circulating concentrations of cytokines and C W were expressed as mean value standard error. Paired t-test was used IiL Cardiac decornpensation FIG. Circulating concentrations of C-reactive protein (CRP), 1 IL-4, and L-6. All patients with acute cardiac decompensation had increased serum concentrations of CRP, interleukin (IL)-4, and IL-6, which decreased significantlywith the resolution of symptoms (p < 0.05). Y. Sato et al.: C-reactive protein and cytokines in heart failure echocardiographic ejection fraction measured on admission (data not shown). Corresponding concentrations in control subjects were 0.15 k 0.01 mgldl (CRP), < 20 p g / d (IL-4), and 1.3 & 0.1 pg/ml (IL-6). Conclusion Our findings indicate that patients with acute cardiac decompensation in absence of infection or myocardial ischemia have increased circulating concentrations of CRP, IL-4, and IL-6. Since the changes in these parameters in patients with chronic left heart failure are dynamic, the distinction between compensated and decompensated state is important when discussing the significanceof acute reactive proteins or cytokines in the pathogenesis of heart failure. Discussion Our data indicate that CRP, E-4, and IL-6 were elevated in all patients during the acute phase and decreased as the signs and symptoms of acute heart decompensationresolved. Since the acute phase response is a nonspecific phenomenon induced by nearly all forms of tissue injury and inflammation, concurrent disorders must be excluded when examining the specific association between concentrations of circulating acute-phaseproteins and acute heart failure. In this study,patients with recent myocardial infarction, angina pectoris, and infectionswere systematically excluded. Interleukin-6 is a proinflammatory cytokine that induces a wide variety of functional responses. It is a major inducer of CRP, and our data confirmeda significantcorrelationbetween CRP and L - 6 in patients with decompensated heart failure. Although the origin of the increasein L-6 in patientswith heart failure remains unknown, it is produced in monocytes/macrophages, endothelialcells, vascular smooth muscle cells, and fibroblasts; it has also been recently reported that hypoxic stress induces cardiac myocyte-derived L-6.*Cardiac decompensation itself, and other organ injuries induced by low cardiac output, hypoperfusion,hypoxia, and venous congestionmay each be sources of IL-6 which, in turn,may induce the production of CRP in patients with acute cardiac decompensation. Interleukin-4inhibits the ability of monocytes to produce IL-1p and TNF-aand is considered an anti-inflammatorycytokine. We found high circulating concentrations of IL-4 in all patients with acute cardiac decompensation and it seems to be an acutely induced cytokine in this clinical setting. The pathologic significanceof IL-4 in patients with heart failure has not been described at the present time. The imprecise onset of acute cardiac decompensation among individualpatients is a limitation of this study.In addition, we have recently reported that several drugs used in the treatment of heart failure, including phosphodiesterase inhibitors, decrease the production of cytokine? Since six of our patients received a phosphodiesteraseinhibitor, it may have had an effect on the measured concentrationsof cytokines.

Journal

Clinical Cardiology – Wiley

Published: Dec 1, 1999

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