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Ann Thorac Surg 2000;70:562-567
© 2000 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Gene expression of inflammatory mediators in different chambers of the human heart

^a Department of Thoracic Surgery Stockholm, Sweden
^b Cardiovascular Research Unit, Center For Molecular Medicine, Karolinska Hospital, Stockholm, Sweden

Address reprint requests to Dr Valen, Crafoord Laboratory of Experimental Surgery L6:00, Karolinska Hospital, S-17176 Stockholm, Sweden
e-mail: guro.valen{at}cmm.ki.se

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Inflammatory genes may be unevenly expressed in different heart chambers.

Methods. Biopsies were taken simultaneously from the right atrium (RA), left atrium (LA), and left ventricle (LV) of 19 patients before cardioplegic arrest during open heart surgery. The mRNA expression of tumor necrosis factor (TNF), interleukin 1ß (IL-1ß), inducible and endothelial nitric oxide synthase (iNOS and eNOS), endothelin-1 (ET-1), E-selectin (CD62E), intercellular adhesion molecule-1 (ICAM-1) and its ligand CD18, and CD25 was evaluated with semiquantitative reverse transcription-polymerase chain reaction (RT-PCR).

Results. Expression of TNF mRNA was higher in RA than LA and LV (p < 0.05), whereas IL-1ß was more expressed in LA than RA (p < 0.05), which was higher than LV (p < 0.0001). There were no significant regional differences in the expression of ICAM-1, CD62E, CD25, iNOS, and eNOS. CD18 was higher in RA than LA (p < 0.05); ET-1 was more expressed in RA than LV (p < 0.04). Patients with stable angina had no expression of eNOS.

Conclusions. Gene expression of inflammatory mediators was detected in the hearts of patients with different cardiovascular disorders, and was unevenly distributed in different heart chambers. Cardiac biopsies should be taken from the same site.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Cardiovascular disorders such as arteriosclerosis are associated with a chronic inflammatory process [1]. In unstable angina, evidence suggests that plaque instability is associated with a local inflammation of the plaque, combined with systemic indices of acute inflammation [2, 3]. The influence of arteriosclerosis and plaque instability on myocardial tissue has not been well characterized. The possible association between inflammation and valvular disease has not been described.

Studies investigating human myocardial expression of inflammatory mediators have mostly been conducted in failing, explanted hearts with severe pathophysiologic changes. In these hearts, expression of inflammatory mediators such as leukocyte adhesion molecules, endothelin-1, nitric oxide synthase, and proinflammatory cytokines appears to be connected to degree of disease [4–9]. Few studies, however, have described gene expression of inflammatory mediators in nonfailing hearts with a milder degree of pathophysiologic change, such as the average patient scheduled for open heart surgery or admitted to the intensive care unit with unstable angina. Increasing knowledge of the cellular and molecular pathology in such patients may in the next step provide tools for improving myocardial protection.

When taking myocardial biopsies during open heart procedures for research purposes, it is from an ethical and practical point of view preferable to sample atrial tissue. In open heart surgery with cardiopulmonary bypass (CPB) biopsies are easily taken from the right atrial auricle in conjunction with cannulation for CPB as this is cut open. Other possible sites are the left atrial auricle, or needle biopsies from the left ventricular wall. Potentially there may be regional differences in gene expression, as several substances such as receptors of the sympathetic nerve system, factors in the renin-angiotensin system, and atrial natriuretic factor are unevenly distributed among the different heart chambers [10–13]. A comparison of gene expression between different sampling sites would clarify how sampling may be performed in future studies.

The aim of the present study was to investigate gene expression of inflammatory mediators in the hearts of patients without cardiac failure, and with different cardiovascular disorders, in order to evaluate possible myocardial inflammation. The pattern of expression in the right atrium, left atrium, and left ventricle was compared in biopsies from 19 patients undergoing open heart procedures with CPB. Specifically, gene expression of endothelial and inducible nitric oxide synthase (eNOS and iNOS), the vasoconstrictor endothelin-1 (ET-1), the leukocyte adhesion molecules E-selectin (CD62E) and intercellular adhesion molecule-1 (ICAM-1) were studied. The leukocyte activation markers CD18 (a ß2 integrin, ligand for ICAM-1) and CD25 (IL-2 receptor chain on activated mononuclear cells) and the cytokines tumor necrosis factor (TNF) and interleukin-1ß (IL-1ß) were also included.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Patient population
The study was approved by the Ethics Committee of the Karolinska Hospital on February 3, 1997, and conforms to the principles outlined in the declaration of Helsinki. Nineteen consecutive patients (7 with unstable angina, 7 with stable angina, and 5 patients with valvular disease or coronary arteriosclerosis plus valvular disease, as described in Table 1) gave informed consent to participate. Unstable patients were defined as rest angina or excertional angina resistant to oral nitroglycerin; upon admission to the coronary care unit transient ischemic ST-segment changes were found; the patients were treated with intravenous nitroglycerin and low molecular weight heparin (Fragmin, Pharmacia & Upjohn, Stockholm, Sweden), and medical therapy with calcium and ß-adrenergic antagonists was optimized. When coronary angiography revealed double- or triple-vessel disease combined with persistant symptoms, the patients were scheduled for acute coronary artery bypass grafting (CABG) and included in the study. The duration of symptoms before acute surgery ranged from 6 to 14 days. Stable patients had excertional angina and positive exercise stress-test combined with double- or triple-vessel disease. Four patients (8, 9, 12 and 13 in Table 1) had moderately reduced ejection fraction preoperatively (0.3 to 0.4). Four patients had diabetes (4, 8, 16, and 17) and 1 plasmacytoma (patient 3 in Table 1); otherwise the preoperative data (ejection fraction > 0.4, number of previous myocardial infarctions, degree of coronary artery disease) were similar between groups with ischemic heart disease.

mRNA extraction and cDNA synthesis
Frozen tissue was homogenized in a microdismembrator, and mRNA extracted using a Dynabeads mRNA direct kit (Dynal A.S., Oslo, Norway), with the protocol supplied by the manufacturers. RNA was extracted twice into a final volume of 40 µL. Single-stranded cDNA synthesis was performed by Superscript II (Life Technologies, Paisley, UK) according to the manufacturer, using random hexamers (Life Technologies) as primers in the presence of RNasin (Promega, Madison, WI).

Semiquantitative PCR
Gene expression of all mediators and all three sampling sites were performed on the same mastermix in 1 patient, in order to avoid differences due to pipetting of small volumes. Each PCR reaction was run in a volume of 25 µL. A master mix was prepared consisting of dNTP (6.25 mmol/L), MgCl₂ (1.5 mmol/L), PCR buffer, 0.02 U Taq polymerase (all Life Technologies), and 5 µCi ³³P-dATP/sample (NEN, DuMedical Scandinavia). After dividing the mastermix into three portions and adding cDNA from one sampling site in each (1 µL per gene) to ensure that all tubes would contain equal amounts of cDNA, samples were aliquoted in separate PCR tubes. Primers were added at a final concentration of 0.2 µmol/L. Instead of measuring the RNA concentration, histone H3, which is expressed at the same level independent of cell cycle, was selected as a housekeeping gene and amplified in all samples [14]. For information on primers see Table 2. Amplification was started in a hot block at 94°C 2.30 minutes, 60°C 30 seconds, and 72°C 45 seconds, followed by cycles of 94°C 30 seconds, 60°C 30 seconds, and 72°C 45 seconds for H3, TNF, IL-1ß, CD18, CD25, E-selectin, and ICAM-1. For iNOS and ET-1 an annealing temperature of 65°C was employed. The linear phase of the PCR reaction was determined, and the number of cycles selected and kept constant throughout the study. For H3, 22 cycles were used; for TNF, IL-1ß, CD18, CD25, and ICAM-1, 26 cycles were used; for iNOS 30 cycles were used; and for ET-1, eNOS, and E-selectin, 32 cycles were used. A control PCR of mastermix without cDNA and with the H3 primer was routinely done in all samples, whereas control reactions on RNA were performed randomly in order to evaluate possible contaminations. All PCR reactions were run at least twice, and the mean value employed for further evaluation.

Calculations and statistics
The ratio between test gene and H3 was calculated in individual samples. The mean ratio of 2 or 3 PCR reactions in each patient was calculated, and employed for further evaluations. Wilcoxon’s signed rank test was used to evaluate differences between sampling sites and between patient groups, as the data were not evenly distributed. A p value less than 0.05 was considered significant. Data are presented as mean ± SEM.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Expression of inflammatory mediators in the human heart
Gene expression of inflammatory mediators in the human heart was studied by reverse transcription-polymerase chain reaction (RT-PCR) analysis of mRNA obtained from myocardial biopsies in conjunction with open heart surgery. To permit semiquantitative evaluation, radiolabelled nucleotides were incorporated, amplifications terminated in the linear phase, and the products separated by a high-resolving polyacrylamide gel electrophoresis. The gels were analyzed by phosphoimaging, and the amount of products related to a housekeeping gene.

Representative results from a patient undergoing acute CABG for unstable angina are showed in Figure 1. All test genes were expressed in samples from this heart, and the results are representative for all patients with unstable angina. With exception of eNOS, the same mRNA species were expressed also in patients with stable coronary heart disease or combined disease (see below).

View larger version (72K): [in this window] [in a new window]   Fig 1. A polyacrylamide gel with radiolabelled reverse transcription-polymerase chain reaction (RT-PCR) products from cardiac tissue of a patient with unstable angina undergoing open heart surgery with cardiopulmonary bypass. Biopsies were taken simultaneously from the left atrium (LA), right atrium (RA), and left ventricle (LV) before cardioplegic arrest. Histone H3 (215 bp) was employed as a reference gene to evaluate the relative amount of test genes, which were tumor necrosis factor (TNF, 444 bp), interleukin-1ß (IL-1ß, 464 bp), intercellular adhesion molecule-1 (ICAM-1, 237 bp), E-selectin (CD62E, 255 bp), CD18 (379 bp), CD25 (312 bp), endothelin-1 (ET-1, 725 bp), inducible nitric oxide synthase (iNOS, 532 bp), and endothelial NOS (eNOS, 737 bp).

Gene expression of TNF was higher in the right atrium than in the left atrium, whereas there were no other significant differences when comparing the three chambers (Fig 2). IL-1ß was differently expressed in all cardiac chambers, with the highest levels in the left atrium and the lowest in the left ventricle. ICAM-1 was equally expressed in all three chambers (Fig 2). Right atrial gene expression of CD62E, CD18, and CD25 tended to be higher than in left atrial or left ventricular tissue, but the difference was significant only for CD18 (Fig 3). Relative mRNA for ET-1 was significantly different only when comparing between the right atrium and the left ventricle (Fig 4). Gene expression of iNOS was lowest in the right atrium, medium in the left atrium, and highest in the left ventricle, while the expression of eNOS was inverse of this (Fig 4). These differences were not significant.

View larger version (36K): [in this window] [in a new window]   Fig 2. Gene expression of tumor necrosis factor (TNF), interleukin-1ß (IL-1ß), and intercellular adhesion molecule-1 (ICAM-1) in human heart biopsies from the right atrium (RA), left atrium (LA), and left ventricle (LV) obtained before cardioplegic arrest during open heart surgery. Reverse transcription-polymerase chain reaction (RT-PCR) was performed, band density measured, and the ratio between test gene and reference gene calculated (= relative mRNA). The left panels show mean ± SEM values from 19 patients, and the right panels show mean ± SEM of subgroups of patients with unstable angina (uCABG, n = 7), stable angina (CABG, n = 7), and valvular or combined disease (VR, n = 5).

View larger version (30K): [in this window] [in a new window]   Fig 3. Gene expression of E-selectin (CD62E), CD18, and CD25 in human heart biopsies from the right atrium (RA), left atrium (LA), and left ventricle (LV) obtained before cardioplegic arrest during open heart surgery (see text to Fig 2).

View larger version (30K): [in this window] [in a new window]   Fig 4. Gene expression of endothelin-1 (ET-1), inducible nitric oxide synthase (iNOS), and endothelial NOS (eNOS) in human heart biopsies (see text to Fig 2).

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
The main finding of the present study was that gene expression of the cytokines TNF and IL-1ß, the leukocyte adhesion molecules ICAM-1 and CD62E, the leukocyte activation markers CD18 and CD25, the vasoconstrictor ET-1, and the vasodilator iNOS was detected in all three investigated chambers of the nonfailing human heart. Relative mRNA for eNOS was detected only in patients with unstable angina or valvular disease. Gene expression of TNF, IL-1ß, CD18, and ET-1 was significantly different in different chambers, with no consistent pattern of distribution. Although most of the other genes tended to be unevenly distributed, that was not significant.

There are few previous studies on the expression of inflammatory mediators in the hearts of patients with a similar degree of disease. Meldrum and coworkers [15] investigated TNF expression in myocardial biopsies of patients similar to ours during CPB and detected TNF protein that increased during CPB. mRNA and protein for TNF were detected in myocardial tissue from patients with dilated cardiomyopathy and advanced left ventricular dysfunction but not in hearts of healthy control subjects or patients with hypertrophic cardiomyopathy [16]. Explanted human hearts of patients with dilated cardiomyopathy contained much more mRNA for IL-1ß than did hearts of patients with ischemic heart disease, whereas TNF mRNA was similar in both pathologies [4]. In infants undergoing open heart surgery for congenital heart disease, gene expression of CD62E and ICAM-1 was measured in atrial tissue before cardioplegic arrest, and the mRNAs increased during reperfusion [17]. Leukocyte adhesion molecules as well as cellular markers or inflammation (CD11a/CD18) were increased in ventricular tissue from explanted hearts compared with healthy controls, with similar levels regardless of the cause of terminal heart failure [5].

Myocardial iNOS gene expression was undetectable [9] or barely detectable [8] in healthy donor hearts, whereas iNOS at both protein and mRNA levels was detected in failing hearts regardless of cause for failure [8, 9]. In contrast, another study found iNOS mRNA coexpressed with TNF in explanted hearts from patients with dilated cardiomyopathy but not in hearts of patients with hypertrophic cardiomyopathy or healthy control subjects [16]. ET-1 expression in failing human hearts was similar between disease groups [6, 18].

Myocardial eNOS expression has not been extensively studied. In one study myocardial eNOS was found barely detectable in 4 nonfailing hearts and clearly expressed in failing hearts [8], while another study found both eNOS mRNA and protein in healthy donor hearts [19]. In the present study the only difference in gene expression between patient groups was found in eNOS, which was detectable only in the hearts of patients with unstable angina or combined disease, but not in those with stable angina or single-valve disease. Of the present mediators, eNOS is the only one whose product is likely to be beneficial for the heart. We speculate that eNOS expression in unstable patients might reflect a compensatory mechanism to maximally dilate the coronary vessels. Based on other findings combined with the present findings, myocardial expression of inflammatory mediators appears to increase with increasing severity of disease. There is no systematic linkage between inflammatory mediators and underlying disease, and it is not determined whether myocardial inflammation is a cause or a consequence of disease. Moreover, we have shown that valvular disease is also associated with myocardial inflammation.

The relative mRNA expression of inflammatory mediators differed among the different chambers. Regional differences in gene expression of components in the renin-angiotensin system [13] and of atrial natriuretic factor [11] have previously been linked to the mechanical stress of increased chamber pressures, which would be an adequate stimulus for gene regulation since both the renin-angiotensin system and atrial natriuretic factor are concerned with maintaining body fluid and electrolyte balance. Gene regulation by mechanical stress may be mediated through shear stress. Of the genes investigated here, shear stress response elements have been identified in the promoter region of eNOS [20], ICAM-1 [21], and ET-1 [22], inducing transcription of eNOS and ICAM-1 but downregulating ET-1. If the stimuli of high pressure may be translated into a shear stress response, one would expect ventricular eNOS and ICAM-1 to be high, and ET-1 low. However, only low ET-1 was found, indicating that other factors beside mechanical stress may be important regulators of these genes.

A possible explanation for chamber differences could be the cellular composition of the chambers. We did not attempt to assess this in the present study, as the size of the ventricular biopsy was a limitation. However, the atria possess a thinner myocardium and relatively thicker epicardial and endocardial layers than the ventricles [23]. Possibly the atrial biopsies contained more nonmyocyte cells (such as adipocytes and fibroblasts), which may have been of influence, as the genes investigated in the present study are not equally expressed in all cell types. Independent of reasons for differences in chamber distribution of inflammatory gene expression, the present study indicates that cardiac biopsies within a study should always be taken from the same site in order to compare patient groups or make comparisons before and after an intervention.

In conclusion, this study shows a set of genes encoding inflammatory mediators to be expressed in the human heart, with modest differences between types of disease but substantial regional differences among chambers. Inflammatory activation may be an important part of the response process to disease of the human heart.

	Acknowledgments

 
The excellent technical assistance of Monika Meckl is gratefully acknowledged. This work was supported by grants from the Swedish Medical Research Council (6818, 11235 and 12665), the Swedish Heart-Lung Foundation, Nanna Swartz’ Foundation, the Foundations Fredrik o Ingrid Thuring, Tore Nilsson, ke Wiberg, Harald o Greta Jeanssons, Sigurd and Elsa Goljes Memory, and the Karolinska Institute.

	References

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