CLINICAL STUDY: CARDIOMYOPATHY
Immunohistologic evidence of myocardial disease in apparently healthy relatives of patients with dilated cardiomyopathy
Niall G. Mahon, MD*,*,
Brendan P. Madden, MD*,
Alida L. P. Caforio, MD, PhD ,
Perry M. Elliott, MD*,
Aldwyn J. Haven, BSc*,
Bruce E. Keogh, MD ,
Michael J. Davies, MD, PhD* and
William J. McKenna, MD*
* Department of Cardiological Sciences, St. George’s Hospital Medical School, London, United Kingdom
Division of Cardiology, Department of Experimental and Clinical Medicine, University of Padova, Padova, Italy
Department of Cardiothoracic Surgery, Queen Elizabeth Hospital, Birmingham, United Kingdom
Manuscript received August 10, 2001;
revised manuscript received October 24, 2001,
accepted November 2, 2001.
* Reprint requests and correspondence: Dr. Niall G. Mahon, Department of Cardiology/F25, Section of Heart Failure Transplant Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
mahonn{at}ccf.org
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Abstract
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OBJECTIVES: This study investigated whether apparently healthy relatives of patients with idiopathic dilated cardiomyopathy (DCM) who have left ventricular enlargement (LVE) have biopsy evidence of underlying myocardial disease.
BACKGROUND: Left ventricular enlargement with normal systolic function is common among asymptomatic relatives of patients with DCM. Although there is circumstantial evidence to suggest that LVE may be a marker of early DCM, its pathophysiologic significance remains uncertain.
METHODS: Over six years, 767 asymptomatic relatives of 183 consecutive patients with DCM were evaluated: 37 (5%) had DCM and 104 (14%) had LVE (left ventricular end-diastolic dimension >112% predicted) with normal systolic function. Right ventricular biopsy was performed in 32 relatives with LVE, 14 patients with symptomatic DCM and 6 control subjects with normal ventricular function undergoing elective coronary artery bypass graft surgery. Histologic and immunohistochemical analyses, including quantitative double immunofluorescence, were performed for leukocyte markers (CD3 and CD68), intercellular adhesion molecule-1 (ICAM-1) and human leukocyte antigen class II antigens (DR and DQ).
RESULTS: Histologic findings consistent with DCM were present in 50% of the patients with DCM, 25% of the relatives with LVE and 0% of the control subjects. The median CD3 count was 2.4/mm2 in patients with DCM, 4/mm2 in relatives with LVE and 0 in control subjects (p = 0.04). Using a threshold of >7 cells/mm2, 21% of patients with DCM and 25% of relatives with LVE were CD3-positive (p = 0.01). Quantitative analysis demonstrated DR expression on 55.8 ± 22.8%, 63.5 ± 18.8% and 30.9 ± 15.7% of the endothelial surface in patients with DCM, relatives and control subjects, respectively (p = 0.003). Corresponding values for ICAM expression were 35.6 ± 15.1%, 36.7 ± 14.5% and 17.3 ± 7.9% (p = 0.013). When combining inflammatory and histologic changes, 28 (86%) of LVE, 14 (100%) of DCM and no control biopsies were abnormal (p < 0.001).
CONCLUSIONS: Most asymptomatic relatives of patients with DCM with LVE have histopathologic and immunopathologic findings similar to those of patients with established disease. Clinical identification and follow-up of such individuals are warranted to prevent presentation with advanced DCM and to enable assessment of interventions aimed at attenuating disease progression.
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Abbreviations and Acronyms
| | LVEDD | | BSA | | body surface area | | DCM | | dilated cardiomyopathy | | HLA | | human leukocyte antigen | | ICAM | | intercellular adhesion molecule | | IgG | | immunoglobulin | | LVE | | left ventricular enlargement | | LVEDD | | left ventricular end-diastolic dimension |
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Idiopathic dilated cardiomyopathy (DCM) typically presents at an advanced stage of left ventricular dilation and dysfunction and accounts for approximately one-third of all new cases of symptomatic congestive cardiac failure and 50% of all patients undergoing heart transplantation (1). The recognition, through recent prospective family evaluation studies, that 25% of patients have familial disease (2–4) raises the possibility that prognosis might be improved by earlier diagnosis and treatment of relatives in a preclinical phase of the disorder. Several mutations in genes encoding for myocyte structural proteins have been shown to be etiologic in individual DCM families (5–15), but the ability to detect early disease by genetic screening is limited by the fact that these mutations account for substantially <5% of disease (16,17). We have previously reported that a proportion of the apparently healthy relatives of patients with DCM have isolated left ventricular enlargement (LVE), and that this may be associated with serologic evidence of immune activation, subtle physiologic abnormalities and risk of progression to overt DCM (3,18,19). However, to target potential therapies effectively and safely, a more definitive demonstration of disease activity is required in such individuals. Recent immunohistochemical studies have shown that patients with DCM have increased expression of human leukocyte antigens (HLAs) and cell adhesion molecules in the myocardial vasculature, as well as cellular infiltration consistent with a chronic low-grade inflammation (20,21). The aim of this study was to determine whether similar histopathologic abnormalities are present in apparently healthy relatives with LVE.
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Methods
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Study group.
Between January 1992 and December 1998, prospective cardiovascular evaluation was offered to the relatives of 370 consecutive patients with DCM attending St. George’s Hospital in London. Evaluation of relatives was offered to all patients with DCM, irrespective of the presence or absence of a family history. A total of 198 patients consented to participate in the study. Evaluation of asymptomatic relatives was approved by and performed in accordance with the local ethics committee and has been described in detail elsewhere (18). Evaluation included clinical assessment, 12-lead electrocardiography and two-dimensional echocardiography. Left ventricular cavity dimensions were corrected for age and body surface area (BSA) according to the formula of Henry et al. (22): percent predicted left ventricular end-diastolic dimension (LVEDD) = measured LVEDD/predicted LVEDD x 100; predicted LVEDD = (45.3 x BSA0.3) – (0.03 x age) – 7.2. Relatives with known coronary disease, hypertension, valvular disease or regular alcohol consumption of >21 U/week in men and >14 U/week in women were excluded (1 U = one-half ounce). In total, 767 relatives met inclusion criteria. Of these, 552 (72%) were assessed as normal, 37 (5%) fulfilled World Health Organization criteria for DCM (23), 25 (3%) had isolated, depressed fractional shortening (<25%) and 104 (14%) had LVE, defined as an unexplained LVEDD >112% of predicted values in the presence of a shortening fraction  25% (18). A sample pedigree is shown in Figure 1.
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Figure 1 Pedigree of a dilated cardiomyopathy family. Solid symbols = affected individuals; half-solid symbols = asymptomatic relatives with left ventricular enlargement.
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Thirty-two consecutive asymptomatic relatives from 25 families attending follow-up visits between January 1998 and June 1999 gave informed, written consent to undergo right ventricular biopsy. The majority were first-degree relatives, three were second-degree and one was a third-degree relative. In addition, 14 consecutive patients with confirmed symptomatic idiopathic DCM presenting during the same period, who had not previously undergone myocardial biopsy were studied. Control tissue was obtained, following informed consent, from six patients undergoing coronary artery bypass graft surgery for ischemic heart disease without left ventricular dysfunction, with tissue obtained at the time of operation from an area of the ventricle not subtended by a diseased vessel. Specific approval for the biopsy protocol was obtained from the local research ethics committee.
Myocardial biopsy.
Patients and relatives underwent fluoroscopically guided right ventricular biopsy through the right internal jugular vein. At least four samples were processed for hematoxylin-eosin staining, and two specimens were snap-frozen in Tissue-Tek (Sakura Finetek, Inc., Torrance, California) media in a cryo-mould and immediately transported on dry ice for storage at –80°C before immunohistochemical analysis. In all cases, myocardial biopsy was performed within three months of a diagnostic echocardiogram.
Histology and immunohistochemistry.
Specimens processed for light microscopy were analyzed by an experienced cardiac histopathologist (M. J. D.), who had no knowledge of the identity and clinical details of the subjects. For immunohistochemistry, serial 4-µm frozen cryostat sections were fixed in acetone for 3 min, incubated for 30 min with mouse monoclonal antibodies to intercellular adhesion molecule-1 (ICAM-1) (CD54, clone 6.5B5, Serotec, Oxford, UK), HLA-DR (clone B.C10, Serotec), HLA-DQ (clone SPV-L3, Serotec), CD3 (clone UCHT1, Serotec) and CD68 (clone EBM11, Dakopatts, Glostrup, Denmark), washed for 15 min in phosphate-buffered saline and incubated for 25 min with affinity-purified biotinylated goat antibodies to mouse immunoglobulin G (IgG) (Dakopatts) (gamma-chain specific). After further washing, the sections were incubated with fluorescein isothiocyanate-conjugated streptavidin (Dakopatts), which labels biotin at a ratio of 3 molecules of streptavidin to 1 molecule of biotin. On sections stained for adhesion molecules and HLA markers, rabbit IgG to factor VIII (Dakopatts) (endothelial cell marker) was applied for 25 min and, after repeat washing, the sections were incubated with tetraethylrhodamine isothiocyanate-conjugated goat anti-rabbit IgG (Sigma, Cambridge, UK). On sections stained for CD3 and CD68, a propidium iodide nuclear stain was applied to facilitate cell counting.
A Zeiss Axioplan (Herts, UK) photomicroscope with ultraviolet epi-illumination equipped with filters for two-color immunofluorescence was used. Cell counts were performed using a grid system. The count for the entire section was obtained, and the area of the specimen was measured using an Optimax (Cambridge, UK) digitizing system to determine cell counts per unit area. In accordance with published data, an inflammatory cell count >7/mm2 was considered elevated (24).
Image analysis was employed to quantify adhesion molecule and class II antigen expression. Double-exposure images obtained from a Photonic-Sciences 3 chip (Millham, UK) color-cooled camera were linked to a Kontron (Munich, Germany) 400 system for computer-assisted analysis. The following measurements were obtained: 1) total area expressing factor VIII (endothelium) as a percentage of the area of the section; and 2) total area expressing both factor VIII and HLA/adhesion molecule (i.e., endothelial-expressed antigen) from double-exposed images. From these measurements, the proportion of endothelial-expressed antigen was calculated (thus controlling for potential discrepancies in the amount of endothelium present in each section). In addition, semiquantitative assessment of staining intensity was performed in a standard fashion with visual grading: negative (N); weak (1+); moderate (2+); and high (3+) (21). All analyses were performed by an investigator blinded to the identity of the coded sections. Figure 2 demonstrates double-staining for ICAM-1 and endothelial markers in a biopsy specimen from a relative with LVE.
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Figure 2 Photomicrographs demonstrating expression of intercellular adhesion molecule-1 (A), endothelial staining (B) and double exposure (C) (x40 magnification) in a biopsy from a relative with left ventricular enlargement.
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Statistical analysis.
All statistical analyses were performed using SPSS for Windows (SPSS Inc., Chicago, Illinois). All variables were tested for normality of distribution using the one-sample Kolmogorov-Smirnov test. Comparisons between normally distributed continuous variables were performed by means of the Student t test or by analysis of variance for more than two groups. Comparisons between continuous variables not normally distributed (CD3, CD68) were performed using the Mann-Whitney U test or the Kruskall-Wallis test for more than two groups. Correlations between normally distributed continuous variables were assessed using Pearson’s correlation coefficient. Correlations between non-normally distributed continuous variables (CD3, CD68) were assessed using Spearman’s rho. Comparisons between dichotomous variables were performed using the chi-square test. A p value <0.05 was considered significant. Results of normally distributed variables are expressed in the text as the mean value ± SD and those of skewed variables are expressed as the median value (interquartile range). Where graphically represented, normally distributed continuous variables are expressed as the mean value, with error bars indicating 1 SEM, and non-normally distributed variables are expressed as the median value.
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Results
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Patient characteristics.
Myocardial biopsies were obtained from all 32 relatives and 14 patients and, except for one case of transient atrial fibrillation requiring cardioversion, all procedures were uncomplicated. The mean age of patients with DCM and relatives with LVE was 43.3 ± 12.9 years and 33.2 ± 12.8 years, respectively (p < 0.05). Seventy percent of patients with DCM and 58% of relatives with LVE were male. Echocardiographic variables are shown in Table 1.
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Table 1 Clinical, Histologic and Immunohistochemical Changes in Patients With DCM, Relatives With LVE and Control Subjects
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Histologic findings.
Myocyte pleomorphism and interstitial fibrosis consistent with DCM were observed in 50% of the patients with DCM, 25% of relatives with LVE and 0% of the control subjects (Table 1). No sample fulfilled the Dallas criteria for myocarditis. There were few clinical distinctions between individuals with and those without abnormal histology. There were nonsignificant trends toward older age (39.5 ± 14.2 years vs. 34.6 ± 12.6 years) and longer follow-up before biopsy (22.7 ± 26.5 months vs. 17.9 ± 17.6 months) in individuals with abnormal histology. A greater degree of ventricular enlargement and lower systolic function in individuals with abnormal histology was accounted for by the greater proportion of these individuals in the DCM group and was not observed when the LVE and DCM groups were analyzed separately.
Immunohistochemistry.
There was a significant increase in inflammatory cells (CD3, CD68) in both patients with DCM and relatives with LVE, as compared with control subjects (Table 1). Using the criterion of >7 cells/mm2, 21% of patients with DCM and 25% of relatives with LVE, but no control subjects, were CD3-positive (p = 0.01). Visual assessment of adhesion molecules and class II antigens using double immunofluorescence demonstrated predominantly endothelial expression of ICAM-1 and HLA-DR. Expression of HLA-DQ was less prominent and was predominantly interstitial. Quantitative assessment demonstrated significantly higher expression of both HLA-DR and ICAM-1 in patients with DCM and relatives with LVE, as compared with control subjects. Quantitative HLA-DR expression correlated significantly with quantitative ICAM-1 expression (r = 0.47, p < 0.001), and quantitative assessment correlated well with semiquantitative measures for both markers (Fig. 3).
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Figure 3 (A) Correlation between quantitative assessment of human leukocyte antigen (HLA)-DR and intercellular adhesion molecule (ICAM)-1 (r = 0.47, p < 0.001). (B) Quantitative expression of HLA-DR in relation to visual assessment (error bars represent 1 SEM). The y axis represents the percentage of endothelial expression. The x axis represents positive (Pos) grade 2+ (moderate intensity) or grade 3+ (high intensity) and negative (Neg) grade 0 (negative) or grade 1+ (weak intensity) by visual assessment. (C) Quantitative expression of ICAM-1 in relation to visual assessment.
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There were modest correlations between CD3+ infiltration and quantitative assessment. Correlation coefficients (Spearman’s rho) for CD3 counts with HLA-DR and ICAM-1 expression were 0.451 (p = 0.001) and 0.279 (p = 0.047), respectively. Percent HLA-DR expression in individuals positive for CD3 infiltration was 70.5 ± 16.3% versus 53.5 ± 21.1% in individuals with <7 cells/mm2 (p = 0.02). Corresponding values for ICAM-1 were 38.9 ± 16.2 and 33.4 ± 15.1 (p = 0.29).
Inflammation and histologic changes.
Endothelial expression of antigen was nonsignificantly higher in individuals without fibrosis than in those with fibrosis (HLA-DR: 62.7 ± 21.6% vs. 58.2 ± 18.5%; ICAM-1: 38.9 ± 15.1% vs. 31.2 ± 12.8%). Similarly, counts of both macrophages and CD3+ cells were higher in individuals without fibrosis than in those with fibrosis (66.8 ± 35.2 vs. 51.4 ± 42.8 and 4.4 vs. 2.1 [median values], respectively; p = 0.05). Although these values did not reach statistical significance, trends for each marker of inflammation measured followed the same direction (Fig. 4). In contrast with the findings in relatives with fibrosis, individuals with inflammation were younger (29.6 ± 12.4 years vs. 41.6 ± 7.3 years, p = 0.03) than patients without inflammation and had been followed for a shorter period before biopsy (17.4 ± 20.6 months vs. 31.6 ± 5.3 months, p = 0.03).
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Figure 4 Relationship between markers of inflammation and the presence of chronic histologic changes of dilated cardiomyopathy. The y axis represents the percentage of endothelial expression of antigen (intercellular adhesion molecule [ICAM] and human leukocyte antigen [HLA-DR]) or median cell counts (CD68+ and CD3+). The error bars represent 1 SEM. The x axis represents the presence or absence of fibrosis and chronic myopathic changes.
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Discussion
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Until now, evidence that LVE is a marker of early disease in the relatives of patients with DCM has been indirect and has included the demonstration of increased frequency of circulating organ-specific antibodies (25) and abnormal cytokine profiles, as well as abnormally low peak oxygen consumption in these asymptomatic individuals (19). Preliminary follow-up data also suggest that some relatives with LVE progress to overt DCM (26). This study provides, for the first time, to the best of our knowledge, direct pathologic confirmation that relatives with LVE have myocardial disease, with inflammatory and/or chronic histopathologic abnormalities present in the majority (86%) of these subjects. This finding may have significant clinical and scientific implications, including the potential, through detection of preclinical disease, to prevent presentation with advanced heart failure or a catastrophic event such as stroke or sudden cardiac death; the facilitation of accurate labeling of relatives for the purposes of genetic studies; and the opportunity to study early-stage rather than advanced-stage disease in which pathologic findings may be nonspecific and uninformative.
Nature of inflammatory changes in LVE.
The inflammatory changes identified in healthy relatives are not florid; rather, they are indicative of a low-grade, indolent process that resembles previously reported findings using sensitive immunohistochemical methods in patients with established cardiomyopathy (20,21,24,27). By incorporating quantitative analysis and a control group to ensure specificity, we have demonstrated significantly increased endothelial expression of adhesion molecules, class II antigens and inflammatory cell infiltration in relatives with LVE. Because relatives with LVE are asymptomatic (i.e., normal systolic function), the inflammatory process cannot be considered secondary to LV dysfunction, such as has been observed in individuals with clinical heart failure, irrespective of etiology (28). Therefore, the results of this study suggest that myocardial inflammation occurs early in the pathogenesis of familial DCM.
Potential stimuli of inflammatory changes in LVE.
The primary stimulus or stimuli of this inflammatory process in the relatives of patients with DCM remain to be elucidated, but potential mechanisms include inherited myocyte structural protein defects (myocardial inflammation has been demonstrated in individuals with DCM secondary to inherited protein defects) (15), organ-specific autoimmunity (25,29,30) and/or persistent viral infection (31). At this time, we have not yet determined whether any of the subjects in this study have an inherited cytoskeletal or other myocyte protein defect. None of the families included had prominent associated clinical features, which characterize many of the genotyped families in the published data, such as conduction system disease or skeletal myopathy (13,15). Genetic evaluation of a number of families represented in this study is in progress. A single gene defect has been identified in only a minority of families with DCM. Whether ongoing research will continue to uncover etiologic mutations accounting for the majority of cases, or whether alternative processes account for different subsets of familial cases, remains to be determined.
The finding of low-grade inflammation on biopsy is consistent with other studies linking inflammatory processes to the pathogenesis of familial DCM, ranging from HLA associations (29) to circulating organ-specific antibodies detectable in patients with DCM (25,30,32). In addition, we have previously reported that circulating organ-specific antibodies are present in asymptomatic relatives at a significantly higher frequency than in control subjects (25). Whether these antibodies indicate a primary immunologic etiology or a secondary process, and whether their presence might prove a useful noninvasive marker of risk of progression remains the subject of ongoing investigation.
Viral infection is also a plausible candidate as a primary inflammatory stimulus. Familial clustering of viral "myocarditis" might be explained on the basis of inherited susceptibility or common environmental factors, and asymptomatic relatives may be ideal individuals in whom to search for viral persistence, because it has been demonstrated in an animal model that the etiologic virus becomes undetectable as the disease progresses to an advanced stage (31). However, nested polymerase chain reaction studies (with a documented in-house lower limit of detection of one copy unit) for the presence of enteroviral ribonucleic acid and adenoviral deoxyribonucleic acid on endomyocardial biopsy specimens from 19 of the relatives with LVE included in the present study failed to show evidence of viral infection among relatives (data not shown).
Relationship between inflammatory changes and fibrosis in LVE and DCM.
Analysis of the relationship between fibrosis and inflammatory abnormalities and between these and clinical variables prompts speculation on the time course of events in the development of DCM. Fibrosis was more commonly found in patients with established DCM than in those with LVE, whereas inflammation tended to be more marked among patients and relatives who did not have fibrosis. These observations suggest that inflammatory processes precede the development of typical histologic findings in DCM, and that patients without these typical changes may both be at greater risk of deterioration and have a greater chance of full recovery, as compared with patients with fibrosis who are at a more stable advanced stage of disease.
The finding that 25% of relatives with LVE had histologic findings similar to those of patients with DCM suggests that some relatives with LVE may have, not early disease as originally hypothesized, established disease. They may represent genetically affected individuals with incomplete penetrance. They may also represent individuals who have recovered from a phenotypically more obvious (albeit unrecognized) disease state. This hypothesis is consistent with recognized features of DCM, including a prolonged asymptomatic prodrome and potential for partial or apparently complete clinical resolution (33).
Study limitations.
The prognostic significance of immunohistochemical findings in relatives is not addressed in this study. The absolute risk of progression in LVE remains to be quantified. Preliminary data from an initial cohort have demonstrated progression in 27% over a median of three years, but longer term follow-up in a larger cohort is required. Ultimately, the clinical challenge is to identify more accurately, ideally using noninvasive markers, those relatives who are at risk of disease progression or the development of a serious complication. At this point, right ventricular biopsy outside of the context of a research protocol cannot be recommended for relatives with LVE.
A limited number of immunohistochemical markers were assessed in this study, because it was not designed to characterize the inflammatory process mechanistically, but simply to determine whether immunohistochemical evidence of myocardial inflammation was present in these apparently healthy relatives. We can conclude that asymptomatic relatives of patients with DCM with minor ventricular abnormalities have myocardial disease. Whether these low-grade inflammatory processes are central to the pathogenesis of the DCM and determination of the primary etiologic stimuli will require further study.
Individuals with isolated, depressed fractional shortening were not studied, because this is less common than LVE in relatives undergoing cardiovascular evaluation. However, it is likely that this finding is also representative of underlying disease and has also been incorporated as a minor criterion into guidelines for family screening (26). By including depressed fractional shortening, the proportion of asymptomatic relatives with abnormalities potentially indicative of underlying disease rises to 25%.
Conclusions.
This study demonstrates that asymptomatic relatives of patients with DCM with minor ventricular abnormalities have histopathologic and immunopathologic findings consistent with the presence of early or mild myocardial disease. Because these ventricular abnormalities are common among relatives, these findings have implications for the performance and interpretation of cardiovascular evaluation in families of patients with DCM. The ability to identify early disease will further our understanding of the pathogenesis of DCM and provide a basis for the evaluation of specific preventive therapy in relatives at risk.
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Footnotes
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This study was supported by a project grant from the British Heart Foundation.
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C Turesson, A Jarenros, and L Jacobsson
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A. L. P. Caforio, N. G. Mahon, and W. J. McKenna
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M. Noutsias, M. Pauschinger, H.-P. Schultheiss, and U. Kuhl
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Abstract
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