© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacing-induced congestive heart failure
aDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
bDepartment of Pathology, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada
cResearch Center and Department of Medicine, Montreal Heart Institute and University of Montereal, 5000 Belanger St., Montreal, Quebec, Canada H1T 1C8
* Corresponding author. Research Center and Department of Medicine, Montreal Heart Institute, University of Montreal, 5000 Belanger St. East, Montreal, Quebec, Canada H1T 1C8. Tel.: +1-514-376-3330; fax: +1-514-376-1355. Email address: nattel{at}icm.umontreal.ca
Received 7 January 2004; revised 10 March 2004; accepted 26 March 2004
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Background: Congestive heart failure (CHF) causes arrhythmogenic remodeling in both atria and ventricles, but differences between atrial and ventricular remodeling in CHF have not been well characterized. Methods and results: We examined atrial and ventricular tissues from dogs with CHF induced by ventricular tachypacing (220–240/min) for 0 (control) or 24 h, or 1, 2 or 5 weeks. Histopathology was used to assess apoptosis, fibrosis, white blood cell infiltration and cell death, ELISA to measure angiotensin-II concentration and Western blot to evaluate protein expression. Ventricular tachypacing-induced CHF was associated with substantially more fibrosis in left atrium (maximum 10±1% at 5 weeks) than in left ventricle (0.4±0.1% at 5 weeks, P<0.01 versus left atrium). Tissue angiotensin-II concentration increased to steady state in atrial tissue at 24 h but increased more slowly in left ventricle, with a maximum that was significantly higher in atrium than ventricle. Ventricular tachypacing caused tissue apoptosis, inflammatory cell infiltration and cell death, with maximum changes in left atrium being faster, transient and larger than in left ventricle. Mitogen activated protein kinase activation was rapid (within 24 h) in left atrium, but smaller and slower (p38, c-Jun N-terminal kinase) or non-significant (extracellular signal-related kinase) in left ventricle. The 25-kDa activated form of transforming growth factor-β1, a particularly important profibrotic mediator in atrium, increased significantly in left atrium, from 2.6±0.6 (control) to 9.2±1.7 (24 h) and 8.1±1.8 optical density units (1 week), but was not significantly changed in ventricle. Conclusions: There are qualitative and quantitative differences in atrial versus ventricular remodeling in experimental ventricular tachypacing-induced CHF, with potentially important consequences for understanding underlying mechanisms and developing new therapeutic approaches.
KEYWORDS Angiotensin; Arrhythmias; Atrial fibrillation; Heart failure; Remodeling
This article is referred to in the Editorial by A. Goette and U. Lendeckel (pages 194–195) in this issue.
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Myocardial remodeling, defined as a disease-induced change in cardiac tissue composition or function, is an important component of the congestive heart failure (CHF) syndrome [1]. Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice and heart failure is one of the most important clinical causes of AF [2]. Clinical AF has been associated with atrial fibrosis [3]. A similar pathological picture is produced, along with a susceptibility to the induction of long-lasting AF, by ventricular tachypacing-induced CHF in the dog [4]. Tachycardia-induced heart failure is reversible upon cessation of tachypacing and, along with reversal of ventricular dysfunction, there is full recovery from CHF-associated atrial electrophysiological [5] and ionic [6] remodeling. However, atrial interstitial fibrosis persists [5,6] and the ability to induce long-lasting AF remains, pointing to a central role for tissue fibrosis in the CHF-associated AF substrate. The likelihood of AF increases with increasing extent of fibrosis, which follows a characteristic set of cellular responses [7]. Ventricular tachypacing-induced CHF also induces ventricular remodeling [8], with some elements (e.g. development of apoptosis, chamber dilation, cell death) qualitatively similar to those observed with atrial remodeling, but also some apparent differences. We were unable to identify studies in the literature that compare the details of atrial versus ventricular remodeling in CHF. The present study was therefore designed to compare the time course and magnitude of changes in tissue angiotensin-II concentration, apoptosis, white-cell infiltration, cell death, fibrosis and activation of mitogen activated protein kinases and transforming growth factor-β (TGFβ), with the use of matched left atrial and left ventricular samples from dogs with tachypacing-induced CHF.
We have previously characterized a number of these variables at the atrial level in the same model [7], but did not at the time plan to analyze ventricular changes and therefore had no stored ventricular tissues from the earlier study. We therefore performed all measurements at both the atrial and ventricular level for each dog in this new series of experimental animals, to eliminate potential contaminating effects of inter-animal, inter-investigator, seasonal and time-related differences on the results of the atrial versus ventricular remodeling comparison.
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2. Materials and methods |
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Animal care procedures followed the guidelines of the Canadian Council on Animal Care were approved by the institutional animal research ethics committee and were consistent with the guidelines of the National Institutes of Health. Five groups of mongrel dogs weighing 24–37 kg (mean weight 26.5±1.0 kg) were subjected to ventricular tachypacing for: 0 (controls) or 24 h, 1, 2 or 5 weeks. Previously described techniques [4–7] were used to pace the right ventricle at 240 bpm for 3 weeks, with the rate then decreased to 220 bpm to limit mortality. On the study day, the pacemaker was deactivated. Dogs were then anaesthetized (morphine, 2 mg/kg s.c.;
-chloralose, 120 mg/kg i.v. loading dose, 29.25 mg/kg/h i.v. maintenance infusion) and ventilated. Body temperature was maintained at 37 °C, and femoral arteries and veins were cannulated. The heart was exposed by median sternotomy, a pericardial sling was created and a fluid-filled catheter was used to obtain right atrial and left ventricular pressures. Dogs were sacrificed by -chloralose overdose and hearts removed for subsequent analysis. For terminal-dUTP nick-end labeling (TUNEL) and histopathological studies, hearts were immersed into 10% neutral buffered formalin and embedded in paraffin. For molecular biology analyses, single left atrial and left ventricular free wall samples from each heart were snap-frozen in liquid nitrogen and kept at –80 °C.
2.1. Histopathology
Lung wet weight to dry weight ratio was determined at autopsy as an indicator of total lung water. Left ventricular chamber diameter was also measured at autopsy. Samples were then taken from the left atrial posterior and inferior walls, and left ventricular anterior, lateral and posterior free walls, with 5-µm sections cut along longitudinal and transverse planes for each region. Since histopathological changes were found to be spatially consistent, results are presented as averages for all atrial and ventricular regions in each dog. Connective tissue content was quantified as previously described [4–7] with the use of SigmaScan software (Jandel Scientific), as a percentage of cross-sectional surface area, excluding blood vessels, on Masson's trichrome-stained sections. To analyze cell death, sections were stained with hematoxylin–phloxin–safran (HPS). Dead (acidophilic) and viable cells were counted in 15 transverse-section fields at 400 x . HPS-stained longitudinal sections were used to quantify white-cell infiltration at high magnification (1000 x) for 12 high-powered fields of each slide.
2.2. TUNEL
Paraffin-embedded sections were deparaffinized, rehydrated and saponified, and marked with biotin-dUTP via deoxynucleotidyl transferase (TdT, Boehringer-Mannheim). Slides were then incubated sequentially with 1:50 extravidin–fluoresceinisothiocyanate (FITC), 1:40 -sarcomeric actin antibody, 1:100 tetramethylrhodamine (TRITC)-coupled anti-mouse IgG and propidium iodide to detect cardiomyocyte apoptosis.
2.3. Western blots
Protein extracts (200 µg) obtained as previously described [7,9] were denatured and subjected to electrophoresis on 12% or 15% sodium dodecyl sulphate (SDS) polyacrylamide gels. Proteins were transferred to nitrocellulose membranes (0.45 µm), blocked for 90 min with 5% nonfat dry milk in 0.1% Tween 80/Tris-buffered saline and incubated overnight in primary antibody solutions. After three washes in 0.1% Tween 80/Tris-buffered saline, membranes were incubated with horseradish peroxidase-conjugated primary antibodies in 5% nonfat dry milk in Tween 80/Tris-buffered saline for 90–120 min, followed by four washes in the same solution. Antibodies were detected with chemiluminescence and bands were quantified by laser densitometry. Each gel contained matched samples from control left atrium and ventricle, as well as from left atrium and ventricle from dogs with different durations of ventricular tachypacing, in order to ensure comparison between control and tachypaced dog tissues under identical handling and exposure conditions. Membranes were then stripped, re-blocked with 5% nonfat dry milk for 2 h and re-probed with GAPDH as an internal standard. Values presented are ratios between target and GAPDH band intensity.
Primary antibodies were: rabbit anti-extracellular signal related kinase (ERK) polyclonal IgG, rabbit anti-p38 polyclonal IgG, rabbit anti-c-Jun N-terminal kinase (JNK) polyclonal IgG (Cell Signaling), rabbit anti-TGFβ1 polyclonal IgG (Santa Cruz) and mouse anti-GAPDH (Research Diagnostics). Mitogen activated protein (MAP) kinases were probed with antibodies raised against phosphorylated forms, which detect only MAP kinases catalytically activated by threonine or tyrosine phosphorylation, as well as with antibodies that detect total MAP kinase expression. No differences were seen in the response of 44 (ERK isoform 1) versus 42 (ERK isoform 2) kDa ERK and 54 versus 46 kDa JNK; therefore results are presented as average band densities of the two moieties.
2.4. Angiotensin-II
Tissue angiotensin-II concentration was measured by enzyme-linked immunosorbent assay (ELISA, Peninsula Laboratories) as previously described [9]. Absorbance at 450 nm was recorded and concentration was calculated from a standard curve generated for each experiment.
2.5. Statistical analysis
All assays were based on separate parallel determinations for left ventricle versus left atrium in each heart, and no pooling of samples was used. Multiple group means were compared by analysis of variance. Dunnett's or Mann–Whitney U-tests were performed when the variance was homodecatic or heterodecatic respectively. Paired Student's t-test or Wilcoxon's signed-ranks test were used to compare mean left atrial with left ventricular values, based on data sets containing paired values obtained from matched tissue samples in each animal. Results are mean±S.E.M. and a two-tailed P<0.05 was considered statistically significant.
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3. Results |
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3.1. Time-dependent development of indices of CHF
Overall group characteristics and hemodynamic data are provided in Table 1. Indices reflecting left ventricular hypertrophy (increased heart weight/body weight ratio) and dilation (augmented left ventricular diameter) were evident by 1 week of ventricular tachypacing, whereas indices more reflective of CHF per se (elevated right atrial pressure, left ventricular end-diastolic pressure, lung wet weight/dry weight ratio) achieved statistically significant differences at 5 weeks.
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3.2. Tissue fibrosis
Under baseline conditions, very little fibrous tissue was apparent in either left atrial (Fig. 1A, left) or left ventricular (Fig. 1B, left) samples, whereas at 5 weeks there was clear tissue fibrosis (Fig. 1A and B, right panels), which was particularly marked at the atrial level. Mean fibrous tissue content increased progressively during ventricular tachypacing in both atrium and ventricle (Fig. 1C), but the fibrous tissue content was substantially and significantly greater in left atrium than ventricle at all points after the onset of tachypacing (e.g., at 5 weeks, 9.9±1.3% in left atrium versus 0.4±0.1% in left ventricle, P<0.01).
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P<0.05, In view of the significant development of tissue fibrosis, we examined changes in P-wave and QRS interval duration as a function of ventricular tachypacing time. Both P-wave and QRS duration increased over time with the development of CHF (Table 2). Consistent with the greater fibrosis in atrial tissue, P-wave duration changes were much larger than those in QRS. Mean P-wave duration at each time point examined correlated with mean percentage fibrosis (r2=0.93).
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3.3. White cell infiltration
Fig. 2A and B shows HPS-stained left atrial and ventricular sections from a control (left) and a 24-h tachypaced (right) dog. After 24 h of ventricular tachypacing, the number of leukocytes in left atrial sections increased substantially, accompanied by perceptible tissue edema and evident cell death. Changes in left ventricular tissue were subtler. The time course of leukocyte infiltration was different in atrial compared to ventricular tissue (Fig. 2C). Left atrial tissue showed a rapid and transient
10-fold rise to a peak value of 2.1±0.2 white blood cells/high-powered field at 24 h, returning to values not significantly different from control by 2 weeks. In left ventricular tissue the leukocyte count showed smaller absolute changes (maximum 0.5±0.1 white blood cells/high-powered field at 1 week, P<0.01 versus maximum value in left atrium) but increases in ventricular leucocyte count were more persistent and remained statistically significant over the entire 5-week ventricular tachypacing interval.
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3.4. Cell death and apoptosis
Non-viable cardiomyocytes were apparent as acidophilic, pink-staining cells in HPS-stained tissue sections from dogs exposed to ventricular tachypacing (Fig. 2A,B, right panels). The number of dead cells in left atrial sections peaked at 6.9±0.9/103 cardiomyocytes after 24-h tachypacing (Fig. 3A), at which point atrial cell death was much greater than ventricular, and decreased progressively thereafter. Non-viable cell count increases were slower but more sustained in left ventricular tissues, with a value (2.0±0.3/103 cardiomyocytes) at 5 weeks that was significantly greater than the atrial value at the same time point.
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The density of TUNEL-positive cells also increased transiently in left atrial tissues, reaching a maximum of
10-fold control at 24 h, contrasting with a slower but more progressive increase in left ventricle (Fig. 3B).
3.5. Tissue angiotensin-II concentrations
Atrial angiotensin-II concentrations increased significantly after 24 h of ventricular tachypacing, reaching 4 times control values and remained elevated thereafter (Fig. 4). Angiotensin-II concentrations increased to a lesser extent in left ventricle, with the increase achieving statistical significance only at 5 weeks, at 2 times control values. Angiotensin-II concentrations were significantly greater in atrial than ventricular tissues at all tachypacing intervals studied.
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3.6. MAP kinase expression
Phosphorylated ERK expression in left atrium increased to a maximum after 24 h and declined slowly thereafter (Fig. 5A). Ventricular tachypacing did not significantly affect phosphorylated ERK expression in left ventricular tissues. Phosphorylated JNK expression peaked at 24 h in left atrium and then returned towards control values (Fig. 5B). A statistically significant increase in ventricular phosphorylated JNK expression was only seen after 5 weeks of tachypacing. Unlike the transient changes in left atrial phosphorylated ERK and JNK expression, increases in atrial phosphorylated p38 expression were sustained over the full range of ventricular tachypacing intervals. There were no significant differences in left atrial versus left ventricular phosphorylated p38 expression over the observation period. Total ERK, p38 and JNK expression did not change significantly with ventricular tachypacing in either left atrium or ventricle (data not shown).
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3.7. TGFβ1
Fig. 6 shows Western blot data for TGFβ1 expression. TGFβ exists in a membrane and matrix bound, inactive
50-kDa form (in a complex including TGFβ1 and latency-associated peptide) and an activated 25-kDa form [10]. Left ventricular bands were generally less intense than left atrial following ventricular tachypacing (Fig. 6A). Ventricular tachypacing transiently increased the intensity of bands corresponding to the 25-kDa activated form in left atrial tissues, whereas changes in left ventricular bands were smaller. The time course of TGFβ1 changes varied somewhat among gels, with increases in atrial expression being clearest at 1 week in the example shown in Fig. 6A. Overall, mean 25-kDa TGFβ band densities increased 3.5- and 3.1-fold at 24 h and 1 week respectively in left atrial tissues (Fig. 6B), but changes in left ventricular samples were smaller and did not reach statistical significance. The intensity of the 50-kDa band was consistent over time, with no changes seen with tachypacing.
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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In this study, we have examined directly atrial versus ventricular remodeling as a function of time in dogs with CHF induced by ventricular tachypacing. There were consistent differences between left atrial and left ventricular responses, with a variety of changes in left atrium (white cell infiltration, apoptosis, MAP kinase and TGFβ activation) being faster, larger and more transient than in left ventricle, and with tissue fibrosis being much more intense in left atrial tissue.
4.1. Atrial versus ventricular remodeling in CHF
Many studies have considered ventricular remodeling in CHF (for overview, see review by Gaballa and Goldman [11]). CHF-related atrial structural remodeling has great significance for the pathophysiology of AF and appears to be a useful paradigm for a broad range of clinical conditions [4]; however, there is relatively little information available about atrial structural remodeling in experimental models. Patients with clinical AF and impaired left ventricular function have an increased rate of atrial TUNEL positivity indicating apoptosis, evidence of caspase-3 activation and of BCL-2 downregulation [12]. Atrial ERK activation [13] and changes in atrial angiotensin receptor expression suggestive of increased angiotensin-II stimulation (downregulation of angiotensin-1 and upregulation of angiotensin-2 receptors) have been noted in AF patients [14]. A variety of changes in atrial signaling systems have been noted in AF patients [15], but the extent to which changes are due to AF per se, as opposed to being a consequence of underlying heart disease, is uncertain.
Atrial structural remodeling is prominent in ventricular tachypacing-induced experimental CHF, in which it appears to play a central role in the AF substrate and associated atrial functional impairment [4–6,16]. Angiotensin-II dependent pathways are involved in the prominent atrial fibrotic remodeling response [7,9,13,14], but inhibition of atrial angiotensin-II accumulation with enalapril does not fully prevent CHF-related atrial fibrosis [7]. There is also evidence for a potential role of matrix metalloproteinases [17,18]. Disintegrin metalloproteinases are activated in CHF [19], and their expression is increased in atrial tissue from AF patients [20]. Enalapril prevents atrial apoptosis and ERK activation induced by 24 h of ventricular tachypacing but does not affect other components of the response, such as total cell death (presumably dominated by non-apoptotic pathways), white-cell infiltration and activation of JNK and p38-kinases [7].
In the present study, we report for the first time detailed comparisons of atrial versus ventricular remodeling and related signaling systems in experimental heart failure. A wide range of alterations, including leukocyte infiltration, cell death, apoptosis and MAP kinase activation, were larger in atrium, occurred earlier and were more transient in atrium compared to ventricle. The basis for this differential response is unclear. Tissue stretch increases local angiotensin-II production and activates a variety of signaling pathways, including those involving MAP kinases [21]. Functional mitral regurgitation is common in ventricular tachypacing-induced CHF [4], results in substantial dilatation and stretch of the thin-walled atria [16], potentially contributing to atrial angiotensin-II production and MAP kinase activation.
MAP kinases play an important role in myocardial remodeling [22]. Recent work indicates that rabbits with 3-week tachypacing-induced CHF have increased ventricular expression of phosphorylated JNK and p38, but not of phosphorylated ERK [23]. We similarly failed to observe changes in ventricular ERK phosphorylation with CHF. In contrast, atrial phosphorylated ERK expression was significantly increased at 24 h to 2 weeks after tachypacing onset, consistent with previous evidence for ERK activation at the atrial level in patients with AF [13] and in previous studies of atrial tissues from dogs with CHF [7]. These results suggest that ERK activation may play a more important role in atrial than ventricular remodeling associated with CHF.
4.2. Potential significance of our findings
The prevention of atrial remodeling is becoming an interesting target for AF therapy, particularly given the serious potential side effects of atrial antiarrhythmic drugs [24]. Both angiotensin converting enzyme inhibitors [7,9] and angiotensin receptor antagonists [25] reduce experimental CHF-related structural remodeling and AF promotion, and angiotensin converting enzyme inhibitors prevent the occurrence of AF in patients with left ventricular dysfunction [26,27]. Whereas a great deal of energy has been (appropriately) expended on defining the mechanisms of ventricular remodeling in CHF, much less attention has been paid to atrial remodeling. A possible rationale for the lack of attention to atrial remodeling might be that it is unnecessary to specifically study atrial remodeling, if essentially the same mechanisms operate at the atrial and ventricular level. The present work demonstrates that this is not the case (i.e., that atrial and ventricular remodeling-related changes differ in experimental CHF), and that specific analyses of the mechanisms operative at the atrial level may be needed to understand atrial remodeling and identify novel therapeutic targets for the prevention of atrial structural remodeling and associated AF.
One important finding of our study was the greater TGFβ1 activation in left atrial compared to left ventricular tissues. TGFβ is an important profibrotic factor [28]. TGFβ1 mRNA concentrations are increased in human atrium by angiotensin-II [29]. Angiotensin receptor inhibition reduces TGFβ1 plasma concentrations and interstitial fibrosis in hypertensive kidney-transplant patients [30], and angiotensin converting enzyme inhibition reduces TGFβ1 mRNA expression and ventricular fibrosis in a rat CHF model [31]. TGFβ1 activation following the stimulation of angiotensin type-1 receptors is a primary mediator of cardiac fibrosis [32]. Inhibition of TGFβ formation prevents left ventricular fibrosis in renovascular hypertension [33]. Targeted cardiac TGFβ1 overexpression produces prominent atrial fibrosis but no significant ventricular fibrosis, despite similar degrees of TGFβ1 overexpression in atria and ventricles [34]. Furthermore, TGFβ overexpressing mice show an enhanced susceptibility to AF [35]. Thus, TGFβ1 activation may be an important contributor to the development of AF-promoting atrial fibrosis in CHF and signaling events leading to increased TGFβ1 activity may be interesting targets for therapy to prevent arrhythmogenic atrial structural remodeling.
The increased atrial inflammatory-cell infiltrate we observed with ventricular tachypacing-induced CHF is interesting in light of the evidence for a role of inflammation in AF [36].
4.3. Potential limitations
The present study evaluated atrial and ventricular remodeling in a well-defined experimental heart-failure model, but extrapolation to clinical CHF should be cautious. The pathophysiology of CHF differs for different experimental and clinical paradigms and, although sustained tachycardia can contribute to or cause clinical CHF [37], the pathophysiology of tachycardia-induced experimental CHF cannot be assumed to apply directly to the broad spectrum of clinical heart failure syndromes. Studies comparing atrial and ventricular remodeling in other CHF models would be of interest, as would comparative analyses of atrial and ventricular tissue samples from CHF patients.
We did not analyze electrophysiological changes in this study. We found in preliminary work that detailed electrophysiological analyses, such as mapping and extensive programmed stimulation, can damage atrial tissues and alter biochemical and histological indices. In addition, recovery of changes following cessation of tachypacing was not studied.
Since atrial cardiomyocytes are smaller than ventricular, the number of cardiac cells for a given volume of atrial tissue is larger than ventricular. Values of indices expressed as a function of tissue volume, mass or area would be relatively smaller for atrium vs. ventricle if expressed as a function of the number of cells. This concept needs to be considered in interpreting our data.
4.4. Conclusions
We compared atrial and ventricular remodeling in an experimental model of CHF, and found significant quantitative and qualitative differences. These differences may have important implications for understanding the mechanisms of CHF-related cardiac remodeling and for the development of novel therapeutic approaches to preventing the AF substrate.
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Acknowledgements |
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The authors thank Chantal Maltais, Nathalie L'Heureux and Evelyn Landry for excellent technical assistance; France Thériault for secretarial help with the manuscript; and Marc Pourrier for help with Western blot analysis. The work was supported by the Canadian Institutes of Health Research, the Paul David Chair in Cardiovascular Electrophysiology of the University of Montreal, the Mathematics of Information Technology and Complex Systems (MITACS) Network of Centers of Excellence and the Quebec Heart and Stroke Foundation. Sophie Cardin is supported by a Heart and Stroke Foundation of Canada graduate studentship award.
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Notes |
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Time for primary review 15 days
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