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J Am Coll Cardiol, 2004; 43:68-76, doi:10.1016/j.jacc.2003.07.030
© 2004 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: HEART FAILURE

The cardiac atria are chambers of active remodeling and dynamic collagen turnover during evolving heart failure

Anjum Khan, MSc*, Gordon W. Moe, MD, FACC*, Nafiseh Nili, PhD*, Effat Rezaei, PhD*, Muhammad Eskandarian, MD*, Jagdish Butany, MD{dagger} and Bradley H. Strauss, MD, PhD, FACC*,*

* Roy and Ann Foss Interventional Cardiology Research Program, Terrence Donnelly Heart Center, St. Michael's Hospital, Toronto, Ontario, Canada
{dagger} University Health Network, University of Toronto, Toronto, Ontario, Canada

Manuscript received February 28, 2003; revised manuscript received July 14, 2003, accepted July 21, 2003.

* Reprint requests and correspondence: Dr. Bradley H. Strauss, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario, Canada M5BIW8.
straussb{at}smh.toronto.on.ca


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: The role of atrial myocytes and extracellular matrix (ECM) changes in atrial chamber remodeling was studied in a canine model of heart failure (HF).

BACKGROUND: Cardiac remodeling is a key process mediating the progression of HF. Studies of the structural mechanisms of cardiac remodeling have been limited to the left ventricle. The structural alterations associated with atrial chamber remodeling in evolving HF have not been studied.

METHODS: Age- and weight-matched dogs were subjected to right ventricular pacing (240 beats/min) for one and three weeks to produce early and severe HF, respectively. Atrial tissues were assessed for myocyte and ECM changes.

RESULTS: Right atrial and left atrial (LA) pressures were significantly increased in early and severe HF. The LA wall tension index was significantly increased at both HF stages by 116% and 443%, respectively. Atrial collagen synthesis and degradation were significantly increased in severe HF. Gelatinase activity was significantly increased at both early and severe stages of HF. Gelatin zymography showed increased matrix metalloproteinases (MMP)-9 with early HF and increased MMP-2 with severe HF. The LA wall tension index was significantly correlated with gelatinase activity and collagen synthesis. Although total atrial collagen content was not changed, disarray of collagen fibers was observed. Atrial myocyte hypertrophy without evidence of apoptosis was also present in severe HF.

CONCLUSIONS: There is marked atrial chamber remodeling in canine pacing-induced HF, which is characterized by myocyte hypertrophy and dynamic collagen turnover. Atrial remodeling may contribute to the development of atrial arrhythmias and pulmonary hypertension and could offer a novel therapeutic target.

Abbreviations and Acronyms
  ACE = angiotensin converting enzyme
  ECM = extracellular matrix
  HF = heart failure
  hpf = high power field
  LA = left atrial/atrium
  LV = left ventricle/ventricular
  MMP = matrix metalloproteinases
  mRNA = messenger RNA
  TIMP = tissue inhibitor of metalloproteinases
  RA = right atrial/atrium
  TUNEL = terminal deoxy nucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling

Although the etiologies of chronic heart failure (HF) may be diverse, a crucial process in the progression of most forms of HF is left ventricular (LV) remodeling. The process of LV remodeling involves changes in both myocyte and extracellular matrix (ECM), including the activation of proteolytic enzymes and alteration in the myocardial collagen organization. These, in turn, lead to alterations in LV chamber geometry and function (1–4).The atrial chambers may also undergo significant geometric remodeling (chamber remodeling) during evolving HF (5–7). Left atrial (LA) volume has been shown to be significantly associated with LV chamber remodeling, diastolic dysfunction, and the degree of mitral regurgitation in patients with dilated cardiomyopathy (7). However, unlike the LV, the structural basis for atrial chamber remodeling process in HF has not been characterized. We hypothesized that atrial chamber remodeling in HF is accompanied by changes in both the atrial myocytes and the ECM. Accordingly, the objectives of the current study were to characterize the cellular and ECM changes in relation to chamber remodeling in the atria during evolving HF. To achieve this goal, we employed a canine model of pacing-induced HF that induces significant LV chamber remodeling, contractile dysfunction, neurohormonal activation, and a phenotype of HF that closely mimics human dilated cardiomyopathy (6,8) and is accompanied by significant biatrial chamber remodeling (5,6,9).


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Experimental preparation.   Age- and weight-matched male dogs were divided into four groups. Eight dogs underwent continuous rapid right ventricular pacing (240 beats/min) for one week and were designated as the group with early HF. A second group of eight dogs was paced for three weeks and designated as the group with severe HF. Because one- and three-week paced dogs were studied at different times to eliminate time-dependent biases, two groups of non-paced normal dogs (n = 5 for the one-week paced dogs, n = 10 for the three-week paced dogs) served as controls. Animal experiments were performed in accordance with the guidelines, "Care and Use of Experimental Animals," issued by the Canadian Council on Animal Care, Ottawa, Canada.

The method of induction of HF and the clinical, radiographic, hemodynamic, and echocardiographic assessments have been described in detail previously (6,8,10). In the paced dogs, hemodynamic and echocardiographic data were obtained after the pacer was reprogrammed off to resume sinus rhythm for at least 20 min. Two-dimensional echocardiography was performed weekly to monitor changes in LV ejection fraction and to ensure the development of LV systolic dysfunction. Images were recorded on half-inch videotape and analyzed off-line. Echocardiographically derived indexes of LV dimensions were calculated using standard formulas as described previously (10). Left atrial cross-sectional areas were obtained at the plane of aortic valve incorporating area defined by both the LA free wall and the appendage. A radius for the LA was derived from the cross-sectional area assuming a circular shape of the chamber (5,9). The product of pulmonary capillary wedge pressure and the radius were used as indexes of LA wall tension (5,9). Due to a difficult echocardiographic window, measurements of right atrial (RA) area were not possible. Hemodynamic measurements were obtained at baseline to ensure normality and repeated before sacrifice, using a micromanometer-tipped catheter introduced via the femoral artery and a thermodilution catheter introduced via the femoral vein. At the end of the in vivo study, the chest was opened under sodium thiopental anesthesia, and the heart arrested with potassium chloride. The heart was removed and rinsed in cold saline. Left atrium and RA samples were taken for biochemical and histological analysis. Additional samples for measuring matrix metalloproteinase (MMP) activity were snap frozen in liquid N2 and stored at –80°C until use.

Histology.   Tissue samples were randomly taken from the atrial free wall, and 5-µm-thick sections were stained with hematoxylin and eosin for cellular morphology and picrosirius red for collagen. Computerized morphometry (Scion Image, Frederick, Maryland) was used to determine the myocyte number and area per high power field (hpf). Measurements were done in at least three randomly selected hpf in each atria.

Collagen synthesis and content.   Collagen synthesis and content in atrial tissues were measured using a previously described method (11). In brief, the tissues were incubated in Dulbecco's modified eagle medium containing 1% fetal calf serum, 14C-proline (0.5 µCi/ml, Amersham Biosciences, Piscataway, New Jersey), and ascorbic acid (50 µg/ml) for 6 h at 37°C. The samples were then digested overnight in cyanogen bromide, which solubilizes proteins by cleaving methionine amino acid bonds, with the exception of elastin, which contains no methionine. For collagen synthesis, 14C-hydroxyproline incorporation was measured and expressed as counts per min/mg tissue. For collagen content, hydroxproline was measured and expressed as µg hydroxyproline/mg tissue.

Western blot analysis for collagen fragments and caspase-3.   Atrial extracts were fractionated on 4% to 12 % tris-glycine gels under reducing or nonreducing conditions for collagen fragments and caspase-3, respectively. Fractionated proteins were electroblotted onto nitrocellulose membranes. For collagen fragments, the membrane was immunoblotted with rabbit polyclonal primary anti-COL2 three-quarters C (dilution 1:1000, HDM Diagnostics & Imaging Inc., Toronto, Ontario, Canada) that specifically recognizes {alpha}-chain fragments of collagen containing approximately 8 amino acid sequences on carboxy terminus. For caspase-3, the membrane was immunoblotted with rabbit polyclonal anti-caspase-3 (CPP32) Ab-4 (NeoMarker, Fremont, California). Anti rabbit IgG-HRP (Santa Cruz Biotechnology, Santa Cruz, California) was used for detection of primary antibody. Detection was performed using enhanced chemiluminescence (Amersham ECL Plus).

Gelatinase activity assays.   Zymography was performed as previously described (11,12). The clear gelatinolytic zones were quantified by densitometric analysis using the Molecular Analyst Software (Bio-RAD, Hercules, California). Gelatinase activity was also measured quantitatively using a gelatin-fluorescein conjugate substrate (EnzChek gelatinase assay, Molecular Probes, Eugene, Oregon) as reported by us previously (12). To confirm the specificity of this assay, samples were incubated with gelatin substrate in the presence of 20 mM GM6001 (MMP inhibitor), 1 mM elafin (serine elastase inhibitor), and 5 mM iodacetamide (cysteine protease inhibitor).

Terminal deoxy nucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL).   Apoptotic cells were identified in 5-µm-thick sections by TUNEL assay using a commercially available kit (ApopTag, Intergen, New York).

Statistical analysis.   All data are presented as mean ± SEM. Statistical comparison between the control and paced groups was done by unpaired Student t test. Because the one-week paced series and three-week paced series were studied at different times, no attempt was made to compare the one-week and the three-week paced dogs. Correlations between changes in wall tension, gelatinase activity, and collagen synthesis in three-week paced LA were made using linear regression analysis by least square fit method. Statistical significance was set at p < 0.05.


   Results
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 Abstract
 Methods
 Results
Discussion
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In vivo hemodynamic and echocardiographic data.   The development of HF in the paced dogs was confirmed by clinical, radiographic, and hemodynamic assessments. In control dogs and one-week paced dogs (early HF), clinical signs of HF were absent. All three-week paced dogs developed severe HF based on the presence of at least two of the three clinical signs of HF (apathy, anorexia, and ascites) and radiographic evidence of pulmonary edema and cardiomegaly. The hemodynamic, echocardiographic, and post-mortem data are shown in Tables 1 and 2. Data of the control groups of normal dogs for the one-week paced and the three-week paced dogs were very similar. With early HF, there was a modest increase in RA and LA pressure, accompanied by a decline in cardiac output. With severe HF, RA and LA pressures and LV end-diastolic pressure were markedly elevated, with significant decline in cardiac output. Echocardiographic analysis showed progressive increase in LV end-diastolic volume. The LV chamber dilation was accompanied by a progressive increase in LA cross-sectional area. Left atrium wall tension index also progressively increased during evolving HF. Compared with the controls, LA wall tension with early and severe HF was greater by 116% and 443%, respectively. Post-mortem LA and RA weights were also increased significantly compared with the respective controls at both early and severe stages of HF, signifying the development of significant atrial hypertrophy.


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  		Table 1 In Vivo Hemodynamic Parameters

 

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  		Table 2 In Vivo Echocardiographic and Post-Mortem Parameters

 
Collagen synthesis and content.   Atrial collagen synthesis was increased significantly in severe HF compared with controls (Table 3). However, collagen content in both atria did not differ from the controls.


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  		Table 3 Collagen Content and Synthesis

 
Collagen degradation.   Collagen fragments were significantly greater in both atria with severe HF compared with the controls (Fig. 1, data for LA not shown).



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  		Figure 1 (Upper panel) Representative Western blot for degraded collagen in an right atrium with severe heart failure (HF). Lanes 1 to 4 are controls. Lanes 5 to 8 are severe HF. (Lower panel) Group data from densitometric analysis. *p < 0.01 versus control.

 
Gelatinase activity.   Both pro- and active forms of MMP-9 activity were increased in LA during early HF compared with controls, whereas MMP-2 remained essentially unchanged (Fig. 2). With severe HF, both pro- and active forms of MMP-2 were significantly increased, whereas no differences were observed in MMP-9 activity. Similar results were observed in the RA (results not shown). In the fluorescence assay, higher levels of gelatinase activity were present in LA at both stages of HF compared with their respective controls (Fig. 3A). There was complete inhibition of gelatinolytic activity by GM6001, indicating that MMPs were responsible for the gelatinolytic activity (Fig. 3B).



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  		Figure 2 Gelatin zymograms of gelatinase activity in the left atrium of control and heart failure (HF) animals. (Upper panels) Early HF. (Lower panels) Severe HF. On the left panels, lanes 1 to 4 represent controls, and lanes 5 to 8 are HF. In early HF, pro- and active matrix metalloproteinases (MMP)-9 are increased, while MMP-2 activity is not significantly changed. In severe HF, pro- and active MMP-2 are significantly increased, while MMP-9 activity is not significantly changed. The corresponding densitometry is shown in the right panels. *p < 0.05 versus respective controls.

 


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  		Figure 3 (A) Quantitative gelatinase assay. (Left panels) Comparison between early heart failure (HF) and respective controls. (Right panels) Comparison between severe HF and respective controls. (Upper panels) Left atrium (LA). (Lower panels) Right atrium (RA). *p < 0.01 versus respective controls; {dagger}p = 0.05 versus control. (B) Effect of protease inhibition on gelatinase activity. Data are means of triplicate assays. There is 100% inhibition of gelatinase activity with GM6001, an matrix metalloproteinases inhibitor.

 
Atrial myocytes.   At severe HF, the atria showed marked myocyte hypertrophy compared with controls (Fig. 4). Bundles of myofibrils were less tightly packed than in controls, and the number of myocytes/hpf was significantly reduced in severe HF, signifying hypertrophy at the myocyte level (Table 4).



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  		Figure 4 Representative photomicrographs of myocytes in left atrium and right atrium stained with H & E stain (x20). The nuclei stain blue and the cytoplasm red. HF = heart failure.

 

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  		Table 4 Atrial Myocyte Morphometry

 
Fibrosis.   Picrosirius staining showed increased endocardial and interstitial fibrosis in both the RA and LA with severe HF (Fig. 5). The interstitial fibrosis was diffuse and patchy in some areas, and muscle necrosis could be seen around areas of intense fibrosis. In contrast, the atria of control hearts contained well-organized collagen bundles interspersed between atrial myocytes.



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  		Figure 5 Representative photomicrographs of left atrium and right atrium stained with picrosirius red (x20). Collagen fibers stain deep red. HF = heart failure.

 
Apoptosis.   There were no significant differences in TUNEL staining in the atria of controls, or at both stages of HF (Fig. 6). There was no evidence of active caspase-3 in control or HF atria, indicating absence of apoptosis (data not shown).



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  		Figure 6 Representative photomicrographs of terminal deoxy nucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling assay. The green stain overlapping red nuclei (arrows) indicates apoptotic nuclei. HF = heart failure.

 
Relationship between pulmonary hemodynamics, atrial wall tension index, and atrial collagen turnover in severe HF.   There was a significant correlation between mean pulmonary artery pressure and gelatinase activity (Fig. 7A). In addition, there were also significant correlations between the changes in LA wall tension index and the two indicators of collagen turnover, collagen synthesis, and gelatinase activity (Figs. 7B and 7C).



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  		Figure 7 Correlations in severe heart failure. (A) Mean pulmonary artery pressure (mPAP) and gelatinase activity. (B) The left atrium (LA) wall tension index and collagen synthesis. (C) The LA wall tension index and gelatinase activity.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Although ventricular remodeling has been described extensively in various models of HF, the biochemical and structural changes that characterize atrial chamber remodeling in HF have not been studied. The principal findings of our study are: 1) significant atrial chamber remodeling occurs during evolving HF, 2) this geometric remodeling is accompanied by atrial myocyte hypertrophy and active collagen turnover, and 3) the perturbations in pulmonary hemodynamics and atrial wall tension are closely correlated to indexes of atrial collagen turnover.

Atrial chamber remodeling.   The canine pacing model demonstrates progressive increase in LA chamber dimensions with marked increases in the post-mortem weights in both atria. These findings are consistent with our previous sequential observations of atrial dimensions (5,6,9,10) and post-mortem measurements of atrial weight (8,13). The atrial myocytes and the collagen matrix are both involved in these progressive remodeling changes.

Atrial myocytes.   Our study indicates a marked increase in the cross-sectional areas of the atrial myocytes in HF which have been previously observed in this model (9). Atrial myocyte hypertrophy, along with the absence of detectable apoptosis, contributes to the increased chamber weight and, therefore, constitutes one of the mechanisms for atrial remodeling. The increase in myocyte area, coupled with increased fibrosis, may account for the reduced number of myocytes observed per hpf. The factors leading to myocyte hypertrophy in the atria are probably similar to those in the ventricle, namely mechanical stretch with the attendant stretch-activated pathways, and the elaboration of various growth factors and cytokines such as angiotensin II, endothelin-1, insulin growth factor-1, interleukin-6, and gp130 (14–18). Our results are consistent with a goat model of sustained atrial fibrillation, which also had markedly increased atrial pressures and myocyte hypertrophy without evidence of atrial myocyte apoptosis (19,20). The lack of detectable apoptosis in the atrium is in contrast with the marked increase in myocyte apoptosis in paced failing canine ventricles (19–23), and, thus, represents a uniquely different mechanism of remodeling in the atria.

Collagen turnover.   Increased turnover of collagen, the principal ECM protein in the atria, constitutes the second mechanism mediating atrial chamber remodeling. The simultaneous increase in both collagen synthesis and markers of collagen degradation indicate a dynamic turnover of the collagen matrix in the atria. Active collagen turnover has been previously reported in the volume-overloaded ventricle leading to the onset of chamber dilation (24). In this study, collagen turnover and alterations in collagen organization in the atria were strongly correlated with LA wall tension index, suggesting a role for hemodynamic load in mediating these atrial ECM changes. These effects may be mediated by angiotensin-II, which is increased both locally in the atria and systemically in HF (25,26). Indeed, infusion of angiotensin-II to rats causes marked fibrosis of both atria (27). In the human atria, a strong correlation between collagen I{alpha} messenger RNA (mRNA) and angiotensin-converting enzyme (ACE) mRNA has also been observed (28). Moreover, treatment with the ACE inhibitor enalapril in this canine model significantly reduced atrial angiotensin-II levels and fibrosis as measured by collagen volume fraction (25).

Our results also indicate increased atrial gelatinolytic activity, even in dogs with early HF when the hemodynamic perturbations are modest. This suggests that remodeling of the ECM may be one of the mechanisms for increased atrial dimension observed in early HF, whereas deteriorating hemodynamics and fluid retention contribute to further increases in atrial size with severe HF. Among the different MMPs that have been identified, MMP-2 and MMP-9, the gelatinases, have been most frequently reported to be increased in the remodeled or failing ventricle (29). Factors known to induce the expression of MMPs in various cell systems include catecholamines, angiotensin II, and endothelin (30–33), which are markedly activated in pacing-induced HF (6). In addition, increased hemodynamic load per se may influence the expression of MMPs, at least in the ventricular myocardium (34). Thus, increased atrial wall tension may be another stimulus for increased MMP activity, which is supported by the correlation between LA wall tension index and gelatinase activity in our study.

Our study also indicates a unique temporal profile of MMP activation in the atria with predominantly MMP-9 activity in early HF, followed by MMP-2 activity in severe HF. In the end-stage human failing ventricle, increases in both MMP-2 and MMP-9 activity have been observed (1,35,36). In this canine HF model, we have recently reported a marked increase in MMP-9 and MMP-13 (interstitial collagenase) in the advanced failing ventricle (37). However, relative myocardial MMP-2 level was unchanged. Therefore, it appears that there is an opposite pattern of MMP-2 and MMP-9 activation in the atrium compared with the ventricle in evolving HF. The reasons for this differential temporal regulation of MMP activity are unclear. Indeed, the pattern of atrial gelatinase activity in HF is similar to the arterial wall after vascular injury, with early MMP-9 activation followed by MMP-2 activation (38).

Extracellular matrix changes occurring in pacing-induced atrial remodeling have been reported previously (9,39). In a dog model of atrial pacing, MMP-9 activity in the LA was increased by 50%, while tissue inhibitor of metalloproteinases (TIMP)-4 protein was decreased by a similar degree (39). Comparison of their study with our current findings, however, is confounded by the fact that their study utilized atrial pacing and only assessed the changes in MMPs and TIMPs at a single time point. In another study that used a ventricular pacing protocol that was similar to ours, LA collagen volume fraction, hydroxyproline, and myocyte cross-sectional area were increased (9).

This study though did not assess serial changes over time, or measurements of collagen synthesis or degradation. A novel finding in our study is that increased atrial collagen turnover in HF was not associated with a significant change in total collagen content, but rather with a marked alteration in collagen organization, with rearrangement of collagen fibers in the atrial interstitium along with patchy deposition of collagen. A similar pattern of collagen rearrangement is also an important remodeling mechanism in the failing ventricle in the pacing model (1,40).

Physiological and clinical relevance.   Our study provides for the first time a link between alterations in atrial myocytes and the collagen matrix, and atrial chamber remodeling. Indexes of collagen turnover (i.e., gelatinase activity and collagen synthesis) are strongly and significantly correlated with alterations in both pulmonary arterial pressure and LV wall tension index. These structural changes in evolving heart failure also have important clinical relevance. First, collagen rearrangement and cellular hypertrophy likely mediate the reported alterations in atrial compliance and function (39,41), which, in turn, contribute to the perturbed pulmonary hemodynamics. Second, the fibrotic changes in the interstitium may constitute a key substrate for the development of atrial arrhythmias. Indeed, increased atrial tissue mass can support multiple re-entry circuits (42), predisposing to atrial arrhythmias such as atrial fibrillation.

In summary, our current data have shown that the atria are chambers of dynamic cellular and ECM remodeling. Marked atrial chamber dilation and elevated pressures are associated with intense collagen turnover. The relationship between LA wall tension unit and collagen turnover provide circumstantial evidence that the described changes in the atrial myocytes and interstium are a crucial response in evolving HF, and may serve as potential therapeutic targets.


   Footnotes
 
Supported by the Heart and Stroke Foundation of Ontario and the Canadian Institute of Health Research and dedicated to the memory of Robyn Strauss Albert.


   References
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 Abstract
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 Discussion
 References
 

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