Skip Navigation

European Journal of Heart Failure 2003 5(6):725-732; doi:10.1016/S1388-9842(03)00153-3
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Omerovic, E.
Right arrow Articles by Waagstein, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Omerovic, E.
Right arrow Articles by Waagstein, F.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2003 European Society of Cardiology

Selective β1-blockade attenuates post-infarct remodelling without improvement in myocardial energy metabolism and function in rats with heart failure

E. Omerovica,*, E. Bollanoa, B. Soussib and F. Waagsteina

a Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at Gothenburg University 413 45 Gothenburg, Sweden
b Lundberg Bioanalysis Laboratory, Sahlgrenska Academy at Gothenburg University 413 45 Gothenburg, Sweden

* Corresponding author. Tel.: +46-31-342-41-58; fax: +46-31-82-37-62. E-mail address: elmir{at}wlab.gu.se


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: To investigate in vivo effects of long-term selective β1-blockade on cardiac energy metabolism, remodelling, function and plasma cytokines in a rat model of post-infarct congestive heart failure (CHF).

Methods: Myocardial infarction (MI) was induced in male rats by ligation of the left coronary artery. Three different groups of rats were studied, MI rats treated with metoprolol (n=17), MI rats treated with saline (n=14) and sham-operated rats (n=12). The treatment with metoprolol 1 mg/kg/h was initiated in the third week post-infarct for a period of 6 weeks. All rats were investigated non-invasively with volume-selective 31P magnetic resonance spectroscopy and echocardiography for evaluation of left ventricular (LV) energy metabolism, morphology and function. Plasma concentration of IL-1β and IL-6 and density of β-adrenergic receptors were analyzed.

Results: Metoprolol attenuated the increase in LV dimensions and volumes. Treatment with metoprolol had no effect on PCr/ATP and LV function. Plasma level of IL-1β was higher and IL-6 was lower in the metoprolol group. Density of β-adrenergic receptors was similar in all three groups.

Conclusion: Selective β1-blockade in rats with chronic CHF attenuates post-infarct structural remodelling, without concomitant improvement in myocardial energy metabolism and function. Improvements in myocardial energy metabolism and function do not precede and are not a prerequisite for an anti-remodelling effect of β1-blockade in the setting of chronic CHF.

Key Words: β-Blockade • Congestive heart failure • Cardiac remodelling • Energy metabolism • 31P magnetic resonance spectroscopy

Received March 7, 2003; Revised May 12, 2003; Accepted July 30, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
In spite of the initial scepticism, the concept of β-blockade in congestive heart failure (CHF) has been confirmed by recently conducted large clinical trials [1–3]. A recent clinical trial has shown that even patients with advanced CHF benefit from this therapy [4]. β-Blockers have therefore become the mainstay of modern pharmacological treatment of patients with CHF. This valuable therapy, however, continues to be under-used in clinical practice. Some estimates indicate that only approximately 10% of all eligible patients receive β-blockers. This may be partially explained by scarcity of knowledge about the mechanisms of action of β-blockers. Although we have learned much about the different pharmacological and pathophysiological aspects of β-blockade in the failing heart during recent years, there is still a need for continuous experimental studies to further clarify cellular and sub-cellular events behind the salutary effects of β-blockade in CHF.

It has been shown that β-blockade acts through several different pathways, including attenuation of the toxic effects of catecholamines [5], attenuation and reversal of pathologic remodelling [6], prevention of apoptosis [7], up-regulation of β-receptors [8], protection from auto-antibodies against β1-receptors [9] and suppression of activation of ‘fetal gene program’ [10].

Our group has recently provided in vivo evidence that short-term and high-dose selective β1-blockade, initiated early post-infarct in the rat model of developing CHF, normalizes myocardial energy metabolism and improves left ventricular (LV) function [11]. These experiments were the first in vivo confirmation of the hypothesis proposed in the early 1970s that β-blockade improves myocardial energy metabolism in the failing heart [12].

In this study we have investigated, in vivo and non-invasively, the effects of long-term selective β1-blockade administered in a low dose, on myocardial energy metabolism, cardiac function and remodelling as well as plasma cytokines and myocardial β-receptors in the rat model of chronic post-infarct CHF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Animals and experimental MI
The study protocol was approved by the Animal Ethics Committee of the Gothenburg University and conducted in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996) for use of experimental animals. The induction of myocardial infarction (MI) was performed on male Sprague–Dawley rats (B & K Universal, Sollentuna, Sweden) weighing 200–250 g. The rats were anesthetized with ketamine hydrochloride 100 mg/kg (Parke-Davis, Morris Plains, USA) and xylazine hydrochloride (Bayer AG, Leverkusen, Germany) 10 mg/kg i.p., intubated and connected to a rodent respirator. MI was induced as previously described [13]. Concisely, left thoracotomy was performed between the fourth and fifth ribs exposing the LV wall. The branch of the left coronary artery was ligated by positioning a suture between the pulmonary artery outflow tract and the left atrium. The lungs were thereafter hyperinflated, positive end-expiratory pressure was applied and the thorax was immediately closed. After 3 weeks the animals were randomized into two groups: (1) metoprolol (n=17), receiving 1 mg/kg/h metoprolol by means of subcutaneously implanted osmotic mini-pumps (Alzet 2ML4, ALZA Corporation, Palo Alto, USA) and (2) saline (n=14), receiving 0.9% NaCl in the same manner. In addition, 12 animals served as sham-operated controls (sham) that underwent the same operative procedure but without ligation of coronary artery.

2.2. Echocardiography and hemodynamics
Transthoracic echocardiography was used to assess LV function and geometry using previously validated 2D, M-mode and Doppler techniques [13]. The echocardiographic investigations were performed at baseline (i.e. 3 weeks post-infarct) and after 6 weeks of treatment (i.e. 9 weeks post-infarct). The animals were anesthetized with ketamine hydrochloride 50 mg/kg and xylazine hydrochloride 10 mg/kg i.p. 2D images were obtained using commercially available ultrasound system equipped with a 10-MHz linear transducer for imaging and 5 MHz for Doppler (GE Ving Med, System five, USA). LV volumes and ejection fraction (EF) were computed using the area–length formula. Pulsed wave Doppler spectra of mitral inflow from the apical four-chamber view were used to asses LV diastolic flow characteristics. Stroke volume (SV) was calculated using Doppler recording from the pulmonary artery. All measurements were averaged on at least three consecutive cardiac cycles. Relative wall thickness (RWT) was calculated according to the formula RWT=2x(PWT/LVID), where PWT is posterior wall thickness and LVID is left ventricular internal diameter. The size of MI was estimated according to the scoring system previously described [13,14]. Only rats with large MI (>1/3 of LV) were included in the study since it has been previously shown that rats with small MI develop neither progressive cardiac remodelling (CR) and heart failure nor changes in myocardial energy status [15].

2.3. In vivo 31P magnetic resonance spectroscopy of the rat heart
MR imaging and spectroscopy experiments were performed on a 2.35 T horizontal magnet with a 20-cm bore (Bruker Biospec 24/30), according to the method previously described [13]. One-time examination was performed at the end of the 6-week treatment period with metoprolol. Myocardial PCr/ATP ratio was corrected for partial saturation and blood contamination. After completion of the 31P MRS examination, the rats were killed by rapid excision of the heart. The weight of LV and right ventricle (RV) were measured separately.

2.4. Radioligand binding for β-receptor assessment
Cardiac tissue without macroscopic adipose or connective tissue was minced and homogenized in buffer (pH 7.5) consisting of 50 mM Tris, HCl and 10 mM MgCl2. The protein concentration of the homogenate was measured according to Lowry et al. [16]. β-Adrenoceptors were determined by the use of (125I) iodocyanopindolol (ICYP). The binding assay was carried out in buffer (pH 7.4) consisting of 50 mM Tris/10 mM MgCl2. Saturation binding isotherms were obtained by incubating homogenates for 1 h with varying concentrations of ICYP at 26 °C. The reaction was terminated by dilution in 5-ml ice cold buffer. The samples were than poured over GF/C 2.5 cm glass microfibre filters (Whatman International, England), under reduced pressure followed by a wash with 15 ml of buffer. Filters were counted in a Campougamma universal counter (LKB, Sweden). The binding parameters Bmax and Kd were determined by non-linear least squares fitting.

2.5. Cytokines, IL-1β, IL-6
The concentrations of IL-1β and IL-6 in plasma were measured using enzyme-linked immunoassays with specific antibodies for rat IL-1β and IL-6 according to the manufacturers’ protocol (R&D Systems, Minneapolis, USA).

2.6. Statistics
Computer software (STATVIEW 5.0.1) was used to perform standard statistical procedure with a calculation of mean value and standard error of the mean (S.E.M.) in the different groups. Fisher's protected least significant difference test, preceded by one-way analysis of variance (ANOVA) and repeated measures ANOVA, was applied to detect significant differences between different treatments for interactions defined in advance. Normal distribution of the data was assessed with Kolmogorov–Smirnov test. When data were not normally distributed, a non-parametric test was applied (Kruskal–Wallice). The P-value <0.05 was considered as statistically significant. All data are presented as mean±S.E.M.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Animals
There was no difference in body weight neither at baseline (i.e. third week post-infarct) nor after 6 weeks of treatment. Right ventricular weight (RVW) and LV weight (LVW), normalized for body weights, showed no difference between the metoprolol and the saline group. RVW and LVW were insignificantly higher in the rats with MI compared to the sham group indicating substantial hypertrophy of the remaining viable myocardium in the metoprolol and saline groups (Table 1).


View this table:
[in this window]
[in a new window]

  		Table 1 Animal characteristics

 
3.2. Echocardiography
Heart rate (HR) was ~20% lower in the metoprolol-treated rats compared to both the saline and the sham group (P<0.01). EF was lower in the rats with MI compared to the sham group both at baseline and after 6 weeks of treatment (P<0.01). There was no difference in EF, SV and fractional shortening after 6 weeks of treatment between the metoprolol and the saline group. No difference between the two groups was found in diastolic function estimated by mitral E/A wave ratio and deceleration time (DT) of mitral inflow. DT was longer in MI rats as compared to the sham (P<0.01). Increase in LV diameter in systole (LVDS) and diastole (LVDD) was attenuated in the metoprolol group (P<0.01) compared to the saline group; however, LVDS and LVDD were still higher in comparison to the sham group (P<0.01). Likewise, increase in end diastolic volume (LVVD) was higher in the saline group as compared to the metoprolol group (P<0.01), while increase in LVVS was insignificantly lower in the metoprolol group (Tables 2 and 3, Fig. 1).


View this table:
[in this window]
[in a new window]

  		Table 2 Effects of β-blockade on cardiac geometry

 


View this table:
[in this window]
[in a new window]

  		Table 3 Effects of β-blockade on LV function

 


Figure 1
View larger version (85K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 M-mode echocardiographic recordings from the rats with MI (a) saline-treated; (b) metoprolol-treated and (c) sham-operated rat. After 6 weeks treatment with metoprolol, LVDD and LVDS were preserved compared to the saline-treated rats in which both LVDD and LVDS increased further, indicating attenuation of post-infarct remodelling by selective β-blockade.

 
3.3. Cardiac energy status assessed by volume-selective in vivo 31P MRS
Nine weeks post-infarct PCr/ATP ratio was lower in the rats with MI, i.e. in the metoprolol group (2.2±0.4) and the saline group (2.1±0.2), as compared to the sham group (3.2±0.6; P<0.01 vs. metoprolol and saline). There was no difference in PCr/ATP ratio between the metoprolol and the control group indicating that 6 weeks treatment with metoprolol did not improve LV energetic status (Fig. 2).


Figure 2
View larger version (10K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 31P MR spectrum from a rat with MI (a) saline-treated; (b) metoprolol-treated and (c) sham-operated rat. Treatment with metoprolol did not affect PCr/ATP ratio. Note lower PCr/ATP ratio in rats with MI (metoprolol and saline) compared to the sham-operated rats. Low PCr/ATP ratio indicates disturbed energy balance in the failing heart as a consequence of continuous biochemical remodelling. PCr, phosphocreatine, {alpha}, β, {gamma}-ATP={alpha}, β and {gamma} phosphorus atoms in adenosine-3-phosphate, 2,3-DPG, 2,3 diphosphoglycerate; PDE, phosphodiesters.

 
3.4. Plasma cytokines
Plasma level of IL-1β increased in the metoprolol group (75.4±7 pg/ml) after treatment in comparison to both the saline group (43.3±6 pg/ml) and the sham group (46.7±3 pg/ml) (both P<0.05). IL-6 was lower in the metoprolol group (31.7±7 pg/ml) as compared both to the saline (67.6±14 pg/ml) and to the sham group (56.4±6.5) (both P<0.05). Although IL-6 was higher in the saline group compared to the sham group, this difference was not significant (Fig. 3).


Figure 3
View larger version (12K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Effects of selective β1-blockade on plasma cytokines IL-1β and IL-6. After 6 weeks of treatment, plasma levels of IL-1β increased, while IL-6 decreased in the metoprolol group. *P<0.05 vs. metoprolol.

 
3.5. β-Adrenergic receptors
Myocardial β-receptor density (Bmax) as well as binding affinity (Kd) was similar among all three groups, i.e. Bmax (fmol/mg) metoprolol=31.4±3.8, saline=35.4±0.16 and sham=28.4±2.2 (P=NS). Kd (nmol/l) metoprolol=0.16±0.02, saline=0.16±0.01 and sham=0.15±0.02 (P=NS).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The most important finding of this study is that treatment with the selective β1-blocker metoprolol in the setting of chronic CHF attenuated post-infarct remodelling without concomitant improvement in LV function or energy metabolism. This dichotomy in response to β-blockade has not been previously reported. Post-infarct CR is a continuous process of alterations in the gene expression, molecular, biochemical and cellular changes that are manifested as changes in size, shape and function of the heart after ischemic injury [17]. Late post-infarct remodelling is generally viewed as a maladaptive process, responsible for the development of myocardial dysfunction leading to the transition from compensated to overt CHF [18]. The pathophysiological mechanisms involved in CR are currently the focus of intensive research and are important targets for pharmacological interventions. One integral part of post-infarct CR is alteration in myocardial energy metabolism [13,19,20]. The sum of biochemical alterations during post-infarct CR results in a disturbed delicate energetic supply–demand balance in cardiomyocytes. Substantial evidence strongly supports the hypothesis that the failing heart is an energy-starved organ [21,22]. This metabolic maladaptation is a consequence of continuous biochemical remodelling of the heart that starts during early post-infarction [13]. The status of cardiac energy metabolism may be estimated by means of PCr/ATP ratio. This index may be obtained in vivo non-invasively from a 31P MRS study and is an indicator of cellular energy reserve [22]. The significance of PCr/ATP was best demonstrated by Neubauer et al. who reported that this ratio is an independent predictor of mortality in patients with CHF [23]. Although our knowledge about myocardial energy metabolism in the failing heart has significantly increased during recent years, there are still many unanswered questions. For example, it is not known how energy metabolism interacts with other cellular pathways that are activated in CR. It is also unknown whether improvement in myocardial energy metabolism precedes or is indeed required for structural and functional improvement of the failing myocardium. The relationship between structural post-infarct CR and energy metabolism has not previously been investigated in vivo in the setting of chronic CHF.

The finding that metoprolol attenuated structural LV dilatation is in accordance with clinical studies. There is substantial evidence that β-blockade not only attenuates but also reverses pathologic remodelling including reversal of LV dilatation and hypertrophy [24]. In these studies a significant improvement in LV function occurred before [25] or concomitantly [26] with a decrease in LV volumes and dimensions. It has therefore been suggested that functional improvement is a prerequisite for the anti-remodelling effect [25]. Our study provides different and intriguing results, namely, that the structural anti-remodelling effect of β-blockade is independent, and may even be isolated from, functional and metabolic improvement. The reason for the discrepancy between our study and clinical observations is not clear, but concomitant therapy with ACE-inhibitors, diuretics and β-blockers may affect CR pathways in a way that achieves faster and simultaneous functional recovery than β-blockade alone. It has been demonstrated that inhibition of both the renin–angiotensin and sympathetic systems has a synergistic anti-remodelling effect [27].

We have previously reported that short-term selective β1-blockade with a high dose of metoprolol initiated early in the post-infarct phase normalizes PCr/ATP ratio and improves LV function without a concomitant anti-remodelling effect [11]. Interestingly, in the present study, we have arrived at opposite results, i.e. LV volumes and dimensions were preserved, while neither PCr/ATP ratio nor LV function improved. What could be the reason for such puzzling results? There are at least three principal factors that must be taken into account. These are dose, time of initiation and duration of the treatment with β-blocker. All three factors may affect CR differently. It has been reported that early and not late initiation of the β-blockade in the post-infarct period may prevent alterations in cellular enzymatic systems, including shift in CK isoenzymes and lactate dehydrogenase [28], suggesting that early treatment may be crucial for reversal of maladaptive alterations in myocardial energy metabolism. Future studies should address the question of whether irreversible biochemical alterations take place after a certain period of time post-infarct, and if there is a ‘window of opportunity’ for inhibition and/or reversal of such disturbances by means of pharmacological intervention. Attenuation of structural dilatation of the heart after MI by β-blockade could be mediated by specific pathways different from those involved in the mediation of improvement in energy metabolism and function. This study supports this theory, since attenuation of LV dilatation was not accompanied by functional and biochemical improvement. The fact that neither LV function nor energy status improved suggests the existence of a close relationship between energy metabolism and function in the failing heart. Unfortunately, in clinical studies where β-blockade was reported to improve LV function, energetic status was not evaluated. Occasionally, indirect measurements were performed showing, for example, that β-blockade decreases utilization of lactate in CHF patients, suggesting an improvement in aerobic metabolism [29]. Taken together, the results from our two experimental studies suggest that β-blocker dose should be up-titrated to the highest recommended, and started early in the treatment of post-infarct CR and CHF. Dose, time of initiation and duration of β-blockade treatment are all important determinants of the total anti-remodelling response to β-blockade.

Another intriguing result of the study is the change in plasma IL-1β and IL-6 after treatment with metoprolol. The level of plasma IL-1β was increased in rats receiving metoprolol, while at the same time IL-6 was decreased. It has been demonstrated that IL-1β and IL-6 exert many negative effects on myocardial function and morphology [30–32]. While a decrease in plasma IL-6 is congruent with an anti-remodelling effect, an increase in IL-1β was an unexpected finding [33]. Given the fact that LV function was not improved, it is tempting to speculate that IL-1β may have contributed to such results. It is generally believed that IL-1β is one of the major mediators of negative biological effects on the myocardium in CHF. However, some studies suggest that IL-1β may also exert cardio-protective effects [34]. It has indeed been demonstrated that IL-1β suppresses activation of ‘fetal gene program’ and decreases expression of proteins such as slow-contracting β-myosin heavy chain (β-MHC) [35]. This is an important issue because a recent study has shown that CHF patients with a favourable response to β-blockade have decreased expression of β-MHC [10].

In conclusion, long-term treatment with β-blockade in rats with chronic CHF attenuates LV remodelling without concomitant improvement in LV function and myocardial bioenergetics. While improvement in myocardial energy metabolism may be an important mechanism of action of β-blockade for improvement in cardiac function, this may not be necessary for structural anti-remodelling effects. Early initiation of β-blockade in a sufficient dose is important for maximization of the benefit of β-blockade in post-infarct CR and CHF.


   Acknowledgements
 
The authors are grateful to Pernilla Sandberg, Stefan Skrtic and Klas-Goran Sjogren for excellent technical assistance. The study was supported by grants from Swedish Heart and Lung Foundation, Swedish Research Council, The Lundberg Foundation Inga-Britt & Arne, Gothenburg Medical Society and SWEGEN (The Post-genomic Research and Technology Programme in South Western Sweden).


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Packer M., Bristow M.R., Cohn J.N., et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. US Carvedilol Heart Failure Study Group. N Engl J Med (1996) 334:1349–1355.[Abstract/Free Full Text]
  2. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13.
  3. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001–2007.
  4. Packer M., Coats A.J., Fowler M.B., et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med (2001) 344:1651–1658.[Abstract/Free Full Text]
  5. Sabbah H.N. The cellular and physiologic effects of beta blockers in heart failure. Clin Cardiol (1999) 22(Suppl_5):V16–V20.[Web of Science][Medline]
  6. Bristow M.R. Beta-adrenergic receptor blockade in chronic heart failure. Circulation (2000) 101:558–569.[Free Full Text]
  7. Sabbah H.N., Sharov V.G., Gupta R.C., Todor A., Singh V., Goldstein S. Chronic therapy with metoprolol attenuates cardiomyocyte apoptosis in dogs with heart failure. J Am Coll Cardiol (2000) 36:1698–1705.[Abstract/Free Full Text]
  8. Heilbrunn S.M., Shah P., Bristow M.R., Valantine H.A., Ginsburg R., Fowler M.B. Increased beta-receptor density and improved hemodynamic response to catecholamine stimulation during long-term metoprolol therapy in heart failure from dilated cardiomyopathy. Circulation (1989) 79:483–490.[Abstract/Free Full Text]
  9. Matsui S., Fu M.L. Prevention of experimental autoimmune cardiomyopathy in rabbits by receptor blockers. Autoimmunity (2001) 34:217–220.[Web of Science][Medline]
  10. Lowes B.D., Gilbert E.M., Abraham W.T., et al. Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents. N Engl J Med (2002) 346:1357–1365.[Abstract/Free Full Text]
  11. Omerovic E., Bollano E., Mobini R., et al. Selective beta(1)-blockade improves cardiac bioenergetics and function and decreases neuroendocrine activation in rats during early postinfarct remodeling. Biochem Biophys Res Commun (2001) 281:491–498.[CrossRef][Web of Science][Medline]
  12. Waagstein F., Hjalmarson A., Varnauskas E., Wallentin I. Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J (1975) 37:1022–1036.[Abstract/Free Full Text]
  13. Omerovic E., Bollano E., Madhu B., et al. Bioenergetic, functional and morphologic consequences of postinfarct cardiac remodeling in the rat. J Mol Cell Cardiol (1999) 31:1685–1695.[CrossRef][Web of Science][Medline]
  14. Baily R.G., Lehman J.C., Gubin S.S., Musch T.I. Non-invasive assessment of ventricular damage in rats with myocardial infarction. Cardiovasc Res (1993) 27:851–855.[Abstract/Free Full Text]
  15. Pfeffer M.A., Pfeffer J.M., Fishbein M.C., et al. Myocardial infarct size and ventricular function in rats. Circ Res (1979) 44:503–512.[Abstract/Free Full Text]
  16. Lowry O.H., Rosebrough N.J., Farr A.L., Randall R.J. Protein measurement with the foline reagent. J Biol Chem (1951) 193:265–275.[Free Full Text]
  17. Cohn J.N., Ferrari R., Sharpe N. Cardiac remodeling-concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol (2000) 35:569–582.[Abstract/Free Full Text]
  18. Vaughan D.E., Pfeffer M.A. Post-myocardial infarction ventricular remodeling: animal and human studies. Cardiovasc Drug Ther (1994) 8:453–460.[CrossRef][Web of Science][Medline]
  19. Zhang J., Wilke N., Wang Y., et al. Functional and bioenergetic consequences of postinfarction left ventricular remodeling in a new porcine model. MRI and 31 P-MRS study. Circulation (1996) 94:1089–1100.[Abstract/Free Full Text]
  20. Laser A., Ingwall J.S., Tian R., et al. Regional biochemical remodeling in non-infarcted tissue of rat heart post-myocardial infarction. J Mol Cell Cardiol (1996) 28:1531–1538.[CrossRef][Web of Science][Medline]
  21. Ingwall J.S. Is cardiac failure a consequence of decreased energy reserve? Circulation (1993) 87:VII-58–VII-62.
  22. Ingwall J.S., Shen W. The chemistry of the ATP in the failing heart. Heart Fail Rev (1999) 4:221–228.[CrossRef]
  23. Neubauer S., Horn M., Cramer M., et al. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation (1997) 96:2190–2196.[Abstract/Free Full Text]
  24. Bristow M., Port J.D. Beta-adrenergic blockade in chronic heart failure. Scand Cardiovasc J Suppl (1998) 47:45–55.[Medline]
  25. Hall S.A., Cigarroa C.G., Marcoux L., Risser R.C., Grayburn P.A., Eichhorn E.J. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. J Am Coll Cardiol (1995) 25:1154–1161.[Abstract]
  26. Groenning B.A., Nilsson J.C., Sondergaard L., Fritz-Hansen T., Larsson H.B., Hildebrandt P.R. Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure. J Am Coll Cardiol (2000) 36:2072–2080.[Abstract/Free Full Text]
  27. Theres H.P., Wagner K.D., Romberg D., et al. Combined treatment with ramipril and metoprolol prevents changes in the creatine kinase isoenzyme system and improves hemodynamic function in rat hearts after myocardial infarction. Cardiovasc Drug Ther (2000) 14:597–606.[CrossRef][Web of Science][Medline]
  28. Laser A., Neubauer S., Tian R., et al. Long-term beta-blocker treatment prevents chronic creatine kinase and lactate dehydrogenase system changes in rat hearts after myocardial infarction. J Am Coll Cardiol (1996) 27:487–493.[Abstract]
  29. Andersson B., Blomstrom-Lundqvist C., Hedner T., Waagstein F. Exercise hemodynamics and myocardial metabolism during long-term beta-adrenergic blockade in severe heart failure. J Am Coll Cardiol (1991) 18:1059–1066.[Abstract]
  30. Blum A., Miller H. Pathophysiological role of cytokines in congestive heart failure. Annu Rev Med (2001) 52:15–27.[CrossRef][Web of Science][Medline]
  31. Long C.S. The role of interleukin-1 in the failing heart. Heart Fail Rev (2001) 6:81–94.[CrossRef][Medline]
  32. Wollert K.C., Drexler H. The role of interleukin-6 in the failing heart. Heart Fail Rev (2001) 6:95–103.[CrossRef][Medline]
  33. Prabhu S.D., Chandrasekar B., Murray D.R., Freeman G.L. Beta-adrenergic blockade in developing heart failure: effects on myocardial inflammatory cytokines, nitric oxide, and remodeling. Circulation (2000) 101:2103–2109.[Abstract/Free Full Text]
  34. Nogae C., Makino N., Hata T., et al. Interleukin 1 alpha-induced expression of manganous superoxide dismutase reduces myocardial reperfusion injury in the rat. J Mol Cell Cardiol (1995) 27:2091–2099.[CrossRef][Web of Science][Medline]
  35. Patten M., Hartogensis W.E., Long C.S. Interleukin-1beta is a negative transcriptional regulator of alpha 1-adrenergic induced gene expression in cultured cardiac myocytes. J Biol Chem (1996) 271:21134–21141.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
K. Brixius, R. Lu, B. Boelck, S. Grafweg, F. Hoyer, C. Pott, U. Mehlhorn, W. Bloch, and R. H. G. Schwinger
Chronic Treatment with Carvedilol Improves Ca2+-Dependent ATP Consumption in Triton X-Skinned Fiber Preparations of Human Myocardium
J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 222 - 227.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
S. T. Pleger, P. Most, M. Boucher, S. Soltys, J. K. Chuprun, W. Pleger, E. Gao, A. Dasgupta, G. Rengo, A. Remppis, et al.
Stable Myocardial-Specific AAV6-S100A1 Gene Therapy Results in Chronic Functional Heart Failure Rescue
Circulation, May 15, 2007; 115(19): 2506 - 2515.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
A.-M. Samuelsson, E. Bollano, R. Mobini, B.-M. Larsson, E. Omerovic, M. Fu, F. Waagstein, and A. Holmang
Hyperinsulinemia: effect on cardiac mass/function, angiotensin II receptor expression, and insulin signaling pathways
Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H787 - H796.
[Abstract] [Full Text] [PDF]

Home page
 J CARDIOVASC PHARMACOL THERHome page
B.-q. Zhu, U. Simonis, G. Cecchini, H.-z. Zhou, L. Li, J. R. Teerlink, and J. S. Karliner
Comparison of Pyrroloquinoline Quinone and/or Metoprolol on Myocardial Infarct Size and Mitochondrial Damage in a Rat Model of Ischemia/Reperfusion Injury
Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2006; 11(2): 119 - 128.
[Abstract] [PDF]

Home page
 JNMHome page
F. Maskali, P. R. Franken, S. Poussier, N. Tran, C. Vanhove, H. Boutley, H. Le Gall, G. Karcher, F. Zannad, P. Lacolley, et al.
Initial Infarct Size Predicts Subsequent Cardiac Remodeling in the Rat Infarct Model: An In Vivo Serial Pinhole Gated SPECT Study
J. Nucl. Med., February 1, 2006; 47(2): 337 - 344.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Omerovic, E.
Right arrow Articles by Waagstein, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Omerovic, E.
Right arrow Articles by Waagstein, F.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?