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European Journal of Heart Failure 2002 4(6):713-718; doi:10.1016/S1388-9842(02)00120-4
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© 2002 European Society of Cardiology

Effects of the calcineurin dependent signaling pathway inhibition by cyclosporin A on early and late cardiac remodeling following myocardial infarction

Tae-jin Youna,b, Hainan Piaoa,b, Jin-sook Kwona,b, So-young Choia,b, Hyung-sam Kima,b, Dae-gyun Parkc, Dong-woon Kima,b, Young-gyu Kimb,d and Myeong-chan Choa,b,*

a Department of Internal Medicine, College of Medicine, Chungbuk National University # 62 Gaeshin-dong, Hungduk-gu, Cheongju 361-711, South Korea
b Medical Research Institute, College of Medicine, Chungbuk National University Cheongju, South Korea
c Department of Internal Medicine, College of Medicine, Hallym University Chuncheon, South Korea
d Department of Neurosurgery, College of Medicine, Chungbuk National University Cheongju, South Korea

* Corresponding author. Tel.: +82-43-269-6356; fax: +82-43-273-3252. E-mail address: mccho{at}med.chungbuk.ac.kr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The calcineurin-mediated signaling pathway has been implicated as one of the crucial pathways in cardiac hypertrophy. However, the role of calcineurin pathway on cardiac remodeling after myocardial infarction (MI) has not been well defined.

Methods: Infarcted rats (n=45) were randomized into calcineurin inhibitor, cyclosporin A (CsA) or vehicle groups, 3 days after MI and treated for 2 weeks (early post-MI cardiac remodeling stage), or randomized 17 days after MI and treated for 2 weeks (late remodeling stage).

Results: Calcineurin pathway inhibition during the early cardiac remodeling stage attenuated the myocardial hypertrophy after MI (P<0.05). However, left ventricular dimensions were further increased and fractional shortening deteriorated with calcineurin inhibition during this stage (P<0.05, each). During late remodeling stage, CsA treatment did not affect myocardial hypertrophy and cardiac dilation following MI.

Conclusion: Our results strongly support the hypothesis that calcineurin pathway mediates compensatory myocardial hypertrophy during the early remodeling stage after MI. However, the calcineurin pathway does not seem to affect the late remodeling after MI.

Key Words: Heart failure • Hypertrophy • Infarction • Remodeling • Calcineurin

Received December 11, 2001; Revised March 18, 2002; Accepted May 21, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
After myocardial infarction (MI), hypertrophy of the surviving myocardium and progressive left ventricular (LV) dilation occur [1–6]. During this cardiac remodeling process, myocardial hypertrophy may compensate for the myocardial dysfunction at least in the acute uncompensated stage after MI. However, myocardial hypertrophy may be deleterious for the myocardial metabolism and architecture and early compensated hypertrophy may decay into maladaptive, decompensated hypertrophy and heart failure (HF), especially given the eccentric nature of cardiac hypertrophy such as in the infarcted or volume overloaded heart [7,8].

Recently, calcineurin, a calcium–calmodulin dependent serine–threonine phosphatase pathway has been implicated to play an important, although some debates are still present, role in the development and maintenance of myocardial hypertrophy, especially in the pressure overloaded myocardium [9–21]. However, the role of the calcineurin pathway in eccentric hypertrophy and cardiac remodeling after MI has not been fully evaluated. Accordingly, we evaluated the effects of calcineurin pathway inhibition, early and late after MI, on LV remodeling using a rat model of MI.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study protocols
2.1.1. Protocol I
First, we evaluated the sequential changes of cardiac hypertrophy and chamber dilatation after MI. To analyze heart weight changes after MI, MI was induced by left coronary artery ligation and animals were then killed 3, 7, 14 and 28 days after the ligation and sequential changes of the cardiac hypertrophy induced were evaluated (n=5, each). To analyze the sequential changes of chamber dilation and cardiac function, MI was produced in other rats (n=5) and sequential changes of LV dimensions and fractional shortening (FS) were evaluated pre-MI, and 14 days and 28 days later by echocardiography.

2.1.2. Protocol II
We evaluated the role of the calcineurin pathway in cardiac remodeling after MI. Three days after the experimental MI, the rats were randomly assigned to early and late treatment groups. Rats in the early treatment group were randomized into calcineurin inhibitor, cyclosporin A (CsA) (25 mg/kg/day, S.C.)-treated-MI (MI-CsA-E, n=10) or vehicle-treated-MI (MI-V-E, n=13) group and treatment was continued for 14 days. Similarly, rats in late treatment group were divided into MI-CsA-L (25 mg/kg/day, S.C., n=10) or MI-V-L (n=12) 17 days after operation and treatment was continued for 14 days. It has previously been demonstrated that 10 mg/kg/day of CsA is sufficient to suppress the tissue calcineurin activity in rats [20]. Normal saline was injected into the vehicle treated rats.

The investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institute of Health (NIH Publication No. 85-23, revised 1996), and all protocols were approved by the Chungbuk National University Animal Care and Use Committee (ACUC).

2.2. Animal model and surgical preparation
Induction of MI was performed as previously described with minor modification [22]. Female Sprague–Dawley rats, 9–10 weeks old, were anesthetized with a mixture of ketamine hydrochloride (100 mg/kg body weight I.M.), and xylazine (10 mg/kg I.M.). Rats were intubated and ventilated under positive pressure using a rodent ventilator (Model 683, Harvard Instruments). A left thoracotomy was performed in the fourth intercostal space, and the pericardium opened. The left coronary artery was enclosed within the myocardium between the left atrial appendage and right ventricular outflow tract with a curved needle and 7–0 silk sutures, and occluded. The chest was then closed in layers and the pneumothorax was evacuated.

2.3. Echocardiographic studies
After 2-week treatment with either CsA or vehicle in both the early and late treatment groups, the rats were anesthetized and echocardiography was performed, as described in a previous study [22]. Initially, using a 7.0 MHz transducer connected to a conventional echocardiographic system (Acouson, 128XP), a two-dimensional short-axis view of the LV was obtained at the level of the papillary muscles. After optimizing the gain setting and confirming both anterior and anterolateral wall akinesia, two-dimensional targeted M-mode tracings were recorded at a paper speed of 100 mm/s. End-systolic and end-diastolic LV internal dimensions were measured from at least three consecutive cardiac cycles on the M-mode tracings, based upon the American Society for Echocardiology (ASE) leading-edge method.

2.4. Hemodynamic measurements
After echocardiographic examination, hemodynamic variables were measured as described in previous study [22]. A catheter (PE 50) was placed in the isolated right carotid artery, and advanced as far as the aorta and left ventricle. The arterial pressure and LV pressure were recorded using polygraph model 7 (Grass Instruments).

2.5. Histologic preparations and morphometric analysis
The heart was arrested in diastole by direct injection of 2–3 ml of 2 M KCl into the LV. It was then excised, weighed and immersed into 10% buffered formalin solution for 24 h. Subsequently, the heart was cut into four transverse slices, the centered two were embedded in paraffin, and histologic sections were prepared and stained with Masson's trichrome. Infarct size was defined by the sum of the epicardial and endocardial circumferences of the fibrous scar tissues divided by the sum of the LV epicardial and endocardial circumferences in the two mid-ventricular sections. Circumferences were calculated by computerized planimetry (Scion Image, Scion Corporation).

2.6. Statistical analysis
Results are expressed as mean±standard error of mean (S.E.M.). Statistical significance was determined using ANOVA and two-tailed Student's t-test (SPSS for Windows). Differences were considered statistically significant when P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Changes of cardiac remodeling indices after MI
Prominent increases in the heart weight to body weight (HW/BW) ratio were observed during the first 2 weeks (especially during the first week) after MI. After this period, the HW/BW remained unchanged (Fig. 1a). Unlike the changes of HW/BW, LV cavity size increased continuously throughout the 4 weeks experimental period after MI (Fig. 1b). Therefore, we arbitrarily defined the first 2 weeks after the MI as the period of early cardiac remodeling and the following 2 weeks as the late remodeling stage after MI (Fig. 1c).


Figure 1
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  		Fig. 1 Changes of LV remodeling indices after experimental MI in rats. Changes of HW/BW ratio after MI. Note that the HW/BW ratio increased up to 14 days after MI and was not significantly changed thereafter (a). Changes of LV dimension and FS after MI. Unlike changes in the HW/BW ratio, LV cavity size increased and FS decreased continuously throughout the 4 weeks experimental period after MI (b). Simultaneous plotting of changes of the HW/BW ratio and LV dimensions after MI. The early phase after MI, showing a progressive increase in the HW/BW ratio and chamber dilation may be distinguished from late phase, which shows chamber dilation without HW/BW change (c).

 
We then evaluated the effects of calcineurin inhibition on cardiac hypertrophy and chamber dilation during the early and late remodeling stages after MI.

3.2. Effects of early calcineurin inhibition after MI
HW/BW ratio (Table 1) and echocardiographic analysis (Fig. 2) of the rats 17 days after MI revealed marked cardiac hypertrophy, LV dilation and systolic dysfunction in MI-V-E rats compared with Sham-operated (Sham-E) rats. CsA treatment during early cardiac remodeling stage attenuated the cardiac hypertrophy observed in the MI-V-E group by 10% (P<0.05) (Table 1). But, LV end-systolic and end-diastolic dimensions increased by 21 and 11% and FS reduced by 17% in MI-CsA-E group compared with the MI-V-E group (P<0.05, each) (Fig. 2).


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  		Table 1 Effects of CsA treatment in early cardiac remodeling stage after MI

 


Figure 2
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  		Fig. 2 Effects of CsA treatment on echocardiographic parameters during the early cardiac remodeling stage after MI. M-mode echocardiograms of the left ventricle 17 days after MI in rats (a). Effects on LVESD, EDD (b) and FS (c). ESD indicates end-systolic dimension; EDD, end-diastolic dimension; FS, fractional shortening. The other abbreviations used are the same as those in Table 1.

 
3.3. Effects of late calcineurin inhibition after MI
No remarkable changes were found in the HW/BW ratio, LV dimension and LV FS in MI-CsA-L vs. MI-V-L (Table 2).


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  		Table 2 Effects of CsA treatment in late cardiac remodeling stage after MI

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
To elucidate the role of the calcineurin pathway in cardiac remodeling after MI, we evaluated the effects of calcineurin inhibition on cardiac hypertrophy, chamber dilation and LV function during the early and late phase after MI.

In protocol I, an increment in the HW/BW ratio and a progressive LV dilation were evident during the first 2 weeks after MI. However, the HW/BW ratio did not increase further 2 weeks despite continued chamber dilation. Therefore, the first 2 weeks after MI with progressive increase in the HW/BW ratio and chamber dilation may be distinguished from the following 2-week period, which presented chamber dilation without further HW/BW ratio change. Apparently, the myocardium shows an active eccentric hypertrophic process in the early phase (1–2 weeks) after MI and a passive dilation in the late phase (i.e. 3–4 weeks) after MI. We arbitrarily defined these two distinguishable phases as the early cardiac remodeling and the late cardiac remodeling stage after MI.

In protocol II, we evaluated the roles of the calcineurin pathway in the early and late remodeling stages after MI. We started CsA administration from 3 days after MI because several reports had demonstrated that the early inhibition of the calcineurin pathway attenuates ischemia–reperfusion injury in some animal models [23–25]. It seems that cardiomyocyte death due to apoptosis or necrosis in myocardial ischemic injury may continue for 40 h after MI [26]. Therefore, we choose a 3-day interval, which appears to be adequate for avoiding CsA effects on ischemia induced cardiomyocyte death.

A number of previous studies have demonstrated that concentric myocardial hypertrophy with pressure overload is effectively attenuated by calcineurin inhibitors, CsA or FK 506 [15–18]. After MI, myocardial hypertrophy presents as an eccentric volume overloaded pattern. In the present study, calcineurin inhibition during the early phase after MI attenuated the myocardial hypertrophy, as assessed by the HW/BW ratio. Our results and recently published data [27] indicate that calcineurin pathway is also crucial for the development of eccentric myocardial hypertrophy after MI, in addition to concentric hypertrophy in the LV pressure overloaded myocardium.

It is well known that LV hypertrophy is a powerful and independent predictor of increased morbidity and mortality in patients with coronary artery disease [28–30]. Increases in muscle mass may imbalance the myocardial oxygen supply, and accompanying collagen deposition in the extracellular matrix may increase myocardial stiffness and act as a focus for ventricular arrhythmia [31–33]. Furthermore, early-compensated hypertrophy may decay into a maladaptive, decompensated hypertrophy and HF [7,8,34]. In pressure overloaded models, the results of calcineurin pathway inhibition on the development of HF have been controversial—inhibition of the calcineurin pathway might increased the mortality due to decompensated HF [35]. In contrast, it might prevent the development of HF [18]. However, the present study shows that LV cavity sizes were greater and FS smaller in the MI-CsA-E than in the MI-V-E group. Therefore, inhibition of calcineurin mediated hypertrophy seems to be detrimental for cardiac remodeling and myocardial function in the early phase after MI and calcineurin-dependent cardiac hypertrophy seems to have a role in compensating for the loss of functioning myocardium, especially in early stage after MI.

Recent data demonstrated that the inhibition of calcineurin by CsA or FK 506 reversed hypertrophy and chamber dilation in calcineurin transgenic mice, tropomodulin-overexpressed mice and pressure overloaded rat [16,17,36]. In this study, the late treatment protocol was applied to determine whether calcineurin inhibition may regress or attenuate the cardiac hypertrophy and/or chamber dilation after MI. However, HW/BW ratio, chamber size and LV function were similar in the MI-CsA-L and MI-V-L groups. These findings suggest that the calcineurin pathway does not participate in late cardiac remodeling after MI.

In summary, calcineurin inhibition with CsA limited myocardial hypertrophy during the early cardiac remodeling stage after MI, but enhanced chamber dilation and LV systolic dysfunction. In the late cardiac remodeling stage, calcineurin inhibition showed no definite effects on myocardial hypertrophy and cardiac dilation. Taken together, our results strongly support the hypothesis that myocardial hypertrophy in the early remodeling phase after MI compensates for the myocardial dysfunction and that the calcineurin pathway has a crucial role in this compensatory hypertrophy. However, it seems that the late cardiac remodeling after MI is not dependent on the calcineurin pathway.


   Acknowledgements
 
This research was supported by the Hallym Academy of Sciences, Hallym University, South Korea, 2001.


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

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