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-skeletal actin expression, ventricular fibrosis and heart function with the degree of pressure overload cardiac hypertrophy in rats
1 Dipartimento di Biologia Evolutiva e Funzionale-Sezione Fisiologia, Università di Parma, 43100 Parma, Italy2 Department of Pathology, University of Geneva, 1211 Geneva, Switzerland
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Abstract |
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-skeletal actin expression and volume fraction of fibrosis in the ventricular myocardium and their functional counterpart in terms of arrhythmogenesis and haemodynamic variables, in rats with different degrees of compensated cardiac hypertrophy induced by infra-renal abdominal aortic coarctation. The following coarctation calibres were used: 1.3 (AC1.3 group), 0.7 (AC0.7) and 0.4 mm (AC0.4); age-matched rats were used as controls (C group). One month after surgery, spontaneous and sympathetic-induced ventricular arrhythmias were telemetrically recorded from conscious freely moving animals, and invasive haemodynamic measurements were performed in anaesthetized animals. After killing, subgroups of AC and C rats were used to evaluate in the left ventricle the expression and spatial distribution of -skeletal actin and the amount of perivascular and interstitial fibrosis. As compared with C, all AC groups exhibited higher values of systolic pressure, ventricular weight and ventricular wall thickness. AC0.7 and AC0.4 rats also showed a larger amount of fibrosis and upregulation of -skeletal actin expression associated with a higher vulnerability to ventricular arrhythmias (AC0.7 and AC0.4) and enhanced myocardial contractility (AC0.4). Our results illustrate the progressive changes in the extracellular matrix features accompanying early ventricular remodelling in response to different degrees of pressure overload that may be involved in the development of cardiac electrical instability. We also demonstrate for the first time a linear correlation between an increase in -skeletal actin expression and the degree of compensated cardiac hypertrophy, possibly acting as an early compensatory mechanism to maintain normal mechanical performance.
(Received 13 October 2005;
accepted after revision 30 January 2006; first published online 1 February 2006)
Corresponding author D. Stilli: Dipartimento di Biologia Evolutiva e Funzionale-Sezione Fisiologia, Università di Parma, Parco Area delle Scienze 11A, 43100, Parma, Italy. Email: donatella.stilli{at}unipr.it
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Introduction |
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It has also been shown that -skeletal actin (-SKA) is expressed during cardiac development and then downregulated after birth in mammals (Carrier et al. 1992). Several studies have demonstrated that -SKA expression increases during cardiac hypertrophy in different animal species including man (Schwartz et al. 1986; Winegrad et al. 1990; Clement et al. 1999; Suurmeijer et al. 2003) and represents a well-accepted marker of this phenomenon. However, the correlations between -SKA upregulation with the degree of compensated cardiac hypertrophy and with changes of cardiac contractility and relaxation are still not known. Similar considerations apply to ventricular fibrosis that develops early in the overloaded ventricular myocardium (Weber, 2000; Stilli et al. 2001).
In the present study we specifically addressed these issues, by analysing alterations of -SKA expression and extracellular matrix features as well as their functional counterparts, such as changes in cardiac electrical activity and haemodynamics, with a rat model of compensated cardiac hypertrophy induced by pressure overload of increasing severity.
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Methods |
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The study population consisted of 82 male 5-month-old Wistar rats (Rattus norvegicus), individually housed in Plexiglass cages from the beginning of the experimental protocol, in a temperature-controlled room (20–24°C), with light on between 7 am and 7 pm. The experimental protocol was approved by the Veterinary Animal Care and Use Committee of the University of Parma and conformed with the National ethical guidelines (Italian Ministry of Health; D.L.vo 116, January 27, 1992).
Experimental protocol
All animals were chronically instrumented with a miniature transmitter for telemetry ECG recording (Model TA11CTA-F40, Data Sciences Int., St. Paul, MN, USA). In 52 rats, abdominal aortic coarctation was also performed during transmitter implantation in order to induce left ventricular hypertrophy (AC group), while the remaining animals were used as a control group (C group). Different calibres of coarctation were used, 1.3 (AC1.3 group; n= 15), 0.7 (AC0.7 group; n= 25) and 0.4 mm (AC0.4 group; n= 12), respectively, leading to a lumen reduction of about 35, 65 and 80%. For each rat, functional measurements were performed 1 month after surgery (aortic ligature and/or transmitter implantation). Long-term telemetry ECG tracings were recorded in baseline conditions and during sympathetic stimulation induced by the exposure to an acute social challenge (resident-intruder test, see below). Two days after ECG recording, invasive haemodynamic measurements were performed before killing, with the animal under anaesthesia. Then the hearts of AC and C rats were subdivided into two subgroups and submitted to the following analyses: (a) electrophoretic and immunoblot analysis (5 AC1.3, 5 AC0.7, 5 AC0.4 and 5 C rats), to quantitatively evaluate -SKA expression in the left ventricular myocardium; and (b) morphometric analysis (10 AC1.3, 20 AC0.7, 7 AC0.4 and 20 C rats) to define the amount of perivascular and interstitial fibrosis in the left ventricular wall. Five C rats were excluded from the analysis because the hearts were not properly arrested in diastole. Finally, part of the hearts employed for morphometry was randomly selected and used to determine the spatial distribution of -SKA by means of immunohistochemical analysis (10 AC1.3, 10 AC0.7, 7 AC0.4 and 10 C rats).
Surgery: transmitter implantation (all rats, n= 82) and aortic coarctation (AC rats, n= 52)
Rats were anaesthetized with droperidol plus fentanyl citrate (Leptofen, Farmitalia-Carlo Erba, Milan, Italy; 0.6 ml kg–1I.M.), and the ECG telemetry transmitter was chronically implanted according to a previously described procedure (Sgoifo et al. 1996b). Briefly, the body of the transmitter was placed into the abdominal cavity and the two electrodes (wire loops) fixed, respectively, to the dorsal surface of the xiphoid process and in the anterior mediastinum close to the right atrium. In AC groups, the abdominal aorta was dissected free, and a silk ligature of the vessel was placed between the two renal arteries (calibres of coarctation: 1.3 mm, AC1.3 group; n= 15; 0.7 mm, AC0.7 group; n= 25; 0.4 mm, AC0.4 group; n= 12; De Chastonay et al. 1983; Stilli et al. 2001). In C rats (n= 30), the ligature was not tied. After surgery, all animals received antibiotic therapy with gentamicin sulphate for three days (Aagent, Fatro, Milan, Italy; 0.2 ml kg–1, I.M.).
ECG data acquisition and ECG processing (all C and AC animals)
One month after surgery (aortic constriction and/or telemetry implantation), three 15 min continuous ECG recordings were performed in each animal: (a) in baseline conditions, when the animal was alone in its home cage; (b) during the exposure to a social challenge obtained by introducing the instrumented rat into the territory of an aggressive conspecific male (resident-intruder test; Martinez et al. 1998), since this procedure is known to produce an intense activation of the sympathetic–adrenomedullary system and the hypotalamic–pituitary–adrenocortical axes (Sgoifo et al. 1996a); and (c) during recovery from stress, when the animal was returned to its cage. The ECG signals were collected by a receiver (Data Sciences) placed under the experimental cage, monitored on an oscilloscope and simultaneously routed to a personal computer via an analog-to-digital conversion board (1 kHz sampling rate) for permanent storage. All experimental sessions were performed during the light phase between 9 am and 1 pm. Then, each 15 minute ECG recording was analysed using a custom-made software package, for measuring the mean R–R interval and interactively detecting ventricular arrhythmic events (VAEs).
Haemodynamic measurements (all C and AC animals)
Rats were anaesthetized with Leptofen, as previously described. Then a microtip pressure transducer (Millar SPC-320, Millar, Houston, TX, USA) connected to a recording system (Power Laboratory ML 845/4 channels, 2Biological Instruments, Besozzo-Varese, Italy) was inserted into the right carotid artery to record systolic (SBP) and diastolic blood pressure (DBP). The pressure transducer was then advanced into the left ventricle to measure LV systolic (LVSP) and end-diastolic pressure (LVEDP), the maximum rate of ventricular pressure rise (+dP/dt) and the maximum rate of ventricular pressure reduction (–dP/dt), as indices of systolic and diastolic function (software package CHART B4.2).
Light microscopy and immunohistochemistry (10 AC1.3, 20 AC0.7, 7 AC0.4 and 20 C rats)
Each rat was anaesthetized with Leptofen and then killed by injecting 2 ml of cadmium chloride solution (100 mM; I.V.), in order to arrest the heart in diastole. The heart was excised. The right ventricle and the left ventricle including the septum were separately weighed and fixed in paraformaldehyde (4%). Seven to ten 1-mm-thick slices were transversely cut from the left ventricle and embedded in paraffin. Two 5-µm-thick serial sections were then obtained from the equatorial transverse slice. One section was stained with Haematoxylin and Eosin and morphometrically analysed at optical microscopy, in order to evaluate: (a) the thickness of the left ventricular free wall (magnification 400x); and (b) the total amount of perivascular and interstitial fibrosis in the left ventricular myocardium. Irregular widening of intercellular spaces due to collagen accumulation with or without inflammatory cellular infiltration was considered as interstitial fibrosis. According to a procedure previously described (Capasso et al. 1990), in each section, a full transmural quantitative assessment of the fibrotic tissue was performed in 60 fields of the left ventricular free wall with the aid of a grid defining a tissue area of 0.160 mm2 and containing 42 sampling points each covering an area of 0.0038 mm2. Specifically, the first field explored was located at the subepicardial level, at the boundary between septal wall and free wall. Then, in the same ventricular region, two additional fields were explored, at the mid- and subendocardial levels. The transmural analysis was repeated for 20 consecutive ventricular regions, to give a total of 60 fields explored (20 for each layer of the left ventricular free wall). Then, to define the volume fraction of fibrosis, the number of points overlying myocardial fibrosis was counted and expressed as a percentage of the total number of points explored. For interstitial fibrosis, the numerical density of fibrotic foci per unit area of myocardium and the average cross-sectional area of the lesion profiles were also determined.
In a subgroup of animals (10 AC1.3, 10 AC0.7, 7 AC0.4 and 10 C rats), the second 5-µm-thick equatorial section was stained with blue aniline Masson's trichrome and used for immunochemistry with anti -SKA (Clement et al. 1999) diluted at 1:10 in Tris-buffered saline (TBS; 10 mM Tris, 154 mM NaCl, pH 7.4). Immunoperoxidase staining was performed essentially as previously described (Schurch et al. 1987). After staining, sections were observed using a Zeiss Axiophot photomicroscope (Carl Zeiss, Oberkochen, Germany). Images were acquired with a high sensibility Axiocam colour camera (Zeiss). Images were subsequently analysed using the software KS400 (Kontron System, Zeiss Vision, Oberkochen, Germany). Using this software, any structure could be selected on the basis of the pixel intensity values in each colour channel. In order to measure the intensity of immunostaining, the image was transformed in grey luminance values ranging from 0 (corresponding to black) to 255 (corresponding to white). Results were given as the percentage of pixel number corresponding to a value below 200 (values above 200 were considered as background).
Electrophoretic and immunoblot analysis (5 AC1.3, 5 AC0.7, 5 AC0.4 and 5 C rats)
Each heart was arrested in diastole as described above and excised. The right and left ventricles were separately weighed and frozen at –80°C. The left ventricular tissue was mechanically fragmented in liquid nitrogen, homogenized in Sample Buffer (62.5 mM Tris-HCl, pH 6.8, 2% sodium dodecyl sulphate (SDS), 10% glycerol, 50 mM DTT and 0.01% Bromophenol Blue) and boiled for 5 min. For each animal, 3 µg protein was separated on 5–20% gradient polyacrylamide gels (Laemmli, 1970) and electroblotted on nitrocellulose membranes (Protran, Schleicher & Schuell, Dassel, Germany) according to Towbin et al. (1979). Membranes were incubated for 2 h at room temperature with anti--SKA antibody (-SKA1, 1:500; Clement et al. 2003), diluted in TBS solution containing 3% bovine serum albumin (BSA) and 0.1% Triton X-100. After three washes with TBS containing 0.1% Triton X-100, a second incubation was performed for 1 h at room temperature with peroxidase-conjugated affinity purified goat antirabbit IgG (Jackson Immunoresearch Laboratories, West Grove, PA, USA) at a dilution of 1:10 000 in TBS containing 0.1% BSA and 0.1% Triton X-100. Peroxidase activity was developed using the ECL Western blotting system (Amersham, Rahn AG, Zürich, Switzerland), according to the manufacturer's instructions. To determine the expression of -SKA, blots were scanned (Arcus II; Agfa, Mortsel, Belgium), and the intensity of the band was quantified by means of the ImageQuant Program (Image Quant Analysis, Molecular Dynamics, Sunnyvale, CA, USA).
Statistical analysis
The SPSS statistical package (SPSS, Chicago, IL, USA) was used. Normal distribution of variables was checked by means of the Kolmogorov–Smirnov test. Statistics of variables normally distributed (all variables except the number of ventricular arrhythmias during baseline and recovery periods) included: means ±S.E.M., one-way analysis of variance (post hoc analysis: Games-Howell test), and linear correlation analysis. Non-parametric statistics (Friedman test and Wilcoxon test; Kruskal–Wallis and Mann–Whitney U test) were used to compare data relating to the incidence of arrhythmias. Statistical significance was set at P < 0.05.
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Results |
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Baseline values of R–R interval were similar in AC and C rats (averaging 190 ± 1.9 ms). In all groups of animals, R–R interval was significantly lowered by social stress (133 ± 1.1 ms, P < 0.001) and did not fully recover during the post-stress period (150 ± 1.2 ms, P < 0.001). No significant differences among groups were observed in R–R interval (Fig. 1).
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The mean values of the systolic arterial blood pressure and left ventricular systolic pressure were significantly higher in all AC groups than in C animals, the amount of increment being clearly dependent on the degree of aortic coarctation (Figs 3A and 4A). Conversely, the diastolic arterial blood pressure was increased only in AC0.4 and AC0.7 animals (Fig. 3B). In AC0.4 rats a substantial increase in the peak positive and negative ventricular dP/dt was also observed (Fig. 4C and D).
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A significant increase of left ventricular weight normalized to body weight (LVW/BWend) and free wall thickness was observed in all groups of banded animals as compared with the C group, while higher values of the right ventricular weight were measured only in the AC0.4 group (Table 1). The LVW/BWend increment was approximately +49% in AC0.4, +30% in AC0.7 and +20% in AC1.3 animals (Table 1).
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-actin isoform expression
When the level of -SKA expression was evaluated by means of immunoblotting, it was significantly increased in AC0.7 and AC0.4 compared to C animals (average increase about 37 and 120%, respectively, P < 0.005; Fig. 6A and B). However, the increase in -SKA expression in AC0.7 compared to the C group was not visible by using immunohistochemistry, indicating that this technique was not sensitive enough to detect subtle differences (Fig. 6C). In contrast, the expression of -cardiac actin in the left ventricular myocardium was similar in AC and C groups (data not shown).
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-SKA staining compared to those located in areas far from fibrotic lesions. Correlations
Significant positive correlations (P < 0.005) were observed between -SKA expression and: (a) maximum rate of ventricular pressure rise (+dP/dt; Fig. 7A); (b) maximum rate of ventricular pressure reduction (–dP/dt; Fig. 7B); and (c) left ventricular weight (Fig. 7C). The left ventricular weight was also positively correlated with the volume fraction of total myocardial fibrosis (P < 0.001; Fig. 7D).
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Discussion |
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Alterations in cardiac function and structure, as well as in -SKA expression, were related to the severity of the hypertrophic stimulus and the corresponding degree of compensatory cardiac hypertrophic response. Definite changes appeared only when the cardiac mass was larger than 20% compared to controls (i.e. in AC0.7 and AC0.4 animals), and involved gradual accumulation of cellular and extracellular left ventricle components, affecting the electromechanical cardiac performance.
The hypertrophic remodelling of the left ventricular myocardium in AC0.7 and AC0.4 groups was associated with the appearance of perivascular and interstitial fibrosis. The structural damage, although limited, was more than twice that in C rats. In accordance with previous findings using the same model of pressure overload (Weber, 2000; Stilli et al. 2001), our results indicate that: (a) quantitatively similar alterations in the ventricular extracellular matrix occur at all degrees of insult, suggesting that the same type of reaction contributes to myocardial remodelling throughout the all process; (b) the fibrotic damage has a limited size even in the presence of a 50% increase in cardiac mass (AC0.4 group); and (c) major changes involve perivascular fibrosis.
Reactivation of the fetal cardiac gene programme is a characteristic feature of hypertrophied and failing hearts that correlates with impaired cardiac function and poor prognosis (Kacimi & Gerdes, 2003; Kostin et al. 2003; Kuwahara et al. 2003). Increased -SKA expression is a known marker of myocardial hypertrophy (Winegrad et al. 1990; Clement et al. 1999). In this study we show for the first time that, in the initial stages of compensated hypertrophy, a linear relationship exists between -SKA expression and the progression of ventricular hypertrophy in response to pressure overload. The increased expression of -SKA was more evident in myocardial fibres surrounding large spots of fibrosis, in agreement with previous data (Clement et al. 1999), but was also present in cardiomyocytes surrounding small areas of interstitial fibrosis, i.e. in ventricular regions exposed to a greater mechanical stress than other regions. In accordance with previous studies (Hewett et al. 1994; Kuwahara et al. 2003), it is possible to interpret the increased expression of -SKA and its specific spatial distribution, at the initial stages of myocardial response to pressure overload, as a compensatory mechanism to maintain normal mechanical cardiac function. This hypopthesis was supported by the finding that -SKA expression was positively correlated with +dP/dt and –dP/dt, indicating that a progressive increase in the protein expression is associated with a progressive increase in myocardial contractility.
In C and AC groups, the increase in heart rate and incidence of ventricular arrhythmias during exposure to social stress compared with baseline values was attributed to the intense sympathetic activation provoked by the social interaction. This interpretation is in agreement with previous studies performed on different rat models, with or without cardiac disorders, showing that social challenge induces a significant sympathetic activation, potentially leading to arrhythmogenesis (Sgoifo et al. 1996a; Stilli et al. 2001). Previous studies have shown that sudden adrenergic stimulation results in a dose-dependent prolongation of action potential duration and induces early and delayed after-depolarizations, suggesting a possible pathway for arrhythmogenesis following adrenergic stimulation in the intact heart (Priori & Corr, 1990; Tatewaki et al. 2003; Lampert et al. 2005). The increased myocardial structural alterations might contribute to enhanced ventricular electrical instability in AC0.7 and AC0.4 rats compared to the other groups. It has been documented (De Mello, 2004) that changes in ventricular structure that involve cardiomyocyte hypertrophy, diffuse and focal extracellular matrix accumulation and recruitment of inflammatory cells are involved in abnormalities of impulse conduction and arrhythmias. Indeed, the development of areas of interstitial fibrosis progressively leads to a morphological and physiological disorganization of the hypertrophied ventricle which includes the rupture of intercellular coupling and impairment of electrical synchronization, favouring arrhythmogenesis. It is conceivable that this mechanism, in addition to the non-uniform regional prolongation of ventricular action potentials already demonstrated in this model of pressure overload hypertrophy (Yan et al. 2001), can lower the threshold of both spontaneous and sympathetic-induced ventricular arrhythmias. The fact that the focal ectopic activity does not initiate more complex ventricular tachyarrhythmias in our experimental model could be explained as a consequence of the limited size of structural damage.
In conclusion, the data reported in the present study illustrate the progressive alterations in the extracellular matrix features accompanying early ventricular remodelling in response to different degrees of pressure overload that may contribute to the development of initial signs of cardiac electrical instability. We also demonstrate that an increased -SKA expression not only represents a very sensitive marker of cardiac hypertrophy but also exerts a role in maintaining normal mechanical performance in compensated hypertrophy, as suggested by the linear relationship between the protein expression and myocardial contractility indices.
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) of each experimental group, during baseline (B), social stress (C) and recovery periods (D). For each experimental condition, the percentage of animals without arrhythmias in each group is also shown. *P < 0.05, **P < 0.005 versus C animals.
