© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Altered cardiac collagen and associated changes in diastolic function of infarcted rat hearts
aDepartment of Pharmacology, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, Rotterdam, The Netherlands
* Corresponding author. Tel.: +31-10-4087-543; fax: +31-10-4089-458 vankerckhoven{at}farma.fgg.eur.nl
Received 5 October 1999; accepted 22 November 1999
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
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Objective: Anti-inflammatory drugs have been shown to modulate collagen deposition during myocardial infarction (MI) induced remodeling. Chronic effects of methylprednisolone (5 mg/kg/day) and low-dose aspirin (25 mg/kg/day) on cardiac collagen and left ventricular diastolic function were studied in rat hearts, 21 days after MI. Methods: Left ventricular function was assessed at baseline and after β-adrenergic stimulation with isoproterenol in isolated perfused hearts, using an intraventricular balloon. After diastolic arrest, left ventricular pressure—volume curves were obtained. Left ventricular dilation was defined as the corresponding left ventricular volume at 20 mmHg left ventricular diastolic pressure. In histological sections, perivascular and interstitial collagen content were quantified morphometrically as the Sirius Red positive area in the non-infarcted interventricular septum. Results: Impaired baseline left ventricular function of MI-hearts was improved by methylprednisolone but not by low-dose aspirin. Isoprotenerol significantly enhanced systolic function in all hearts, whereas it augmented the decrease in left ventricular diastolic pressure only in methylprednisolone-treated MI-hearts. The rightward shift of the pressure—volume curve after MI was aggravated by methylprednisolone but not with low-dose aspirin treatment. Low-dose aspirin reduced perivascular but not interstitial collagen whereas methylprednisolone decreased both perivascular and interstitial collagen. Conclusions: Our findings indicate that MI-induced collagen deposition in the spared myocardium can be affected by chronic therapy with low-dose aspirin or methylprednisolone. The effects on interstitial collagen seemed reflected in an altered left ventricular diastolic function.
KEYWORDS Infarction; Remodeling
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Large myocardial infarction (MI) is known to induce alterations in the collagen matrix of both the infarcted and non-infarcted region of the heart. In the course of post-MI remodeling, infarcted tissue is replaced by scar tissue with a high collagen content while in the non-infarcted tissue collagen content is increased as well [1,2]. Deposition of collagen in the non-infarcted myocardium has been related to an increased myocardial stiffness and impaired diastolic heart function [3–5]. In addition, the structural remodeling of the myocardial collagen matrix appears to contribute considerably to left ventricular (LV) dilation [6] and progression of LV dysfunction [7,8].
In a previous study, we have shown in a rat MI-model that chronic administration of aspirin, in a non anti-inflammatory dose, prevented collagen accumulation in the spared myocardium in the first two weeks after MI [9]. This observation was associated with improved in vivo hemodynamics and absence of further increased LV cavity dimensions [10]. On the other hand, high-dose aspirin, providing plasma levels associated with anti-inflammatory actions in humans was shown to be able to inhibit both the synthesis [11] and degradation of collagen in other rat tissues [12]. Furthermore, anti-inflammatory therapy after MI may lead to a too large reduction of the tensile strength of the LV collagen network resulting in aggravation of chamber dilation, as has been reported with non-steroid anti-inflammatory drugs (NSAIDs) as well as with steroids [13–15]. Moreover, chronic treatment with steroids and NSAIDs have been shown to retard collagen deposition in scar tissue resulting in infarct thinning [16,17]. Thus, although post-MI cardiac fibrosis may contribute to impaired cardiac function it is not clear whether the infarcted heart would benefit from anti-fibrotic treatment.
Therefore, in the present study the effects of chronical methylprednisolone and low-dose aspirin on interstitial and perivascular collagen deposition in 3-week-old infarcted rat hearts were investigated, and related to effects on LV diastolic function.
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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2.1 Animals
Male Wistar rats (Harlan, Zeist, The Netherlands) weighing 270–300 g were housed in groups of two or three on a 12-h light–dark cycle with standard rat chow and water available ad libitum. The animals were subjected to sham-surgery or coronary artery ligation.
All experiments were carried out after approval of the University ethics committee for the use of experimental animals and conform with the Guide for Care and Use of Laboratory Animals.
2.2 Myocardial infarction
Under pentobarbital anesthesia (60 mg/kg i.p.), MI was induced by ligation of the left anterior descending coronary artery [18]. Briefly, after intubation of the trachea, an incision was made in the skin overlying the fourth intercostal space, with the overlying muscles separated and kept aside. The animals were put on positive pressure ventilation (frequency 65–70/min, tidal volume 3 ml) and the thoracic cavity was opened by cutting the intercostal muscles. The heart was carefully pushed to the left and 6-0 silk suture was looped under the left descending coronary artery near the origin of the pulmonary artery. After returning the heart to its normal position, the suture was tied. The intercostal space was closed by pulling the ribs with 3-0 silk, the muscles were returned to their normal position and the skin incision was sutured. Sham-operated animals underwent the same surgical procedure, without the actual coronary artery ligation. Proper occlusion of the coronary artery resulted in an extensive transmural infarction comprising a major part of the LV free wall, with small variations in size [19]. Infarct size was determined by planimetry at mid-ventricular levels in transverse slices [20] as the percentage of LV circumference [9].
2.3 Experimental protocols
Infarcted rats were randomized to receive saline, aspirin or methylprednisolone. Aspirin (25 mg/kg; lysine-acetylsalicylic, Aspégic®, Lorex B.V., Maarssen, The Netherlands) was dissolved in saline and administered as daily i.p. injections of 1 ml/kg, starting 2 days before surgery until the end of the experiment at 21 days after surgery. Methylprednisolone (5 mg/kg; methylprednisolone sodium succinate, Methypresol®, Pharmachemie B.V., Haarlem, The Netherlands) was given as daily i.p. injections starting at the end of the acute inflammatory phase [18], from 7 days to 21 days after surgery.
Untreated control rats were receiving once daily saline injections of 1 ml/kg i.p. from 2 days before until 21 days after surgery (control for asprin treatment) or from 7 days to 21 days after surgery (control for methylprednisolone treatment). Because of no differences between controls, data were pooled.
2.4 Left ventricular function
At the end of the protocol, the hearts were rapidly excized under pentobarbital anesthesia and mounted for perfusion with an oxygenated Krebs—Henseleit buffer (composition in mM: NaCl 125, KCl 4.7, CaCl2 1.35, NaHCO3 20, NaH2PO4 0.4, D-glucose 10; pH=7.4; 37°C) at a constant pressure of 85 mmHg, using the Langendorff technique. Hearts were paced at 350 beats per min (4 V, 2 ms). LV function was measured as isovolumetric developed pressure against a fluid-filled latex balloon placed in the left ventricle, and connected via a fluid-filled catheter to a miniature low-volume displacement pressure transducer. The LV end-diastolic pressure was set to 10 mmHg by adjusting the balloon volume. Although this value for LV end-diastolic pressure is above the physiological values of sham-hearts, this was performed to be able to obtain any β-agonist mediated decreases of the LV diastolic pressure. Coronary flow was measured by a flow probe (Transonic Systems, Ithaca, NY, USA) placed in the tubing just before the ostia of the coronary arteries.
After a stabilization period of 15 min, variables were measured at baseline. In order to determine maximal LV performance during β-agonist stimulation, responses to increasing doses of isoprotenerol (L-isoprotenerol hydrochloride, Sigma Chemicals, St. Louis, USA), ranging from 10–9 to 10–5 M, were determined. For each dose, 100 µl of isoprotenerol solution, dissolved in saline, was injected into the perfusing medium just before entering the coronary arteries. During the administration of isoprotenerol pacing was set to 450 beats per min in order to minimize arrythmias.
After a re-stabilization period, hearts were arrested in diastole with a 0.5-ml injection of a 1 M potassium chloride into the perfusing buffer. At 10 to 20 different LV balloon volumes, diastolic pressures in the range of 0 to 40 mmHg were obtained. For each heart, values were fitted into: pressure=c.ek.volume+a. As a measure for LV dilation the corresponding volume at 20 mmHg LV pressure, V20, was calculated.
2.5 Ventricular hypertrophy
After completion of the functional measurements, hearts were removed from the Langendorff preparation and weighed after exclusion of the atria and large vessels. Ventricular hypertrophy was defined as the ratio of ventricular weight and body weight.
2.6 Collagen content
Briefly, ventricles were cut into four transversal slices from apex to base and fixed with 3.6% phosphate-buffered formaldehyde for at least 24 h. After fixation, the slices were dehydrated and paraffin-embedded. Deparaffinized 5-µm thick sections were incubated for 5 min with 0.2% (wt/vol) aqueous phosphomolybdic acid and subsequently incubated for 45 min with 0.1% Sirius Red F3BA (C.l. 35780, Polysciences, Northampton, UK) in saturated aqueous picric acid, washed for 2 min with 0.01 M HCl, dehydrated and mounted with Entellan (Merck, Darmstadt, Germany).
Collagen content was quantified by morphometry. In the interventricular septum, remote from the infarcted area, interstitial collagen was determined as the Sirius Red positive area in 40 high power fields per heart [9,21]. Areas that enclosed signs of replacement fibrosis or blood vessels, were excluded from analysis. Perivascular collagen was measured around 12 resistance arteries (lumen diameter <150 µm) per heart, in the non-infarcted interventricular septum and viable left ventricular free wall. Perivascular collagen area was corrected for luminal area of the vessel [22].
2.7 Data analysis
All data are presented as means±S.E.M. Data of infarcted rats were only included if the infarction comprised the major part of the LV free wall, since small infarctions are found to be hemodynamically fully compensated [23,24]. Estimation of infarct size by macroscopic appearance has proven to be a reliable method to recognize too small infarctions (<20%) [19]. Differences between groups were analyzed (SigmaStatTM, Jandel Scientific, Erkrath, Germany) using one-way analysis of variance (ANOVA) followed by Bonferroni’s post-hoc t-tests for multiple group comparisons [25]. Responses to increasing doses isoprotenerol in the different experimental groups were analyzed using two-way ANOVA for repeated measurements. Differences were considered statistically significant if P<0.05.
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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3.1 Ventricular hypertrophy
Three weeks after MI, infarct size as well as body and ventricular weight were measured in the different experimental groups (Table 1). Compensatory hypertrophy in MI-hearts, defined by the ventricular weight body weight ratio, was indicated by a 14% rise of ventricular mass despite replacement of the major part of the LV free wall by lighter scar tissue. Treatment with low-dose aspirin did not affect cardiac hypertrophy when compared to hearts from untreated MI-rats. Both body and ventricular weight of methylprednisolone-treated MI-rats were significantly reduced when compared to untreated MI-rats. However, this resulted in an unchanged ventricular weight body weight ratio. No differences in infarct size were observed between the different groups.
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3.2 Cardiac collagen
Photomicrographs of picrosirius red stained sections of interventricular septum containing interstitial and perivascular collagen for the different experimental groups are shown in Fig. 1. Post-MI remodeling is associated with an increase in both interstitial and perivascular collagen. Whereas methylprednisolone treatment reduced interstitial as well as perivascular collagen deposition, low-dose aspirin only affected perivascular collagen. These observations were substantiated by the actual measurements as shown in Fig. 2.
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Methylprednisolone, however, reduced both interstitial and perivascular collagen when compared to untreated MI-hearts. Moreover, methylprednisolone treatment did not significantly reduce scar collagen (34±4% in methylprednisolone-treated MI-hearts versus 43±5% in untreated MI-hearts).
3.3 Left ventricular function
Variables of LV function as well as cardiac perfusion measured at baseline in isolated perfused rat hearts are summarized in Table 2. In Fig. 3, the effects of increasing doses of isoprotenerol on LV function are shown.
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LV systolic dysfunction in untreated MI-hearts was evidenced from a decreased baseline LV systolic pressure and peak velocity of LV contraction +dP/dtmax. Methylprednisolone-treated MI-hearts showed an improved LV systolic function as manifested by an increased baseline +dP/dtmax, whereas maximal values obtained after isoprotenerol infusion were not different from hearts of untreated MI-rats. Cardiac perfusion at baseline was not changed in untreated MI-hearts when compared to sham-hearts. This was neither altered by treatment with aspirin or methylprednisolone. Cardiac perfusion in methylprednisolone-treated MI-hearts was significantly lower at maximal stimulation with 10–5 M isoprotenerol (12.1±0.8 ml/min.g) when compared to untreated MI-hearts (16.0±1.1 ml/min.g). In low-dose aspirin-treated MI-hearts, LV function nor cardiac perfusion were significantly different from untreated MI-hearts at baseline and after isoprotenerol.
Diastolic dysfunction in MI-hearts was substantiated by a significantly reduced baseline –dP/dtmax which was not altered by low-dose aspirin or methylprednisolone. In methylprednisolone-treated MI-hearts, isoprotenerol significantly augmented the decrease in LV end-diastolic pressure when compared to sham-hearts and untreated MI-hearts. The LV end-diastolic pressure in low-dose aspirin-treated MI-hearts did not differ from untreated MI-hearts at any timepoint.
3.4 Diastolic pressure—volume curves
Post MI-remodeling of the left ventricle resulted into a rightward shift of the diastolic pressure—volume (PV) curve (Fig. 4). Furthermore, the diastolic PV curves of MI-hearts (n=13) were less steep compared to sham-hearts (n=25), as indicated by significantly reduced k-values of the exponential PV relationship: 76±8 (10–4) versus 118±7 (10–4) in hearts from sham-operated rats. Low-dose aspirin-treated MI-hearts (n=9) manifested no alterations in the diastolic PV curves when compared to untreated MI-hearts, whereas methylprednisolone (n=6) resulted in a further rightward shift of the diastolic PV relationship. LV dilation of MI-hearts, as indicated by an increased LV volume at 20 mmHg pressure (V20=0.850±0.037 in sham and 1.268±0.066 ml/kg in non-treated infarcted hearts) was not affected by aspirin (V20=1.250±0.107 ml/kg) but significantly aggravated by methylprednisolone (V20=1.496±0.079 ml/kg). The steepness k of the diastolic PV relationship remained unchanged in both low-dose aspirin [58±8 (10–4)] and methylprednisolone [96±13 (10–4)] treated MI-hearts when compared to untreated MI-hearts.
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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The present study was carried out to investigate whether treatment with aspirin or methylprednisolone would attenuate cardiac collagen and alter LV diastolic function in the 3-week-old post-MI remodeled rat heart. In a previous study, we have shown that a daily dose of 25 mg/kg/day (low-dose) aspirin inhibits thromboxane but not prostaglandin synthesis as the rat dose equivalent to chronic low-dose aspirin treatment in patients [9]. This low-dose of aspirin prevented interstitial and perivascular fibrosis in the spared myocardium, while leaving wound healing and reactive hypertrophy relatively unaffected during the first two weeks of post-MI remodeling. Besides a possible delay in the development, aspirin treatment showed no effect on in vitro LV dysfunction. However, 3 weeks of this low-dose aspirin treatment is associated with improved in vivo hemodynamics in conscious rats [10].
The effects of low-dose aspirin were compared with the effects of methylprednisolone treatment which has been shown to aggravate post-MI LV dilation [15]. In order to avoid interference with the initial wound healing, methylprednisolone treatment was started 1 week after MI, at the end of the acute inflammatory phase [18].
4.1 Collagen and diastolic pressure—volume relationship
In the present study, LV dilation in MI-hearts was indicated by a rightward shift of the diastolic PV relationship and substantiated by an increased volume at 20 mmHg. Post-MI remodeling induced accumulation of both interstitial and perivascular collagen in the non-infarcted interventricular septum. Although LV stiffness is strongly determined by collagen concentration and degree of fibrosis [3], the steepness of the diastolic PV relationship in MI-hearts decreased. This phenomenon may be explained by an effect of changed LV geometry on the steepness of the PV relationship. Indeed, early after MI the PV curve is shifted to the left with increased stiffness, while during the process of remodeling a rightward shift of the PV relation and decreased LV stiffness were observed [8].
Methylprednisolone was shown to retard the rate of MI healing, cause scar thinning and induce cavity dilation in MI-rats [15]. To limit the effects on healing and scar formation, treatment with methylprednisolone was started one week after MI. As was previously shown for aspirin, where at 2 weeks post-MI infarct collagen content was already normalized [9], methylprednisolone did not significantly reduce scar collagen content. In agreement with the studies of Mannisi, chronic treatment with methylprednisolone in MI-rats resulted in a further rightward shift of the diastolic PV curves, indicating aggravation of LV dilation whereas low-dose aspirin did not affect the diastolic PV relationship in MI-hearts. In previous studies, deleterious effects of methylprednisolone treatment in terms of LV dilation have been explained by its interference with replacement fibrosis in the infarcted area [14,15] in addition to its effects on collagen in the non-infarcted myocardium. It could also be possible that methylprednisolone did aggravate the initial process of breakdown of pre-existing collagen fibers correlating with post-MI infarction [6]. Aggravation of LV dilation in MI-hearts treated with methylprednisolone is associated with both decreased interstitial and perivascular collagen. On the other hand, therapy with low-dose aspirin did not aggravate LV dilation and only reduced perivascular collagen. This observation suggests that a too strong prevention of interstitial collagen build-up in the non-infarcted myocardium may promote LV dilation. In addition, prevention of collagen deposition by methylprednisolone or low-dose aspirin was not associated with alterations in diastolic stiffness.
The changes in the diastolic PV relationship related to collagen may also be explained by an effect on the physical properties of the collagen network in MI-hearts rather than the absolute amount of collagen. In the present study, only total collagen content was measured. Changes in collagen type, degree of cross-linking, fiber organization and fiber thickness could also alter the mechanical properties of the myocardium as reported by previous investigators [26].
4.2 Left ventricular function
LV systolic dysfunction 3 weeks after MI was evidenced from a decreased baseline LV systolic pressure and +dP/dtmax. Depressed LV function was not attributed to differences in cardiac perfusion, since this was not different between sham- and MI-hearts at any timepoint. As expected, isoprotenerol infusion augmented contractile function and relaxation in all experimental groups.
Treatment with methylprednisolone improved baseline +dP/dtmax, but maximal values with isoprotenerol were not different from untreated MI-hearts. Glucocorticosteroids are known to be able to increase β-receptor number. A higher β-receptor number/responsiveness at similar endogenous stimulation would explain a higher baseline contractility. Moreover, methylprednisolone was shown to accelerate the recovery of the decrease in β-adrenergic responsiveness caused by successive administrations isoprotenerol in rat hearts [27]. Interesting in this regard is the significant lower perfusion of methylprednisolone-treated MI-hearts, seen at the highest dose of isoprotenerol. Treatment with low-dose aspirin did not change LV function or myocardial perfusion compared to untreated MI-hearts.
LV diastolic dysfunction in MI-hearts was substantiated by a significantly reduced baseline –dP/dtmax which was not altered by low-dose aspirin or methylprednisolone. However, β-stimulation with isoprotenerol induced a significant decrease in diastolic pressure in methylprednisolone, but not in low-dose aspirin or untreated MI-hearts. A possible explanation for the enhanced active relaxation observed in methylprednisolone-treated hearts could be related to its effects on interstitial collagen network. Moreover, besides a reduction of total collagen amount, methylprednisolone has been reported to have a pronounced effect on the tensile strength of the collagen network [28], which could have contributed to the altered active relaxation in the isolated MI-heart. This could also explain the aggravated LV dilation seen in methylprednisolone-treated MI-hearts. Although generally regarded as detrimental, if the rightward shift of the PV-curve at similar slope would be responsible for the improved active relaxation with β-stimulation, even some benefit may be considered. Alternatively, the above described interactions between methylprednisolone and the β-adrenergic pathway could as well be involved in the improved diastolic function. Nevertheless, an enhanced relaxation normally would be associated with an increased perfusion. Therefore it remains difficult to explain why an augmented relaxation seen after maximal isoprotenerol was associated with a decreased cardiac perfusion in the methylprednisolone-treated hearts.
4.3 Conclusions
The present findings indicate that pharmacological interference with the deposition of collagen in the non-infarcted myocardium may result in an altered LV diastolic function. Changes in interstitial rather than perivascular collagen seem to be important in the regulation of passive as well as active relaxation of the isolated heart. Whether improving LV relaxation could beneficially influence cardiac function remains to be elucidated.
Time for primary review 16 days.
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