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1Department of Anatomy and Cell Biology, 2Internal Medicine, and 3Cardiovascular Center, University of Iowa Carver College of Medicine; 4Department of Veterans Affairs Medical Center, Iowa City, Iowa; and 5Institut de Recherches Internationales Servier, Courbevoie, France
Submitted 12 January 2007 ; accepted in final form 21 March 2007
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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1 in the myocardium, as well as the plasma level of the ANG II peptide, were lower in treated rats 14 days after MI. Therefore, our data reveal that improved maximal myocardial perfusion and coronary reserve in MI + IVA rats are most likely the result of reduced periarteriolar collagen rather than enhanced arteriolar growth.
myocardial infarction; coronary circulation; coronary vessels; renin-angiotensin system
Since adequate tissue perfusion is key for survival and effective function of hypertrophied myocytes in the remaining overloaded LV myocardium, the recovery of normal tissue perfusion in this region has become a major focus of several studies (14, 15), including those from our laboratory (5, 20). Because the major cause of limited myocardial perfusion and coronary reserve in post-MI hearts was long thought to be a failure to match the adaptive growth of the intramyocardial vasculature to the degree of myocyte hypertrophy, earlier studies, which were conducted on young and young-adult rats, were designed either to reduce myocyte hypertrophy (14, 24) or to promote the growth of the coronary vasculature (20).
MI in humans occurs primarily in middle-aged and senescent individuals, which raises the concern that young animals are not the most relevant models for studies evaluating post-MI modifications and assessing post-MI treatments. By using infarcted middle-aged rats in our recent studies (5, 6), we have been able to show that a marked deficit in myocardial perfusion occurs even when the growth of coronary resistance vessels (arterioles) parallels or exceeds the magnitude of cardiac myocyte enlargement. Moreover, when we promoted further arteriolar growth in post-MI hearts by inducing chronic heart rate reduction (HRR) by using atenolol (a 1-selective adrenoceptor blocker), the maximal myocardial perfusion improved significantly but still remained lower than would have been predicted based on the extent of enlargement of the arteriolar bed (5). Considering these findings, we proposed that factors besides the ratio of arteriolar growth to the degree of cardiac myocyte hypertrophy might contribute to the level of myocardial perfusion in the middle-aged, post-MI heart. Support for this supposition can be found in the earlier observations of Gervais et al. (10), who showed that in young infarcted rats in which hypertrophy had been prevented but myocardial fibrosis had been allowed to develop naturally, perfusion within the surviving LV myocardium was not fully restored. On the basis of this accumulating evidence, we hypothesized that in infarcted middle-aged rats the extent of perivascular fibrosis may affect myocardial perfusion.
Although there have been reports indicating that fibrosis of coronary arteries does not contribute to the regulation of myocardial perfusion in infarcted rats (13, 17, 24, 29), the effects of fibrosis in the coronary arterioles has never been evaluated. Thus we designed our current study to investigate whether the extent of periarteriolar collagen is a factor in maximal myocardial perfusion in infarcted middle-aged rats in which adaptive arteriolar growth occurs in response to chronic HRR.
In our previous work, we used either alinidine (20) or atenolol (5) to reduce the heart rate in infarcted rats. In recent years, the new compound ivabradine (IVA) has been shown to reduce heart rate via selective inhibition of the hyperpolarization-activated pacemaker (If) current in sinoatrial cells (30). It does so without exerting negative inotropy and, importantly, IVA-induced HRR reduces the interstitial collagen content in infarcted young rats (21). However, neither the effect of IVA on the adaptive growth of coronary vessels nor its consequences for perivascular fibrosis in post-MI hearts has been previously addressed. The current study explores these issues.
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MATERIALS AND METHODS |
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Animals and experimental protocols.
As detailed previously (5, 20), a large transmural MI was induced in 12-mo-old male Sprague-Dawley rats (Harlan, Indianapolis, IN) anesthetized with a ketamine (100 mg/kg ip)-xylazine (10 mg/kg ip) mixture. The mortality rate among infarcted rats was 
30%. On the day after surgery, echocardiography (ECG) was conducted to confirm a large ischemic-infarcted zone in the left ventricle, and then the IVA (Institut de Recherches Internationales Servier, Courbevoie, France) was administered intraperitoneally to randomly selected infarcted rats (MI + IVA) via ALZET osmotic pumps (DURECT, Cupertino, CA) at a dose of 10.5 mg·kg–1·day–1 (dissolved in 5% dextrose). Untreated MI and sham-operated rats (sham) received the pumps containing 5% dextrose only. Four separate groups of MI, MI + IVA, and sham rats were studied (Fig. 1A). In the first group, the pumps were removed 4 wk after the initiation of treatment, and, 48 h later, LV ECG parameters and myocardial perfusion were assessed, following which the rats were euthanized and the hearts were used for morphological analysis. In the second group, starting on day 0, 4, or 11 after surgery, the rats received 5-bromo-2'-deoxyuridine (BrdU; Sigma, St. Louis, MO) for 72 h intraperitoneally via ALZET osmotic pumps at a dose of 12.5 mg·kg–1·day–1. On day 3, 7, or 14 after MI, the hearts of these rats were collected for morphological analysis. In the third group, the rats were killed on day 3, 7, or 14 after surgery, and the hearts were collected for Western blot analysis. In the fourth group, the rats were euthanized on day 7 or 14 after surgery, and blood samples were collected for ANG II radioimmunoassay.
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1.5- to 2-mm distal to the infarct edge, as described previously (5, 6). Heart rate monitoring. Heart rate in conscious unrestrained rats was monitored 24 h after surgery and then every week by using cutaneous clips and BioAmp differential amplifier coupled to a PowerLab data acquisition system (ADInstruments, Castle Hill, Australia).
Echocardiographic analysis. Two-dimensional short- and long-axis images of the left ventricles of post-MI rats slightly anesthetized with ketamine (50 mg/kg ip) were obtained by using an Acuson Sequoia echocardiograph (Mountain View, CA) equipped with an 8.0-MHz sector-array transducer. Planimetric measurements were used to estimate the size of the ischemic-infarcted zone. LV end-diastolic and end-systolic volumes were calculated using the area-length method. Heart rate was determined by using pulse-wave Doppler interrogation of mitral inflow. On the basis of these parameters, stroke volume, cardiac output and ejection fraction were calculated.
Myocardial perfusion studies. Myocardial perfusion in the LVFW and septum was determined by using the neutron-activated stable-isotope-labeled microspheres technique (BioPAL, Worcester, MA) both at rest (baseline) and after maximal endothelium-independent vasodilation induced by dipyridamole, as detailed previously (5, 6, 20). Myocardial perfusion was then expressed as baseline and maximal coronary conductance per 100 g of tissue, and coronary perfusion reserve was calculated as maximal conductance divided by baseline conductance.
LV weight measurement, infarct size estimation, tissue sampling, and preparation. In groups 1 and 2 (Fig. 1A), the hearts were arrested in diastole and fixed with 4% paraformaldehyde, as detailed previously (5, 6). The atria and the right ventricular free wall were removed, and the hearts were cut transversely into parallel slices. In the first group, the left ventricle was weighed. For hearts that had undergone MI, the LV slices were digitized and infarct size was estimated by using Image-Pro Plus 5.1 software (Media Cybernetics, Silver Spring, MD), as detailed previously (5, 20). Infarct size was expressed as a percentage of the LVFW. From each heart in groups 1 and 2, one midventricular slice was embedded in paraffin. In the remaining LV slices from the first group, the myocardium from the LVFW and septum was excised, weighed, and used for microsphere counting.
Hearts from the third group (Fig. 1A) were excised, and the samples of myocardium from the LVFW and septum were frozen in liquid nitrogen for Western blot analyses, as described previously (6).
Histology, immunohistochemistry, and microscopy.
Eight-micrometer-thick sections were cut from paraffin-embedded LV slices. In group 1 (Fig. 1A), the sections were either labeled with a Cy3-conjugated anti-smooth muscle (SM) 
-actin antibody (Sigma, St. Louis, MO) or double labeled with Alexa Fluor 594-conjugated Bandeiraea Simplicifolia lectin-I (BS-I) (Molecular Probes, Eugene, OR) and anti-laminin antibody (Sigma) as detailed previously (5). Picrosirius red staining was used to visualize interstitial and perivascular collagen. In group 2, the sections were double labeled with Cy3-conjugated anti-SM -actin and anti-BrdU antibodies (Chemicon International, Temecula, CA). Alexa Fluor 488-conjugated goat anti-rabbit IgG and goat anti-mouse IgG (Molecular Probes) were used for visualization of anti-laminin and anti-BrdU antibodies, respectively. Light and fluorescence images were captured on a computer using a Nikon Eclipse E-600 microscope equipped with a Nikon digital DXM 1200 camera.
Morphometric and stereologic analyses.
All analyses were performed by using Image-Pro Plus 5.1 software (Media Cybernetics). SM -actin-positive vessels (5 to 54 µm in diameter) were used to calculate the arteriolar length and volume densities, whereas vessels labeled with BS-I lectin (<5 µm in diameter) were used to estimate capillary density, as detailed previously (5). Cross-sectional area and the density of laminin-outlined cardiac myocytes were estimated for the same regions used in capillary analysis. A capillary-to-myocyte ratio was calculated based on the densities calculated for capillaries and myocytes.
For the sections stained with picrosirius red, the interstitial collagen content was estimated as the percentage of the total area occupied by fibrillar collagen and cardiac myocytes. Perivascular collagen content was defined as the ratio of the area occupied by the fibrillar collagen surrounding the resistance vessel (including all fibrillar collagen located between the external border of the vessel media and the neighboring cardiac myocytes) to the vessel area as outlined by the external media border (i.e., complete media + lumen). For each heart (5–6 per group), 8 to 14 resistance vessels (10 to 200 µm in luminal diameter) per LVFW or the septum were evaluated.
For each BrdU-labeled heart, we analyzed 100 arterioles per LVFW or the septum. The arterioles with at least one perivascular cell nucleus (presumably fibroblast) that stained positively with an anti-BrdU antibody were counted. The number of arterioles associated with BrdU-positive fibroblasts was expressed for each region as a percentage of the total arterioles examined.
Western blot analysis.
The analyses were performed as detailed previously (6, 20). The primary antibodies used for protein analysis were the following: VEGF (A-20), Flk-1 (Q-20), Flt-1 (C-17), Tie-2 (C-20), AT1 (N-10), and AT2 (H-143) (Santa Cruz Biotechnology, Santa Cruz, CA); angiopoietin-1 (Ang 11-S) and angiopoietin-2 (Ang 21-S) (Alpha Diagnostic International, San Antonio, TX); transforming growth factor (TGF)-1 and GAPDH (clone 6C5) (Chemicon International). The corresponding IRDye-800-conjugated secondary antibodies were then applied, and membranes were analyzed using the Odyssey Infrared Imaging System (LI-COR, Lincoln, NE). The protein expression was assessed by means of quantitative densitometry analysis and then normalized to the corresponding GAPDH expression in each sample. The level of expression for each individual protein was expressed as the fold change from the level in sham rats (denoted as one).
Plasma collection, extraction of ANG II peptide, and RIA. The blood was collected into BD Vacutainer tubes (BD Diagnostics, Franklin Lakees, NJ) containing K2EDTA and the angiotensinase inhibitor Bestatin (40 µg/ml; Roche Applied Science, Indianapolis, IN). The blood was then centrifuged (2,000 g) at 4°C for 20 min, and the plasma samples were collected, and stored at –80°C. Plasma levels of ANG II peptide were determined using the BUHLMANN ANG II double-antibody RIA kit (ALPCO Diagnostics, Windham, NH) following the manufacturer's protocol.
Statistical analysis. Data are expressed as means ± SE. One-way ANOVA followed by the Tukey-Kramer post test was used for multigroup comparisons. An unpaired t-test was used to assess intergroup differences. P < 0.05 was selected to denote significant differences.
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RESULTS |
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18% higher than that in sham rats (482.3 ± 6.5 vs. 407.7 ± 6.3 beats/min). In the MI group, it remained significantly elevated at 1, 2, and 3 wk after surgery by 13%, 10%, and 5%, respectively (Fig. 1B). IVA treatment of infarcted rats, begun 24 h after surgery, consistently reduced heart rate by 25% (relative to that of the sham group) during the 4-wk treatment period. As shown in Fig. 1B, the heart rate in MI + IVA rats returned to levels matching MI and sham values by 48 h after cessation of treatment. The termination of IVA treatment in this group of MI + IVA rats (Fig. 1A, group 1) abolished the potential impacts of IVA on echocardiography, blood flow measurements, and tissue sampling for morphometric analyses.
Infarct size and LV hypertrophy.
Infarct size and LV weight were comparable in MI and MI + IVA rats, indicating a relatively similar magnitude of cardiac hypertrophy in the surviving LV myocardium of both post-MI groups (Table 1). Moreover, since LV weight-to-body weight ratio in MI and MI + IVA rats remained relatively comparable to that of sham rats, it appeared that the growth of surviving LV myocardium in both post-MI groups fully compensated for the loss of cardiac myocytes due to a large MI. It is important to mention that although MI + IVA rats showed a significantly greater LV weight-to-body weight ratio compared with MI rats, such an increase was likely accounted for by 7% lower body weight in the MI + IVA group at the end of experiment.
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25% higher than that in MI rats and was associated with a markedly lower end-systolic volume. Furthermore, the increase in LV end-diastolic pressure was smaller in rats from the MI + IVA group than in those from the MI group, indicating a lesser degree of diastolic LV dysfunction.
Myocardial perfusion.
Whereas coronary conductance (flow/perfusion pressure) at rest was significantly higher in both the LVFW and septum of MI rats, the values for animals in the MI + IVA group were similar to those of the sham groups (Table 2). Maximal coronary conductance was reduced by 30% in both the LVFW and septum of MI rats. In contrast, it was relatively preserved in both regions of hearts from the MI + IVA group. As a result, coronary perfusion reserve was significantly impaired in the LVFW and septum of MI rats, whereas it remained comparable in animals from the MI + IVA and sham groups (Fig. 2).
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The analysis of arterioles (length and volume densities), in contrast, revealed that the arteriolar beds of the LVFW and the septum expanded to similar extents in both post-MI groups (compare with sham rats; Fig. 3). On the other hand, the resistance vessels in MI + IVA rat hearts (both LVFW and septum) were significantly reduced in terms of the perivascular collagen content; decreases of 40% compared with MI rats and 30% compared with sham rats are noted (Table 4). Further evaluation of these vessels revealed that the most substantial reduction in perivascular collagen occurred in the arterioles (10–45 µm in diameter) and in small to medium arteries (46–75 µm in diameter) of MI + IVA rats (Fig. 4). However, such intergroup differences were not noted for the large coronary arteries (>76 µm in diameter).
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39%) level of Tie-2 protein that was detected in the LVFW of MI + IVA rats 3 days after MI. DNA synthesis in periarteriolar fibroblasts. In all post-MI rats, DNA synthesis in periarteriolar fibroblasts was significantly activated compared with that in sham rats during the 2-wk period following coronary artery ligation (Fig. 5). For all three post-MI time points (3, 7, and 14 days), the percentage of arterioles in which fibroblasts were BrdU positive was similar (Fig. 5C). This finding indicates that the reduced accumulation of collagen in the resistance vessels of the LVFW and septum in MI + IVA rats was not due to a lower proliferation rate in periarteriolar fibroblasts.
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1 protein expression.
To elucidate whether HRR affects the fibrosis-mediating components of the renin-angiotensin system (RAS) in post-MI hearts, the protein expression of ANG II receptors type 1 (AT1) and type 2 (AT2) and TGF-1 were assessed on days 7 and 14 after MI (Fig. 6A). On day 7, the levels of both AT1 and TGF-1 in the LVFWs of MI + IVA rats were significantly lower (by 30%) than those in MI rats, whereas both proteins were comparably upregulated in the septa of hearts from both postinfarction groups (Fig. 6B). One week later, these proteins were expressed at significantly elevated levels within both LV regions of the MI rats but were comparable in MI + IVA rats and the sham rats, i.e., they were by 37% and 39% lower than those in MI rats, respectively (Fig. 6B). In contrast to the dynamics of AT1 and TGF-1 proteins, those of AT2 were found to be straightforward. AT2 was markedly reduced in the LVFW and septum of both post-MI groups (in comparison to sham rats) on days 7 and 14 after MI (data not shown), indicating that downregulation of this protein is likely a characteristic of all infarcted rats.
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34%) higher than that in MI + IVA rats, the latter level being comparable to that measured in sham rats.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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25% in MI + IVA rats than that in untreated MI rats. Most importantly, the improvement of LV function, and especially myocardial perfusion and coronary perfusion reserve, in MI + IVA rats was associated with a significantly reduced level of interstitial and periarteriolar collagen. The attenuation of periarteriolar collagen in MI + IVA rats was not due to a lower proliferation rate in periarteriolar fibroblasts but was associated with markedly lower levels of myocardial AT1 and TGF-1 protein expressions, as well as of circulating ANG II petide. These findings suggest that chronic IVA-induced HRR in some way attenuates the fibrogenic mediators of the RAS in infarcted middle-aged rats.
Because a marked deficit of tissue perfusion has often been detected in the LV myocardium of young and young-adult rats following a large MI (10, 13, 14, 16, 18, 20), it has been generally assumed that inadequate growth of coronary resistance vessels relative to the magnitude of cardiac myocyte enlargement is the prime cause of such a deficiency (13, 14, 24). This supposition has been further supported by the fact that myocardial perfusion could be improved in post-MI hearts by either reducing myocyte hypertrophy (14, 15) or inducing arteriolar growth (20). On the other hand, in our recent studies using middle-aged rats, we documented that surviving LV regions exhibited a deficit in myocardial perfusion, although expansion of the arteriolar bed in post-MI hearts was adequate to compensate for myocyte growth (5, 6). Moreover, when further arteriolar growth was stimulated in these rats by inducing chronic HRR via a 1-blockade, the improvement in maximal myocardial perfusion was not of the magnitude expected based on the level of arteriolar bed expansion (5). Taken together, these observations suggested that factors other than the adequacy of arteriolar growth contribute to the level of myocardial perfusion in the post-MI hearts of middle-aged rats. Our current results, showing that preservation of maximal myocardial perfusion and coronary reserve in post-MI hearts under conditions of IVA-induced HRR is not due to an expanded arteriolar bed, support this idea.
Considering the facts that in various animal experimental models other factors, such as perfusion pressure (7), heart rate (9), extravascular compression forces (8, 28), vascular remodeling due to medial thickening (2) or perivascular fibrosis (11), and coronary capillary resistance (12), have been implicated in the alterations of maximal myocardial perfusion, their contribution to the difference in the level of maximal perfusion in our two groups of infarcted rats cannot be excluded. However, since our data indicate that perfusion pressure, heart rate, and the size of capillary bed were similar in MI + IVA and MI rats, neither of these factors could affect the level of maximal myocardial perfusion. Furthermore, although LV end-diastolic pressure, i.e., an extravascular compression force, was lower in IVA-treated than untreated post-MI rats, its impact on the total transmural myocardial perfusion appears to be insignificant because this force acted primarily on the vasculature adjacent to the endocardium (8, 27). Most importantly, because it is well known that medial thickening does not occur in coronary vessels of post-MI hearts (13, 15, 24), perivascular fibrosis remains the only factor that would be capable of affecting the level of myocardial perfusion in IVA-treated and untreated infarcted rats. Consistent with this thought, our current findings indicate that improved myocardial perfusion in MI + IVA rats is associated with a reduced periarteriolar collagen.
Other investigators have stated that perivascular, and in particular periarterial, fibrosis does not play a significant role in the regulation of maximal myocardial perfusion in post-MI hearts (13, 17, 24, 29). This assumption is based on two lines of experimental evidence. On the one hand, maximal myocardial perfusion has been shown to remain similar to that in sham rats for 3 wk after MI in the presence of marked periarterial fibrosis (13, 17, 29). On the other hand, this parameter was markedly lower in the experimental group 7 or 8 wk after MI, even though the MI rats were similar to the sham rats in terms of periarterial fibrosis (13, 24). Therefore, at both time points, the degree of myocardial hypertrophy in the post-MI heart accounted for the unchanged or reduced level of maximal myocardial perfusion, respectively. In contrast, we have found no correlation between the degree of myocyte hypertrophy and the improvement of maximal perfusion in MI + IVA rats compared with MI rats.
We assume that the discrepancy between our study and those that were performed earlier can be explained by differences in experimental design, such as the age of the rats, the dose and type of vasodilator agent used, the protocols applied to test myocardial perfusion and to fix vessels, and, most importantly, the size of resistance vessels for which collagen content was evaluated. Specifically, we observed that only arterioles and small arteries had attenuated perivascular collagen in MI + IVA rats, whereas the collagen content in arteries larger than 76 µm in diameter was similar for the two post-MI groups. Since a majority of the earlier studies did not discriminate between resistance vessels with diameter under 150 µm (13, 17, 24, 29), it is difficult to accurately interpret the differences reported for this aspect of myocardial perfusion. However, our current findings allow us to suggest that the amelioration of perivascular collagen content in arterioles and small arteries, rather than in large arteries, is one of the most important benefits of chronic IVA-induced HRR in post-MI hearts of middle-aged rats, because these vessels are the principal determinant of maximal myocardial perfusion in the surviving LV myocardium.
From the fact that elucidating the particular mechanism that underlies the anti-fibrogenic action of IVA-induced HRR during the post-MI remodeling lies outside the methodology and the scope of the current study, we can only hypothesize about the potential regulatory components that may be involved. First, since we found no difference in proliferation rate in periarteriolar fibroblasts in the LV myocardium of IVA-treated and untreated groups, our data suggest that the reduced level of periarteriolar collagen in MI + IVA rats is most likely due to altered collagen turnover, i.e., a disbalance between collagen synthesis and degradation. Second, considering the fact that, in rats, normal cardiac aging (1) as well as post-MI remodeling of surviving LV myocardium (3) are both associated with excessive accumulation of collagen around intramural coronary vessels, we suppose that chronically induced HRR in our infarcted middle-aged rats had in some way interfered with the regulatory mechanisms in both these fibrogenic processes. Such an idea is consistent with our current findings, which demonstrate that the level of periarteriolar collagen content in MI + IVA rats is significantly lower than those in untreated MI rats as well as in age-matched sham-operated animals.
The regulation of interstitial and perivascular collagen turnover within the surviving LV myocardium of infarcted rats is a very complex process involving interactions between circulating hormones, especially from the RAS, and from a diverse array of locally produced anti- and pro-fibrogenic regulatory peptides and cytokines, including TGF-1 (25, 31). In line with these findings, our current data indicate a relationship between reduced periarteriolar collagen in MI + IVA rats and reductions in the level of circulating ANG II peptide and myocardially expressed TGF-1. Therefore, these particular factors are most likely to have contributed to the lower levels of periarteriolar fibrosis observed in post-MI hearts of rats treated with IVA compared with untreated infarcted rats. This idea is partially supported by the study of Ratajska et al. (22), who pointed out that rats with a chronically elevated circulating ANG II level exhibit perivascular fibrosis exclusively in coronary arterioles. More recently, it has been also shown that, in such rats, the elevated level of circulating ANG II initiates perivascular fibrosis via AT1 receptor and upregulates several pro-fibrogenic mediators, including TGF-1 (32).
On the other hand, there is some evidence suggesting that ANG II and its AT1 receptor are not involved in periarterial fibrosis in infarcted rats (24). Furthermore, since anti-inflammatory drugs have also been shown to regulate periarterial collagen content in post-MI hearts (17, 29), we cannot exclude the possibility that chronic IVA-induced HRR might affect some regulatory components of the inflammatory events in the surviving LV myocardium of infarcted middle-aged rats. This would, at least in part, explain why the content of interstitial and periarteriolar collagen in MI + IVA rats was significantly lower than that in age-matched, sham-operated animals. According to a recent study performed on outbred normotensive Sprague-Dawley rats, the hearts of these rats undergoes spontaneous myocarditis during aging that involves interstitial and perivascular fibrosis (19). Therefore, it seems plausible that chronic IVA-induced HRR in some way may attenuate spontaneous ageing-related events that involve perivascular and interstitial inflammatory reactions. An alternative explanation for a reduced accumulation of myocardial collagen in middle-aged MI + IVA rats compared with that in MI and sham rats is that chronic IVA-induced HRR might affect the level of expression and/or collagenolytic activity of cardiac matrix metalloproteinases (MMP). Since it was previously shown by others (23) that the decrease in collagenolytic activity of MMP-1 and MMP-2 could account for collagen accumulation in the myocardium of aged rats, one cannot rule out the possibility that chronic IVA-induced HRR might in some way modify the level of MMP activity and, hence, attenuate an aging-associated inhibition in collagen degradative pathway. Thus one limitation of our study is that we cannot rule out some other factors, besides the fibrosis-mediating components of the RAS, which may also contribute to the reduced periarteriolar collagen content in the surviving LV myocardium of middle-aged MI + IVA rats. However, we intend to further address such an important issue in our future studies.
In summary, the present findings demonstrate that improvement of myocardial perfusion in the LV myocardium of infarcted middle-aged rats following a 4-wk period of IVA-induced HRR is due to a reduced level of periarteriolar collagen rather than to expanded growth of coronary arterioles. Moreover, the results show that reduced deposition of periarteriolar collagen in IVA-treated, infarcted middle-aged rats is not associated with a lower proliferation rate of periarteriolar fibroblasts but is probably a result of an inhibitory effect of IVA-induced HRR on circulating and myocardial fibrosis-mediating components of the RAS.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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1-adrenoceptor blockade promotes growth of arterioles and preserves coronary perfusion reserve in postinfarcted heart. Am J Physiol Heart Circ Physiol 288: H2684–H2693, 2005.This article has been cited by other articles:
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  L. P. Christensen, R.-l. Zhang, W. Zheng, J. J. Campanelli, E. I. Dedkov, R. M. Weiss, and R. J. Tomanek Postmyocardial infarction remodeling and coronary reserve: effects of ivabradine and beta blockade therapy Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H322 - H330. [Abstract] [Full Text] [PDF]
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P. Milliez, S. Messaoudi, J. Nehme, C. Rodriguez, J.-L. Samuel, and C. Delcayre Beneficial effects of delayed ivabradine treatment on cardiac anatomical and electrical remodeling in rat severe chronic heart failure Am J Physiol Heart Circ Physiol, February 1, 2009; 296(2): H435 - H441. [Abstract] [Full Text] [PDF]
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 G. Heusch, A. Skyschally, P. Gres, P. van Caster, D. Schilawa, and R. Schulz Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine: protection beyond heart rate reduction Eur. Heart J., September 2, 2008; 29(18): 2265 - 2275. [Abstract] [Full Text] [PDF]
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 M. Maczewski and U. Mackiewicz Effect of metoprolol and ivabradine on left ventricular remodelling and Ca2+ handling in the post-infarction rat heart Cardiovasc Res, July 1, 2008; 79(1): 42 - 51. [Abstract] [Full Text] [PDF]
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 G. M. De Ferrari, A. Mazzuero, L. Agnesina, A. Bertoletti, M. Lettino, C. Campana, P. J. Schwartz, and L. Tavazzi Favourable effects of heart rate reduction with intravenous administration of ivabradine in patients with advanced heart failure Eur J Heart Fail, June 1, 2008; 10(6): 550 - 555. [Abstract] [Full Text] [PDF]
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 V. Ciobotaru, M. Heimburger, L. Louedec, C. Heymes, R. Ventura-Clapier, P. Bedossa, B. Escoubet, J.-B. Michel, J.-J. Mercadier, and D. Logeart Effect of Long-Term Heart Rate Reduction by If Current Inhibition on Pressure Overload-Induced Heart Failure in Rats J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 43 - 49. [Abstract] [Full Text] [PDF]
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P < 0.001 vs. MI.
P < 0.05 vs. MI + IVA at day 7;