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Keywords:

  • ivabradine;
  • atenolol;
  • collagen;
  • infarct expansion

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. LITERATURE CITED

Chronic heart rate reduction (HRR) therapy following myocardial infarction, using either the pure HRR agent ivabradine or the β-blocker atenolol, has been shown to preserve maximal coronary perfusion, via reduction of perivascular collagen and a decrease in renin-angiotensin system activation. In addition ivabradine, but not atenolol, treatment attenuated the decline in ejection fraction and decreased left ventricular wall stress. In this study, we tested the hypothesis that cell survival within the infarct region was enhanced by these two pharmacological agents. Four weeks after ligating the left anterior descending coronary artery, the percentage of the LV that contained the infarct was similar in the untreated (MI) rats and those chronically treated with ivabradine (MI + IVA) or atenolol (MI + ATEN). However, the mean thickness (mm) of the ventricular wall containing the scar was significantly greater in the MI + IVA, 1.54 (P ≤ 0.01) and the MI + ATEN 1.32, compared to 1.1 in the MI group, due to a 2-fold greater area of surviving cardiomyocytes (P ≤ 0.01) in the treated rats compared to the untreated group. Regions of cell survival were usually in the subepicardium, with cardiomyocytes surrounding veins or venules. However, some hearts displayed surviving cells along the endocardium. These data suggest that HRR by either ivabradine or atenolol facilitates a more favorable O2 microenvironment via improved venous flow and decreased O2 demand. We conclude that chronic HRR by these agents may serve to limit infarct expansion and wall thinning and may serve to reduce the potential for ventricular rupture. Anat Rec, 2010. © 2010 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. LITERATURE CITED

It is well-established that high heart rate is an independent risk factor for coronary artery disease (Palatini and Julius, 2004; Fox et al., 2007). In patients with an acute myocardial infarction, a high heart rate at the time of hospital admission correlates with mortality (Hanania et al., 2004). This is not surprising in view of the fact that about 80%–90% of myocardial perfusion occurs during diastole, which is decreased as heart rate increases. Thus, heart rate reduction (HRR) tends to optimize coronary blood flow and reduces O2 consumption. When HRR was induced via pharmacological therapy or chronic pacing in young experimental animals, myocardial capillary growth was stimulated (Brown et al., 1994; Zheng et al., 1999; Lamping et al., 2005). Moreover, when pharmacological HRR therapy is provided to experimental animals with myocardial infarctions, growth of capillaries (Lei et al., 2004; Van Kerckhoven et al., 2004) and arterioles (Lei et al., 2004) occurs. Based on this evidence, one can appreciate that HRR in the postinfarcted heart may attenuate morbidity and mortality.

One of the major advances in patient care following myocardial infarction is the utility of β-blockers (Goldberger et al., 2008), which reduce heart rate and O2 demand. Additionally, there is evidence that β-blocker carvedilol has a beneficial effect on ventricular remodeling in patients with myocardial infarctions (Doughty et al., 2004). Although β-blockers reduce heart rate, they are not considered to be “pure” heart rate reducing drugs (DiFrancesco and Borer, 2007). In contrast, ivabradine (Iva) is considered to be a specific heart rate lowering agent because it inhibits the hyperpolarization-activated sino-atrial pacemaker current (If) which functions during early phase of diastolic depolarization by blocking the Na/K ions from inside the cell membrane (Sulfi and Timmis, 2006). One advantage of ivabradine over β-blockers is that it lacks the negative inotropic effects characteristic of β-blockers (Fox et al., 2006). Moreover, ivabradine, compared to the β-blocker atenolol, increases diastolic time more and does not decrease dP/dtmax or postsystolic wall thickening (Lucats et al., 2007). Considering the differences in mechanisms of action of these two classes of drugs, we treated rats with myocardial infarctions with atenolol, a β-blocker, (Dedkov et al., 2005) and ivabradine (Dedkov et al., 2007b). As the later had a more favorable effect on ejection fraction, we then compared the effects of the two drugs at comparable heart rates on a variety of structural and functional parameters (Christensen et al., 2009). Although both heart rate reducing drugs preserved maximal myocardial perfusion and reduced arteriolar perivascular collagen density, ivabradine, but not atenolol, had a more favorable effect on remodeling as evidenced by an attenuation of the decline in ejection fraction and a lowered left ventricular end-diastolic volume to LV mass ratio.

The focus of our previous studies has been on the surviving myocardium, i.e., the border and remote regions of the left ventricle. In contrast, this study addressed the remodeling adaptive process of the infarct region which contributes to ventricular dilation and wall motion abnormalities (Braunwald and Pfeffer, 1991; Pfeffer and Braunwald, 1991).

The assumption that the infarct scar is inert, i.e., composed primarily of collagen, is not valid because studies during the last decade have demonstrated the presence of myofibroblasts and contractile behavior (Sun and Weber, 2000; Sun et al., 2002). The contractile role of scar myofibroblasts was first documented by Gabbiani et al. (1972). The idea that the composition of the infarct scar can be altered has been addressed by studies that have shown scar modification by local activation or implantation of progenitor cells (Imanishi et al., 2008; Rota et al., 2008), thus enhancing our optimism regarding therapeutic interventions after myocardial infarction. As the thickness and collagen content of the scar may affect ventricular function, one important therapeutic goal should be to limit infarct expansion and thinning.

Our current study was based on the hypothesis that HRR therapy alters the composition of the infarct region within the LV wall. Because ventricular remodeling and function are age-dependent, as documented in several studies (Raya et al., 1997; Bujak et al., 2008; Przyklenk et al., 2008), our data are based on middle-aged (12 months) rats. Compared to young rats, vascular and myocardial adaptations are more limited in this age group (Dedkov et al., 2007a, b; Christensen et al., 2009).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. LITERATURE CITED

We utilized 12 month-old male Sprague-Dawley rats according to procedures approved by the University of Iowa Animal Care and Use Committee in accordance with regulations of the NIH Animal Welfare Act Guide for the Care and Use of Laboratory Animals. These animals were used in a previous study that compared the effects of two heart rate lowering drugs, ivabradine and atenolol, on the coronary vasculature and circulation, growth factors and ventricular function (Christensen et al., 2009). In that study, rats were treated for 1, 2, and 4 weeks with the HR reducing drugs started 1 day following the induction of myocardial infarction by permanent ligation of the left anterior descending coronary artery. Data from these two groups were compared to an untreated group with myocardial infarction. The data in this study are based on archival histological sections from the previous study.

Tissue Preparation and Morphometry

Tissue samples from three groups of rats were compared: (1) myocardial infarction (MI) and no HRR therapy; (2) MI + ivabradine treatment (MI + IVA), and (3) MI + atenolol treatment (MI + ATEN). The hearts from the 1 and 2 week treatment groups were removed from rats that had been decapitated and a portion was fixed by immersion in 4% paraformaldehyde. Sections from these hearts were used only for qualitative analysis. Rats from the 4 week groups were anesthetized with ketamine (100 mg/kg + xylazine 10 mg/kg, i.p.) and their hearts arrested in diastole with lidocaine and perfuse-fixed with 4% paraformaldehyde. Six micron sections cross-sections of the ventricles were cut and stained with Masson's Trichrome solution. In the 4 week groups, we employed morphometric techniques to quantify the characteristics of the LV infarct region. The sections were obtained at a level of the heart midway between the base and apex. For the 1 and 2 week groups, we studied 8–9 hearts/group/time point. The number of hearts analyzed in the 4 week groups was as follows: MI = 10, MI + IVA = 13 and MI + ATEN = 18. Thickness of the LV wall containing the scar tissue (infarcted region) was determined from digitized images; the region was divided into six segments and the mean value of six measurements was recorded. To determine the percent of the infarcted region occupied by surviving cells, we used point-counting. A transparent grid with intersecting points was overlaid on a micrograph of the infarcted portion of the ventricle. The number of points falling on surviving cardiomyocytes was counted and divided by the total number of points falling on the test area (100×) to yield a percent of the infarct region occupied by surviving cardiomyocytes. Each sample region included 290–575 points.

Statistics

Significant differences (P ≤ 0.05) between group means were determined by ANOVA and Bonferroni's method. Data are expressed as means ± SEM.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. LITERATURE CITED

One week following coronary artery ligation (Fig. 1), a difference in percent of cardiomyocyte survival can be seen in panels A (MI) and B (MI + IVA). The latter has a broader rim of surviving cells adjacent to the epicardium. We noted that both ivabradine and atenolol treated rats displayed such regions of surviving cells, typically surrounding veins or venules. At this time point there are large regions of granulation tissue (inflammatory cells and fibroblasts) in most hearts (panels C and D) and collagen accumulation in some arteries and arterioles in regions of degeneration. Some cardiomyocytes are just undergoing irreversible damage as seen in F, G, and H. These cells are usually at the periphery of the infarct and are characterized by contraction bands (shortened sarcomeres), indicative of irreversible damage. Two weeks after coronary artery ligation, there still exists cardiomyocytes that are undergoing degeneration and collagen replacement; granulation tissue is still present in many regions (Fig. 2). The late degeneration of cardiomyocytes is more prevalent in the treated groups, as noted by cardiomyocytes with contraction bands (A and B). Areas of surviving cardiomyocytes at 2 weeks were also greater in the two treated groups, a finding that is consistent with the observations at 1 week.

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Figure 1. Micrographs of infarcted regions of the left ventricle 1 week after coronary artery ligation. (A) MI from untreated group illustrates that loss of cardiomyocytes but presence of surviving cells (SC) near the epicardium, surrounding venules, and under the endocardium. Some dense collagen is evident (Co). (B) Ivabradine treatment results in a greater number of surviving cells, most of which surround venules or veins in the subepicardial region. Surviving cells beneath the subepicardium are also seen. (C and D) Infarction regions from rats in the untreated group. (C) An untreated MI displays some surviving cells and areas of necrosis (demarcated by the broken lines). Granulation tissue (GT) is present in most of the LV wall. (D) Higher power of necrotic myocytes and granulation tissue. (E) Collagen sites in areas of necrosis and in an artery (Ar) in MI + ATEN specimen. (F) More advanced collagen deposition (blue) near degenerating myocytes (note contraction bands at arrows) and in adventitia of arteriole (Ar). (G,H) Specimen from MI + ATEN group. Surviving cells (SC) in G above region of degenerating myocytes; in H detail of contraction bands of myocytes undergoing degeneration. Bar = 400 μm in A–C, 200 μm in D–H.

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Figure 2. Two weeks postinfarction. Some cardiomyocytes, (from MI + IVA group) apparent survivors of the first week are degenerating (A, B). Collagen deposition (Co) occurs in these regions. (C) MI specimen also shows collagen deposition and large areas of granulation tissue. (D) MI + IVA specimen with a mixture of surviving and degenerating myocytes and collagen in the adventitia of arterioles (A). Bar = 200 μm.

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Four weeks after ligation of the left descending coronary artery a substantial infarction of the LV anterior wall was evident (Fig. 3). Although the percentage of the LV that was infarcted was similar in the treated and nontreated groups (Fig. 5), the composition of the infarct differed (Figs. 4 and 5). As noted previously (Christensen, et al., 2009), treatment with either ivabradine or atenolol reduced HR to virtually identical degrees (19% at the end of the 4 week treatment period). The major effect of HRR in both treated groups was a significant increase in surviving cells (Figs. 4 and 5). Using morphometry, we quantified the percent of the infarct area occupied by cardiomyocytes and found that the MI + IVA and MI + ATEN hearts had virtually twice the value found in MI hearts (Fig. 5). As a consequence, the thickness of the infarcted region was 43% (P ≤ 0.01) and 23% (P ≤ 0.05) greater in the MI + IVA and MI + ATEN groups, respectively than in the MI group. Although the trend toward a greater thickness of the infarct region favored ivabradine treatment, the difference between the means of the two treatment groups was not statistically significant (P = 0.19). As documented in Fig. 5, the thicker infarct regions in the treated groups were primarily due to a much greater number of surviving cardiomyocytes. The MI (untreated) group displayed the greatest consistency with regard to the proportion of the infarct region consisting of surviving cardiomyocytes; all 10 of the hearts in this group had surviving regions <20% and a median value of 10%. In contrast, 61% and 50% of the MI + IVA and MI + ATEN groups, respectively had surviving regions >20%. The median values for these groups were 18% and 21%, respectively. Cardiomyocyte diameters, however, were larger in the infarct region of the two treated groups, compared to the mean value of the untreated group (Table 1). As previously documented (Dedkov et al., 2005, 2007b) and noted in this study, postinfarcted hearts undergo a greater degree of hypertrophy in the border zone (a region adjacent to the infarct). Thus, the treatments affected both a greater cardiomyocyte survival and hypertrophy in the infarct region.

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Figure 3. Variation in infarct region composition seen in cross-sections of the left ventricle. (A) A typical untreated MI has relatively small areas of surviving cardiomyocytes mostly under the endocardium (arrow). (B) An infarct with some surviving cells beneath both the endocardium and epicardium (arrows). (C, D) infarcts from atenolol (C) and ivabradine (D) treated rats. In (C) there is a large area of surviving cardiomyocytes in the inner portion of the ventricular wall (between dashed lines) and some surviving cells near the epicardium (arrow). In (D) there are broad regions of surviving cells near both the endocardium and epicardium (arrows). Hearts from both ivabradine and atenolol treated rats display similar variations in the location of surviving cardiomyocytes. In all four hearts cell survival is high in papillary muscles (P). Bar = 5 mm.

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Figure 4. Four weeks postinfarction. (A, B) Infarcted regions from MI group illustrating variation in thickness and myocyte survival (SC). Dense collagen (CO) is also variable in these regions. Compared to untreated rats, ivabradine (C) and atenolol (D, E) treatments facilitate greater myocyte survival (SC). Survival typically occurs adjacent to venules or veins (V). (F) This MI specimen has almost no surviving cells, surrounding veins or venules. (G) This MI + IVA specimen, with a relatively low proportion of the infarct region with surviving myocytes, illustrates that the surviving cells surround venules near the epicardium. (H) Many hearts with infarcts had endocardial regions with cartilage, as seen here. Bar = 400 μm in A–C, 200 μm in D–G and 50 μm in H.

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Figure 5. Morphometry of myocardial infarct region. Percent of the left ventricle which contains an infarct region indicates similar values for the three groups. However, the mean infarct thickness is greater in the two treated groups. This percent of the infarct area that contains surviving cardiomyocytes is significantly greater in the two treated groups compared to the nontreated group. The percent of the infarct with surviving myocardial cells is expressed as total area of infarct region/area occupied by cardiomyocytes. Data are means ± SEM. *P ≤ 0.05, **P ≤ 0.01. Number of animals per group: MI = 10, MI + IVA = 13, MI + ATEN = 18.

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Table 1. Cardiomyocyte mean diameters (Mean ± SEM) in three regions of hearts with infarctions
GroupLeft ventricular region
InfarctBorderRemote
  • Mean ± SE are shown.

  • *

    Statistically significant differences (P ≤ .05) compared to MI group.

MI18.37 ± 0.3621.2 ± 0.3218.5 ± 0.20
MI + IVA22.5 ± 0.26*22.6 ± 0.2917.9 ± 0.15
MI + ATEN22.0 ± 0.22*22.8 ± 0.3417.9 ± 0.36

Figure 4 illustrates the variation in infarct region thickness, cell survival and connective tissue contribution 4 weeks after coronary artery ligation. By this time, both loose and dense connective tissue has replaced cardiomyocytes and granulation tissue. Although cell survival is usually most notable adjacent to the epicardium close to veins and venules, other variations were observed. Occasionally the largest mass of surviving cells was adjacent to the endocardium (Fig. 4D). In other hearts, we noted clusters of surviving cells in the middle of the infarct region (panel C). Large areas of surviving cells were, with rare exception, observed only in the ivabradine and atenolol treated groups. Of the 10 hearts from the MI (untreated group), only 2 displayed notable regions of cell survival and 6 had minor areas of surviving cardiomyocytes. In contrast, 9 of 13 hearts in the MI + IVA and 15 of 18 in the MI + ATEN displayed notable, usually large, regions of surviving cells (Fig. 5C–E). The scar portion of the infarct region contained some blood vessels that were undergoing morphological alterations, such as collagen replacement of portions of the media, while others appeared normal. Endocardial projections of groups of cartilage cells surrounded by dense connective tissue could occasionally be found in all three of the groups studied.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. LITERATURE CITED

Myocardial infarction triggers a series of events that result in scar formation (Frangogiannis, 2006). The inflammatory phase is evident within a few hours after infarction and includes activation of the complement cascade, generation of reactive oxygen species, and activation of chemokines, cytokines, and adhesion molecules. These molecules facilitate inflammatory cell recruitment and degradation of the extracellular matrix. This inflammatory response triggers myofibroblast differentiation and activation as well as synthesis of bioactive molecules important for the synthesis of the new extracellular matrix (Frangogiannis, 2006; Spinale, 2007). In the infarcted heart, myofibroblasts have been shown to produce natriuretic peptides and adrenomedulin, molecules that may influence the reparative process of fibrosis (Calderone et al., 2006). This proliferative phase is characterized by the presence of granular tissue. The formation of a collagenous scar occurs during the 2nd week following infarction (Frangogiannis, 2006). Myocardial infarction in the rat may effect 45% of LV mass, but is accompanied by a significant compensatory cardiomyocyte hypertrophy (Anversa et al., 1985). At least in the rat model, cardiomyocyte hypertrophy is adequate in compensating for the loss of these cells in the infarct region (Dedkov et al., 2005, 2007b). Meanwhile, ventricular remodeling involves myocyte slippage which results in ventricular dilation (Olivetti et al., 1990).

Although previous studies have quantified the infarct region with regard to a percent of the ventricle, our study is the first to document cardiomyoctye survival in the infarct region and to demonstrate that heart rate reduction therapy enhances cardiomyocyte survival. The histological analysis provided here is based on the hearts subjected to myocardial infarction and subsequent treatment with either ivabradine or atenolol. These hearts were previously analyzed for a variety of parameters (Christensen et al., 2009) as summarized in the next section.

Heart Rate Reduction as Postinfarction Therapy

Our recent study comparing the effects of chronic treatment of postinfarcted rats with ivabradine and atenolol showed that both of these treatments preserved maximal myocardial perfusion and prevented an increase in end diastolic pressure, a sign of heart failure (Christensen et al., 2009). Moreover, ivabradine therapy attenuated the decline in EF typical of the postinfarcted heart. Although HRR had little or no effect on growth factors, angiogenesis and arteriogenesis in these middle-aged rats, perivascular collagen in myocardial arterioles was lower after infarction in the rats that were chronically treated by either the β-blocker, atenolol, or the If current inhibitor, ivabradine (Christensen et al., 2009). These findings revealed that HRR may have normalized maximal perfusion by altering arteriolar adventitia. One possible explanation for the attenuation of the decline in ejection fraction with ivabradine, but not atenolol, treatment could be the greater magnitude of compensatory hypertrophy of the surviving myocardium consequently, a lower left ventricular end diastolic volume/left ventricular mass compared to both untreated and atenolol-treated rats with MI's. These treatment groups had lower plasma angiotensin II and lower myocardial angiotensin receptor 1 protein levels 1 week after infarction. Our findings led us to consider possible differences in scar content as a factor underlying the favorable effects of HRR after myocardial infarction.

Data from our current study, obtained from the same animals as our previous study (Christensen et al., 2009) described earlier, provide support for two major additional conclusions. First, HRR by either the If current inhibitor, ivabradine or the β-blocker, atenolol increases the mean thickness of the infarcted region of the LV subjected to myocardial infarction. Second, the higher transmural thickness is a consequence of increased survival of cardiomyocytes rather than increased scar material. Evidence for enhanced cardiomyocyte survival in the two treated groups was noted 1 week after coronary artery ligation. At this early time point, clusters of surviving cells were frequently seen, most often around veins or venules near the epicardium. The persistence of these regions of surviving cells at 2 and 4 weeks indicates that the survival was not transient. Contraction band necrosis, which we noted at 1 and 2, but not 4 weeks, indicates irreversible injury. Contraction bands are usually observed after reperfusion of the ischemic heart (Sommers and Jennings, 1964; Herdson et al., 1965; Kloner et al., 1974; Humphrey and Vanderwee, 1986) and their presence is accelerated by reperfusion (reflow) (Kloner et al., 1974). In hearts with a permanently occluded artery, contraction bands are usually limited to the periphery of an infarct (Herdson et al., 1965), a finding that is consistent with our observations in the current study. Taken together, these findings suggest that both ivabradine and atenolol therapy initiated on the day following infarction provided a better environment for cardiomyocyte survival.

Causes of Cardiomyocyte Survival

Although both ivabradine and atenolol are HR reducing drugs, this property does not necessarily explain cardiomyocyte survival in the face of coronary artery ligation. One would expect that, from an anatomical standpoint, the perfusion fields supplied by the ligated artery would be affected similarly on both treated and non-treated rats. Clearly, cardiomyocyte survival is dependent on sufficient O2 availability, which indicates that foci with surviving cardiomyocytes had adequate O2 levels. Accordingly, the most common site of surviving cells was adjacent to veins and venules. Because the rats treated with ivabradine or atenolol had more frequent and larger areas of surviving cells, these drugs may have facilitated a more favorable O2 microenvironment. In a study utilizing regional blood perfusion measurements and ultrastructural analysis of cell survival, we determined that if myocardial perfusion is maintained above 50% of normal for 24 hr, a substantial number of cardiomyocytes will survive (Tomanek et al., 1981).

The first possible explanation for the increase in cardiomyocyte survival with ivabradine or atenolol is that the lower HR in these groups allowed a more favorable venous blood flow by prolonging the diastolic interval and the time interval when extravascular forces are minimal. In this regard, it is noteworthy that the pure HR-reducing agent ivabradine causes a greater increase in diastolic time compared to β-blockade therapy, since the latter also shows lusitropic effects, thus reducing LV wall stress to a greater extent (Colin, 2002, 2003). This property of ivabradine may explain, at least in part, the tendency toward a greater prevention of infarct thinning observed in this study in the ivabradine treated group and the greater attenuation of ejection fraction decline compared to atenolol documented in our previous study (Christensen et al., 2009). Furthermore, the reduction in end diastolic pressure with either ivabradine or atenolol (Christensen et al., 2009) reduces compression of the myocardium, thus preserving ventricular flow.

The second possible explanation is that cardiomyocyte survival was linked to a lower O2 requirement as indicated by data that have documented lower MVO2 during exercise in dogs administered either ivabradine or atenolol (Colin et al., 2003). Both drugs given for 4 weeks in patients with stable angina improved exercise duration significantly (Tardif et al., 2005). Finally, a combination of these factors may be responsible for the improved cell survival in the hearts from treated rats. Nevertheless, while no differences in overall infarct size were observed in this study with either HR-reducing agent administered postinfarction, pretreatment with ivabradine reduced infarct size in pigs subjected to hypoperfusion followed by reperfusion (Heusch et. al., 2008). This effect was noted even when administered after the onset of ischemia.

Functional Significance

The attenuation of myocardial infarct thinning documented in this study is of clinical significance. It was quantified by (Fishbein et al., 1978) in the rat and is characterized by a progressive decrease in infarct thickness over a 21-day period following coronary artery occlusion. The largest drop (36%) occurs during the first 3 days. By 21 days, the infarcted wall thickness was decreased by 64%. Our data indicate that chronic HRR via ivabradine or atenolol had a major beneficial impact on the LV portion that included the infarct scar by attenuating wall thinning as evidenced by the fact that these groups had wall thickness values that were significantly greater than those of the nontreated group. This smaller reduction in the thickness of the infarcted region of the LV can be largely accounted for by the fact that percent of the infarct region occupied by surviving cardiomyocytes in the treated groups was double that of the untreated MI rats. Infarct expansion is a distortion of ventricular topography that occurs soon after infarction and is due to thinning and disproportionate dilation of the infarct segment of the ventricular wall. Patients who have substantial transmural thinning and an increase in infarct segment length have a higher mortality than patients who do not demonstrate infarct expansion (Weiss et al., 1991). Infarct expansion results in ventricular dilation associated with decreased exercise capacity and a higher frequency of heart failure symptoms (Weisman and Healy, 1987) and is a major factor predisposing patients to cardiac rupture (Sun et al., 2004).

Data presented here support the conclusion that ivabradine and atenolol both lessen wall stress and provide a better O2 microenvironment, thus enhancing cardiomyocyte survival, which reduces ventricular thinning of the infarct region. Thus, the latter should serve to minimize the potential of ventricular rupture. Ivabradine has advantages over atenolol because it increases diastolic time to a greater extent, thus increasing O2 supply and reducing wall stress. These effects may underlie the attenuation of the decline in EF provided by this pure HR-reducing agent after myocardial infarction.

LITERATURE CITED

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. LITERATURE CITED
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