PRECLINICAL STUDY
Chronic Monotherapy With Rosuvastatin Prevents Progressive Left Ventricular Dysfunction and Remodeling in Dogs With Heart Failure
Valerio Zacà, MD,
Sharad Rastogi, MD,
Makoto Imai, MD,
Mengjun Wang, MD,
Victor G. Sharov, PhD,
Alice Jiang, MD,
Sidney Goldstein, MD, FACC and
Hani N. Sabbah, PhD, FACC*
Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Henry Ford Health System, Detroit, Michigan.
Manuscript received November 27, 2006;
revised manuscript received April 9, 2007,
accepted April 10, 2007.
* Reprint requests and correspondence: Dr. Hani N. Sabbah, Cardiovascular Research, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202. (Email: hsabbah1{at}hfhs.org).
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Abstract
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Objectives: This study examined the effects of long-term monotherapy with rosuvastatin (RSV) on the progression of left ventricular (LV) dysfunction and remodeling in dogs with heart failure (HF).
Background: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or "statins" possess other noncholesterol-lowering properties that include inhibiting proinflammatory cytokines, attenuating LV hypertrophy, and stimulating the release of bone marrow-derived stem cells (BMSCs).
Methods: Twenty-one dogs with microembolization-induced HF were randomized to 3 months oral monotherapy with low-dose (LD) RSV (0.5 mg/kg once daily, n = 7), high-dose (HD) RSV (3.0 mg/kg once daily, n = 7), or to no therapy (control group, n = 7). The change ( ) from pre- to post-therapy (treatment effect) in LV end-diastolic volume (EDV) and end-systolic volume (ESV) and ejection fraction (EF) was measured. Protein level of tumor necrosis factor (TNF)- in LV tissue and the number of circulating Sca-1–positive BMSCs was also determined. Blood and LV tissue from 6 normal dogs was obtained and used for comparison.
Results: There were no differences in EDV, ESV, and EF between control group and LD RSV. In contrast, EDV and ESV were significantly lower, and EF was significantly higher in HD RSV compared with control group. High-dose, but not LD, RSV also normalized protein levels of TNF- and was associated with a significant increase in the number of circulating BMSCs.
Conclusions: In dogs with HF, chronic therapy with HD RSV prevents progressive LV dysfunction and dilation. This benefit may be partly derived from normalization of TNF- expression and partly from increased mobilization of BMSCs.
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Abbreviations and Acronyms
| | BMSC = bone marrow-derived stem cell | | CVD = cardiovascular disease | | ECM = extracellular matrix | | EDV = end-diastolic volume | | EF = ejection fraction | | EPC = endothelial progenitor cell | | ESV = end-systolic volume | | HD = high-dose | | HF = heart failure | | HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A | | LD = low-dose | | LV = left ventricular/ventricle | | MCSA = myocyte cross-sectional area | | MI = myocardial infarction | | MMP = matrix metalloproteinase | | ODD = oxygen diffusion distance | | RSV = rosuvastatin | | TNF = tumor necrosis factor | | VFIF = volume fraction of interstitial fibrosis | | VFRF = volume fraction of replacement fibrosis |
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The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly referred to as statins, modulate the activity of the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis (1). In recent years, evidence from several large clinical trials has shown that statins reduce morbidity and mortality in patients with virtually all stages of cardiovascular disease (CVD) (2). As a result, statins are currently recommended as a treatment of choice in the primary and secondary prevention of atherosclerotic CVD (3).
Statins have also been shown to possess a host of other noncholesterol-lowering properties including ability to reduce systemic inflammation (4), improve endothelial function (5), stimulate angiogenesis (6), and mobilize bone marrow-derived stem cells (BMSCs) (7–9), all of which can contribute to the improvement of left ventricular (LV) function and prevention or attenuation of progressive LV remodeling in heart failure (HF). These properties constitute a rationale for the chronic use of this class of drugs in the prevention and treatment of HF. To date, only a few experimental (10–12) and observational (13–15) studies have reported a beneficial effect of statins in HF.
Rosuvastatin (RSV), a relatively new molecule, has emerged as an effective HMG-CoA reductase inhibitor with respect to lipid-lowering activity in low- to high-risk patients, showing a safety and tolerability profile similar to commonly used doses of other statins (16). In the present study, we investigated the effects of early long-term monotherapy with RSV on LV function and remodeling in dogs with intracoronary microembolization-induced HF.
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Methods
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Experimental model.
The canine model of chronic HF used in this study was previously described in detail (17). In this preparation, LV dysfunction is produced by multiple intracoronary microembolizations that result in loss of viable myocardium. The model manifests many of the sequelae of HF observed in humans including marked and progressive depression of LV systolic and diastolic function, reduced cardiac output, and increased LV filling pressures. In the present study, 21 healthy mongrel dogs, weighing between 20 to 30 kg, underwent serial coronary microembolizations to produce HF. Embolizations were performed 1 to 3 weeks apart and were discontinued when LV ejection fraction (EF), determined angiographically, was between 30% and 40%. All the procedures were performed during cardiac catheterization under general anesthesia and sterile conditions. Animals were sedated with intravenous oxymorphone hydrochloride (0.22 mg/kg) and diazepam (0.17 mg/kg), and a plane of anesthesia was maintained with 1% to 2% isofluorane. The study was approved by Henry Ford Health System Institutional Animal Care and Use Committee and conformed to the National Institute of Health "Guide and Care for Use of Laboratory Animals" and the "Position of the American Heart Association on Research Animal Use."
Study protocol.
Two weeks after the last embolization, dogs underwent a prerandomization left and right cardiac catheterization. One day later, dogs were randomized to 3 months oral monotherapy with low-dose (LD) RSV (0.5 mg/kg once daily, n = 7), high-dose (HD) RSV (3.0 mg/kg once daily, n = 7), or no therapy at all (control group, n = 7). At the end of the follow-up period, a final left and right cardiac catheterization was performed. At the end of the cardiac catheterization and while under general anesthesia, the chest was opened and the heart rapidly removed for histological and biochemical examination. Whole blood and LV tissue were obtained from all HF dogs as well as from 6 normal dogs for comparisons with control and RSV-treated dogs. Blood samples were used to measure total cholesterol and triglyceride.
Hemodynamic and angiographic measurements.
Hemodynamic and angiographic measurements were made at baseline, before any microembolization, at the time of randomization, before initiation of therapy (pretreatment), and at the end of 3 months of therapy (post-treatment). Aortic and LV pressures were measured with catheter-tip micromanometers (Millar Instruments, Houston, Texas). Left ventriculograms were obtained with the dog placed on its right side and recorded on 35-mm cine film at 30 frame/s during the injection of 20 ml of contrast material (RENO-M-60, Squibb, Princeton, New Jersey). Correction for image magnification was made with a radiopaque calibrated grid placed at the level of the LV. Left ventricular end-systolic volume (ESV) and end-diastolic volume (EDV) were calculated from LV silhouettes using the area-length method, and EF was calculated as previously described (18). Stroke volume was calculated as the difference between LV EDV and ESV. Cardiac output was calculated as the product of stroke volume and heart rate. Extrasystolic and postextrasystolic beats were excluded from any analysis.
Histomorphometric measurements.
From each heart, including hearts from normal dogs, 3 transverse slices (approximately 3-mm thick), 1 each from basal, middle, and apical thirds of the LV, were obtained. From each slice, transmural tissue blocks were obtained and embedded in paraffin blocks. Transmural tissue blocks were also obtained from the free wall segment of the slice, mounted on cork using Tissue-Tek embedding medium, and rapidly frozen in isopentane precooled in liquid nitrogen and stored at –70°C until used. The volume fraction of replacement fibrosis (VFRF); volume fraction of interstitial fibrosis (VFIF); myocyte cross-sectional area (MCSA), a measure of cardiomyocyte hypertrophy; capillary density; and oxygen diffusion distance (ODD) were measured as previously described (19).
Expression of tumor necrosis factor- (TNF-), matrix metalloproteinase (MMP)-2, and circulating BMSC counts.
All tissue and blood samples were submitted for analysis without treatment regimen identifiers. Protein levels of TNF- and MMP-2 were measured in LV homogenate by Western blots. Primary antibodies specific to each protein were diluted based on the supplier’s instructions. In all instances, the antibody was present in excess over the antigen, and the density of each protein band was in the linear scale. Band intensity was quantified in densitometric units. Circulating, Sca-1–positive BMSCs were isolated from whole blood. Sca-1–positive BMSC cells include mesenchymal, multipotent adult progenitor, and Hoechst side population cells (20). Samples were centrifuged over a Ficoll-Hypaque gradient, and isolated cells were stained with primary and secondary antibodies containing immunofluorescence (SC-8266, Santa Cruz Biotechnology, Inc., Santa Cruz, California). Sca-1–positive BMSCs were counted using a hemocytometer coupled to fluorescent microscopy.
Statistical analysis.
All angiographic and histomorphometric analyses were performed in a blinded manner. Intragroup comparisons of hemodynamic and angiographic variables for each of the 3 study groups were made between measurements obtained just before initiation of therapy and measurements made after completion of 3 months of therapy. Student paired t test was used for comparisons of pretreatment versus post-treatment measures. To ensure that all study measures were similar at baseline before any embolizations and at the time of randomization before initiation of therapy (pretreatment), intergroup comparisons were made using a 1-way analysis of variance (ANOVA) with alpha set at 0.05. If the overall ANOVA was significant, then pairwise comparisons were performed using the Student-Newman-Keuls test. To assess treatment effect, the change () in each measure from pretreatment to post-treatment was calculated for each of the 3 study arms. To determine whether significant differences in were present between the control group and each of the 2 treatment groups, an ANOVA was performed with alpha set at 0.05. If the overall ANOVA was significant, then pairwise comparisons were performed using the Student-Newman-Keuls test. Histomorphometric results as well as protein expression results and BMSC counts obtained in all 3 study groups and in a group of normal dogs were examined using ANOVA with alpha set at 0.05. If significance was attained by overall ANOVA, pairwise comparisons were performed using the Student-Newman-Keuls test. For all pairwise comparisons, a probability value  0.05 was considered significant. All data are reported as the mean ± SEM.
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Results
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All 21 study animals survived the entire study. Baseline data for all groups are shown in Table 1. Baseline hemodynamic and angiographic findings were within the normal range for mongrel dogs in our laboratory. There were no significant differences in any baseline parameters between control dogs and dogs randomized to either LD or HD RSV (Table 1). Similarly, there were no significant differences between the 3 study groups in any of the parameters obtained at pretreatment (Table 2). There were no significant differences in total cholesterol or triglycerides at any of the study time points (Tables 1 and 2).
Hemodynamic and angiographic findings.
Three months after randomization, control dogs showed a significant deterioration of LV EF accompanied by a significant increase of LV EDV and LV ESV (Table 2). Similarly, 3 months of therapy with LD RSV was associated with a reduction of LV EF and an increase of both LV EDV and ESV. In dogs treated with HD RSV, LV EF increased significantly whereas LV volumes remained essentially unchanged (Table 2). Heart rate, mean aortic pressure, and LV end-diastolic pressure remained essentially unchanged in all 3 study groups (Table 2). Stroke volume and cardiac output did not change in control and LD RSV dogs, but increased significantly in dogs randomized to HD RSV (Table 2).
Comparisons of treatment effect.
The changes () between pretreatment and post-treatment LV EF, EDV, and ESV are shown in Figure 1. Compared with that seen in control animals, HD RSV but not LD RSV prevented progressive LV dysfunction and dilation. High-dose RSV significantly increased LV EF compared with that in control dogs and LD RSV-treated dogs (Fig. 1). Both LV EDV and ESV were significantly smaller in the HD RSV group than those seen in control or LD RSV groups (Fig. 1). There were no significant differences in heart rate, mean aortic pressure, and LV end-diastolic pressure among the 3 study groups. The change in stroke volume was not significantly different between control dogs (–0.71 ± 0.64) and LD RSV dogs (–0.5 ± 0.43) but was significantly higher in HD RSV dogs (1.43 ± 0.3, p = 0.011 vs. control group; p = 0.003 vs. LD RSV). Similarly, the change in cardiac output did not differ between control group (–0.13 ± 0.09) and LD RSV group (0.03 ± 0.04) but was significantly higher in the HD RSV group (0.21 ± 0.05, p = 0.006 vs. control group; p = 0.016 vs. LD RSV).
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Figure 1 Ventriculographic Measures of LV Function and Size
Bar graphs depicting change () in left ventricular (LV) ejection fraction (EF), LV end-diastolic volume (EDV), and LV end-systolic volume (ESV) between pretreatment and post-treatment in control dogs, dogs randomized to low-dose (LD) rosuvastatin (RSV), or dogs randomized to high-dose (HD) RSV. *p < 0.05 versus control group;  p < 0.05 versus LD RSV.
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Histomorphometric findings.
Histomorphometric findings are shown in Table 3. Compared with that in normal dogs, VFRF was significantly increased in control dogs. There was a modest but insignificant decrease in VFRF in LD and HD RSV dogs compared with that in control dogs. Volume fraction of interstitial fibrosis was significantly higher in control dogs than that in normal dogs. The LD RSV had no effect on VFIF whereas HD RSV significantly decreased VFIF compared with that in control animals (Table 3). Compared with that in normal dogs, MCSA was larger in control animals and decreased with both LD and HD RSV. In control dogs, capillary density was significantly lower and ODD significantly longer compared with those in normal dogs. Treatment with LD RSV had no effect on capillary density and ODD, whereas HD RSV tended to normalize both (Table 3).
Effects of RSV on TNF-, MMP-2, and BMSC.
Compared with those in normal dogs, LV protein levels of TNF- and MMP-2 were significantly increased in control HF dogs. High-dose RSV but not LD RSV normalized protein levels of TNF- and MMP-2 (Fig. 2). The number of BMSCs was significantly reduced in control HF dogs compared with that in normal dogs (Fig. 3). High-dose RSV therapy was associated with a 3-fold increase in the number of circulating BMSCs compared with that in normal dogs and a 7-fold increase compared with that in control animals (Fig. 3).
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Discussion
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The present study demonstrates that early, long-term monotherapy with HD RSV prevents the progressive LV dysfunction and remodeling in dogs with moderate HF. This conclusion is supported by the findings that 3 months of therapy with HD RSV increased LV EF and prevented progressive LV enlargement thus preventing progressive LV global remodeling. The magnitude of improvement of LV EF and global remodeling was similar to that seen in this model after long-term therapy with the angiotensin-converting enzyme inhibitor enalapril (18). Furthermore, the benefits observed with HD RSV on LV function and remodeling were associated, at the cellular level, with a lower VFIF, increased capillary density, improved ODD, and reduced cardiomyocyte hypertrophy. These positive histomorphometric changes were also present, albeit to a lesser extent, in dogs receiving LD RSV. High-dose RSV, but not LD, also normalized LV tissue expression of TNF- and MMP-2. In addition, high-dose RSV induced a significant increase in the number of circulating BMSCs. All of these favorable observations provide strong support for the notion that RSV, at least at high doses used in this study, prevents worsening of the HF state.
Effects of RSV on LV function and global remodeling.
The observation of a preserved cardiac function and an attenuated LV global remodeling in dogs randomized to HD RSV is in agreement with evidence derived from previous studies of statins in acute myocardial infarction (MI). In animal models of MI, long-term statin therapy initiated early after the MI was associated with increased survival and with improvement of systolic and diastolic LV function along with an attenuation of global LV remodeling (10–12). Results from clinical studies also suggest that statins may improve LV systolic function by attenuating the remodeling process in patients with HF (13–15). Node et al. (13) observed a significant improvement in LV function and a reduction in LV volumes in patients with idiopathic dilated cardiomyopathy randomized to 14 weeks of therapy with simvastatin compared with placebo. Recently atorvastatin was shown to be effective in improving the clinical status of patients with nonischemic forms of HF by improving LV systolic function and decreasing LV volumes when added to standard optimal therapy (14,15).
Anti-inflammatory effects of RSV.
Long-term therapy with statins has also been shown to decrease circulating plasma levels of proinflammatory cytokines (13–15) suggesting that statins may improve cardiac function in HF, at least in part, by modulating the systemic inflammatory state. Tumor necrosis factor- appears to play a pivotal role among the many proinflammatory cytokines that contribute to the progression of HF by inducing cardiomyocyte hypertrophy, apoptosis, and promoting the induction of the fetal gene program (21). Recent studies have suggested that TNF- may promote LV remodeling also by adverse remodeling of the myocardial extracellullar matrix. Decreased expression of TNF- results in reduced activation of the gelatinases MMP-2 and -9, and reduced collagen deposition and denaturation (22). These observations support the hypothesis that inhibition of TNF- may represent an important determinant of the statin-mediated attenuation of myocardial fibrosis and hypertrophy that is ultimately reflected in attenuation of global LV remodeling. In the present study, chronic therapy with HD RSV was associated with normalization of LV myocardial protein expression of TNF- and MMP-2.
Effects of RSV on myocardial fibrosis and cardiomyocyte hypertrophy.
Myocardial fibrosis and maladaptive extracellular matrix (ECM) remodeling are common findings in the failing heart (23). The MMPs play a crucial role in regulating ECM turnover and, hence, myocardial structural geometry. Enhanced MMP activation in patients with HF may contribute to progressive LV dilation and dysfunction (23). Statins have been shown to exert direct inhibitory effects on MMP-1 expression in human vascular endothelial cells (24) and to attenuate the increase in MMP-2 level in post-MI (11). Previous reports showed that selective MMP inhibition attenuates progression of LV dysfunction and remodeling in experimental models of HF, mainly through a reduction of the extent of replacement and interstitial fibrosis (25). In the present study, HD RSV was associated not only with reduced myocardial MMP-2 expression and VFIF but also with a significant decrease in MCSA, a measure of cardiomyocyte hypertrophy. Statins have been reported to exert antihypertrophic effects in various experimental settings (26) by inhibiting the isoprenylation of small G-proteins such as Rac and Rho (27), and also angiotensin II and noradrenaline (26).
Effects of RSV on capillary density and mobilization of BMSCs.
In dogs randomized to HD RSV, we observed a significant increase in capillary density and in capillary-to-cell ratio. These changes were associated with a 7-fold increase in the number of circulating BMSCs compared with that in control animals. Statins may induce angiogenesis by activating the protein kinase Akt-signaling pathway known to promote endothelial cell survival and nitric oxide production (6). Activation of the Akt pathway has also been suggested as the mechanism underlying statin- and vascular endothelial growth factor-induced endothelial progenitor cell (EPC) differentiation and mobilization from the bone marrow (7,8). Consistent with these findings, it has been reported that statins increase the number of EPCs and enhance their proliferative and migratory activity both in experimental models of MI (12) and in patients with chronic stable angina (9). Evidence is accumulating that statin-mediated mobilization of EPCs may be involved in myocardial neovascularization (28). Asahara et al. (28) showed that after permanent ligation of the left anterior descending coronary artery in mice, bone marrow-derived EPCs are incorporated into foci of neovascularization at the border of the infarct contributing to postnatal vasculogenesis. In the present study, dogs randomized to high-dose RSV showed a marked increase in the number of circulating BMSCs, the latter a recognized determinant deemed critical for colonization and transdifferentiation of BMSCs in the injured myocardium (29). Studies have shown that circulating BMSCs exhibited the plastic property to differentiate into EPCs and several cell lineages including cardiac cell (7,29,30).
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Potential Clinical Implications and Conclusions
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The results of the present study provide additional evidence to sustain a biological rationale for the use of statins as an adjunctive treatment of HF in humans. The potential therapeutic role of statins in patients with HF has thus far been investigated in only a few small noncontrolled observational studies (14,31). A recent study suggested that aggressive therapy with high-dose statins does not provide the same benefits obtained with lower doses (32). These unexpected results need to be confirmed through studies designed to directly compare the effects of different doses of statins. At present, 2 large randomized clinical trials are underway that examine the effects of RSV on the mortality, morbidity, and functional status of patients with established symptomatic HF of both ischemic and nonischemic etiology (33,34).
In the present study, the HDs and LDs of RSV were chosen to achieve a similar plasma concentration as seen in humans. This, however, in and of itself, does not ensure that the outcome seen in dogs will be the same as that seen in humans. Bioavailability, metabolic profile, and protein binding properties of RSV can differ between dogs and humans, a fact that often makes extrapolations among species difficult. One thing, however, is perhaps more certain in that the results of the present study raise the possibility that statins such as RSV might exert benefits in HF that are additional to those that occur through reductions in low-density lipoprotein and other atherogenic lipoproteins. Pleiotropic effects might result from direct effects of plasma drug on myocardial endothelial cells and/or cardiomyocytes and/or inflammatory cells in the myocardium or from the changes in circulating stem cells.
The results of the present study indicate that early long-term monotherapy with HD RSV prevents progressive LV dysfunction and attenuates global and structural LV remodeling in dogs with moderate HF. These beneficial effects are likely to be due, at least in part, to normalization of TNF- and MMP-2 expression and possibly to enhanced mobilization of BMSCs. Additional studies are needed to determine whether RSV or other statins have incremental benefit in this canine model of HF over standard therapy for HF such as angiotensin-converting enzyme inhibitors and beta-blockers.
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Footnotes
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Supported, in part, by research grants from AstraZeneca U.S. and the National Heart, Lung, and Blood Institute grant PO1 HL074237-04. All authors are full-time employees of Henry Ford Health System.
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S. Rastogi, M. Imai, V. G. Sharov, S. Mishra, and H. N. Sabbah
Darbepoetin-{alpha} prevents progressive left ventricular dysfunction and remodeling in nonanemic dogs with heart failure
Am J Physiol Heart Circ Physiol,
December 1, 2008;
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H2475 - H2482.
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S. Rastogi, V. G. Sharov, S. Mishra, R. C. Gupta, B. Blackburn, L. Belardinelli, W. C. Stanley, and H. N. Sabbah
Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure
Am J Physiol Heart Circ Physiol,
November 1, 2008;
295(5):
H2149 - H2155.
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A. N. DeMaria, J. J. Bax, O. Ben-Yehuda, P. Clopton, G. K. Feld, G. S. Ginsburg, B. H. Greenberg, J. D. Knoke, W. Y.W. Lew, J. A.C. Lima, et al.
Highlights of the Year in JACC 2007
J. Am. Coll. Cardiol.,
January 29, 2008;
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490 - 512.
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Abstract
Methods
p < 0.05 versus LD RSV. Abbreviations as in 