Untreated Myocardial Infarction Group Research Articles

Effects of pirfenidone on scar size and ventricular remodeling after myocardial infarction: a preclinical study.

An intense fibrotic response after myocardial infarction (MI) may lead to scar expansion and left ventricular (LV) remodeling. We investigated the effects of the antifibrotic drug pirfenidone in this setting. Male Wistar rats were randomized to: sham procedure (n = 13), reperfused MI-induced by ligating the left anterior descending artery (LAD) for 45 min (n = 17), reperfused MI plus standard therapy (aspirin, angiotensin-converting enzyme inhibitor, beta blocker, and mineralocorticoid receptor antagonist) (n = 17), reperfused MI plus pirfenidone alone (n = 17), or reperfused MI plus standard therapy and pirfenidone (n = 17). Rats surviving MI induction underwent cardiac magnetic resonance scans after 72 h and 30 days from MI, and were sacrificed on day 31. Rats completing the whole protocol numbered 11 in the sham group, 9 in the untreated MI group, 8 in the standard treatment group, 9 in the pirfenidone alone group, and 9 in the standard treatment plus pirfenidone group. No significant differences emerged between LV volumes, ejection fraction or mass at 30 days or the differences from 72 h to 30 days. Small, nonsignificant differences between rats on pirfenidone alone vs. those on standard therapy emerged. The total extent of LV fibrosis, quantified as area and percentage of the tissue sample, did not differ significantly between rats on pirfenidone alone vs. those on standard therapy alone. Pirfenidone does not have additional effects on LV remodeling or fibrosis compared with standard therapy, but its effects are similar to standard therapy alone.

Electroacupuncture improves cardiac function after myocardial infarction by regulating the mobilization and migration of endogenous stem cells.

The aim of this study was to explore the role and mechanisms of electroacupuncture (EA) in the regulation of chemokines in endogenous stem cell mobilization and myocardial regeneration after myocardial infarction (MI). An MI model was constructed in adult male Sprague-Dawley rats by ligating the left anterior descending coronary artery. After 4 weeks of treatment, echocardiography was used to detect changes in cardiac function, and Masson's trichrome staining was used to detect collagen deposition. In addition, immunofluorescence staining was applied to examine von Willebrand factor (vWF)-positive vessels, the expression of cardiac troponin T (cTnT) and proliferation marker Ki67, and the number of c-kit-positive, C-X-C chemokine receptor type 4 (CXCR4)-positive, and Sca-1-positive endogenous stem cells in the infarcted area. In addition, the expression of stromal cell-derived factor (SDF)-1 and stem cell factor (SCF) was detected. EA increased the ejection fraction after MI, reduced collagen deposition and cellular apoptosis, and increased the number of blood vessels compared with an untreated model group. EA significantly promoted cellular proliferation, except for myocardial cells, and significantly increased the number of c-kit-, CXCR4- and Sca-1-positive stem cells. Moreover, the expression of SDF-1 and SCF in myocardial tissue in the EA group was significantly higher than that in the (untreated) MI group. EA appears to promote angiogenesis and reduce collagen deposition, thus improving the cardiac function of rats with MI. The underlying mechanism of action may involve endogenous stem cell mobilization mediated by SDF-1/CXCR4 and SCF/c-kit.

Intermedin 1-53 Ameliorates Atrial Fibrosis and Reduces Inducibility of Atrial Fibrillation via TGF-β1/pSmad3 and Nox4 Pathway in a Rat Model of Heart Failure

New drugs to block the occurrence of atrial fibrillation (AF) based on atrial structural remodeling (ASR) are urgently needed. The purpose of this study was to study the role of intermedin 1-53 (IMD1-53) in ASR and AF formation in rats after myocardial infarction (MI). Heart failure was induced by MI in rats. Fourteen days after MI surgery, rats with heart failure were randomized into control (untreated MI group, n = 10) and IMD-treated (n = 10) groups. The MI group and sham group received saline injections. The rats in the IMD group received IMD1-53, 10 nmol/kg/day intraperitoneally for 4 weeks. The AF inducibility and atrial effective refractory period (AERP) were assessed with an electrophysiology test. Additionally, the left-atrial diameter was determined, and heart function and hemodynamic tests were performed. We detected the area changes of myocardial fibrosis in the left atrium using Masson staining. To detect the protein expression and mRNA expression of transforming growth factor-β1 (TGF-β1), α-SMA, collagen Ⅰ, collagen III, and NADPH oxidase (Nox4) in the myocardial fibroblasts and left atrium, we used the Western blot method and real-time quantitative polymerase chain reaction (PCR) assays. Compared with the MI group, IMD1-53 treatment decreased the left-atrial diameter and improved cardiac function, while it also improved the left-ventricle end-diastolic pressure (LVEDP). IMD1-53 treatment attenuated AERP prolongation and reduced atrial fibrillation inducibility in the IMD group. In vivo, IMD1-53 reduced the left-atrial fibrosis content in the heart after MI surgery and inhibited the mRNA and protein expression of collagen type Ⅰ and III. IMD1-53 also inhibited the expression of TGF-β1, α-SMA, and Nox4 both in mRNA and protein. In vivo, we found that IMD1-53 inhibited the phosphorylation of Smad3. In vitro, we found that the downregulated expression of Nox4 was partly dependent on the TGF-β1/ALK5 pathway. IMD1-53 decreased the duration and inducibility of AF and atrial fibrosis in the rats after MI operation. The possible mechanisms are related to the inhibition of TGF-β1/Smad3-related fibrosis and TGF-β1/Nox4 activity. Therefore, IMD1-53 may be a promising upstream treatment drug to prevent AF.

Pericardial Grafting of Cardiac Progenitor Cells in Self-Assembling Peptide Scaffold Improves Cardiac Function After Myocardial Infarction

Many studies have explored cardiac progenitor cell (CPC) therapy for heart disease. However, optimal scaffolds are needed to ensure the engraftment of transplanted cells. We produced a three-dimensional hydrogel scaffold (CPC-PRGmx) in which high-viability CPCs were cultured for up to 8 weeks. CPC-PRGmx contained an RGD peptide-conjugated self-assembling peptide with insulin-like growth factor-1 (IGF-1). Immediately after creating myocardial infarction (MI), we transplanted CPC-PRGmx into the pericardial space on to the surface of the MI area. Four weeks after transplantation, red fluorescent protein-expressing CPCs and in situ hybridization analysis in sex-mismatched transplantations revealed the engraftment of CPCs in the transplanted scaffold (which was cellularized with host cells). The average scar area of the CPC-PRGmx-treated group was significantly smaller than that of the non-treated group (CPC-PRGmx-treated group = 46 ± 5.1%, non-treated MI group = 59 ± 4.5%; p < 0.05). Echocardiography showed that the transplantation of CPC-PRGmx improved cardiac function and attenuated cardiac remodeling after MI. The transplantation of CPCs-PRGmx promoted angiogenesis and inhibited apoptosis, compared to the untreated MI group. CPCs-PRGmx secreted more vascular endothelial growth factor than CPCs cultured on two-dimensional dishes. Genetic fate mapping revealed that CPC-PRGmx-treated mice had more regenerated cardiomyocytes than non-treated mice in the MI area (CPC-PRGmx-treated group = 0.98 ± 0.25%, non-treated MI group = 0.25 ± 0.04%; p < 0.05). Our findings reveal the therapeutic potential of epicardial-transplanted CPC-PRGmx. Its beneficial effects may be mediated by sustainable cell viability, paracrine function, and the enhancement of de novo cardiomyogenesis.

PROTECTIVE EFFECTS OF IVABRADINE (ALONE AND COMBINED WITH ATENOLOL OR ENALAPRIL) ON EXPERIMENTALLY-INDUCED ACUTE MYOCARDIAL INFARCTION IN ALBINO RATS

Background: Cardiovascular disease (CVD) is the leading cause of death worldwide. Deaths are mostly attributable to coronary artery disease (CAD). Ivabradine, a pure heart rate lowering agent, acts by inhibiting the pacemaker If current in the sinoatrial node. It can be used for treatment of heart failure and stable angina with the main drugs for CVD. Objectives: To determine the cardioprotective effects of ivabradine pretreatment alone and in combination with each of atenolol and enalapril on acute myocardial infarction (MI) in rats. Materials & Methods: Eighty four rats were divided into seven groups (12 rats each): Group 1: sham-operated group; Group 2: control (untreated) MI group; Group 3: ivabradine-pretreated group; Group 4: atenolol-pretreated group; Group 5: enalapril-pretreated group; Group 6: ivabradine and atenolol-pretreated group; and Group 7: ivabradine and enalapril-pretreated group. Rats received drugs orally by gavage daily for 6 days. On the sixth day, acute MI was induced by persistent complete left coronary artery ligation. The parameters studied were mean arterial blood pressure, ECG changes (heart rate, ST height and T-wave voltage), serum levels of creatine kinase MB isoenzyme (CK-MB), cardiac troponin-I (cTnI), high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-brain-type natriuretic peptide (NT-proBNP), tissue levels of superoxide dismutase (SOD), reduced glutathione (GSH), Bcl-2-associated X protein (Bax) and the % of infarct size of the left ventricle. Results: Coronary artery ligation resulted in significant elevation in ST height, T-wave voltage, serum levels of CK-MB, cTnI, hs-CRP and NT-proBNP and tissue levels of Bax, with significant reduction of the tissue levels of SOD & GSH and produced 54% infarct size of the left ventricle. Oral pretreatment with ivabradine has cardioprotective effect against acute MI as evidenced by significantly lower ST height, T-wave voltage, serum levels of CK-MB, cTnI, hs-CRP and NT-proBNP and tissue levels of Bax, with significantly higher tissue levels of SOD & GSH and significantly lower infarct size (into 39%). Oral pretreatment with combination of ivabradine and atenolol produced greater cardioprotection against acute MI than observed with ivabradine alone evidenced by significantly lower ST height, T-wave voltage, serum levels of CK-MB, cTnI, hs-CRP and NT-proBNP and tissue level of Bax, with significantly higher tissue levels of SOD & GSH and significantly lower infarct size (into 23%). Although, the effects of oral pretreatment with combination of ivabradine and enalapril on ST height, T-wave voltage, tissue levels of SOD & GSH and % of infarct size were not significantly different from that of ivabradine; however, this combination caused significant reduction of serum levels of CK-MB, cTnI, hs-CRP and NT-proBNP and tissue level of Bax as compared to the effect of ivabradine alone. Conclusion: Ivabradine possesses protective effects against acute MI and these effects are lower than the protective effects of atenolol; but higher than that of enalapril. Concomitant administration of ivabradine with either atenolol or enalapril provides greater cardioprotection against acute MI than ivabradine alone and these effects are greatest when ivabradine is combined with atenolol. Keywords: cardiovascular disease, acute coronary syndrome, myocardial infarction, If current, ivabradine, atenolol, enalapril

Allogeneic Transplantation of Fetal Membrane–Derived Mesenchymal Stem Cell Sheets Increases Neovascularization and Improves Cardiac Function after Myocardial Infarction in Rats

Mesenchymal stem cell (MSC) transplantation has been pursued as a new method to repair damaged myocardium. We focused on the fetal membrane (FM) as an alternative source to bone marrow (BM)-derived MSCs. In this study, we investigated whether transplantation of allogeneic FM-MSC sheets could attenuate myocardial dysfunction in a rat chronic myocardial infarction (MI) model. Sheets of allogeneic FM-MSC or autologous BM-MSC were transplanted into the scarred myocardium 4 weeks after coronary ligation. Four weeks after transplantation, both allogeneic FM-MSC and autologous BM-MSC sheets had significantly improved cardiac function and reduced myocardial fibrosis compared with the untreated MI group. In both MSC sheet-transplanted groups, the peri-infarct regional capillary density was increased. Some engrafted MSCs formed vascular structures and were positive for lectin I and α-smooth muscle actin. The numbers of engrafted cells and differentiated cells were very low after both types of MSC sheet transplantation. CD3 T cells did not increase in the transplantation site, but CD163 M2 macrophages increased in the groups transplanted with allogeneic FM-MSC and autologous BM-MSC. Transplantation of allogeneic FM-MSC or autologous BM-MSC sheets attenuated myocardial dysfunction in a rat MI model to a similar degree. The engraftment rate of transplanted cells and immune cell infiltration into the transplanted area did not differ between the two types of MSC transplants. M2 macrophage induction has possible involvement in the therapeutic effects of MSC transplantation. Allogeneic FM-MSC sheet transplantation might be a new therapeutic strategy after MI.

Additive Amelioration of Oxidative Stress and Cardiac Function by Combined Mineralocorticoid and Angiotensin Receptor Blockers in Postinfarct Failing Hearts

Reactive oxygen species are exacerbating factors in failing hearts. We examined whether spironolactone, a mineralocorticoid receptor antagonist, provides additional effects to olmesartan, an angiotensin II receptor blocker, on oxidative stress in postinfarct failing hearts. Congestive heart failure due to myocardial infarction (MI) was induced by the coronary artery ligation in rats. Three weeks later, the rats were divided into 4 groups: an untreated MI group, spironolactone (100 mg·kg·d)-treated MI group, olmesartan (10 mg·kg·d)-treated MI group, and combination-treated (spironolactone and olmesartan) MI group. After 7 weeks of MI, monotherapy improved left ventricular dilatation and function, and suppressed myocardial lipid peroxidation, in association with an attenuation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent and mitochondrial superoxide production. Moreover, combination therapy caused a synergistic improvement in these indices. In experiments using cultured myocytes, aldosterone (100 nmole/L) and angiotensin II (100 nmole/L) enhanced both sources of superoxide production, although these humoral factors affected NADPH oxidase subunits (p47phox and gp91phox) differently. In conclusion, aldosterone and angiotensin II increase NADPH oxidase-dependent and mitochondrial superoxide production in myocytes, and the combination of an angiotensin II receptor blocker and mineralocorticoid receptor antagonist has a synergistic attenuation of cardiac oxidative stress, leading to an improvement in cardiac function in postinfarct failing hearts.

Abstract 17977: Mir-133 Transfection in Mscs Downregulates Critical Pro-Apoptotic Genes in the Infarct Heart and Improves Cardiac Function

Cell-based therapy (cardiomyoplasty) is one of the most promising techniques for repair and regeneration of the infarcted myocardium. Mesenchymal stem cells (MSCs) are pluripotent, adult stem cells that are easily expanded in culture, and can differentiate into numerous lineages, including vascular endothelial cells and cardiomyocytes. Unfortunately, a major impediment to the improvement of cardiac function following stem cell transplantation has been survival of the cells in the infarct myocardium due to the severely hypoxic nature of this tissue. The lack of oxygen and nutrients ultimately leads to apoptosis of the majority of the transplanted stem cells, thereby limiting engraftment and the chance of favorable outcome. microRNAs (miRNAs) are major post-transcriptional regulatory molecules that mainly suppress protein translation through binding their 3’UTR. microRNA-133a (miR-133a) is highly downregulated in hypertrophy and congestive heart failure in patients and in our animal model of myocardial infarction (MI). We found that transfecting MSCs with miR-133a decreases hypoxia-reoxygenation (6h of hypoxia, 12h reoxygenation) induced cell death and improves survival of MSCs. Similarly, transplantation of miR-133a transfected MSCs in rat (Fisher-344) hearts subjected to myocardial infarction (MI) by temporarily ligating the left coronary artery (LAD) and release, there was a significant improvement in cardiac function and decreased fibrosis when compared with MSC or MI groups. In addition, we performed a 96-well PCR array for apoptosis-related genes. The results from PCR array showed a 3-fold downregulation of ABL1 (c-abl oncogene 1, non-receptor tyrosine kinase) and BFAR (Bifunctional apoptosis regulator genes) in miR-133+MSCs as compared with the untreated MI group. This study demonstrated for the first time that the combination of miR-133a mimics along with MSCs improves cardiac function, decreases fibrosis and pro-apoptotic ABL1 and BFAR genes in the infarcted heart.

Cardioprotective effect of dexrazoxane in a rat model of myocardial infarction: Anti-apoptosis and promoting angiogenesis

ObjectivesDexrazoxane (DZR) is a clinically approved agent for preventive treatment of doxorubicin-induced cardiotoxicity. The objective of this study was to investigate the cardioprotective effects of DZR in a rat model of myocardial infarction (MI). MethodsSprague–Dawley rats were randomly divided into four groups: MI (n=16), MI+DZR (n=16), SHAM-operated (n=14) and DZR-only (n=9). MI animals were subjected to left anterior descending coronary artery ligation. DZR was administered as a single dose at 125mg/kg intraperitoneally. Four weeks after treatment, cardiac function by echocardiography, infarct size, capillary density in the infarct border zone, bone marrow-derived endothelial progenitor cells (EPCs), and cardiac expression of Bax were measured. ResultsOur results demonstrated that MI animals had compromised heart parameters. DZR treatment in MI animals resulted in reduction in infarct size (P=0.013) and improved cardiac functions in terms of fractional shortening (P=0.004) and ejection fraction (P=0.004). The capillary density (P=0.008) and bone marrow-derived EPCs (P<0.05) were higher in the MI+DZR group than those in the untreated MI group. Bax expression was down-regulated in heart tissues of MI+DZR animals (P=0.043). ConclusionsOur study demonstrated that DZR exerted a cardioprotective effect in the rat model of MI, and the mechanism might be associated with anti-apoptosis and increased neovascularization.

Distinctive Effects of Carvedilol in the Non-Infarct Zone: Remodelling of the Ligated Rat Heart Linked to Oxidative Stress

In this study, an experimental rat ligated heart model was used to observe the effect of treatment with carvedilol, metoprolol and metoprolol plus a highly selective alpha(1)-adrenergic blocking agent, bunazosin, after acute myocardial infarction (MI). Compared with an untreated MI group, all drug-treated groups demonstrated attenuation of inflammatory mediators, activation of nuclear factor-kappaB (NF-kappaB), and increased levels of mRNA and active protein for the collagenases matrix metallopeptidase (MMP)-8 and MMP-13 in the non-infarct zone of the ventricle, as well as inhibition of the increase of left ventricular end-diastolic pressure. Supplementation of metoprolol with bunazosin did not add greatly to the effects of metoprolol alone. Of the three drug treatments, carvedilol showed a uniquely potent antioxidant activity that may strengthen its capacity to inhibit oxidative stress, the release of inflammatory mediators and activation of NF-kappaB. This study may help provide a mechanistic explanation for the greater benefits shown by carvedilol compared with metoprolol in treating heart failure.

Myocardial oxygenation and functional recovery in infarct rat hearts transplanted with mesenchymal stem cells

Stem cell therapy for myocardial tissue repair is limited by the poor survival of transplanted cells, possibly because of inadequate supply of oxygen and nutrients. The purpose of this study was to assess the oxygenation level and functional recovery after allogenic transplantation of mesenchymal stem cells (MSC) in a rat model of myocardial infarction (MI). Myocardial oxygen tension (Po(2)) was measured by electron paramagnetic resonance oximetry using an implantable oxygen-sensing spin probe (OxySpin). MSCs incubated with OxySpins showed substantial uptake of the probe without affecting its oxygen sensitivity or calibration. The cells internalized with OxySpins were able to differentiate into osteogenic, adipogenic, cardiomyocyte, and endothelial cell lineages. The labeled cells tested positive for CD44 and CD29 markers and negative for the hematopoietic markers CD14 and CD45. For the in vivo studies, MI was induced in rats by permanently ligating the left anterior descending coronary artery. MSCs with OxySpins were transplanted in the infarct region of hearts. A significant increase in Po(2) was observed in the MSC group compared with the untreated MI group (18.1 +/- 2.6 vs. 13.0 +/- 1.8 mmHg, n = 4, P < 0.05) at 4 wk after transplantation. Echocardiography showed a significant improvement in ejection fraction and fraction shortening, which inversely correlated with the magnitude of fibrosis in the treated hearts. The cell-transplanted hearts also showed an increase in vascular endothelial growth factor level and capillary density in the infarct region. The study established our ability to measure and correlate changes in myocardial tissue oxygenation with cardiac function in infarcted rat hearts treated with MSCs.

Spironolactone Modulates Expressions of Cardiac Mineralocorticoid Receptor and 11.BETA.-Hydroxysteroid Dehydrogenase 2 and Prevents Ventricular Remodeling in Post-Infarct Rat Hearts

Aldosterone antagonists have been reported to prevent ventricular remodeling after myocardial infarction (MI) via their action to extracellular matrix (ECM). However, it remains largely unknown whether aldosterone antagonists attenuate myocyte loss in the remodeling process. The present study examined whether spironolactone prevents myocyte apoptosis and improves post-infarct ventricular remodeling in rats. MI was achieved by permanent occlusion of the left coronary artery. Administration of spironolactone (100 mg/kg/day) was started immediately after MI. Sprague-Dawley rats were divided into four groups: 1) sham, 2) spironolactone-treated sham, 3) untreated MI, 4) spironolactone-treated MI. Echocardiographic parameters (left ventricular [LV] diastolic dimension [LVDd], fractional shortening [%FS]), hemodynamic parameters (LV systolic pressure [LVSP], LV end-diastolic pressure [LVEDP], dP/dt(max) and dP/dt(min)) and collagen accumulation quantitated by Masson's Trichrome staining were significantly improved in the spironolactone-treated MI group on the 14th day, compared with the untreated MI group. Moreover, the percentage of apoptotic myocytes evaluated by terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assay was significantly lower in the spironolactone-treated MI group on the 2nd (3.54% vs. 5.79% in untreated MI group), 7th (0.65% vs. 1.37% in untreated MI group) and 14th days (0.11% vs. 0.16% in untreated MI group). Real time reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that the expression of mineralocorticoid receptor (MR) mRNA and that of 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) mRNA, which is known to confer aldosterone selectivity on MR, were upregulated in the untreated MI group, and that spironolactone significantly suppressed the expression of these genes. Moreover, spironolactone significantly inhibited aldosterone-induced apoptosis in cultured rat cardiac myocytes in a dose-dependent fashion. Our study demonstrates that, in addition to their effect on ECM, aldosterone antagonists inhibit myocyte apoptosis and prevent post-infarct ventricular remodeling by modulating the expression levels of MR and 11beta-HSD2, which are enhanced in the remodeling heart.

The Long-Acting Ca2+-Channel Blocker Azelnidipine Prevents Left Ventricular Remodeling After Myocardial Infarction

Long-acting Ca2+-channel blockers have been reported to be effective in treating ischemic heart disease. However, their effects on cardiac remodeling after myocardial infarction (MI) are still unclear. We performed this study to examine the effect of azelnidipine on left ventricular (LV) remodeling, including systolic and diastolic dysfunction, in rats with MI. MI was induced by ligation of the left anterior descending artery. The rats were then separated into 3 groups: a sham-operated group (n = 9), untreated MI group (n = 10), and azelnidipine-treated MI group (n = 10). Four weeks after MI, hemodynamic measurements and Doppler echocardiographic assessment were performed. LV weight and LV end-diastolic dimension were significantly higher in the untreated MI group than in the sham-operated group. Azelnidipine significantly prevented the increases in these parameters. Azelnidipine also improved the ejection fraction (42 ± 3%, P<0.05) and the E wave to A wave ratio (3.2 ± 0.5, P<0.05), compared with the untreated MI group (31 ± 3% and 5.3 ± 0.8, respectively). In conclusion, azelnidipine can prevent LV remodeling and improve systolic and diastolic function after MI. Administration of long-acting Ca2+-channel blockers after MI is an effective strategy for treating MI.

Effects of early angiotensin-converting enzyme inhibition on cardiac gene expression after acute myocardial infarction.

ACE inhibition after myocardial infarction (MI) has been shown to have beneficial effects on cardiac anatomy and function. The purpose of this study was to examine the effects of ACE inhibition on cardiac gene expression after MI. Rats were randomized to receive captopril or no treatment 1 day after MI. Eight weeks later, cardiac function and hemodynamics were measured by use of indwelling catheters and perivascular flow probes. Myocardial gene expression was assessed with DNA microarrays and real-time reverse transcription-polymerase chain reaction. The ratios of heart and left ventricular weights to body weight were significantly increased by MI and normalized by captopril. Cardiac index and stroke volume index were lower in the untreated MI group than in sham controls but were normal in the MI+captopril group. Thirty-seven genes were found to be differentially expressed between the untreated MI group and sham controls; 31 were induced and 6 repressed. Captopril partially or completely inhibited changes in 10 of the genes. The 37 genes clustered into 11 functional groups, and 6 had >/=1 genes whose expression was modified by ACE inhibition. ACE inhibition after MI inhibits cardiac hypertrophy, preserves cardiac function, and attenuates changes in myocardial gene expression. Gene expression profiling reveals, however, that some elements of the pathophysiology may be unaffected by the treatment and be targets for new therapies.