Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts.

Metastasis-associated protein, S100A4 is suggested as a marker for fibrosis in several organs. It also modulates DNA binding of p53 and affects its function. However, the functional role of S100A4 in the myocardium has remained unclear. Therefore, we investigated the role of S100A4 and its relationship with p53 in cardiac fibrosis. In Dahl-rat hypertensive heart disease model, S100A4 was upregulated in the hypertrophic myocardium and further activated during transition to heart failure (HF). It was expressed in various cells including fibroblasts. In in vitro cardiac fibroblasts, the knockdown of S100A4 significantly suppressed both cell proliferation and collagen expressions. S100A4 co-localized and interacted with p53 in the nucleus. S100A4 knockdown increased the expression of p53-downstream genes, p21 and mdm2, and concomitant knockdown of p53 recovered cell proliferation and collagen expression. Transverse aortic constriction (TAC) was performed in S100A4 knockout (KO) mice, which showed a similar baseline-phenotype to wild type (WT) mice. Although there was no difference in hypertrophic response, KO mice showed reduced interstitial fibrosis, decreased myofibroblasts, and suppressed expressions of collagens and profibrotic cytokines in the left ventricle. Also, DNA microarray analysis showed that S100A4 knockout in vivo had a significant impact on expressions of p53-associated genes. These findings suggest that S100A4 modulates p53 function in fibroblasts and thereby mediates myocardial interstitial fibrosis through two distinct mechanisms; cell proliferation and collagen expression. Blockade of S100A4 may have therapeutic potential in cardiac hypertrophy and HF by attenuating cardiac fibrosis.

Percutaneous balloon valvuloplasty for bioprosthetic mitral valve stenosis.

Percutaneous transcatheter mitral valvuloplasty is the indicated treatment of choice for symptomatic native mitral valve stenosis, but there have been limited reports of successful procedures of balloon valvuloplasty for bioprosthetic mitral valve stenosis. We present the case of a 62-year-old woman suffering from progressive dyspnea due to bioprosthetic mitral valve stenosis. The measured mean pressure gradient across the mitral valve was 30 mmHg and the mitral valve area was 0.73 cm(2). Redoing mitral replacement was considered high risk and was refused by the patient. Percutaneous balloon valvuloplasty was performed with an Inoue balloon catheter inflated to 20 mm. The patient's symptoms immediately improved after the procedure, with no procedure-related complications. The mean pressure gradient across the valve decreased to 19 mmHg, and the mitral valve area increased to 1.21 cm(2) in postprocedural echocardiography. We conducted a literature search and identified 26 cases of balloon valvuloplasty for degenerated bioprosthetic valves. Of these, 14 cases were bioprosthetic mitral valves, and the results were favorable. However, more case reports are required to establish an evidence base for future expert recommendation of balloon valvuloplasty of prosthetic mitral valve. Meanwhile, balloon valvuloplasty will serve a niche role in highly selected patients with prosthetic mitral valve stenosis.

A conserved role for phosphatidylinositol 3-kinase but not Akt signaling in mitochondrial adaptations that accompany physiological cardiac hypertrophy.

Physiological cardiac hypertrophy is associated with mitochondrial adaptations that are characterized by activation of PGC-1alpha and increased fatty acid oxidative (FAO) capacity. It is widely accepted that phosphatidylinositol 3-kinase (PI3K) signaling to Akt1 is required for physiological cardiac growth. However, the signaling pathways that coordinate physiological hypertrophy and metabolic remodeling are incompletely understood. We show here that activation of PI3K is sufficient to increase myocardial FAO capacity and that inhibition of PI3K signaling prevents mitochondrial adaptations in response to physiological hypertrophic stimuli despite increased expression of PGC-1alpha. We also show that activation of the downstream kinase Akt is not required for the mitochondrial adaptations that are secondary to PI3K activation. Thus, in physiological cardiac growth, PI3K is an integrator of cellular growth and metabolic remodeling. Although PI3K signaling to Akt1 is required for cellular growth, Akt-independent pathways mediate the accompanying mitochondrial adaptations.

Effects of machine-assisted cycling on exercise capacity and endothelial function in elderly patients with heart failure.

BACKGROUND: Conventional exercise training (ET) for elderly patients with heart failure (HF) includes low-intensity stretching and gait training. The effects of 2 types of low-intensity ET - machine-assisted cycling and conventional ET - on exercise capacity and endothelial function of elderly patients with HF was investigated in the present study. METHODS AND RESULTS: Twenty-seven elderly patients with HF (mean age: 79.5 years) were randomly assigned to either a machine-assisted cycling group or a conventional ET group. At baseline and after 2 weeks of ET, all patients were tested for 6-minute walk distance (6MWD) and digital reactive hyperemia-peripheral arterial tonometry (RH-PAT). After 2 weeks of ET, a significant increase in 6MWD was observed in both groups with no significant difference between the groups. RH-PAT index significantly increased in patients aged ≤80 (1.55±0.33 to 1.93±0.62, P=0.035) and a trend toward increase in RH-PAT index in the machine-assisted cycling group was observed (1.59±0.52 to 1.93±0.63, P=0.053), although no change was observed in the conventional ET group. In the multivariate model, patients' age and machine-assisted cycling were associated with the increases in RH-PAT index (P<0.05). CONCLUSIONS: Machine-assisted cycling appeared to be as effective as conventional ET on exercise capacity in elderly patients with HF. Additionally, machine-assisted cycling has the potential to improve endothelial function in these patients.

Constitutive SIRT1 overexpression impairs mitochondria and reduces cardiac function in mice.

Heart failure is associated with a change in cardiac energy metabolism. SIRT1 is a NAD(+)-dependent protein deacetylase, and important in the regulation of cellular energy metabolism. To examine the role of SIRT1 in cardiac energy metabolism, we created transgenic mice overexpressing SIRT1 in a cardiac-specific manner, and investigated cardiac functional reserve, energy reserve, substrate uptake, and markers of mitochondrial function. High overexpression of SIRT1 caused dilated cardiomyopathy. Moderate overexpression of SIRT1 impaired cardiac diastolic function, but did not cause heart failure. Fatty acid uptake was decreased and the number of degenerated mitochondria was increased dependent on SIRT1 gene dosage. Markers of reactive oxygen species were decreased. Changes in morphology and reactive oxygen species were associated with the reduced expression of genes related to mitochondrial function and autophagy. In addition, the respiration of isolated mitochondria was decreased. Cardiac function was normal in transgenic mice expressing a low level of SIRT1 at baseline, but the mice developed cardiac dysfunction upon pressure overload. In summary, the constitutive overexpression of SIRT1 reduced cardiac function associated with impaired mitochondria in mice.

PI3K(p110 alpha) protects against myocardial infarction-induced heart failure: identification of PI3K-regulated miRNA and mRNA.

OBJECTIVE: Myocardial infarction (MI) is a serious complication of atherosclerosis associated with increasing mortality attributable to heart failure. Activation of phosphoinositide 3-kinase [PI3K(p110 alpha)] is considered a new strategy for the treatment of heart failure. However, whether PI3K(p110 alpha) provides protection in a setting of MI is unknown, and PI3K(p110 alpha) is difficult to target because it has multiple actions in numerous cell types. The goal of this study was to assess whether PI3K(p110 alpha) is beneficial in a setting of MI and, if so, to identify cardiac-selective microRNA and mRNA that mediate the protective properties of PI3K(p110 alpha). METHODS AND RESULTS: Cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110 alpha) activity (caPI3K-Tg and dnPI3K-Tg, respectively) were subjected to MI for 8 weeks. The caPI3K-Tg subjected to MI had better cardiac function than nontransgenic mice, whereas dnPI3K-Tg had worse function. Using microarray analysis, we identified PI3K-regulated miRNA and mRNA that were correlated with cardiac function, including growth factor receptor-bound 14. Growth factor receptor-bound 14 is highly expressed in the heart and positively correlated with PI3K(p110 alpha) activity and cardiac function. Mice deficient in growth factor receptor-bound 14 have cardiac dysfunction. CONCLUSIONS: Activation of PI3K(p110 alpha) protects the heart against MI-induced heart failure. Cardiac-selective targets that mediate the protective effects of PI3K(p110 alpha) represent new drug targets for heart failure.

Inter- and intra-observer variability for assessment of the synergy between percutaneous coronary intervention with TAXUS and cardiac surgery (SYNTAX) score and association of the SYNTAX score with clinical outcome in patients undergoing unprotected left main stenting in the real world.

BACKGROUND: The Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) score was proposed as a method to evaluate the complexity of coronary anatomy. However, the reproducibility of assessment for the SYNTAX score in unprotected left main coronary artery (ULMCA) disease has not yet been adequately evaluated. The purpose of this study is to assess inter- and intra-observer variability for the assessment of the SYNTAX score in patients undergoing ULMCA stenting in daily clinical practice. METHODS AND RESULTS: The SYNTAX score of 101 consecutive patients who underwent ULMCA stenting with sirolimus-eluting stent was independently assessed by 2 experienced interventional cardiologists. One of the 2 cardiologists evaluated all the cases again 6 months after the initial assessment. The κ value for inter-observer variability in estimating the SYNTAX score was 0.62 according to the dichotomized analysis (≥ 33, < 33) and 0.58 according to the tertile analysis (< 23, 23 ≤ - < 33, ≥ 33), while the intra-observer variability was 0.78 and 0.69, respectively. Patients with a high SYNTAX score (≥ 33, n = 55) compared with those with low or intermediate score (< 33, n = 46) had a significantly higher rate of target-lesion revascularization (TLR) of the ULMCA lesion at 2 years (24% vs. 4.4%, P = 0.01). CONCLUSIONS: Both inter- and intra-observer variability for estimating the SYNTAX score were within an acceptable range and a high SYNTAX score showed a higher rate of TLR in patients undergoing ULMCA stenting in daily clinical practice.

Impact of diabetes on cardiovascular outcomes in hemodialysis patients undergoing coronary revascularization.

BACKGROUND: Among hemodialysis (HD) patients, those who have diabetes have poorer cardiovascular outcomes than non-diabetic patients, but the impact of diabetes on cardiovascular outcomes has not been fully elucidated in HD patients undergoing coronary revascularization. METHODS AND RESULTS: We identified 375 HD patients (203 diabetes, 172 non-diabetes) and 9,006 patients without HD (3,455 diabetes, 5,551 non-diabetes) in the database of the CREDO-Kyoto registry of patients undergoing their first coronary revascularization. In non-HD patients, significantly higher risks of death (10.8% vs. 7.7%, P < 0.0001; adjusted hazard ratio (HR) 1.29, P < 0.0001) and major adverse cardiovascular events (MACE), a composite of death, myocardial infarction and stroke (18.8% vs. 13.3%, P < 0.0001; HR 1.36, P < 0.0001) were seen in diabetic patients than in non-diabetic patients through 4-year follow-up. Analysis in HD patients showed that the duration of HD before first coronary revascularization was significantly shorter in diabetic patients than in non-diabetic patients (median interval: 858 vs. 2,216 days, P < 0.0001). In contrast to the results in non-HD patients, the risks of death (41.9% vs. 39.1%, P=0.75; HR 0.98, P=0.93) and MACE (45.6% vs. 45.8%, P=0.83; HR 0.87, P=0.50) after first revascularization were comparable between diabetic and non-diabetic HD patients. There were significant interactions between HD and diabetes for death and for MACE. CONCLUSIONS: HD patients who require coronary revascularization have extremely poor outcomes irrespective of concomitant diabetes.

Suppression of phosphoinositide 3-kinase prevents cardiac aging in mice.

BACKGROUND: Heart failure is a typical age-associated disease. Although age-related changes of heart are likely to predispose aged people to heart failure, little is known about the molecular mechanism of cardiac aging. METHODS AND RESULTS: We analyzed age-associated changes in murine heart and the manner in which suppression of the p110alpha isoform of phosphoinositide 3-kinase activity modified cardiac aging. Cardiac function declined in old mice associated with the expression of senescence markers. Accumulation of ubiquitinated protein and lipofuscin, as well as comprehensive gene expression profiling, indicated that dysregulation of protein quality control was a characteristic of cardiac aging. Inhibition of phosphoinositide 3-kinase preserved cardiac function and attenuated expression of the senescence markers associated with enhanced autophagy. Suppression of target of rapamycin, a downstream effector of phosphoinositide 3-kinase, also prevented lipofuscin accumulation in the heart. CONCLUSIONS: Suppression of phosphoinositide 3-kinase prevented many age-associated changes in the heart and preserved cardiac function of aged mice.

Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia presenting at cardiology departments. A limited understanding of the molecular mechanisms responsible for the development of AF has hindered treatment strategies. The purpose of this study was to assess whether reduced activation of phosphoinositide 3-kinase (PI3K, p110alpha) makes the compromised heart susceptible to AF. Risk factors for AF, including aging, obesity, and diabetes, have been associated with insulin resistance that leads to depressed/defective PI3K signaling. However, to date, there has been no link between PI3K(p110alpha) and AF. To address this question, we crossed a cardiac-specific transgenic mouse model of dilated cardiomyopathy (DCM) with a cardiac-specific transgenic mouse expressing a dominant negative mutant of PI3K (dnPI3K; reduces PI3K activity). Adult ( approximately 4.5 months) double-transgenic (dnPI3K-DCM), single-transgenic (DCM-Tg, dnPI3K-Tg), and nontransgenic mice were subjected to morphological, functional/ECG, microarray, and biochemical analyses. dnPI3K-DCM mice developed AF and had depressed cardiac function as well as greater atrial enlargement and fibrosis than DCM-Tg mice. AF was not detected in other groups. Aged DCM-Tg mice ( approximately 15 months) with a similar phenotype to dnPI3K-DCM mice (4.5 months) did not develop AF, suggesting loss of PI3K activity directly contributed to the AF phenotype. Furthermore, increasing PI3K activity reduced atrial fibrosis and improved cardiac conduction in DCM-Tg mice. Finally, in atrial appendages from patients with AF, PI3K activation was lower compared with tissue from patients in sinus rhythm. These results suggest a link between PI3K(p110alpha) and AF.

Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism.

AIMS: The ability of lipopolysaccharide (LPS) pre-treatment to induce cardioprotection following ischaemia/reperfusion (I/R) has been well documented; however, the mechanisms have not been fully elucidated. LPS is a Toll-like receptor 4 (TLR4) ligand. Recent evidence indicates that there is cross-talk between the TLR and phosphoinositide 3-kinase/Akt (PI3K/Akt) signalling pathways. We hypothesized that activation of PI3K/Akt signalling plays a critical role in LPS-induced cardioprotection. METHODS AND RESULTS: To evaluate this hypothesis, we pre-treated mice with LPS 24 h before the hearts were subjected to ischaemia (45 min) and reperfusion (4 h). We examined activation of the PI3K/Akt/GSK-3beta signalling pathway. The effect of PI3K/Akt inhibition on LPS-induced cardioprotection was also evaluated. LPS pre-treatment significantly reduced infarct size (71.25%) compared with the untreated group (9.3+/-1.58 vs. 32.3+/-2.92%, P<0.01). Cardiac myocyte apoptosis and caspase-3 activity in LPS-pre-treated mice were significantly reduced following I/R. LPS pre-treatment significantly increased the levels of phospho-Akt, phospho-GSK-3beta, and heat shock protein 27 in the myocardium. Pharmacological inhibition of PI3K by LY294002 or genetic modulation employing kinase-defective Akt transgenic mice abolished the cardioprotection induced by LPS. CONCLUSION: These results indicate that LPS-induced cardioprotection in I/R injury is mediated through a PI3K/Akt-dependent mechanism.

Cardiac effects of acute administration of a protonophore in a rat model.

OBJECTIVES: Excessive use of uncoupling agents, previously used as weight loss agents, has led to the increase in body temperature and death. The aim of the present study was to evaluate the acute cardiac effects of mitochondrial protonophore in a rat model at a high dose, and its specific influence on cardiac substrate uptake. METHODS: Eight-week-old male Sprague-Dawley rats were intraperitoneally injected with the protonophore carbonyl cyanide m-chloro phenyl hydrazone (CCCP; 4 mg/kg) or vehicle (dimethyl sulfoxide). Blood pressure, heart rate (HR) and systolic function were recorded. Substrate uptake was monitored by radioactive tracers. KEY FINDINGS: Compared to the control group, the respiratory rate and body temperature increased, the left ventricle was dilated, and systolic function transiently deteriorated in the CCCP group. There was no difference in blood pressure and HR between the two groups. In cardiac substrate uptake, glucose uptake showed a 95% increase (P < 0.05), and fatty acid uptake showed a 52% decrease (P < 0.05) in CCCP-administered group. CONCLUSIONS: The deleterious effects on cardiac function and the changes in substrate uptake were observed when administered with the protonophore at a high dose.

Akt/protein kinase B promotes organ growth in transgenic mice.

One of the least-understood areas in biology is the determination of the size of animals and their organs. In Drosophila, components of the insulin receptor phosphoinositide 3-kinase (PI3K) pathway determine body, organ, and cell size. Several biochemical studies have suggested that Akt/protein kinase B is one of the important downstream targets of PI3K. To examine the role of Akt in the regulation of organ size in mammals, we have generated and characterized transgenic mice expressing constitutively active Akt (caAkt) or kinase-deficient Akt (kdAkt) specifically in the heart. The heart weight of caAkt transgenic mice was increased 2.0-fold compared with that of nontransgenic mice. The increase in heart size was associated with a comparable increase in myocyte cell size in caAkt mice. The kdAkt mutant protein attenuated the constitutively active PI3K-induced overgrowth of the heart, and the caAkt mutant protein circumvented cardiac growth retardation induced by a kinase-deficient PI3K mutant protein. Rapamycin attenuated caAkt-induced overgrowth of the heart, suggesting that the mammalian target of rapamycin (mTOR) or effectors of mTOR mediated caAkt-induced heart growth. In conclusion, Akt is sufficient to induce a marked increase in heart size and is likely to be one of the effectors of the PI3K pathway in mediating heart growth.

Deletion of ribosomal S6 kinases does not attenuate pathological, physiological, or insulin-like growth factor 1 receptor-phosphoinositide 3-kinase-induced cardiac hypertrophy.

Ribosomal S6 kinases (S6Ks) have been depicted as critical effectors downstream of growth factor pathways, which play an important role in the regulation of protein synthesis by phosphorylating the ribosomal protein, S6. The goal of this study was to determine whether S6Ks regulate heart size, are critical for the induction of cardiac hypertrophy in response to a pathological or physiological stimulus, and whether S6Ks are critical downstream effectors of the insulin-like growth factor 1 (IGF1)-phosphoinositide 3-kinase (PI3K) pathway. For this purpose, we generated and characterized cardiac-specific S6K1 and S6K2 transgenic mice and subjected S6K1(-/-), S6K2(-/-), and S6K1(-/-) S6K2(-/-) mice to a pathological stress (aortic banding) or a physiological stress (exercise training). To determine the genetic relationship between S6Ks and the IGF1-PI3K pathway, S6K transgenic and knockout mice were crossed with cardiac-specific transgenic mice overexpressing the IGF1 receptor (IGF1R) or PI3K mutants. Here we show that overexpression of S6K1 induced a modest degree of hypertrophy, whereas overexpression of S6K2 resulted in no obvious cardiac phenotype. Unexpectedly, deletion of S6K1 and S6K2 had no impact on the development of pathological, physiological, or IGF1R-PI3K-induced cardiac hypertrophy. These studies suggest that S6Ks alone are not essential for the development of cardiac hypertrophy.

The metabolic profile of a rat model of chronic kidney disease.

BACKGROUND: The kidney is always subjected to high metabolic demand. The aim of this study was to characterize metabolic profiles of a rat model of chronic kidney disease (CKD) with cardiorenal syndrome (CRS) induced by prolonged hypertension. METHODS: We used inbred male Dahl salt-sensitive (DS) rats fed an 8% NaCl diet from six weeks of age (high-salt; HS group) or a 0.3% NaCl diet as controls (low-salt; LS group). We analyzed function, pathology, metabolome, and the gene expression related to energy metabolism of the kidney. RESULTS: DS rats with a high-salt diet showed hypertension at 11 weeks of age and elevated serum levels of creatinine and blood urea nitrogen with heart failure at 21 weeks of age. The fibrotic area in the kidneys increased at 21 weeks of age. In addition, gene expression related to mitochondrial function was largely decreased. The levels of citrate and isocitrate increased and the gene expression of alpha-ketoglutaratedehydrogenase and succinyl-CoA synthetase decreased; these are enzymes that metabolize citrate and isocitrate, respectively. In addition, the levels of succinate and acetyl Co-A, both of which are metabolites of the tricarboxylic acid (TCA) cycle, decreased. CONCLUSIONS: DS rats fed a high-salt diet were deemed a suitable model of CKD with CRS. Gene expression and metabolites related to energy metabolism and mitochondria in the kidney significantly changed in DS rats with hypertension in accordance with the progression of renal injury.

Kyoto Congestive Heart Failure (KCHF) study: rationale and design.

AIMS: Over the last decade, major developments in medicine have led to significant changes in the clinical management of heart failure patients. This study was designed to evaluate the recent trends in clinical characteristics, management, and short-term and long-term prognosis of patients with acute decompensated heart failure (ADHF) in Japan. METHODS AND RESULTS: The Kyoto Congestive Heart Failure study is a prospective, observational, multicentre cohort study, enrolling consecutive ADHF patients from 19 participating hospitals in Japan from November 2014 to March 2016. A total of 4000 patients will be enrolled into the study and patients' anthropometric, socio-economic, and clinical data from hospital admission to discharge will be collected. In addition, in a pre-determined subgroup of patients (n=1500), a longitudinal follow-up for 2 years is scheduled. CONCLUSIONS: The Kyoto Congestive Heart Failure study will provide valuable information regarding patients with ADHF in the real-world clinical practice of Japan and will be indispensable for future clinical and policy decision-making with respect to heart failure.

Rapamycin attenuates load-induced cardiac hypertrophy in mice.

BACKGROUND: Cardiac hypertrophy, or an increase in heart size, is an important risk factor for cardiac morbidity and mortality. The mammalian target of rapamycin (mTOR) is a component of the insulin-phosphoinositide 3-kinase pathway, which is known to play a critical role in the determination of cell, organ, and body size. METHODS AND RESULTS: To examine the role of mTOR in load-induced cardiac hypertrophy, we administered rapamycin, a specific inhibitor of mTOR, to mice with ascending aortic constriction. Activity of p70 ribosomal S6 kinase 1 (S6K1), an effector of mTOR, was increased by 3.8-fold in the aortic-constricted heart. Pretreatment of mice with 2 mg. kg-1. d-1 of rapamycin completely suppressed S6K1 activation and S6 phosphorylation in response to pressure overload. The heart weight/tibial length ratio of vehicle-treated aortic-banded mice was increased by 34.4+/-3.6% compared with vehicle-treated sham-operated mice. Rapamycin suppressed the load-induced increase in heart weight by 67%. Attenuation of cardiac hypertrophy by rapamycin was associated with attenuation of the increase in myocyte cell size induced by aortic constriction. Rapamycin did not cause loss of body weight, lethality, or left ventricular dysfunction. CONCLUSIONS: mTOR or its target(s) seems to play an important role in load-induced cardiac hypertrophy. Because systemic administration of rapamycin has been used successfully for the treatment of transplant rejection in clinical practice, it may be a useful therapeutic modality to suppress cardiac hypertrophy in patients.

Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload.

BACKGROUND: Rapamycin is a specific inhibitor of the mammalian target of rapamycin (mTOR). We recently reported that administration of rapamycin before exposure to ascending aortic constriction significantly attenuated the load-induced increase in heart weight by approximately 70%. METHODS AND RESULTS: To examine whether rapamycin can regress established cardiac hypertrophy, mice were subjected to pressure overload (ascending aortic constriction) for 1 week, echocardiography was performed to verify an increase in ventricular wall thickness, and mice were given rapamycin (2 mg x kg(-1) x d(-1)) for 1 week. After 1 week of pressure overload (before treatment), 2 distinct groups of animals became apparent: (1) mice with compensated cardiac hypertrophy (normal function) and (2) mice with decompensated hypertrophy (dilated with depressed function). Rapamycin regressed the pressure overload-induced increase in heart weight/body weight (HW/BW) ratio by 68% in mice with compensated hypertrophy and 41% in mice with decompensated hypertrophy. Rapamycin improved left ventricular end-systolic dimensions, fractional shortening, and ejection fraction in mice with decompensated cardiac hypertrophy. Rapamycin also altered the expression of some fetal genes, reversing, in part, changes in alpha-myosin heavy chain and sarcoplasmic reticulum Ca2+ ATPase. CONCLUSIONS: Rapamycin may be a therapeutic tool to regress established cardiac hypertrophy and improve cardiac function.