Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure.

BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

Hippo pathway deficiency reverses systolic heart failure after infarction.

Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs, such as the heart are particularly vulnerable to organ failure. Once established, heart failure commonly results in mortality. The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration, is upregulated in human heart failure. Here we show that deletion of the Hippo pathway component Salvador (Salv) in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared with controls. Using translating ribosomal affinity purification, we isolate cardiomyocyte-specific translating messenger RNA. Hippo-deficient cardiomyocytes have increased expression of proliferative genes and stress response genes, such as the mitochondrial quality control gene, Park2. Genetic studies indicate that Park2 is essential for heart repair, suggesting a requirement for mitochondrial quality control in regenerating myocardium. Gene therapy with a virus encoding Salv short hairpin RNA improves heart function when delivered at the time of infarct or after ischaemic heart failure following myocardial infarction was established. Our findings indicate that the failing heart has a previously unrecognized reparative capacity involving more than cardiomyocyte renewal.

Systolic heart failure induced by butylparaben in zebrafish is caused through oxidative stress and immunosuppression.

Due to Butylparaben (BuP) widespread application in cosmetics, food, pharmaceuticals, and its presence as an environmental residue, human and animal exposure to BuP is common, potentially posing hazards to both human and animal health. Congenital heart disease is already a serious problem. However, the effects of BuP on the developing heart and its underlying mechanisms remain unclear. Here, zebrafish embryos were exposed to environmentally and human-relevant concentrations of BuP (0.6 mg/L, 1.2 mg/L, and 1.8 mg/L, calculated but not measured) at 6 h post-fertilization (hpf) and were treated until 72 hpf. Exposure to BuP led to cardiac morphological defects and cardiac dysfunction in zebrafish embryos, manifesting symptoms similar to systolic heart failure. The etiology of BuP-induced systolic heart failure in zebrafish embryos is multifactorial, including cardiomyocyte apoptosis, endocardial and atrioventricular valve damage, insufficient myocardial energy, impaired Ca2+ homeostasis, depletion of cardiac-resident macrophages, cardiac immune non-responsiveness, and cardiac oxidative stress. However, excessive accumulation of reactive oxygen species (ROS) in the cardiac region and cardiac immunosuppression (depletion of cardiac-resident macrophages and cardiac immune non-responsiveness) may be the predominant factors. In conclusion, this study indicates that BuP is a potential hazardous substance that can cause adverse effects on the developing heart and provides evidence and insights into the pathological mechanisms by which BuP leads to cardiac dysfunction. It may help to prevent the BuP-based congenital heart disease heart failure in human through ameliorating strategies and BuP discharge policies, while raising awareness to prevent the misuse of preservatives.

Neutrophil degranulation biomarkers characterize restrictive echocardiographic pattern with diastolic dysfunction in patients with diabetes.

OBJECTIVE: To investigate the potential association between neutrophil degranulation and patterns of myocardial dysfunction in a cohort of patients with type 2 diabetes mellitus (T2DM). BACKGROUND: Two distinct phenotypes of diabetic cardiomyopathy have been described: a restrictive phenotype with diastolic dysfunction (restrictive/DD) and a dilative phenotype with systolic dysfunction (dilative/SD). However, the underlying determinants of these two patterns are not yet recognized. METHODS: In this single-centre, observational, cross-sectional study, 492 patients were recruited. Ultrasonographic measurements were performed by two experienced sonographers, blinded to the clinical data of the participants. Serum biomarkers of neutrophil degranulation were measured by enzyme-linked immunosorbent sandwich assay (ELISA). RESULTS: After adjustment for confounders, resistin, myeloperoxidase, matrix metalloproteinase 8 and matrix metalloproteinase 9/tissue inhibitor of metalloproteinases 1 complex were positively associated with the restrictive/DD pattern compared with the normal pattern. Similarly, MPO was positively associated with the dilative/SD pattern compared with the normal pattern, and resistin was negatively associated with the dilative/SD pattern compared with the restrictive/DD pattern. CONCLUSIONS: Neutrophil degranulation is associated with the restrictive/DD echocardiographic pattern in patients with T2DM, but not with the normal pattern and dilative/SD patterns. Neutrophils could have a pivotal role in the pathogenesis of myocardial dysfunction, and particularly diastolic dysfunction, in patients with T2DM.

Cardiac Myosin Activation for the Treatment of Systolic Heart Failure.

ABSTRACT: Left ventricular systolic dysfunction is the hallmark pathology in heart failure with reduced ejection fraction. Increasing left ventricular contractility with beta-adrenergic receptor agonists, phosphodiesterase-3 inhibitors, or levosimendan has failed to improve clinical outcomes and, in some situations, increased the risk of sudden cardiac death. Beta-adrenergic receptor agonists and phosphodiesterase-3 inhibitors retain an important role in advanced heart failure. Thus, there remains an unmet need for safe and effective therapies to improve left ventricular systolic function. Two novel cardiac myotropes, omecamtiv mecarbil and danicamtiv, target cardiac myosin to increase left ventricular systolic performance. Neither omecamtiv mecarbil nor danicamtiv affects cardiomyocyte calcium handling, the proposed mechanism underlying the life-threatening arrhythmias associated with cardiac calcitropes and calcium sensitizers. Phase 2 clinical trials have demonstrated that these cardiac myosin activators prolong left ventricular systolic ejection time and promote left ventricular and atrial reverse remodeling. At higher plasma concentrations, these agents may be associated with myocardial ischemia and impaired diastolic function. An ongoing phase 3 clinical trial will estimate the clinical efficacy and safety of omecamtiv mecarbil. An additional study of these agents, which have minimal hemodynamic and renal effects, is warranted in patients with advanced heart failure refractory to guideline-directed neurohormonal blockers.

Multi-Omics Approach Profiling Metabolic Remodeling in Early Systolic Dysfunction and in Overt Systolic Heart Failure.

Metabolic remodeling plays an important role in the pathophysiology of heart failure (HF). We sought to characterize metabolic remodeling and implicated signaling pathways in two rat models of early systolic dysfunction (MOD), and overt systolic HF (SHF). Tandem mass tag-labeled shotgun proteomics, phospho-(p)-proteomics, and non-targeted metabolomics analyses were performed in left ventricular myocardium tissue from Sham, MOD, and SHF using liquid chromatography-mass spectrometry, n = 3 biological samples per group. Mitochondrial proteins were predominantly down-regulated in MOD (125) and SHF (328) vs. Sham. Of these, 82% (103/125) and 66% (218/328) were involved in metabolism and respiration. Oxidative phosphorylation, mitochondrial fatty acid ß-oxidation, Krebs cycle, branched-chain amino acids, and amino acid (glutamine and tryptophan) degradation were highly enriched metabolic pathways that decreased in SHF > MOD. Glycogen and glucose degradation increased predominantly in MOD, whereas glycolysis and pyruvate metabolism decreased predominantly in SHF. PKA signaling at the endoplasmic reticulum-mt interface was attenuated in MOD, whereas overall PKA and AMPK cellular signaling were attenuated in SHF vs. Sham. In conclusion, metabolic remodeling plays an important role in myocardial remodeling. PKA and AMPK signaling crosstalk governs metabolic remodeling in progression to SHF.

Expression of sex steroid receptors and aromatase in adipose tissue in different body regions in men with coronary artery disease with and without ischemic systolic heart failure.

Background: The hormonal metabolism of adipose tissue differs across regions of fat. This issue has never been verified in male patients with coronary artery disease (CAD) with and without systolic heart failure (SHF).Methods: We examined 90 male patients with CAD with and without SHF and 42 healthy controls.Results: In patients with CAD with and without SHF, androgen receptor (AR) expression in adipose tissue of the lower leg was higher than AR expression of the thoracic wall and epicardial adipose tissue (EAT) (both p < .0001 for SHF patients and both p < .001 for patients without SHF). Expression of aromatase in adipose tissue of the lower leg among patients with CAD and SHF was higher than aromatase expression of the thoracic wall and EAT (p < .001 and p < .05, respectively), and in patients without SHF, it was higher only than aromatase expression of the thoracic wall (p < .05). There were no differences in expression of estrogen receptor (ER) between three regions of adipose tissue both in men with CAD with and without SHF.Conclusions: In male patients with CAD, site-related differences of adipose tissue in expression of AR and aromatase are present regardless of coexisting SHF with the highest hormonal activity within peripheral subcutaneous adipose tissue.

READY: relative efficacy of loop diuretics in patients with chronic systolic heart failure-a systematic review and network meta-analysis of randomised trials.

The majority of patients with chronic heart failure (HF) receive long-term treatment with loop diuretics. The comparative effectiveness of different loop diuretics is unknown. We searched PubMed, clinicaltrials.gov , the Cochrane Central Register of Controlled Trials and the European Union Clinical Trials Register for randomised clinical trials exploring the efficacy of the loop diuretics azosemide, bumetanide, furosemide or torasemide in patients with HF. Comparators included placebo, standard medical care or any other active treatment. The primary endpoint was all-cause mortality. Secondary endpoints included cardiovascular mortality, HF-related hospitalisation and any combined endpoint thereof. Hypokalaemia and acute renal failure were defined as additional safety endpoints. Evidence was synthesised using network meta-analysis (NMA). Thirty-four trials reporting on 2647 patients were included. The overall quality of evidence was rated as moderate. NMA demonstrated no significant differences between loop diuretics with respect to all-cause mortality, cardiovascular mortality or hypokalaemia. In contrast, torasemide ranked best in terms of HF hospitalisation, and there was a trend towards benefits with torasemide with regard to occurrence of acute renal failure. Sensitivity analyses excluding trials with a follow-up < 6 months, trials with a cross-over design and those including < 25 patients confirmed the main results. We found no significant superiority of either loop diuretic with respect to mortality and safety endpoints. However, clinicians may prefer torasemide, as it was associated with fewer HF-related hospitalisations.

Resistance exercise enhances oxygen uptake without worsening cardiac function in patients with systolic heart failure: a systematic review and meta-analysis.

Recent literature suggests that resistance training (RT) improves peak oxygen uptake ([Formula: see text] peak), similarly to aerobic exercise (AE) in patients with heart failure (HF), but its effect on cardiac remodeling is controversial. Thus, we examined the effects of RT and AE on [Formula: see text] peak and cardiac remodeling in patients with heart failure (HF) via a systematic review and meta-analysis. MEDLINE, EMBASE, Cochrane Library and CINAHL, AMEDEO and PEDro databases search were extracted study characteristics, exercise type, and ventricular outcomes. The main outcomes were [Formula: see text] peak (ml kg-1 min-1), LVEF (%) and LVEDV (mL). Fifty-nine RCTs were included. RT produced a greater increase in [Formula: see text] peak (3.57 ml kg-1 min-1, P < 0.00001, I 2 = 0%) compared to AE (2.63 ml kg-1 min-1, P < 0.00001, I 2 = 58%) while combined RT and AE produced a 2.48 ml kg-1 min-1 increase in [Formula: see text]; I 2 = 69%) compared to control group. Comparison among the three forms of exercise revealed similar effects on [Formula: see text] peak (P = 0.84 and 1.00, respectively; I 2 = 0%). AE was associated with a greater gain in LVEF (3.15%; P < 0.00001, I 2 = 17%) compared to RT alone or combined exercise which produced similar gains compared to control groups. Subgroup analysis revealed that AE reduced LVEDV (- 10.21 ml; P = 0.007, I 2 = 0%), while RT and combined RT and AE had no effect on LVEDV compared with control participants. RT results in a greater gain in [Formula: see text] peak, and induces no deleterious effects on cardiac function in HF patients.

Effect of Interleukin-1 Blockade on Left Ventricular Systolic Performance and Work: A Post Hoc Pooled Analysis of 2 Clinical Trials.

BACKGROUND: Interleukin-1 (IL-1) blockade seems to improve anaerobic exercise in patients with systolic heart failure through improved left ventricular (LV) systolic performance. However, it is unclear whether IL-1 blockade affects LV systolic performance. METHODS: We pooled data from 2 clinical trials of patients with systolic heart failure who were randomized to IL-1 blockade or placebo. We estimated changes in LV systolic performance (LV ejection fraction [LVEF] and end-systolic elastance [LVEes]) and pressure-volume area (PVA), a surrogate of oxygen consumption, after 14 days of treatment. RESULTS: LVEF increased from 30% (24%-38%) to 36% (29%-43%) between baseline and day 14 only in anakinra-treated patients (P = 0.03 for within-group change and P = 0.02 for between-group change compared with placebo). LVEes increased from 1.0 mm Hg/mL (0.7-1.5) to 1.3 mm Hg/mL (0.8-1.6) in anakinra-treated patients between baseline and day 14 but not in placebo-treated patients (P = 0.03 for within-group change and P = 0.08 for between-group change). A change in PVA between baseline and 14 days was not detected in either anakinra or placebo patients. CONCLUSIONS: In this post hoc analysis, LVEes and LVEF increased significantly in patients treated with an IL-1 blocker but not in placebo-treated patients. An effect of IL-1 blockade on calculated PVA was not detected.

Role of Ivabradine in the Treatment of Patients With Cardiovascular Disease.

OBJECTIVE: To review the role of heart rate in myocardial ischemia and heart failure with reduced ejection fraction (HFrEF) as well as ivabradine's pharmacology and pharmacokinetics, clinical trials, and place in therapy. DATA SOURCES: We conducted MEDLINE searches from 1980 to October 2015 using the terms heart failure, HFrEF, angina, f-channel inhibitor, and ivabradine, with forward and backward citation tracking. STUDY SELECTION AND DATA EXTRACTION: English-language trials assessing ivabradine were obtained. Studies and narrative reviews of the topic areas were incorporated if they provided relevant data to inform the practicing clinician. DATA SYNTHESIS: In the SIGNIFY (Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease) trial, there was no difference in the primary composite end point of cardiovascular (CV) mortality or nonfatal myocardial infarction with ivabradine use in patients with stable coronary artery disease (CAD) versus placebo (P = 0.20). In the subgroup with Canadian Cardiovascular Society angina class ≥II, there was an 18% increase in the primary end point with ivabradine versus placebo (P = 0.02). In HFrEF patients, ivabradine reduced CV mortality or heart failure hospitalizations versus placebo, as seen in the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial; P < 0.05). CONCLUSIONS: The SIGNIFY trial negated much of the enthusiasm for using ivabradine in CAD. Ivabradine is a promising therapy in HFrEF based on the results of the SHIFT, but it is an adjunctive therapy, not a substitute for drugs with proven mortality benefits.

Experimental heart failure modelled by the cardiomyocyte-specific loss of an epigenome modifier, DNMT3B.

Differential DNA methylation exists in the epigenome of end-stage failing human hearts but whether it contributes to disease progression is presently unknown. Here, we report that cardiac specific deletion of Dnmt3b, the predominant DNA methyltransferase in adult mouse hearts, leads to an accelerated progression to severe systolic insufficiency and myocardial thinning without a preceding hypertrophic response. This was accompanied by widespread myocardial interstitial fibrosis and myo-sarcomeric disarray. By targeted candidate gene quantitative RT-PCR, we discovered an over-activity of cryptic splice sites in the sarcomeric gene Myh7, resulting in a transcript with 8 exons missing. Moreover, a region of differential methylation overlies the splice site locus in the hearts of the cardiac-specific conditional knockout (CKO) mice. Although abundant and complex forms of alternative splice variants have been reported in diseased hearts and the contribution of each remains to be understood in further detail, our results demonstrate for the first time that a link may exist between alternative splicing and the cardiac epigenome. In particular, this gives the novel evidence whereby the loss of an epigenome modifier promotes the development and progression of heart disease.

The small-molecule fast skeletal troponin activator, CK-2127107, improves exercise tolerance in a rat model of heart failure.

Heart failure-mediated skeletal myopathy, which is characterized by muscle atrophy and muscle metabolism dysfunction, often manifests as dyspnea and limb muscle fatigue. We have previously demonstrated that increasing Ca(2+) sensitivity of the sarcomere by a small-molecule fast skeletal troponin activator improves skeletal muscle force and exercise performance in healthy rats and models of neuromuscular disease. The objective of this study was to investigate the effect of a novel fast skeletal troponin activator, CK-2127107 (2-aminoalkyl-5-N-heteroarylpyrimidine), on skeletal muscle function and exercise performance in rats exhibiting heart failure-mediated skeletal myopathy. Rats underwent a left anterior descending coronary artery ligation, resulting in myocardial infarction and a progressive decline in cardiac function [left anterior descending coronary artery heart failure (LAD-HF)]. Compared with sham-operated control rats, LAD-HF rat hindlimb and diaphragm muscles exhibited significant muscle atrophy. Fatigability was increased during repeated in situ isokinetic plantar flexor muscle contractions. CK-2127107 produced a leftward shift in the force-Ca(2+) relationship of skinned, single diaphragm, and extensor digitorum longus fibers. Exercise performance, which was assessed by rotarod running, was lower in vehicle-treated LAD-HF rats than in sham controls (116 ± 22 versus 193 ± 31 seconds, respectively; mean ± S.E.M.; P = 0.04). In the LAD-HF rats, a single oral dose of CK-2127107 (10 mg/kg p.o.) increased running time compared with vehicle treatment (283 ± 47 versus 116 ± 22 seconds; P = 0.0004). In summary, CK-2127107 substantially increases exercise performance in this heart failure model, suggesting that modulation of skeletal muscle function by a fast skeletal troponin activator may be a useful therapeutic in heart failure-associated exercise intolerance.

Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure.

BACKGROUND: Trimethylamine-N-oxide (TMAO) has been linked to increased cardiovascular risk. We aimed to determine the prognostic value of TMAO and its dietary precursors, choline and betaine, in heart failure (HF). METHODS AND RESULTS: In 112 patients with chronic systolic HF with comprehensive echocardiographic evaluation, we measured plasma TMAO, choline, and betaine by mass spectrometry. Median (interquartile range) TMAO levels, choline, and betaine levels were 5.8 (3.6-12.1) µmol/L, 10.9 (8.4-14.0) µmol/L, and 43.8 (37.1-53.0) µmol/L, respectively, and were correlated with each other (all P < .0001 for both). TMAO levels were significantly higher in patients with diabetes mellitus (9.4 [4.9-13.2] vs 4.8 [3.4-9.8] µmol/L; P = .005) and in subjects with New York Heart Association functional class III or greater (7.0 [4.7-14.8] vs 4.7 [3.4-11.3] µmol/L; P = .02). Elevated TMAO, choline, and betaine levels were each associated with higher plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and more advanced left ventricular diastolic dysfunction, but not systolic dysfunction or inflammatory and endothelial biomarkers. Higher choline (hazard ratio [HR] 1.64, 95% CI 1.22-2.20; P = .001), betaine (HR 1.51, 95% CI 1.10-2.08; P = .01), and TMAO (HR 1.48, 95% CI 1.10-1.96; P = .01) predicted increased risk for 5-year adverse clinical events (death/transplantation). Only higher TMAO levels predicted incident adverse clinical events independently from age, estimated glomerular filtration rate, mitral E/septal Ea, and NT-proBNP levels (HR 1.46, 95% CI 1.03-2.14; P = .03). CONCLUSION: Elevated plasma TMAO, choline, and betaine levels are each associated with more advanced left ventricular diastolic dysfunction and portend poorer long-term adverse clinical outcomes in chronic systolic HF. However, only higher plasma TMAO was associated with poor prognosis after adjustment for cardiorenal indices.

Altered Levels of Fatty Acids and Inflammatory and Metabolic Mediators in Epicardial Adipose Tissue in Patients With Systolic Heart Failure.

BACKGROUND: Adipose tissue has endocrine properties, secreting a wide range of mediators into the circulation, including factors involved in cardiovascular disease. However, little is known about the potential role of adipose tissue in heart failure (HF), and the aim of this study was to investigate epicardial (EAT) and subcutaneous (SAT) adipose tissue in HF patients. METHODS AND RESULTS: Thirty patients with systolic HF and 30 patients with normal systolic function undergoing thoracic surgery were included in the study. Plasma was sampled and examined with the use of enzyme-linked immunosorbent assays, whereas SAT and EAT biopsies were collected and examined by means of reverse-transcription polymerase chain reaction and gas chromatography. Significantly higher expressions of mRNA encoding interleukin-6, adrenomedullin, peroxisome proliferator-activated receptor α, and fatty acid (FA)-binding protein 3, as well as higher levels of monounsaturated FA and palmitoleic acid, were seen in the EAT of HF patients, whereas the levels of docosahexaenoic acid were lower. Palmitoleic acid levels in EAT were correlated with 2 parameters of cardiac remodeling: increasing left ventricular end-diastolic diameter and N-terminal pro-B-type natriuretic peptide. CONCLUSIONS: Our results demonstrate adipose tissue depot-specific alterations of synthesis of FA and inflammatory and metabolic mediators in systolic HF patients. EAT may be a source of increased circulatory and myocardial levels of these mediators through endocrine actions.

Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet.

BACKGROUND: The pathogenesis of diabetic cardiomyopathy (DCM) involves the enhanced activation of peroxisome proliferator activating receptor (PPAR) transcription factors, including the most prominent isoform in the heart, PPARα. In cancer cells and adipocytes, post-translational modification of PPARs have been identified, including ligand-dependent degradation of PPARs by specific ubiquitin ligases. However, the regulation of PPARs in cardiomyocytes and heart have not previously been identified. We recently identified that muscle ring finger-1 (MuRF1) and MuRF2 differentially inhibit PPAR activities by mono-ubiquitination, leading to the hypothesis that MuRF3 may regulate PPAR activity in vivo to regulate DCM. METHODS: MuRF3-/- mice were challenged with 26 weeks 60% high fat diet to induce insulin resistance and DCM. Conscious echocardiography, blood glucose, tissue triglyceride, glycogen levels, immunoblot analysis of intracellular signaling, heart and skeletal muscle morphometrics, and PPARα, PPARß, and PPARγ1 activities were assayed. RESULTS: MuRF3-/- mice exhibited a premature systolic heart failure by 6 weeks high fat diet (vs. 12 weeks in MuRF3+/+). MuRF3-/- mice weighed significantly less than sibling-matched wildtype mice after 26 weeks HFD. These differences may be largely due to resistance to fat accumulation, as MRI analysis revealed MuRF3-/- mice had significantly less fat mass, but not lean body mass. In vitro ubiquitination assays identified MuRF3 mono-ubiquitinated PPARα and PPARγ1, but not PPARß. CONCLUSIONS: These findings suggest that MuRF3 helps stabilize cardiac PPARα and PPARγ1 in vivo to support resistance to the development of DCM. MuRF3 also plays an unexpected role in regulating fat storage despite being found only in striated muscle.

Clinical observation of umbilical cord mesenchymal stem cell treatment of severe systolic heart failure.

The aim of this study was to evaluate the effectiveness of umbilical cord mesenchymal stem cells (MSCs) in the treatment of chronic systolic heart failure. Fifty-nine hospitalized patients with heart failure were randomly divided into a treatment group (30 patients) and a control group (29 patients). The treatment group received treatment with medication as well as intracoronary transplantation of umbilical cord MSCs, and the control group, only medication. The cardiac structure, function change, and rehospitalization and mortality rates of the 2 groups were observed before and 1 and 6 months after treatment. One month after the transplantation of umbilical cord MSCs, the incidence of fatigue, chest tightness, and dyspnea was high in the treatment group. The 6-min walking distance of the treatment group was found to be significantly higher than that of the control group (P < 0.05); in addition, the NT-proBNP level, left ventricular ejection fraction, and mortality rate of the treatment group were statistically lower than those of the control group (P < 0.05). Readmission rates showed a downward trend, but the difference was not statistically significant (P > 0.05). Using umbilical cord MSCs in the treatment of congestive heart failure can help improve cardiac remodeling and cardiac function and reduce the mortality rate.

[Carriage of A Allele of Polymorphic Marker G(-238)A of TNF Gene Is Associated With Unfavorable Prognosis in Patients With Chronic Systolic Heart Failure].

AIM: to elucidate association between polymorphic markers of interleukin-6 (Il-6) and tumor necrosis factor (TNF) genes and unfavorable outcomes in patients with chronic heart failure (CHF). MATERIAL AND METHODS: We determined levels of TNF and Il-6 and genotypes of polymorphic markers G(-238)A of TNF gene (rs361525) and G(--174)C of IL-6 gene (rs1800795) in 151 patients (mean age 64.5 years) hospitalized because of decompensation of systolic CHF (left ventricular ejection fraction ≤ 40%) after stabilization of their state. Unfavorable outcomes were registered during follow-up for 2 years. RESULTS: Mean levels of NT-proBNP, Il-6, and TNF were 2481.1 ± 199.86 fmol/ml, 21.8 7.46 rg/ml, and 10.07 ± 0.65 rg/ml, respectively. 138 (94.4%), 13 (8.6%) and 0 patients were carriers of genotypes GG, AG, and AA of polymorphic marker G(-238)A of TNF gene, respectively; 54 (35.8%), 69 (45.7%), and 28 (18.5%) patients carried genotypes GG, GC, and CC of polymorphic marker G(-174)C gene IL-6, respectively. There was no association between Il-6, TNF levels and carriage of either of genotypes as well as unfavorable clinical course of CHF. Mean survival time before repetitive episode of CHF decompensation (including lethal one) was significantly shorter among carriers of A allele compared with carriers of G allele of polymorphic marker G(-238)A of TNF gene (243 ± 97.7 and 947 ± 78 days, respectively, p = 0.018). Mean time before all cause death was also shorter in carriers of A compared with carriers of G allele (289 ± 122.9 and 1039 ± 73.3 days, respectively, p = 0.03). The studied polymorphism of IL-6 gene had no prognostic value. CONCLUSION: We obtained data on association between carriage of A allele of polymorphic marker G(-238)A of TNF gene and unfavorable prognosis in patients with CHF and inpraired left ventricular systolic function.

Analysis of skeletal muscle gene expression patterns and the impact of functional capacity in patients with systolic heart failure.

BACKGROUND: Declining physical function is common among systolic heart failure (HF) patients and heralds poor clinical outcomes. We hypothesized that coordinated shifts in expression of ubiquitin-mediated atrophy-promoting genes are associated with muscle atrophy and contribute to decreased physical function. METHODS: Systolic HF patients (left ventricular ejection fraction [LVEF] ≤40%) underwent skeletal muscle biopsies (nondominant vastus lateralis) and comprehensive physical assessments. Skeletal muscle gene expression was assessed with the use of real-time polymerase chain reaction. Aerobic function was assessed with the use of cardiopulmonary exercise and 6-minute walk tests. Strength capacity was assessed with the use of pneumatic leg press (maximum strength and power). Serologic inflammatory markers also were assessed. RESULTS: 54 male patients (66.6 ± 10.0 years) were studied: 24 systolic HF patients (mean LVEF 28.9 ± 7.8%) and 30 age-matched control subjects. Aerobic and strength parameters were diminished in HF versus control. FoxO1 and FoxO3 were increased in HF versus control (7.9 ± 6.2 vs 5.0 ± 3.5, 6.5 ± 4.3 vs 4.3 ± 2.8 relative units, respectively; P ≤ .05 in both). However, atrogin-1 and MuRF-1 were similar in both groups. PGC-1α was also increased in HF (7.9 ± 5.4 vs. 5.3 ± 3.6 relative units; P < .05). Muscle levels of insulin-like growth factor (IGF) 1 as well as serum levels of tumor necrosis factor α, C-reactive protein, interleukin (IL) 1ß, and IL-6 were similar in HF and control. CONCLUSION: Expression of the atrophy-promoting genes FoxO1 and FoxO3 were increased in skeletal muscle in systolic HF compared with control, but other atrophy gene expression patterns (atrogin-1 and MuRF-1), as well as growth promoting patterns (IGF-1), were similar. PGC-1α, a gene critical in enhancing mitochondrial function and moderating FoxO activity, may play an important counterregulatory role to offset ubiquitin pathway-mediated functional decrements.

Loss of angiotensin-converting enzyme-2 exacerbates diabetic cardiovascular complications and leads to systolic and vascular dysfunction: a critical role of the angiotensin II/AT1 receptor axis.

RATIONALE: Diabetic cardiovascular complications are reaching epidemic proportions. Angiotensin-converting enzyme-2 (ACE2) is a negative regulator of the renin-angiotensin system. We hypothesize that loss of ACE2 exacerbates cardiovascular complications induced by diabetes. OBJECTIVE: To define the role of ACE2 in diabetic cardiovascular complications. METHODS AND RESULTS: We used the well-validated Akita mice, a model of human diabetes, and generated double-mutant mice using the ACE2 knockout (KO) mice (Akita/ACE2(-/y)). Diabetic state was associated with increased ACE2 in Akita mice, whereas additional loss of ACE2 in these mice leads to increased plasma and tissue angiotensin II levels, resulting in systolic dysfunction on a background of impaired diastolic function. Downregulation of SERCA2 and lipotoxicity were equivalent in Akita and Akita/ACE2KO hearts and are likely mediators of the diastolic dysfunction. However, greater activation of protein kinase C and loss of Akt and endothelial nitric oxide synthase phosphorylation occurred in the Akita/ACE2KO hearts. Systolic dysfunction in Akita/ACE2KO mice was linked to enhanced activation of NADPH oxidase and metalloproteinases, resulting in greater oxidative stress and degradation of the extracellular matrix. Impaired flow-mediated dilation in vivo correlated with increased vascular oxidative stress in Akita/ACE2KO mice. Treatment with the AT1 receptor blocker, irbesartan rescued the systolic dysfunction, normalized altered signaling pathways, flow-mediated dilation, and the increased oxidative stress in the cardiovascular system. CONCLUSIONS: Loss of ACE2 disrupts the balance of the renin-angiotensin system in a diabetic state and leads to an angiotensin II/AT1 receptor-dependent systolic dysfunction and impaired vascular function. Our study demonstrates that ACE2 serves as a protective mechanism against diabetes-induced cardiovascular complications.