Empagliflozin effects on iron metabolism as a possible mechanism for improved clinical outcomes in non-diabetic patients with systolic heart failure.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve clinical outcomes in patients with heart failure (HF), but mechanisms of action are incompletely understood. In the EMPA-TROPISM trial, empagliflozin reversed cardiac remodeling and increased physical capacity in stable non-diabetic patients with systolic HF. Here we explore, post hoc, whether treatment effects in this cohort, comprising patients who had a high prevalence of iron deficiency, were related to iron metabolism. Myocardial iron content estimated by cardiac magnetic resonance T2* quantification increased after initiation of empagliflozin but not placebo (treatment effect: P = 0.01). T2* changes significantly correlated with changes in left ventricular volumes, mass and ejection fraction, peak oxygen consumption and 6-minute walking distance; concomitant changes in red blood cell indices were consistent with augmented hematopoiesis. Exploratory causal mediation analysis findings indicated that changes in myocardial iron content after treatment with empagliflozin may be an important mechanism to explain its beneficial clinical effects in patients with HF.ClinicalTrials.gov: NCT03485222 .

The vasculature: a therapeutic target in heart failure?

It is well established that the vasculature plays a crucial role in maintaining oxygen and nutrients supply to the heart. Increasing evidence further suggests that the microcirculation has additional roles in supporting a healthy microenvironment. Heart failure is well known to be associated with changes and functional impairment of the microvasculature. The specific ablation of protective signals in endothelial cells in experimental models is sufficient to induce heart failure. Therefore, restoring a healthy endothelium and microcirculation may be a valuable therapeutic strategy to treat heart failure. This review article will summarize the current understanding of the vascular contribution to heart failure with reduced or preserved ejection fraction. Novel therapeutic approaches including next generation pro-angiogenic therapies and non-coding RNA therapeutics, as well as the targeting of metabolites or metabolic signalling, vascular inflammation and senescence will be discussed.

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.

Effectiveness of angiotensin-neprilysin inhibitor treatment versus renin-angiotensin system blockade in older adults with heart failure in clinical care.

OBJECTIVE: To evaluate the effectiveness of angiotensin receptor-neprilysin inhibitor (ARNI) versus renin-angiotensin system (RAS) blockade alone in older adults with heart failure with reduced ejection fraction (HFrEF). METHODS: We conducted a cohort study using US Medicare fee-for-service claims data (2014-2017). Patients with HFrEF ≥65 years were identified in two cohorts: (1) initiators of ARNI or RAS blockade alone (ACE inhibitor, ACEI; or angiotensin receptor blocker, ARB) and (2) switchers from an ACEI to either ARNI or ARB. HR with 95% CI from Cox proportional hazard regression and 1-year restricted mean survival time (RMST) difference with 95% CI were calculated for a composite outcome of time to first worsening heart failure event or all-cause mortality after adjustment for 71 pre-exposure characteristics through propensity score fine-stratification weighting. All analyses of initiator and switcher cohorts were conducted separately and then combined using fixed effects. RESULTS: 51 208 patients with a mean age of 76 years were included, with 16 193 in the ARNI group. Adjusted HRs comparing ARNI with RAS blockade alone were 0.92 (95% CI 0.84 to 1.00) among initiators and 0.79 (95% CI 0.74 to 0.85) among switchers, with a combined estimate of 0.84 (95% CI 0.80 to 0.89). Adjusted 1-year RMST difference (95% CI) was 4 days in the initiator cohort (-1 to 9) and 12 days (8 to 17) in the switcher cohort, resulting in a pooled estimate of 9 days (6 to 12) favouring ARNI. CONCLUSION: ARNI treatment was associated with lower risk of a composite effectiveness endpoint compared with RAS blockade alone in older adults with HFrEF.

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.

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.

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.

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.

[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.

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.

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.

Eplerenone: a review of its use in patients with chronic systolic heart failure and mild symptoms.

Eplerenone (Inspra®) is a selective mineralocorticoid receptor antagonist (MRA). In the EU, it is approved for use (in addition to standard optimal therapy) to reduce the risk of cardiovascular (CV) mortality and morbidity in adult patients with chronic systolic heart failure (HF) and mild symptoms. This article reviews the efficacy and tolerability of eplerenone in this indication and briefly summarizes its pharmacology. In the EMPHASIS-HF study, relative to placebo, the addition of eplerenone to optimal background therapy significantly reduced the risk of death from CV causes or hospitalization for HF in patients with chronic systolic HF and mild symptoms. Benefits of eplerenone therapy over placebo were also observed in several secondary outcomes, including: death from any cause or hospitalization for HF; death from any cause; hospitalization for any reason; or hospitalization for HF. Eplerenone was generally well tolerated in this study, with the most frequent adverse event being hyperkalaemia, which is a known adverse event of the drug class. Sexual adverse events (e.g. gynecomastia) occurred in <1 % of eplerenone recipients, reflecting the selectivity of eplerenone for mineralocorticoid receptors. Based on these results, European guidelines have been updated and recommend the use of an MRA to reduce the risk of HF hospitalization and premature death in all patients with persisting symptoms (New York Heart Association class II-IV) and a left-ventricular ejection fraction of ≤35 %, despite treatment with ACE inhibitor (or an angiotensin receptor blocker if an ACE inhibitor is not tolerated) and a ß-blocker.

Cardiac insulin-resistance and decreased mitochondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy.

BACKGROUND: Cardiac hypertrophy is accompanied by significant alterations in energy metabolism. Whether these changes in energy metabolism precede and contribute to the development of heart failure in the hypertrophied heart is not clear. METHODS AND RESULTS: Mice were subjected to cardiac hypertrophy secondary to pressure-overload as a result of an abdominal aortic constriction (AAC). The rates of energy substrate metabolism were assessed in isolated working hearts obtained 1, 2, and 3 weeks after AAC. Mice subjected to AAC demonstrated a progressive development of cardiac hypertrophy. In vivo assessment of cardiac function (via echocardiography) demonstrated diastolic dysfunction by 2 weeks (20% increase in E/E'), and systolic dysfunction by 3 weeks (16% decrease in % ejection fraction). Marked cardiac insulin-resistance by 2 weeks post-AAC was evidenced by a significant decrease in insulin-stimulated rates of glycolysis and glucose oxidation, and plasma membrane translocation of glucose transporter 4. Overall ATP production rates were decreased at 2 and 3 weeks post-AAC (by 37% and 47%, respectively) because of a reduction in mitochondrial oxidation of glucose, lactate, and fatty acids that was not accompanied by an increase in myocardial glycolysis rates. Reduced mitochondrial complex V activity was evident at 3 weeks post-AAC, concomitant with a reduction in the ratio of phosphocreatine to ATP. CONCLUSIONS: The development of cardiac insulin-resistance and decreased mitochondrial oxidative metabolism are early metabolic changes in the development of cardiac hypertrophy, which create an energy deficit that may contribute to the progression from hypertrophy to heart failure.

A multiparametric clinical and echocardiographic score to risk stratify patients with chronic systolic heart failure: derivation and testing.

Although echo Doppler and biomarkers are the most common examinations performed worldwide in heart failure (HF), they are rarely considered in risk scores. In outpatients with chronic HF and left ventricular ejection fraction (LVEF) ≤45%, data on clinical status, echo Doppler variables, aminoterminal pro-type B natriuretic peptide (NT-proBNP), estimated glomerular filtration rate (eGFR), and drug therapies were combined to build up a multiparametric score. We randomly selected 250 patients to produce a derivation cohort and 388 patients were used as a testing cohort. Follow-up lasted 29 ± 23 months. The univariable predictors that entered into the multivariable Cox model were as follows: furosemide daily dose >25 mg, inability to tolerate angiotensin converting enzyme (ACE) inhibitors, inability to tolerate ß-blockers, age >75 years, New York Heart Association (NYHA) >2, eGFR<60 mL/min, NT-proBNP plasma levels above the median, tricuspid plane systolic excursion (TAPSE) ≤14 mm, LV end-diastolic volume index (LVEDVi) >96 mL/m(2) , moderate-to-severe mitral regurgitation (MR) and LVEF <30%. The scores of prognostic factors were obtained with the respective odds ratio divided by the lower odd ratio: 4 points for furosemide dose, 3 points for age, NT-proBNP, LVEDVi, TAPSE, 2 points for inability to tolerate ß-blockers, inability to tolerate ACE inhibitors, NYHA, eGFR<60 mL/min, moderate-to-severe MR, 1 point for LVEF. The multiparametric score predicted all-cause mortality either in the derivation cohort (68.4% sensitivity, 79.5% specificity, area under the curve [AUC] 78.7%) or in the testing cohort (73.7% sensitivity, 71.3% specificity, AUC 77.2%). All-cause mortality significantly increased with increasing score both in the derivation and in the testing cohort (P < 0.0001). In conclusion, this multiparametric score is able to predict mortality in chronic systolic HF.

Expression and complex formation of MMP9, MMP2, NGAL, and TIMP1 in porcine myocardium but not in skeletal muscles in male pigs with tachycardia-induced systolic heart failure.

Matrix metalloproteinases (MMPs) are involved in the remodeling of extracellular matrix in various tissues. Their functioning could be related to the formation of complexes, containing MMP9, MMP2, tissue inhibitor of metalloproteinases type 1 (TIMP1), and neutrophil gelatinase-associated lipocalin (NGAL). Such complexes have not been investigated in either myocardial or skeletal muscles. We examined 20 male pigs with heart failure (HF), and 5 sham-operated animals. There were no differences in the mRNA expression of MMP9, MMP2, TIMP1, and NGAL between diseased and healthy animals, in either left ventricle (LV) myocardium or skeletal muscles. In LV from both diseased and healthy animals, in nonreducing and nondenaturing conditions, we demonstrated the presence of high molecular weight (HMW) complexes (130, 170, and 220 kDa) containing MMP9, TIMP1, and NGAL (also MMP2 in 220 kDa complex) without proteolytic activity, and a proteolytically active 115 kDa MMP9 form together with 72 and 68 kDa bands (proMMP2 and MMP2). Proteolytically active bands were also spontaneously released from HMW complexes. In skeletal muscles from both diseased and healthy animals, in nonreducing and nondenaturing conditions, we found no HMW complexes, and proteolytic activity was associated with the presence of 72 and 68 kDa bands (proMMP2 and MMP2).