Sound Touch Elastography for Noninvasive Assessment of Liver Stiffness in Patients With Chronic Heart Failure.

Heart failure (HF) can damage various organs, including the liver, a phenomenon known as "cardiohepatic syndrome." The latter is characterized by liver congestion and hepatic artery hypoperfusion, which can lead to liver damage. In this study, we aimed to assess liver damage quantitatively in chronic HF (CHF) with sound touch elastography (STE). A total of 150 subjects were enrolled, including HF with reduced ejection fraction (HFrEF) groups (left ventricular ejection fraction ≤40%, n = 45), HF with mildly reduced ejection fraction (HFmrEF) groups (left ventricular ejection fraction between 41% and 49%, n = 40), and right-sided HF (RHF) groups (n = 25); normal groups (n = 40). Liver stiffness measurement (LSM) was performed in all subjects by STE. The other hepatic parameters were also measured. The LSM was 5.4 ± 1.1 kPa in normal subjects and increased slightly to 5.9 ± 0.7 kPa in patients with HFmrEF. However, the HFrEF and RHF groups had significantly higher LSMs of 8.4 ± 2.0 kPa and 10.3 ± 2.7 kPa, respectively. The LSM of HFrEF was significantly higher than that of HFmrEF, whereas the increase in LSM in patients with RHF was significant relative to HFmrEF and HFrEF. In addition, the other parameters showed abnormal values in only RHF and HFrEF. In conclusion, STE is a useful clinical technique for the noninvasive evaluation of liver stiffness associated with CHF, which could help patients with CHF manage their treatment regimens.

Mineralocorticoid receptor antagonists for chronic heart failure: a meta-analysis focusing on the number needed to treat.

Aims: Recent studies have shown that mineralocorticoid receptor antagonists (MRAs) can decrease mortality in patients with heart failure; however, the application of MRAs in current clinical practice is limited because of adverse effects such as hyperkalemia that occur with treatment. Therefore, this meta-analysis used the number needed to treat (NNT) to assess the efficacy and safety of MRAs in patients with chronic heart failure. Methods: We meta-analysed randomized controlled trials (RCTs) which contrasted the impacts of MRAs with placebo. As of March 2023, all articles are published in English. The primary outcome was major adverse cardiovascular events (MACE), and secondary outcomes included all-cause mortality, cardiovascular death, myocardial infarction (MI), stroke, and adverse events. Results: We incorporated seven studies with a total of 9,056 patients, 4,512 of whom received MRAs and 4,544 of whom received a placebo, with a mean follow-up period of 2.1 years. MACE, all-cause mortality, and cardiovascular mortality were all reduced by MRAs, with corresponding numbers needed to treat for benefit (NNTB) of 37, 28, and 34; as well as no impact on MI or stroke. MRAs increased the incidence of hyperkalemia and gynecomastia, with the corresponding mean number needed to treat for harm (NNTH) of 18 and 52. Conclusions: This study showed that enabling one patient with HF to avoid MACE required treating 37 patients with MRAs for 2.1 years. MRAs reduce MACE, all-cause mortality, and cardiovascular death; however, they increase the risk of hyperkalemia and gynecomastia.

The Effects of a Cardiac Rehabilitation Program on Endothelial Progenitor Cells and Inflammatory Profile in Patients with Chronic Heart Failure of Different Severity.

Endothelial dysfunction and inflammation are common pathophysiological characteristics of chronic heart failure (CHF). Endothelial progenitor cells (EPCs) are recognized as useful markers of vascular damage and endothelial repair. The aim of this study was to investigate the effects of a cardiac rehabilitation program on EPCs and inflammatory profile in CHF patients of different severity. Forty-four patients with stable CHF underwent a 36-session cardiac rehabilitation program. They were separated into two different subgroups each time, according to the median peak VO2, predicted peak VO2, VE/VCO2 slope, and ejection fraction. EPCs, C-reactive protein (CRP), interleukin 6 (IL-6), interleukin 10 (IL-10), and vascular endothelial growth factor (VEGF) were measured. Flow cytometry was used for the quantification of EPCs. Mobilization of EPCs increased and the inflammatory profile improved within each severity group (p < 0.05) after the cardiac rehabilitation program, but there were no statistically significant differences between groups (p > 0.05). A 36-session cardiac rehabilitation program has similar beneficial effects on the mobilization of EPCs and on the inflammatory profile in patients with CHF of different severity.

Analysis of the clinical features and risk factors of kidney injury in patients with chronic heart failure-a retrospective cohort study.

Background: Heart failure (HF) often leads to kidney injury and increased morbidity and mortality. Factors contributing to kidney injury in HF patients had not been elucidated completely. This study sought to comprehensively evaluate the risk factors and clinical features of kidney injury in patients with chronic heart failure (CHF) and to provide more evidence for the management of these patients. Methods: Adult patients with CHF admitted to Beijing Anzhen Hospital, Capital Medical University from January 2022 to May 2022 were included in this study. The primary endpoints were the independent risk factors for the development of kidney injury. A multivariate logistic regression model was used for the exploration of the risk factors. Results: A total of 193 patients were included in this study, of whom 86 (44.5%) developed kidney injury. The independent risk factors for kidney injury in patients with CHF included sex (male) [odds ratio (OR): 4.30, 95% confidence interval (CI): 1.72-10.7, P=0.001], hypertension (OR: 3.68, 95% CI: 1.64-8.29, P=0.001), and stroke (OR: 3.82, 95% CI: 1.25-11.6, P=0.01). Kidney injury was significantly positively correlated with age (OR: 1.03, 95% CI: 1.008-1.06, P=0.01) and potassium (OR: 3.70, 95% CI: 1.58-8.67, P=0.002), and significantly negatively correlated with angiotensin receptor blocker (ARB) application (OR: 0.26, 95% CI: 0.11-0.61, P=0.001), serum albumin concentration (OR: 0.88, 95% CI: 0.81-0.96, P=0.005), hemoglobin concentration (OR: 0.97, 95% CI: 0.95-0.99, P=0.006), and left ventricular ejection fraction (LVEF; OR: 0.95, 95% CI: 0.92-0.98, P=0.01). Conclusions: Kidney injury occurred in more than half of the patients with CHF during hospitalization. The independent risk factors for kidney injury in the CHF patients included sex (male), hypertension, and stroke. Kidney injury was positively correlated with age and serum potassium, and negatively correlated with serum albumin, hemoglobin concentration, LVEF, and ARB application.

Soluble Guanylyl Cyclase Activators-Promising Therapeutic Option in the Pharmacotherapy of Heart Failure and Pulmonary Hypertension.

Endogenous nitric oxide (NO)-dependent vascular relaxation plays a leading role in the homeostasis of the cardiovascular, pulmonary, and vascular systems and organs, such as the kidneys, brain, and liver. The mechanism of the intracellular action of NO in blood vessels involves the stimulation of the activity of the soluble cytosolic form of guanylyl cyclase (soluble guanylyl cyclase, sGC), increasing the level of cyclic 3'-5'-guanosine monophosphate (cGMP) in smooth muscle and subsequent vasodilation. In recent years, a new group of drugs, soluble guanylyl cyclase stimulators, has found its way into clinical practice. Based on the CHEST-1 and PATENT-1 trials, riociguat was introduced into clinical practice for treating chronic thromboembolic pulmonary hypertension (CTEPH). In January 2021, the FDA approved the use of another drug, vericiguat, for the treatment of heart failure.

Qishen Yiqi dropping pills improve cardiomyocyte hypertrophy via the lncRNA TINCR/miR-193b-3p/RORA axis.

Background: This study was designed to explore the therapeutic effect and mechanism of action of Qishen Yiqi dropping pills (QYDP) in chronic heart failure (CHF) via a long non-coding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) axis. Here, the mechanism of action of the lncRNA terminal differentiation-induced non-coding RNA (TINCR), miR-193b-3p, and RAR-related orphan receptor A (RORA) mRNA was analyzed in an angiotensin (Ang) II-induced H9C2 cardiomyocyte hypertrophy model treated with QYDP. Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to analyze the gene expression changes of lncRNA, miRNA, and mRNA in H9C2 induced by QYDP on Ang II. The Gene Expression Omnibus (GEO) was used to analyze differentially expressed genes (DEGs) potentially affecting CHF progression. Cell Counting Kit-8 (CCK-8) was used to analyze the effect of QYDP on the proliferation of H9C2, RNA pull-down was used to analyze the binding of lncRNA and miRNA, and dual luciferase was used to analyze the targeting of miRNA and lncRNA or mRNA. Results: Ang II induced TINCR and RORA downregulation, miR-193b-3p upregulation, and hypertrophy in the H9C2 cardiomyocytes, which were alleviated by QYDP. In contrast, TINCR inhibition reversed the effects of QYDP by increasing miR-193b-3p expression and downregulating RORA expression. According to subsequent double luciferase and RNA pull-down experiments, TINCR adsorbed miR-193b-3p by acting as a competitive endogenous RNA sponge and miR-193b-3p directly targeted RORA. Lastly, we showed that the Ang-II-induced inhibition of TINCR and RORA expression and promotion of cardiac hypertrophy were both reversed by a TINCR overexpression plasmid (ov-TINCR), whereas the effects of ov-TINCR were suppressed by a miR-193b-3p mimic. Conclusions: Administration of QYDP improves Ang II-induced H9C2 cardiomyocyte hypertrophy and increase cell proliferation rate through the TINCR/miR-193b-3p/RORA axis.

A longitudinal assessment of chronic care pathways in real-life: self-care and outcomes of chronic heart failure patients in Tuscany.

BACKGROUND: Worldwide healthcare systems face challenges in assessing and monitoring chronic care pathways and, even more, the value generated for patients. Patient-reported outcomes measures (PROMs) represent a valid Real-World Evidence (RWE) source to fully assess health systems' performance in managing chronic care pathways. METHODS: The originality of the study consists in the chance of adopting PROMs, as a longitudinal assessment tool for continuous monitoring of patients' adherence to therapies and self-care behavior recommendations in clinical practice and as a chance to provide policy makers insights to improve chronic pathways adopting a patient perspective. The focus was on PROMs of patients with chronic heart failure (CHF) collected in the Gabriele Monasterio Tuscan Foundation (FTGM), a tertiary referral CHF centre in Pisa, Italy. During the hospital stay, CHF patients were enrolled and received a link (via SMS or email) to access to the first questionnaire. Follow-up questionnaires were sent 1, 7 and 12 months after the index hospitalisation. Professionals invited 200 patients to participate to PROMs surveys. 174 answers were digitally collected at baseline from 2018 to 2020 and analysed. Quantitative and qualitative analyses were conducted, using Chi2, t-tests and regression models together with narrative evidence from free text responses. RESULTS: Both quantitative and qualitative results showed FTGM patients declared to strongly adhere to the pharmacological therapy across the entire pathway, while seemed less careful to adhere to self-care behavior recommendations (e.g., physical activity). CHF patients that performed adequate Self-Care Maintenance registered outcome improvements. Respondents declared to be supported by family members in managing their adherence. CONCLUSIONS: The features of such PROMs collection model are relevant for researchers, policymakers and for managers to implement interventions aimed at improving pathway adherence dimensions. Among those, behavioral economics interventions could be implemented to increase physical activity among CHF patients since proven successful in Tuscany. Strategies to increase territorial care and support patients' caregivers in their daily support to patients' adherence should be further explored. Systematic PROMs collection would allow to monitor changes in the whole pathway organization. This study brings opportunities for extending such monitoring systems to other organizations to allow for reliable benchmarking opportunities.

Qishen Yiqi dropping pills improve isoproterenol-induced cardiomyocyte hypertrophy by regulating X-inactive specific transcript (XIST) expression in rats.

Background: This study aimed to explore the potential mechanism of Qishen Yiqi dropping pills (QYDPs) in the treatment of chronic heart failure (CHF) by regulating the expression of lncRNAs during CHF. Methods: Differences in the expression of the long non-coding RNA (lncRNA), X-inactive specific transcript (XIST), in an isoproterenol (ISO)-induced cardiomyocyte hypertrophy model treated with QYDPs was analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR). A cell counting kit-8 (CCK8) assay, flow cytometry (FCM), and enzyme linked immunosorbent assay (ELISA) were used to analyze the protective effects of QYDPs on the proliferation rate, apoptosis, myocardial enzyme, oxidative stress, and inflammation of cardiomyocytes, as well as the molecular mechanism of XIST. Results: Our results showed that in the ISO-induced cardiomyocyte hypertrophy model, XIST expression and apoptosis were increased, the cell proliferation rate was decreased, and myocardial enzyme levels increased [i.e., increased lactate dehydrogenase (LDH) and creatine kinase (CK) levels]. Furthermore, cellular oxidative stress [i.e., increased malondialdehyde (MDA) levels and decreased superoxide dismutase (SOD) levels] and inflammatory response [i.e., increased interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α protein secretion] were also promoted. QYDP treatment effectively mitigated the effects of ISO induction. Subsequently, we found that suppressing XIST expression reversed the effect of ISO induction, whereas overexpression (ov) of XIST enhanced the effect of ISO induction. Finally, this study confirmed that QYDP treatment improved the ISO-induced decrease in proliferation, apoptosis, and promotion of oxidative stress and inflammatory response in cardiomyocytes, whereas ov of XIST partially negated the effect of QYDPs. Conclusions: QYDPs protected H9c2 cells from ISO-induced damage by downregulating XIST expression.

Cardiac cycle time-corrected electromechanical activation time greater than 15% is an independent risk factor for major adverse cardiovascular events in chronic heart failure outpatients.

Objectives: This study aimed to investigate the predictive value of cardiac cycle time-corrected electromechanical activation time (EMATc) for major adverse cardiovascular events (MACEs) in outpatients with chronic heart failure (CHF) in comparison with other clinic indexes. Methods: This prospective observational study at Beijing Anzhen Hospital from January 01, 2015 to January 01 2018 enrolled 120 CHF patients who were admitted for acute onset of CHF and followed up after discharge for 616.5 days (range: 202.75-875.25 days). Based on the different endpoints, cardiogenic death, all-cause death, and HF-related readmission, patients were assigned to the following groups: cardiogenic death and non-cardiogenic death groups, all-cause death and survival groups, and HF readmission and non-readmission groups. EMATc and other clinic indexes were measured and compared between these groups. Cox regression analysis was used to identify independent risk factors for MACEs. Results: The hazard ratio for EMATc>15% for cardiogenic death was 3.493 (P=0.046), suggesting that an EMATc>15% was an independent risk factor for cardiogenic death in CHF patients. The hazard ratios for B-type natriuretic peptide (BNP) >400 ng/L for all-cause death and CHF readmission were 3.810 (P=0.008) and 2.764 (P=0.031), respectively. Thus, BNP >400 ng/L was an independent risk factor for all-cause death and readmission for CHF. EF<40% was not found to be a significant risk factor for MACEs. Conclusions: BNP level can predict the risk for poor prognosis in CHF patients. EMATc>15% is an independent risk factor for cardiogenic death and should be considered as a supplement to serum BNP level and other clinical indexes for predicting cardiogenic death in CHF outpatients.

Application value of myocardial work technology by non-invasive echocardiography in evaluating left ventricular function in patients with chronic heart failure.

BACKGROUND: Accurate evaluation of left ventricular (LV) systolic function is the premise for diagnosing and treating chronic heart failure. This study aimed to explore the incremental value of echocardiographic myocardial work in evaluating the LV systolic dysfunction in patients with chronic heart failure. METHODS: A total of 206 participants were enrolled, including 155 patients with chronic heart failure and 51 healthy controls (HC). The chronic heart failure patients were divided into three groups according to LV ejection fraction (LVEF): Heart failure with preserved ejection fraction (HFpEF group, 54 cases, LVEF ≥50%), heart failure with mid-range ejection fraction (HFmrEF group, 50 cases, 40%≤ LVEF <50%), and heart failure with reduced ejection fraction (HFrEF group, 51 cases, LVEF <40%). Except for the conventional echocardiographic parameters, the left ventricular myocardial work parameters, including the global myocardial work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE), were calculated in the study participants. One-way analysis of variance test followed by Fisher's least significant difference (LSD) t-test were used to obtain parameters with significant differences, which were then fed into a machine learning model established for subsequent multi-classification of the four groups. The selected myocardial work parameters with high importance rankings resulting from the machine learning model were further compared with the traditional LVEF in the multi-classification of the four groups. RESULTS: All conventional echocardiographic parameters were significantly different between the HFmrEF and HFrEF groups, but only E/e', left atrium showed notable differences between the HFpEF and HC groups (P<0.05). All myocardial work parameters were markedly different between the four groups (P<0.05). LVEF and GWI were more important than the other parameters according to the multi-classification machine learning model. The multi-classification diagnostic performances of LVEF, GWI, and LVEF + GWI were 82%, 88%, and 98%, respectively, which confirmed that GWI + LVEF could complementarily improve the diagnosis accuracy in classifying the four groups, with a performance increase of approximately 10% than each individually. CONCLUSIONS: GWI can play a complementary role to LVEF in the early diagnosis of HFpEF patients from the HC group and improve the clinical evaluation accuracy in chronic heart failure patients. Echocardiographic myocardial work should be utilized along with conventional LVEF to evaluate the systolic function of chronic heart failure patients in clinical practice.

[Chronic heart failure due to Qi deficiency and blood stasis and intervention mechanism of Compound Renshen Buqi Granules:a proteomics-based study].

Compound Renshen Buqi Granules have been widely used to treat chronic heart failure(CHF) due to Qi deficiency and blood stasis, but the mechanism of action remains unclear. This paper explored the pathogenesis of CHF due to Qi deficiency and blood stasis and the intervention mechanism of Compound Renshen Buqi Granules based on quantitative proteomics for uncovering the biological basis. SD rats were divided into the normal control(N) group, normal+Compound Renshen Buqi Granules(ND) group, model(M) group, model+Compound Renshen Buqi Granules(D) group, and positive control(Y) group. The rat model of CHF due to Qi deficiency and blood stasis was established by ligation of the left anterior descending(LAD) coronary artery and chronic sleep deprivation. The rats in the ND group and D group were provided with Compound Renshen Buqi Granules, while those in the Y group received valsartan. Six weeks later, the serum was sampled and the data-dependent acquisition(DDA) was employed for the non-targeted quantitative proteomics analysis of the differences in protein expression among groups, followed by the targeted analysis of differentially expressed proteins(DEPs) generated by data-independent acquisition(DIA). Compared with the N group, the rats in the M group pre-sented with decreased body weight, grip strength, and pulse amplitude and increased RGB value on the tongue surface. The pathomorphological examination revealed inflammatory cell infiltration, cell degeneration and necrosis, tissue fibrosis, etc. After the intervention with Compound Renshen Buqi Granules, multiple indicators were reversed. As demonstrated by proteomics results, there were 144 and 111 DEPs found in the M group and ND group in comparison with the N group. Compared with the M group, 107 and 194 DEPs were found in the D group and the Y group, respectively. Compared with the ND group, 119 DEPs were detected in the D group. As illustrated by DIA-based verification, the quantitative results of six proteins in each group were consistent with those by DDA. The syndrome indicators and pathomorphological examination results demonstrated that the protein expression profile of rats with CHF due to Qi deficiency and blood stasis changed obviously. However, Compound Renshen Buqi Granules were able to reverse the differential expression of immune proteins to regulate CHF of Qi deficiency and blood stasis syndrome, which has provided clues for figuring out the pathogenesis of CHF due to Qi deficiency and blood stasis and the intervention mechanism of Compound Renshen Buqi Granules.

Inflammation in Human Heart Failure: Major Mediators and Therapeutic Targets.

Inflammation has been recognized as a major pathophysiological contributor to the entire spectrum of human heart failure (HF), including HF with reduced ejection fraction, HF with preserved ejection fraction, acute HF and cardiogenic shock. Nevertheless, the results of several trials attempting anti-inflammatory strategies in HF patients have not been consistent or motivating and the clinical implementation of anti-inflammatory treatments for HF still requires larger and longer trials, as well as novel and/or more specific drugs. The present work reviews the different inflammatory mechanisms contributing to each type of HF, the major inflammatory mediators involved, namely tumor necrosis factor alpha, the interleukins 1, 6, 8, 10, 18, and 33, C-reactive protein and the enzymes myeloperoxidase and inducible nitric oxide synthase, and their effects on heart function. Furthermore, several trials targeting these mediators or involving other anti-inflammatory treatments in human HF are also described and analyzed. Future therapeutic advances will likely involve tailored anti-inflammatory treatments according to the patient's inflammatory profile, as well as the development of resolution pharmacology aimed at stimulating resolution of inflammation pathways in HF.

Enrichment analysis of differentially expressed genes in chronic heart failure.

BACKGROUND: The study explores the differentially expressed genes in the heart tissue of patients with chronic heart failure (CHF) and normal heart tissue, thus providing information for further research on the pathogenesis of CHF. METHODS: The Gene Expression Omnibus (GEO) database was used to download the whole transcriptome sequencing results of CHF patients (GSE2656, n=49). Transcriptome sequencing results of 44 normal left ventricular tissues were randomly screened and downloaded using the Genotype-Tissue Expression (GTEX) database (n=44). We explored the differentially expressed genes between CHF tissue and normal heart tissue. Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis were performed for differentially expressed genes. Growth hormone-releasing hormone (GHRH) was used as a representative differential gene for serological sample verification by the enzyme linked immunosorbent assay (ELISA). RESULTS: A total of 902 differentially expressed genes between CHF and normal heart tissues were screened, including 354 up-regulated genes and 548 down-regulated genes. GO enrichment analysis showed that the differentially expressed genes were significantly enriched in the extracellular and sequence-specific DNA binding domains. KEGG enrichment demonstrated that the differential genes were enriched in neuroactive ligand-receptor interaction, the calcium signaling pathway, vascular smooth muscle contraction, and other signaling pathways. ELISA results showed that the expression level of GHRH in patients with heart failure was significantly higher than that in healthy subjects (P<0.05). CONCLUSIONS: A total of 902 differentially expressed genes were found in CHF tissues compared with normal heart tissues. Signaling pathways such as neuroactive ligand-receptor interaction, the calcium ion signaling pathway, and vascular smooth muscle contraction may be related to the pathogenesis of CHF.

Current Modulation of Guanylate Cyclase Pathway Activity-Mechanism and Clinical Implications.

For years, guanylate cyclase seemed to be homogenic and tissue nonspecific enzyme; however, in the last few years, in light of preclinical and clinical trials, it became an interesting target for pharmacological intervention. There are several possible options leading to an increase in cyclic guanosine monophosphate concentrations. The first one is related to the uses of analogues of natriuretic peptides. The second is related to increasing levels of natriuretic peptides by the inhibition of degradation. The third leads to an increase in cyclic guanosine monophosphate concentration by the inhibition of its degradation by the inhibition of phosphodiesterase type 5. The last option involves increasing the concentration of cyclic guanosine monophosphate by the additional direct activation of soluble guanylate cyclase. Treatment based on the modulation of guanylate cyclase function is one of the most promising technologies in pharmacology. Pharmacological intervention is stable, effective and safe. Especially interesting is the role of stimulators and activators of soluble guanylate cyclase, which are able to increase the enzymatic activity to generate cyclic guanosine monophosphate independently of nitric oxide. Moreover, most of these agents are effective in chronic treatment in heart failure patients and pulmonary hypertension, and have potential to be a first line option.

Aerobic exercise improves cardiac function in rats with chronic heart failure through inhibition of the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1).

BACKGROUND: To explore the beneficial effects and underlying mechanisms of aerobic exercise on chronic heart failure (CHF). METHODS: A CHF rat model was induced via left anterior descending coronary artery ligation. Four weeks post-surgery, CHF rats received aerobic exercise training over an 8-week period and cardiac function indexes including xxx were analyzed. To investigate the mechanisms involved in the aerobic exercise-induced benefits on CHF, overexpression of the long non-coding RNA MALAT1 was examined both in vivo and in vitro. Furthermore, the interaction between MALAT1 and the microRNA miR-150-5p and the downstream PI3K/Akt signaling pathway was investigated. RESULTS: Compared to the control group, the CHF rats showed evidence of left ventricular dysfunction including aggravated cardiac function indexes and lung to body weight ratio. The Masson staining demonstrated a significant degree of blue-stained fibrotic myocardial tissue in CHF rats compared to control rats. Furthermore, the levels of collagen I and collagen II were also markedly increased in CHF rats. Aerobic exercise improved cardiac function and left ventricular remodeling in rats with CHF. There was a significant reduction in the levels of the reactive oxygen species (ROS), inflammatory cytokines including TNF-α, IL-6, and IL-1ß, and inflammatory mediums containing the matrix metalloproteinases (MMPs) MMP-2 and MMP-9. Moreover, CHF rats receiving aerobic exercise showed decreased myocardial apoptosis and increased expression of autophagy-related proteins including beclin-1 and LC3B-II. Overexpression of the lncRNA MALAT1 eliminated all the beneficial effects related to aerobic exercise in CHF rats. Subsequent investigations demonstrated that miR-150-5p expression was up-regulated in CHF-Tr rats and down-regulated in CHF-Tr-MALAT1 rats. Furthermore, the downstream PI3K/Akt signaling pathway was re-activated in CHF-Tr-MALAT1 rats. In vitro experiments revealed that overexpression of MALAT1 reduced the miR-150-5p levels, resulting in increased cellular apoptosis and less autophagy. In addition, overexpression of MALAT1 suppressed the downstream PI3K/Akt signaling pathway. Restoring miR-150-5p level with a miR-150-5p mimic decreased the cellular apoptosis and increased autophagy, and the downstream PI3K/Akt signaling pathway was re-activated. CONCLUSIONS: Aerobic exercise improved cardiac function through inhibition of the lncRNA MALAT1 in CHF, and the potential mechanisms may be mediated via the miR-150-5p/PI3K/Akt signaling pathway.

Iron deficiency is an independent risk factor of increased myocardial energy expenditure in chronic heart failure patients.

BACKGROUND: Chronic heart failure (CHF) is a major public health burden and is associated with high morbidity, mortality, and cost. Recent studies demonstrated iron metabolism and myocardial energy metabolism were altered in CHF patients. In this study, we aimed to analyze the effects and correlations of iron metabolism on myocardial energy metabolism in CHF. METHODS: One hundred and thirty patients with CHF [age: 66.2±11.5 years, males: 58.5% and New York Heart Association (NYHA) class (II/III/IV): 67/43/20] were included. Serum concentrations of ferritin, transferrin saturation (Tsat), and soluble transferrin receptor (sTfR) were quantified as the indexes of iron metabolism, and echocardiography was used to assess myocardial energy expenditure (MEE) levels. Iron deficiency (ID) was defined as ferritin <100 or 100-300 µg/L with Tsat <20%. RESULTS: Patients with CHF were divided into two groups based on iron status. The prevalence of ID in CHF was 36.9%, and increased with the severity of CHF, reaching 80.0% in those with NYHA class IV (NYHA class II/III/IV: 17.9% vs. 46.5% vs. 80.0%, P=0.000). The demographic characteristics [age, sex, body mass index (BMI), blood pressure, and heart rate] and hemoglobin (HGB) concentrations in two groups were similar (all P>0.05). MEE was significantly higher in the ID group (92.7±23.0 vs. 65.6±20.8 cal/min, P=0.000), while NYHA classes II and III was significantly higher in the ID group (71.6±16.4 vs. 60.3±14.8 cal/min, P=0.022; 88.9±10.4 vs. 69.1±20.1 cal/min, P=0.000). In univariable linear regression models, the presence of ID, higher NYHA class, increased N-terminal pro-B-type natriuretic peptide (NT-proBNP), sTfR, left ventricular internal diastolic diameter (LVIDd), as well as reduced ferritin, Tsat levels, and lower left ventricular ejection fraction (LVEF) were associated with elevated MEE levels (all P<0.05). In multivariable regression models, the presence of ID, reduced Tsat. and increased sTfR remained independent predictors of elevated MEE levels after adjustment for all variables that showed a significant association with MEE (all P<0.05). CONCLUSIONS: The prevalence of ID is high in CHF and is associated with the severity of cardiac dysfunction. The presence of ID as well as reduced Tsat and increased sTfR concentrations are associated with elevated MEE levels in CHF.

Chronic heart failure due to Qi deficiency and blood stasis and intervention mechanism of Compound Renshen Buqi Granules:a proteomics-based study / 中国中药杂志

Compound Renshen Buqi Granules have been widely used to treat chronic heart failure(CHF) due to Qi deficiency and blood stasis, but the mechanism of action remains unclear. This paper explored the pathogenesis of CHF due to Qi deficiency and blood stasis and the intervention mechanism of Compound Renshen Buqi Granules based on quantitative proteomics for uncovering the biological basis. SD rats were divided into the normal control(N) group, normal+Compound Renshen Buqi Granules(ND) group, model(M) group, model+Compound Renshen Buqi Granules(D) group, and positive control(Y) group. The rat model of CHF due to Qi deficiency and blood stasis was established by ligation of the left anterior descending(LAD) coronary artery and chronic sleep deprivation. The rats in the ND group and D group were provided with Compound Renshen Buqi Granules, while those in the Y group received valsartan. Six weeks later, the serum was sampled and the data-dependent acquisition(DDA) was employed for the non-targeted quantitative proteomics analysis of the differences in protein expression among groups, followed by the targeted analysis of differentially expressed proteins(DEPs) generated by data-independent acquisition(DIA). Compared with the N group, the rats in the M group pre-sented with decreased body weight, grip strength, and pulse amplitude and increased RGB value on the tongue surface. The pathomorphological examination revealed inflammatory cell infiltration, cell degeneration and necrosis, tissue fibrosis, etc. After the intervention with Compound Renshen Buqi Granules, multiple indicators were reversed. As demonstrated by proteomics results, there were 144 and 111 DEPs found in the M group and ND group in comparison with the N group. Compared with the M group, 107 and 194 DEPs were found in the D group and the Y group, respectively. Compared with the ND group, 119 DEPs were detected in the D group. As illustrated by DIA-based verification, the quantitative results of six proteins in each group were consistent with those by DDA. The syndrome indicators and pathomorphological examination results demonstrated that the protein expression profile of rats with CHF due to Qi deficiency and blood stasis changed obviously. However, Compound Renshen Buqi Granules were able to reverse the differential expression of immune proteins to regulate CHF of Qi deficiency and blood stasis syndrome, which has provided clues for figuring out the pathogenesis of CHF due to Qi deficiency and blood stasis and the intervention mechanism of Compound Renshen Buqi Granules.

Network Pharmacology-based Analysis on Mechanism of Aconiti Lateralis Radix Praeparata and Epimedii Folium in Treatment of Chronic Heart Failure / 中国实验方剂学杂志

Objective:To explore the mechanism of the prescription consisting Aconiti Lateralis Radix Praeparata and Epimedii Folium in the treatment of chronic heart failure （CHF） based on network pharmacology，followed by verification in H9c2 myocardial cells with hypoxia-reoxygenation injury <italic>in vitro</italic> and in zebrafish with vascular endothelial growth factor receptor （VEGFR） tyrosine kinase inhibitor Ⅱ （VRI） -induced vascular insufficiency. Method:The active ingredients in Aconiti Lateralis Radix Praeparata and Epimedii Folium were searched from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP），the corresponding target genes from the Universal Protein Resource （UniProt）， and the CHF-related targets from Online Mendelian Inheritance in Man （OMIM） and GeneCards. Both the active ingredient-potential target network and the active ingredient-CHF-related target network were generated using Cytoscape 3.6.1， followed by the protein-protein interaction （PPI） network construction and Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genome （KEGG） enrichment analysis based on MetaScape. H9c2 myocardial cells exposed to hypoxia-reoxygenation were selected for determining the proliferation-promoting effect by methyl thiazolyl tetrazolium （MTT） assay. The protein expression of B-cell lymphoma-2（Bcl-2）， Bcl-2-associated X protein（Bax），cysteinyl aspartate-specific protease-3（Caspase-3）， protein kinase B（PKB/Akt），phosphorylated protein kinase B（p-Akt），phosphorylated extracellular signal-regulated kinases 1/2 （p-ERK1/2），extracellular signal-regulated kinase 1/2 （ERK1/2）， and poly adenosine diphosphate ribose polymerase（PARP）was detected by Western blotting. The efficacy of the prescription in promoting angiogenesis was verified in a zebrafish model of VRI-induced vascular injury. Result:There were 28 active ingredients for the prescription， 209 corresponding targets， 1 296 CHF-related targets， and 94 common gene targets shared by the prescription and CHF. PPI network clustering suggested that Aconiti Lateralis Radix Praeparata and Epimedii Folium alleviated CHF by interfering with cell differentiation and metabolism and angiogenesis. GO analysis revealed that CHF relief was achieved via the intervention in such biological processes as cell migration，vascular development， and angiogenesis. Pharmacodynamic experiments verified that Epimedii Folium （10 mg·L^-1） alone and the prescription （10 mg·L^-1）both enhanced the proliferation of H9c2 myocardial cells under the hypoxia-reoxygenation condition （<italic>P</italic><0.05），while the latter also increased the expression of Bcl-2，Bcl-2/Bax， and PARP （<italic>P</italic><0.05） and reduced the expression of Caspase-3， Akt， and ERK （<italic>P</italic><0.05）. The prescription at the concentrations of 0.3 and 0.1 g·L^-1 promoted angiogenesis （<italic>P</italic><0.05）. Conclusion:Aconiti Lateralis Radix Praeparata and Epimedii Folium exert the therapeutic effect against CHF via multiple ingredients，multiple targets， and multiple channels. Such combination promotes the proliferation of H9c2 myocardial cells under hypoxic condition and protects zebrafish from vascular injury by up-regulating the expression of Bcl-2 and PARP，increasing Bcl-2/Bax ratio，and down-regulating the expression of Caspase-3，Akt， and ERK.

Establishment of exercise intensity for patients with chronic heart failure equivalent to anaerobic threshold based on 6-minute walking test.

BACKGROUND: The study aimed to investigate the relationship between the aerobic exercise intensity determined by 6-minute walking distance (6MWD) and its counterpart based on anaerobic threshold (AT) in chronic heart failure (CHF) individuals for exploring suitable means for CHF exercise rehabilitation. METHODS: We retrospectively analyzed data in patient with CHF, who performed cardiopulmonary exercise test (CPET) and 6-minute walking test (6MWT) uniformly. Anthropometric characteristics, left ventricular ejection fraction (LVEF), and multiple parameters of 6MWT and AT were collected. RESULTS: The results of the analysis revealed that the 6MWD was correlated with the AT positively [CHF group: r=0.433, heart failure with reduced ejection fraction (HFrEF) group: r=0.395, heart failure with intermediate ejection fraction (HFmEF) group: r=0.477, heart failure with preserved ejection fraction (HFpEF) group: r=0.445; all P<0.05]. The regression analysis showed that the linear equation model developed can predict exercise intensity based on AT (EIAT) by exercise intensity based on 6MWD (EI6MWD), the aerobic exercise intensity based on AT and 6MWD respectively, of CHF patients. CONCLUSIONS: There is a correlation between EI6MWD and EIAT. 74.6-87.4% of EI6MWD in patients with CHF is equivalent to EIAT. It is feasible to establish the aerobic exercise intensity of patients with CHF equivalent to AT based on 6MWD.

Obstructive sleep apnea versus central sleep apnea: prognosis in systolic heart failure.

BACKGROUND: In chronic heart failure (CHF), obstructive sleep apnea (OSA) and Cheyne-Stokes respiration (CSR) are associated with increased mortality. The present study aimed to evaluate the prognostic effect of CSR compared to OSA, in otherwise similar groups of CHF patients. METHODS: Screening for sleep-disordered breathing (SDB) was conducted among patients with CHF of New York Heart Association (NYHA) class II-IV, and left ventricular ejection fraction (LVEF) of ≤45%. The study included 43 patients (4 women) with >25% CSR during sleeping time, and 19 patients (2 women) with OSA and an apnea-hypopnea index (AHI) of ≥6. Patients were followed for a median of 1,371 days. The primary endpoint was mortality, and the secondary endpoint was combined mortality and hospital admissions. RESULTS: Baseline parameters did not significantly differ between groups, but CSR patients were older and had higher AHI values than OSA patients. Five OSA patients (26%) died, and 14 (74%) met the combined end-point of death or hospitalization. CSR patients had significantly higher risk for both end-points, with 23 (53%) deaths [log-rank P=0.040; HR, 2.70 (1.01-7.22); P=0.047] and 40 (93%) deaths or readmissions [log-rank P=0.029; HR, 1.96 (1.06-3.63); P=0.032]. After adjustment for confounding risk factors, the association between CSR and death remained significant [HR, 4.73 (1.10-20.28); P=0.037], hospital admission rates were not significantly different. CONCLUSIONS: Among patients with CHF, CSR was associated with higher mortality than OSA independently of age and cardiac systolic function. CSR was also an age-independent predictor of unfavorable outcome, but hospital admission rates were not significantly different between the two groups after adjustment.