Immune patterns of cuproptosis in ischemic heart failure: A transcriptome analysis.

Cuproptosis is a recently discovered programmed cell death pattern that affects the tricarboxylic acid (TCA) cycle by disrupting the lipoylation of pyruvate dehydrogenase (PDH) complex components. However, the role of cuproptosis in the progression of ischemic heart failure (IHF) has not been investigated. In this study, we investigated the expression of 10 cuproptosis-related genes in samples from both healthy individuals and those with IHF. Utilizing these differential gene expressions, we developed a risk prediction model that effectively distinguished healthy and IHF samples. Furthermore, we conducted a comprehensive evaluation of the association between cuproptosis and the immune microenvironment in IHF, encompassing infiltrated immunocytes, immune reaction gene-sets and human leukocyte antigen (HLA) genes. Moreover, we identified two different cuproptosis-mediated expression patterns in IHF and explored the immune characteristics associated with each pattern. In conclusion, this study elucidates the significant influence of cuproptosis on the immune microenvironment in ischemic heart failure (IHF), providing valuable insights for future mechanistic research exploring the association between cuproptosis and IHF.

Development and validation of a nomogram for major adverse cardiovascular events after chronic total occlusion percutaneous coronary intervention for ischemic heart failure.

BACKGROUND: Chronic total occlusion percutaneous coronary intervention (CTO-PCI) is an available means of revascularization in patients with ischemic heart failure (IHF). However, the prognosis of IHF patients undergoing CTO-PCI remains unclear due to the lack of reliable clinical predictive tools. AIM: This study aimed to establish a nomogram for major adverse cardiovascular events (MACE) after CTO-PCI in IHF patients. METHODS: Sixty-seven potential predictive variables for MACE in 560 IHF patients undergoing CTO-PCI were screened using least absolute shrinkage and selection operator regression. A nomogram was constructed based on multivariable Cox regression to visualize the risk of MACE, and then evaluation was carried out using the concordance index (C-index), time-independent receiver operating characteristic (timeROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: During a median follow-up of 32.0 months, there were 208 MACE occurrences. Seven variables were selected for nomogram construction: age, left ventricular ejection fraction, left ventricular end-diastolic diameter, N-terminal precursor B-type diuretic peptide, bending, and use of intravascular ultrasound and beta-blockers. The C-index was 0.715 (0.680-0.750) and the internal validation result was 0.715 (0.676-0.748). The timeROC area under the curve at 6 months, 1 year, and 2 years was 0.750 (0.653-0.846), 0.747 (0.690-0.804), and 0.753 (0.708-0.798), respectively. The calibration curves and DCA showed the nomogram had acceptable calibration and clinical applicability. CONCLUSIONS: We developed a simple and efficient nomogram for MACE after CTO-PCI in IHF patients, which helps in early risk stratification and postoperative management optimization.

Expression of Osteopontin and Gremlin 1 Proteins in Cardiomyocytes in Ischemic Heart Failure.

A relevant role of osteopontin (OPN) and gremlin 1 (Grem1) in regulating cardiac tissue remodeling and formation of heart failure (HF) are documented, with the changes of OPN and Grem1 levels in blood plasma due to acute ischemia, ischemic heart disease-induced advanced HF or dilatative cardiomyopathy being the primary focus in most of these studies. However, knowledge on the early OPN and Grem1 proteins expression changes within cardiomyocytes during remodeling due to chronic ischemia remains insufficient. The aim of this study was to determine the OPN and Grem1 proteins expression changes in human cardiomyocytes at different stages of ischemic HF. A semi-quantitative immunohistochemical analysis was performed in 105 myocardial tissue samples obtained from the left cardiac ventricles. Increased OPN immunostaining intensity was already detected in the stage A HF group, compared to the control group (p < 0.001), and continued to increase in the stage B HF (p < 0.001), achieving the peak of immunostaining in the stages C/D HF group (p < 0.001). Similar data of Grem1 immunostaining intensity changes in cardiomyocytes were documented. Significantly positive correlations were detected between OPN, Grem1 expression in cardiomyocytes and their diameter as well as the length, in addition to positive correlation between OPN and Grem1 expression changes within cardiomyocytes. These novel findings suggest that OPN and Grem1 contribute significantly to reorganization of cellular geometry from the earliest stage of cardiomyocyte remodeling, providing new insights into the ischemic HF pathogenesis.

SMYD1a protects the heart from ischemic injury by regulating OPA1-mediated cristae remodeling and supercomplex formation.

SMYD1, a striated muscle-specific lysine methyltransferase, was originally shown to play a key role in embryonic cardiac development but more recently we demonstrated that loss of Smyd1 in the murine adult heart leads to cardiac hypertrophy and failure. However, the effects of SMYD1 overexpression in the heart and its molecular function in the cardiomyocyte in response to ischemic stress are unknown. In this study, we show that inducible, cardiomyocyte-specific overexpression of SMYD1a in mice protects the heart from ischemic injury as seen by a > 50% reduction in infarct size and decreased myocyte cell death. We also demonstrate that attenuated pathological remodeling is a result of enhanced mitochondrial respiration efficiency, which is driven by increased mitochondrial cristae formation and stabilization of respiratory chain supercomplexes within the cristae. These morphological changes occur concomitant with increased OPA1 expression, a known driver of cristae morphology and supercomplex formation. Together, these analyses identify OPA1 as a novel downstream target of SMYD1a whereby cardiomyocytes upregulate energy efficiency to dynamically adapt to the energy demands of the cell. In addition, these findings highlight a new epigenetic mechanism by which SMYD1a regulates mitochondrial energetics and functions to protect the heart from ischemic injury.

Low-Intensity Focused Ultrasound Ameliorates Ischemic Heart Failure Related to the Cholinergic Anti-Inflammatory Pathway.

OBJECTIVES: This study aims to determine the effect of low-intensity focused ultrasound (LIFU) in ischemic heart failure (IHF) and explore the potential neuroimmune mechanism. METHODS: Sprague-Dawley rats were subjected to ultrasound (US) with specific parameters, and electrocardiograms were recorded to analyze the effect of LIFU and/or vagal denervation on heart rate. Thereafter, myocardial infarction (MI) was induced by left anterior artery ligation, and LIFU was performed three times a day for 25 days after MI. Echocardiography, Masson staining, and ELISA were used to evaluate the effect of LIFU on the structure and function of the heart. Finally, ELISA, flow cytometry, qRT-PCR, and Western blot analysis were performed to determine the effect of LIFU on the inflammation and the expression of the cholinergic anti-inflammatory pathway (CAP)-related mediators. RESULTS: LIFU reduced heart rate in rats (control vs LIFU, P < .01), and vagotomy (VT) eliminated this effect of LIFU on heart rate (VT vs LIFU + VT, P > .01). LIFU-ameliorated IHF in terms of cardiac structure and function (MI vs MI + LIFU, P < .01), but VT abrogated the beneficial effect of LIFU (MI + VT vs MI + LIFU + VT, P > .01). After the treatment of LIFU, decreased levels of inflammatory cytokines, increased proportion of anti-inflammatory macrophages, and increased expression of CAP-related mediators (MI vs MI + LIFU, P < .01). CONCLUSIONS: LIFU ameliorates IHF whereas the CAP plays a promising role. LIFU has the potential to be a novel nonpharmacological and noninvasive therapy for the treatment of coronary artery disease and other cardiovascular diseases.

Interaction of HSP70-2 gene polymorphism with body mass index and alcohol consumption on the prognosis of Uyghur patients with ischemic heart failure. / HSP70-2åŸºå› å¤šæ€æ€§ä¸Žä½“è´¨æŒ‡æ•°ã€é¥®é ’çš„äº¤äº’ä½œç”¨å¯¹ç»´å¾å°”æ—ç¼ºè¡€æ€§å¿ƒåŠ›è¡°ç«­æ‚£è€ é¢„åŽçš„å½±å“.

OBJECTIVES: To investigate the interaction of HSP70-2 gene polymorphism with body mass index (BMI) and alcohol consumption on the prognosis of Uyghur patients with ischemic heart failure (IHF). METHODS: A total of 205 Uyghur patients with IHF admitted in Urumqi Friendship Hospital from June 2014 to June 2017 were enrolled; 200 age and sex-matched healthy Uyghur physical examiners in the hospital were enrolled as healthy controls. The HSP70-2 gene +1267 polymorphism was detected by PCR. Multivariate unconditional logistic regression was used to analyze the risk factors associated with prognosis in patients with IHF, and the relative excess risk of interaction (RERI) was calculated by crossover analysis to determine the interaction of HSP70-2 gene polymorphism with BMI and alcohol consumption. RESULTS: Patients were followed up for 3 years, there were 56 cases with poor prognosis (27.32%) and 149 cases with good prognosis (72.68%). Compared with the healthy control group and the good prognosis group, the poor prognosis group had a significantly higher proportion of subjects with alcohol consumption, abnormal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels as well as lower BMI and left ventricular ejection fraction (all P<0.05). There were significant differences in distributions of HSP70-2 genotype AA/AG/GG and A/G allele between the good prognosis group and the poor prognosis group (both P<0.05). There were significant differences in the distribution of HSP70-2 genotype (χ2=45.42, P<0.01) and A/G allele among IHF patients with different NYHA cardiac function class; the frequency of A allele of HSP70-2 gene increased, and G allele decreased with the increase of cardiac function class (χ2=19.14, P<0.01). Multivariate logistic regression analysis showed that alcohol consumption as well as abnormal ALT and AST were risk factors for poor prognosis in patients with IHF, while BMI and GG type of HSP70-2 gene (compared with AA type) were protective factors (all P<0.05). Crossover analysis showed a significant additive interaction between BMI and HSP70-2 gene polymorphism (RERI=1.15, 95%CI: 0.54-1.76, P<0.01), and for patients carrying HSP70-2 gene type AA/AG, BMI<26.5 kg/m2 increased the risk of poor prognosis (OR=7.47, 95%CI: 2.51-22.22, P<0.01); there was no significant additive interaction between alcohol consumption and HSP70-2 gene polymorphism (RERI=0.56, 95%CI: －6.07-7.20, P>0.05). CONCLUSIONS: The HSP70-2 gene polymorphism interacts with BMI in Uyghur IHF patients, and BMI<26.5 kg/m2 increases the risk of poor prognosis in IHF patients carrying the HSP70-2 AA/AG genotype.

Chaperone-mediated autophagy protects cardiomyocytes against hypoxic-cell death.

Chaperone-mediated autophagy (CMA) is a chaperone-dependent process of selective cytosolic protein turnover that targets specific proteins to lysosomes for degradation. Enhancing protein degradation mechanisms has been shown to be beneficial in multiple models of cardiac disease, including myocardial infarction (MI) and ischemia-reperfusion (I/R) injury. However, the causal role of CMA in cardiomyocyte injury and death is largely unknown. Hypoxia is an important contributor to both MI and I/R damage, which are major, precedent causes of heart failure. Upregulating CMA was hypothesized to protect against hypoxia-induced cardiomyocyte death. Lysosome-associated membrane protein 2a (Lamp2a) overexpression and knockdown were used to causally study CMA's role in hypoxically stressed cardiomyocytes. LAMP2a protein levels were used as both a primary indicator and driver of CMA function. Hypoxic stress was stimulated by CoCl2 treatment, which increased LAMP2a protein levels (+1.4-fold) and induced cardiomyocyte apoptosis (+3.2-4.0-fold). Lamp2a siRNA knockdown (-3.2-fold) of control cardiomyocytes increased apoptosis (+1.8-fold) suggesting that loss of CMA is detrimental for cardiomyocyte survival. However, there was neither an additive nor a synergistic effect on cell death when Lamp2a-silenced cells were treated with CoCl2. Conversely, Lamp2a overexpression (+3.0-fold) successfully reduced hypoxia-induced apoptosis by ∼50%. LAMP2a was also significantly increased (+1.7-fold) in ischemic heart failure patient samples, similar to hypoxically stressed cardiomyocytes. The failing ischemic hearts may have had insufficient CMA activation. To our knowledge, this study for the first time establishes a protective role for CMA (via Lamp2a overexpression) against hypoxia-induced cardiomyocyte loss and reveals the intriguing possibility that CMA activation may offer a cardioprotective treatment for ischemic heart disease.

Nuclear Tkt promotes ischemic heart failure via the cleaved Parp1/Aif axis.

Transketolase (Tkt), an enzyme in pentose phosphate pathway, has been reported to regulate genome instability and cell survival in cancers. Yet, the role of Tkt after myocardial ischemic injury remains to be elucidated. Label-free proteomics revealed dramatic elevation of Tkt in murine hearts after myocardial infarction (MI). Lentivirus-mediated Tkt knockdown ameliorated cardiomyocyte apoptosis and preserved the systolic function after myocardial ischemic injury. In contrast, Tkt overexpression led to the opposite effects. Inducible conditional cardiomyocyte Tkt-knockout mice were generated, and cardiomyocyte-expressed Tkt was found to play an intrinsic role in the ischemic heart failure of these model mice. Furthermore, through luciferase assay and chromatin immunoprecipitation, Tkt was shown to be a direct target of transcription factor Krüppel-like factor 5 (Klf5). In cardiomyocytes under ischemic stress, Tkt redistributed into the nucleus. By binding with the full-length poly(ADP-ribose) polymerase 1 (Parp1), facilitating its cleavage, and activating apoptosis inducible factor (Aif) subsequently, nuclear Tkt demonstrated its non-metabolic functions. Overall, our study confirmed that elevated nuclear Tkt plays a noncanonical role in promoting cardiomyocyte apoptosis via the cleaved Parp1/Aif pathway, leading to the deterioration of cardiac dysfunction.

Effectiveness of Implantable Cardioverter Defibrillator in Patients With Non-Ischemic Heart Failure With Systolic Dysfunction　- Subanalysis of the Nippon Storm Study.

BACKGROUND: The prospective observational Nippon Storm Study aggregated clinical data from Japanese patients receiving implantable cardioverter-defibrillator (ICD) therapy. This study investigated the usefulness of prophylactic ICD therapy in patients with non-ischemic heart failure (NIHF) enrolled in the study.Methods and Results: We analyzed 540 NIHF patients with systolic dysfunction (left ventricular ejection fraction <50%). Propensity score matching was used to select patient subgroups for comparison; 126 patients were analyzed in each of the primary (PP) and secondary (SP) prophylaxis groups. The incidence of appropriate ICD therapy during follow-up in the PP and SP groups was 21.4% and 31.7%, respectively (P=0.044). The incidence of electrical storm (ES) was higher in SP than PP patients (P=0.024). Cox proportional hazard analysis revealed that increased serum creatinine in SP patients (hazard ratio [HR] 1.18; 95% confidence interval [CI] 1.02-1.33; P=0.013) and anemia in PP patients (HR 0.92; 95% CI 0.86-0.98; P=0.008) increased the likelihood of appropriate ICD therapy, whereas long-lasting atrial fibrillation in PP patients (HR, 0.64 [95% CI, 0.45-0.91], P=0.013) decreased that likelihood. CONCLUSIONS: In propensity score-matched Japanese NIHF patients, the incidence of appropriate ICD therapy and ES was significantly higher in SP than PP patients. Impaired renal function in SP patients and anemia in PP patients increased the likelihood of appropriate ICD therapy, whereas long-lasting atrial fibrillation reduced that likelihood in PP patients.

Tankyrase Inhibition Attenuates Cardiac Dilatation and Dysfunction in Ischemic Heart Failure.

Hyperactive poly(ADP-ribose) polymerases (PARP) promote ischemic heart failure (IHF) after myocardial infarction (MI). However, the role of tankyrases (TNKSs), members of the PARP family, in pathogenesis of IHF remains unknown. We investigated the expression and activation of TNKSs in myocardium of IHF patients and MI rats. We explored the cardioprotective effect of TNKS inhibition in an isoproterenol-induced zebrafish HF model. In IHF patients, we observed elevated TNKS2 and DICER and concomitant upregulation of miR-34a-5p and miR-21-5p in non-infarcted myocardium. In a rat MI model, we found augmented TNKS2 and DICER in the border and infarct areas at the early stage of post-MI. We also observed consistently increased TNKS1 in the border and infarct areas and destabilized AXIN in the infarct area from 4 weeks onward, which in turn triggered Wnt/ß-catenin signaling. In an isoproterenol-induced HF zebrafish model, inhibition of TNKS activity with XAV939, a TNKSs-specific inhibitor, protected against ventricular dilatation and cardiac dysfunction and abrogated overactivation of Wnt/ß-catenin signaling and dysregulation of miR-34a-5p induced by isoproterenol. Our study unravels a potential role of TNKSs in the pathogenesis of IHF by regulating Wnt/ß-catenin signaling and possibly modulating miRNAs and highlights the pharmacotherapeutic potential of TNKS inhibition for prevention of IHF.

Lim Domain Binding 3 (Ldb3) Identified as a Potential Marker of Cardiac Extracellular Vesicles.

Extracellular vesicles (EVs) are considered as transporters of biomarkers for the diagnosis of cardiac diseases, playing an important role in cell-to-cell communication during physiological and pathological processes. However, specific markers for the isolation and analysis of cardiac EVs are missing, imposing limitation on understanding their function in heart tissue. For this, we performed multiple proteomic approaches to compare EVs isolated from neonate rat cardiomyocytes and cardiac fibroblasts by ultracentrifugation, as well as EVs isolated from minced cardiac tissue and plasma by EVtrap. We identified Ldb3, a cytoskeletal protein which is essential in maintaining Z-disc structural integrity, as enriched in cardiac EVs. This result was validated using different EV isolation techniques showing Ldb3 in both large and small EVs. In parallel, we showed that Ldb3 is almost exclusively detected in the neonate rat heart when compared to other tissues, and specifically in cardiomyocytes compared to cardiac fibroblasts. Furthermore, Ldb3 levels, specifically higher molecular weight isoforms, were decreased in the left ventricle of ischemic heart failure patients compared to control groups, but not in the corresponding EVs. Our results suggest that Ldb3 could be a potential cardiomyocytes derived-EV marker and could be useful to identify cardiac EVs in physiological and pathological conditions.

The efficacy of trimetazidine in non-ischemic heart failure patients: a meta-analysis of randomized controlled trials.

Trimetazidine has been reported to benefit patients with heart failure (HF) and angina. The impact of trimetazidine on non-ischemic HF remains unclear. We reviewed clinical trials to investigate whether trimetazidine could improve exercise endurance, life quality, and heart function in non-ischemic HF patients. We searched the Cochrane Central Register of Controlled Trials, EMBASE, PubMed, and Web of science for randomized clinical trials published before April 30th, 2020; Studies limited to patients with non-ischemic HF, aged ≥18 years, comparing trimetazidine with conventional therapy with/without placebo. Outcome measurements included primary outcomes (6 minutes walking test (6-MWT)) and secondary outcomes (life quality scores, echocardiography parameters, biomarker, peak oxygen consumption). The follow-up period was longer than three months. This study was registered with international prospective register of systematic reviews (PROSPERO) (CRD42020182982). Six studies with 310 cases were included in this research. Trimetazidine significantly improved 6-MWT (weighted mean difference (WMD) = 48.51 m, 95% confidence interval (CI) [29.41, 67.61], p < 0.0001, I2 = 0%), left ventricle ejection fraction (LVEF) (WMD = 3.09%, 95% CI [1.09, 5.01], p = 0.002, I2 = 0%) at 3 months, and LVEF (WMD = 6.09%, 95% CI [3.76, 8.42], p < 0.0001, I2 = 12%) at 6 months. Furthermore, it reduced peak oxygen consumption (WMD = -2.24 mL/kg per minute, 95% CI [-4.09, -0.93], p = 0.02). This meta-analysis suggested that trimetazidine might be an effective strategy for improving exercise endurance and cardiac function in patients with non-ischemic HF.

Incremental value of myocardial wall motion and thickening to perfusion alone by gated SPECT myocardial perfusion imaging for viability assessment in patients with ischemic heart failure.

PURPOSE: The objective of this study was to assess the incremental value of myocardial wall motion and thickening compared with perfusion alone obtained from gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in diagnosing myocardial viability in patients with ischemic heart failure. METHODS: Eighty-three consecutive patients with ischemic heart failure who underwent both 99mTc-MIBI gated SPECT MPI and 18F-FDG positron emission tomography (PET) myocardial metabolic imaging were retrospectively enrolled. SPECT/PET myocardial viability was defined as the reference standard. Segmental myocardial perfusion, wall motion, and thickening were measured by an automated algorithm from gated SPECT MPI. Univariate and stepwise multivariate analysis were conducted to establish an optimal multivariate model for predicting hibernating myocardium and scar. RESULTS: Among the 1411 segments evaluated, 774 segments had normal perfusion and 637 segments had decreased perfusion. The latter were classified by 18F-FDG PET into 338 hibernating segments and 299 scarred segments. The multivariate regression analysis showed that the model that combined myocardial perfusion uptake with wall motion and thickening scores had the optimal predictive efficiency to distinguish hibernating myocardium from scar in the segments with decreased perfusion. The model had the largest C-statistic (0.753 vs 0.666, P < 0.0001), and the global chi-square was increased from 53.281 to 111.234 when compared with perfusion alone (P < 0.001). CONCLUSIONS: Assessment of myocardial wall motion and thickening in addition to conventional perfusion uptake in the segments with decreased perfusion enables better differentiation of hibernating myocardium from scar in patients with ischemic heart failure. Considering wide availability and high cost-effectiveness, regional myocardial function integrated with perfusion on gated SPECT MPI has great promise to become a clinical tool in the assessment of myocardial viability.

Complex electrophysiological remodeling in postinfarction ischemic heart failure.

Heart failure (HF) following myocardial infarction (MI) is associated with high incidence of cardiac arrhythmias. Development of therapeutic strategy requires detailed understanding of electrophysiological remodeling. However, changes of ionic currents in ischemic HF remain incompletely understood, especially in translational large-animal models. Here, we systematically measure the major ionic currents in ventricular myocytes from the infarct border and remote zones in a porcine model of post-MI HF. We recorded eight ionic currents during the cell's action potential (AP) under physiologically relevant conditions using selfAP-clamp sequential dissection. Compared with healthy controls, HF-remote zone myocytes exhibited increased late Na+ current, Ca2+-activated K+ current, Ca2+-activated Cl- current, decreased rapid delayed rectifier K+ current, and altered Na+/Ca2+ exchange current profile. In HF-border zone myocytes, the above changes also occurred but with additional decrease of L-type Ca2+ current, decrease of inward rectifier K+ current, and Ca2+ release-dependent delayed after-depolarizations. Our data reveal that the changes in any individual current are relatively small, but the integrated impacts shift the balance between the inward and outward currents to shorten AP in the border zone but prolong AP in the remote zone. This differential remodeling in post-MI HF increases the inhomogeneity of AP repolarization, which may enhance the arrhythmogenic substrate. Our comprehensive findings provide a mechanistic framework for understanding why single-channel blockers may fail to suppress arrhythmias, and highlight the need to consider the rich tableau and integration of many ionic currents in designing therapeutic strategies for treating arrhythmias in HF.

Long Non-Coding RNA SOX2 Overlapping Transcript Aggravates H9c2 Cell Injury via the miR-215-5p/ZEB2 Axis and Promotes Ischemic Heart Failure in a Rat Model.

Heart failure is a common cardiovascular disease, which has been regarded as one of the highest health care costs with high morbidity and mortality in the western countries. Long noncoding RNAs have been widely reported to regulate the initiation or progression of cardiovascular diseases. However, the specific role of SOX2 overlapping transcript (SOX2-OT) in ischemic heart failure remains uncharacterized. The present study aimed to explore the function and mechanism of SOX2-OT in ischemic heart failure. The starBase website was used to predict potential miRNAs or target mRNAs. Western blot assay was implemented to test collagen protein levels. Functional assays were conducted to evaluate the effects of SOX2-OT on H9c2 cell viability and apoptosis. RNA pull down and luciferase reporter assays were used to confirm the combination between miR-215-5p and SOX2-OT. We found out that SOX2-OT level was increased by oxygen glucose deprivation/reoxygenation treatment in H9c2 cells. Silencing of SOX2-OT ameliorated cell injury by promoting cell viability, inhibiting cell apoptosis and reducing productions of collagens. Mechanistically, miR-215-5p was confirmed to bind with SOX2-OT after prediction and screening. In addition, we discovered that miR-215-5p negatively regulated zinc finger E-box binding homeobox 2 (ZEB2) protein level by directly binding with ZEB2 3' untranslated region. Finally, we verified that SOX2-OT aggravated cell injury by targeting ZEB2 in H9c2 cells. In conclusion, SOX2-OT aggravated heart failure in vivo and promoted H9c2 cell injury via the miR-215-5p/ZEB2 axis in vitro, implying a novel insight into heart failure treatment.

Myocardial phenotypes and dysfunction in HFpEF and HFrEF assessed by echocardiography and cardiac magnetic resonance.

Heart failure (HF) with either reduced or preserved ejection fraction is an increasingly prevalent condition. Cardiac imaging plays a central role in trying to identify the underlying cause of the underlying systolic and diastolic dysfunction, as the imaging findings have implications for patient's management and individualised treatment. The imaging modalities used more frequently in patients with heart failure in clinical routine are echocardiography and cardiac magnetic resonance. Both techniques keep some strengths and weakness due to their spatial and temporal resolution. Notably, several features in the diagnostic algorithm of heart failure with preserved systolic function (HFpEF) may be improved by an integrated approach. This review focuses on the role of each modality in characterising cardiac anatomy, systolic and diastolic function as well as myocardial tissue characterisation in the most common phenotypes of dilated and hypertrophied hearts.

LncRNA promoted inflammatory response in ischemic heart failure through regulation of miR-455-3p/TRAF6 axis.

OBJECTIVES: Ischemic heart failure (IHF) is the most common cause of death globally. Growing evidence shows abnormal expression of long non-coding RNAs in heart failure patients. This study aims to investigate the effect of sex-determining region Y-box 2 (SOX2) overlapping transcript (SOX2-OT) on the regulation of the inflammatory response in ischemic heart failure. METHODS: IHF rat and oxygen and glucose deprivation (OGD) cell models were established. qRT-PCR was employed to investigate the expression of SOX2-OT. ELISA, western blot and cell viability/apoptosis assays were performed to assess the effects of SOX2-OT. Online software program was used to identify miRNAs that target SOX2-OT, followed by validation using RNA pull-down. Potential targets of miRNAs were searched, and examined by immunoblotting, qRT-PCR and luciferase reporter assay. RESULTS: SOX2-OT was up-regulated in IHF and OGD. Knockdown of SOX2-OT promoted cell proliferation, decreased apoptosis rate and cell oxidative damage, and ameliorated inflammatory response. SOX2-OT contains binding sites for miR-455-3p, miR-5586-3p and miR-1252-5p. RNA pull-down confirmed the binding ability between SOX2-OT and miR-455-3p. TRAF6 is a direct target of miR-455-3p. Moreover, the regulatory activity of SOX2-OT on inflammatory response was partially through its negative regulation of miR-455-3p, which directly regulates TRAF6. Down-regulation of SOX2-OT improved myocardial dysfunction in IHF rat. CONCLUSIONS: Our results reveal that SOX2-OT may be a driver of IHF through repression of miR-455-3p, and miR-455-3p alleviates IHF by targeting TRAF6. Therefore, SOX2-OT/miR-455-3p/TRAF6 may be a potential target for advanced therapeutic strategy for IHF.

Heart failure etiology and risk of right heart failure in adult left ventricular assist device support: the European Registry for Patients with Mechanical Circulatory Support (EUROMACS).

Objectives: Development of right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation remains a leading cause of perioperative morbidity, end-organ dysfunction and mortality. The objective of this study was to investigate whether the etiology of HF (ischemic HF versus non-ischemic HF) affects the risk of RVF within admission for LVAD implantation and during long-term follow-up. Methods: Between January 2011 and June 27, 2018, 3536 patients were prospectively enrolled into EUROMACS registry. Adult patients (>18 years) who received a first time LVAD were included. When excluding patients with congenital, restrictive, hypertrophic, valvular cardiomyopathies, and myocarditis the total population consisted of 2404 patients. Results: The total cohort consists of 2404 patients. Mean age were 55 years and predominantly male sex [2024 (84.2%)]. At the time of LVAD implantation 1355 (56.4%) patients had ischemic HF and 1049 (43.6%) patients had non-ischemic HF. The incidence of RVF was significantly increased in the non-ischemic HF group in the adjusted model (p = .026). The relative risk difference for RVF in patients with non-ischemic HF was in the adjusted model increased by an absolute value of 5.1% (95% CI: 0.61-9.6). In the ischemic HF group 76 patients (13.4%) developed late RVF and 62 patients (14.8%) in the non-ischemic HF group (p = .56). No differences in occurrence of RVF between HF etiology was observed after 2 and 4 years of follow-up, respectively (crude: p = .25, adjusted (sex and age) p = .2 and crude: p = .59, adjusted (sex and age) p = .44). Conclusions: Patients with non-ischemic HF undergoing LVAD had an increased incidence of early RVF compared to patients with ischemic HF in a large European population. During follow-up after discharge 14% patients developed RVF. We recommend HF etiology to be considered in identifying patients who are at risk for postoperative RVF after LVAD implantation.

Effect of Statins on Mortality in Heart Failure With Preserved Ejection Fraction Without Coronary Artery Disease　- Report From the JASPER Study.

BACKGROUND: Statins might be associated with improved survival in patients with heart failure with preserved ejection fraction (HFpEF). The effect of statins in HFpEF without coronary artery disease (CAD), however, remains unclear. Methods and Results: From the JASPER registry, a multicenter, observational, prospective cohort with Japanese patients aged ≥20 years requiring hospitalization with acute HF and LVEF ≥50%, 414 patients without CAD were selected for outcome analysis. Based on prescription of statins at admission, we divided patients into the statin group (n=81) or no statin group (n=333). We followed them for 25 months. The association between statin use and primary (all-cause mortality) and secondary (non-cardiac death, cardiac death, or rehospitalization for HF) endpoints was assessed in the entire cohort and in a propensity score-matched cohort. In the propensity score-matched cohort, 3-year mortality was lower in the statin group (HR, 0.21; 95% CI: 0.06-0.72; P=0.014). The statin group had a significantly lower incidence of non-cardiac death (P=0.028) and rehospitalization for HF (P<0.001), but not cardiac death (P=0.593). The beneficial effect of statins on mortality did not have any significant interaction with cholesterol level or HF severity. CONCLUSIONS: Statin use has a beneficial effect on mortality in HFpEF without CAD. The present findings should be tested in an adequately powered randomized clinical trial.

[Comparative analysis of clinical effects according to syndrome differentiation of Qili Qiangxin Capsules on ischemic heart failure: Meta-analysis].

Databases including CNKI,Wan Fang,CBM,VIP,PubMed and Cochrane Library were searched to collect qualified researches,and the quality of articles was evaluated according to scales. Meta-analysis including subgroup analysis was performed by using Rev Man 5. 3 software and Meta-regression test was performed by using Stata 12. 0 software. All of these methods were used to systematically evaluate the safety and clinical efficacy of Qili Qiangxin Capsules in treatment of ischemic heart failure under two circumstances( with or without syndrome differentiation). A total of 22 randomized controlled trials( RCTs) involving 1 942 patients were included,with generally low quality. RESULTS: of Meta-analysis showed that as compared with the routine Western treatment alone,additional use of Qili Qiangxin Capsules could improve the clinical efficacy( RR = 1. 21,95%CI[1. 16,1. 27],P<0. 000 01) in treatment of ischemic heart failure,with its combined effect of syndrome differentiation group greater than that of non-syndrome differentiation group( P= 0. 03,I~2= 78. 9%),Meta-regression( sig = 0. 9,P = 0. 057); left ventricular ejection fraction( WMD = 7. 28,95% CI[5. 18,9. 38],P<0. 000 01),with combined effect of syndrome differentiation group greater than that of non-syndrome differentiation group( P= 0. 01,I2= 83. 2%),Meta-regression( I~2= 81. 09%,R2= 29. 08%,sig = 0. 47,P = 0. 029); 6-minute walk test( WMD = 33. 20,95%CI[24. 70,41. 70 ],P < 0. 000 01); left ventricular end diastolic diameter( WMD =-4. 61,95% CI[-5. 38,-3. 84 ],P <0. 000 01); left ventricular end diastolic volume( WMD =-34. 43,95%CI[-38. 81,-30. 05],P< 0. 000 01); and left ventricular end systolic volume( WMD =-9. 60,95% CI[-13. 16,-6. 05],P < 0. 000 01). Adverse effects were reported in 11 patients taking Qili Qiangxin Capsules and in 20 patients with routine treatment group,tolerable in both groups. None of the patients had obvious abnormality in liver and kidney function. Qili Qiangxin Capsules were effective and safe in the treatment of ischemic heart failure,which can further improve clinical efficacy as compared with routine treatment alone. Qili Qiangxin Capsules with syndrome differentiation showed more significant effects than those without syndrome differentiation,indicating better efficacy of clinical syndrome differentiation. However,these conclusions still need to be verified with more high-quality and large-sample literature.