Hydrogen sulfide protects cardiomyocytes from doxorubicin-induced ferroptosis through the SLC7A11/GSH/GPx4 pathway by Keap1 S-sulfhydration and Nrf2 activation.

Recent studies have demonstrated that ferroptosis, a novel form of nonapoptotic regulated cell death plays an important role in doxorubicin (DOX)-induced cardiotoxicity (DoIC). Hydrogen sulfide (H2S) is emerging as the third important gaseous mediator in cardiovascular system. However, whether H2S has an effect on DOX-induced ferroptosis remains unknown. Here, we found that DOX not only triggered cardiomyocyte ferroptosis but also significantly inhibited the synthesis of endogenous H2S in the murine model of chronic DoIC. Application of NaHS, an H2S donor obviously activated the SLC7A11/GSH/GPx4 antioxidant pathway and thus alleviated DOX-induced ferroptosis and cardiac injury in mice. In contrast, cardiac-specific knockout of cystathionine γ-lyase gene (Cse) in mice (Csef/f/Cre+) to abolish the cardiac synthesis of endogenous H2S evidently exacerbated DOX-induced ferroptosis and cardiac dysfunction. A further suppression of SLC7A11/GSH/GPx4 pathway was obtained in Csef/f/Cre+ mice with DoIC, as compared to Csef/f/Cre- mice with DoIC. The aggravation caused by cardiac-specific Cse deficiency was remarkably rescued by exogenous supplementation of NaHS. Moreover, in DOX-stimulated H9c2 cardiomyocytes, pretreatment with NaHS dose-dependently enhanced the activity of SLC7A11/GSH/GPx4 pathway and subsequently mitigated ferroptosis and mitochondrial impairment. On the contrary, transfection with Cse siRNA in DOX-stimulated H9c2 cardiomyocytes markedly inhibited SLC7A11/GSH/GPx4 pathway, thus leading to aggravated ferroptosis and more damage to mitochondrial structure and function. In addition, the protective effect of NaHS on DOX-induced ferroptosis was closely related to the S-sulfhydrated Keap1, which in turn promoted nuclear translocation of Nrf2 and the transcription of SLC7A11 and GPx4. In conclusion, our findings suggest that H2S may exert protective effect on DoIC by inhibiting DOX-induced ferroptosis via Keap1/Nrf2-dependent SLC7A11/GSH/GPx4 antioxidant pathway.

Uric acid-lowering therapy with benzbromarone in hypertension with asymptomatic hyperuricemia: a randomized study focusing left ventricular diastolic function.

BACKGROUND: Both hypertension and hyperuricemia are closely associated with the morbidity and mortality of heart failure with preserved ejection fraction (HFpEF). However, there is limited evidence on the effect of uric acid-lowering therapy on left ventricular (LV) diastolic function in this population. In this randomized study, we prescribed benzbromarone, a uric acid-lowering drug, to those with hypertension and asymptomatic hyperuricemia to investigate its clinical benefits by evaluating LV diastolic function, incidence of HFpEF and hospitalization for heart failure and cardiovascular death. METHODS: 230 participants were randomly assigned into two groups: uric acid-lowering group (benzbromarone) and control groups (without uric acid-lowering drug). The primary endpoint was LV diastolic function evaluated by echocardiography. The secondary endpoint of composite endpoints is the combination of new-onset HFpEF, hospitalization for heart failure and cardiovascular death. RESULTS: After a median of 23.5 months' follow-up (16-30 months), the primary endpoint reflected by E/e' in benzbromarone group reached a significant improvement when compared to control group (p <.001). Composite endpoints occurred in 11 patients of the control group while only 3 patients occurred in the benzbromarone group (p = .027). We also presented the favorable trend of freedom from the composite endpoints or new-onset HFpEF using Kaplan-Meier curve by log-rank test in benzbromarone group (p = .037 and p = .054). CONCLUSIONS: Our study demonstrated the efficiency of benzbromarone in hypertensive patients with concomitant asymptomatic hyperuricemia, including the benefits on ameliorating LV diastolic dysfunction as well as improving composite endpoints.

Hydrogen sulfide alleviates heart failure with preserved ejection fraction in mice by targeting mitochondrial abnormalities via PGC-1α.

AIM: Increasing evidence has proposed that mitochondrial abnormalities may be an important factor contributing to the development of heart failure with preserved ejection fraction (HFpEF). Hydrogen sulfide (H2S) has been suggested to play a pivotal role in regulating mitochondrial function. Therefore, the present study was designed to explore the protective effect of H2S on mitochondrial dysfunction in a multifactorial mouse model of HFpEF. METHODS: Wild type, 8-week-old, male C57BL/6J mice or cardiomyocyte specific-Cse (Cystathionine γ-lyase, a major H2S-producing enzyme) knockout mice (CSEcko) were given high-fat diet (HFD) and l-NAME (an inhibitor of constitutive nitric oxide synthases) or standardized chow. After 4 weeks, mice were randomly administered with NaHS (a conventional H2S donor), ZLN005 (a potent transcriptional activator of PGC-1α) or vehicle. After additional 4 weeks, echocardiogram and mitochondrial function were evaluated. Expression of PGC-1α, NRF1 and TFAM in cardiomyocytes was assayed by Western blot. RESULTS: Challenging with HFD and l-NAME in mice not only caused HFpEF but also inhibited the production of endogenous H2S in a time-dependent manner. Meanwhile the expression of PGC-1α and mitochondrial function in cardiomyocytes were impaired. Supplementation with NaHS not only upregulated the expression of PGC-1α, NRF1 and TFAM in cardiomyocytes but also restored mitochondrial function and ultrastructure, conferring an obvious improvement in cardiac diastolic function. In contrast, cardiac deletion of CSE gene aggravated the inhibition of PGC-1α-NRF1-TFAM pathway, mitochondrial abnormalities and diastolic dysfunction. The deleterious effect observed in CSEcko HFpEF mice was partially counteracted by pre-treatment with ZLN005 or supplementation with NaHS. CONCLUSION: Our findings have demonstrated that H2S ameliorates left ventricular diastolic dysfunction by restoring mitochondrial abnormalities via upregulating PGC-1α and its downstream targets NRF1 and TFAM, suggesting the therapeutic potential of H2S supplementation in multifactorial HFpEF.

The Imbalance of p53-Park7 Signaling Axis Induces Iron Homeostasis Dysfunction in Doxorubicin-Challenged Cardiomyocytes.

Doxorubicin (DOX)-induced cardiotoxicity (DoIC) is a major side effect for cancer patients. Recently, ferroptosis, triggered by iron overload, is demonstrated to play a role in DoIC. How iron homeostasis is dysregulated in DoIC remains to be elucidated. Here, the authors demonstrate that DOX challenge exhibits reduced contractile function and induction of ferroptosis-related phenotype in cardiomyocytes, evidenced by iron overload, lipid peroxide accumulation, and mitochondrial dysfunction. Compared to Ferric ammonium citrate (FAC) induced secondary iron overload, DOX-challenged cardiomyocytes show a dysfunction of iron homeostasis, with decreased cytoplasmic and mitochondrial iron-sulfur (FeS) cluster-mediated aconitase activity and abnormal expression of iron homeostasis-related proteins. Mechanistically, mass spectrometry analysis identified DOX-treatment induces p53-dependent degradation of Parkinsonism associated deglycase (Park7) which results in iron homeostasis dysregulation. Park7 counteracts iron overload by regulating iron regulatory protein family transcription while blocking mitochondrial iron uptake. Knockout of p53 or overexpression of Park7 in cardiomyocytes remarkably restores the activity of FeS cluster and iron homeostasis, inhibits ferroptosis, and rescues cardiac function in DOX treated animals. These results demonstrate that the iron homeostasis plays a key role in DoIC ferroptosis. Targeting of the newly identified p53-Park7 signaling axis may provide a new approach to prevent DoIC.

Delivery of mitochondria confers cardioprotection through mitochondria replenishment and metabolic compliance.

Mitochondrial dysfunction is a hallmark of heart failure. Mitochondrial transplantation has been demonstrated to be able to restore heart function, but its mechanism of action remains unresolved. Using an in-house optimized mitochondrial isolation method, we tested efficacy of mitochondria transplantation in two different heart failure models. First, using a doxorubicin-induced heart failure model, we demonstrate that mitochondrial transplantation before doxorubicin challenge protects cardiac function in vivo and prevents myocardial apoptosis, but contraction improvement relies on the metabolic compatibility between transplanted mitochondria and treated cardiomyocytes. Second, using a mutation-driven dilated cardiomyopathic human induced pluripotent stem cell-derived cardiomyocyte model, we demonstrate that mitochondrial transplantation preferentially boosts contraction in the ventricular myocytes. Last, using single-cell RNA-seq, we show that mitochondria transplantation boosts contractility in dystrophic cardiomyocytes with few transcriptomic alterations. Together, we provide evidence that mitochondria transplantation confers myocardial protection and may serve as a potential therapeutic option for heart failure.

Motion profile and control design of fast steering mirror for backscanning step and stare imaging.

Fast steering mirrors (FSMs) have been used for decades to improve the performance of electro-optical imaging systems, such as airborne imaging systems and space-based optical surveillance systems. With the advantage of increasing the accuracy of image motion compensation and the efficiency of scanning imaging, backscanning step-and-stare imaging has become the main approach to realizing wide-area surveillance for airborne imaging systems. According to the operating mode and motion profile of the FSM in the imaging system, a combined optimized profile (COP) is designed to avoid abrupt changes in the velocity and acceleration of the FSM. The angular position sensor based on a four-quadrant detector is used in FSMs to expand the measuring range and cut the cost at the expense of larger measurement noise. Combining a Kalman filter with a disturbance observer and zero-phase error tracking control, a control method is proposed to improve the control precision and bandwidth while suppressing measurement noise. Simulation and experimental results show that the profile designed by COP is smooth enough to meet the special requirements of FSM's backscanning image motion compensation and that the Kalman filter-based FSM control method can significantly improve the control accuracy.

Diabetic cardiomyopathy: a brief summary on lipid toxicity.

Diabetes mellitus (DM) is a serious epidemic around the globe, and cardiovascular diseases account for the majority of deaths in patients with DM. Diabetic cardiomyopathy (DCM) is defined as a cardiac dysfunction derived from DM without the presence of coronary artery diseases and hypertension. Patients with either type 1 or type 2 DM are at high risk of developing DCM and even heart failure. Metabolic disorders of obesity and insulin resistance in type 2 diabetic environments result in dyslipidaemia and subsequent lipid-induced toxicity (lipotoxicity) in organs including the heart. Although various mechanisms have been proposed underlying DCM, it remains incompletely understood how lipotoxicity alters cardiac function and how DM induces clinical heart syndrome. With recent progress, we here summarize the latest discoveries on lipid-induced cardiac toxicity in diabetic hearts and discuss the underlying therapies and controversies in clinical DCM.

p53-Dependent Mitochondrial Compensation in Heart Failure With Preserved Ejection Fraction.

Background Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of patients with heart failure. Clinically, HFpEF prevalence shows age and gender biases. Although the majority of patients with HFpEF are elderly, there is an emergence of young patients with HFpEF. A better understanding of the underlying pathogenic mechanism is urgently needed. Here, we aimed to determine the role of aging in the pathogenesis of HFpEF. Methods and Results HFpEF dietary regimen (high-fat diet + Nω-Nitro-L-arginine methyl ester hydrochloride) was used to induce HFpEF in wild type and telomerase RNA knockout mice (second-generation and third-generation telomerase RNA component knockout), an aging murine model. First, both male and female animals develop HFpEF equally. Second, cardiac wall thickening preceded diastolic dysfunction in all HFpEF animals. Third, accelerated HFpEF onset was observed in second-generation telomerase RNA component knockout (at 6 weeks) and third-generation telomerase RNA component knockout (at 4 weeks) compared with wild type (8 weeks). Fourth, we demonstrate that mitochondrial respiration transitioned from compensatory state (normal basal yet loss of maximal respiratory capacity) to dysfunction (loss of both basal and maximal respiratory capacity) in a p53 dosage dependent manner. Last, using myocardial-specific p53 knockout animals, we demonstrate that loss of p53 activation delays the development of HFpEF. Conclusions Here we demonstrate that p53 activation plays a role in the pathogenesis of HFpEF. We show that short telomere animals exhibit a basal level of p53 activation, mitochondria upregulate mtDNA encoded genes as a mean to compensate for blocked mitochondrial biogenesis, and loss of myocardial p53 delays HFpEF onset in high fat diet + Nω-Nitro-L-arginine methyl ester hydrochloride challenged murine model.

Secretion of miRNA-326-3p by senescent adipose exacerbates myocardial metabolism in diabetic mice.

BACKGROUND: Adipose tissue homeostasis is at the heart of many metabolic syndromes such as diabetes. Previously it has been demonstrated that adipose tissues from diabetic patients are senescent but whether this contributes to diabetic cardiomyopathy (DCM) remains to be elucidated. METHODS: The streptozotocin (STZ) type 1 diabetic mice were established as animal model, and adult mouse ventricular myocytes (AMVMs) isolated by langendorff perfusion as well as neonatal mouse ventricular myocytes (NMVMs) were used as cell models. Senescent associated ß galactosidase (SA-ß-gal) staining and RT-qPCR were used to identify the presence of adipose senescence in diabetic adipose tissue. Senescent adipose were removed either by surgery or by senolytic treatment. Large extracellular vesicles (LEVs) derived from adipose tissue and circulation were separated by ultracentrifugation. Cardiac systolic and diastolic function was evaluated through cardiac ultrasound. Cardiomyocytes contraction function was evaluated by the Ionoptix HTS system and live cell imaging, mitochondrial morphology and functions were evaluated by transmission electron microscope, live cell fluorescent probe and seahorse analysis. RNA-seq for AMVMs and miRNA-seq for LEVs were performed, and bioinformatic analysis combined with RT-qPCR and Western blot were used to elucidate underlying mechanism that senescent adipose derives LEVs exacerbates myocardial metabolism. RESULTS: SA-ß-gal staining and RT-qPCR identified the presence of adipose tissue senescence in STZ mice. Through surgical as well as pharmacological means we show that senescent adipose tissue participates in the pathogenesis of DCM in STZ mice by exacerbates myocardial metabolism through secretion of LEVs. Specifically, expression of miRNA-326-3p was up-regulated in LEVs isolated from senescent adipose tissue, circulation, and cardiomyocytes of STZ mice. Up-regulation of miRNA-326-3p coincided with myocardial transcriptomic changes in metabolism. Functionally, we demonstrate that miRNA-326-3p inhibited the expression of Rictor and resulted in impaired mitochondrial and contractile function in cardiomyocytes. CONCLUSION: We demonstrate for the first time that senescent adipose derived LEVs exacerbates myocardial metabolism through up-regulated miRNA-326-3p which inhibits Rictor in cardiomyocytes. Furthermore, reducing senescence burden in adipose tissue is capable of relieving myocardial metabolism disorder in diabetes mellitus.

Initial Invasive or Conservative Strategy in Heart Failure With Preserved Ejection Fraction and Coronary Artery Disease.

Background: In patients with both heart failure with preserved ejection fraction (HFpEF) and coronary artery disease (CAD), whether adopting an initial invasive strategy benefits better in clinical outcomes compared with those who received an initial conservative strategy remains inconclusive. Methods: With data from the heart failure (HF) cohort study, we analyzed patients who had HFpEF and CAD amenable to the invasive intervention using propensity score matching of 1:1 ratio to compare the initial invasive strategy and the initial conservative strategy of medical therapy alone. The primary outcome was the composite endpoints of all-cause mortality or cardiovascular hospitalization, and the secondary outcome was all-cause mortality or cardiovascular hospitalization. Results: Of 1,718 patients, 706 were treated with the invasive strategy and 1,012 with the conservative strategy initially. Propensity score matching was used to assemble a matched cohort of 1,320 patients receiving the invasive intervention (660 patients) or the medical therapy alone (660 patients). With a follow-up of 5 years, 378 (57.3%) in the invasive-strategy group and 403 (61.1%) in the conservative-strategy group reached the primary endpoint, and there was no significant difference in the rate of the primary endpoint (P = 0.162). The initial invasive strategy only improved the secondary outcome of cardiovascular hospitalization (P = 0.035). Also, the multivariable Cox regression model revealed that antiplatelet therapy, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB), or statin prescription was associated with a decreased risk of the primary outcome. Conclusion: In this well-profiled, propensity-matched cohort of patients with HFpEF and CAD, the addition of invasive intervention to medical therapy did not improve the long-term composite of all-cause mortality or cardiovascular hospitalization.

Protective Effect of Crocin on Immune Checkpoint Inhibitors-Related Myocarditis Through Inhibiting NLRP3 Mediated Pyroptosis in Cardiomyocytes via NF-κB Pathway.

Purpose: Immune checkpoint inhibitors (ICIs)-related myocarditis is now one of the most critical immune-related adverse effects (irAEs) in tumor immunotherapy, which has raised great concern in cardio-oncology. The pathogenesis involved in cardiac injury remains elusive. Crocin, the main component of saffron, has shown distinct functions in cardioprotective and anti-inflammation properties. We therefore aimed to investigate the potential effect of crocin on the protection of ICIs-related myocarditis and its underlying molecular mechanism. Methods: We immunized the BALB/c mice with murine cardiac troponin I (cTnI) peptide and additionally gave anti-mouse programmed death 1 (PD-1) to induce the mouse model of ICIs-related myocarditis. Mice were treated with crocin at different dosages. In vitro, HL-1 cells were pre-incubated with crocin at different concentrations and then stimulated with lipopolysaccharide (LPS). Myocardial contractile functions, myocardial inflammation and fibrosis, and myocardial injury were assessed. The expressions of pyroptosis-related proteins and nuclear factor-κB (NF-κB) pathway were evaluated. Results: Crocin treatment could partially reverse the ICIs-related myocarditis in terms of improving heart function, ameliorating inflammation and fibrosis in the myocardium, and alleviating myocardial injury. Mechanistically, ICIs administration significantly activated pyrin domain-containing protein 3 (NLRP3) inflammasome in cardiomyocytes. Crocin treatments significantly downregulated the expression of NLRP3, cleaved gasdermin D (GSDMD), cleaved caspase1, interleukin-1ß (IL-1ß), and IL-18. Besides, crocin inhibited the activation of NF-κB pathway, which performed as reducing the phosphorylation of p-NF-kappa-B inhibitor-α (p-IκBα), degradation of IκBα, phosphorylation of p65 and p65 DNA binding activity both in vivo and in vitro. Conclusion: By reversing the pyroptosis in cardiomyocytes, crocin treatment in a mouse model exerted great potential to aid in the prevention of ICIs-related myocarditis from a novel target.

Optimal management of blood glucose, blood pressure and atrial fibrillation to reduce the risk of heart failure with preserved ejection fraction.

BACKGROUND: Type 2 diabetes mellitus (T2DM), hypertension and atrial fibrillation (AF) are risk factors for heart failure with preserved ejection fraction (HFpEF). AIM: To examine the effects of the simultaneous control of all three conditions on new-onset HFpEF in this population. METHODS: This prospective cohort study enrolled 552 patients with T2DM, hypertension and AF, but without clinical signs or symptoms of heart failure. The participants were followed up for 5 years to examine the effects of glycaemic control (haemoglobin A1c: <7.0%, 7.0%-8.0% and >8.0%), blood pressure (BP) control (systolic BP: <120, 120-140 and >140 mmHg) or rhythm versus rate control for AF on new-onset HFpEF. RESULTS: With a follow up of 5 years, the new-onset HFpEF occurred in 62 of 552 enrolled participants. Among the different control level for diabetes, hypertension and AF, the intensive blood glucose (BG) control, poor BP control and rate control of AF had the highest risk of new-onset HFpEF, and the conservative BG control, intensive BP control and rhythm control of AF had the lowest risk of new-onset HFpEF. Multivariable Cox regression analysis showed that both poor BP control (hazard ratio (HR): 1.421, 95% confidence interval (CI): 1.013-1.992, P = 0.042) and rate control of AF (HR: 1.362, 95% CI: 1.006-1.821, P = 0.033) were independently associated with the development of new-onset HFpEF. CONCLUSION: This study demonstrated that, besides intensive BP control, conservative BG control and rhythm control of AF were crucial factors to delay the progression of HFpEF among patients with T2DM, hypertension and AF.

MiR-21-3p Inhibits Adipose Browning by Targeting FGFR1 and Aggravates Atrial Fibrosis in Diabetes.

A relationship between excess epicardial adipose tissue (EAT) and the risk of atrial fibrillation (AF) has been reported. Browning of EAT may be a novel approach for the prevention or treatment of AF by attenuating atrial fibrosis. Previous studies have identified microRNA-21 (miR-21) as a regulatory factor in atrial fibrosis. The present study examined the role of different subtypes of miR-21 in adipose browning and atrial fibrosis under hyperglycemic conditions. Wild type and miR-21 knockout C57BL/6 mice were used to establish a diabetic model via intraperitoneal injection of streptozotocin. A coculture model of atrial fibroblasts and adipocytes was also established. We identified miR-21-3p as a key regulator that controls adipocyte browning and participates in atrial fibrosis under hyperglycemic conditions. Moreover, fibroblast growth factor receptor (FGFR) 1, a direct target of miR-21-3p, decreased in this setting and controlled adipose browning. Gain and loss-of-function experiments identified a regulatory pathway in adipocytes involving miR-21a-3p, FGFR1, FGF21, and PPARγ that regulated adipocyte browning and participated in hyperglycemia-induced atrial fibrosis. Modulation of this signaling pathway may provide a therapeutic option for the prevention and treatment of atrial fibrosis or AF in DM.

Irisin ameliorates doxorubicin-induced cardiac perivascular fibrosis through inhibiting endothelial-to-mesenchymal transition by regulating ROS accumulation and autophagy disorder in endothelial cells.

The dose-dependent toxicity to cardiomyocytes has been well recognized as a central characteristic of doxorubicin (DOX)-induced cardiotoxicity (DIC), however, the pathogenesis of DIC in the cardiac microenvironment remains elusive. Irisin is a new hormone-like myokine released into the circulation in response to exercise with distinct functions in regulating apoptosis, inflammation, and oxidative stress. Recent advances revealed the role of irisin as a novel therapeutic method and an important mediator of the beneficial effects of exercise in cardioprotection. Here, by using a low-dose long-term mouse DIC model, we found that the perivascular fibrosis was involved in its myocardial toxicity with the underlying mechanism of endothelial-to-mesenchymal transition (EndMT). Irisin treatment could partially reverse DOX-induced perivascular fibrosis and cardiotoxicity compared to endurance exercise. Mechanistically, DOX stimulation led to excessive accumulation of ROS, which activated the NF-κB-Snail pathway and resulted in EndMT. Besides, dysregulation of autophagy was also found in DOX-treated endothelial cells. Restoring autophagy flux could ameliorate EndMT and eliminate ROS. Irisin treatment significantly alleviated ROS accumulation, autophagy disorder, NF-κB-Snail pathway activation as well as the phenotype of EndMT by targeting uncoupling protein 2 (UCP2). Our results also initially found that irisin was mainly secreted by cardiomyocytes in the cardiac microenvironment, which was significantly reduced by DOX intervention, and had a protective effect on endothelial cells in a paracrine manner. In summary, our study indicated that DOX-induced ROS accumulation and autophagy disorders caused an EndMT in CMECs, which played a role in the perivascular fibrosis of DIC. Irisin treatment could partially reverse this phenomenon by regulating UCP2. Cardiomyocytes were the main source of irisin in the cardiac microenvironment. The current study provides a novel perspective elucidating the pathogenesis and the potential treatment of DIC.

Association of Circulating Irisin Levels and the Characteristics and Prognosis of Coronary Artery Disease.

BACKGROUND: Irisin is a new muscle factor discovered in recent years that shows a strong association with metabolic diseases. However, its role in coronary artery disease (CAD) is still controversial. We performed this study to determine the relationship of serum irisin with the characteristics and prognosis of CAD. MATERIALS AND METHODS: Patients with acute coronary syndrome (ACS) (n = 355), stable coronary artery disease (SCAD) (n = 162), nonobstructive coronary artery disease (NO-CAD) (n = 126) and normal coronary arteries (n = 109) were enrolled. An enzyme-linked immunosorbent assay kit was used to measure serum irisin concentrations. Major adverse cardiovascular events (MACEs) of patients with SCAD (n = 132) and ACS (n = 331) after percutaneous coronary intervention (PCI) were recorded during a 12-month follow-up. Receiver-operator characteristic (ROC) curve analysis was used to explore predictors of CAD. Kaplan-Meier survival analysis and the Cox proportional hazards regression model were used to explore the association between serum irisin levels and MACEs. RESULTS: Serum irisin levels in patients with ACS, SCAD, NO-CAD and normal coronary arteries were 196.62±72.05 ng/ml, 216.81±79.69 ng/ml, 245.26±77.92 ng/ml and 300.17±76.74 ng/ml, respectively (p<0.001). ROC curve analysis indicated that serum irisin concentrations were a valuable biomarker of coronary lesions (AUC=0.799), CAD (AUC=0.734) and ACS (AUC=0.681). Survival analysis demonstrated that patients with high irisin levels exhibited a higher event-free survival rate in both the SCAD and ACS groups after successful PCI. CONCLUSIONS: Serum irisin levels were significantly decreased in patients with CAD. Patients with ACS exhibited the lowest serum irisin levels. Furthermore, serum irisin levels were interrelated with prognosis in patients with CAD after PCI.

Characteristics, prognosis and treatment response in distinct phenogroups of heart failure with preserved ejection fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. We aimed to derive HFpEF phenotype-based groups based on clinical features using machine learning, and to compare clinical characteristics, outcomes and treatment response across the phenogroups. METHODS: We applied model-based clustering to 11 clinical and laboratory variables collected in 970 HFpEF patients. An additional 290 HFpEF patients was enrolled as a validation cohort. During 5-year follow-up, all-cause mortality was used as the primary endpoints, and composite endpoints (all-cause mortality or HF hospitalization) were set as the secondary endpoint. RESULTS: We identified three phenogroups, for which significant differences in the age and gender, the prevalence of concomitant ischaemic heart disease, atrial fibrillation and type 2 diabetes mellitus, the burden of B-type natriuretic peptide level and HF symptoms. Patients with phenogroup 3 had higher all-cause mortality or composite endpoints, whereas patients in phenogroup 1 had less adverse events after 5-year follow-up. Moreover, it was indicated that beta-blockers or angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB) use was associated with a lower risk of all-cause mortality or composite endpoints in phenogroup 3, instead of the other phenogroups. This HFpEF phenogroup classification, including its ability to stratify risk, was successfully replicated in a prospective validation cohort. CONCLUSION: Machine-learning based clustering strategy is used to identify three distinct phenogroups of HFpEF that are characterized by significant differences in comorbidity burden, underlying cardiac abnormalities, and long-term prognosis. Beta-blockers or ACEI/ARB therapy is associated with a lower risk of adverse events in specific phenogroup.

Microfluidic fabrication of inhalable large porous microspheres loaded with H2S-releasing aspirin derivative for pulmonary arterial hypertension therapy.

Hydrogen sulfide (H2S) has recently emerged as a novel gaseous mediator with protective actions in the treatment of pulmonary arterial hypertension (PAH). However, the therapeutic potential of H2S in PAH has been substantially hampered due to the lack of appropriate donors that could mimic the slow and continuous generation of H2S in vivo. Large porous microspheres (LPMs) have low density and large surface area leading to excellent absorption capabilities and aerodynamic properties. They are extensively studied as pulmonary delivery carriers for controlled and sustained release of drug molecules in the treatment of pulmonary disorders. Therefore, we hypothesized that LPMs containing H2S-releasing aspirin derivative (ACS14), a novel synthetic H2S donor may be a feasible option to facilitate the use of H2S in PAH treatment. LPMs were prepared with a biodegradable polymer, poly(lactic-co-glycolic acid) (PLGA) by a microfluidic technique. Surface morphology, lung deposition characteristics, safety and H2S release profiles of the formulation were evaluated. The resulting ACS14-containing LPMs (ACS14 MSs) displayed excellent aerodynamic properties (mass median aerodynamic diameter of 4.4 ± 0.4 µm), desirable drug loading and entrapment efficiency (25.8 ± 2.7% and 77.4 ± 6.9%, respectively) with slow and sustained H2S release for 24 h and negligible cytotoxicity (~95% cell viability). Daily intratracheally administered with ACS14 MSs elicited improvement in the severity of PAH in a rat model of monocrotaline-induced PAH, with comparable efficacy to oral administration with sildenafil, a conventional PAH treatment. It also inhibited the process of endothelial-to-mesenchymal transition (EndMT), an important process in vascular remodeling of PAH by suppressing the induction of NF-κB-Snail pathway. Moreover, ACS14 MSs dose-dependently inhibited TGF-ß1-induced EndMT and the activation of NF-κB-Snail pathway in human pulmonary artery endothelial cells. In conclusion, our findings demonstrated that the designed microfluidics-assisted ACS14-containing LPMs have shown great potential to be used as an inhalable and efficacious H2S donor in the treatment of PAH.

Association between long-term prescription of febuxostat and the progression of heart failure with preserved ejection fraction in patients with hypertension and asymptomatic hyperuricemia.

Both hypertension and hyperuricemia are closely associated with the morbidity and mortality of heart failure. This study was designed to evaluate the influences of long-term xanthine oxidase inhibitor (febuxostat) prescription on left ventricular hypertrophy (LVH), left ventricular (LV) diastolic function, and new-onset heart failure with preserved ejection fraction (HFpEF) in these patients. Using a propensity score matching of 1:2 ratio, this retrospective claims database study compared febuxosatat prescription (n = 96) and non-urate-lowering therapy (n = 192) in patients with hypertensive left ventricular hypertrophy (LVH) and asymptomatic hyperuricemia. With a follow-up of 36 months, febuxostat significantly decreased the level of serum uric acid as well as generated more prominent improvement in LVH and LV diastolic function. Besides, the new-onset symptomatic HFpEF occurred in 2 of 96 patients in febuxostat group and 13 of 192 patients in non-urate-lowering group (P = 0.091). No increased risk for major adverse cardiovascular events in patients prescribed with febuxostat was noted. In conclusion, long-term febuxostat exposure was associated with protective effects in terms of LVH or LV diastolic dysfunction in patients with hypertensive LVH and asymptomatic hyperuricemia. Febuxostat also displayed a trend for reduced risk of new-onset HFpEF in this population.

miR-146a attenuates apoptosis and modulates autophagy by targeting TAF9b/P53 pathway in doxorubicin-induced cardiotoxicity.

Clinical therapy of doxorubicin (DOX) is limited due to its cardiotoxicity. miR-146a was proved as a protective factor in many cardiovascular diseases, but its role in chronic DOX-induced cardiotoxicity is unclear. The objective of this study was to demonstrate the role of miR-146a in low-dose long-term DOX-induced cardiotoxicity. Experiments have shown that DOX intervention caused a dose-dependent and time-dependent cardiotoxicity involving the increased of apoptosis and dysregulation of autophagy. The cardiotoxicity was inhibited by overexpressed miR-146a and was more severe when miR-146a was downgraded. Further research proved that miR-146a targeted TATA-binding protein (TBP) associated factor 9b (TAF9b), a coactivator and stabilizer of P53, indirectly destroyed the stability of P53, thereby inhibiting apoptosis and improving autophagy in cardiomyocytes. Besides, miR-146a knockout mice were used for in vivo validation. In the DOX-induced model, miR-146a deficiency made it worse whether in cardiac function, cardiomyocyte apoptosis or basal level of autophagy, than wild-type. In conclusion, miR-146a partially reversed the DOX-induced cardiotoxicity by targeting TAF9b/P53 pathway to attenuate apoptosis and adjust autophagy levels.