Adipsin inhibits Irak2 mitochondrial translocation and improves fatty acid ß-oxidation to alleviate diabetic cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DCM) causes the myocardium to rely on fatty acid ß-oxidation for energy. The accumulation of intracellular lipids and fatty acids in the myocardium usually results in lipotoxicity, which impairs myocardial function. Adipsin may play an important protective role in the pathogenesis of DCM. The aim of this study is to investigate the regulatory effect of Adipsin on DCM lipotoxicity and its molecular mechanism. METHODS: A high-fat diet (HFD)-induced type 2 diabetes mellitus model was constructed in mice with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg). Liquid chromatography-tandem mass spectrometry (LC-MS/MS), glutathione-S-transferase (GST) pull-down technique, Co-immunoprecipitation (Co-IP) and immunofluorescence colocalization analyses were used to investigate the molecules which can directly interact with Adipsin. The immunocolloidal gold method was also used to detect the interaction between Adipsin and its downstream modulator. RESULTS: The expression of Adipsin was significantly downregulated in the HFD-induced DCM model (P < 0.05). Adipose tissue-specific overexpression of Adipsin significantly improved cardiac function and alleviated cardiac remodeling in DCM (P < 0.05). Adipsin overexpression also alleviated mitochondrial oxidative phosphorylation function in diabetic stress (P < 0.05). LC-MS/MS analysis, GST pull-down technique and Co-IP studies revealed that interleukin-1 receptor-associated kinase-like 2 (Irak2) was a downstream regulator of Adipsin. Immunofluorescence analysis also revealed that Adipsin was co-localized with Irak2 in cardiomyocytes. Immunocolloidal gold electron microscopy and Western blotting analysis indicated that Adipsin inhibited the mitochondrial translocation of Irak2 in DCM, thus dampening the interaction between Irak2 and prohibitin (Phb)-optic atrophy protein 1 (Opa1) on mitochondria and improving the structural integrity and function of mitochondria (P < 0.05). Interestingly, in the presence of Irak2 knockdown, Adipsin overexpression did not further alleviate myocardial mitochondrial destruction and cardiac dysfunction, suggesting a downstream role of Irak2 in Adipsin-induced responses (P < 0.05). Consistent with these findings, overexpression of Adipsin after Irak2 knockdown did not further reduce the accumulation of lipids and their metabolites in the cardiac myocardium, nor did it enhance the oxidation capacity of cardiomyocytes expose to palmitate (PA) (P < 0.05). These results indicated that Irak2 may be a downstream regulator of Adipsin. CONCLUSIONS: Adipsin improves fatty acid ß-oxidation and alleviates mitochondrial injury in DCM. The mechanism is related to Irak2 interaction and inhibition of Irak2 mitochondrial translocation.

Adipsin alleviates cardiac microvascular injury in diabetic cardiomyopathy through Csk-dependent signaling mechanism.

BACKGROUND: Microvascular complications are associated with an overtly increased risk of adverse outcomes in patients with diabetes including coronary microvascular injury which manifested as disruption of adherens junctions between cardiac microvascular endothelial cells (CMECs). However, particular mechanism leading to diabetic coronary microvascular hyperpermeability remains elusive. METHODS: Experimental diabetes was induced in mice with adipose tissue-specific Adipsin overexpression (AdipsinLSL/LSL-Cre) and their respective control (AdipsinLSL/LSL). In addition, cultured CMECs were subjected to high glucose/palmitic acid (HG + PA) treatment to simulate diabetes for a mechanistic approach. RESULTS: The results showed that Adipsin overexpression significantly reduced cardiac microvascular permeability, preserved coronary microvascular integrity, and increased coronary microvascular density. Adipsin overexpression also attenuated cardiac dysfunction in diabetic mice. E/A ratio, an indicator of cardiac diastolic function, was improved by Adipsin. Adipsin overexpression retarded left ventricular adverse remodeling, enhanced LVEF, and improved cardiac systolic function. Adipsin-enriched exosomes were taken up by CMECs, inhibited CMECs apoptosis, and increased CMECs proliferation under HG + PA treatment. Adipsin-enriched exosomes also accelerated wound healing, rescued cell migration defects, and promoted tube formation in response to HG + PA challenge. Furthermore, Adipsin-enriched exosomes maintained adherens junctions at endothelial cell borders and reversed endothelial hyperpermeability disrupted by HG + PA insult. Mechanistically, Adipsin blocked HG + PA-induced Src phosphorylation (Tyr416), VE-cadherin phosphorylation (Tyr685 and Tyr731), and VE-cadherin internalization, thus maintaining CMECs adherens junctions integrity. LC-MS/MS analysis and co-immunoprecipitation analysis (Co-IP) unveiled Csk as a direct downstream regulator of Adipsin. Csk knockdown increased Src phosphorylation (Tyr416) and VE-cadherin phosphorylation (Tyr685 and Tyr731), while abolishing Adipsin-induced inhibition of VE-cadherin internalization. Furthermore, Csk knockdown counteracted Adipsin-induced protective effects on endothelial hyperpermeability in vitro and endothelial barrier integrity of coronary microvessels in vivo. CONCLUSIONS: Together, these findings favor the vital role of Adipsin in the regulation of CMECs adherens junctions integrity, revealing its promises as a treatment target against diabetic coronary microvascular dysfunction. Graphical abstract depicting the mechanisms of action behind Adipsin-induced regulation of diabetic coronary microvascular dysfunction.

Fibroblast-specific activation of Rnd3 protects against cardiac remodeling in diabetic cardiomyopathy via suppression of Notch and TGF-ß signaling.

Rationale: Extracellular matrix (ECM) remodeling, a key pathological feature in diabetic cardiomyopathy (DCM), is triggered by oxidative stress, inflammation, and various metabolic disorders in the heart. Cardiac fibroblasts (CFs) are the primary source of ECM proteins and the ultimate effector cells in ECM remodeling. CFs are turned on and differentiated into myofibroblasts in response to profibrotic signaling. Rnd3 is a small Rho-GTPase involved in the regulation of cell-cycle distribution, cell migration, and cell morphogenesis. Emerging evidence suggests a link between Rnd3 expression and onset of cardiovascular diseases. However, the role of Rnd3 in DCM remains unknown. Methods: Flow cytometry was employed to separate different types of cardiac cells. Type 2 diabetes mellitus was established in Rnd3 fibroblast-specific knockout and transgenic mice. RNA sequencing and chromatin immunoprecipitation assay were used to discern signaling pathways involved. Results: Rnd3 expression was reduced in cardiac tissues of diabetic mice, with CFs being the primary cell type. Fibroblast-specific upregulation of Rnd3 in vivo was protective against DCM, whereas Rnd3 downregulation in fibroblasts accentuated cardiac oxidative stress, fibrosis, ventricular remodeling, and dysfunction. Moreover, in vitro Rnd3 overexpression significantly attenuated reactive oxygen species production, CF migration and proliferation under high levels of glucose (35 mmol/L) and palmitic acid (500 µmol/L) challenge. Furthermore, RNA sequencing indicated that Notch and TGF-ß signaling were significantly suppressed upon Rnd3 overexpression. Mechanistically, Rnd3 regulated Notch and TGF-ß signaling by interacting with NICD and ROCK1, respectively. Specifically, glucotoxicity and lipotoxicity control Rnd3 expression by regulating the binding of Nr1H2 and Rnd3 promoter. Conclusions: Our findings provide compelling evidence in that fibroblast-specific activation of Rnd3 protects against cardiac remodeling in DCM, indicating promises of targeting Rnd3 in the treatment of DCM.

Inhibition of macrophage-derived foam cells by Adipsin attenuates progression of atherosclerosis.

Phagocytosis of oxidized low-density lipoprotein (OxLDL) by macrophages yields "foam cells" and serves as a hallmark of atherosclerotic lesion. Adipsin is a critical component of the complement activation pathway. Recent evidence has indicated an obligatory role for Adipsin in pathological models including ischemia-reperfusion and sepsis. Adipsin levels are significantly decreased in patients with asymptomatic carotid atherosclerosis, implying the role for Adipsin as a potential marker of asymptomatic carotid atherosclerosis. This study was designed to evaluate the role for Adipsin in atherosclerosis and the mechanisms involved using both in vivo and in vitro experiments. ApoE-/-/AdipsinTg mice were constructed and were fed a high-fat diet for 12 weeks. Compared with ApoE-/- mice, area of the sclerotic plaques was reduced, along with lower macrophage deposition within the plaque in ApoE-/-/AdipsinTg mice. RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were stimulated with oxLDL (50 µg/ml). Adenovirus vectors containing the Adipsin gene were transfected into macrophages. Lipid accumulation was observed by Oil red O staining. Western blot and reverse transcription-polymerase chain reaction data revealed that Adipsin overexpression inhibited oxLDL-induced lipid uptake and foam cell formation and upregulation of CD36 and PPARγ in Ad-Adipsin-transfected macrophages. In addition, the PPARγ-specific agonist GW1929 reversed Adipsin overexpression-evoked inhibitory effect on lipid uptake. These results demonstrate unequivocally that Adipsin inhibits lipid uptake in a PPARγ/CD36-dependent manner and prevents the formation of foam cells, implying that Adipsin may be a potential therapeutic target against atherosclerosis.

Exosomes derived from pericardial adipose tissues attenuate cardiac remodeling following myocardial infarction by Adipsin-regulated iron homeostasis.

As a vital adipokine, Adipsin is closely associated with cardiovascular risks. Nevertheless, its role in the onset and development of cardiovascular diseases remains elusive. This study was designed to examine the effect of Adipsin on survival, cardiac dysfunction and adverse remodeling in the face of myocardial infarction (MI) injury. In vitro experiments were conducted to evaluate the effects of Adipsin on cardiomyocyte function in the face of hypoxic challenge and the mechanisms involved. Our results showed that Adipsin dramatically altered expression of proteins associated with iron metabolism and ferroptosis. In vivo results demonstrated that Adipsin upregulated levels of Ferritin Heavy Chain (FTH) while downregulating that of Transferrin Receptor (TFRC) in peri-infarct regions 1 month following MI. Adipsin also relieved post-MI-associated lipid oxidative stress as evidenced by decreased expression of COX2 and increased GPX4 level. Co-immunoprecipitation and immunofluorescence imaging prove a direct interaction between Adipsin and IRP2. As expected, cardioprotection provided by Adipsin depends on the key molecule of IRP2. These findings revealed that Adipsin could be efficiently delivered to the heart by exosomes derived from pericardial adipose tissues. In addition, Adipsin interacted with IRP2 to protect cardiomyocytes against ferroptosis and maintain iron homeostasis. Therefore, Adipsin-overexpressed exosomes derived from pericardial adipose tissues may be a promising therapeutic strategy to prevent adverse cardiac remodeling following ischemic heart injury.

Effect of aggressive diuresis in acute heart failure with reduced and preserved ejection fraction.

AIMS: Heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) had distinct haemodynamic characteristics in the setting of acute heart failure. The aim of our study is to evaluate the differential response to aggressive diuresis in HFrEF and HFpEF. METHODS AND RESULTS: Patients in the Diuretic Optimization Strategies Evaluation trial with left ventricular ejection fraction measurement were included (n = 300) and classified into HFrEF [left ventricular ejection fraction (LVEF) < 40%] (n = 193) and HFpEF (LVEF ≥ 40%) (n = 107). Effect of high-dose vs. low-dose furosemide strategy was compared separately in HFrEF and HFpEF. In HFrEF, high-dose strategy did not increase change in creatinine or cystatin C at 72 h [treatment difference: -0.05, 95% confidence interval (CI): -0.14 to 0.03 mg/dL; P = 0.23 for creatinine, and treatment difference: -0.06, 95% CI: -0.15 to 0.02 mg/dL; P = 0.15 for cystatin C] compared with low-dose strategy, but there were significantly more net fluid loss, weight loss, and congestion-free patients at 72 h in high-dose group. It was also associated with a significantly lower risk of composite clinical outcome of death, total hospitalizations, and unscheduled visits due to heart failure. In HFpEF, high-dose strategy significantly increased change in creatinine and cystatin C at 72 h (treatment difference: 0.16; 95% CI: 0.02-0.30 mg/dL; P = 0.03 for creatinine, and treatment difference: 0.26; 95% CI: 0.09-0.43 mg/dL; P = 0.003 for cystatin C), but did not significantly affect net fluid loss, weight loss, proportion of congestion-free patients at 72 h, and risk of the composite clinical outcome. CONCLUSIONS: Acute heart failure on the basis of HFrEF and HFpEF responded differently to aggressive diuresis. Future trials should be designed separately for HFrEF and HFpEF.

Prognostic Implication of Liver Function Tests in Heart Failure With Preserved Ejection Fraction Without Chronic Hepatic Diseases: Insight From TOPCAT Trial.

Background: Liver dysfunction is prevalent in patients with heart failure (HF), but the prognostic significance of liver function tests (LFTs) remains controversial. Heart failure with preserved ejection fraction (HFpEF) had been introduced for some time, but no previous study had focused on LFTs in HFpEF. Thus, we aim to evaluate the prognostic significance of LFTs in well-defined HFpEF patients. Methods and Results: We conveyed a post-hoc analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT). The primary outcome was the composite of cardiovascular mortality, HF hospitalization, and aborted cardiac arrest, and the secondary outcomes were cardiovascular mortality and HF hospitalization. In Cox proportional hazards models, aspartate transaminase (AST) and alanine transaminase (ALT) were not associated with any of the outcomes. On the contrary, increases in total bilirubin (TBIL) and alkaline phosphatase (ALP) were associated with increased risks of the primary outcome [TBIL: adjusted hazard ratio (HR), 1.17; 95% confidence interval (CI) 1.08-1.26; ALP: adjusted HR, 1.12; 95% CI 1.04-1.21], cardiovascular mortality (TBIL: adjusted HR, 1.16; 95% CI 1.02-1.31; ALP: adjusted HR, 1.16; 95% CI 1.05-1.28), and HF hospitalization (TBIL: adjusted HR, 1.22; 95% CI 1.12-1.33; ALP: adjusted HR, 1.12; 95% CI 1.03-1.23). Conclusion: Elevated serum cholestasis markers TBIL and ALP were significantly associated with a poor outcome in HFpEF patients without chronic hepatic diseases, while elevated ALT and AST were not.

Living Alone and Clinical Outcomes in Patients With Heart Failure With Preserved Ejection Fraction.

OBJECTIVE: In patients with heart failure with preserved ejection fraction (HFpEF), whether living alone could contribute to a poor prognosis remains unknown. We sought to investigate the association of living alone with clinical outcomes in patients with HFpEF. METHODS: Symptomatic patients with HFpEF with a follow-up of 3.3 years (data collected from August 2006 to June 2013) in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial were classified as patients living alone and those living with others. The primary outcome was defined as a composite of cardiovascular death, aborted cardiac arrest, or HF hospitalization. RESULTS: A total of 3103 patients with HFpEF were included; 25.2% of them were living alone and were older, predominantly female, and less likely to be White and have more comorbidities compared with the other patients. After multivariate adjustment for confounders, living alone was associated with increased risks of HF hospitalization (hazard ratio [HR] = 1.29, 95% confidence interval [CI] = 1.03-1.61) and any hospitalization (HR = 1.26, 95% CI = 1.12-1.42). A significantly increased risk of any hospitalization (HR = 1.16, 95% CI = 1.01-1.34) was also observed in the Americas-based sample. In addition, each year increase in age, female sex, non-White race, New York Heart Association functional classes III and IV, dyslipidemia, and chronic obstructive pulmonary disease were independently associated with living alone. CONCLUSIONS: We assessed the effect of living arrangement status on clinical outcomes in patients with HFpEF and suggested that living alone was associated with an independent increase in any hospitalization.Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00094302.

Comparative Effectiveness and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients.

BACKGROUND AND PURPOSE: Several observational studies have compared the effect of the non-vitamin K antagonist oral anticoagulants to each other in patients with atrial fibrillation. However, confounding by indication is a major problem when comparing non-vitamin K antagonist oral anticoagulant treatments in some of these studies. This meta-analysis was conducted to compare the effectiveness and safety between non-vitamin K antagonist oral anticoagulant and non-vitamin K antagonist oral anticoagulant by only including the propensity score matching studies. METHODS: We systematically searched the PubMed and Ovid databases until May 2020 to identify relevant observational studies. Hazard ratios (HRs) and 95% CIs of the reported outcomes were collected and then pooled by a random-effects model complemented with an inverse variance heterogeneity or quality effects model. RESULTS: A total of 17 retrospective cohort studies were included in this meta-analysis. Compared with dabigatran use, the use of rivaroxaban was significantly associated with increased risks of stroke or systemic embolism (HR, 1.16 [95% CI, 1.05-1.29]) and major bleeding (HR, 1.32 [95% CI, 1.24-1.41]), whereas the use of apixaban was associated with a reduced risk of major bleeding (HR, 0.78 [95% CI, 0.67-0.90]) but not stroke or systemic embolism (HR, 0.84 [95% CI, 0.56-1.28]). Compared with rivaroxaban use, the use of apixaban was associated with a decreased risk of major bleeding (HR, 0.63 [95% CI, 0.54-0.73]) but not stroke or systemic embolism (HR, 0.83 [95% CI, 0.67-1.04]). Reanalyses with the inverse variance heterogeneity or quality effects model produced similar results as the random-effects model. CONCLUSIONS: Current observational comparisons with propensity score matching methods suggest that apixaban might be a better choice compared with dabigatran or rivaroxaban for stroke prevention in atrial fibrillation patients.

C2HEST score predicts clinical outcomes in heart failure with preserved ejection fraction: a secondary analysis of the TOPCAT trial.

BACKGROUND: The C2HEST score has been validated for predicting AF in the general population or post-stroke patients. We aimed to assess whether this risk score could predict incident AF and other clinical outcomes in heart failure with preserved ejection fraction (HFpEF) patients. METHODS: A total of 2202 HFpEF patients without baseline AF in the TOPCAT trial were stratified by baseline C2HEST score. Cox proportional hazard model and competing risk regression model was used to explore the relationship between C2HEST score and outcomes, including incident AF, stroke, all-cause death, cardiovascular death, any hospitalization, and HF hospitalization. The discriminative ability of the C2HEST score for various outcomes was assessed by calculating the area under the curve (AUC). RESULTS: The incidence rates of incident AF, stroke, all-cause death, cardiovascular death, any hospitalization, and HF hospitalization were 1.79, 0.70, 3.81, 2.42, 15.50, and 3.32 per 100 person-years, respectively. When the C2HEST score was analyzed as a continuous variable, increased C2HEST score was associated with increased risk of incident AF (HR 1.50, 95% CI 1.29-1.75), as well as increased risks of all-cause death, cardiovascular death, any hospitalization, and HF hospitalization. The AUC for the C2HEST score in predicting incident AF (0.694, 95% CI 0.640-0.748) was higher than all-cause death, cardiovascular death, any hospitalization, or HF hospitalization. CONCLUSIONS: The C2HEST score could predict the risk of incident AF as well as death and hospitalization with moderately good predictive abilities in patients with HFpEF. Its simplicity may allow the possibility of quick risk assessments in busy clinical settings.

Usefulness of CHADS2, R2CHADS2, and CHA2DS2-VASc scores for predicting incident atrial fibrillation in heart failure with preserved ejection fraction patients.

AIMS: Coexisting of atrial fibrillation (AF) in patients with heart failure with preserved ejection fraction (HFpEF) could increase the risk of mortality. In this study, we aimed to assess the values of the CHADS2, R2CHADS2, and CHA2DS2-VASc scores for AF prediction in HFpEF patients. METHODS AND RESULTS: We performed a retrospective analysis on symptomatic HFpEF patients in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. Associations of the CHADS2, R2CHADS2, and CHA2DS2-VASc scores with the risk of incident AF in HFpEF patients without baseline AF (n = 2202) were assessed using the multivariable competing risk regression models. The discriminatory performances of these scores were calculated using the C-index. During a median follow-up of 3.3 years, the average incidence of AF was 1.80 per 100 patient-years in HFpEF patients. When score was analysed as a continuous variable, per 1-point increase in the CHADS2 (hazard ratio [HR] = 1.42, 95% confidence interval [CI]: 1.20-1.68, C-index: 0.71), R2CHADS2 (HR = 1.25, 95% CI: 1.10-1.42, C-index: 0.69), or CHA2DS2-VASc (HR = 1.30, 95% CI: 1.16-1.46, C-index: 0.70) scores was associated with an increased risk of incident AF. When score was analysed as a categorical variable, patients with CHADS2 ≥ 3 (HR = 2.62, 95% CI: 1.70-4.04), R2CHADS2 ≥ 3 (HR = 2.55, 95% CI: 1.56-4.17), or CHA2DS2-VASc ≥ 4 (HR = 2.54, 95% CI: 1.59-4.07) had a higher risk of incident AF compared with the corresponding controls. CONCLUSIONS: Our data first suggest that the CHADS2, R2CHADS2, and CHA2DS2-VASc scores could predict the risk of incident AF in HFpEF patients with modest predictive abilities.

Major depression and clinical outcomes in patients with heart failure with preserved ejection fraction.

OBJECTIVE: Limited data have been published concerning about depression in heart failure with preserved ejection fraction (HFpEF). Besides, among HFpEF patients with depression, the efficacy of antidepressants is poorly defined. Therefore, our current study was aimed to examine the relationship between major depression and clinical outcomes in HFpEF patients and further address the effects of antidepressants on prognosis in patients with major depression and HFpEF. METHODS: A total of 1431 patients enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) were divided into 2 groups according to the baseline depression status. Major depression was diagnosed if the Patient Health Questionnaire-9 score (PHQ-9) ≥ 10. Univariable and multivariable Cox proportional hazards models tested the association of major depression with outcomes and the effects of antidepressants among HFpEF patients with major depression during a follow-up of 6 years. RESULTS: 26.7% (382/1431) of patients were diagnosed with major depression. After multivariable adjustment, major depression at baseline was not significantly associated with cardiovascular outcomes (fully adjusted hazard ratio (aHR) 0.95 [0.76-1.18] for primary outcomes; aHR: 0.86 [0.67-1.10] for HF hospitalization; aHR: 1.06 [0.91-1.23] for any hospitalization; aHR: 1.00 [0.70-1.43] for cardiovascular death; aHR: 1.24 [0.96-1.61] for all-cause death). Additionally, among HFpEF patients with major depression, the use of antidepressants was not associated with adverse events (P > .05 for all analyses). CONCLUSIONS: In HFpEF patients, major depression at baseline did not increase mortality or rehospitalization. Additionally, treatment with antidepressants might not improve prognosis among HFpEF patients with major depression. Future studies are warranted to explore the effects of antidepressants on HFpEF patients with depression.

Influence of polypharmacy on patients with heart failure with preserved ejection fraction: a retrospective analysis on adverse outcomes in the TOPCAT trial.

BACKGROUND: Polypharmacy is common in heart failure (HF), whereas its effect on adverse outcomes in patients with HF with preserved ejection fraction (HFpEF) is unclear. AIM: To evaluate the prevalence, prognostic impacts, and predictors of polypharmacy in HFpEF patients. DESIGN AND SETTING: A retrospective analysis performed on patients in the Americas region (including the US, Canada, Argentina, and Brazil) with symptomatic HF and a left ventricular ejection fraction ≥45% in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial, an international, randomised, double-blind, placebo-controlled study conducted during 2006-2013 in six countries. METHOD: Patients were categorised into four groups: controls (<5 medications), polypharmacy (5-9 medications), hyperpolypharmacy, (10-14 medications), and super hyperpolypharmacy (≥15 medications). The outcomes and predictors in all groups were assessed. RESULTS: Of 1761 participants, the median age was 72 years; 37.5% were polypharmacy, 35.9% were hyperpolypharmacy, and 19.6% were super hyperpolypharmacy, leaving 7.0% having a low medication burden. In multivariable regression models, three experimental groups with a high medication burden were all associated with a reduction in all-cause death, but increased risks of HF hospitalisation and all-cause hospitalisation. Furthermore, several comorbidities (dyslipidemia, thyroid diseases, diabetes mellitus, and chronic obstructive pulmonary disease), a history of angina pectoris, diastolic blood pressure <80 mmHg, and worse heart function (the New York Heart Association functional classification level III and IV) at baseline were independently associated with a high medication burden among patients with HFpEF. CONCLUSION: A high prevalence of high medication burden at baseline was reported in patients with HFpEF. The high medication burden might increase the risk of hospital readmission, but not the mortality.

Clinical implication of pulmonary hospitalization in heart failure with preserved ejection fraction: from the TOPCAT.

AIMS: The aim of the study was to explore the risk factors and evaluate the prognostic implication of pulmonary hospitalization on heart failure (HF) with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We performed a secondary analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT). A total of 1714 patients with HFpEF were analysed in our study. In the multivariate Cox proportional hazards regression analysis, history of chronic obstructive pulmonary disease (COPD), smoking, bone fracture after the age of 45, and previous HF hospitalization were identified as independent risk factors for pulmonary hospitalization. To evaluate the prognostic significance of pulmonary hospitalization, patients were categorized into five groups according to the causes of their first hospitalization. The all-cause and cardiovascular (CV) mortality risks in these five groups were compared using time-varying Cox proportional hazards model. Compared with patients without hospitalization during follow-up, those with pulmonary hospitalization were associated with a 204% increase [hazard ratio (HR) 3.04, 95% confidence interval (CI) 2.07-4.47, P < 0.001] and 164% increase (HR 2.64, 95% CI 1.60-4.36, P < 0.001) in risks of all-cause and CV mortality, respectively, while the corresponding risk increases associated with HF hospitalization were 146% (HR 2.46, 95% CI 1.74-3.48, P < 0.001) for all-cause mortality and 186% (HR 2.86, 95% CI 1.87-4.36, P < 0.001) for CV mortality. CONCLUSIONS: Pulmonary hospitalization was associated with a significant increase in risks of all-cause and CV mortality, which was comparable with that associated with HF hospitalization. The results suggested that pulmonary hospitalization could be another important clinical endpoint of HFpEF.

Efficacy and safety of xuezhikang once per day versus two times per day in patients with mild to moderate hypercholesterolaemia (APEX study): a protocol for a multicentre, prospective randomised controlled, open-label, non-inferiority study.

INTRODUCTION: Reduction in low-density lipoprotein cholesterol (LDL-C) improves clinical outcomes in patients with coronary artery disease. However, rates of lipid-lowering medication adherence are far from ideal. Reducing dosage frequency from multiple dosing to once-daily dosing may improve patients' medication adherence. Xuezhikang (XZK), an extract of Chinese red yeast rice, contains a family of naturally occurring statins and is traditionally prescribed as 600 mg two times per day. A comParative Efficacy study of XZK (APEX study) is designed to test the hypothesis that XZK prescribed 1200 mg once per day (OD group) is non-inferior to 600 mg two times per day (TD group) in patients with hypercholesterolaemia. METHODS AND ANALYSIS: The APEX study is a multicentre, prospective randomised controlled, open-label, non-inferiority study. We plan to recruit 316 patients aged ≥18 years with a diagnosis of mild to moderate hypercholesterolaemia for primary prevention. Patients will be randomised (1:1) to OD group and TD group. The OD group take XZK 1200 mg once per day after dinner while TD group take a traditional dose of 600 mg, two times per day after meals. Participants will have an 8-week medication period and be followed up at weeks 0, 4 and 8. The primary end point is the mean percentage change from baseline to week 8 in serum LDL-C. Secondary end points are safety and lipid-lowering effect on other lipoproteins and compliance. Data analyses will be on the intention-to-treat principle using non-inferiority analysis. ETHICS AND DISSEMINATION: The research had been approved by the Clinical Research and Laboratory Animal Ethics Committee of the First Affiliated Hospital, Sun Yat-sen University ((2017)286). The results will be reported through peer-reviewed journals, seminars and conference presentations. TRIAL REGISTRATION NUMBER: ChiCTR-IIR-17013660.

Prognostic Value of Cysteine-Rich Protein 61 Combined with N-Terminal Pro-B-Type Natriuretic Peptide for Mortality in Acute Heart Failure Patients with and without Chronic Kidney Disease.

BACKGROUND: The ability of most biomarkers, such as N-terminal pro-B-type natriuretic peptide (NT-proBNP), to predict prognosis in heart failure can be affected by the state of renal function; therefore, there is the need for a biomarker that can predict prognosis accurately without the influence of renal function. The prognostic value of cysteine-rich protein 61 (CYR61/CCN1) in acute heart failure (AHF) patients has been proven. METHODS: A total of 248 patients hospitalized with AHF were recruited in this study, and serum CCN1 levels, NT-proBNP levels, and other necessary data of patients were collected upon admission. The correlation of serum CCN1 with estimated glomerular filtration rate (eGFR) was investigated, and the logistic regression model was used to investigate the prognostic value of serum CCN1 for 3-month mortality. RESULTS: Fifty-four of 248 patients died (21.8%) during a 3-month follow-up. Serum CCN1 had no significant correlation with eGFR (rho = -0.088, p = 0.167). In the overall population and patients without chronic kidney disease, results showed that both serum CCN1 and NT-proBNP were significantly associated with 3-month mortality. In patients with chronic kidney disease, serum CCN1 was significantly associated with 3-month mortality in logistic regression analysis (odds ratio = 2.40, p = 0.002) while NT-proBNP was not. Further in tertile group comparison, in patients with chronic kidney disease, higher tertile levels of serum CCN1 had a significantly higher risk of 3-month mortality compared to the lower tertile ones (odds ratio = 4.17, p = 0.013), but that of NT-proBNP did not. CONCLUSION: Serum CCN1 level is not associated with eGFR, and it maintains the prognostic value in AHF patients with chronic kidney disease. CCN1 could be a potential novel prognostic biomarker in AHF patients with chronic kidney disease.

Association of Cyr61-cysteine-rich protein 61 and short-term mortality in patients with acute heart failure and coronary heart disease.

Aim: The protein CCN1/CYR61 exerts critical functions in myocardial ischemic injury. We sought to investigate the prognostic value of CCN1 in patients with acute heart failure (AHF) and coronary heart disease (CAD). Methodology: We prospectively enrolled 113 patients with AHF and CAD. Patients were followed for all-cause mortality during a 30-day follow-up. Logistic models were used to estimate the association of CCN1 concentrations with 30-day mortality. Results: In multivariate logistic regression model, CCN1 was a significant predictor of 30-day mortality independent of current markers. Enhanced Feedback for Effective Cardiac Treatment risk score was recommended as one of the selected multivariable risk scores to predict outcome in AHF. CCN1 improved risk stratification for all-cause mortality when added to the Enhanced Feedback for Effective Cardiac Treatment risk scores at 30 days. Conclusion: We found CCN1 is independently associated with 30-day mortality in patients with AHF and CAD.

Prognostic Significance of Serum Cysteine-Rich Protein 61 in Patients with Acute Heart Failure.

BACKGROUND/AIMS: Cyr61-cysteine-rich protein 61 (CCN1/CYR61) is a multifunctional matricellular protein involved in the regulation of fibrogenesis. Animal experiments have demonstrated that CCN1 can inhibit cardiac fibrosis in cardiac hypertrophy. However, no study has been conducted to assess the relation between serum CCN1 and prognosis of acute heart failure (AHF). METHODS: We measured the serum CCN1 levels of 183 patients with AHF, and the patients were followed up for 6 months. The associations between CCN1 levels and some clinical covariates, especially left ventricular ejection fraction (LVEF), estimated glomerular filtration rate (eGFR), atrial fibrillation and age, were estimated. The AHF patients were followed up for 6 months. The endpoint was all-cause mortality. Kaplan-Meier curve analysis and multivariable Cox proportional hazards analysis were employed to evaluate the prognostic ability of CCN1. We used calibration, discrimination and reclassification to assess the mortality risk prediction of adding CCN1. RESULTS: Serum CCN1 concentrations in AHF patients were significantly increased compared with those in individuals without AHF (237 pg/ml vs. 124.8 pg/ml, p< 0.001). CCN1 level was associated with the level of NT-proBNP (r=0.349, p< 0.001) and was not affected by LVEF, eGFR, age or atrial fibrillation in AHF patients. Importantly, Kaplan-Meier curve analysis illustrated that the AHF patients with serum CCN1 level > 260 pg/ ml had a lower survival rate (p< 0.001). Multivariate Cox hazard analysis suggests that CCN1 functions as an independent predictor of mortality for AHF patients (LgCCN1, hazard ratio 5.825, 95% confidence interval: 1.828-18.566, p=0.003). In addition, the inclusion of CCN1 in the model with NT-proBNP significantly improved the C-statistic for predicting death (0.758, p< 0.001). The integrated discrimination index was 0.019 (p< 0.001), and the net reclassification index increased significantly after addition of CCN1 (23.9%, p=0.0179). CONCLUSIONS: CCN1 is strongly predictive of 6-month mortality in patients with AHF, suggesting serum CCN1 as a promising candidate prognostic biomarker for AHF patients.

Thermodilutional Confirmation of Coronary Microvascular Dysfunction in Patients With Recurrent Angina After Successful Percutaneous Coronary Intervention.

BACKGROUND: Recurrent angina (RA) after percutaneous coronary intervention (PCI) remains a challenging problem that confronts cardiologists in routine clinical practice. In patients without epicardial coronary causes, RA is commonly speculated as resulting from coronary microvascular dysfunction. The aim of this study was to investigate the coronary microvascular function in patients with RA late after successful PCI and without epicardial stenosis at the time of repeat angiography. METHODS: We studied 39 consecutive patients with RA in whom PCI was successfully performed 6 to 12 months previously because of angina and single-vessel disease and without restenosis and disease progression at the time of repeat angiography. Twelve subjects without RA were recruited as the control group. Thermodilution-derived coronary flow reserve (CFR) and index of microvascular resistance (IMR) were measured using a pressure-temperature sensor-tipped coronary wire. The exercise treadmill test was performed according to the Bruce protocol. RESULTS: Patients with RA showed significantly higher IMR and lower CFR than control subjects, in the target arteries and in the reference vessels (P < 0.05). The hyperemic IMR was more remarkably increased in the target arteries than in the reference vessels (29.3 ± 11.7 vs 24.4 ± 9.7; P = 0.008). The hyperemic IMR was increased and the CFR was impaired more significantly in patients with a positive exercise treadmill test (P < 0.05). CONCLUSIONS: Using an intracoronary thermodilution method, to our knowledge, we have for the first time confirmed that, in patients who underwent successful coronary stenting and without epicardial stenosis at repeat angiography late after PCI, coronary microvascular dysfunction was responsible for the RA.

Enhancer of zeste homolog 2 as an independent prognostic marker for cancer: a meta-analysis.

BACKGROUND: Novel biomarkers are of particular interest for predicting cancer prognosis. This study aimed to explore the associations between enhancer of zeste homolog 2 (EZH2) and patient survival in various cancers. METHODS: Relevant literature was retrieved from PubMed and Web of Science databases. Pooled hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. RESULTS: Forty-nine studies (8,050 patients) were included. High EZH2 expression was significantly associated with shorter overall (hazard ratio [HR] 1.74, 95% CI: 1.46-2.07), disease-free (HR 1.59, 95% CI: 1.27-1.99), metastasis-free (HR 2.19, 95% CI: 1.38-3.47), progression-free (HR 2.53, 95% CI: 1.52-4.21), cancer-specific (HR 3.13, 95% CI: 1.70-5.74), and disease-specific (HR 2.29, 95% CI: 1.56-3.35) survival, but not recurrence-free survival (HR 1.38, 95% CI: 0.93-2.06). Moreover, EZH2 expression significantly correlated with distant metastasis (OR 3.25, 95% CI: 1.07-9.87) in esophageal carcinoma; differentiation (OR 3.00, 95% CI: 1.37-6.55) in non-small cell lung cancer; TNM stage (OR 3.18, 95% CI: 2.49-4.08) in renal cell carcinoma; and histological grade (OR 4.50, 95% CI: 3.33-6.09), estrogen receptor status (OR 0.15, 95% CI: 0.11-0.20) and progesterone receptor status (OR 0.30, 95% CI: 0.23-0.39) in breast cancer. CONCLUSIONS: Our results suggested that EZH2 might be an independent prognostic factor for multiple survival measures in different cancers.