Spironolactone Improves the All-Cause Mortality and Re-Hospitalization Rates in Acute Myocardial Infarction with Chronic Kidney Disease Patients.

Background: Mineralocorticoid receptor antagonists (MRA) improve outcomes in chronic kidney disease (CKD) and acute myocardial infarction (AMI) patients. However, the lack of evidence regarding long-term clinical outcomes in the use of MRA, including spironolactone, in patients with AMI combined with CKD. Objectives: This study aimed to investigate whether spironolactone could significantly reduce the risk of all-cause mortality and re-admission in patients with AMI and CKD. Methods: In this single center, observational, retrospective, registry based clinical study, a total of 2,465 AMI patients were initially screened; after excluding patients with estimated glomerular filtration rate more than 60 ml/min/1.73 m2, 360 patients in the standard treatment group and 200 patients in the spironolactone group met the criteria. All enrolled patients follow-up for 30 months. The primary outcomes were all-cause mortality and re-admission. The key safety outcome was hyperkalemia rates during the 30 months follow-up period. Results: 160 (44.4%) and 41 (20.5%) patients in the standard treatment and spironolactone groups died, respectively [hazard ratio (HR): 0.389; 95% confidence interval (CI): 0.276-0.548; p < 0.001]. Re-admission occurred in 217 (60.3%) and 95 (47.5%) patients in the standard treatment and spironolactone groups, respectively (HR: 0.664; 95% CI: 0.522-0.846; p = 0.004). The spironolactone group was divided into two based on the daily dose, low dose group (no more than 40 mg) and high dose group (more than 40 mg); the differences in the mortality rate between low dose group (16.7%) and the standard treatment group (44.4%) (HR: 0.309; 95% CI: 0.228-0.418; p < 0.001) and high dose group (34.1%) (HR: 0.429; 95% CI: 0.199-0.925; p = 0.007) were significant. The differences in re-hospitalization rate between low dose group (43.6%) and the standard treatment group (60.3%) (HR: 0.583; 95% CI: 0.457-0.744; p < 0.001) and high dose group (61.4%) (HR: 0.551; 95% CI: 0.326-0.930; p = 0.007) was significant. Hyperkalemia occurred in 18 (9.0%) and 18 (5.0%) patients in the spironolactone group and standard treatment group, respectively (HR: 1.879; 95% CI: 0.954-3.700; p = 0.068). Whereas, Hyperkalemia occurred in high dose group (20.5%) significantly more often than in the standard treatment group (p < 0.001) and low dose group (5.8%) (p = 0.003). Conclusion: Using MRA, such as spironolactone, may substantially reduce the risk of both all-cause mortality and re-admission in patients with AMI and CKD; the use of low-dose spironolactone has the best efficacy and safety. However, this was a relatively small sample size, single center, observational, retrospective, registry based clinical study and further prospective evaluation in adequately powered randomized trials were needed before further use of spironolactone in AMI with CKD population.

A prognostic nomogram for long-term major adverse cardiovascular events in patients with acute coronary syndrome after percutaneous coronary intervention.

BACKGROUND: Accurate prediction of major adverse cardiovascular events (MACEs) is very important for the management of acute coronary syndrome (ACS) patients. We aimed to construct an effective prognostic nomogram for individualized risk estimates of MACEs for patients with ACS after percutaneous coronary intervention (PCI). METHODS: This was a prospective study of patients with ACS after PCI from January 2013 to July 2019 (n = 2465). After removing patients with incomplete clinical information, a total of 1986 patients were randomly divided into evaluation (n = 1324) and validation (n = 662) groups. Predictors included in the nomogram were determined by a multivariate Cox proportional hazards regression model based on the training set. Receiver operating characteristic (ROC) curves and calibration curves were used to assess the discrimination and predictive accuracy of the nomogram, which were then compared with those of the classic models. The clinical utility of the nomogram was assessed by X-tile analysis and Kaplan-Meier curve analysis. RESULTS: Independent prognostic factors, including lactate level, age, left anterior descending branch stenosis, right coronary artery stenosis, brain natriuretic peptide level, and left ventricular ejection fraction, were determined and contained in the nomogram. The nomogram achieved good areas under the ROC curve of 0.712-0.762 in the training set and 0.724-0.818 in the validation set and well-fitted calibration curves. In addition, participants could be divided into two risk groups (low and high) according to this model. CONCLUSIONS: A simple-to-use nomogram incorporating lactate level effectively predicted 6-month, 1-year, and 4-year MACE incidence among patients with ACS after PCI.

CIDEC silencing attenuates diabetic nephropathy via inhibiting apoptosis and promoting autophagy.

OBJECTIVE: The role of cell death-inducing DFF45-like effector C (CIDEC) in insulin resistance has been established, and it is considered to be an important trigger factor for the progression of diabetic nephropathy (DN). We intend to explore whether CIDEC plays an important role in the regulation of DN and its potential mechanism. METHODS: High-fat diet and low dose streptozotocin were used to establish type 2 diabetic rat model. We investigate the role of CIDEC in the pathogenesis and process of DN through histopathological analysis, western blot and gene silencing. Meanwhile, the effect of CIDEC on renal tubular epithelial cells stimulated by high glucose was also verified. RESULTS: DM group exhibited glucose and lipid metabolic disturbance, with hypertrophy of kidneys, damaged renal function, increased apoptosis, decreased autophagy, glomerulosclerosis and interstitial fibrosis. CIDEC gene silencing improved metabolic disorder and insulin resistance, alleviated renal hypertrophy and renal function damage, decreased glomerular and tubular apoptosis, increased autophagy and inhibited renal fibrosis. At the cellular level, high glucose stimulation increased CIDEC expression in renal tubular epithelial cells, accompanied by increased apoptosis and decreased autophagy. CIDEC gene silencing can improve autophagy and reduce apoptosis. At the molecular level, CIDEC gene silencing also decreased the expression of early growth response factor (EGR)1 and increased the expression of adipose triglyceride lipase (ATGL). CONCLUSION: CIDEC gene silencing may delay the progression of DN by restoring autophagy activity and inhibiting apoptosis with the participation of EGR1and ATGL.

Soluble ST2 in Patients with Nonvalvular Atrial Fibrillation and Prediction of Heart Failure.

Atrial fibrillation (AF) is the most common clinically relevant arrhythmia. AF is a strong independent risk factor for the subsequent development of heart failure (HF). HF and AF can interact to perpetuate and exacerbate each other. Soluble ST2 (sST2) is a biomarker of cardiomyocyte stretch that is useful in the diagnosis and prognosis of HF. Its role in the field of AF has not yet been well investigated. We studied the concentration of sST2 in a cohort of 174 subjects (62.1% men; mean age, 65.6 ± 10.3 years [± standard deviation (SD) ]) with nonvalvular AF and 116 age-matched patients with sinus rhythm (SR). Subjects were subdivided into 3 groups: paroxysmal AF, persistent AF, and SR. Plasma sST2 concentrations were measured using an electrochemiluminescence-based immunoassay. The sST2 level was higher in persistent AF patients (P < 0.05) and paroxysmal AF patients (P < 0.05) than in SR patients. No significant difference was found between persistent AF and paroxysmal AF. sST2 was correlated with left atrial diameter (LAD) (r = 0.21; P < 0.01). During a median follow-up time of 6 months, 43 subjects with non-valvular AF in the study had HF. Cox proportional hazard analysis revealed both sST2 and LAD were independent predictors of HF. sST2 concentrations are higher in AF than SR. Plasma sST2 may be a useful biomarker in predicting HF in patients with AF.

High molecular weight fibroblast growth factor-2 as a promising prognostic biomarker to predict the occurrence of heart failure in atrial fibrillation patients.

Heart failure (HF) has a significant effect on the prognosis of the patients with atrial fibrillation (AF), and also it is an important risk factor for overall mortality. High molecular weight fibroblast growth factor-2 (Hi-FGF-2) is emerging as a prognostic marker with HF and AF. The aim of this study was to prove that Hi-FGF-2 would predict occurrence of HF in the patients with AF. Subjects diagnosed with paroxysmal AF (Group paAF), persistent AF (Group peAF) and sinus rhythm (Group SR) were enrolled in the study. Serum Hi-FGF-2 concentration was measured by ELISA at baseline. Multivariable logistic models and receiver operating characteristic (ROC) curve analysis were established to predict the prognosis of AF subjects. 260 patients were enrolled in the study: 104 (40.0%) admitted for sinus rhythm (Group SR) and 156 (60.0%) with AF (Group paAF and Group peAF). The Hi-FGF-2 levels were much lower in the Group SR (58.2 ± 27.1 ng/L) than in the Group AF. Furthermore, the Group peAF (84.3 ± 34.1 ng/L) had higher Hi-FGF-2 levels than the Group paAF (72.9 ± 35.8 ng/L). Serum Hi-FGF-2 levels were classified into trisection in the multivariable logistic model (T1 < 57.3 ng/L, 57.3 < T2 < 86.5 ng/L, and T3 > 86.5 ng/L). Hi-FGF-2 showed good predictive ability for new-onset HF in the patients with AF. The occurrence of HF was associated significantly with increased tertile of serum Hi-FGF-2 levels (T2: OR 5.922, 95% CI 1.109-31.626, P = 0.037 and T3: OR 8.262, 95% CI 1.735-39.343, P = 0.008). ROC curve analysis showed that the area under curves for Hi-FGF-2 were 0.720 (P < 0.0001). Hi-FGF-2 has a significant meaning in AF subjects. Further to this, higher circulating Hi-FGF-2 was highly related to persistent AF, and Hi-FGF-2 may be an independent risk factor of occurrence HF in AF subjects.

Relaxin Ameliorates Renal Fibrosis and Expression of Endothelial Cell Transition Markers in Rats of Isoproterenol-Induced Heart Failure.

There may be cardio-renal interactions in rats of isoproterenol-induced heart failure, which may be associated with renal fibrosis and endothelial-to-mesenchymal transition (EndMT). Since its discovery, relaxin (RLX) which was regarded as a reproductive hormone for a long time, is recently considered an effective antifibrotic hormone in cardiac and renal fibrosis. We studied whether RLX diminished renal fibrosis in rats of isoproterenol (Iso)-induced heart failure and investigated the mechanism. Fifty male Sprague-Dawley rats were separated into five groups for treatment: control; Iso subcutaneously injection to induce heart failure, which led to renal fibrosis; RLX subcutaneously injection at low, medium and high dose (0.2, 2, 20 µg·kg-1·d-1 for 21 d). Indices of cardiac function and organ fibrosis were examined. Expression and changes in levels of collagen, cluster of differentiation 31 (CD31), α-smooth muscle actin (SMA), and transforming growth factor ß (TGF-ß) were measured in renal tissues. In rats with heart failure induced by Iso, treatment with RLX significantly ameliorated cardiac function and inhibited cardiac and renal fibrosis. RLX decreased renal collagen types I and III deposition, increased CD31 expression, and decreased the expression of α-SMA and TGF-ß, thereby possibly indicating inhibited renal EndMT in kidneys. Iso-induced heart and renal fibrosis was inhibited even greater with high-dose RLX, so the antifibrotic effect of RLX may be dose-related. In conclusion, RLX may ameliorate renal fibrosis in rats of Iso-induced heart failure, and it is infered that prevention of the EndMT may be one of the possible potential signaling pathways.

Potential Roles of Serum Caveolin-3 Levels in Patients with Atrial Fibrillation.

Objective: To explore serum caveolin-3 (Cav-3) levels in patients with atrial fibrillation (AF) and to evaluate the role of Cav-3 as a biomarker for AF and incident heart failure (HF). Methods: Three hundred and five patients were enrolled in the study and divided into three groups: sinus rhythm (Group SR), paroxysmal AF (Group paAF), and persistent AF (Group peAF). Serum Cav-3 concentrations were measured by enzyme-linked immunosorbent assay at baseline. Clinical characteristics, and laboratory data were collected during hospitalization, and a follow-up of 12-months was carried out. Results: Serum Cav-3 concentrations were significantly decreased on the Group SR and the highest concentrations of Cav-3 in patients were found on the Group peAF (516.7 ± 274.0 vs. 609.3 ± 287.0 vs. 688.3 ± 264.6 ng/L, P < 0.05). Left atrial diameter (LAD) in the Group peAF was significantly higher than in the Group paAF, and the Group SR had significantly lower LAD than the Group paAF and Group peAF. The risks of new-onset HF in the Group SR, Group paAF, and Group peAF were 8.1, 14.5, and 28.6%, respectively. There was a significant difference between the Group peAF and the other two groups. Serum Cav-3 concentrations were trisected in AF participants (lower tertile: ≤498, middle tertile: >498-703, upper tertile: ≥703). In further tertile studies, subjects in the lower tertile of Cav-3 concentrations were more likely to become paroxysmal AF and had much lower LAD (P < 0.05). And in the middle and upper tertiles, participants with AF tended to suffer from HF compared to the lower group (P < 0.05). Conclusion: We provide evidence that Cav-3 has a significant meaning in AF patients. The levels of Cav-3 may be related to the LAD and new-onset HF.

Anti-Fibrosis Effect of Relaxin and Spironolactone Combined on Isoprenaline-Induced Myocardial Fibrosis in Rats via Inhibition of Endothelial-Mesenchymal Transition.

BACKGROUND: The effect of relaxin and spironolactone combined on myocardial fibrosis has not been reported. Thus, we investigated the effect of the combined therapy on isoprenaline-induced myocardial fibrosis and the mechanism. METHODS: Rats were injected subcutaneously with isoprenaline to induce myocardial fibrosis and underwent subcutaneous injection with relaxin (2 µg·kg-1·d-1) and given a gavage of spironolactone (30 mg·kg-1·d-1) alone or combined for 14 days. In vitro, the endothelial-mesenchymal transition was induced with transforming growth factor ß (TGF-ß) in human umbilical vein endothelial cells (HUVECs) pretreated with relaxin, 200 ng/ml, and/or spironolactone, 1uM. RESULTS: Relaxin and spironolactone used alone or combined improved cardiac function and decreased cardiac weight indices; reduced fibrous tissue proliferation; reduced levels of type I and III collagen; decreased the expression of α-smooth muscle actin (α-SMA) and transforming growth factor-ß1 (TGF-ß1), and increased the expression of cluster of differentiation-31 (CD31) in rats with isoprenaline-induced myocardial fibrosis. In vitro, compared with TGF-ß treatment, relaxin and spironolactone used alone or combined with TGF-ß decreased cell mobility, α-SMA and vimentin levels but increased vascular endothelial cadherin (VE-cadherin) and endothelial CD31levels. Especially, combined therapy had more remarkable effect than relaxin and spironolactone used alone both in vitro and in vivo. CONCLUSION: Relaxin and spironolactone combined affected isoprenaline-induced myocardial fibrosis in rats that the mechanism might be inhibition of the cardiac endothelial-mesenchymal transition.

Relaxin Level in Patients With Atrial Fibrillation and Association with Heart Failure Occurrence: A STROBE Compliant Article.

Atrial fibrillation (AF) is the most common arrhythmia requiring medical treatment and has been associated with enhanced atrial fibrosis and heart failure (HF). Relaxin (RLX), an antifibrosis and antiinflammatory peptide hormone, may be used to evaluate atrial fibrosis and is associated with HF occurrence in AF. We aimed to clarify the clinical significance of RLX level in patients with AF.We measured circulating levels of RLX and other fibrosis-related factors in 311 patients with sinus rhythm (SR; n = 116) or AF (n = 195). All discharged AF patients were followed up for the occurrence of HF for a mean of 6 months.Circulating levels of RLX were significantly different in patients with AF as compared with SR (P < 0.001), and in the subgroup analysis of AF. RLX level was correlated with left atrial diameter (LAD; R = 0.358, P < 0.001). Among followed up AF patients, on Kaplan-Meier curve analysis, patients with the third RLX tertile (T3) had a significantly higher HF rate than those with the 1st tertile (T1) (P = 0.002) and the cut-off value was 294.8 ng/L (area under the ROC curve [AUC] = 0.723). On multivariable analysis, HF occurrence with AF was associated with increased tertile of serum RLX level (odds ratio [OR] 2.659; confidence interval [95% CI] 1.434-4.930; P = 0.002).RLX is associated with fibrosis-related biomarkers and significantly elevated in AF. RLX was related to the HF occurrence in patients with AF.

Anti-fibrosis effect of scutellarin via inhibition of endothelial-mesenchymal transition on isoprenaline-induced myocardial fibrosis in rats.

Scutellarin (SCU) is the major active component of breviscapine and has been reported to be capable of decreasing myocardial fibrosis. The aim of the present study is to investigate whether SCU treatment attenuates isoprenaline-induced myocardial fibrosis and the mechanisms of its action. Rats were injected subcutaneously with isoprenaline (Iso) to induce myocardial fibrosis and rats in the SCU treatment groups were intraperitoneally infused with SCU (10 mg·kg-1·d-1 or 20 mg·kg-1·d-1, for 14 days). Post-treatment, cardiac functional measurements and the left and right ventricular weight indices (LVWI and RVWI, respectively) were analysed. Pathological alteration, expression of type I and III collagen, Von Willebrand factor, α-smooth muscle actin, cluster of differentiation-31 (CD31), and the Notch signalling proteins (Notch1, Jagged1 and Hes1) were examined. The administration of SCU resulted in a significant improvement in cardiac function and decrease in the cardiac weight indices; reduced fibrous tissue proliferation; reduced levels of type I and III collagen; increased microvascular density; and decreased expression of α-smooth muscle actin and increased expression of CD31, Notch1, Jagged1 and Hes1 in isoprenaline-induced myocardial fibrosis in rats. Our results suggest that SCU prevents isoprenaline-induced myocardial fibrosis via inhibition of cardiac endothelial-mesenchymal transition potentially, which may be associated with the Notch pathway.

[Ixeris sonchifolia induced vasoconstriction effect and its mechanism in rat thoracic aorta].

OBJECTIVE: To investigate the vasoconstriction effect of Ixeris sonchifolia in rat thoracic aortic rings and the underlying mechanisms. METHOD: I. sonchifolia 10-160 g x L(-1) was cumulatively added into organ bath to observe the isometric tension of thoracic aortic rings with intact endothelium or denuded endothelium in basal tension, preconstricted by phenylephrine (PE) or potassium chloride (KCl), and thoracic aortic rings with intact endothelium preincubated frist with captopril, phosphoramidon and indomethacin, respectively, then preconstricted by PE and KCl. The response was recorded and expressed by "relative contraction". RESULT: Cumulative administration of I. sonchifolia 10-160 g x L(-1) did not affect the vasomotion of aortic rings with endothelium or without endothelium in basal tension. Exposure of intact endothelium rings preconstricted by PE or KCl to I. sonchifolia at concentration (20-160 g x L(-1) induced a significant constriction, which was inhibited by preincubation with captopril, but was not inhibited by preincubation with phosphoramidon or indomethacin. Exposure of endothelium-denuded rings preconstricted by PE or KCl to I. sonchifolia at concentration (10 to approximately 160 g x L(-1) did not effect the vasoconstriction. CONCLUSION: The results indicate that I. sonchifolia (20 to approximately 160 g x L(-1) can contract the rat thoracic aortic rings with endothelium. The effect of contraction may enhance angiotensin converting enzyme activity and promote endothelium to synthesize angiotensin II. It has no relationship to endothelin or thromboxane A2.