Downregulation of Cypher induces apoptosis in cardiomyocytes via Akt/p38 MAPK signaling pathway.

Background: Dilated cardiomyopathy (DCM) is considered as the most common form of non-ischemic cardiomyopathy with a high mortality worldwide. Cytoskeleton protein Cypher plays an important role in maintaining cardiac function. Genetic studies in human and animal models revealed that Cypher is involved in the development of DCM. However, the underlying molecular mechanism is not fully understood. Accumulating evidences suggest that apoptosis in myocytes may contribute to DCM. Thus, the purpose of this study is to define whether lack of Cypher in cardiomyocytes can elevate apoptosis signaling and lead to DCM eventually. Methods and Results: Cypher-siRNA sufficiently inhibited Cypher expression in cardiomyocytes. TUNEL-positive cardiomyocytes were increased in both Cypher knockdown neonatal rat cardiomyocytes and Cypher knockout mice hearts, which were rare in the control group. Flow cytometry further confirmed that downregulation of Cypher significantly increased myocytes apoptosis in vitro. Cell counting kit-8 assay revealed that Cypher knockdown in H9c2 cells significantly reduced cell viability. Cypher knockdown was found to increase cleaved caspase-3 expression and suppress p21, ratio of bcl-2 to Bax. Cypher-deficiency induced apoptosis was linked to downregulation of Akt activation and elevated p-p38 MAPK accumulation. Pharmacological activation of Akt with SC79 attenuated apoptosis with enhanced phosphorylation of Akt and reduced p-p38 MAPK and Bax expression. Conclusions: Downregulation of Cypher participates in the promotion of cardiomyocytes apoptosis through inhibiting Akt dependent pathway and enhancing p38 MAPK phosphorylation. These findings may provide a new potential therapeutic strategy for the treatment of DCM.

Antagonistic effect between tigecycline and meropenem: successful management of KPC-producing Klebsiella pneumoniae infection.

INTRODUCTION: A woman infected by carbapenem-resistant Klebsiella pneumoniae is reported in this study. CASE REPORT: Tigecycline and meropenem combination was used, and indeed, in vitro checkerboard synergy test confirmed the antagonism between the two antibiotics. Thus, meropenem was ceased and single high-dose tigecycline was successful against the infection. Subsequent experiments showed that the isolates of the KPC-2-producing K. pneumoniae ST11 clone caused the infection. CONCLUSION: Therefore, tigecycline and meropenem combination should be used with caution.

Efficacy and tolerability of adding coenzyme A 400 U/d capsule to stable statin therapy for the treatment of patients with mixed dyslipidemia: an 8-week, multicenter, double-blind, randomized, placebo-controlled study.

BACKGROUND: Patients with mixed hyperlipidemia usually are in need of combination therapy to achieve low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) target values for reduction of cardiovascular risk. This study investigated the efficacy and safety of adding a new hypolipidemic agent, coenzyme A (CoA) to stable statin therapy in patients with mixed hyperlipidemia. METHODS: In this multi-center, 8-week, double-blind study, adults who had received ≥8 weeks of stable statin therapy and had hypertriglyceridemia (TG level at 2.3-6.5 mmol/L) were randomized to receive CoA 400 U/d or placebo plus stable dosage of statin. Efficacy was assessed by the changes in the levels and patterns of lipoproteins. Tolerability was assessed by the incidence and severity of adverse events (AEs). RESULTS: A total of 304 patients with mixed hyperlipidemia were randomized to receive CoA 400 U/d plus statin or placebo plus statin (n = 152, each group). After treatment for 8 weeks, the mean percent change in TG was significantly greater with CoA plus statin compared with placebo plus statin (-25.9% vs -4.9%, respectively; p = 0.0003). CoA plus statin was associated with significant reductions in TC (-9.1% vs -3.1%; p = 0.0033), LDL-C (-9.9% vs 0.1%; p = 0.003), and non- high-density lipoprotein cholesterol (-13.5% vs -5.7%; p = 0.0039). There was no significant difference in the frequency of AEs between groups. No serious AEs were considered treatment related. CONCLUSIONS: In these adult patients with persistent hypertriglyceridemia, CoA plus statin therapy improved TG and other lipoprotein parameters to a greater extent than statin alone and has no obviously adverse effect. TRIAL REGISTRATION: Current Controlled Trials ClinicalTrials.gov ID NCT01928342.

Causal associations between CD40/CD40L and aortic diseases: A mendelian randomization study.

Background: CD40 and CD40L have been reported as associated with aortic dissection (AD) and aortic aneurysm (AA), but the causality of the associations has not been established yet. Methods: We conducted a two-sample Mendelian randomization (MR) study to assess the causal inference between CD40/CD40L and aortic diseases including AD and AA. The instrumental variables (IVs) for CD40 and CD40L were selected from a high-quality protein quantitative trait loci dataset released by a genomic study involving 30,931 individuals of European ancestry. The genome-wide association studies summary statistics for AD and AA were from the FinnGen Release 7, with 288638 controls for all outcomes of interests, 680 cases for AD and 6,092 cases for AA, also from European ancestry. For AA subtypes, there were 5,881 cases of thoracic AA (TAA) and 2,434 cases of abdominal AA (AAA) respectively. Inverse-variance weighted and Wald ratio were applied for calculating causal estimates. Horizontal pleiotropy and heterogeneity were assessed using MR-Egger regression analysis and Cochran Q test, respectively. Leave-one-out analyses were further performed. Results: Three single-nucleotide polymorphisms (SNPs) for CD40 and one SNP for CD40L were selected as IVs. We found genetic proxied CD40 levels inversely associated with the risk of AD (odds ratio [OR]: 0.777, 95% confidence interval [CI]: 0.618-0.978, p = 0.031) and AA (OR: 0.905, 95% CI: 0.837-0.978, p = 0.012), consistent across TAA (both p < 0.050). There were trends of increased risks of AD and AA in the presence of CD40L while not reaching statistical significance. No significant horizontal pleiotropy or heterogeneity was observed. Conclusion: Our MR study provides evidence supporting the causal association between CD40 and the reduced risks of both AD and AA.

Association of cancer antigen 125 with long-term prognosis in light-chain cardiorenal amyloidosis.

BACKGROUND: Light-chain (AL) cardiorenal amyloidosis has been characterized as type 5 cardiorenal syndrome with fluid overload and poor prognosis. Cancer antigen 125 (CA125) has the potential for use in evaluating fluid load and prognosis for heart failure. However, less details for CA125 in AL cardiorenal amyloidosis have been reported. METHODS: Sixty patients diagnosed with AL cardiorenal amyloidosis were enrolled in this retrospective study. Patients were divided into two groups according to the cutoff point of CA125 level (35 U/mL). Logistic regression was used to screen variables associated with CA125. Cox regression analyses was utilized to verify the prognostic potential of CA125. RESULTS: The mean age was 61±8 years, and 68% of the participants were male. Compared to patients with normal CA125 levels (≤35 U/mL), patients with high levels of CA125 (>35 U/mL) had a higher proportion of New York Heart Association class >II, pericardial effusion, and edema, as well as a lower level of albumin and left ventricular longitudinal strain (LVLS). Logistic regression showed age, albumin, and LVLS to be independently associated with CA125. Seventeen (28%) patients died during the follow-up. Multivariate model including CA125, estimated glomerular filtration rate, E/e' and left ventricular ejection fraction showed acceptable prognostic potential (C-index= 0.829, 95%CI 0.749 to 0.909). CA125 remained an independent prognostic factor (HR=1.018, 95%CI 1.005 to 1.031, P=0.008) after adjusting for the remaining three variates and provided a significant incremental effect to the risk determined from them (C-index 0.829 vs 0.784, P=0.037). CONCLUSIONS: Serum CA125 level was associated with long-term prognosis of AL cardiorenal amyloidosis.

Impact of Left Atrial Sphericity Index on the Outcome of Catheter Ablation for Atrial Fibrillation.

Left atrial sphericity index (LASI) is one significant geometric remodeling parameter to evaluate the prognosis of atrial fibrillation (AF). We aimed to determine whether transthoracic echocardiography (TTE)-derived LASI may help predict the outcomes following AF radiofrequency catheter ablation (RFCA). This prospective study enrolled 190 consecutive AF patients who underwent TTE 24 h before RFCA. LASI was calculated as the ratio of left atrial maximum volume to spherical volume. After 1-year follow-up, 56 patients (29.5%) relapsed. Multivariate Cox regression showed that LASI (hazard ratio = 1.48, 95% Cl 1.15-1.92, P = 0.003) was an independent predictor of AF recurrence. Stratifying patients into four subgroups with different LAVI showed that high LASI value indicated a high risk of recurrence, especially in patients with mildly and moderately enlarged atria (the recurrence rate was 0% vs. 26.3%, P = 0.049; 9.5% vs. 40.9%, P = 0.018, respectively). In conclusion, TTE-derived LASI may be useful to predict AF recurrence after RFCA.

Primary percutaneous coronary intervention in a COVID-19 patient with ST-segment elevation myocardial infarction after lung transplantation: a case report.

We present an unusual case of a patient with bilateral-lung transplantation due to severe coronavirus disease 2019 (COVID-19), who subsequently suffered complications with acute myocardial infarction and underwent primary percutaneous coronary intervention (PCI).

Risk of patients with hypertrophic cardiomyopathy undergoing noncardiac surgery.

OBJECTIVE: To determine the risk of noncardiac surgery in patients with hypertrophic cardiomyopathy. METHODS: We reviewed the medical records of all patients who were diagnosed as hypertrophic cardiomyopathy at Peking Union Medical College Hospital from January 1998 to August 2006 and identified 24 patients who subsequently underwent noncardiac surgery. RESULTS: There were no intraoperative cardiac events. Postoperative cardiac events were identified in 3 patients including 1 death due to acute myocardial infarction and 2 episodes of transient hypotension. CONCLUSIONS: The risk of anesthesia and noncardiac surgery is low in patients with hypertrophic cardiomyopathy. During the perioperative period, beta-blockers and/or calcium channel blockers should be given; vasodilator and inotropic agents should be avoided due to the side effects on hemodynamics.

Efficacy of statin monotherapy or in combination with coenzyme a capsule in patients with metabolic syndrome and mixed dyslipidemia.

BACKGROUND: Patients with metabolic syndrome are at increased risk for cardiovascular disease. Combination lipid-lowering therapy is often needed in patients with metabolic syndrome and mixed dyslipidemia. The aim of this study was to compare the effect of statin combined with a new hypolipidemic agent, coenzyme A (CoA) with moderate-dose statin monotherapy in subjects with metabolic syndrome and mixed dyslipidemia by evaluating data from a subgroup of patients with metabolic syndrome and mixed dyslipidemia from a previously conducted randomized study. METHODS: In the present post hoc analysis, 212 patients were included, receiving statin monotherapy (n = 94) or statin combined with CoA 400 U/day (n = 118) for 8 weeks. The lipoprotein profile was determined at baseline and week 8 visits. Attainment of low-density lipoprotein-cholesterol (LDL-C) < 100 mg/dL, non-high-density lipoprotein-cholesterol (HDL-C) < 130 mg/dL, and the combined goal of these two parameters was also evaluated. RESULTS: The mean percent change was more prominent with CoA plus statin compared with placebo plus statin in triglyceride (TG) (-32.5% vs. -8.7%, respectively; P = 0.0002), total cholesterol (-9.6% vs. -3.6%, P = 0.013), LDL-C (-7.5% vs. 2.1%, P = 0.033), and non-HDL-C (-14.3% vs. -6.4%, P = 0.011). Treatment with CoA plus statin resulted in larger percentages of participants attaining lipid goals for LDL-C (70.3% vs. 56.4%, P = 0.044), non-HDL-C (60.2% vs. 45.7%, P = 0.039), and the combined goal of LDL-C and non-HDL-C (57.6% vs. 42.6%, P = 0.038) than statin monotherapy. CONCLUSION: These results demonstrate that CoA plus statin therapy was more effective in improving lipoprotein parameters than statin alone in patients with metabolic syndrome and mixed hyperlipidemia.

Low serum testosterone level was associated with extensive coronary artery calcification in elderly male patients with stable coronary artery disease.

BACKGROUND: Coronary artery calcification (CAC) is a pandemic condition in elderly patients with coronary artery disease (CAD) and associated with a worse prognosis. Although available data have shown an association between testosterone levels in men and CAD, the association between testosterone and CAC in elderly male patients with CAD remains unknown. METHODS: A total of 211 consecutive male patients (age ≥ 65 years) who underwent first multidetector computed tomography and following angiography were enrolled from our institution between March 2009 and September 2014. CAD was angiographically documented as significant stenoses (reduction ≥ 50% of the lumen diameter) on any major coronary vessel. The standard Agatston calcium score was calculated. The relationship of serum testosterone level with the CAC score measured by multidetector computed tomography in elderly male patients with stable CAD was evaluated. For data analyses, the CAC score was divided into four categories: ≤ 10, 11-99, 100-399, and ≥ 400, corresponding to minimal, moderate, increased, and extensive calcification. RESULTS: Patients with higher CAC scores had significantly lower testosterone levels than patients with lower CAC scores (P = 0.048). In logistic regression analysis, testosterone level remained an independent predictor of extensive CAC (odds ratio 0.997, 95% confidence interval 0.994-0.999, P = 0.043). CONCLUSION: Our findings indicate an inverse association between testosterone level and the susceptibility to extensive CAC in elderly men with stable CAD.

Comprehensive assessment of the association of WNK4 polymorphisms with hypertension: evidence from a meta-analysis.

The relationship between with-no-lysine [K] kinase 4 (WNK4) gene polymorphisms and hypertension has been widely investigated, However, the studies yielded contradictory results. To evaluate these inconclusive findings comprehensively, we therefore performed a meta-analysis. Ten articles encompassing 16 independent case-control studies with 6089 hypertensive cases and 4881 normotensive controls were selected for this meta-analysis. Four WNK4 gene polymorphisms were identified (G1155942T, G1156666A, T1155547C, and C6749T). The results showed statistically significant associations of G1155942T polymorphism (allelic genetic model: odds ration or OR = 1.62, 95% confidence interval or CI: 1.11-2.38, P = 0.01; dominant model: OR = 1.85, 95% CI: 1.07-3.19, P = 0.03) and C6749T polymorphism (allele contrast: OR = 2.04, 95% CI: 1.60-2.59, P<0.01; dominant model: OR = 2.04, 95%CI: 1.59-2.62, P<0.01; and homozygous model: OR = 5.01, 95% CI: 1.29-19.54, P = 0.02) with hypertension risk. However, neither C1155547T nor G1156666A was associated significantly with hypertension susceptibility. In conclusion, this meta-analysis suggested that WNK4 G1155942T and C6749T gene polymorphisms may contribute to the susceptibility and development of hypertension. Further well-designed studies with larger sample size are required to elucidate the association of WNK4 gene multiple polymorphisms with hypertension risk.

[Study on the efficiency of the European System for Cardiac Operative Risk Evaluation (EuroSCORE) in predicting in-hospital mortality of the patients with percutaneous coronary intervention].

OBJECTIVE: To investigate the efficiency of European System for Cardiac Operative Risk Evaluation (EuroSCORE) in predicting in-hospital mortality for the patients after percutaneous coronary intervention (PCI). METHODS: Retrospective analysis was conducted on the patients who had undergone PCI in our hospital since year 2005 to 2007. We used both cumulative EuroSCORE score and logistic EuroSCORE to predict the in-hospital morality and to analyze the correlation between the predicted mortality and the actual mortality. RESULTS: According to the additive EuroSCORE, we divided the patients into three groups, the additive EuroSCORE 0-2 were divided into low-risk group, 3-5 were divided into mid-risk group and ≥ 6 into high-risk group. The actual in-hospital mortality rates were 0%, 0.47% and 6.09% respectively. The EuroSCORE model demonstrated an overall relation between the EuroSCORE ranking and the incidence of in-hospital mortality (P<0.001). Results from the multivariable logistic regression analysis showed that the EuroSCORE was an independent in-hospital mortality predictor (P<0.01). CONCLUSION: The EuroSCORE risk model and the in-hospital mortality were significantly correlated, indicating that the model was a promising method for predicting the in-hospital mortality of PCI patients.