Biosynthetic production of anticoagulant heparin polysaccharides through metabolic and sulfotransferases engineering strategies.

Heparin is an important anticoagulant drug, and microbial heparin biosynthesis is a potential alternative to animal-derived heparin production. However, effectively using heparin synthesis enzymes faces challenges, especially with microbial recombinant expression of active heparan sulfate N-deacetylase/N-sulfotransferase. Here, we introduce the monosaccharide N-trifluoroacetylglucosamine into Escherichia coli K5 to facilitate sulfation modification. The Protein Repair One-Stop Service-Focused Rational Iterative Site-specific Mutagenesis (PROSS-FRISM) platform is used to enhance sulfotransferase efficiency, resulting in the engineered NST-M8 enzyme with significantly improved stability (11.32-fold) and activity (2.53-fold) compared to the wild-type N-sulfotransferase. This approach can be applied to engineering various sulfotransferases. The multienzyme cascade reaction enables the production of active heparin from bioengineered heparosan, demonstrating anti-FXa (246.09 IU/mg) and anti-FIIa (48.62 IU/mg) activities. This study offers insights into overcoming challenges in heparin synthesis and modification, paving the way for the future development of animal-free heparins using a cellular system-based semisynthetic strategy.

Association of hypertension burden with stroke risk in patients with heart failure with preserved ejection fraction.

Introduction: Whether the hypertension burden is associated with stroke incidence is inconclusive. In this study, we aimed to investigate the relationship between hypertension burden and stroke risk in patients with heart failure with preserved ejection fraction (HFpEF). Methods: HFpEF patients from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial were divided into three groups (low, medium, and high risk) according to their hypertension burden values. Higher hypertension burden risk represented the longer duration of hypertension. We evaluated the association of hypertension burden with stroke risk using Fine and Gray's competing risk models. Results: A total of 3431 HFpEF patients (mean age: 68.5 ± 9.58 years, 51.6% females) were enrolled. During a median follow-up of 3.3 years, per 10-point increase in hypertension burden was associated with any stroke (hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.08-1.21), new-onset stroke (HR 1.14, 95% CI 1.07-1.21), and ischemic stroke (HR 1.10, 95% CI 1.02-1.17). When hypertension burden was analyzed as a categorical variable, any stroke risk was increased in the medium- (HR 1.59, 95% CI 1.01-2.40) and high-risk (HR 3.19, 95% CI 2.05-4.97) groups when compared with the low-risk group. For the outcomes of new-onset (HR 2.92, 95% CI 1.80-4.74) and ischemic stroke (HR 2.46, 95% CI 1.41-4.29), similar results were observed in patients with high-versus low-risk hypertension burden. Conclusions: Increasing hypertension burden was associated with an increased risk of stroke, suggesting that shortening hypertension duration might appropriately minimize the stroke incidence in HFpEF patients.

Novel ß1,4 N-acetylglucosaminyltransferase in de novo enzymatic synthesis of hyaluronic acid oligosaccharides.

The efficiency of de novo synthesis of hyaluronic acid (HA) using Pasteurella multocida hyaluronate synthase (PmHAS) is limited by its low catalytic activity during the initial reaction steps when monosaccharides are the acceptor substrates. In this study, we identified and characterized a ß-1,4-N-acetylglucosaminyl-transferase (EcGnT) derived from the O-antigen gene synthesis cluster of Escherichia coli O8:K48:H9. Recombinant ß1,4 EcGnT effectively catalyzed the production of HA disaccharides when the glucuronic acid monosaccharide derivative 4-nitrophenyl-ß-D-glucuronide (GlcA-pNP) was used as the acceptor. Compared with PmHAS, ß1,4 EcGnT exhibited superior N-acetylglucosamine transfer activity (~ 12-fold) with GlcA-pNP as the acceptor, making it a better option for the initial step of de novo HA oligosaccharide synthesis. We then developed a biocatalytic approach for size-controlled HA oligosaccharide synthesis using the disaccharide produced by ß1,4 EcGnT as a starting material, followed by stepwise PmHAS-catalyzed synthesis of longer oligosaccharides. Using this approach, we produced a series of HA chains of up to 10 sugar monomers. Overall, our study identifies a novel bacterial ß1,4 N-acetylglucosaminyltransferase and establishes a more efficient process for HA oligosaccharide synthesis that enables size-controlled production of HA oligosaccharides. KEY POINTS: • A novel ß-1,4-N-acetylglucosaminyl-transferase (EcGnT) from E. coli O8:K48:H9. • EcGnT is superior to PmHAS for enabling de novo HA oligosaccharide synthesis. • Size-controlled HA oligosaccharide synthesis relay using EcGnT and PmHAS.

Comparison of liver fibrosis scores for predicting mortality and morbidity in heart failure with preserved ejection fraction.

AIMS: Liver fibrosis scores (LFSs) are non-invasive and effective tools for estimating cardiovascular risks. To better understand the advantages and limitations of currently available LFSs, we determined to compare the predictive values of LFSs in heart failure with preserved ejection fraction (HFpEF) for primary composite outcome, atrial fibrillation (AF), and other clinical outcomes. METHODS AND RESULTS: This was a secondary analysis of the TOPCAT trial, and 3212 HFpEF patients were enrolled. Five LFSs, namely, non-alcoholic fatty liver disease fibrosis score (NFS), fibrosis-4 score (FIB-4), BARD, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, and Health Utilities Index (HUI) scores were adopted. Cox proportional hazard model and competing risk regression model were performed to assess the associations between LFSs and outcomes. The discriminatory power of each LFS was evaluated by calculating the area under the curves (AUCs). During a median follow-up of 3.3 years, a 1-point increase in the NFS [hazard ratio (HR) 1.10; 95% confidence interval (CI) 1.04-1.17], BARD (HR 1.19; 95% CI 1.10-1.30), and HUI (HR 1.44; 95% CI 1.09-1.89) scores was associated with an increased risk of primary outcome. Patients with high levels of NFS (HR 1.63; 95% CI 1.26-2.13), BARD (HR 1.64; 95% CI 1.25-2.15), AST/ALT ratio (HR 1.30; 95% CI 1.05-1.60), and HUI (HR 1.25; 95% CI 1.02-1.53) were at an increased risk of primary outcome. Subjects who developed AF were more likely to have high NFS (HR 2.21; 95% CI 1.13-4.32). High levels of NFS and HUI scores were a significant predictor of any hospitalization and hospitalization for heart failure. The AUCs for the NFS in predicting primary outcome (0.672; 95% CI 0.642-0.702) and incident of AF (0.678; 95% CI 0.622-0.734) were higher than other LFSs. CONCLUSIONS: In light of these findings, NFS appears to have superior predictive and prognostic utility compared with AST/ALT ratio, FIB-4, BARD, and HUI scores. CLINICAL TRIAL REGISTRATION: (https://clinicaltrials.gov). Unique identifier: NCT00094302.

Essen Stroke Risk Score Predicts Clinical Outcomes in Heart Failure Patients with Preserved Ejection Fraction: Evidence from the TOPCAT trial.

BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with increased risks of stroke and other adverse outcomes. AIMS: This study sought to determine whether the Essen Stroke Risk Score (ESRS) could predict the risks of adjudicated clinical outcomes in patients with HFpEF from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. METHODS: We evaluated associations of baseline ESRS with clinical outcomes by using the Cox proportional hazard model with competing risk regression. The diagnostic accuracy of the ESRS was assessed using the C-index and calibration data. RESULTS: Of 3,441 HFpEF patients with a mean follow-up of 3.3 years, the risk of stroke ranged from 0.32% per year at an ESRS of 1 to 2 points to 1.71% per year at a score of ≥6 points. Each point increase in ESRS was associated with increased risks of primary composite outcome (hazard ratios [HRs] = 1.31; 95% confidence intervals [CIs]: 1.23-1.40; C-index = 0.68), stroke (HR = 1.33 [95% CI: 1.16-1.53]; C-index = 0.68), myocardial infarction (HR = 1.60 [95% CI: 1.40-1.83]; C-index = 0.75), HF hospitalization (HR = 1.30 [95% CI: 1.20-1.41]; C-index = 0.71), any hospitalization (HR = 1.20, 95% CI: 1.15-1.26; C-index = 0.68), cardiovascular death (HR = 1.32 [95% CI: 1.20-1.44]; C-index = 0.68), and all-cause death (HR = 1.37, [95% CI: 1.28-1.48]; C-index = 0.68). The calibration curves showed that the ESRS had a better agreement between predicted and observed stroke risks compared with the R2CHADS2, CHADS2, or CHA2DS2-VASC stroke scores. CONCLUSION: The ESRS had modest discriminatory abilities for predicting stroke as well as other adverse outcomes including myocardial infarction, hospitalization, and death in HFpEF patients. ESRS might have better calibration performance than R2CHADS2, CHADS2, or CHA2DS2-VASC in HFpEF at high risk for stroke. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT00094302.

An Updated Meta-Analysis of DOACs vs. VKAs in Atrial Fibrillation Patients With Bioprosthetic Heart Valve.

Background: Current guidelines recommend the utilization of direct-acting oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation (AF). However, the optimal anticoagulation strategy for AF patients with bioprosthetic heart valves (BPHV) remains controversial. Therefore, we conducted this meta-analysis to explore the effect of DOACs versus vitamin K antagonists (VKAs) in this population. Methods: We systematically searched the PubMed and Embase databases until November 2021 for studies reporting the effect of DOACs versus VKAs in AF patients with BPHV. Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using the random-effects model with an inverse variance method. Results: We selected four randomized clinical trials and seven observational studies (2236 DOAC- and 6403 VKAs-users). Regarding the effectiveness outcomes, there were no significant differences between DOACs and VKAs in stroke or systemic embolism (RR = 0.74, 95%CI: 0.50-1.08), ischemic stroke (RR = 1.08, 95%CI: 0.76-1.55), all-cause death (RR = 0.98, 95%CI: 0.86-1.12), and cardiovascular death (RR = 0.85, 95%CI: 0.40-1.80). In terms of the safety outcomes, DOACs was associated with lower risks of major bleeding (RR = 0.70, 95%CI: 0.59-0.82) and intracranial bleeding (RR = 0.42, 95%CI: 0.26-0.70), but the risks of any bleeding (RR = 0.85, 95%CI: 0.65-1.13) and gastrointestinal bleeding (RR = 0.92, 95%CI: 0.73-1.17) are not significantly different when compared with VKAs. The subgroup analysis with follow-up as a covariate revealed that the DOACs had lower risks of SSE (RR = 0.59, 95%CI: 0.37-0.94) and major bleeding (RR = 0.69, 95%CI: 0.58-0.81) in patients with a mean follow-up of more than 24 months, but no statistical differences were found in patients with the follow-up less than 24 months (SSE: RR = 1.10, 95%CI: 0.92-1.32; major bleeding: RR = 0.91, 95%CI: 0.42-2.01). Conclusions: In AF with BPHV, patients on DOACs experienced a reduced risk of major bleeding and intracranial bleeding compared with VKAs, while the risks of stroke, cardiovascular death, and all-cause mortality were similar.

Association of Coffee Consumption With Atrial Fibrillation Risk: An Updated Dose-Response Meta-Analysis of Prospective Studies.

Background: Several published studies have examined the association of coffee consumption with atrial fibrillation (AF) risk, but their findings are still controversial. Therefore, we performed a systematic review and dose-response meta-analysis of prospective studies to determine the relationship between coffee consumption and the risk of incident AF. Methods: We systematically retrieved the PubMed and Embase databases until October 2021 for pertinent studies that reported the association of coffee consumption (caffeinated or decaffeinated coffee) with AF risk. A cubic spline random-effects model was used to fit the potential dose-response curve. The effect estimates were expressed as adjusted risk ratios (RRs) and 95% CIs. Results: A total of 10 prospective studies (11 cohorts) involving 30,169 AF events and 723,825 participants were included. In the dose-response analysis, there was a linear inverse association between coffee intake and risk of AF although not statistically significant (P non-linearity = 0.25). Compared with participants with no coffee consumption, the RRs (95% CI) of AF risk estimated directly from the dose-response curve were 1.01 (0.98-1.03), 1.00 (0.97-1.04), 0.99 (0.92-1.02), 0.95 (0.89-1.01), 0.94 (0.87-1.01), 0.89 (0.79-1.02), and 0.87 (0.76-1.02) for 1-7 cups of coffee per day, respectively. One cup per day increased in coffee consumption was associated with a 2% reduced risk of AF (RR = 0.98, 95% CI: 0.97-1.00, P = 0.02). Conclusions: Our evidence from this meta-analysis suggested that coffee consumption had a trend toward reducing the risk of AF in a dose-response manner. Further studies could be conducted to reinforce our findings.

Associations of Antidepressants With Atrial Fibrillation and Ventricular Arrhythmias: A Systematic Review and Meta-Analysis.

Background: Several published studies have disagreements on whether the use of antidepressants is associated with increased risk of arrhythmias. In this study, we performed this meta-analysis to assess the association of antidepressants with cardiac arrhythmias in patients who require antidepressants. Methods: The PubMed and Embase databases were systematically searched until December 2021 to find studies that investigated the association between antidepressant use and cardiac arrhythmias. Studies that assessed the effects of any antidepressant on arrhythmias in patients who require antidepressants compared with those who require no antidepressants were included. We used a random-effects model to pool the adjusted risk ratios (RRs) and 95% confidence intervals (CIs). The stability of the results was examined by omitting an individual study at a time. Results: A total of 3,396 studies were screened and 6 studies with 2,626,746 participants were finally included in this meta-analysis. When compared with no antidepressants, the use of antidepressants was significantly associated with an increased risk of atrial fibrillation (RR = 1.37, 95% CI: 1.16-1.61). However, there was no difference in the risk of ventricular arrhythmias or sudden cardiac death (RR = 1.33, 95% CI: 0.88-2.01) between the two studied groups. In the subgroup analysis, tricyclic antidepressants (RR = 1.12, 95% CI: 0.89-1.41), selective serotonin reuptake inhibitors (RR = 1.46, 95% CI: 0.63-3.38), and selective serotonin reuptake inhibitors (RR = 0.99, 95% CI: 0.97-1.01) did not increase the risk of ventricular arrhythmias and/or sudden cardiac death. Conclusion: Recently published data suggested that the use of antidepressants did not increase the risk of ventricular arrhythmias or sudden cardiac death. Antidepressants were associated with an increased risk of atrial fibrillation but that still needs further confirmation.

The Role of 6-Minute Walk Test Guided by Impedance Cardiography in the Rehabilitation Following Knee Arthroplasty: A Randomized Controlled Trial.

Objective: To explore the effect of the 6-minute walk test (6MWT) guided by non-invasive cardiac output on the rehabilitation of patients with knee osteoarthritis following artificial total knee arthroplasty. Methods: About 66 patients with knee osteoarthritis planned to undergo artificial total knee arthroplasty were included from March 2019 to October 2019, and randomly assigned to the intervention group or control group. Under the guidance of a clinical rehabilitation physician, orthopedic physician, and cardiologist, a home rehabilitation exercise program based on 6MWT and non-invasive cardiac output was formulated for patients with knee osteoarthritis. The participants of the intervention group conducted full rehabilitation training supervision and guidance through the WeChat platform to ensure their rehabilitation pieces of training were completed safely and effectively. As for the control group, patients were just given rehabilitation training manuals at the time of discharge and completed the training by themselves. Results: At 6 months post-operatively, 6-minute walk distance (413.88 ± 44.61 vs. 375.00 ± 40.53 m, P < 0.05), active metabolic equivalent (4.13 ± 0.29 vs. 3.88 ± 0.27, P < 0.05), stroke volume after 6MWT (114.97 ± 12.05 vs. 98.38 ± 16.43 ml, P < 0.05), and cardiac output (11.92 ± 1.68 vs. 9.79 ± 1.82 l/min, P < 0.05) of the intervention group were significantly higher than those of the control group. The symptom evaluation scores of the intervention group were also better than those of the control group. Conclusions: The multidisciplinary post-operative rehabilitation exercise training program is beneficial to the recovery of lower limb function and the improvement of exercise capacity after knee replacement, and it also helps to improve the non-invasive hemodynamic indicators related to the cardiac function of the patient. Clinical Trial Registration: http://www.chictr.org.cn/index.aspx.

Notoginsenoside R1 Protects Against High Glucose-Induced Cell Injury Through AMPK/Nrf2 and Downstream HO-1 Signaling.

Notoginsenoside R1 (NGR1), the primary bioactive compound found in Panax notoginseng, is believed to have antihypertrophic and antiapoptotic properties, and has long been used to prevent and treat cardiovascular diseases. However, its potential role in prevention of diabetic cardiomyopathy remains unclear. The present study aimed to investigate the mechanism of NGR1 action in high glucose-induced cell injury. H9c2 cardiomyocytes were cultured in a high-glucose medium as an in-vitro model, and apoptotic cells were visualized using TUNEL staining. Expression of Nrf2 and HO-1 was measured using Western blotting or reverse transcription-quantitative PCR (RT-qPCR). The Nrf2 small interfering (si) RNA was transfected into cardiomyocytes using Opti-MEM containing Lipofectamine® RNAiMAX. NGR1 protected H9c2 cardiomyocytes from cell death, apoptosis and hypertrophy induced by high glucose concentration. Expression of auricular natriuretic peptide and brain natriuretic peptide was remarkably reduced in NGR1-treated H9C2 cells. Western blot analysis showed that high glucose concentration markedly inhibited AMPK, Nrf2 and HO-1, and this could be reversed by NGR1 treatment. However, the cardioprotective effect of NGR1 was attenuated by compound C, which reverses Nrf2 and HO-1 expression levels, suggesting that AMPK upregulates Nrf2 and HO-1 gene expression, protein synthesis and secretion. Transfection of H9C2 cells with Nrf2 siRNA markedly reduced the cardioprotective effect of NGR1 via reduced expression of HO-1. These results indicated that NGR1 attenuated high glucose-induced cell injury via AMPK/Nrf2 signaling and its downstream target, the HO-1 pathway. We conclude that the cardioprotective effects of NGR1 result from upregulation of AMPK/Nrf2 signaling and HO-1 expression in cardiomyocytes. Our findings suggest that NGR1 treatment might provide a novel therapy for diabetic cardiomyopathy.

Metformin attenuates angiotensin II-induced cardiomyocyte hypertrophy by upregulating the MuRF1 and MAFbx pathway.

Pathological cardiac hypertrophy induced by aging and neurohumoral activation, such as angiotensin II (Ang II) activation, is an independent risk factor for heart failure. The muscle really interesting new gene-finger protein-1 (MuRF1) and muscle atrophy F-box (MAFbx) pathway has been previously reported to be an important mechanism underlying the pathogenesis of cardiac hypertrophy. Metformin is currently the first-line blood glucose-lowering agent that can be useful for the treatment of cardiovascular diseases. However, the potential role of metformin in the modulation of MuRF1 and MAFbx in cardiomyocyte hypertrophy remains poorly understood. The present study used H9c2 cells, a cardiomyocyte cell model. The surface area of cultured rat H9c2 myoblasts was measured and the expression levels of MuRF1 and MAFbx were quantified using western blot or reverse transcription-quantitative PCR. H9c2 cells were transfected with MuRF1 and MAFbx small interfering (si) RNA. The present study revealed that Ang II treatment significantly increased the cell surface area of model cardiomyocytes. Additionally, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNA and protein expression was increased following this treatment. Ang II also downregulated MuRF1 and MAFbx protein and mRNA expression. In the H9C2, treatment with metformin attenuated hypertrophic remodeling. In addition, expression of ANP and BNP was significantly reduced in metformin-treated H9C2 cells. The results indicated that metformin increased the activity of MuRF1 and MAFbx and upregulated their expression, the knockdown of which resulted in deteriorative Ang II-induced cell hypertrophy, even following treatment with metformin. Taken together, data from the present study suggest that metformin can prevent cardiac hypertrophy through the MuRF1 and MAFbx pathways.

Effect of Rivaroxaban or Apixaban in Atrial Fibrillation Patients with Stage 4-5 Chronic Kidney Disease or on Dialysis.

BACKGROUND: Anticoagulant treatment in non-valvular atrial fibrillation (AF) patients with severe chronic kidney disease (CKD) or on dialysis remains a matter of debate. The object of this study was to quantify the benefit-risk profiles of rivaroxaban or apixaban versus warfarin in AF patients with stage 4-5 CKD or on dialysis. METHOD: A comprehensive search of the Cochrane Library, PubMed, Ovid, and Google Scholar databases was performed for eligible studies that comparing the effect and safety of rivaroxaban or apixaban versus warfarin in AF patients with stage 4-5 CKD or on dialysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were abstracted, and then pooled using a random-effects model. RESULTS: A total of seven studies, one post hoc analysis of RCT and six observational cohorts, were included in this meta-analysis. Compared with warfarin use, the use of rivaroxaban or apixaban was significantly associated with reduced risks of all-cause death (HR = 0.82, 95% CI 0.72-0.93) and gastrointestinal bleeding (HR = 0.87, 95% CI 0.80-0.95). There were no significant differences in the risks of stroke or systemic embolism (rivaroxaban, HR = 0.71, 95% CI 0.43-1.19; apixaban, HR = 0.86, 95%CI 0.68-1.09) and major bleeding (rivaroxaban, HR = 0.96, 95% CI 0.64-1.45; apixaban, HR = 0.56, 95%CI 0.28-1.12). CONCLUSIONS: Current evidence suggests that rivaroxaban or apixaban are safe and at least as effective as warfarin in patients with AF and stage 4-5 CKD or on dialysis.

Cardiac hemodynamic response to the 6-minute walk test in patients with intestinal carcinoma undergoing bevacizumab treatment.

BACKGROUND: Exercise capacity is evaluated using the 6-minute walk test (6MWT) in various cardiovascular diseases. Bevacizumab (BEV) has been associated with significant risk of cardiovascular complications. The aim of this study was to investigate BEV-related influences on cardiac hemodynamic response to 6MWT. METHODS: We prospectively studied 24 patients with intestinal carcinoma to assess the hemodynamic response during 6MWT, of whom eight underwent BEV treatment. Obtained data was analyzed to identify hemodynamic differences between BEV and non-BEV treated patients. RESULTS: Twenty-four patients with stage IV intestinal carcinoma consented to assessment after the completion of three cycles of BEV-combined chemotherapy (age, 46.4±16.7 years) or standard chemotherapy alone (age, 56.4±13.7 years). In comparison with non-BEV treated patients, BEV-treated patients walked less (484.3±42.4 vs. 503.0±48.2, P=0.339). These two groups manifested similar hemodynamic response during the 6MWT. The change of hemodynamic parameters at 1 minute after completion of 6MWT was defined as hemodynamic parameter recovery. BEV-treated patients had significantly lower change of left cardiac work index (LCWi), cardiac index (CI), cardiac output (CO) and stroke volume (SV) after 6MWT. Interestingly, in BEV-treated patients CI change after 6MWT was predominantly related to the decrease in SV instead of heart rate (HR) as suggested by a higher standardized beta coefficient (0.883 vs. 0.657) and semi-partial correlations (0.821 vs. 0.677). CONCLUSIONS: Estimation of hemodynamic response to 6MWT is feasible, and may provide useful information of myocardial damage in BEV-treated patients.

Irregular orthodromic atrioventricular reentrant tachycardia using the left lateral accessory pathway due to intermittent mitral isthmus block.

Mitral isthmus block during left lateral accessory pathway ablation has been reported in the past. Here, we document for the first time an irregular atrioventricular reciprocating tachycardia due to alternating mitral isthmus block and mitral isthmus delay, resulting in different atrioventricular node conduction times and tachycardia cycle length.

Association between retinal arterial narrowing and left ventricular diastolic dysfunction in masked hypertensives.

Morphological change in retinal vessel diameters has been reported to be associated with negative cardiovascular outcomes, but its association with left ventricular diastolic dysfunction (LVDD) is not clear. This study aimed to examine the association between echocardiographic markers of LVDD and retinal vascular diameters, in untreated masked hypertension (MH). In this observational study, 105 MH patients without other cardiovascular risks were included (mean age 48.4 ± 5.7, female 72.4%). All individuals underwent extensive clinical and laboratory investigations, including echocardiography, ambulatory blood pressure monitoring, and retinal vascular diameters measured by optical coherence tomography. In the group, LVDD was diagnosed in 36 participants evaluated by left ventricular volume index, E/A and E/e' ratio. Compared to non-LVDD, LVDD subjects displayed narrower retinal arteriolar diameter (139.1 ± 33.8 vs 165.1 ± 29.1; adjusted P = .007) and wider retinal venular diameter (237.9 ± 42.2 vs 214.9 ± 44.8; adjusted P = .045). Significant and independent associations were demonstrated for retinal arteriolar narrowing and E/A ratio (adjusted ß = 0.744, P = .031) and for retinal arteriolar diameter and E/e' ratio (adjusted ß = -0.158, P = .001) after controlling for age, gender, body mass index, ambulatory systolic blood pressure, low-density lipoprotein cholesterol, and retinal venular diameter. In untreated MH subjects, retinal arteriolar diameter, a marker of microvascular damage, was independently associated with echocardiographic markers of diastolic dysfunction. These findings might underscore the hypothesis that microvascular disease could contribute to cardiac remodeling.

Angiopoietin-Like Protein 7 and Short-Term Mortality in Acute Heart Failure.

INTRODUCTION: Angiopoietin-like protein 7 (ANGPTL7) is involved in extracellular matrix expression and inflammatory responses. However, the prognostic utility of ANGPTL7 among patients with acute heart failure (AHF) remains unclear. OBJECTIVE: To evaluate the association between ANGPTL7 and short-term mortality due to AHF. METHODS AND RESULTS: Patients with AHF were prospectively studied. Serum levels of ANGPTL7 were measured by an enzyme-linked immunosorbent assay. Associations between 30- and 90-day mortality and tertiles of ANGPTL7 were assessed by multivariate logistic regression models. The study comprised 142 patients. Median patient age was 68 years, and 69.7% were male. There were 20 deaths within 30 days and 37 deaths within 90 days. Crude rates of 30-day mortality in low, intermediate, and high tertiles of ANGPTL7 were 4.6, 14.6, and 22.9%, respectively. Crude rates of 90-day mortality of corresponding tertiles were 15.2, 25.0, and 37.5%. After adjusting for potential confounders, including NT-proBNP, the high tertile of ANGPTL7 was associated with a significantly increased risk of both 30-day mortality (odds ratio [OR]: 6.77, 95% confidence interval [CI]: 1.41-32.61, p = 0.017) and 90-day mortality (OR: 3.78, 95% CI: 1.38-10.36, p = 0.010) compared with the low tertile of ANGPTL7. Although mortality risk tended to be higher in the intermediate tertile than the low tertile, it did not reach statistical significance (OR: 3.75, 95% CI: 0.73-19.14, p = 0.113 for 30-day mortality; OR: 1.88, 95% CI: 0.66-5.34, p = 0.236 for 90-day mortality). CONCLUSIONS: Serum level of ANGPTL7 was independently associated with short-term mortality among patients with AHF.

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.

Nocturnal systolic hypertension is a risk factor for cardiac damage in the untreated masked hypertensive patients.

The nocturnal blood pressure (BP) has been identified as a prognostic factor for cardiovascular events. This study aimed to investigate the association between different patterns of nocturnal masked hypertension (MH) and the echocardiographic parameters in the untreated nocturnal MH patients. A total of 721 untreated MH patients (309 females and 412 males, mean age = 56.59 ± 15.20 years) from June 2006 and June 2016 were included and divided into nocturnal systolic MH (n = 77), nocturnal diastolic MH (n = 232), and nocturnal systolic/diastolic MH (n = 412) groups according to the ambulatory blood pressure monitoring. Baseline characteristics, office BP values, ambulatory BP monitoring parameters, and echocardiographic parameters were compared among the three groups. The independent factors associated with echocardiographic parameters were analyzed by multivariate linear regression. The nocturnal systolic group had the highest ratio of males, mean age, and office systolic BP (SBP), and the lowest office, 24-hour, daytime, nocturnal diastolic BP and heart rate among the three groups. The nocturnal diastolic group had the lowest interventricular septum (IVS) thickness, left atrium (LA) dimension, and left ventricular (LV) mass among the three groups. Multivariate linear regression analysis revealed that 24-hour, daytime, and nocturnal SBPs were all positively associated with LA dimension, IVS thickness, and LV mass (all B were positive and P < .050). Pearson's correlation analysis showed that nocturnal SBP was positively correlated with LA dimension, IVS thickness, and LV mass. These results suggested that different patterns of nocturnal MH had different echocardiographic outcomes. Nocturnal SBP was the independent factor associated with the echocardiographic parameters.

Diastolic Reverse Dipping Pattern Is the Predictor for the Echocardiographic Changes in the Untreated Masked Hypertensive Patients.

BACKGROUND: The prognostic value of the dipping categories of diastolic blood pressure (DBP) is unknown. This study aimed to investigate the association between DBP dipping categories of diastolic blood pressure and echocardiographic changes in untreated masked hypertension (MH) patients. METHODS: This retrospective study included 721 untreated MH patients between June 2006 and June 2016. Nocturnal dipping categories were defined according to the percentage decrease in nocturnal blood pressure (BP) compared to daytime BP as follows: non-dipping: decrease 0% to <10%, dipping: decrease 10% to 20%, reverse dipping: decrease <0%, and extreme dipping: decrease >20%. The echocardiographic findings were analyzed. RESULTS: The 4 echocardiographic parameters (left atrium [LA] dimension, interventricular septum [IVS] thickness, linear left ventricular end-diastolic dimension [LVEDD], and left ventricular [LV] mass) were significantly different among the 4 DBP dipping categories. Multivariate linear regression analysis showed that DBP reverse dipping pattern was associated with higher IVS thickness (B: 0.53, 95% CI: 0.24 to 0.82; P < 0.001) and LV mass (B: 12.36, 95% CI: 2.38 to 22.35; P = 0.015), whereas DBP extreme dipping was associated with lower LVEDD (B: -7.05, 95% CI: -11.30 to -2.80; P = 0.001).The nocturnal systolic hypertension was associated with higher IVS thickness (B: 0.42, 95% CI: 0.14 to 0.71; P = 0.003) and LV mass (B:14.21, 95% CI: 4.54 to 23.88; P = 0.004). The nocturnal systolic blood pressure was associated with LA dimension, IVS thickness, left ventricular posterior wall thickness, and LV mass (all Ps < 0.05). CONCLUSIONS: These results suggest that specific DBP dipping categories and nocturnal systolic hypertension were the predictive factors for the echocardiographic changes in untreated MH patients.