The interaction between hyperuricemia and low-density lipoprotein cholesterol increases the risk of 1-year post-discharge all-cause mortality in ST-segment elevation myocardial infarction patients.

BACKGROUND AND AIMS: Hyperuricemia is a known risk factor for cardiovascular diseases, but little is known on whether the association between hyperuricemia and poor outcomes in ST-segment elevation myocardial infarction (STEMI) is modified by low-density lipoprotein cholesterol (LDL-c). This study aimed to investigate the effect of the interaction between hyperuricemia and LDL-c on the risk of 1-year post-discharge all-cause mortality in STEMI patients. METHODS AND RESULTS: A total of 1396 STEMI patients were included. Cox proportional hazards models were used to determine the association between hyperuricemia and 1-year all-cause mortality in the overall population and subgroups stratified based on LDL-c levels (<3.0 mmol/L or ≥3.0 mmol/L). Multivariate analysis indicated that hyperuricemia was associated with 1-year mortality (HR: 2.66; 95% CI: 1.30-5.47; p = 0.008). However, the prognostic effect of hyperuricemia was only observed in patients with LDL-c level ≥3.0 mmol/L (HR: 12.90; 95% CI: 2.98-55.77; p < 0.001), but not in those with LDL-c level <3.0 mmol/L (HR: 0.91, 95% CI: 0.30-2.79, p = 0.875). The interaction between hyperuricemia and LDL-c levels had a significant effect on 1-year mortality. CONCLUSION: Hyperuricemia was associated with increased 1-year post-discharge mortality in patients with LDL-c level≥ 3.0 mmol/L, but not in those with LDL-c level< 3.0 mmol/L.

Anti-diabetic drug canagliflozin hinders skeletal muscle regeneration in mice.

Canagliflozin is an antidiabetic medicine that inhibits sodium-glucose cotransporter 2 (SGLT2) in proximal tubules. Recently, it was reported to have several noncanonical effects other than SGLT2 inhibiting. However, the effects of canagliflozin on skeletal muscle regeneration remain largely unexplored. Thus, in vivo muscle contractile properties recovery in mice ischemic lower limbs following gliflozins treatment was evaluated. The C2C12 myoblast differentiation after gliflozins treatment was also assessed in vitro. As a result, both in vivo and in vitro data indicate that canagliflozin impairs intrinsic myogenic regeneration, thus hindering ischemic limb muscle contractile properties, fatigue resistance recovery, and tissue regeneration. Mitochondrial structure and activity are both disrupted by canagliflozin in myoblasts. Single-cell RNA sequencing of ischemic tibialis anterior reveals a decrease in leucyl-tRNA synthetase 2 (LARS2) in muscle stem cells attributable to canagliflozin. Further investigation explicates the noncanonical function of LARS2, which plays pivotal roles in regulating myoblast differentiation and muscle regeneration by affecting mitochondrial structure and activity. Enhanced expression of LARS2 restores the differentiation of canagliflozin-treated myoblasts, and accelerates ischemic skeletal muscle regeneration in canagliflozin-treated mice. Our data suggest that canagliflozin directly impairs ischemic skeletal muscle recovery in mice by downregulating LARS2 expression in muscle stem cells, and that LARS2 may be a promising therapeutic target for injured skeletal muscle regeneration.

[Expression of Nod-like receptor protein 3 inflammasome in peripheral blood mononuclear cells of children with Kawasaki disease in the acute stage].

OBJECTIVE: To study the association of Nod-like receptor protein 3 (NLRP3) inflammasome with inflammatory response in the acute stage and coronary artery lesion (CAL) in children with Kawasaki disease (KD). METHODS: A total of 42 children with KD who were hospitalized from January to October 2017 were enrolled as the KD group, among whom 9 had CAL (CAL group) and 33 had no CAL (NCAL group). Fifteen age- and gender-matched children with pneumonia and pyrexia were enrolled as the pneumonia-pyrexia group. Fifteen healthy children were enrolled as the healthy control group. Real-time PCR was used to measure the mRNA expression of NLRP3 inflammasome (NLRP3, ASC and caspase-1) in peripheral blood mononuclear cells. The Spearman rank correlation test was used to investigate the correlation of NLRP3 mRNA expression with serum levels of C-reactive protein, erythrocyte sedimentation rate, interleukin-6, interleukin-1ß, procalcitonin, albumin and prealbumin. RESULTS: The KD group had significantly higher mRNA expression of NLRP3, ASC and caspase-1 in the acute stage than the pneumonia-pyrexia and healthy control groups (P<0.05). The CAL group had significantly higher mRNA expression of NLRP3 than the NCAL group (P<0.05). NLRP3 mRNA expression was correlated with C-reactive protein, interleukin-6, interleukin-1ß, and prealbumin levels in children with KD in the acute stage (rs=0.449, 0.376, 0.427, and -0.416 respectively; P<0.05). CONCLUSIONS: NLRP3 inflammasome may participate in inflammatory response in the acute stage and the development of CAL in children with KD.

[Establishment of cardiac remodeling model in FVB/N mice by intraperitoneal injection of isoproterenol].

OBJECTIVE: To explore the feasibility of intraperitoneal injection of isoproterenol (ISO) to induce cardiac remodeling in FVB/N mice. METHODS: Forty-eight FVB/N mice were divided into back subcutaneous saline group (subcutaneous saline group), intraperitoneal saline group, back subcutaneous ISO group (subcutaneous ISO group), and intraperitoneal ISO group according to the route of administration of saline or ISO. ISO (30 µg/g body weight/day) was given to the subcutaneous ISO group and the intraperitoneal ISO group, twice daily with an interval of 12 hours, for 14 consecutive days. The subcutaneous saline group and the intraperitoneal saline group were injected with an equal volume of saline. The left ventricular end-diastolic posterior wall thickness was measured by echocardiography, and the ratio of heart weight to tibia length was determined. Hematoxylin-eosin staining was used to determine the myocardial fiber diameter. Picric-sirius red staining was used to determine the myocardial collagen deposition area. Quantitative real-time PCR was used to measure the mRNA expression of collagen I. RESULTS: Compared with the subcutaneous ISO, subcutaneous saline, and intraperitoneal saline groups, the intraperitoneal ISO group had increased sizes of the cardiac cavity and the heart. Compared with the subcutaneous saline and intraperitoneal saline groups, the subcutaneous ISO group showed no significant changes in the gross morphology of the cardiac cavity and the heart. The intraperitoneal ISO group showed significant increases in the ratio of heart weight to tibia length, myocardial fiber diameter, left ventricular end-diastolic posterior wall thickness, myocardial collagen area percentage, and the mRNA expression of collagen I compared with the subcutaneous ISO, subcutaneous saline, and intraperitoneal saline groups (P<0.01). There were no significant differences in the above five indices between the subcutaneous ISO group and the subcutaneous saline and intraperitoneal saline groups (P>0.05). No significant difference in the mortality rate was found between the subcutaneous ISO and intraperitoneal ISO groups (P>0.05). CONCLUSIONS: Intraperitoneal injection of ISO can induce cardiac hypertrophy and fibrosis in FVB/N mice.

Influence of Body Mass Index on the Activated Clotting Time Under Weight-Based Heparin Dose.

BACKGROUND: Activated clotting time (ACT) has been successfully applied during percutaneous coronary intervention (PCI) to monitor the extent of thrombin inhibition and anti-coagulation from unfractionated heparin (UFH) aiming to reduce the incidence of thrombotic adverse events and hemorrhagic complications. And this investigation was to explore the influence of body mass index (BMI) on ACT in patients received weight-based dose of UFH during PCI treatment. METHODS: 78 male patients undergoing coronary angiography or PCI treatment with a mean age of 63.86 ± 6.89 years were enrolled in this study. The patients were statistically divided into four quartiles according to their BMI. The ACT values were recorded as ACT0 , ACT5 , ACT10 , ACT30 and ACT60 , respectively. Taking the preoperative ACT0 as reference, and the differences of the other ACT values with ACT0 was indicated as ΔACTs. ACT values peaked at 5 min in 33.33% of the patients, 10 min in 51.33% of the patients and 30 min in 15.34% of the patients, respectively. RESULTS: In addition, significant differences were found in overall maximum post-UFH ACT values among all BMI quartiles. UFH doses per blood volume were significantly different among the BMI quartiles, showing a positive association with BMI quartiles; further evidence revealed that the areas under the ΔACT-time curves increased gradually from quartile I to quartile IV. The proportions of ACT60 > 250 s and ACT60 > 300 s were found to be positively correlated with the increased BMI at 60 min after heparin loading. CONCLUSIONS: The results of our study have shown that a standardized dosing nomogram that uses the actual body weight to calculate the heparin doses may result in UFH overdose for patients with higher BMI compared to patients with lower BMI.

Integrated Analysis of circRNA-miRNA-mRNA ceRNA Network in Cardiac Hypertrophy.

Cardiac hypertrophy is an adaptive cardiac response that accommodates the variable hemodynamic demands of the human body during extended periods of preload or afterload increase. In recent years, an increasing number of studies have pointed to a potential connection between myocardial hypertrophy and abnormal expression of non-coding RNAs. Circular RNA (circRNA), as one of the non-coding RNAs, plays an essential role in cardiac hypertrophy. However, few studies have systematically analyzed circRNA-related competing endogenous RNA (ceRNA) regulatory networks associated with cardiac hypertrophy. Therefore, we used public databases from online prediction websites to predict and screen differentially expressed mRNAs and miRNAs and ultimately obtained circRNAs related to cardiac hypertrophy. Based on this result, we went on to establish a circRNAs-related ceRNA regulatory network. This study is the first to establish a circRNA-mediated ceRNA regulatory network associated with myocardial hypertrophy. To verify the results of our analysis, we used PCR to verify the differentially expressed mRNAs and miRNAs in animal myocardial hypertrophy model samples. Our findings suggest that three mRNAs (Col12a1, Thbs1, and Tgfbr3), four miRNAs (miR-20a-5p, miR-27b-3p, miR-342-3p, and miR-378a-3p), and four related circRNAs (circ_0002702, circ_0110609, circ_0013751, and circ_0047959) may play a key role in cardiac hypertrophy.

Short-Term Postoperative Use of Rivaroxaban to Prevent Radial Artery Occlusion After Transradial Coronary Procedure: The RESTORE Randomized Trial.

BACKGROUND: Adequate procedural anticoagulation is crucial for radial artery occlusion (RAO) prevention in patients undergoing transradial access coronary catheterization, although the effect of postprocedural anticoagulation lack thorough investigation. The aim of this study was to evaluate the clinical value of short-term postoperative anticoagulation with rivaroxaban for 24 hours and 1-month RAO prevention in patients who received transradial coronary procedures. METHODS: A total of 382 patients were randomized to receive either placebo (control group) or rivaroxaban 10 mg once daily for a period of 7 days (rivaroxaban group) to evaluate the effect of the rivaroxaban in the prevention of 24 hours and 1-month RAO assessed by Doppler ultrasound. RESULTS: There was no significant difference in the incidence of 24-hour RAO (8.9% versus 11.5%; P=0.398) between the rivaroxaban group and control group (odds ratio, 0.75 [95% CI, 0.39-1.46]; P=0.399). In contrast, the 1-month RAO (3.8% versus 11.5%; P=0.011) was significantly reduced in patients who received rivaroxaban as compared with those who did placebo (odds ratio, 0.22 [95% CI, 0.08-0.65]; P=0.006). For patients with 24-hour RAO, the rivaroxaban group was associated with higher recanalization rate of the radial artery (69.2% versus 30.0%; P=0.027) compared with the control group. No significant differences can be observed between the 2 groups for access-site complications or bleeding events. CONCLUSIONS: Short-term postoperative anticoagulation with rivaroxaban did not reduce the rate of 24-hour RAO but improved 1-month RAO, because of higher recanalization of the radial artery. However, larger clinical trials are needed to prove our results. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR1900026974.

Interaction between Hyperuricemia and Admission Lactate Increases the Risk of Acute Kidney Injury in Patients with ST-Segment Elevation Myocardial Infarction.

BACKGROUND AND OBJECTIVE: Acute kidney injury (AKI) is a common complication associated with adverse outcomes among patients with ST-segment elevation myocardial infarction (STEMI). This is conflicting information about the relationship between hyperuricemia and AKI in STEMI. This work aimed to investigate the effect of the interaction between hyperuricemia and lactate on the risk of AKI. METHODS: We analyzed 2,008 consecutive STEMI patients between January 2014 and January 2019. Hyperuricemia was defined as a serum uric acid level >7 mg/dL for males and >6 mg/dL for females. AKI was defined based on the Kidney Disease: Improving Global Outcomes (KDIGO). Logistic regression models were applied to establish the relationship between hyperuricemia and AKI in the overall population and subgroups stratified as per lactate levels at admission (≤2.2 mmol/L or >2.2 mmol/L). RESULTS: In total, we included 1,887 STEMI patients. Multivariate analysis showed that hyperuricemia is associated with the risk of AKI (OR: 1.34; 95% CI: 1.01-1.77; p = 0.045). Nonetheless, the predictive effect of hyperuricemia was only observed in patients with lactate level >2.2 mmol/L (OR: 2.05; 95% CI: 1.36-3.10; p < 0.001), but not in those with lactate level ≤2.2 mmol/L (OR: 0.86, 95% CI: 0.56-1.32; p = 0.493). The interaction between hyperuricemia and lactate levels demonstrated a significant effect on AKI. CONCLUSIONS: In summary, hyperuricemia increases the risk of AKI in STEMI patients with lactate levels> 2.2 mmol/L, but not in those with lactate levels ≤2.2 mmol/L.

Lactate level and lactate clearance for acute kidney injury prediction among patients admitted with ST-segment elevation myocardial infarction: A retrospective cohort study.

Background: Hyperlactatemia is a prognostic marker among patients with ST-segment elevation acute myocardial infarction (STEMI). However, the predictive value of lactate and the dynamic change associated with acute kidney injury (AKI) among patients with STEMI, remain poorly understood. We aimed to compare single lactate values at admission (Lacadm) and 12 h after admission (Lac12h) with lactate clearance (LC) 12 h after admission for AKI prediction in patients with STEMI. Methods: A total of 1,784 patients with STEMI were included. The study endpoint was AKI occurrence during hospitalization. The predictive value of lactate levels measured at admission and 12 h after admission and LC for AKI prediction was determined using multivariate logistic regression analyses and compared with receiver operator characteristic (ROC) curve analysis. Results: Overall, AKI was observed in 353 (19.8%) patients. In multivariate logistic regression analyses, Lacadm ≥ 4.3 mmol/L (OR: 1.53; 95% CI: 1.01-2.30), Lac12h ≥ 2.1 mmol/L (OR: 1.81; 95% CI: 1.36-2.42), and LC ≥ -7.5% (OR: 0.40; 95% CI: 0.30-0.53) were the independent predictive factors for AKI after adjusting for confounders. ROC curve analysis results revealed that Lac12h (0.639; 95% CI: 0.616-0.661) exhibited a significantly higher area under the curve (AUC) than those of Lacadm (0.551; 95% CI: 0.527-0.574) and LC (0.593; 95% CI: 0.570-0.616) in the prediction of AKI. LC (△AUC = 0.037, p < 0.001) and Lac12h (△AUC = 0.017, p = 0.029) enhanced the discrimination capacity of Mehran Risk Score (MRS) for AKI among patients undergoing emergency coronary angiography. Conclusion: Lac12h is more effective for AKI prediction among patients with STEMI than Lacadm and LC. Furthermore, Lac12h and LC enhance the prediction capacity of MRS for AKI among patients after emergency coronary angiography.

Impact of Pre-Revascularization and Post-Revascularization Cardiac Arrest on Survival Prognosis in Patients With Acute Myocardial Infarction and Following Emergency Percutaneous Coronary Intervention.

Objectives: To evaluate the effects of occurrence and timing of sudden cardiac arrest (SCA) on survival in patients with acute myocardial infarction (AMI) who underwent emergency percutaneous coronary intervention (PCI). Methods: We analyzed 1,956 consecutive patients with AMI with emergency PCI from 2014 to 2018. Patients with cardiac arrest events were identified, and their medical records were reviewed. Results: Patients were divided into non-cardiac arrest group (NCA group, n = 1,724), pre-revascularization cardiac arrest (PRCA group, n = 175), and post-revascularization SCA (POCA group, n = 57) according to SCA timing. Compared to NCA group, PRCA group and POCA group presented with higher brain natriuretic polypeptide (BNP), more often Killip class 3/4, atrial fibrillation, and less often completed recovery of coronary artery perfusion (all p < 0.05). Both patients with PRCA and POCA showed increased 30-day all-cause mortality when compared to patients with NCA (8.0 and 70.2% vs. 2.9%, both p < 0.001). However, when compared to patients with NCA, patients with PRCA did not lead to higher mortality during long-term follow-up (median time 917 days) (16.3 vs. 18.6%, p = 0.441), whereas patients with POCA were associated with increased all-cause mortality (36.3 vs. 18.6%, p < 0.001). Multivariate analysis identified Killip class 3/4, atrial fibrillation, high maximum MB isoenzyme of creatine kianse, and high creatinine as predictive factors for POCA. In Cox regression analysis, POCA was found as a strong mortality-increase predictor (HR, 8.87; 95% CI, 2.26-34.72; p = 0.002) for long-term all-cause death. Conclusions: POCA appeared to be a strong life-threatening factor for 30-day and long-term all-cause mortality among patients with AMI who admitted alive and underwent emergency PCI. However, PRCA experience did not lead to a poorer long-term survival in patients with AMI surviving the first 30 days.

The prevalence, predictors, and outcomes of spontaneous echocardiographic contrast or left ventricular thrombus in patients with HFrEF.

AIMS: This study aimed to determine prevalence, predictors, and association with ischaemic stroke risk of spontaneous echocardiographic contrast (SEC) or left ventricular thrombus (LVT) in patients with heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Clinical, echocardiographic, and follow-up data from January 2009 through February 2019 were retrospectively extracted from electronic medical records of patients with heart failure with left ventricular ejection fraction < 40% by echocardiography on admission, with follow-up to February 2020. Of 9485 consecutive patients with HFrEF, 123 (1.3%) presented LVT and 331 (3.5%) presented SEC. Patients with vs. those without SEC/LVT had larger left ventricular end-diastolic volume (199.5 ± 77.7 vs. 165.8 ± 61.3 mL, P < 0.001), lower left ventricular ejection fractions (29.5 ± 7.0% vs. 33.7 ± 5.5%, P < 0.001), and more often ischaemic cardiomyopathy, apical aneurysm, chronic kidney diseases, and smoking habit. In Cox regression analysis, SEC and LVT were independent predictors for ischaemic stroke occurrence [hazard ratio (HR) = 2.40, 95% confidence interval (CI): 1.74-3.31; HR = 4.52, 95% CI: 2.77-7.40, both P < 0.001]. In patients with those without SEC or LVT, stroke risk was higher among those not on anticoagulants (HR = 2.55, 95% CI: 1.85-3.53; HR = 4.71, 95% CI: 2.84-7.81, both P < 0.001), but similar among those on anticoagulants (P > 0.05). In patients with sinus rhythm, the associations between SEC/LVT and ischaemic stroke persist with HRs of 2.57 (95% CI: 1.69-3.92) and 5.74 (95% CI: 3.38-9.75). CONCLUSIONS: In patients with HFrEF, SEC was not uncommon and increased risk of ischaemic stroke as well as LVT. Anticoagulants could play a role in the reduction of stroke risk, suggesting that patients with SEC/LVT, even those in sinus rhythm, would benefit from systemic anticoagulation treatment.

The association of resting postoperative systolic, diastolic, and mean blood pressure and pulse pressure with short- and long-term mortality in patients with acute coronary syndrome undergoing primary percutaneous coronary intervention.

BACKGROUND: Admission blood pressure was closely associated with adverse cardiac events in acute coronary syndrome (ACS) patients. However, data regarding comparison of resting postoperative systolic, diastolic, and mean blood pressure and pulse pressure with short- and long-term mortality in patients with acute coronary syndrome undergoing primary percutaneous coronary intervention (PCI) was still lacking. METHODS: The study analyzed 1987 ACS patients undergoing primary PCI, between January 2014 and October 2018. The primary outcomes were in-hospital cardiac and long-term all-cause mortality. RESULTS: Bar tendency chart and adjusted odds ratios showed that the resting postoperative SBP≤100 mmHg, PP≤30 mmHg and MAP≤70 mmHg have higher in-hospital cardiac (SBP: adjusted OR=9.42, 95% CI: 1.95-45.53, P<0.01; PP: adjusted OR=8.61, 95% CI: 2.53-29.30, P<0.01; MAP: adjusted OR=4.01, 95% CI: 1.61-9.98, P<0.01) and long-term all-cause mortality (SBP: adjusted HR=4.18, 95% CI: 1.43-12.23, P<0.01; PP: adjusted HR=3.71, 95% CI: 1.66-8.24, P<0.01; MAP: adjusted HR=2.54, 95% CI: 1.14-5.65, P<0.01), and the relationship between resting postoperative SBP and in-hospital cardiac or long-term all-cause mortality seemed to follow a J-shaped curve with increased event rates at low and high groups. CONCLUSIONS: The resting postoperative SBP≤100 mmHg, PP≤30 mmHg and MAP≤70 mmHg are independent adverse prognosticators in ACS patients undergoing primary PCI, and the relationship between SBP and mortality looks like a J-shaped curve.

Clinical characteristics and outcomes in patients with echocardiographic left ventricular spontaneous echo contrast.

BACKGROUND: Spontaneous echo contrast (SEC) is a known precursor to thrombus formation and thromboembolic events. This study aims to demonstrate the clinical characteristics and outcomes of patients with left ventricular spontaneous echo contrast (LV-SEC). METHODS: Patients with consecutive echocardiogram performed from October 2009 to September 2019 were enrolled in this retrospective, single-center study. Those with LV-SEC were included, while patients complicated by left ventricular thrombus, with history of infective endocarditis, prosthetic valves, or lost to follow-up were excluded. The clinical endpoint was 1-year thromboembolic events (i.e. stroke and peripheral embolism). RESULTS: Among 417 patients (mean age 63.5 ± 14.7 years; 86.8% men) with LV-SEC, the incidence of 1-year embolism was 12.9%. In multivariate Cox proportional hazard model, significant risk factors for thromboembolic event were age [hazard ratio (HR) = 1.022, 95% confidence interval (CI): 1.000-1.045], atrial fibrillation (AF) (HR = 2.292, 95% CI: 1.237-4.244), hemoglobin (HR = 1.032, 95% CI: 1.017-1.047), left ventricular ejection fraction (LVEF) (HR = 1.021, 95% CI: 1.002-1.041), and anticoagulant therapy (HR = 0.310, 95% CI: 0.168-0.572). For patients with repeated measurements for echocardiography, D-dimer (HR = 1.137, 95% CI: 1.051-1.231), and △LVEF (HR = 0.961, 95% CI: 0.928-0.996) were independently associated with the persistent LV-SEC. CONCLUSION: The present study reported a high incidence of 1-year thromboembolic event in patients with LV-SEC. Age, AF, hemoglobin, LVEF were independent risk factors for 1-year embolism and a reduced risk of embolism was observed among patients with anticoagulation therapy. Additionally, D-dimer and △LVEF are independently associated with the persistent LV-SEC.

Specific Interaction of the Human Mitochondrial Uncoupling Protein 1 with Free Long-Chain Fatty Acid.

The mitochondrial uncoupling protein 1 (UCP1) generates heat by causing proton leak across the mitochondrial inner membrane that requires fatty acid (FA). The mechanism by which UCP1 uses FA to conduct proton remains unsolved, and it is also unclear whether a direct physical interaction between UCP1 and FA exists. Here, we have shown using nuclear magnetic resonance that FA can directly bind UCP1 at a helix-helix interface site composed of residues from the transmembrane helices H1 and H6. According to the paramagnetic relaxation enhancement data and molecular dynamics simulation, the FA acyl chain appears to fit into the groove between H1 and H6 while the FA carboxylate group interacts with the basic residues near the matrix side of UCP1. Functional mutagenesis showed that mutating the observed FA binding site severely reduced UCP1-mediated proton flux. Our study identifies a functionally important FA-UCP1 interaction that is potentially useful for mechanistic understanding of UCP1-mediated thermogenesis.

Synthesis and anti-inflammatory activities investigation of sinomenine derivatives on ring C.

Eighteen sinomenine derivatives on ring C were prepared, and their anti-inflammatory activities were also investigated. Most of these derivatives showed mild to moderate activities. Compounds 4a, 4c and 5b showed better anti-inflammatory activity. So further modification of the ring C in sinomenine should be worthwhile.