Lipidome, central carbon metabolites, and sleep rhythm in coronary heart disease with nontraditional risks: An exploratory pilot study.

Aims: Altered lipid, energy metabolism and sleep disorders had been linked with coronary heart disease (CHD), however, the metabolic signatures and sleep rhythm in non-obstructive coronary atherosclerosis-CHD remain unclear. This pilot study aims to investigate the lipidome and central carbon metabolites profiles and associated sleep characteristics among CHD patients without traditional risk factors. Methods: From January to July 2021, 15 CHD patients and 15 healthy controls were randomly selected from the cardiology unit of Zhongshan Hospital, Shanghai. A total of 464 lipids and 45 central carbon metabolites (CCM) were quantified in blood plasma. Metabolic signatures were selected through orthogonal projections to latent structures discriminant analysis (OPLS-DA) and principal component analysis (PCA) was conducted to link the profiles of identified metabolites with CHD risk, sleep patterns, cardiometabolic traits and cardiac electrophysiologic parameters. Results: Using OPLS-DA, we identified 40 metabolites (variable influence on projection >1) that were altered in CHD patients, with 38 lipids, including 25 triacylglycerols (TAGs), 8 diacylglycerols (DAGs), being elevated and two CCM metabolites (i.e., succinic acid and glycolic acid) being reduced. Using PCA, four principal components (PCs) were identified and associated with increased risk of CHD. Specifically, one standard unit increasement in the PC that was characterized by high levels of DAG (18:1) and low succinic acid and the PC that was characterized by high levels of two sphingomyelins [SM (26:0) and SM (24:0)] was associated with 21% [odds ratio (OR) = 1.21, 95% CI: 1.02,1.43] and 14% (OR = 1.14,1.02,1.29) increased risk of CHD, respectively. Further regression analyses confirmed that the identified metabolites and the four PCs were positively associated with TG and ALT. Interestingly, glycolic acid was negatively associated with sleep quality and PSQI. Participants with night sleep mode tended to have a high level of the identified lipids, especially FFA (20:4). Conclusion: In the present pilot study, our findings provide clues on alterations of lipid and energy metabolism in CHD patients without traditional risk factors, with multiple triacylglycerols and diacylglycerols metabolites seemingly elevated and certain nonlipids metabolites (e.g., succinic acid and glycolic acid) decreased in cases. Considering the limit sample size, further studies are warranted to confirm our results.

Indobufen or Aspirin on Top of Clopidogrel After Coronary Drug-Eluting Stent Implantation (OPTION): A Randomized, Open-Label, End Point-Blinded, Noninferiority Trial.

BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin as a background therapy has become the standard care after percutaneous coronary intervention. However, some adverse noncardiac effects limited the use of aspirin in clinical practice. Thus, evaluation of pharmacological alternatives to aspirin is attractive. Previous data indicated that indobufen could lessen the unwanted side effects of aspirin while retaining the antithrombotic efficacy, but its combination with a P2Y12 inhibitor still lacks randomized clinical trial evidence. METHODS: In this randomized, open-label, noninferiority trial, patients with negative cardiac troponin undergoing coronary drug-eluting stent implantation were randomly assigned in a 1:1 ratio to receive either indobufen-based DAPT (indobufen 100 mg twice a day plus clopidogrel 75 mg/d for 12 months) or conventional DAPT (aspirin 100 mg/d plus clopidogrel 75 mg/d for 12 months). The primary end point was a 1-year composite of cardiovascular death, nonfatal myocardial infarction, ischemic stroke, definite or probable stent thrombosis, or Bleeding Academic Research Consortium criteria type 2, 3, or 5 bleeding. The end points were adjudicated by an independent Clinical Event Committee. RESULTS: Between January 11, 2018, and October 12, 2020, 4551 patients were randomized in 103 cardiovascular centers: 2258 patients to the indobufen-based DAPT group and 2293 to the conventional DAPT group. The primary end point occurred in 101 patients (4.47%) in the indobufen-based DAPT group and 140 patients (6.11%) in the conventional DAPT group (absolute difference, -1.63%; Pnoninferiority<0.001; hazard ratio, 0.73 [95% CI, 0.56-0.94]; P=0.015). Cardiovascular death, nonfatal myocardial infarction, ischemic stroke, and stent thrombosis were observed in 0.13%, 0.40%, 0.80%, and 0.22% of patients in the indobufen-based DAPT group and 0.17%, 0.44%, 0.83%, and 0.17% of patients in the conventional DAPT group (all P>0.05). The occurrence of Bleeding Academic Research Consortium criteria type 2, 3, or 5 bleeding events was lower in the indobufen-based DAPT group compared with the conventional DAPT group (2.97% versus 4.71%; hazard ratio, 0.63 [95% CI, 0.46-0.85]; P=0.002), with the main decrease in type 2 bleeding (1.68% versus 3.49%; hazard ratio, 0.48 [95% CI, 0.33-0.70]; P<0.001). CONCLUSIONS: In Chinese patients with negative cardiac troponin undergoing drug-eluting stent implantation, indobufen plus clopidogrel DAPT compared with aspirin plus clopidogrel DAPT significantly reduced the risk of 1-year net clinical outcomes, which was driven mainly by a reduction in bleeding events without an increase in ischemic events. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR-IIR-17013505.

Ticagrelor Pharmacokinetics and Pharmacodynamics in Chinese Patients with STEMI and NSTEMI Without Opioid Administration.

INTRODUCTION: The pharmacodynamics (PD) and pharmacokinetics (PK) study of ticagrelor loading dose (LD) in Chinese patients with acute coronary syndrome (ACS) without opioid administration has never been investigated. Therefore, the aim of this study was to evaluate the antiplatelet effects and the PK parameters of ticagrelor in Chinese patients with ACS without opioid administration. METHODS: A sample size of 30 eligible patients with ACS were enrolled in this study. Blood samples were obtained predose and 1, 2, 4, 8, and 12 h after 180 mg LD of ticagrelor. P2Y12 reactivity units (PRU) and plasma concentrations of ticagrelor and its two metabolites were measured. RESULTS: In total, 15 patients were admitted to ST segment elevation myocardial infarction (STEMI) and non-ST segment elevation myocardial infarction (NSTEMI) groups, respectively. For patients with NSTEMI, PRU declined significantly during the first 4 h and maintained a relatively stable antiplatelet effect from 4 to 12 h after LD. A similar trend was found in the STEMI group without significant differences of PRU in each designed time compared with patients with NSTEMI (P > 0.05). Tmax of metabolite AR-C124910XX was 4 h after LD for both groups. There were no significant differences for drug concentration, Cmax, or AUC of ticagrelor and AR-C124910XX between patients with STEMI and NSTEMI (P > 0.05). CONCLUSIONS: For Chinese patients with ACS, at least 4 h was needed to achieve an adequate antiplatelet effect for ticagrelor LD. There were no differences in PK or PD between Chinese patients with STEMI and NSTEMI. CLINICAL TRIAL REGISTRATION: ChiCTR1800014764.

The role of the sodium current complex in a nonreferred nationwide cohort of sudden infant death syndrome.

BACKGROUND: Sudden infant death syndrome (SIDS) is the most common cause of death in infants between the age of 1 month and 1 year. Rare variants in Nav1.5 encoded by SCN5A are known to play a role in SIDS; however, the combined role of the sodium current complex is unknown. OBJECTIVE: The purpose of this study was to investigate the role of the sodium current complex in a nonreferred nationwide cohort of SIDS cases. METHODS: DNA was extracted from dried blood spot samples from the Danish Neonatal Screening Biobank. In total, 66 non-referred SIDS cases born in Denmark in the period of 2000-2006 were screened for genetic variants in the 8 major genes involved in the regulation of the Nav1.5 channel complex: SCN5A, SCN1B, SCN2B, SCN3B, SCN4B, GPD1L, SNTA1, and CAV3. Patch-clamp analyses were performed on variants not previously characterized. RESULTS: In total, 8 patients (12%) had nonsynonymous rare variants in the sodium current genes. SCN5A harbored 6 rare variants (R458C, R535*, S1103Y, R1193Q, S1609L, and Q1909R); CAV3, 1 rare variant (T78M); GPD1L, 1 rare variant (R220H); and SCN3B, 1 rare variant (L10P). Four variants were considered likely pathogenic and 5 variants of unknown significance. SCN5A R1193Q and GPD1L R220H (both considered variants of unknown significance) were present in the same infant. Functional analysis of variants not previously characterized (R458C, S1609L, and Q1909R in SCN5A) predominantly revealed increased transient and sustained sodium current. CONCLUSION: In a nonreferred nationwide Danish cohort of SIDS cases, up to 5/66 (7.5%) of SIDS cases can be explained by genetic variants in the sodium channel complex genes.

[Effects of thyroid hormone on islet ß cell function among type 2 diabetics with normal thyroid function].

OBJECTIVE: To explore the effects of thyroid hormone on islet ß cell function among type 2 diabetics with normal thyroid function. METHODS: A total of 266 type 2 diabetics with normal thyroid function were recruited. Their clinical, biochemical parameters and thyroid related hormones were measured. And acute insulin response (AIR) was examined by arginine stimulating test. RESULTS: The serum levels of triiodothyronine (T3) ((1.49 ± 0.03), (1.59 ± 0.03), (1.70 ± 0.04) µmol/L) and free triiodothyronine (FT3) ((4.01 ± 0.08), (4.37 ± 0.09), (4.44 ± 0.07) pmol/L) were significantly different among tertile groups of AIR (both P < 0.01) while those of thyroxine (T4), free thyroxine (FT4) and thyroid stimulating hormone (TSH) showed no significant differences among tertile groups of AIR (all P > 0.05). A significant positive correlation existed between lnAIR and T3, FT3 (r = 0.303, 0.302, both P < 0.01). T4 and FT4 were not correlated with lnAIR (both P>0.05). AIR was significantly different among tertile groups of T3 ((2.38 ± 0. 12), (2.64 ± 0.12) and (3.03 ± 0.10) mU/L) and FT3 ((2.34 ± 0.11), (2.69 ± 0.13), (2.99 ± 0.10) mU/L, P < 0.01). AIR were not significantly different among tertile groups of T4, FT4 and TSH (all P > 0.05). Multivariate linear regression demonstrated that T3 and FT3 level were independently associated with AIR (ß = 0.686, 95% CI 0.289-0.884, P = 0.001, ß = 0.296, 95% CI 0.125-0.467, P = 0.01). CONCLUSIONS: Significant positive associations exist between serum T3, FT3 and AIR in type 2 diabetics with normal thyroid function. Serum T3 and FT3 may be the independent risk factors of predicting islet beta cell function in type 2 diabetics with normal thyroid function. However, it remains to be determined whether or not normal physiological concentrations of T3 and FT3 are protective factors for islet ß cell functions among type 2 diabetics.

The prevalence of mutations in KCNQ1, KCNH2, and SCN5A in an unselected national cohort of young sudden unexplained death cases.

INTRODUCTION: Sudden unexplained death account for one-third of all sudden natural deaths in the young (1-35 years). Hitherto, the prevalence of genopositive cases has primarily been based on deceased persons referred for postmortem genetic testing. These deaths potentially may represent the worst of cases, thus possibly overestimating the prevalence of potentially disease causing mutations in the 3 major long-QT syndrome (LQTS) genes in the general population. We therefore wanted to investigate the prevalence of mutations in an unselected population of sudden unexplained deaths in a nationwide setting. METHODS: DNA for genetic testing was available for 44 cases of sudden unexplained death in Denmark in the period 2000-2006 (equaling 33% of all cases of sudden unexplained death in the age group). KCNQ1, KCNH2, and SCN5A were sequenced and in vitro electrophysiological studies were performed on novel mutations. RESULTS: In total, 5 of 44 cases (11%) carried a mutation in 1 of the 3 genes corresponding to 11% of all investigated cases (R190W KCNQ1, F29L KCNH2 (2 cases), P297S KCNH2 and P1177L SCN5A). P1177L SCN5A has not been reported before. In vitro electrophysiological studies of P1177L SCN5A revealed an increased sustained current suggesting a LQTS phenotype. CONCLUSION: In a nationwide setting, the genetic investigation of an unselected population of sudden unexplained death cases aged 1-35 years finds a lower than expected number of mutations compared to referred populations previously reported. We therefore conclude that the prevalence of mutations in the 3 major LQTS associated genes may not be as abundant as previously estimated.

Sodium current and potassium transient outward current genes in Brugada syndrome: screening and bioinformatics.

BACKGROUND: Brugada syndrome (BrS) is a primary arrhythmia syndrome characterized by the occurrence of malignant ventricular arrhythmias. Previously, the genes SCN1B, SCN3B, MOG1, and KCND3 have been associated with BrS. Recent data from exome screening efforts permit better discrimination between low-frequency genetic variants and true monogenetic disease-causing variants. We aimed to screen the genes SCN1B through SCN4B, MOG1, CAV3, and KCND3 for variations in a population of SCN5A negative Danish and Iranian BrS patients, as well as research prior associations using newly released exome data. METHODS: Screening of all exons and splice sites was performed using Sanger sequencing. Bioinformatic searches were performed in the Single-nucleotide polymorphism database (build 132) and in the National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project (ESP) for both previously published variant-BrS associations and newly uncovered variations within the noted genes. RESULTS: A total of 42 BrS patients were screened, and 2 different nonsynonymous mutations in SCN1Bb (H162P and R214Q) were found in 2 different Danish patients. The variants were not found in 216 Danish controls, but R214Q was present in ESP data (5 of 841 alleles). No other mutations were found. Previously BrS-associated mutations in KNCD3 and SCN3B were also present in ESP data. This was not the case for MOG1, but a nonsense polymorphism was present in 0.5% of alleles. CONCLUSIONS: Our study supports the association of SCN1Bb with BrS. However, recently released exome data make some of the prior associations of BrS with genes SCN3B, MOG1, and KCND3 less likely.

[Efficacy of ibutilide for cardioversion of persistent atrial fibrillation during radiofrequency ablation].

OBJECTIVE: The aim of this study was to investigate the efficiency and safety of ibutilide for cardioversion of persistent atrial fibrillation (AF) during radiofrequency ablation. METHODS: Eighteen patients (16 males) with persistent atrial fibrillation were enrolled in this study. All patients underwent circumferential pulmonary vein ablation guided by a Carto three-dimensional mapping system. In addition, linear ablation at the top of the left atrium and the isthmus of mitral valves and complex fractionated atrial electrogram (CAFE) ablation were performed. All patients were still in either atrial fibrillation or atrial flutter after ablation, the patients were treated with 1 mg intravenous ibutilide injection within 10 minutes after unsuccessful ablation. Intravenous injection was stopped in case of sinus rhythm (SR) restoration or occurrence of severe adverse reactions such as ventricular tachycardia. Cardioversion rate within 30 min and adverse reactions within 4 h were observed. Patients were divided into either conversion group or non-conversion group according to whether AF was converted to sinus rhythm within 30 minutes after injection. RESULTS: Eleven patients (61.11%) converted to SR after ibutilide injection. There were no significant differences in gender, age, body mass index, left atrium and left ventricular function between conversion group and non-conversion groups. The average conversion time was (13.80 ± 7.64) min, left atrium scar area ratio was significantly larger in non-conversion group (12.40 ± 11.03)% than in conversion group (5.12 ± 3.83)%, P < 0.05. Ibutilide significantly prolonged the average wavelength of the AF wave (171.8 ± 29.5) ms vs. (242.0 ± 40.0) ms at baseline, P < 0.01. The QT interval at 30 min after ibutilide injection (0.39 ± 0.21) s was significantly longer than before injection (0.51 ± 0.08) s, P < 0.05. There was no serious arrhythmias or other adverse reactions post ibutilide injection. CONCLUSIONS: Ibutilide is highly effective and safe agent for cardioversion in patients underwent unsuccessful ablation. Left atrium scar area ratio is an important determinant for the conversion rate in this cohort.