Effect of Mavacamten on Chinese Patients With Symptomatic Obstructive Hypertrophic Cardiomyopathy: The EXPLORER-CN Randomized Clinical Trial.

Importance: Mavacamten has shown clinical benefits in global studies for patients with obstructive hypertrophic cardiomyopathy (oHCM), but evidence in the Asian population is lacking. Objective: To evaluate the safety and efficacy of mavacamten compared with placebo for Chinese patients with symptomatic oHCM. Design, Setting, and Participants: This phase 3, randomized, double-blind, placebo-controlled clinical trial was conducted at 12 hospitals in China. Between January 4 and August 5, 2022, patients with oHCM and a left ventricular outflow tract (LVOT) gradient of 50 mm Hg or more and New York Heart Association (NYHA) class II or III symptoms were enrolled and received treatment for 30 weeks. Interventions: Patients were randomized 2:1 to receive mavacamten (starting at 2.5 mg once daily) or placebo for 30 weeks. Main Outcomes and Measures: The primary end point was change in Valsalva LVOT peak gradient from baseline to week 30. Left ventricular outflow tract gradients and left ventricular ejection fraction (LVEF) were assessed by echocardiography, while left ventricular mass index (LVMI) was determined by cardiac magnetic resonance imaging. Analysis was performed on an intention-to-treat basis. Results: A total of 81 patients (mean [SD] age, 51.9 [11.9] years; 58 men [71.6%]) were randomized. Mavacamten demonstrated a significant improvement in the primary end point compared with placebo (least-squares mean [LSM] difference, -70.3 mm Hg; 95% CI, -89.6 to -50.9 mm Hg; 1-sided P < .001). Similar trends were demonstrated for resting LVOT peak gradient (LSM difference, -55.0 mm Hg; 95% CI, -69.1 to -40.9 mm Hg). At week 30, more patients receiving mavacamten than placebo achieved a Valsalva LVOT peak gradient less than 30 mm Hg (48.1% [26 of 54] vs 3.7% [1 of 27]), less than 50 mm Hg (59.3% [32 of 54] vs 7.4% [2 of 27]), and NYHA class improvement (59.3% [32 of 54] vs 14.8% [4 of 27]). Greater improvements were also observed with mavacamten regarding the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (LSM difference, 10.2; 95% CI, 4.4-16.1), N-terminal pro-B-type natriuretic peptide level (proportion of geometric mean ratio, 0.18; 95% CI, 0.13-0.24), high-sensitivity cardiac troponin I level (proportion of geometric mean ratio, 0.34; 95% CI, 0.27-0.42), and LVMI (mean difference, -30.8 g/m2; 95% CI, -41.6 to -20.1 g/m2). Safety and tolerability were similar between mavacamten and placebo. No patients experienced LVEF less than 50%. Conclusions: Mavacamten significantly improved Valsalva LVOT gradient vs placebo for Chinese patients. All secondary efficacy end points were also improved. Mavacamten was well tolerated with no new safety signals. This study supports the efficacy and safety of mavacamten in diverse populations, including Chinese patients. Trial Registration: ClinicalTrials.gov Identifier: NCT05174416.

Silencing of circARHGAP12 inhibits the progression of atherosclerosis via miR-630/EZH2/TIMP2 signal axis.

Atherosclerosis (AS) is a common disease that seriously threatens human health. So far, the pathogenesis of AS has not been fully understood. This project investigates the effects of circARHGAP12 on AS and its regulatory mechanism. ApoE-/- knockout mice (ApoE) were adopted and reared with a high-fat diet to construct an AS model. Lentivirus was established to knock down the expression of circARHGAP12 in mice. After 12 weeks, the aorta was removed and the expression of circARHGAP12 was detected. Vascular oil red O staining was used to detect the degree of AS. The expression of inflammatory factors was detected by ELISA. Aortic smooth muscle cells (MASMCs) were cultured to evaluate the effects of circARHGAP12 on the phenotype of MASMCs. RNA pull-down and luciferase assay were used to verify the downstream target genes of circARHGAP12. In addition, the effects of circARHGAP12 on MASMCs proliferation and migration were detected by MTT and transwell assay. Compared with the normal group, the expression of circARHGAP12 in the MASMCs under ox-LDL treatment was elevated, and circARHGAP12 silencing could inhibit AS in vitro and in vivo. The results of the mechanism study showed that circARHGAP12 can directly bind with miR-630. In addition, miR-630 can also target EZH2 to modulate the transcription of TIMP2 and to influence the migration of MASMCs. circARHGAP12 is upregulated in AS. CircARHGAP12 knockdown can inhibit the progression of AS. This study expands on the role of circRNA in AS and provides potential targets for the treatment of AS.

MiR-18a-5p contributes to enhanced proliferation and migration of PASMCs via targeting Notch2 in pulmonary arterial hypertension.

AIM: This study is undertaken to investigate the role and molecular mechanisms of miR-18a-5p in regulating pulmonary arterial hypertension (PAH) pathogenesis. METHODS: Gene expression and protein levels were determined by qRT-PCR and western blot, respectively; Cell counting kti-8 and Transwell migration assays were used to determine the biological functions of miR-18a-5p in pulmonary arterial smooth muscle cells (PASMCs); bioinformatics analysis, luciferase reporter assays were used to elucidate the mechanisms of miR-18a-5p. RESULTS: MiR-18a-5p was up-regulated in the clinical samples from PAH patients. PASMCs treated with hypoxia exhibited enhanced proliferative ability and upregulated miR-18a-5p expression. Knockdown of miR-18a-5p attenuated hypoxia-induced hyper-proliferation and enhanced migratory potential of PASMCs; while miR-18a-5p overexpression promoted PASMC proliferation and migration. Further mechanistic studies showed that Notch2 was a direct target of miR-18a-5p and was repressed by miR-18a-5p overexpression. The rescue studies indicated that Notch2 overexpression counteracted the enhanced proliferation and migration induced by miR-18a-5p mimics in PASMCs. Similarly, Notch2 overexpression also block the effects caused by hypoxia in PASMCs. Moreover, Notch2 expression was down-regulated in the PAH patients and was negatively correlated with miR-18a-5p expression. In vivo animal studies further revealed the up-regulation of miR-18a-5p and the down-regulation of Notch2 in the PAH rats. CONCLUSIONS: Collectively, this study identified the up-regulated miR-18a-5p in the PAH patients; our data suggest that miR-18a-5p contributes to the enhanced proliferation and migration of PASMCs via repressing Notch2 expression.

Exosomes derived from oxLDL-stimulated macrophages induce neutrophil extracellular traps to drive atherosclerosis.

This study aimed to investigate the role and underlying mechanism of exosomes secreted by oxidized low-density lipoprotein (oxLDL)-stimulated macrophages in the progression of atherosclerosis (AS). Exosomes from peripheral blood of AS patients or oxLDL-treated macrophages were co-cultured with human neutrophils. Neutrophil extracellular traps (NETs) were detected by immunofluorescence staining. The levels of inflammatory cytokines were quantified by enzyme-linked immunosorbent assay (ELISA). The expression levels of miR-146a and superoxide dismutase 2 (SOD2) were determined by quantitative real-time PCR (qRT-PCR) and western blot. The generation of intracellular reactive oxygen species (ROS) was observed by using dichlorofluorescin diacetate (DCFH-DA). ApoE-deficient mice were fed with high-fat diet (HFD) to induce AS. Atherosclerotic plaques were evaluated by Oil red O (ORO) and hematoxylin-eosin (HE) staining. Our results showed that miRNA-146a was enriched in serum-derived exosomes of AS patients and oxLDL-treated macrophage THP-1-derived exosomes. Importantly, exosomal miR-146a secreted by oxLDL-treated macrophages promoted ROS and NETs release via targeting SOD2. In addition, intravenous administration of oxLDL-treated THP-1 cells-derived exosomes into AS mice significantly deteriorated AS in vivo. Our findings indicate that exosomal miR-146a derived from oxLDL-treated macrophages promotes NETs formation via inducing oxidative stress, which might provide a novel scientific basis for the understanding of AS progression.

The Relationship between Simple Snoring and Metabolic Syndrome: A Cross-Sectional Study.

PURPOSE: This cross-sectional study was performed to assess the relationship between simple snoring and metabolic syndrome (MetS). METHODS: A total of 5635 participants including 300 healthy volunteers without snoring allegedly were initially included from 2007 to 2016. Polysomnographic variables, anthropometric measurements, and biochemical indicators were collected. The polynomial linear trend test was used to assess the linear trend across snoring intensity for metabolic score, and logistic regression was used to evaluate the odds ratios (ORs) for MetS after controlling for age, sex, obesity, smoking status, and alcohol consumption. RESULTS: The final study population consisted of 866 participants. Simple snorers showed more severe metabolic disorders and higher prevalence of MetS than nonsnorers. A significant linear trend was observed between snoring intensity and metabolic score. Simple snoring was significantly associated with increased odds for MetS among all participants (OR = 2.328, 95% CI: 1.340-4.045) and female participants (OR = 2.382, 95% CI: 1.136-4.994) after multivariable adjustment. With regard to MetS components, simple snoring was significantly associated with increased odds for hypertension (OR = 1.730, 95% CI: 1.130-2.650), abdominal obesity (OR = 1.810, 95% CI: 1.063-3.083), and hyper-triglycerides (TG) (OR = 1.814, 95% CI: 1.097-2.998) among all participants, with hypertension (OR = 3.493, 95% CI: 1.748-6.979) among males and with abdominal obesity (OR = 2.306, 95% CI: 1.245-4.270) and hyper-TG (OR = 2.803, 95% CI: 1.146-6.856) among females after multivariable adjustment. CONCLUSIONS: After excluding the influence of repeated apnea and hypoxia, simple snoring was still significantly associated with MetS, especially in women. Furthermore, the associations were more obvious for hypertension among males and for abdominal obesity and hyper-TG among females. In addition to OSA, simple snoring also should be valued.

Pediatric Obstructive Sleep Apnea is Associated With Changes in the Oral Microbiome and Urinary Metabolomics Profile: A Pilot Study.

STUDY OBJECTIVES: Several cross-sectional studies have reported associations between oral diseases and obstructive sleep apnea (OSA). However, there have been no reports regarding the structure and composition of the oral microbiota with simultaneous evaluation of potential associations with perturbed metabolic profiles in pediatric OSA. METHODS: An integrated approach, combining metagenomics based on high-throughput 16S rRNA gene sequencing, and metabolomics based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry and gas chromatography coupled with time-of-flight mass spectrometry, was used to evaluate the oral microbiome and the urinary metabolome. RESULTS: 16S rRNA gene sequencing indicated that the oral microbiome composition was significantly perturbed in pediatric OSA compared with normal controls, especially with regard to Firmicutes, Proteobacteria, Bacteroidetes, Fusobacteria, and Actinobacteria. Moreover, metabolomics profiling indicated that 57 metabolites, 5 of which were metabolites related to the microflora of the digestive tract, were differentially present in the urine of pediatric patients with OSA and controls. Co-inertia and correlation analyses revealed that several oral microbiome changes were correlated with urinary metabolite perturbations in pediatric OSA. However, this correlation relationship does not imply causality. CONCLUSIONS: High-throughput sequencing revealed that the oral microbiome composition and function were significantly altered in pediatric OSA. Further studies are needed to confirm and determine the mechanisms underlying these findings.

Independent relationships between cardinal features of obstructive sleep apnea and glycometabolism: a cross-sectional study.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with abnormal glycometabolism; however, the cardinal features of OSA, such as sleep fragmentation (SF) and intermittent hypoxia (IH), have yet to show clear, independent associations with glycometabolism. METHODS: We enrolled 1834 participants with suspected OSA from July 2008 to July 2013 to participate in this study. Polysomnographic variables, biochemical indicators, and physical measurements were collected for each participant. Multiple linear regression analyses were used to evaluate independent associations between cardinal features of OSA and glycometabolism. Logistic regressions were used to determine the odds ratios (ORs) for abnormal glucose metabolism across microarousal index (MAI) and oxygen desaturation index (ODI) quartiles. The effect of the interaction between MAI and ODI on glycometabolism was also evaluated. RESULTS: The MAI was independently associated with fasting insulin levels (ß = 0.024, p = 0.001) and the homeostasis model assessment of insulin resistance (HOMA-IR; ß = 0.006, p = 0.002) after multiple adjustments of confounding factors. In addition, the ORs for hyperinsulinemia across higher MAI quartiles were 1.081, 1.349, and 1.656, compared with the lowest quartile (p = 0.015 for a linear trend). Similarly, the ODI was independently associated with fasting glucose levels (ß = 0.003, p < 0.001), fasting insulin levels (ß = 0.037, p < 0.001), and the HOMA-IR (ß = 0.010, p < 0.001) after adjusting for multiple factors. The ORs for hyperglycemia across higher ODI quartiles were 1.362, 1.231, and 2.184, compared with the lowest quartile (p < 0.05 for a linear trend). In addition, the ORs for hyperinsulinemia and abnormal HOMA-IR across ODI quartiles had the same trends. There was no interaction between MAI and ODI with respect to glycometabolism. CONCLUSION: SF was independently associated with hyperinsulinemia, and IH was independently associated with hyperglycemia, hyperinsulinemia, and an abnormal HOMA-IR. We found no interaction between SF and IH with respect to OSA-related abnormal glycometabolism.

Excessive daytime sleepiness and metabolic syndrome in men with obstructive sleep apnea: a large cross-sectional study.

PURPOSE: Excessive daytime sleepiness is a common symptom in obstructive sleep apnea (OSA). Previous studies have showed that excessive daytime sleepiness is associated with some individual components of metabolic syndrome. We performed a large cross-sectional study to explore the relationship between excessive daytime sleepiness and metabolic syndrome in male OSA patients. METHODS: A total of 2241 suspected male OSA patients were consecutively recruited from 2007 to 2013. Subjective daytime sleepiness was assessed using the Epworth sleepiness scale. Anthropometric, metabolic, and polysomnographic parameters were measured. Metabolic score was used to evaluate the severity of metabolic syndrome. RESULTS: Among the male OSA patients, most metabolic parameters varied by excessive daytime sleepiness. In the severe group, male OSA patients with excessive daytime sleepiness were more obese, with higher blood pressure, more severe insulin resistance and dyslipidemia than non-sleepy patients. Patients with metabolic syndrome also had a higher prevalence of excessive daytime sleepiness and scored higher on the Epworth sleepiness scale. Excessive daytime sleepiness was independently associated with an increased risk of metabolic syndrome (odds ratio =1.242, 95% confidence interval: 1.019-1.512). No substantial interaction was observed between excessive daytime sleepiness and OSA/ obesity. CONCLUSIONS: Excessive daytime sleepiness was related to metabolic disorders and independently associated with an increased risk of metabolic syndrome in men with OSA. Excessive daytime sleepiness should be taken into consideration for OSA patients, as it may be a simple and useful clinical indicator for evaluating the risk of metabolic syndrome.

Smoking, obstructive sleep apnea syndrome and their combined effects on metabolic parameters: Evidence from a large cross-sectional study.

Metabolic disorders have been separately associated with obstructive sleep apnea syndrome (OSAS) and smoking. However, no study has examined their interactions with metabolic parameters, including insulin resistance and dyslipidemia. To investigate whether the combination of OSAS and smoking results in an additive detriment in metabolic disorder parameters, we enrolled consecutive adult men during 2014-2015. Fasted blood samples were taken to determine glucose, insulin, and lipid levels. A questionnaire including an item on smoking pack-year exposure was administered, and the Epworth Sleepiness Scale and overnight polysomnography were performed. Smokers showed higher levels of glucose, insulin, total cholesterol (TC), triglycerides (TG), and low density lipoprotein-cholesterol (LDL-C), but lower high-density lipoprotein cholesterol (HDL-C) levels, than did non-smokers. In addition, the risks for insulin resistance increased with OSAS severity without fully adjustment. An OSAS × smoking interaction was found in insulin resistance after adjusting for potential confounding factors (p = 0.025). Although the difference was not significant, cessation of cigarette smoking seems to have a little benefit for smoking patients with OSAS. A synergistic effect was observed between smoking and OSAS on metabolic disorder parameters. Cessation of cigarette smoking may experience minor benefit for insulin resistance and lipid metabolism in patients with OSAS.

Effects of continuous positive airway pressure on neurocognitive architecture and function in patients with obstructive sleep apnoea: study protocol for a multicentre randomised controlled trial.

OBJECTIVES: Many clinical studies have indicated that obstructive sleep apnoea (OSA), the most common chronic sleep disorder, may affect neurocognitive function, and that treatment for continuous positive airway pressure (CPAP) has some neurocognitive protective effects against the adverse effects of OSA. However, the effects of CPAP treatment on neurocognitive architecture and function remain unclear. Therefore, this multicentre trial was designed to investigate whether and when neurocognitive architecture and function in patients with OSA can be improved by CPAP treatment and to explore the role of gut microbiota in improving neurocognitive function during treatment. METHODS/DESIGN: This study will be a multicentre, randomised, controlled trial with allocation concealment and assessor blinding. A total of 148 eligible patients with moderate to severe OSA will be enrolled from five sleep centres and randomised to receive CPAP with best supportive care (BSC) intervention or BSC intervention alone. Cognitive function, structure and function of brain regions, gut microbiota, metabolites, biochemical variables, electrocardiography, echocardiography, pulmonary function and arterial stiffness will be assessed at baseline before randomisation and at 3, 6 and 12 months. ETHICS AND DISSEMINATION: This study has been approved by the Medical Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People's Hospital (approval number 2015-79). The results from this study will be published in peer-reviewed journals and at relevant conferences. TRIAL REGISTRATION NUMBER: NCT02886156; pre-results.

Prevalence and Predictors of Atherogenic Serum Lipoprotein Dyslipidemia in Women with Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is associated with dyslipidemia. However, no study has focused on dyslipidemia in women with OSA. The aim of this study was to determine the prevalence and risk factors for dyslipidemia in women with OSA. Between 2007 and 2013, 570 eligible female patients with suspected OSA were consecutively recruited. The analyzed data consisted of polysomnography parameters, biochemical indicators, and anthropometric measurements. Serum lipid levels and dyslipidemia were compared. Binary logistic regression and multivariate linear regression models were used to determine the independent risk factors influencing serum lipids. After multivariate adjustment, there were essentially no major differences in serum lipid levels among patients with no to mild, moderate, and severe OSA nor did serum lipid levels change with OSA severity. Dyslipidemia in total cholesterol, triglycerides, low-density lipoprotein cholesterol, apolipoproteins(apo) B and apoE increased with OSA severity, but only in non-obese subjects and those <55 years of age. Age, body mass index, waist to hip ratio, glucose and insulin were major risk factors for most serum lipids after multivariate adjustments. Our results indicate that, in women with OSA, age, obesity/central obesity, and insulin resistance are major determinants of dyslipidemia.

Meta-analysis of all-cause and cardiovascular mortality in obstructive sleep apnea with or without continuous positive airway pressure treatment.

PURPOSE: The associations between obstructive sleep apnea (OSA) and all-cause and cardiovascular mortality are well established but are not entirely consistent. To accurately evaluate these associations as well as the therapeutic effects of continuous positive airway pressure (CPAP), we conducted a comprehensive meta-analysis of all eligible cohort studies. METHODS: Electronic literature databases (i.e., PubMed and Embase) were searched for relevant studies published before January 2016 that evaluated the associations between OSA and all-cause or cardiovascular mortality. Random-effect models were used to calculate the pooled hazard ratio (HR) and corresponding 95 % confidence intervals (CIs) for categorical risk estimates. The therapeutic effects of CPAP treatment for all-cause and cardiovascular mortality in OSA were examined through the meta-analysis. RESULTS: The 27 cohort studies included in the meta-analysis included 3,162,083 participants. Compared to the control group, the pooled HR of all-cause mortality was 1.19 (95 % CI, 0.86-1.65) for mild OSA, 1.28 (0.96-1.69) for moderate OSA, and 2.13 (1.68-2.68) for severe OSA. The pooled HR of cardiovascular mortality was 1.24 (0.53-2.55) for mild OSA, 2.05 (0.57-5.47) for moderate OSA, and 2.73 (1.94-3.85) for severe OSA. All-cause mortality (HR 0.66; 0.59-0.73) and cardiovascular mortality (HR 0.37; 0.16-0.54) were significantly lower in CPAP-treated than in untreated patients. There were no differences in cardiovascular mortality in CPAP-treated OSA patients vs. normal control subjects (HR 0.82; 0.52-1.29). CONCLUSIONS: Greater attention should be paid to severe OSA, as it is an independent predictor for risk for all-cause and cardiovascular mortality. CPAP is an effective treatment that reduces risk of mortality.

Changes in cerebral metabolites in obstructive sleep apnea: a systemic review and meta-analysis.

Cognitive impairment is associated with changes in cerebral metabolites in patients with obstructive sleep apnea (OSA). Several studies have used magnetic resonance spectroscopy (MRS) to detect variations in cerebral metabolites; however, the results have been inconsistent. This meta-analysis summarizes the differences in cerebral metabolites between patients with OSA and controls. Two electronic databases, PubMed and Embase, were searched for articles (published before March 31, 2016) describing studies that used MRS to evaluate the cerebral metabolite changes. The overall effects were measured using the weighted mean difference with a 95% confidence interval. Subgroup analysis and sensitivity analysis were used to explore the sources of between-study heterogeneity and the stability of the results. Publication bias was also evaluated. Thirteen studies were ultimately included. In the hippocampus, the N-acetylaspartate (NAA)/creatine ratio was lower in patients with OSA. In the frontal lobe, only the NAA/choline ratio was lower in patients with OSA. Cerebral metabolites are significantly altered in the hippocampus in patients with OSA. Further clinical studies are needed to explore the underlying mechanisms between OSA and the changes in cerebral metabolites in the brain.