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Abstract Background The prognostic significance of obstructive sleep apnea (OSA) in patients with unstable angina (UA) based on remnant cholesterol (RC) or triglyceride (TG) levels remains unclear. This study aims to evaluate the effects of the interaction between RC, TG, and OSA on cardiovascular outcomes in UA patients. Methods In this prospective cohort study, OSA was diagnosed when apnea-hypopnea index of ≥ 15 events/h. Patients with high RC (HRC, n = 370) or high TG (HTG, n = 362) included RC or TG in the highest tertile, and those in the middle and lowest tertiles were defined as normal RC (NRC, n = 736) or normal TG (NTG, n = 744). The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), including cardiovascular death, myocardial infarction, ischemia stroke, ischemia-driven revascularization, or hospitalization for UA. Results A total of 1,106 eligible UA patients were enrolled, among which 560 (50.6%) had OSA. RC and TG levels were increased in OSA patients, but there was no difference in the prevalence of OSA between the NRC and HRC or NTG and HTG groups. During a median follow-up of 1.9 (1.1, 3.0) years, OSA was associated with an increased risk of MACCE occurrence compared to non-OSA in UA patients with HRC (adjusted HR 2.06; 95% CI 1.20–3.51, P = 0.008), but not in those with NRC (adjusted HR 1.21; 95% CI 0.84–1.75, P = 0.297). The incremental risk in HRC was attributable to higher rates of hospitalization for UA and ischemia-driven revascularization. Results for HTG and NTG were similar. Conclusion OSA was associated with a worse prognosis in UA patients with HRC or HTG, emphasizing the necessity of identifying OSA presence in this population. Trial registration Clinicaltrials.gov; No: NCT03362385.

ObjectiveObstructive sleep apnea (OSA) and thyroid dysfunction frequently overlap clinically and are risk factors for cardiovascular disease. The free triiodothyronine to free thyroxine (FT3/FT4) ratio as a novel biomarker of cardiovascular disease prognosis, but the impact of the FT3/FT4 ratio on the prognosis of OSA in patients with acute coronary syndromes (ACS) remains uncertain.MethodsIn this prospective cohort study, 2160 patients with ACS were recruited and underwent portable sleep monitoring at Beijing Anzhen Hospital from June 2015 to January 2020. OSA was diagnosed when apnea-hypopnea index of ≥15 events/h. Patients were further divided into tertiles according to FT3/FT4 ratio. All patients had scheduled follow-up visits at 1, 3, 6, 9 and 12 months after discharge, with subsequent outpatient visits or telephone follow-up visits every 6 months. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), including cardiovascular death, myocardial infarction (MI), stroke, ischemia-driven revascularization, or hospitalization for unstable angina or heart failure.ResultsAmong 1,547 euthyroid patients enrolled (mean age, 56.0 ± 10.5 years), 812 patients (52.5%) had OSA. The FT3/FT4 ratio between OSA and non-OSA patients was not significantly different. During 2.8 (1.4, 3.5) years follow up, the risk of MACCE increased with the decreasing FT3/FT4 tertiles in patients with OSA (tertile3 as reference, tertile2: hazard ratio (HR) 1.26, 95% CI: 0.85-1.86, P = 0.255; tertile1: 1.60, 95% CI 1.11-2.32; P = 0.013). After adjustment for confounders, the lowest FT3/FT4 tertile was still independently associated with an increased risk of MACCE (adjusted HR 1.66, 95% CI 1.11-2.50, P = 0.015).ConclusionLower FT3/FT4 ratio associated with poor prognosis in patients with ACS and OSA.

Abstract Background Sporadic studies have examined the impact of OSA on ACS patients by homocysteine (Hcy) level. This study attempted to comprehensively evaluate the effects of the interaction between Hcy and OSA on long-term cardiovascular outcomes in ACS patients. Methods In this prospective, large-scale cohort study, 2160 patients admitted for ACS were recruited to undergo overnight sleep monitoring. OSA was diagnosed when apnea–hypopnea index ≥ 15 events/h. Patients with normohomocysteinemia (NHcy) were defined as having serum Hcy ≤ 15 μmol/L, and the others had hyperhomocysteinemia (HHcy). The primary endpoint was major adverse cerebrocardiovascular event (MACCE), a composite of cardiovascular death, myocardial infarction, stroke, ischemia-driven revascularization and hospitalization for unstable angina and heart failure. Results A total of 1553 eligible ACS patients (average age: 56.3 ± 10.5 years) were enrolled, among which 819 (52.7%) had OSA, and 988 (63.6%) were with NHcy. OSA did not significantly affect the level of Hcy. During a median follow-up of 2.9 (1.6, 3.5) years, after adjustment for clinical confounders, OSA was associated with increased risk for MACCE occurrence versus non-OSA ones in ACS patients with NHcy (adjusted hazard ratio [HR] = 1.36, 95% confidence interval [CI] 1.02–1.83, P = 0.039), but not in those with HHcy (adjusted HR = 0.92, 95%CI 0.62–1.36, P = 0.668). There was an absence of interaction between homocysteine level and OSA in relation to MACCE (interaction P = 0.106). Conclusions OSA was independently associated with worse prognosis in ACS patients with NHcy. Our study emphasized the necessity to identify potential presence of OSA in such a population. Trial registration: ClinicalTrials.gov; Number: NCT03362385; URL: www.clinicaltrials.gov .

Objective: This study was aimed at investigating the effects of the neutrophil-to-lymphocyte ratio (NLR) on the long-term prognosis of patients with acute coronary syndrome (ACS) and obstructive sleep apnea (OSA). Methods: This prospective study enrolled patients with ACS and OSA at Anzhen Hospital between June 2015 and January 2020. OSA was defined by an apnea-hypopnea index ≥15 events·h −1 . Baseline NLR was classified as high or low, according to the median. The primary endpoint was major adverse cardiovascular events (MACE), comprising cardiovascular death, recurrent myocardial infarction, stroke, and ischemia-driven revascularization. Results: A total of 1011 patients with ACS and OSA were enrolled, 506 of whom were in the high NLR (≥2.54) group. No significant differences in sleep monitoring indicators were observed. During a median follow-up of 2.8 (1.4, 3.6) years, a non-linear correlation between NLR and the incident risk of MACE was observed. After adjustment for clinically relevant confounders, a high NLR was independently associated with elevated MACE risk (adjusted HR = 1.45, 95% CI: 1.02–2.06, P = 0.040). Conclusions: In patients with ACS and OSA, a high NLR was associated with poorer clinical outcomes during long-term follow-up. Trial registration: ClinicalTrials.gov ; Number: NCT03362385; URL: www.clinicaltrials.gov .

Abstract Background Angiogenesis plays a critical role on post-infarction heart failure (PIHF), the presence of which facilitates additional blood supply to maintain the survival of residual cardiomyocytes. The sigma-1 receptor (S1R) has been substantiated to stimulate angiogenesis, with the effect on a model of PIHF remaining unknown. Aims This study aims to investigate the effects of S1R on PIHF and the underlying mechanisms involved. Methods Rats were implemented left anterior descending artery ligation followed by rearing for 6 weeks to induce a phenotype of heart failure. Daily intraperitoneal injection of S1R agonist or antagonist for 5 weeks was applied from 2nd week after surgery. The effects exerted by S1R were detected by echocardiography, hemodynamic testing, western blot, Sirius red dyeing, ELISA, immunohistochemistry and fluorescence. We also cultured HUVECs to verify the mechanisms in vitro. Results Stimulation of S1R significantly ameliorated the cardiac function resulted from PIHF, in addition to the observation of reduced fibrosis in the peri-infarct region and the apoptosis of residual cardiomyocytes, which were associated with augmentation of microvascular density in peri-infarct region through activation of the JAK2/STAT3 pathway. We also indicated that suppression of JAK2/STAT3 pathway by specific inhibitor in vitro reversed the pro-angiogenic effects of S1R on HUVECs, which further confirmed that angiogenesis, responsible for PIHF amelioration, by S1R stimulation was in a JAK2/STAT3 pathway-dependent manner. Conclusion S1R stimulation improved PIHF-induced cardiac dysfunction and ventricular remodeling through promoting angiogenesis by activating the JAK2/STAT3 pathway.

Abstract Background Oxidative stress is an important factor involved in the progress of heart failure. The current study was performed to investigate whether pinocembrin was able to ameliorate post-infarct heart failure (PIHF) and the underlying mechanisms. Methods Rats were carried out left anterior descending artery ligation to induce myocardial infarction and subsequently raised for 6 weeks to produce chronic heart failure. Then pinocembrin was administrated every other day for 2 weeks. The effects were evaluated by echocardiography, western blot, Masson’s staining, biochemical examinations, immunohistochemistry, and fluorescence. In vitro we also cultured H9c2 cardiomyocytes and cardiac myofibroblasts to further testify the mechanisms. Results We found that PIHF-induced deteriorations of cardiac functions were significantly ameliorated by administrating pinocembrin. In addition, the pinocembrin treatment also attenuated collagen deposition and augmented vascular endothelial growth factor receptor 2 in infarct border zone along with an attenuated apoptosis, which were related to an amelioration of oxidative stress evidenced by reduction of reactive oxygen species (ROS) in heart tissue and malondialdehyde (MDA) in serum, and increase of superoxide dismutase (SOD). This were accompanied by upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) pathway. In vitro experiments we found that specific Nrf2 inhibitor significantly reversed the effects resulted from pinocembrin including antioxidant, anti-apoptosis, anti-fibrosis and neovascularization, which further indicated the amelioration of PIHF by pinocembrin was in a Nrf2/HO-1 pathway-dependent manner. Conclusion Pinocembrin ameliorated cardiac functions and remodeling resulted from PIHF by ROS scavenging and Nrf2/HO-1 pathway activation which further attenuated collagen fibers deposition and apoptosis, and facilitated angiogenesis.

AbstractObjective Ventricular arrhythmias (VAs) are a common complication of chronic ischaemic heart failure (CIHF). The purpose of this study is to investigate the efficacy of pinocembrin in a rat model of VAs induced by CIHF and further examine the possible mechanism.Methods Rats were subjected to ligation of left anterior descending coronary artery to mimic CIHF and then received pinocembrin treatment daily for 2 months. The vivo electrophysiology were performed to determine the effect of pinocembrin on ventricular electrical activity. The expression of Cav1.2, Kv4.2, and NGF was determined by Western blot. The structural change of ventricle was tested by the Echocardiography, Masson staining, and HE staining. The effect of pinocembrin on sympathetic nerve-related markers was detected by the immunostaining and the ELISA was used to test for biomarkers associated with heart failure.Results Pinocembrin increased the expression of ion channel protein Cav1.2 and Kv4.3, ameliorated the shortening of action potential duration (APD) and reduced the incidence and duration of ventricular fibrillation (VF). Pinocembrin also reduced the expression of nerve growth factor (NGF) and improved the autonomic nerve remodelling. In addition, pinocembrin reduced the area of infarct area and myocardial fibrosis, accompanied by increasing the expression of connexin protein 43 (CX43).Conclusion We demonstrate that pinocembrin reduces cardiac nerve remodelling and protects against Vas induced by CIHF. The findings suggest that pinocembrin can be a promising candidate for the treatment of VAs.

Background: Depression is associated with the increased risk of mortality and morbidity and is an independent risk factor for many cardiovascular diseases. Depression may promote cardiac arrhythmias, but little is known about the mechanisms. Pinocembrin mitigated depressive-like behaviors and exhibited cardioprotective effects in several models; however, whether pinocembrin benefits ventricular arrhythmias in depression models has not been elucidated. Thus, this study was to evaluate the effects of pinocembrin on ventricular fibrillation susceptibility in rat models of depression.Methods: Male Sprague-Dawley rats were randomly assigned into control, control + pinocembrin, MDD (major depressive disorder), and MDP (MDD + pinocembrin) groups, respectively. Depressive-like behaviors, ventricular electrophysiological parameters, electrocardiogram parameters, heart rate variability, ventricular histology, serum norepinephrine, tumor necrosis factor-α, and interleukin-1β were detected. Protein levels in left ventricle were measured by Western blot assays.Results: Compared with the MDD group, pinocembrin significantly mitigated depressive-like behaviors, prolonged ventricular effective refractory period, action potential duration, QT, and corrected QT (QTc) interval, improved heart rate variability, decreased Tpeak–Tend interval, ventricular fibrillation inducibility rate, ventricular fibrosis, ventricular positive nerve densities, and protein expression of tyrosine hydroxylase and growth associated protein-43, reduced serum norepinephrine, tumor necrosis factor-α, interleukin-1β concentrations, and the expression levels of p-IκBα and p-p65, and increased the protein expression of Cx43, Cav1.2, and Kv.4.2 in the MDP group.Conclusion: Pinocembrin attenuates ventricular electrical remodeling, autonomic remodeling, and ion-channel remodeling, lowers ventricular fibrosis, and suppresses depression-induced inflammatory responses, providing new insights in pinocembrin and ventricular arrhythmias in depressed patients.