Prevalence and clinical characteristics of sleep-disordered breathing in patients with heart failure of different left ventricular ejection fractions.

PURPOSES: The prevalence of sleep-disordered breathing (SDB) is high in patients with heart failure (HF), while the prevalence of SDB in HF with different left ventricular ejection fractions (LVEF) has rarely been reported. We aimed to explore the prevalence and clinical characteristics of SDB in patients with HF having different LVEF. METHODS: Patients with stable HF were consecutively enrolled. All patients underwent portable overnight cardiorespiratory polygraphy and echocardiography. According to their LVEF, the patients were divided into the HFrEF (HF with reduced EF, EF < 40%), HFmrEF (HF with mid-range EF, 40 ≤ EF < 50), and HFpEF groups (HF with preserved EF, EF ≥ 50%). The prevalence and clinical data of SDB among the 3 groups were then compared. RESULTS: A total of 252 patients, including 134 men, were enrolled in the study. The prevalence of SDB in patients with HF was 70%. Obstructive sleep apnea (OSA) was diagnosed in 48% and central sleep apnea (CSA) in 22%. The prevalence of SDB in the HFrEE, HFmrEF, and HFpEF groups was 86%, 86%, and 62%, respectively (P = 0.001). The prevalence of OSA among the 3 groups was 42%, 47%, and 49%, respectively (P = 0.708), while the prevalence of CSA among the 3 groups was 44%, 40%, and 13% (P < 0.001). Logistic regression analysis revealed that age and BMI were independent risk factors for OSA in patients with HF, while LVEF and smoking were independent risk factors for CSA in patients with HF. Correlational analyses revealed that LVEF was negatively correlated with apnea-hypopnea index (AHI) (r = -0.309, P < 0.001) and central apnea index (CAI) ( r = -0.558, P < 0.001), while there was no significant correlation with obstructive apnea index (OAI). The ROC curve revealed that LVEF could predict the occurrence of CSA and SDB, with AUC = 0.683 (95%CI 0.600-0.767, P < 0.001) and AUC = 0.630 (95%CI 0.559-0.702, P = 0.001), but not of OSA. CONCLUSIONS: SDB was highly common in HF, and the prevalence of SDB was different in HF with different LVEF, mainly due to the difference in cardiac functions. The prevalence and severity of SDB in HFrEF and HFmrEF were significantly higher than those in HFpEF, which was mainly related to the increase in CSA. When HFmrEF was similar to HFrEF in cardiac functions, the prevalence, type, and severity of SDB were similar between the two groups. Changes in LVEF had a significant impact on CAI, but not on OAI. LVEF can predict the occurrence of CSA and SDB to a certain extent.

Chronic intermittent hypoxia accelerates cardiac dysfunction and cardiac remodeling during cardiac pressure overload in mice and can be alleviated by PHD3 overexpression.

Obstructive sleep apnea (OSA) accelerates the progression of chronic heart failure (CHF). OSA is characterized by chronic intermittent hypoxia (CIH), and CIH exposure accelerates cardiac systolic dysfunction and cardiac remodeling in a cardiac afterload stress mouse model. Mechanistic experiments showed that long-term CIH exposure activated hypoxia-inducible factor 1α (HIF-1α) expression in the mouse heart and upregulated miR-29c expression and that both HIF-1α and miR-29c simultaneously inhibited sarco-/endoplasmic reticulum calcium ATPase 2a (SERCA2a) expression in the mouse heart. Cardiac HIF-1α activation promoted cardiomyocyte hypertrophy. SERCA2a expression was suppressed in mouse heart in middle- and late-stage cardiac afterload stress, and CIH exposure further downregulated SERCA2a expression and accelerated cardiac systolic dysfunction. Prolyl hydroxylases (PHDs) are physiological inhibitors of HIF-1α, and PHD3 is most highly expressed in the heart. Overexpression of PHD3 inhibited CIH-induced HIF-1α activation in the mouse heart while decreasing miR-29c expression, stabilizing the level of SERCA2a. Although PHD3 overexpression did not reduce mortality in mice, it alleviated cardiac systolic dysfunction and cardiac remodeling induced by CIH exposure.

Sleep-disordered breathing in heart failure patients with different etiologies.

BACKGROUND: The prevalence of sleep-disordered breathing (SDB) is closely related to the severity of heart failure (HF), and the severity of HF is different in patients with HF of different etiologies. HYPOTHESIS: This study aimed to explore the prevalence of SDB in patients with HFof different etiologies. METHODS: Hospitalized HF patients were consecutively enrolled. All patients underwent portable overnight cardiorespiratory polygraphy. Patients were divided into five groups according to the etiology of HF: ischemic, hypertensive, myocardial, valvular, and arrhythmic. The prevalence of SDB and clinical data was compared among the five groups. RESULTS: In total, 248 patients were enrolled in this study. The prevalence of SDB in HF was 70.6%, with the prevalence of obstructive sleep apnea (OSA) at 47.6% and central sleep apnea (CSA) at 23.0%. Patients were divided into five groups: ischemic, hypertensive, myocardial, valvular, and arrhythmic. The prevalence of SDB among the five groups was 75.3%, 81.4%, 77.8%, 51.9%, and 58.5% (p = .014), respectively. The prevalence of OSA among the five groups was 42.7%, 72.1%, 36.1%, 37.0%, and 49.1% (p = .009), whereas the CSA was 32.6%, 9.3%, 41.7%, 14.8%, and 9.4% (p < .001), respectively. CONCLUSIONS: SDB is common in HF patients. The prevalence and types of SDB varied in HF with different etiologies, which may be related to the different severities of HF. SDB was highly prevalent in patients with ischemic, hypertensive, and myocardial HF. Hypertensive HF patients were mainly complicated with OSA, while myocardial HF patients were mainly complicated with CSA. Both conditions were highly prevalent in ischemic HF patients. The prevalence of SDB was relatively low in valvular and arrhythmic HF patients, and OSA was the main type.

Effects of chronic intermittent hypoxia on left cardiac function in young and aged mice.

Obstructive sleep apnea (OSA) is an independent risk factor for cardiovascular disease that is characterized by chronic intermittent hypoxia (CIH), and its impact is related to age. This study aims to assess the age-related impact of CIH on cardiac function and to further explore the mechanism. After 8 wk of severe CIH exposure, the hearts of young mice showed slight physiological hypertrophy, decreased diastolic function, and collagen I accumulation but no obvious change in contractile function. However, the contractile function of the hearts of aged mice was severely decreased. CIH exposure promoted the fragmentation of mitochondria in the hearts of aged mice and decreased the mitochondrial membrane potential of cardiomyocytes, but these effects were not observed in young mice exposed to the same conditions. CIH induced significant decreases in basal respiration, maximum respiration, and ATP production in cardiac mitochondria of aged mice compared with those of young mice. The assessment of mitochondrial-related proteins showed that young mouse hearts had upregulated adaptive nuclear respiratory factors (Nrf)1/2 sirtuin (SIRT)1/3 and transcription factor A (TFAM) expression that stabilized mitochondrial function in response to CIH exposure. Aged mouse hearts exhibited maladaptation to CIH exposure, and downregulation of SIRT1 and TFAM expression resulted in mitochondrial dysfunction.

Protective effect of sphingosine-1-phosphate for chronic intermittent hypoxia-induced endothelial cell injury.

Intermittent hypoxia (IH) induced by obstructive sleep apnea (OSA) is the key factor in oxidative stress and the concomitant inflammation of endothelial cells (ECs). In recent years, the lipid sphingosine-1-phosphate (S1P) has been reported to probably play a central role in inflammatory diseases. However, its role in IH-induced endothelial injury remains uncertain. In this study, we investigated the IH-induced ECs inflammation and apoptosis, as well as the role of S1P in both. First, human umbilical vein endothelial cells (HUVECs) were treated with IH to explore the mechanism of S1P and S1P microbubbles (S1P-MBs) in HUVECs with altered function. The intracellular reactive oxygen species (ROS) significantly increased after IH treatment, which further resulted in the increased efficiency of cell apoptosis. Following the S1P and S1P-MBs treatments, the lower Bax protein and Cyt c protein levels in HUVECs indicated the protective effects of S1P for CIH-induced ECs injury. The reason may be that the enhanced expression levels of Gα(i) and S1P receptor 1 in S1P and S1P-MBs treatment groups could actively increase intracellular p-Akt and p-eNOS protein levels, which counteract the increased ROS secondary to inflammation from IH. Therefore, the Akt/eNOS signaling pathway induced by S1P may be important in protecting IH-induced ECs injury. Furthermore, the S1P-MBs may be designed as a novel S1P dosage formulation to protect the body from the ECs injuries in the future.

Prolyl 4-Hydroxylase Domain Protein 3 Overexpression Improved Obstructive Sleep Apnea-Induced Cardiac Perivascular Fibrosis Partially by Suppressing Endothelial-to-Mesenchymal Transition.

BACKGROUND: Intermittent hypoxia (IH) induced by obstructive sleep apnea is the key factor involved in cardiovascular fibrosis. Under persistent hypoxia condition, endothelial cells respond by endothelial-to-mesenchymal transition (EndMT), which is associated with cardiovascular fibrosis. Prolyl 4-hydroxylase domain protein 3 (PHD3) is a cellular oxygen sensor and its expression increased in hypoxia. However, its role in obstructive sleep apnea-induced EndMT and cardiovascular fibrosis is still uncertain. We investigated the potential mechanism of obstructive sleep apnea-induced cardiac perivascular fibrosis and the role of PHD3 in it. METHODS AND RESULTS: In vivo, C56BL/6 mice were exposed to IH for 12 weeks. PHD3 expression was changed by lentivirus-mediated short-hairpin PHD3 and lentivirus carrying PHD3 cDNA. EndMT related protein levels, histological and functional parameters were detected after 12 weeks. In vitro, human umbilical vein endothelial cells were treated with IH/short-hairpin PHD3/lentivirus carrying PHD3 cDNA to explore the mechanism of PHD3 in altered function of human umbilical vein endothelial cells. We found that chronic intermittent hypoxia increase PHD3 expression and EndMT. In vivo, IH accelerate cardiac dysfunction and aggravate collagen deposition via the process of EndMT. And, when PHD3 were overexpressed, cardiac dysfunction and collagen excessive deposition were improved. In vitro, IH induced EndMT, which endow human umbilical vein endothelial cells spindle morphology and an enhanced ability to migration and collagen secretion. PHD3 overexpression in cultured human umbilical vein endothelial cells ameliorated IH-induced EndMT through inactivating hypoxia-inducible factor 1 alpha and small mothers against decapentaplegic 2 and 3. CONCLUSIONS: Obstructive sleep apnea-induced cardiac perivascular fibrosis is associated with EndMT, and PHD3 overexpression might be beneficial in the prevention of it by inhibiting EndMT. PHD3 overexpression might have therapeutic potential in the treatment of the disease.

Therapeutic effects of Qishen Yiqi Dropping Pill on myocardial injury induced by chronic hypoxia in rats.

The present study was designed to determine the effects of a traditional Chinese medicine, called Qishen Yiqi Dropping Pill on chronic hypoxia-induced myocardial injury. To establish a rat chronic hypoxia model to be used in the evaluation of the therapeutic effects of the Qishen Yiqi Dropping Pill, Sprague-Dawley (SD) rats were randomly divided into three groups: the control, model, and treatment groups (n = 10 per group). The animals were housed in a plexiglass container. The control animals were under normal oxygen concentration and the model and treatment groups were exposed to air and nitrogen for 5 weeks. The rats in the treatment group were orally administered the Qishen Yiqi Dropping pill (35 mg·kg(-1)·d(-1)) for 5 weeks. After the treatment, the cardiac function and morphology were analyzed, and the expression levels of hypoxia-inducible factor 1α (HIF-1α) were determined using Western blotting. Our results indicated that the cardiac function was impaired, cell apoptosis was enhanced, and HIF-1α expression was up-regulated in the model group, compared to the control group. These changes were ameliorated by the treatment with the Qishen Yiqi Dropping Pill. In conclusion, Qishen Yiqi Dropping pill can ameliorate myocardial injury induced by chronic hypoxia, improve cardiac function, and decrease myocardial cell apoptosis, which may provide a basis for its clinical use for the treatment of chronic cardiovascular diseases.

Effect and mechanism of Qishen Yiqi Pills on adriamycin- induced cardiomyopathy in mice.

AIM: To study the effect and probable mechanism of Qishen Yiqi Pills on adriamycin (ADR)-induced cardiomyopathy in mice. METHODS: Sixty-four mice were randomly divided into (1) the ADR group: saline (1 mL/100 g) administered every day by intragavage, ADR (4 mg·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks; (2) the ADR + Qishen Yiqi Pills I group: ADR (4 mg·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks, and at the beginning of the third week Qishen Yiqi Pills (3.5 mg/100 g) administered by intragavage every day for four weeks; (3) the ADR + Qishen Yiqi Pills II group: ADR (4 mg·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks, and at the same time Qishen Yiqi Pills (3.5 mg/100 g) administered by intragavage every day for four weeks; (4) the control group: saline (1 mL/100 g) administered every day by intragavage, saline (1 mL·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks. Six weeks later, cardiac function, myocardial pathology, and expression of Bcl-2 and Bax were evaluated. RESULTS: 1. The left ventricular diastolic diameter and the left ventricular systolic diameter were significantly increased (P < 0.05) and the left ventricular ejection fraction was significantly decreased (P < 0.05) in the ADR group, and the cardiac function of both the ADR + Qishen Yiqi Pills I group and the ADR + Qishen Yiqi Pills II group improved. 2. Myocardial morphologic observation showed that the myocardial fibers were disordered, there was cell edema, and gap widening in the ADR group. The degree of myocardial cell injury was reduced in the ADR + Qishen Yiqi Pills I group and ADR + Qishen Yiqi Pills II group compared with the ADR group. 3. The expression of Bax in the ADR group was significantly up-regulated, and the expression of Bcl-2 was significantly downregulated in the ADR group compared with the ADR + Qishen Yiqi Pills I group, the ADR + Qishen Yiqi Pills II group, and the control group (P < 0.05). CONCLUSIONS: Qishen Yiqi Pills can effectively improve the cardiac function of ADR-induced cardiomyopathy, and the earlier it is used is better. The probable mechanism of action may be the inhibition of the apoptosis of myocardial cells.

Tissue kallikrein is related to the severity of coronary artery disease.

BACKGROUND: The impairment of the tissue kallikrein (KLK1)-kinin system (KKS) may result in atheroma development. However, it remains unclear if the KKS correlates with coronary artery disease (CAD). METHODS: KLK1, VEGF and hs-CRP plasma levels were measured in 100 patients newly diagnosed with CAD and 33 CAD-free controls. Patients were followed-up for the incidence of major adverse cardiovascular events (MACE) for 8months to 2y. Gene expression of KLK1, CD105 and CD68 was assessed in human coronary endarterectomy specimens. RESULTS: Patients with CAD and acute coronary syndrome (ACS) had significantly elevated KLK1 levels. In addition, the concentration of hs-CRP was increased in ACS patients. A strong positive correlation between plasma KLK1 and the severity of CAD was also demonstrated, suggesting that high KLK1 levels are an independent predictor for CAD. MACE during follow-up significantly correlated with KLK1 levels in the ACS group. Unstable coronary plaques demonstrated markedly increased KLK1 levels, macrophage infiltration and high microvessel density. Additionally, KLK1 staining primarily colocalized with macrophages. CONCLUSIONS: In the present study, plasma KLK1 levels were a useful predictor for the presence and extent of CAD. More extensive studies are, however, necessary in order to validate these findings.

Long-term effects of bone marrow-derived cells transplantation in patients with acute myocardial infarction: a meta-analysis.

BACKGROUND: The long-term effects of bone marrow-derived cells (BMC) transplantation in patients with acute myocardial infarction (AMI) have not been established. The present meta-analysis of randomized controlled trials with follow-up ≥ 2 years was performed to investigate the long-term effects of BMC therapy in patients after AMI. METHODS: Specific terms were used to conduct a systematic literature search of MEDLINE, EMBASE, the Cochrane Library and the Cochrane Central Register of Controlled Trials, and the China Biological Medicine Disk database from their inception to March 2012. A standardized protocol was used to extract information, and random effect model was used to analyze all data except major adverse events. RESULTS: Five trials comprising 510 patients were included. Compared with controls, BMC therapy significantly improved left ventricular ejection fraction (LVEF) (4.18%, 95%CI: 2.02% to 6.35%, P = 0.0002), while mildly but not significantly reduced left ventricular end-systolic volume (-4.47 ml, 95%CI: -10.92 to 1.99, P = 0.17) and left ventricular end-diastolic volume (-2.29 ml, 95%CI: -9.96 to 5.39, P = 0.56). Subgroup analysis revealed that significant improvement of LVEF induced by BMC therapy could be observed in patients with baseline LVEF ≤ 42%, but disappeared in those with baseline LVEF > 42%. There were trends in favor of BMC therapy for most major clinical adverse events, though most differences were not significant. CONCLUSIONS: Intracoronary BMC infusion in patients with AMI seems to be safe and may further improve LVEF on top of standard therapy; especially the beneficial effects could last for long term. The findings need to be validated in the future.