Important Role of Endogenous Nerve Growth Factor Receptor in the Pathogenesis of Hypoxia-Induced Pulmonary Hypertension in Mice.

Pulmonary arterial hypertension (PAH) remains a disease with poor prognosis; thus, a new mechanism for PAH treatment is necessary. Circulating nerve growth factor receptor (Ngfr)-positive cells in peripheral blood mononuclear cells are associated with disease severity and the prognosis of PAH patients; however, the role of Ngfr in PAH is unknown. In this study, we evaluated the function of Ngfr using Ngfr gene-deletion (Ngfr-/-) mice. To elucidate the role of Ngfr in pulmonary hypertension (PH), we used Ngfr-/- mice that were exposed to chronic hypoxic conditions (10% O2) for 3 weeks. The development of hypoxia-induced PH was accelerated in Ngfr-/- mice compared to littermate controls. In contrast, the reconstitution of bone marrow (BM) in Ngfr-/- mice transplanted with wild-type BM cells improved PH. Notably, the exacerbation of PH in Ngfr-/- mice was accompanied by the upregulation of pulmonary vascular remodeling-related genes in lung tissue. In a hypoxia-induced PH model, Ngfr gene deletion resulted in PH exacerbation. This suggests that Ngfr may be a key molecule involved in the pathogenesis of PAH.

Effect of pulmonary vein isolation on the relationship between left atrial reverse remodeling and sympathetic nerve activity in patients with atrial fibrillation.

PURPOSE: Catheter ablation (CA) to isolate the pulmonary vein, which is an established treatment for atrial fibrillation (AF), is associated with left atrium reverse remodeling (LARR). The intrinsic cardiac autonomic nervous system includes the ganglion plexi adjacent to the pulmonary vein in the left atrium (LA). However, little is known about the effect of CA on the relationship between LARR and sympathetic nerve activity in patients with AF. METHODS: This study enrolled 22 AF patients with a normal left ventricular ejection fraction (LVEF) aged 64.6 ± 12.9 years who were scheduled for CA. Sympathetic nerve activity was evaluated by direct recording of muscle sympathetic nerve activity (MSNA) before and 12 weeks after CA. Blood pressure, heart rate (HR), HR variability, and echocardiography were also measured. RESULTS: The heart rate increased significantly after CA (63 ± 10.9 vs. 70.6 ± 7.7 beats/min, p < 0.01), but blood pressure did not change. A high frequency (HF) and low frequency (LF) of HR variability decreased significantly after ablation, but no significant change in LF/HF was observed. CA significantly decreased MSNA (38.9 ± 9.9 vs. 28 ± 9.1 bursts/min, p < 0.01). Moreover, regression analysis revealed a positive correlation between the percentage change in MSNA and the LA volume index (r = 0.442, p < 0.05). CONCLUSIONS: Our results show that CA for AF reduced MSNA and the decrease was associated with the LA volume index in AF patients with a normal LVEF. These findings suggest that LARR induced by CA for AF decrease sympathetic nerve activity.

Endogenous muscle atrophy F-box is involved in the development of cardiac rupture after myocardial infarction.

Muscle atrophy F-box (MAFbx/atrogin-1), an E3 ubiquitin ligase, is a crucial mediator of skeletal muscle atrophy and cardiac hypertrophy in response to pressure overload and exercise. The role of MAFbx in the regulation of cardiac remodeling after myocardial infarction (MI) remains unclear. Permanent coronary ligation of the left coronary artery was performed on MAFbx knockout (KO) and wild-type (WT) mice and MAFbx expression in the WT mice was shown to be significantly increased in the left ventricles after MI. The mortality rate due to post-MI cardiac rupture was significantly decreased in MAFbx KO mice compared to that in the WT mice. DNA microarray and mRNA expression analyses revealed that the upregulation of genes involved in inflammatory processes and cell motility of leukocytes and neutrophils, including Mmp9, Il1b, Cxcl2, and Nlrp3, was significantly attenuated in MAFbx KO mice 1 day after MI. MAFbx downregulation inhibited nuclear factor-κB (Nfkb) activation after MI. Flow cytometry results demonstrated that the myocardial infiltration of neutrophils was suppressed in MAFbx KO mice 1 day after MI. Nlrp3 and Il1b protein levels were decreased in MAFbx KO mice compared with those in the WT mice. MAFbx downregulation significantly attenuated Tnfa-induced Cxcl2, Il1b, and Nlrp3 expression in cardiomyocytes. We conclude that MAFbx plays an important role in the mediation of excessive inflammation, including neutrophil infiltration, inflammasome formation, and production of proinflammatory cytokines through the activation of Nfkb, promoting cardiac rupture after MI.

Diabetes impairs the angiogenic capacity of human adipose-derived stem cells by reducing the CD271+ subpopulation in adipose tissue.

Type 2 diabetes mellitus is an important risk factor for cardiovascular diseases (CVDs). Therapeutic angiogenesis using adipose-derived stem cells (ADSCs) is attractive for CVD therapy. However, although it would be critical for ADSC application on CVD therapy, whether and how diabetes impairs human ADSC therapeutic potential is still uncertain. In this study, we aimed to investigate the impact of diabetes on the angiogenic potential of ADSCs in patients with CVDs, with special focus on stemness-related genes and cellular alteration of ADSCs. We established cultured ADSCs from diabetic (DM-ADSCs) and non-diabetic patients (nonDM-ADSCs) with CVDs. DM-ADSCs demonstrated limited proliferative capacity and reduced paracrine capacity of VEGF, with lower expression of the stemness gene SOX2. Angiogenic capacity and ADSC engraftment were assessed using xenograft experiments in a hindlimb ischemia model of athymic nude mice. Consistent with the results of in vitro assays, DM-ADSCs did not rescue limb ischemia. In contrast, nonDM-ADSCs induced neovascularization with enhanced engraftment. To elucidate the mechanism underlying these ADSC changes, we compared the surface marker profiles of freshly isolated ADSCs obtained from diabetic and non-diabetic patients by flow cytometry. Among studied subsets, the CD34+CD31-CD271+ subpopulation was reduced in the adipose tissues of diabetic patients. In addition, SOX2 expression and proliferative capacity were considerably reduced in nonDM-ADSCs derived from the stromal vascular fraction (SVF) with depletion of CD271+ cells (p < 0.01). Our observations elucidated that reduced CD271+ subpopulation is critical for the impairment of ADSCs in diabetic patients. Further investigations on the CD271+ subset of ADSCs might provide novel insights into the mechanisms and solutions for diabetes-related ADSC dysfunction in cell therapy.

Sphigosine-1-phosphate receptor 1 promotes neointimal hyperplasia in a mouse model of carotid artery injury.

Vascular remodeling, resulting from proliferation and migration of vascular smooth muscle cells (VSMCs), is a major cause of atherosclerosis and restenosis. The lysophospholipid mediator sphingosine-1-phosphate (S1P) regulates proliferation and migration of VSMCs via S1P-specific G protein-coupled receptors, including S1P receptor 1 (S1PR1) to S1PR3. However, the role of S1PR1 in vascular remodeling is not well understood. Therefore, in this study, we aimed to investigate the effect of S1PR1 on neointimal hyperplasia in a carotid artery ligation mouse model using transgenic C57Bl/6 mice that overexpressed S1PR1 (Tg-S1PR1) under the control of α-smooth muscle actin promoter. We found that S1PR1 expression in carotid artery was upregulated after carotid artery ligation in non-transgenic (nTg) mice. Tg-S1PR1 mice showed enhanced ligation-induced neointimal hyperplasia with increased neointimal cell proliferation, compared with control nTg mice. VSMCs isolated from Tg-S1PR1 mice showed enhanced proliferation and migration in response to S1P stimulation. VSMCs from Tg-S1PR1 mice showed greater expression of interleukin-6 (IL-6) compared with nTg mouse-derived VSMCs, and administration of IL-6-neutralizing antibody into Tg-S1PR1 mice suppressed neointimal hyperplasia. These results suggest that S1P-S1PR1 signaling plays an important role in neointimal hyperplasia after vascular injury via IL-6 production.

Coronary sinus catheter placement via left cubital vein for phrenic nerve stimulation during pulmonary vein isolation.

Phrenic nerve (PN) stimulation is essential for the elimination of PN palsy during balloon-based pulmonary vein isolation (PVI). Although ultrasound-guided vascular access is safe, insertion of a PN stimulation catheter via central venous access carries a potential risk of the development of mechanical complications. We evaluated the safety of a left cubital vein approach for positioning a 20-electrode atrial cardioversion (BeeAT) catheter in the coronary sinus (CS), and the feasibility of right PN pacing from the superior vena cava (SVC) using proximal electrodes of the BeeAT catheter. In total, 106 consecutive patients who underwent balloon-based PVI with a left cubital vein approach for BeeAT catheter positioning were retrospectively assessed. The left cubital approach was successful in 105 patients (99.1%), and catheter insertion into the CS was possible for 104 patients (99.0%). Among these patients, constant right PN pacing from the SVC was obtained for 89 patients (89/104, 85.6%). In five patients, transient loss of right PN capture occurred during right pulmonary vein ablation. No persistent right PN palsy was observed. Small subcutaneous hemorrhage was observed in eight patients (7.5%). Neuropathy, pseudoaneurysm, arteriovenous fistula, and perforations associated with the left cubital approach were not detected. Body mass index was significantly higher in the right PN pacing failure group than in the right PN pacing success group (26.2 ± 3.2 vs. 23.8 ± 3.8; P = 0.025). CS catheter placement with a left cubital vein approach for right PN stimulation was found to be safe and feasible. Right PN pacing from the SVC using a BeeAT catheter was successfully achieved in the majority of the patients. This approach may prove to be preferable for non-obese patients.

Optimal lesion size index to prevent conduction gap during pulmonary vein isolation.

INTRODUCTION: A novel real-time lesion size index (LSI) that incorporates contact force (CF), time, and power has been developed for safe and effective catheter ablation. The optimal LSI was evaluated to eliminate gap formation during pulmonary vein isolation (PVI). METHODS AND RESULTS: Consecutive patients were enrolled, who underwent their first PVI using a fiber-optic CF-sensing catheter for atrial fibrillation between December 2016 and October 2017. The CF parameters, force-time integral (FTI), and LSI for 3095 ablation points in 34 patients were evaluated. The FTI and LSI in the lesions with gaps or dormant conduction (gaps/DC) were significantly lower than those in the lesion without gaps/DC (FTI: 140.5 ± 54.5 and 232.4 ± 121.4 g s, P < 0.0001; LSI: 4.0 ± 0.6 and 4.7 ± 0.9, P < 0.0001, respectively). On receiver operating characteristic curve analysis, the optimal LSI threshold was 4.05 (sensitivity, 63.4%; specificity, 76.3%). The LSI of <5.25 predicted a gap or DC with a high sensitivity (sensitivity, 97.6%; specificity, 25.7%). In the posterior wall, which was 37% thinner than the nonposterior wall, a lower LSI of <3.95 showed a relatively high sensitivity (92.3%) and specificity (65.6%). CONCLUSIONS: The LSI can be used to predict gaps/DC during the PVI procedure. An LSI of 5.2 may be a suitable target for effective lesion formation. An LSI of 4.0 may be acceptable in the posterior wall, especially in areas adjacent to the esophagus.

Occult constrictive pericardial disease emerging 40 years after chest radiation therapy: a case report.

BACKGROUND: The main etiology of constrictive pericarditis (CP) has changed from tuberculosis to therapeutic mediastinal radiation and cardiac surgery. Occult constrictive pericardial disease (OCPD) is a covert disease in which CP is manifested in a condition of volume overload. CASE PRESENTATION: A 60-year-old patient with a history of thoracic radiation therapy for non-Hodgkin's lymphoma (40 years earlier) was transferred to our hospital for treatment of repeated congestive heart failure. For a preoperative hemodynamic study, pre-hydration with intravenous normal saline (50 mL/hour) was used to manifest the pericardial disease and prevent contrast-induced nephropathy. The hemodynamic study showed a right ventricular dip-plateau pattern and discordance of right and left ventricular systolic pressures during inspiration, which was not seen in the volume-controlled state. These responses were concordant with OCPD. A pericardiectomy, aortic valve replacement, and mitral and tricuspid valve repair were performed. Postoperatively, the heart failure was controlled with standard medication. CONCLUSIONS: This case revealed a volume-induced change in hemodynamics in OCPD with severe combined valvular heart disease, which suggests the importance of considering OCPD in patients who had undergone radiation therapy 40 years before.

Comparison of Human Selenoprotein P Determinants in Serum between Our Original Methods and Commercially Available Kits.

Selenoprotein P (SeP) is a selenium (Se)-rich extracellular protein. SeP is identified as a hepatokine, causing insulin resistance in type 2 diabetes. Thus, the measurement of SeP in serum has received much attention, and several enzyme-linked immunosorbent assay (ELISA) kits for SeP determination are now commercially available. In the present study, we determined the serum SeP levels by our original ELISA and sol particle homogeneous immunoassay (SPIA) methods and also by commercially available kits, and these determinants were compared. We found a kit-dependent correlation of the determinants with our methods. These results suggest that the selection of kit is critical for comparison with our previous reports and for discussing the relationship between the serum SeP levels and disease condition.

Endogenous Selenoprotein P, a Liver-Derived Secretory Protein, Mediates Myocardial Ischemia/Reperfusion Injury in Mice.

Selenoprotein P (SeP), a liver-derived secretory protein, functions as a selenium supply protein in the body. SeP has been reported to be associated with insulin resistance in humans through serial analysis of gene expression. Recently, SeP has been found to inhibit vascular endothelial growth factor-stimulated cell proliferation in human umbilical vein endothelial cells, and impair angiogenesis in a mouse hind limb model. In this study, the role of SeP in ischemia/reperfusion (I/R) injury has been investigated. SeP knockout (KO) and littermate wild-type (WT) mice were subjected to 30 min of myocardial ischemia followed by 24 h of reperfusion. The myocardial infarct area/area at risk (IA/AAR), evaluated using Evans blue (EB) and 2,3,5-triphenyltetrazolium chloride (TTC) staining, was significantly smaller in SeP KO mice than in WT mice. The number of terminal de-oxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive nuclei was significantly lower in SeP KO mice than in WT mice. In addition, caspase-3 activation was reduced in SeP KO mice compared to that in WT mice. Furthermore, phosphoinositide 3-kinase/Akt and Erk levels were examined for the reperfusion injury salvage kinase (RISK) pathway. Interestingly, SeP KO significantly increased the phosphorylation of IGF-1, Akt, and Erk compared to that in WT mice after I/R. Finally, I/R-induced myocardial IA/AAR was significantly increased in SeP KO mice overexpressing SeP in the liver compared to other SeP KO mice. These results, together, suggest that inhibition of SeP protects the heart from I/R injury through upregulation of the RISK pathway.

Significant correlation between renal 123I-metaiodobenzylguanidine scintigraphy and muscle sympathetic nerve activity in patients with primary hypertension.

BACKGROUND: Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy is used as a noninvasive imaging method for assessing cardiac sympathetic nerve activity. We tested the hypothesis that renal 123I-MIBG imaging is correlated with muscle sympathetic nerve activity (MSNA) in patients with primary hypertension. METHODS: Thirty-one consecutive patients with primary hypertension were included. Multiunit MSNA was recorded from the peroneal nerve to evaluate direct efferent sympathetic nerve activity. Planar renal and cardiac 123I-MIBG images were acquired. Early and delayed kidney-to-mediastinum ratio (K/M), early and delayed heart-to-mediastinum ratio (H/M), and washout rates (WR) were calculated. RESULTS: In 27 of 31 patients, blood pressure was controlled on antihypertensive medication. Mean systolic and diastolic blood pressures were 118 ± 18 and 67 ± 15 mmHg, respectively. Although early and late K/M and H/M were not significantly correlated with MSNA, both cardiac and average renal WR were significantly correlated with MSNA (r = 0.45, P = .0035 and r = 0.68, P < .001, respectively). Right and left renal WR were similarly correlated with MSNA. Renal WR was significantly higher than cardiac WR (43.2% vs 25.8%, P < .001) in these patients with hypertension. CONCLUSIONS: Renal 123I-MIBG WR was significantly associated with multiunit MSNA. Renal 123I-MIBG imaging offers a noninvasive clinical methodology for assessing renal sympathetic nerve function.

General anesthesia improves contact force and reduces gap formation in pulmonary vein isolation: a comparison with conscious sedation.

Compared to conscious sedation (CS), the use of general anesthesia (GA) in pulmonary vein isolation (PVI) is associated with a lower recurrence rate of atrial fibrillation (AF). GA may improve catheter stability and mapping system accuracy compared to CS, but its influence on contact force (CF) parameters during ipsilateral PVI has not previously been investigated. The study population comprised 176 consecutive patients (107 in GA group and 69 in CS group) with AF who underwent their first PVI procedure. We retrospectively assessed CF parameters, force-time integral (FTI), FTI/wall thickness during anatomical ipsilateral PVI and long-term outcome after ablation. Complete PVI with single continuous circular lesions around the ipsilateral PVs was achieved in 54 patients (50.5%) in the GA group but only 24 patients (34.8%) in the CS group (P = 0.04). The distribution of gaps did not differ between the groups. All CF parameters were significantly higher in the GA group than in the CS group (average CF: 19.4 ± 8.7 vs. 16.7 ± 7.7 g, P < 0.0001; FTI: 399.0 ± 262.5 vs. 293.9 ± 193.4 gs, P < 0.0001; FTI/wall thickness: 155.5 ± 106.1 vs. 115.7 ± 85.5 gs, P < 0.0001). GA was associated with lower AF recurrence rate in patients with paroxysmal AF but not with persistent AF. Compared with CS, GA improves CF parameters, FTI and FTI/wall thickness, and reduced gap formation after ipsilateral PVI.

Augmented single-unit muscle sympathetic nerve activity in heart failure with chronic atrial fibrillation.

Atrial fibrillation (AF) is a common complication in heart failure (HF) patients. However, it remains unclear whether irregular ventricular response patterns induced by AF increase sympathetic nerve activity. We measured resting multi- and single-unit muscle sympathetic nerve activity (MSNA) in 21 age-matched HF patients with chronic AF (n = 11) rhythm or sinus rhythm (SR, n = 10). The multi-unit MSNA, which was expressed as total activity, was similar between HF + AF patients and HF + SR patients. However, the single-unit MSNA in HF + AF patients was significantly greater than that in HF + SR patients (62 ± 9 spikes min(-1) vs. 42 ± 4 spikes min(-1), P < 0.05). Moreover, the incidence of multiple firing of single-unit MSNA within a given burst was augmented in HF + AF patients as compared with HF + SR patients (48 ± 8% vs. 26 ± 3%, P < 0.01). A significant negative relationship was observed between the reduced diastolic pressure induced by a prolonged cardiac interval in AF subjects and single-unit MSNA frequency within one cardiac interval in each HF + AF subject. The firing characteristics of single-unit MSNA were different between HF patients with AF and HF patients with SR; particularly, those with a prolonged long RR interval showed multiple firings of single-unit MSNA. These findings suggest that AF per se leads to the instantaneous augmentation of single-unit MSNA induced by decreased diastolic pressure, which might partially contribute to disease progression in HF patients.

Circulating nerve growth factor receptor positive cells are associated with severity and prognosis of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) remains a disease with a poor prognosis, so early detection and treatment are very important. Sensitive and non-invasive markers for PAH are urgently required. This study was performed to identify sensitive markers of the clinical severity and prognosis of PAH. Patients diagnosed with PAH (n = 30) and control participants (n = 15) were enrolled in this observational study. Major EPC and MSC markers (including CD34, CD133, VEGFR2, CD90, PDGFRα, and NGFR) in peripheral blood mononuclear cells (PBMNCs) were assessed by flow cytometry. Associations of these markers with hemodynamic parameters (e.g. mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac index) were assessed. Patients with PAH were followed up for 12 months to assess the incidence of major adverse events, defined as death or lung transplantation. Levels of circulating EPC and MSC markers in PBMNCs were higher in patients with PAH than in control participants. Among the studied markers, nerve growth factor receptor (NGFR) was significantly positively correlated with hemodynamic parameters. During the 12-month follow-up period, major-event-free survival was significantly higher in patients with PAH who had relatively low frequencies of NGFR positive cells than patients who had higher frequencies. These results suggested that the presence of circulating NGFR positive cells among PBMNCs may be a novel biomarker for the severity and prognosis of PAH.

Renal iodine123-metaiodobenzylguanidine scintigraphy relates to muscle sympathetic nervous activity in heart failure with reduced ejection fraction.

BACKGROUND: Renal denervation is effective for modulating augmented sympathetic nerve activity (SNA) in heart failure with reduced ejection fraction (HFrEF). We have demonstrated that renal iodine123-metaiodobenzylguanidine (123I-MIBG) scintigraphy is associated with muscle sympathetic nerve activity (MSNA) in patients with hypertension. However, it is unclear whether renal 123I-MIBG scintigraphy is useful for assessment of SNA in HFrEF. METHODS: The study population consisted of 24 HFrEF patients and 11 healthy subjects as controls. Patients with HFrEF underwent 123I-MIBG scintigraphy and hemodynamics using a Swan-Ganz catheter (SGC). HFrEF was defined as echocardiography with left ventricular ejection fraction (LVEF) < 50%. MSNA was measured from the peroneal nerve for direct evaluation of SNA. Renal 123I-MIBG scintigraphy was performed simultaneously with cardiac scintigraphy. The early and delayed kidney-to-mediastinum ratio (K/M), early and delayed heart-to-mediastinum ratio (H/M), and washout rate (WR) were calculated. RESULTS: LVEFs were 35% ± 11% in patients with HFrEF and 63% ± 10% in the controls (p < 0.01). The WR of cardiac 123I-MIBG showed no relation to MSNA, but was related to stroke volume (r = 0.45, p < 0.05). In contrast, the WR of renal 123I-MIBG scintigraphy (average of both sides) showed a strong correlation with MSNA (BI, r = 0.70, p < 0.01; BF, r = 0.66, p < 0.01); however, no significant correlations were detected between renal 123I-MIBG scintigraphy and SGC results. CONCLUSIONS: The WR of renal 123I-MIBG scintigraphy may reflect MSNA. Further studies are needed to clarify the relationship between renal 123I-MIBG imaging and renal SNA.

A case of pulmonary arterial hypertension with chronic hepatitis that resulted in hepatosplenomegaly after administration of prostaglandin I2.

The prognosis of pulmonary arterial hypertension (PAH) has significantly improved over the past two decades due to advances in medications, including pulmonary vasodilators. However, the side effects of these drugs remain problematic in some patients. A 51-year-old woman with chronic hepatitis C was diagnosed with PAH 7 years before presenting to our hospital. She was unable to continue her treatment with pulmonary vasodilators due to various side effects. She had a World Health Organization functional class of IV and was started on continuous infusion of prostaglandin I2 (PGI2). This therapy improved her symptoms, including dyspnea and fatigue. However, she began to complain of abdominal distension after 4 months of PGI2 therapy. Computed tomography showed significant hepatosplenomegaly. Her abdominal distension improved slightly after decreasing PGI2 treatment, but her dyspnea on exertion was exacerbated. She died 12 years after diagnosis of PAH due to uncontrollable heart failure. Here, we describe a rare case of PAH with hepatosplenomegaly after administration of PGI2. .

Different prognosis between severe and very severe obstructive sleep apnea patients; Five year outcomes.

BACKGROUND: Obstructive sleep apnea (OSA) is characterized by augmented sympathetic nerve activity. In our previous study, patients with OSA and an apnea-hyperpnea index (AHI)>55events/h showed increased single-unit muscle sympathetic nerve activity compared to patients with OSA and AHI of 30-55events/h. However, the prognostic impact in these patients remains unclear. METHODS: Ninety-one OSA patients were included. All patients who had indication for continuous positive airway pressure (CPAP) were treated with CPAP. Patients were divided into three groups: mild/moderate OSA (S), AHI<30events/h (n=44); severe OSA (SS), AHI 30-55events/h (n=29); and very severe OSA (VSS), AHI>55events/h (n=18). The primary endpoint was a composite outcome composed of death, cardiovascular events, stroke, and heart failure with hospitalization. RESULTS: In the 5-year follow-up, the primary event rate in the SS group [3 events (7%)] was the same as that in the S group [3 events (10%)]. However, the VSS group showed a significantly higher primary event rate among the three groups [6 events (33%), p<0.05]. In Cox regression analysis, the VSS group had the highest hazard ratio compared to other risk factors. CONCLUSIONS: CPAP was effective for preventing cardiovascular disease in patients with severe OSA, however patients with very severe OSA still had a high event rate, indicating that CPAP treatment might be insufficient to reduce the OSA-related risk burden in patients with very severe OSA. Additional systemic medical treatment for CPAP might be needed in patients with very severe OSA.

Hokuriku-plus familial hypercholesterolaemia registry study: rationale and study design.

INTRODUCTION: Familial hypercholesterolaemia (FH) is an autosomal-dominant inherited genetic disease. It carries an extremely high cardiovascular risk associated with significantly elevated low-density lipoprotein (LDL) cholesterol. The diagnostic rate of this disease in some European nations is quite high, due to the presence of multiple prospective registries. On the other hand, few data-and in particular multicentre data-exist regarding this issue among Japanese subjects. Therefore, this study intends to assemble a multicentre registry that aims to comprehensively assess cardiovascular risk among Japanese FH patients while taking into account their genetic backgrounds. METHODS AND ANALYSIS: The Hokuriku-plus FH registry is a prospective, observational, multicentre cohort study, enrolling consecutive FH patients who fulfil the clinical criteria of FH in Japan from 37 participating hospitals mostly in Hokuriku region of Japan from April 2020 to March 2024. A total of 1000 patients will be enrolled into the study, and we plan to follow-up participants over 5 years. We will collect clinical parameters, including lipids, physical findings, genetic backgrounds and clinical events covering atherosclerotic and other important events, such as malignancies. The primary endpoint of this study is new atherosclerotic cardiovascular disease (ASCVD) events. The secondary endpoints are as follows: LDL cholesterol, secondary ASCVD events and the occurrence of other diseases including hypertension, diabetes and malignancies. ETHICS AND DISSEMINATION: This study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. This study protocol has been approved by the Institutional Review Board at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000038210.

G12/13 and Gq mediate S1P2-induced inhibition of Rac and migration in vascular smooth muscle in a manner dependent on Rho but not Rho kinase.

AIMS: The lysophospholipid mediator sphingosine-1-phosphate (S1P) activates G protein-coupled receptors (GPCRs) to induce potent inhibition of platelet-derived growth factor (PDGF)-induced Rac activation and, thereby, chemotaxis in rat vascular smooth muscle cells (VSMCs). We explored the heterotrimeric G protein and the downstream mechanism that mediated S1P inhibition of Rac and cell migration in VSMCs. METHODS AND RESULTS: S1P inhibition of PDGF-induced cell migration and Rac activation in VSMCs was abolished by the selective S1P(2) receptor antagonist JTE-013. The C-terminal peptides of Galpha subunits (Galpha-CTs) act as specific inhibitors of respective G protein-GPCR coupling. Adenovirus-mediated expression of Galpha(12)-CT, Galpha(13)-CT, and Galpha(q)-CT, but not that of Galpha(s)-CT or LacZ or pertussis toxin treatment, abrogated S1P inhibition of PDGF-induced Rac activation and migration, indicating that both G(12/13) and G(q) classes are necessary for the S1P inhibition. The expression of Galpha(q)-CT as well as Galpha(12)-CT and Galpha(13)-CT also abolished S1P-induced Rho stimulation. C3 toxin, but not a Rho kinase inhibitor or a dominant negative form of Rho kinase, abolished S1P inhibition of PDGF-induced Rac activation and cell migration. The angiotensin II receptor AT(1), which robustly couples to G(q), did not mediate either Rho activation or inhibition of PDGF-induced Rac activation or migration, suggesting that activation of G(q) alone was not sufficient for Rho activation and resultant Rac inhibition. However, the AT(1) receptor fused to Galpha(12) was able to induce not only Rho stimulation but also inhibition of PDGF-induced Rac activation and migration. Phospholipase C inhibition did not affect S1P-induced Rho activation, and protein kinase C activation by a phorbol ester did not mimic S1P action, suggesting that S1P inhibition of migration or Rac was not dependent on the phospholipase C pathway. CONCLUSION: These observations together suggest that S1P(2) mediates inhibition of Rac and migration through the coordinated action of G(12/13) and G(q) for Rho activation in VSMCs.

Differential effects of lipophilic and hydrophilic statins on muscle sympathetic nerve activity in heart failure with preserved left ventricular ejection fraction.

Augmented sympathetic nerve activity is associated with heart failure with preserved left ventricular ejection fraction (HFpEF). Lipophilic statins reduce sympathetic nerve activity in patients with heart failure with reduced left ventricular ejection fraction. However, little is known about whether all types of statins, regardless of solubility, reduce sympathetic nerve activity in HFpEF. We evaluated the effect of atorvastatin, a lipophilic statin, and rosuvastatin, a hydrophilic statin, on muscle sympathetic nerve activity (MSNA) in HFpEF patients. This study was conducted as a prospective, randomized, open-label, crossover trial. Ten HFpEF patients with untreated hyperlipidemia participated in this study. Subjects were assigned to either the atorvastatin (lipophilic) or the rosuvastatin (hydrophilic) group with each drug administered for 8 weeks. Atorvastatin and rosuvastatin treatment resulted in a similar reduction in low-density lipoprotein cholesterol (LDL-C) levels. There was no difference in the effect of either treatment on blood pressure, heart rate, or left ventricular function. Atorvastatin significantly decreased MSNA frequency compared with baseline (31.5 ±â€¯6.3 vs. 47.5 ±â€¯10.7 bursts/min, p < 0.01), but rosuvastatin had no effect on MSNA (40.9 ±â€¯7.3 bursts/min). MSNA was significantly lower in the atorvastatin group than rosuvastatin group (p < 0.05). However, the reduction in MSNA seen in either group did not correlate with the reduction in LDL-C. No significant differences were observed in either the baroreflex control of heart rate or MSNA between the two groups. These results suggest that lipophilic statins have a favorable effect on sympathetic nerve activity beyond lowering LDL-C in HFpEF, but hydrophilic statins do not.