Performance of heart rate adjusted heart rate variability for risk stratification of sudden cardiac death.

PURPOSE: As a non-invasive tool for the assessment of cardiovascular autonomic function, the predictive value of heart rate variability (HRV) for sudden cardiac death (SCD) risk stratification remains unclear. In this study, we investigated the performance of the individualized heart rate (HR) adjusted HRV (HRVI) for SCD risk stratification in subjects with diverse risks. METHODS: A total of 11 commonly used HRV metrics were analyzed in 192 subjects, including 88 healthy controls (low risk group), 82 hypertrophic cardiomyopathy (HCM) patients (medium risk group), and 22 SCD victims (high risk group). The relationship between HRV metrics and HR was examined with long-term and short-term analysis. The performance HRVI was evaluated by area under the receiver operating characteristic curve (AUC) and covariance of variation (CV). RESULTS: Most of the HRV metrics were exponentially decayed with the increase of HR, while the exponential power coefficients were significantly different among groups. The HRVI metrics discriminated low, medium and high risk subjects with a median AUC of 0.72[0.11], which was considerably higher than that of the traditional long-term (0.63[0.04]) and short-term (0.58[0.05]) HRV without adjustment. The average CV of the HRVI metrics was also significantly lower than traditional short-term HRV metrics (0.09 ± 0.02 vs. 0.24 ± 0.13, p < 0.01). CONCLUSIONS: Subjects with diverse risks of SCD had similar exponential decay relationship between HRV metrics and HR, but with different decaying rates. HRVI provides reliable and robust estimation for risk stratification of SCD.

Tailored Interventions to Improve Medication Adherence for Cardiovascular Diseases.

Over the past half-century, medical research on cardiovascular disease (CVD) has achieved a great deal; however, medication adherence is unsatisfactory. Nearly 50% of patients do not follow prescriptions when taking medications, which limits the ability to maximize their therapeutic effects and results in adverse clinical outcomes and high healthcare costs. Furthermore, the effects of medication adherence interventions are disappointing, and tailored interventions have been proposed as an appropriate way to improve medication adherence. To rethink and reconstruct methods of improving medication adherence for CVD, the literature on tailored interventions for medication adherence focusing on CVD within the last 5 years is retrieved and reviewed. Focusing on identifying nonadherent patients, detecting barriers to medication adherence, delivering clinical interventions, and constructing theories, this article reviews the present state of tailored interventions for medication adherence in CVD and also rethinks the present difficulties and suggests avenues for future development.

Stimulation of ß-adrenoceptors up-regulates cardiac expression of galectin-3 and BIM through the Hippo signalling pathway.

BACKGROUND AND PURPOSE: Expression of the pro-fibrotic galectin-3 and the pro-apoptotic BIM is elevated in diseased heart or after ß-adrenoceptor stimulation, but the underlying mechanisms are unclear. This question was addressed in the present study. EXPERIMENTAL APPROACH: Wild-type mice and mice with cardiac transgenic expression of ß2 -adrenoceptors, mammalian sterile-20 like kinase 1 (Mst1) or dominant-negative Mst1, and non-specific galectin-3 knockout mice were used. Effects of the ß-adrenoceptor agonist isoprenaline or ß-adrenoceptor antagonists were studied. Rat cardiomyoblasts (H9c2) were used for mechanistic exploration. Biochemical assays were performed. KEY RESULTS: Isoprenaline treatment up-regulated expression of galectin-3 and BIM, and this was inhibited by non-selective or selective ß-adrenoceptor antagonists (by 60-70%). Cardiac expression of galectin-3 and BIM was increased in ß2 -adrenoceptor transgenic mice. Isoprenaline-induced up-regulation of galectin-3 and BIM was attenuated by Mst1 inactivation, but isoprenaline-induced galectin-3 expression was exaggerated by transgenic Mst1 activation. Pharmacological or genetic activation of ß-adrenoceptors induced Mst1 expression and yes-associated protein (YAP) phosphorylation. YAP hyper-phosphorylation was also evident in Mst1 transgenic hearts with up-regulated expression of galectin-3 (40-fold) and BIM as well as up-regulation of many YAP-target genes by RNA sequencing. In H9c2 cells, isoprenaline induced YAP phosphorylation and expression of galectin-3 and BIM, effects simulated by forskolin but abolished by PKA inhibitors, and YAP knockdown induced expression of galectin-3 and BIM. CONCLUSIONS AND IMPLICATIONS: Stimulation of cardiac ß-adrenoceptors activated the Mst1/Hippo pathway leading to YAP hyper-phosphorylation with enhanced expression of galectin-3 and BIM. This signalling pathway would have therapeutic potential. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.

Activation of the STAT3/microRNA-21 pathway participates in angiotensin II-induced angiogenesis.

Angiotensin II (AngII) facilitates angiogenesis that is associated with the continuous progression of atherosclerotic plaques, but the underlying mechanisms are still not fully understood. Several microRNAs (miRNAs) have been shown to promote angiogenesis; however, whether miRNAs play a crucial role in AngII-induced angiogenesis remains unclear. This study evaluated the functional involvement of miRNA-21 (miR-21) in the AngII-mediated proangiogenic response in human microvascular endothelial cells (HMECs). We found that AngII exerted a proangiogenic role, indicated by the promotion of proliferation, migration, and tube formation in HMECs. Next, miR-21 was found to be upregulated in AngII-treated HMECs, and its specific inhibitor potently blocked the proangiogenic effects of AngII. Subsequently, we focused on the constitutive activation of STAT3 in the AngII-mediated proangiogenic process. Bioinformatic analysis indicated that STAT3 acted as a transcription factor initiating miR-21 expression, which was verified by ChIP-PCR. A reporter assay further identified three functional binding sites of STAT3 in the miR-21 promoter region. Moreover, phosphatase and tensin homolog (PTEN) was recognized as a target of miR-21, and STAT3 inhibition restored AngII-induced reduction in PTEN. Similarly, the STAT3/miR-21 axis was shown to mediate AngII-provoked angiogenesis in vivo, which was demonstrated by using the appropriate inhibitors. Our data suggest that AngII was involved in proangiogenic responses through miR-21 upregulation and reduced PTEN expression, which was, at least in part, linked to STAT3 signaling. The present study provides novel insights into AngII-induced angiogenesis and suggests potential treatment strategies for attenuating the progression of atherosclerotic lesions and preventing atherosclerosis complications.

Celastrol alleviates angiotensin II­mediated vascular smooth muscle cell senescence via induction of autophagy.

Reactive oxygen species (ROS) production has been implicated in the promotion of cellular senescence. Celastrol, a quinone methide triterpenoid isolated from the Celastraceae family, exerts antioxidant effects and enhances autophagy in various cell types. Since autophagy serves an important role in regulating ROS, it was hypothesized that the antioxidant effect of celastrol is via enhanced autophagy, thus inhibiting cell senescence. Therefore, the present study used a Senescence ß­Galactosidase Staining kit, western blot analysis and cell cycle analysis to investigate whether celastrol alleviates angiotensin (Ang) II­induced cellular senescence by upregulating autophagy in vascular smooth muscle cells (VSMCs). The results demonstrated that celastrol reduced Ang II­induced senescence of VSMCs. Ang II­induced generation of ROS and the subsequent VSMC senescence were counteracted by pretreatment with celastrol, determined by a ROS assay kit. Celastrol significantly upregulated VSMC autophagy, which reduced intracellular ROS and the subsequent cellular senescence induced by Ang II. Furthermore, celastrol markedly suppressed activity of the mechanistic target of rapamycin signaling pathway in VSMCs. In conclusion, the present study demonstrated that celastrol counteracts VSMC senescence probably by reducing ROS production via activation of autophagy, which may hold promise for the prevention and treatment of aging­associated cardiovascular disorders such as atherosclerosis.

Roles of High Mobility Group Box 1 in Cardiovascular Calcification.

Calcific disease of the cardiovascular system, including atherosclerotic calcification, medial calcification in diabetes and calcific aortic valve disease, is an important risk factor for many adverse cardiovascular events such as ischemic cardiac events and subsequent mortality. Although cardiovascular calcification has long been considered to be a passive degenerative occurrence, it is now recognized as an active and highly regulated process that involves osteochondrogenic differentiation, apoptosis and extracellular vesicle release. Nonetheless, despite numerous studies on the pathogenesis of cardiovascular calcification, the underlying mechanisms remain poorly understood. High mobility group box 1 (HMGB1), a nuclear protein bound to chromatin in almost all eukaryotic cells, acts as a damage-associated molecular pattern (DAMP) when released into the extracellular space upon cell activation, injury or death. Moreover, HMGB1 also functions as a bone-active cytokine participating in bone remodeling and ectopic calcification pathogenesis. However, studies on the roles of HMGB1 in promoting cardiovascular calcification are limited to date, and the mechanisms involved are still unclear. In this review, we summarize recent studies investigating the mechanism of cardiovascular calcification and discuss multiple roles of HMGB1 in its development.

Up-Regulated Expression of Matrix Metalloproteinases in Endothelial Cells Mediates Platelet Microvesicle-Induced Angiogenesis.

BACKGROUND/AIMS: Platelet microvesicles (PMVs) contribute to angiogenesis and vasculogenesis, but the mechanisms underlying these contributions have not been fully elucidated. In the present study, we investigated whether PMVs regulate the angiogenic properties of endothelial cells (ECs) via mechanisms extending beyond the transport of angiogenic regulators from platelets. METHODS: In vitro Matrigel tube formation assay and in vivo Matrigel plug assay were used to evaluate the pro-angiogenic activity of PMVs. The effects of PMVs on the migration of human umbilical vein endothelial cells (HUVECs) were detected by transwell assay and wound-healing assay. Real-time PCR and western blot were conducted to examine mRNA and protein expression of pro-angiogenic factors in HUVECs. Matrix metalloproteinase (MMP) activity was assayed by gelatin zymography. Moreover, the effects of specific MMP inhibitors were tested. RESULTS: PMVs promoted HUVEC capillary-like network formation in a dose-dependent manner. Meanwhile, PMVs dose-dependently facilitated HUVEC migration. Levels of MMP-2 and MMP-9 expression and activity were up-regulated in HUVECs stimulated with PMVs. Inhibition of MMPs decreased their pro-angiogenic and pro-migratory effects on HUVECs. Moreover, we confirmed the pro-angiogenic activity of PMVs in vivo in mice with subcutaneous implantation of Matrigel, and demonstrated that blockade of MMPs attenuated PMV-induced angiogenesis. CONCLUSION: The findings of our study indicate that PMVs promote angiogenesis by up-regulating MMP expression in ECs via mechanism extending beyond the direct delivery of angiogenic factors.

HMGB1 Induces Secretion of Matrix Vesicles by Macrophages to Enhance Ectopic Mineralization.

Numerous clinical conditions have been linked to ectopic mineralization (EM). This process of pathological biomineralization is complex and not fully elucidated, but thought to be started within matrix vesicles (MVs). We hypothesized that high mobility group box 1 (HMGB1), a cytokine associated with biomineralizing process under physiological and pathological conditions, induces EM via promoting MVs secretion from macrophages. In this study, we found that HMGB1 significantly promoted secretion of MVs from macrophages and subsequently led to mineral deposition in elevated Ca/Pi medium in vitro. Transmission electron microscopy of calcifying MVs showed formation of hydroxyapatite crystals in the vesicle interior. Subcutaneous injection into mice with MVs derived from HMGB1-treated cells showed a greater potential to initiate regional mineralization. Mechanistic experiments revealed that HMGB1 activated neutral sphingomyelinase2 (nSMase2) that involved the receptor for advanced glycation end products (RAGE) and p38 MAPK (upstream of nSMase2). Inhibition of nSMase2 with GW4869 or p38 MAPK with SB-239063 prevented MVs secretion and mineral deposition. Collectively, HMGB1 induces MVs secretion from macrophages at least in part, via the RAGE/p38 MAPK/nSMase2 signaling pathway. Our findings thus reveal a novel mechanism by which HMGB1 induces ectopic mineralization.

Higher Plasma Concentrations of Platelet Microparticles in Patients With Acute Coronary Syndrome: A Systematic Review and Meta-analysis.

BACKGROUND: Platelet microparticles (PMP), shedding on platelet activation, have been proposed as key components in the procoagulant and proinflammatory process. The aim of this study was to clarify the correlation between plasma PMP concentration and the presence of acute coronary syndrome (ACS). METHODS: We searched for potential relevant studies in PubMed, EMBASE, the Cochrane Library, and Web of Science databases before December 2015. After screening for eligibility, 11 observational studies that tested the plasma concentration of PMP in patients with ACS were retrieved for comprehensive review, quality assessment, and data extraction. RESULTS: Seven studies (64%) provided explicit information between healthy controls and patients with ACS. Five studies (45%) addressed the plasma levels of PMP between patients with ACS and patients with stable angina. Moreover, 5 studies (45%) compared changes in PMP concentration before and after percutaneous coronary intervention (PCI) in patients with ACS. The results showed a significant difference in plasma PMP levels between the patients with ACS and healthy controls, with the pooled standardized mean difference of 1.95 (95% confidence intervals, 0.87-3.02; P < 0.0001). And the plasma concentration of PMP in patients with ACS was higher before PCI than after PCI (standardized mean difference, -0.97; 95% confidence interval, -1.91 to -0.03; P = 0.043). Four of the five studies described that patients with ACS had higher plasma PMP concentration than patients with stable angina, but there was no significant difference between these 2 patient cohorts. CONCLUSIONS: PMP is a promising biomarker for the development of ACS. Moreover, PCI, the most common treatment for ACS, could effectively decrease the plasma concentration of PMP, indicating PMP as a prognostic factor.

Staphylococcal SSL5-induced platelet microparticles provoke proinflammatory responses via the CD40/TRAF6/NFκB signalling pathway in monocytes.

Pathogens-induced platelet activation contributes to inflammation in cardiovascular diseases, but underlying mechanisms remain elusive. Staphylococcal superantigen-like protein 5 (SSL5) is a known activator of platelets. Here we examined whether SSL5 is implicated in Staphylococcus aureus (S. aureus)-induced inflammation and potential mechanisms involved. As expected, we show that SSL5 activates human platelets and induces generation of platelet microparticles (PMPs). Flow cytometry and scanning electron microscopy studies demonstrate that SSL5-induced PMPs (SSL5-PMPs) bind to monocytes, causing aggregate formation. In addition, SSL5-PMPs provoke monocyte expression and release of inflammatory mediators, including interleukin-1ß (IL-1ß), tumour necrosis factor-α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) in a dose- and time-dependent manner. SSL5-PMPs also enhance MCP-1-induced monocyte migration. Blockade of CD40 and CD40 ligand (CD40L) interactions with neutralising antibodies significantly reduce monocyte release of inflammatory mediators and migration induced by SSL5-PMPs. SiRNA-mediated silencing of CD40 or TNF receptor (TNFR)-associated factor 6 (TRAF6) gene largely abrogates phosphorylation and nuclear translocation of NFκB (p65). In conclusion, SSL5 provokes the release of inflammatory mediators in monocytes, at least in part, via PMPs-mediated activation of the CD40/TRAF6/NFκB signalling pathway, though it normally inhibits leukocyte function. Our findings thus reveal a novel mechanism by which S. aureus induces inflammation.

Clinical efficiency and safety analysis of transcatheter closure of multiple atrial septal defects in adults.

BACKGROUND: Transcatheter closure of atrial septal defects (ASDs) is currently a reliable alternative to surgery, even though challenging in patients with multiple ASDs. HYPOTHESIS: The aim of this study was to evaluate the clinical efficiency and safety of transcatheter closure in multiple ASDs. METHODS: Multiple ASDs were diagnosed by transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE). The occlusive condition and distance between 2 adjacent ASDs were measured by TTE examination. Then, the number and size of the occluder(s) was determined. TTE examinations were performed after transcatheter closure as follow-up. RESULTS: The transcatheter procedure was successful in 15 patients with multiple ASDs, using a single occluder in 9 patients and 2 occluders in the remaining 6 patients. Overall, 21 ASD occluders were implanted. During a follow-up period of 6 mo to 5 y, a slight residual shunt was found in 1 patient without any symptoms; a moderate residual shunt was identified at the inferior vena cava and the occluder was removed by surgery 1 mo after procedure. Other complications, including endocarditis, arrhythmia, thromboembolism, and atrioventricular valve damage were not recorded in any of the 15 patients during the follow-up period. CONCLUSION: Transcatheter closure of multiple ASDs is safe and efficient. Two occluders are necessary for the distance of 2 ASDs more than 7 mm, and a single occluder is sufficient for those 7 mm or less.

Clinical efficiency and safety analysis of transcatheter interventional therapy for compound congenital cardiovascular abnormalities.

OBJECTIVE: To investigate the efficiency and safety of transcatheter interventional therapy for compound congenital cardiovascular abnormalities. METHODS: From Nov 2001 to Jun 2006, a total of 36 patients (17 male, 19 female), aged 17.20 +/- 10.52, with compound congenital cardiovascular abnormalities underwent transcatheter interventional procedure. These patients included 11 with perimembranous ventricular septal defect (PVSD) and patent ductus arteriosus (PDA), 8 patients with PVSD and atrial septal defect (ASD), 8 patients with ASD and PDA, 7 patients with ASD and pulmonary stenosis (PS), 1 patient with ASD and mitral stenosis(MS), 1 patient with coarctation of aorta (COA) and PDA. According to the principle of "easy first, hard second," balloon valvuloplasties of PS or MS were performed before the closure of PVSD, and of PDA and ASD. Electrocardiogram and transthoracic echocardiogram were examined at 4 days, 1, 2, 6 and 12 months, respectively, after each procedure. RESULTS: Transcatheter interventional therapy for compound congenital cardiovascular abnormalities was successful in all patients. Among these, 2 occluders were planted in each of 27 patients, 7 patients with ASD combined with PS and 1 patient with ASD combined with MS underwent successfully performed balloon valvuloplasty and ASD closure, 1 patient with COA combined with PDA underwent successfully performed balloon valvuloplasty and subsequent covered stent implantation. No patient encountered serious adverse events during the (30.5 +/- 14.6) months of follow-up. CONCLUSIONS: Transcatheter interventional therapy for compound congenital cardiovascular abnormalities could obtain satisfactory results with technical feasibility.