Neil Ruparelia

Anti-Inflammatory Effects of Nicotinic Acid in Human Monocytes Are Mediated by GPR109A Dependent Mechanisms

Objective—Nicotinic acid (NA) treatment has been associated with benefits in atherosclerosis that are usually attributed to effects on plasma lipoproteins. The NA receptor GPR109A is expressed in monocytes and macrophages, suggesting a possible additional role for NA in modulating function of these immune cells. We hypothesize that NA has the potential to act directly on monocytes to alter mediators of inflammation that may contribute to its antiatherogenic effects in vivo. Methods and Results—In human monocytes activated by Toll-like receptor (TLR)-4 agonist lipopolysaccharide, NA reduced secretion of proinflammatory mediators: TNF-&agr; (by 49.2±4.5%); interleukin-6 (by 56.2±2.8%), and monocyte chemoattractant protein-1 (by 43.2±3.1%) (P<0.01). In TLR2 agonist, heat-killed Listeria monocytogenes-activated human monocytes, NA reduced secretion of TNF-&agr; (by 48.6±7.1%), interleukin-6 (by 60.9±1.6%), and monocyte chemoattractant protein-1 (by 59.3±5.3%) (P<0.01; n=7). Knockdown of GPR109A by siRNA resulted in a loss of this anti-inflammatory effect in THP-1 monocytes. However, inhibition of prostaglandin D2 receptor by MK0524 or COX2 by NS398 did not alter the anti-inflammatory effects of NA observed in activated human monocytes. Preincubation of THP-1 monocytes with NA 0.1 mmol/L reduced phosphorylated IKK&bgr; by 42±2% (P<0.001) IKB-&agr; by 54±14% (P<0.01). Accumulation of nuclear p65 NF-&kgr;B in response to lipopolysaccharide treatment was also profoundly inhibited, by 89±1.3% (n=4; P<0.01). NA potently inhibited monocyte adhesion to activated HUVEC, and VCAM, mediated by the integrin, very late antigen 4. Monocyte chemotaxis was also significantly reduced (by 45.7±1.2%; P<0.001). Conclusion—NA displays a range of effects that are lipoprotein-independent and potentially antiatherogenic. These effects are mediated by GPR109A and are independent of prostaglandin pathways. They suggest a rationale for treatment with NA that is not dependent on levels of plasma cholesterol and possible applications beyond the treatment of dyslipidemia.

A leukocyte-mimetic magnetic resonance imaging contrast agent homes rapidly to activated endothelium and tracks with atherosclerotic lesion macrophage content.

Objective—Endothelial cell activation is an important mediator of monocyte recruitment to sites of vascular inflammation. We hypothesized that high-affinity dual-ligand microparticles of iron oxide (MPIO), targeted to P-selectin and vascular cell adhesion molecule-1 (PV-MPIO), would identify activated endothelial cells during atherosclerosis progression. Methods and Results—In vivo magnetic resonance imaging in apolipoprotein E-deficient mice showed rapid binding of PV-MPIO to the aortic root, which was maximal 30 minutes post-MPIO injection and maintained at 60 minutes. Minimal binding was observed for control IgG-MPIO. Intensely low magnetic resonance signal areas, corresponding to PV-MPIO binding, were detected early (14 weeks), during foam cell formation. Contrast effects increased at 20 weeks during fibrofatty lesion development (P<0.05), but reduced by 30 weeks (P<0.01). Across all lesion severities, magnetic resonance imaging contrast effects correlated with lesion macrophage area quantified by immunohistochemistry (R=0.53; P<0.01). Near-infrared fluorescently labeled PV-MPIO were shown, by flow cytometry, to bind only activated endothelial cells and not to macrophages. Using en face immunofluorescence, we further demonstrate selective PV-MPIO accumulation at atherosclerosis-susceptible sites, with minimal binding to atherosclerosis-spared regions. Conclusion—This high-affinity leukocyte-mimetic magnetic resonance imaging agent reveals endothelial activation. PV-MPIO demonstrate exceptionally rapid in vivo steady state accumulation, providing conspicuous magnetic resonance contrast effects that can be objectively quantified. In atherosclerosis progression, PV-MPIO tracked closely with the burden and distribution of plaque macrophages, not merely plaque size. On a biocompatible platform, this approach has potential for quantitative magnetic resonance imaging of inflammatory disease activity.

Niacin in Cardiovascular Disease: Recent Preclinical and Clinical Developments

Niacin has been used for more than 50 years in the treatment of cardiovascular disease, although its use has largely been superseded by better-tolerated lipid-modulating interventions. There has been a renewed interest in the HDL-cholesterol raising properties of niacin, with the appreciation that substantial cardiovascular risk remains despite effective treatment of LDL-cholesterol. This coincides with increasing evidence that the complex functional properties of HDL are not well reflected by measurement of HDL-cholesterol alone. In addition to favorable actions on lipoproteins, it is becoming apparent that niacin may also possess lipoprotein independent or pleiotropic effects including the inhibition of inflammatory pathways mediated by its receptor GPR109A, which is expressed by adipocytes and some leukocytes. In this article we consider emerging and prior clinical trial data relating to niacin. We review recent data in respect of mechanisms of action on lipoproteins, which remain complex and incompletely understood. We discuss the recent reports of anti-inflammatory effects of niacin in adipocytes and through bone marrow derived cells and vascular endothelium. These novel observations come at an interesting time, with current imaging and outcome studies leaving outstanding questions on niacin efficacy in statin-treated patients.

Acute myocardial infarction activates distinct inflammation and proliferation pathways in circulating monocytes, prior to recruitment, and identified through conserved transcriptional responses in mice and humans

The immune system plays critical roles in myocardial injury and repair following acute myocardial infarction (AMI). Evidence from experimental models strongly implicates monocytes as critical to these processes and their specific targeting results in a significant reduction in infarct size and improved healing. It is currently unclear if monocytes play a similarly important role in humans. Examining changes in the patterns of gene expression can address this question. Here, we show that the peripheral blood monocyte response following AMI is conserved between species and that monocytes appear to be ‘programmed’ prior to their arrival at sites of myocardial injury. This investigation may translate to the future development of therapeutics to treat patients presenting with AMI that importantly would be effective in the hours after the onset of ischaemia.

Perioperative Management of Anticoagulation during Device Implantation—The UK Perspective

Background:  Increasing numbers of patients taking oral anticoagulation are presenting for device implantation. Cessation of anticoagulation in the perioperative period may expose patients to increased risk of thromboembolic events, while continuing anticoagulation may increase the risk of bleeding. There are few guidelines or randomized controlled trials to guide perioperative management.

Who Is Thrombogenic: The Scaffold or the Doctor? Back to the Future!

Twenty years ago, Drs. Patrick Serruys and Carlo Di Mario wrote an editorial in Circulation titled “Who Was Thrombogenic: The Stent or the Doctor?” [(1)][1], that discussed optimal stent implantation technique. They highlighted the critical roles played by both the use of intravascular

Effects of niacin on atherosclerosis and vascular function

Purpose of review Niacin has been used for more than 50 years in the management of atherosclerosis and is associated with improved patient outcomes. The routine use of niacin has been superseded in recent years with the advent of newer lipid-modulating interventions. Recently, however, there has been a renewed interest in its use due to the appreciation of its many beneficial effects on atherosclerosis and endothelial function, both ‘lipid-targeted’ and ‘pleiotropic’. This review will consider the effects of niacin in the setting of clinical trials and will critically evaluate proposed mechanisms of action. Recent findings The identification of the GPR109A receptor has promoted a greater insight into niacins mechanism of action, with demonstrated beneficial effects on endothelial function and inflammation, in addition to its lipid modulation role. Summary Whether niacin itself is used routinely in the future will depend on the outcomes of two large outcome trials (AIM-HIGH and HPS2-THRIVE). In the future, however, with even better understanding of niacin pharmacology, new drugs may be able to be engineered to capture aspects of niacin that capitalize on the benefits more specifically and also more selectively, to avoid troublesome side-effects.

Clinical outcomes following bioresorbable scaffold implantation for bifurcation lesions: Overall outcomes and comparison between provisional and planned double stenting strategy

The aim of this study was to investigate clinical outcomes of patients treated with a provisional stenting (PS) versus a double stenting (DS) strategy for coronary bifurcation lesions with bioresorbable scaffolds (BRS). There are limited data available with regards to outcomes following BRS implantation for bifurcation lesions. A total of 132 bifurcation lesions treated with BRS between 2012 and 2014 were analyzed. Of the total of 132 bifurcation lesions, 10 lesions were treated without crossover stenting. 99 lesions (81%) were treated with a PS strategy and 23 lesions (19%) with a DS strategy. The DS group consisted of patients with a greater number of true bifurcation lesions (PS 52.0% vs. DS 91.3%: P < 0.001). In the PS group, seven lesions (7.1%) were crossed‐over to T‐stenting. In the DS group, 13 lesions (57%) were treated with BRS to the side branch (SB). A hybrid stenting technique [BRS to the main branch, and metallic drug‐eluting stent (DES) to the SB] was utilized in 10 (43%) lesions. Target lesion revascularization (TLR) rates were 5.5% for PS and 11.2% for DS (P = 0.49) at 1‐year follow‐up. Definite scaffold thrombosis did not occur at the site of any bifurcation lesion. These findings suggest that BRS implantation for bifurcation lesions is technically feasible. The rates of TLR tended to be higher in the DS group compared to when a PS strategy was employed. Larger studies are eagerly awaited to determine longer‐term follow‐up of this treatment strategy.

Transfemoral Implantation of a Fully Repositionable and Retrievable Transcatheter Valve for Noncalcified Pure Aortic Regurgitation.

OBJECTIVES This study sought to evaluate the use of the Direct Flow Medical (DFM) transcatheter heart valve (Direct Flow Medical, Santa Rosa, California) for the treatment of noncalcific pure aortic regurgitation (AR). BACKGROUND The treatment of noncalcific AR has remained a relative contraindication with transcatheter heart valves due to challenges in anchoring devices in the absence of calcium, concerns of valve embolization, and the high risk of significant residual paravalvular leak. METHODS The study population consisted of patients treated for severe noncalcific pure AR with transfemoral implantation of a DFM transcatheter heart valve at 6 European centers. The primary endpoint was the composite endpoint of device success and the secondary endpoint was the composite early safety endpoint (according to the VARC-2 criteria). RESULTS Eleven high-risk (STS score 8.84 ± 8.9, Logistic EuroSCORE 19.9 ± 7.1) patients (mean age 74.7 ± 12.9 years) were included. Device success was achieved in all patients. In 1 patient, the initial valve prosthesis was retrieved after pull-through, and a second valve was successfully deployed. The early safety endpoint was reached in 91% of the patients, with 1 patient requiring surgical aortic valve replacement secondary to downward dislocation of the prosthesis that was successfully managed with surgical aortic valve replacement. DFM implantation resulted in excellent hemodynamics with none or trivial paravalvular regurgitation in 9 patients and a transprosthetic gradient of 7.7 ± 5.1 mm Hg at 30-day follow up. All patients derived symptomatic benefit following the procedure, with 72% in New York Heart Association functional class I or II. CONCLUSIONS This study reports the feasibility of treating severe noncalcific AR with the Direct Flow prosthesis via the transfemoral route.

Predictors of restenosis following contemporary subintimal tracking and reentry technique: The importance of final TIMI flow grade

To identify predictors of restenosis after recanalization of chronic total occlusions (CTOs) with the Subintimal Tracking And Reentry (STAR) technique.