Jonghanne Park

Coronary Flow Reserve and Microcirculatory Resistance in Patients With Intermediate Coronary Stenosis.

BACKGROUND The prognostic impact of microvascular status in patients with high fractional flow reserve (FFR) is not clear. OBJECTIVES The goal of this study was to investigate the implications of coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) in patients who underwent FFR measurement. METHODS Patients with high FFR (>0.80) were grouped according to CFR (≤2) and IMR (≥23 U) levels: group A, high CFR with low IMR; group B, high CFR with high IMR; group C, low CFR with low IMR; and group D, low CFR with high IMR. Patient-oriented composite outcome (POCO) of any death, myocardial infarction, and revascularization was assessed. The median follow-up was 658 days (interquartile range: 503.8 to 1,139.3 days). RESULTS A total of 313 patients (663 vessels) were assessed with FFR, CFR, and IMR. Correlation (r = 0.201; p < 0.001) and categorical agreement (kappa value = 0.178; p < 0.001) between FFR and CFR were modest. Low CFR was associated with higher POCO than high CFR (p = 0.034). There were no significant differences in clinical and angiographic characteristics among groups. Patients with high IMR with low CFR had the highest POCO (p = 0.002). Overt microvascular disease (p = 0.008), multivessel disease (p = 0.033), and diabetes mellitus (p = 0.033) were independent predictors of POCO. Inclusion of a physiological index significantly improved the discriminant function of a predictive model (relative integrated discrimination improvement 0.467 [p = 0.037]; category-free net reclassification index 0.648 [p = 0.007]). CONCLUSIONS CFR and IMR improved the risk stratification of patients with high FFR. Low CFR with high IMR was associated with poor prognosis. (Clinical, Physiological and Prognostic Implication of Microvascular Status; NCT02186093).

Adipokine resistin is a key player to modulate monocytes, endothelial cells, and smooth muscle cells, leading to progression of atherosclerosis in rabbit carotid artery.

OBJECTIVES We investigated the effects of human resistin on atherosclerotic progression and clarified its underlying mechanisms. BACKGROUND Resistin is an adipokine first identified as a mediator of insulin resistance in murine obesity models. But, its role in human pathology is under debate. Although a few recent studies suggested the relationship between resistin and atherosclerosis in humans, the causal relationship and underlying mechanism have not been clarified. METHODS We cloned rabbit resistin, which showed 78% identity to human resistin at the complementary deoxyribonucleic acid level, and its expression was examined in 3 different atherosclerotic rabbit models. To evaluate direct role of resistin on atherosclerosis, collared rabbit carotid arteries were used. Histological and cell biologic analyses were performed. RESULTS Rabbit resistin was expressed by macrophages of the plaque in the 3 different atherosclerotic models. Peri-adventitial resistin gene transfer induced macrophage infiltration and expression of various inflammatory cytokines, resulting in the acceleration of plaque growth and destabilization. In vitro experiments elucidated that resistin increased monocyte-endothelial cell adhesion by upregulating very late antigen-4 on monocytes and their counterpart vascular cell adhesion molecule-1 on endothelial cells. Resistin augmented monocyte infiltration in collagen by direct chemoattractive effect as well as by enhancing migration toward monocyte chemotactic protein-1. Administration of connecting segment-1 peptide, which blocks very late antigen-4 × vascular cell adhesion molecule-1 interaction, ameliorated neointimal growth induced by resistin in vivo. CONCLUSIONS Our results indicate that resistin aggravates atherosclerosis by stimulating monocytes, endothelial cells, and vascular smooth muscle cells to induce vascular inflammation. These findings provide the first insight on the causal relationship between resistin and atherosclerosis.

Comparison Among Drug-Eluting Balloon, Drug-Eluting Stent, and Plain Balloon Angioplasty for the Treatment of In-Stent Restenosis : A Network Meta-Analysis of 11 Randomized, Controlled Trials

OBJECTIVES A Bayesian network meta-analysis was performed comparing the efficacy and safety of drug-eluting balloons (DEB), drug-eluting stents (DES), or plain old balloon angioplasty (POBA) for treatment of in-stent restenosis (ISR). BACKGROUND Optimal treatment options for ISR have not been well established. METHODS Randomized, controlled trials comparing DEB, DES, and POBA for the treatment of ISR after percutaneous coronary intervention with bare metal stent or DES were included. The primary outcome was target lesion revascularization (TLR). The pairwise posterior median odds ratio (OR) with 95% credible interval (CrI) was the effect measure. RESULTS This analysis included 2,059 patients from 11 RCTs. The risk of TLR was markedly lower in patients treated with DEB (OR: 0.22, 95% CrI: 0.10 to 0.42) or DES (OR: 0.24, 95% CrI: 0.11 to 0.47) than in those treated with POBA in a random-effects model. In a comparison of DEB and DES, the risk of TLR (OR: 0.92, 95% CrI: 0.43 to 1.90) was similar. The risk of MI or all-cause mortality was lowest in the DEB group compared with the DES and POBA groups, which did not meet statistical significance. The risk of major adverse cardiac events, which was mainly driven by TLR, was also significantly lower in the DEB or and DES group (OR: 0.28, 95% CrI: 0.14 to 0.53) than in the POBA group, but it was similar between the DEB and DES groups (OR: 0.84, 95% CrI: 0.45 to 1.50). The probability of being ranked as the best treatment was 59.9% (DEB), 40.1% (DES), and 0.1% (POBA) in terms of TLR, whereas it was 63.0% (DEB), 35.3% (POBA), and 1.7% (DES) in terms of MI. CONCLUSIONS Local drug delivery by DEB or DES for ISR lesions was markedly better than POBA in preventing TLR, but not for MI or mortality. Among the 2 different strategies of drug delivery for ISR lesions, treatment with DEB showed a trend of less development of MI than did treatment with DES.

Stent Coated With Antibody Against Vascular Endothelial-Cadherin Captures Endothelial Progenitor Cells, Accelerates Re-Endothelialization, and Reduces Neointimal Formation

Objective—In contrast to CD34, vascular endothelial-cadherin (VE-cadherin) is exclusively expressed on the late endothelial progenitor cells (EPC) whereas not on the early or myeloid EPC. Thus, VE-cadherin could be an ideal target surface molecule to capture circulating late EPC. In the present study, we evaluated whether anti-VE–cadherin antibody-coated stents (VE-cad stents) might accelerate endothelial recovery and reduce neointimal formation through the ability of capturing EPC. Methods and Results—The stainless steel stents were coated with rabbit polyclonal anti-human VE-cadherin antibodies and exposed to EPC for 30 minutes in vitro. The number of EPC that adhered to the surface of VE-cad stents was significantly higher than bare metal stents (BMS) in vitro, which was obliterated by pretreatment of VE-cad stent with soluble VE-cadherin proteins. We deployed VE-cad stents and BMS in the rabbit right and left iliac arteries, respectively. At 48 hours after stent deployment in vivo, CD-31–positive endothelial cells adhered to VE-cad stent significantly more than to BMS. At 3 days, scanning electron microscopy showed that over 90% surface of VE-cad stents was covered with endothelial cells, which was significantly different from BMS. At 42 days, neointimal area that was filled with smooth muscle cells positive for actin or calponin was significantly smaller in VE-cad stents than in BMS by histological analysis (0.95±0.22 versus 1.34±0.43 mm2, respectively, P=0.02). Immuno-histochemical analysis revealed that infiltration of inflammatory cells was not significantly different between 2 stents. Conclusion—VE-cad stents captured EPC successfully in vitro, accelerated endothelial recovery on stent, and eventually reduced neointimal formation in vivo.

Integrated Myocardial Perfusion Imaging Diagnostics Improve Detection of Functionally Significant Coronary Artery Stenosis by 13N-ammonia Positron Emission Tomography

Background—Recent evidence suggests that the diagnostic accuracy of myocardial perfusion imaging is improved by quantifying stress myocardial blood flow (MBF) in absolute terms. We evaluated a comprehensive quantitative 13N-ammonia positron emission tomography (13NH3-PET) diagnostic panel, including stress MBF, coronary flow reserve (CFR), and relative flow reserve (RFR) in conjunction with relative perfusion defect (PD) assessments to better detect functionally significant coronary artery stenosis. Methods and Results—A total of 130 patients (307 vessels) with coronary artery disease underwent both 13NH3-PET and invasive coronary angiography with fractional flow reserve (FFR) measurement. Diagnostic accuracy, optimal cut points, and discrimination indices of respective 13NH3-PET quantitative measures were compared, with FFR as standard reference. The capacity to discern disease with stepwise addition of stress MBF, CFR, and RFR to qualitatively assessed relative PD was also gauged, using the category-free net reclassification index. All quantitative measures showed significant correlation with FFR (PET-derived CFR, r=0.388; stress MBF, r=0.496; and RFR, r=0.780; all P<0.001). Optimal respective cut points for FFR ⩽0.8 and ⩽0.75 were 1.99 and 1.84 mL/min per g for stress MBF and 2.12 and 2.00 for PET-derived CFR. Discrimination indices of quantitative measures that correlated with FFR ⩽0.8 were all significantly higher than that of relative PD (area under the curve: 0.626, 0.730, 0.806, and 0.897 for relative PD, CFR, stress MBF, and RFR, respectively; overall comparison P<0.001). The capacity for functionally significant coronary stenosis was incrementally improved by the successive addition of CFR (net reclassification index=0.629), stress MBF (net reclassification index=0.950), and RFR (net reclassification index=1.253; all P<0.001) to relative PD. Conclusions—Integrating quantitative 13NH3-PET measures with qualitative myocardial perfusion assessment provides superior diagnostic accuracy and improves the capacity to detect functionally significant coronary artery stenosis. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01621438 and NCT01366404.

Dipeptidyl Peptidase-4 Inhibitor Increases Vascular Leakage in Retina through VE-cadherin Phosphorylation

The inhibitors of CD26 (dipeptidyl peptidase-4; DPP4) have been widely prescribed to control glucose level in diabetic patients. DPP4-inhibitors, however, accumulate stromal cell-derived factor-1α (SDF-1α), a well-known inducer of vascular leakage and angiogenesis both of which are fundamental pathophysiology of diabetic retinopathy. The aim of this study was to investigate the effects of DPP4-inhibitors on vascular permeability and diabetic retinopathy. DPP4-inhibitor (diprotin A or sitagliptin) increased the phosphorylation of Src and vascular endothelial-cadherin (VE-cadherin) in human endothelial cells and disrupted endothelial cell-to-cell junctions, which were attenuated by CXCR4 (receptor of SDF-1α)-blocker or Src-inhibitor. Disruption of endothelial cell-to-cell junctions in the immuno-fluorescence images correlated with the actual leakage of the endothelial monolayer in the transwell endothelial permeability assay. In the Miles assay, vascular leakage was observed in the ears into which SDF-1α was injected, and this effect was aggravated by DPP4-inhibitor. In the model of retinopathy of prematurity, DPP4-inhibitor increased not only retinal vascularity but also leakage. Additionally, in the murine diabetic retinopathy model, DPP4-inhibitor increased the phosphorylation of Src and VE-cadherin and aggravated vascular leakage in the retinas. Collectively, DPP4-inhibitor induced vascular leakage by augmenting the SDF-1α/CXCR4/Src/VE-cadherin signaling pathway. These data highlight safety issues associated with the use of DPP4-inhibitors.

Endothelial progenitor cells functionally express inward rectifier potassium channels

Since the first isolation of endothelial progenitor cells (EPCs) from human peripheral blood in 1997, many researchers have conducted studies to understand the characteristics and therapeutic effects of EPCs in vascular disease models. Nevertheless, the electrophysiological properties of EPCs have yet to be clearly elucidated. The inward rectifier potassium channel (Kir) performs a major role in controlling the membrane potential and cellular events. Here, via the whole cell patch-clamp technique, we found inwardly rectifying currents in EPCs and that these currents were inhibited by Ba(2+) (100 μM) and Cs(+) (1 mM), known as Kir blockers, in a dose-dependent manner (Ba(2+), 91.2 ± 1.4% at -140 mV and Cs(+), 76.1 ± 6.9% at -140 mV, respectively). Next, using DiBAC(3), a fluorescence indicator of membrane potential, we verified that Ba(2+) induced an increase of fluorescence in EPCs (10 μM, 123 ± 2.8%), implying the depolarization of EPCs. At the mRNA and protein levels, we confirmed the existence of several Kir subtypes, including Kir2.x, 3.x, 4.x, and 6.x. In a functional experiment, we observed that, in the presence of Ba(2+), the number of tubes on Matrigel formed by EPCs was dose-dependently reduced (10 μM, 62.3 ± 6.5%). In addition, the proliferation of EPCs was increased in a dose-dependent fashion (10 μM, 157.9 ± 17.4%), and specific inhibition of Kir2.1 by small interfering RNA also increased the proliferation of EPCs (116.2 ± 2.5%). Our results demonstrate that EPCs express several types of Kir which may modulate the endothelial function and proliferation of EPCs.

Efficacy of Short-Term High-Dose Statin Pretreatment in Prevention of Contrast-Induced Acute Kidney Injury: Updated Study-Level Meta-Analysis of 13 Randomized Controlled Trials

Background There have been conflicting results across the trials that evaluated prophylactic efficacy of short-term high-dose statin pre-treatment for prevention of contrast-induced acute kidney injury (CIAKI) in patients undergoing coronary angiography (CAG). The aim of the study was to perform an up-to-date meta-analysis regarding the efficacy of high-dose statin pre-treatment in preventing CIAKI. Methods and Results Randomized-controlled trials comparing high-dose statin versus low-dose statin or placebo pre-treatment for prevention of CIAKI in patients undergoing CAG were included. The primary endpoint was the incidence of CIAKI within 2–5days after CAG. The relative risk (RR) with 95% CI was the effect measure. This analysis included 13 RCTs with 5,825 total patients; about half of them (n = 2,889) were pre-treated with high-dose statin (at least 40 mg of atorvastatin) before CAG, and the remainders (n = 2,936) pretreated with low-dose statin or placebo. In random-effects model, high-dose statin pre-treatment significantly reduced the incidence of CIAKI (RR 0.45, 95% CI 0.35–0.57, p<0.001, I2 = 8.2%, NNT 16), compared with low-dose statin or placebo. The benefit of high-dose statin was consistent in both comparisons with low-dose statin (RR 0.47, 95% CI 0.34–0.65, p<0.001, I2 = 28.4%, NNT 19) or placebo (RR 0.34, 95% CI 0.21–0.58, p<0.001, I2 = 0.0%, NNT 16). In addition, high-dose statin showed significant reduction of CIAKI across various subgroups of chronic kidney disease, acute coronary syndrome, and old age (≥60years), regardless of osmolality of contrast or administration of N-acetylcystein. Conclusions High-dose statin pre-treatment significantly reduced overall incidence of CIAKI in patients undergoing CAG, and emerges as an effective prophylactic measure to prevent CIAKI.

Computational fluid dynamic measures of wall shear stress are related to coronary lesion characteristics

Objective To assess the distribution of pressure and shear-related forces acting on atherosclerotic plaques and their association with lesion characteristics using coronary CT angiography (cCTA)-based computational fluid dynamics (CFD) model of epicardial coronary arteries. Methods Patient-specific models of epicardial coronary arteries were reconstructed from cCTA in 80 patients (12 women, 63.8±9.0 years). The pressure and wall shear stress (WSS) in left anterior descending coronary arteries were assessed using CFD. High-risk plaques were defined as the presence of at least one of the following adverse plaque characteristics: low-density plaque, positive remodelling, napkin-ring sign and spotty calcification. Results At resting condition, 39.5% of stenotic segments (% diameter stenosis 52.3±14.4%) were exposed to high WSS (>40 dyne/cm2). When the stenotic lesion was subdivided into three segments, the distribution of WSS was different from that of pressure change and its magnitude was highest at minimal lumen area (p<0.001). High pressure gradient, proximal location, small lumen and short length were independent determinants of WSS (all p<0.05). The plaques exposed to the highest WSS tertile had a significantly greater proportion of high-risk plaques. The addition of WSS to % diameter stenosis significantly improved the measures of discrimination and reclassification of high-risk plaques (area under the curves from 0.540 to 0.718, p=0.031; net reclassification index 0.827, p<0.001). Conclusions The cCTA-based CFD method can improve the identification of high-risk plaques and the risk stratification for coronary artery disease patients by providing non-invasive measurements of WSS affecting coronary plaques.

Clinical implications of three-vessel fractional flow reserve measurement in patients with coronary artery disease

Aims There are limited data on the clinical implications of total physiologic atherosclerotic burden assessed by invasive physiologic studies in patients with coronary artery disease. We investigated the prognostic implications of total physiologic atherosclerotic burden assessed by total sum of fractional flow reserve (FFR) in three vessels (3V-FFR). Methods and results A total of 1136 patients underwent FFR measurement in three vessels (3V FFR-FRIENDS study, NCT01621438). The patients were classified into high and low 3V-FFR groups according to the median value of 3V-FFR (2.72). The primary endpoint was major adverse cardiac events (MACE, a composite of cardiac death, myocardial infarction and ischaemia-driven revascularization) at 2 years. Mean angiographic percent diameter stenosis and FFR were 43.7 ± 19.3% and 0.90 ± 0.08, respectively. There was a negative correlation between 3V-FFR and estimated 2-year MACE rate (P < 0.001). The patients in low 3V-FFR group showed a higher risk of 2-year MACE than those in the high 3V-FFR group [(7.1% vs. 3.8%, hazard ratio (HR) 2.205, 95% confidence interval (CI) 1.201-4.048, P = 0.011]. The higher 2-year MACE rate was mainly driven by the higher rate of ischaemia-driven revascularization in the low 3V-FFR group (6.2% vs. 2.7%, HR 2.568, 95% CI 1.283-5.140, P = 0.008). In a multivariable adjusted model, low 3V-FFR was an independent predictor of MACE (HR 2.031, 95% CI 1.078-3.830, P = 0.029). Conclusion Patients with high total physiologic atherosclerotic burden assessed by 3V-FFR showed higher risk of 2-year clinical events than those with low total physiologic atherosclerotic burden. The difference was mainly driven by ischaemia-driven revascularization for both functionally significant and insignificant lesions at baseline. Three-vessel FFR might be used as a prognostic indicator in patients with coronary artery disease. Clinical trial registration 3V FFR-FRIENDS study (https://clinicaltrials.gov/ct2/show/NCT01621438, NCT01621438).