Long-Term Clinical Effects of Carotid Intraplaque Neovascularization in Patients with Coronary Artery Disease.

OBJECTIVE: To investigate the predictive value of intraplaque neovascularization (IPN) for cardiovascular outcomes. MATERIALS AND METHODS: We evaluated 217 patients with coronary artery disease (CAD) (158 men; mean age, 68 ± 10 years) with a maximal carotid plaque thickness ≥ 1.5 mm for the presence of IPN using contrast-enhanced ultrasonography. We compared patients with (n = 116) and without (n = 101) IPN during the follow-up period and investigated the predictors of major adverse cardiovascular events (MACE), including cardiac death, myocardial infarction, coronary artery revascularization, and transient ischemic accident/stroke. RESULTS: During the mean follow-up period of 995 ± 610 days, the MACE rate was 6% (13/217). Patients with IPN had a higher maximal thickness than those without IPN (2.86 ± 1.01 vs. 2.61 ± 0.84 mm, p = 0.046). Common carotid artery-peak systolic velocity, left ventricular mass index (LVMI), and ventricular-vascular coupling index were significantly correlated with MACE. However, on multivariate Cox regression analysis, increased LVMI was independently related to MACE (p < 0.05). The presence of IPN could not predict MACE. CONCLUSION: The presence of IPN was related to a higher plaque thickness but could not predict cardiovascular outcomes better than conventional clinical factors in patients with CAD.

Reduced Coronary Flow Reserve Is Associated with Impaired Ventricular-vascular Interaction in Patients with Obstructive Sleep Apnea.

Background and Objectives: Obstructive sleep apnea (OSA) is associated with cardiac and arterial damage and adverse cardiovascular outcomes. We aimed to determine whether coronary flow reserve (CFR), which represents microvascular dysfunction, might be associated with the ventricular-vascular coupling index (VVI), which represents the afterload-adjusted contractility in patients with OSA. Methods: We enrolled 281 patients (257 males; mean age, 43±11 years) with newly diagnosed OSA. Transthoracic echocardiography was performed, and adenosine-associated CFR was measured in the left anterior descending coronary artery. We evaluated the differences between the patients with normal CFR ≥2.5 and reduced CFR <2.5. VVI was calculated using the effective arterial elastance (Ea) and left ventricular (LV) end-systolic elastance (Ees) as follows: 10×Ea/Ees. Results: The normal CFR group (n=214) showed increased Ees (7.28±2.31 vs. 8.14±2.33 mmHg/mL, p=0.016) and preserved VVI (3.17±1.53 vs. 2.78±1.20, p=0.044) compared with the reduced CFR group (n=67). There were no differences in LV dimension, LV ejection fraction, left atrial-volume index, E/e', left atrial strain and LV global longitudinal strain between the 2 groups (all p>0.05). CFR was significantly correlated to Ees (r=0.139; p=0.023) and VVI (r=-0.137; p=0.025). Conclusions: Reduced CFR is associated with decreased Ees and impaired VVI in OSA patients. It suggests the necessity of more intensive observation in OSA patients with reduced CFR to improve cardiovascular outcomes.

Electroacupuncture prevents endothelial dysfunction induced by ischemia-reperfusion injury via a cyclooxygenase-2-dependent mechanism: A randomized controlled crossover trial.

OBJECTIVE: Exploring clinically effective methods to reduce ischemia-reperfusion (IR) injury in humans is critical. Several drugs have shown protective effects, but studies using other interventions have been rare. Electroacupuncture (EA) has induced similar protection in several animal studies but no study has investigated how the effects could be translated and reproduced in humans. This study aimed to explore the potential effect and mechanisms of EA in IR-induced endothelial dysfunction in humans. METHODS: This is a prospective, randomized, crossover, sham-controlled trial consisting of two protocols. Protocol 1 was a crossover study to investigate the effect of EA on IR-induced endothelial dysfunction. Twenty healthy volunteers were randomly assigned to EA or sham EA (sham). Flow mediated dilation (FMD) of the brachial artery (BA), nitroglycerin-mediated endothelial independent dilation, blood pressure before and after IR were measured. In protocol 2, seven volunteers were administered COX-2 inhibitor celecoxib (200 mg orally twice daily) for five days. After consumption, volunteers underwent FMD before and after IR identical to protocol 1. RESULTS: In protocol 1, baseline BA diameter, Pre-IR BA diameter and FMD were similar between the two groups (p = NS). After IR, sham group showed significantly blunted FMD (Pre-IR: 11.41 ± 3.10%, Post-IR: 4.49 ± 2.04%, p < 0.001). However, EA protected this blunted FMD (Pre-IR: 10.96 ± 5.30%, Post-IR: 9.47 ± 5.23%, p = NS, p < 0.05 compared with sham EA after IR). In protocol 2, this protective effect was completely abolished by pre-treatment with celecoxib (Pre-IR: 11.05 ± 3.27%; Post-IR: 4.20 ± 1.68%, p = 0.001). CONCLUSION: EA may prevent IR-induced endothelial dysfunction via a COX-2 dependent mechanism.

The pharmacodynamics of low and standard doses of ticagrelor in patients with end stage renal disease on hemodialysis.

BACKGROUND: Patients with end-stage renal disease (ESRD) on maintenance hemodialysis (HD) respond poorly to clopidogrel. We assessed the utility of low-dose ticagrelor in ESRD patients on maintenance HD. METHODS: In this single-center, prospective, randomized pharmacodynamic study, 52 ESRD patients on HD were prescribed clopidogrel (300mg loading dose [LD], then 75mg daily), standard-dose ticagrelor (180mg LD, then 90mg twice daily), or low-dose ticagrelor (90mg LD, then 90mg daily) for 14days. Platelet function was evaluated before and after therapy via light transmittance aggregometry and the VerifyNow™ P2Y12 assay. RESULTS: The adenosine diphosphate (ADP)-induced maximal extent of platelet aggregation differed significantly between the low-dose ticagrelor and clopidogrel groups (ANCOVA, p=0.04 after stimulation with 5µmol/L ADP; p<0.01 after stimulation with 20µmol/L ADP). Inhibition of platelet aggregation increased significantly in the order of clopidogrel, low-dose ticagrelor, and standard-dose ticagrelor, as revealed by adjusted intergroup comparison analysis (ANCOVA, p=0.04 after stimulation with 5µmol/L ADP; p=0.005 after stimulation with 20µmol/L ADP). The rates of onset of the antiplatelet effect curves from 0 to 5h after administration of the LDs were greater in the standard- and low-dose ticagrelor groups than in the clopidogrel group. Significant sequential reductions in P2Y12 reaction units were noted, in the following order: clopidogrel, low-dose ticagrelor, and standard-dose ticagrelor (ANCOVA, p<0.001). No bleeding occurred in the low-dose ticagrelor group. CONCLUSIONS: Low-dose ticagrelor afforded greater platelet inhibition than did clopidogrel in ESRD patients on HD.

Evaluation of the vascular protective effects of new oral anticoagulants in high-risk patients with atrial fibrillation (PREFER-AF): study protocol for a randomized controlled trial.

BACKGROUND: Atrial fibrillation (AF) is known to be associated with several pathophysiological mechanisms including endothelial dysfunction of the heart and arterial vessels. Recent evidence suggests that new oral anticoagulant (NOAC) treatment may improve endothelial function and the inflammatory process involved in atherosclerosis in AF patients. This study is designed to determine the efficacy of NOAC therapy in the prevention of endothelial dysfunction and the progression of atherosclerosis of AF subjects. METHOD/DESIGN: AF patients with a CHA2DS2-VASc score >2 and no previous history of overt coronary disease, severe peripheral arterial disease (PAD) or major stroke will be registered and randomly assigned either to the NOAC group (dabigatran or rivaroxaban) or the warfarin group in this prospective, randomized, 2-year follow-up study. Reactive hyperemia peripheral arterial tonometry (RH-PAT) measurements reflecting endothelial function will be conducted using the Endo-PAT2000 device. Left and right carotid intima-media thickness (IMT) will be measured at baseline, 12 months, and 24 months. The primary endpoint is defined as change in Reactive Hyperemia Index (RHI) at 12 months. Secondary endpoints included changes in the right and left maximum IMT of the common carotid artery (CCA) and internal carotid artery (ICA), the mean IMT of the CCA and ICA at 24 months, and 24-month cardiovascular events including cardiac death, stroke, acute myocardial infarction (AMI), overall cause of death, withdrawal of drug, or bleeding events. DISCUSSION: This is the first study to evaluate the efficacy of NOAC therapy for the prevention of endothelial dysfunction and progression of atherosclerosis in AF subjects. These findings are expected to expand the knowledge of NOAC pleotropic action in AF patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02544932 , registered on 7 September 2015.

Layer-specific analysis of dobutamine stress echocardiography for the evaluation of coronary artery disease.

Although dobutamine stress echocardiography (DSE) is a well-defined tool for the diagnosis of coronary artery disease (CAD), false-negative and false-positive results still occur. This study investigated the diagnostic role of layer-specific analysis using 2-dimensional speckle-tracking echocardiography (STE) during DSE.A total of 121 patients who underwent DSE and showed normal wall motion and ejection fraction during baseline echocardiography were enrolled. All patients underwent coronary angiography after DSE within 2 weeks. The patients were divided into the following 4 groups according to DSE results and CAD status: negative DSE with no significant CAD (n = 73), positive DSE with significant CAD (n = 16), negative DSE with significant CAD (n = 17), and positive DSE with no significant CAD (n = 15). Layer-specific global longitudinal strain (GLS) was assessed in the endocardium, mid-myocardium, and epicardium by STE techniques.Patients with significant CAD were older, more male and showed higher glucose level compared to patients without CAD. But coronary risk factors and previous medications were not different between patients with and without CAD. There were no significant differences in whole myocardium or layer-specific GLS found in the baseline echocardiography. During recovery echocardiography, endocardial GLS was significantly different between patients with and without CAD, regardless of the DSE results. A receiver-operating characteristic curve analysis showed that endocardial GLS (>-16%) was superior for identifying significant CAD during the DSE recovery stage. Diagnostic accuracy was improved by applying the results of endocardial GLS compared with visual estimation of DSE.The assessment of layer-specific strain by STE during DSE was feasible, and the evaluation of poststress endocardial function is a more sensitive tool for the detection of CAD.

Aortic arch calcification on chest X-ray combined with coronary calcium score show additional benefit for diagnosis and outcome in patients with angina.

BACKGROUND: The coronary artery calcium (CAC) and aortic arch calcification (AoAC) are individually associated with cardiovascular disease and outcome. This study investigated the predictive value of AoAC combined with CAC for cardiovascular diagnosis and outcome in patients with angina. METHODS: A total of 2018 stable angina patients who underwent chest X-ray and cardiac multi-detector computed tomography were followed up for four years to assess adverse events, which were categorized as cardiac death, stroke, myocardial infarction, or repeated revascularization. The extent of AoAC on chest X-ray was graded on a scale from 0 to 3. RESULTS: During the four years of follow-up, 620 patients were treated by coronary stenting and 153 (7%) adverse events occurred. A higher grade of AoAC was associated with a higher CAC score. Cox regression showed that the CAC score, but not AoAC, were associated with adverse events. In patients with CAC score < 400, AoAC showed an additive predictive value in detecting significant coronary artery disease (CAD). A gradual increases in the risk of adverse events were noted if AoAC was present in patients with similar CAC score. CONCLUSIONS: As AoAC is strongly correlated with the CAC score regardless of age or gender, careful evaluation of CAD would be required in patients with AoAC on conventional chest X-rays.

Effects of Statin Therapy on Clinical Outcomes of Survivors of Acute Myocardial Infarction with Severe Systolic Heart Failure.

OBJECTIVE: Large randomized trials have failed to show a beneficial effect of statin treatment in chronic HF. The investigators tried to evaluate the long-term effects of statin therapy in patients with new onset heart failure (HF) following acute myocardial infarction (AMI). METHODS: Between January 2008 and December 2011, a total of 13,616 AMI patients were enrolled in the Korea Acute Myocardial Infarction Registry (KAMIR) which was a prospective, multi-center, nationwide, web-based database of AMI in Korea. From this database, we studied 1,055 patients with AMI who had newly developed severe acute HF [left ventricular ejection fraction ≤ 40%] and were discharged alive. The patients were divided into two groups, a statin group (n = 756) and a no-statin group (n = 299). We investigated the one-year major adverse cardiovascular events (MACEs), including all-cause mortality, MI, and any revascularization of each group. We then performed a propensity-score matched analysis. RESULTS: In the original cohort, one-year MACEs were similar between the two groups (16.5% vs. 14.7% in the statin or no-statin groups; p = 0.47). Propensity-score matching yielded 256 pairs, and in that population we observed comparable results in terms of MACEs (18.0% vs. 12.5% in the statin or no-statin groups, p = 0.11) and mortality (5.1% vs. 3.5% in the statin or no-statin groups, p = 0.51). Cox-regression analysis revealed that statin therapy was not an independent predictor for occurrence of a MACE [Hazard ratio (HR) 1.11, 95% CI 0.79-1.57, p = 0.54] or all-cause mortality (HR 1.42, 95% CI 0.75-2.70, p = 0.28). CONCLUSION: Statin therapy was not associated with a reduction in the long-term occurrence of MACEs or mortality in survivors of AMI with severe acute HF in this retrospective cohort study.

Early prediction of myocardial viability after acute myocardial infarction by two-dimensional speckle tracking imaging.

BACKGROUND: Identifying the transmural extent of myocardial necrosis and the degree of myocardial viability in acute myocardial infarction (AMI) is important clinically. The aim of this study was to assess myocardial viability using two-dimensional speckle tracking imaging (2D-STI) in patients with AMI. METHODS: 2D-STI was performed at initial presentation, three days, and six months after primary percutaneous coronary intervention (PCI) in 30 patients with AMI, who had a left anterior descending coronary artery (LAD) culprit lesion. In addition, 20 patients who had minimal stenotic lesions (< 30% stenosis) on coronary angiography were also included in the control group. At six months dobutamine echocardiography was performed for viability assessment in seven segments of the LAD territory. According to the recovery of wall motion abnormality, segments were classified as viable or non-viable. RESULTS: A total of 131 segments were viable, and 44 were nonviable. Multivariate analysis revealed significant differences between the viable and nonviable segments in the peak systolic strain, the peak systolic strain rate at initial presentation, and peak systolic strain rate three days after primary PCI. Among these, the initial peak systolic strain rate had the highest predictive value for myocardial viability (hazard ratio: 31.22, P < 0.01). CONCLUSIONS: 2D-STI is feasible for assessing myocardial viability, and the peak systolic strain rate might be the most reliable predictor of myocardial viability in patients with AMI.

Effects of electroacupuncture on endothelial function and circulating endothelial progenitor cells in patients with cerebral infarction.

This study evaluated the effects of electroacupuncture (EA) on endothelial function and endothelial progenitor cells (EPC) in patients with cerebral infarction. In a randomized, placebo-controlled, crossover study, 20 patients with cerebral infarction were randomized into two treatment groups: EA or placebo. Before and after each intervention, pulse amplitude tonometry (PAT) was used to assess endothelial function and peripheral blood was analyzed for the number of EPCs. Circulating EPCs were quantified by flow cytometry as CD45(low) CD34(+) KDR2(+) cells. Plasma vascular endothelial growth factor (VEGF) and interleukin (IL)-10 levels were measured. Seven days later, crossover was performed on each group, with each group receiving the other treatment using the same protocol. The PAT hyperemia ratio ranged from 1.57 ± 0.41 to 2.04 ± 0.51 after EA, representing a significant improvement (P = 0.002); however, there was no improvement in the placebo group (P = 0.48). Circulating EPCs, as measured by flow cytometry, increased to 110.6 ± 74.3/100 µL in the EA group (P = 0.001) but did not change in the placebo group (45.9 ± 35.3/100 µL, P = 0.08). The increases in the number of EPCs and the PAT ratio after treatment were correlated (r = 0.78, P < 0.001). Plasma VEGF levels increased with EA compared to baseline (261.2 ± 34.0 vs 334.9 ± 80.5 pg/mL, P = 0.003). The number of circulating EPCs was positively correlated with plasma levels of VEGF (r = 0.50, P = 0.02). In conclusion, EA induced improvement of EPC levels and the PAT ratio in patients with cerebral infarction.

Platelet reactivity after receiving clopidogrel compared with ticagrelor in patients with kidney failure treated with hemodialysis: a randomized crossover study.

BACKGROUND: Patients with kidney failure treated with maintenance hemodialysis (HD) are poor responders to clopidogrel. More beneficial platelet-inhibiting strategies in HD patients therefore are required. STUDY DESIGN: Single-center, prospective, randomized, crossover study. SETTING & PARTICIPANTS: 25 HD patients in Seoul, Korea. INTERVENTION: Patients were randomly assigned to receive clopidogrel (300mg loading, 75mg once daily for maintenance dose) or ticagrelor (180mg loading, 90mg twice daily for maintenance dose) for 14 days, and after a 14-day washout period, crossover treatment for another 14 days. All patients received aspirin (100mg/d). OUTCOMES & MEASUREMENTS: Platelet function was evaluated predosing and at 1, 5, and 48 hours and 14 days after the first loading dose. During the offset phase, platelet function was assessed at 1 hour and 2, 4, and 14 days after the last dose by light transmittance aggregometry and the VerifyNow P2Y12 assay, and patients were genotyped for the CYP2C19*2 allele. Maximal extent of aggregation, inhibition of platelet aggregation (IPA), P2Y12 reaction units (PRUs), and percentage of inhibition were evaluated. We performed per-protocol analysis, excluding patients who did not complete the protocol. RESULTS: 9 patients did not complete the protocol (7 patients due to adverse events; 2, nonadherence). Higher IPA occurred with ticagrelor than with clopidogrel at 1, 5, and 48 hours and 14 days after loading. By 5 hours after loading, a greater proportion of patients in the ticagrelor group than in the clopidogrel group achieved IPA>50% (75% vs 12%, respectively; P<0.05) and IPA>70% (44% vs 0%, respectively; P<0.05). Rates (slope) of onset and offset of the antiplatelet effect were faster in patients receiving ticagrelor than for those receiving clopidogrel (P<0.05). Regardless of CYP2C19*2 allele, the ticagrelor group had significantly lower PRUs at all times than the clopidogrel group. LIMITATIONS: Single-center study with a small number of patients, not a double-blind study, and not intention-to-treat analysis. CONCLUSIONS: Ticagrelor may result in more rapid and greater platelet inhibition than clopidogrel in patients with kidney failure receiving HD.

Impact of lysophosphatidylcholine on survival and function of UEA-1(+)acLDL (+) endothelial progenitor cells in patients with coronary artery disease.

Lysophosphatidylcholine (LPC) generated from oxidized low-density lipoprotein by lipoprotein-associated phospholipase A2 plays a key role in plaque inflammation and vulnerability. Endothelial progenitor cells (EPCs) can repair injured endothelium and exert anti-inflammatory effects of vulnerable plaque. We study the impact and mechanisms of LPC on UEA-1 and acLDL binding EPCs (UEA-1(+)acLDL(+) EPCs). UEA-1(+)acLDL(+) EPCs from coronary artery disease (CAD) patients were cultured and exposed to LPC at different concentrations and different timepoints. We determined the significant concentration (40 µM). UEA-1(+)acLDL(+) EPCs were preincubated for 30 min with pravastatin (20 µM) with LY249002, a specific inhibitor of the Akt signaling pathway, and exposed for 24 h to LPC 40 µM. The survival, migration, adhesion, and proliferation of UEA-1(+)acLDL(+) EPCs were assessed. To examine the mechanisms of LPC toxicity and pravastatin effects, phosphorylated Akt and endothelial nitric oxide synthase (eNOS) levels and the ratio of Bcl-2/Bax protein expression were assessed. LPC induced apoptosis and impaired migration and adhesion of UEA-1(+)acLDL(+) EPCs significantly. The detrimental effects of LPC were attenuated by pravastatin. However, when UEA-1(+)acLDL(+) EPCs were pretreated with pravastatin and LY249002, a specific inhibitor of the Akt signaling pathway, simultaneously, the beneficial effects of pravastatin were abolished. Furthermore, LPC suppressed Akt and eNOS phosphorylation and increased Bcl-2/Bax expression. The effects of LPC on Akt/eNOS and Bcl-2/Bax activity were reversed by pravastatin. In conclusion, LPC inhibited UEA-1(+)acLDL(+) EPCs survival and impaired its functions, and these were attributable to inhibition of the Akt/eNOS and Bcl-2/Bax pathway. Pravastatin reversed the detrimental action of LPC. These findings suggest that LPC inhibition can be a possible strategy for CAD through EPC revitalization.

Comparison of peripheral arterial tonometry and flow-mediated vasodilation for assessment of the severity and complexity of coronary artery disease.

OBJECTIVE: Noninvasive flow-mediated vasodilation (FMD) is a widely used method to assess endothelial function, but its technical difficulty and problems remain obstacles for use in clinical practice. Reactive hyperemia-peripheral arterial tonometry (RH-PAT) was developed as a simpler and more reproducible method. We compared FMD and RH-PAT in patients with stable angina. Furthermore, the differences in these two techniques according to coronary artery disease (CAD) severity and complexity were also assessed. MATERIALS AND METHODS: We consecutively enrolled 80 patients who underwent elective coronary angiography. Endothelial function was assessed before angiography using brachial artery FMD and RH-PAT. The complexity and extent of the coronary lesions were assessed angiographically. The extent of CAD was defined as the number of diseased coronary arteries (>70%) and complexity of CAD was assessed by the SYNTAX score algorithm. RESULTS: In the overall study group (61±9 years, 57% men), the mean FMD was 8.5±5.1% and the mean reactive hyperemia index (RHI) measured by RH-PAT was 1.7±0.4. A significant correlation was observed between FMD and RHI irrespective of sex, diabetes, or presence of CAD. FMD and RHI were significantly lower in patients with multivessel and complex CAD. A receiver-operating characteristic curve analysis showed that both techniques were comparable in terms of predicting the presence of CAD and complexity. CONCLUSION: Assessment of RH-PAT could be a less operator-dependent and noninvasive method of evaluating vascular endothelial function in patients with stable angina.

Biochemical and clinical correlation of intraplaque neovascularization using contrast-enhanced ultrasound of the carotid artery.

OBJECTIVE: Several biomarkers reflecting inflammatory or proteolytic activity have been known to represent plaque vulnerability. Moreover, a recent study confirmed that contrast-enhanced ultrasound (CEUS) can visualize intraplaque neovascularization (IPN) and demonstrate plaque vulnerability. In this study, we tried to demonstrate that IPN detected by CEUS was correlated with several well-known biomarkers and clinical outcome in patients with coronary artery disease (CAD). METHODS: Patients with stable CAD were screened by conventional carotid ultrasound and patients with carotid plaque thickness more than 2 mm were performed by CEUS for the presence of IPN. Plasma levels of biomarkers and clinical outcomes were evaluated. RESULTS: Among consecutive 89 patients fulfilled the inclusion criteria, 30 patients without IPN (group 1) and 59 patients with IPN (group 2) were analyzed. There were no significant difference in baseline characteristics except for mean age (62.9±10.1 yrs versus 68.4±9.6 yrs, p=0.015). On multivariate analysis, only MMP-9 (p=0.021, 95% CI 1.002-1.027) showed a significant association with IPN. But patients with IPN showed only trend for a history of cardiovascular disease (CVD) (44% versus 30%, p=0.19) and one-year cardiovascular events (CVE) (6.8% versus 3.3%, p=0.50) compared to group 1. Maximum plaque thickness (p=0.04, 95% CI 1.230-6.322) showed a significant correlation with the clinical outcome including CVD or CVE. CONCLUSION: MMP-9 correlated with IPN on CEUS. For clinical implication, however, large prospective studies are needed.

Effect of platelet reactivity, endothelial function, and inflammatory status on outcomes in patients with stable angina pectoris on clopidogrel therapy.

Although high on-treatment platelet reactivity (HTPR) is an important predictor of clinical outcomes in patients undergoing coronary stenting, it is unknown whether endothelial dysfunction and HTPR are associated. We examined the platelet function, peripheral vascular function, endothelial progenitor cell (EPC) number, platelet activation markers, high-sensitivity C-reactive protein (hs-CRP) level, and clinical outcomes in patients receiving chronic clopidogrel therapy. We consecutively enrolled 91 patients who underwent follow-up angiography because of chest discomfort. All patients took aspirin and clopidogrel for an average of 498 ± 138 days. Platelet reactivity was assessed by light transmittance aggregometry (maximal platelet aggregation by 5 µmol/L of adenosine diphosphate ≤50% in group 1 [optimal response] and >50% as group 2 [HTPR]). Flow-mediated dilation of the brachial artery and brachial-ankle pulse wave velocity (PWV), numbers of EPCs isolated from peripheral blood, platelet activation markers (soluble CD40 ligand and soluble P-selectin), and hs-CRP levels were assessed before follow-up angiography. There were no significant differences in baseline characteristics and previous percutaneous coronary intervention (PCI) data between groups 1 (n = 59) and 2 (n = 32). Group 2 showed poorer flow-mediated dilation (6.1 ± 4.1% vs 12.9 ± 6.2%, p <0.001), pulse wave velocity (1925.4 ± 362.2 vs 1571.0 ± 306.5 ms, p <0.001), and lower circulating EPCs by flow cytometry (21.9 ± 14.7 vs 65.2 ± 30.1 per 10 fields, p <0.001) compared with group 1. Significantly higher levels of soluble CD40 ligand, soluble P-selectin, and hs-CRP were observed in group 2. In multivariate analysis, elevated hs-CRP level, but not HTPR, was independently associated with repeated PCI. In patients with angina, HTPR was associated endothelial dysfunction and elevated hs-CRP, although elevated hs-CRP level was significantly associated with poorer outcomes.

Effect of cilostazol addition or clopidogrel doubling on platelet function profiles in diabetic patients undergoing a percutaneous coronary intervention.

BACKGROUND: We investigated the pharmacodynamic effect of cilostazol addition (100 mg twice, Triple) or clopidogrel doubling (150 mg daily, Double) on standard dual antiplatelet therapy in type 2 diabetes mellitus (T2DM) patients with clopidogrel resistance undergoing a percutaneous coronary intervention. METHODS AND RESULTS: This was a prospective, randomized, cross-over platelet function study. Percent inhibition less than 20% was used as the cutoff value of clopidogrel resistance. After percutaneous coronary intervention, a total of 50 T2DM patients with clopidogrel resistance were assigned to receive cilostazol 100 mg twice daily or clopidogrel 150 mg daily for 28 days; afterwards, they received cross-over treatment for another 28 days. Eight patients were excluded because of side effects and follow-up loss. The platelet function test using VerifyNow was performed at three time points: at baseline (T0), 28 days after randomization (T1), and 28 days after cross-over treatment (T2).A total of 42 T2DM patients completed the study protocol. The clopidogrel resistance improved significantly following cilostazol addition or clopidogrel doubling treatment compared with baseline (52.9±27.0 in Triple, 45.4±16.8% in Double, P<0.001 in both). This effect continued after cross-over treatment (58.1±26.1 and 41.0±20.0%, respectively, both P<0.05). A head-to-head comparison between two groups showed a lower P2Y12 reaction unit (PRU) and higher percentage of platelet inhibition in the Triple than those in the Double group (PRU, 138.7±88.2 vs. 198.8±19.5, P=0.049; %platelet inhibition, 58.1±26.1 vs. 40.97±20.0, P=0.048). CONCLUSION: Adjunctive treatment with cilostazol in T2DM patients on standard dual antiplatelet therapy might be a more effective strategy for overcoming clopidogrel resistance than clopidogrel doubling treatment.

Cardioprotective effects of exenatide in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of exenatide myocardial protection in revascularization study.

OBJECTIVE: Experimental evidence suggests that exenatide, a glucagon-like peptide 1 receptor analogue, has significant cardiovascular protective effects in various conditions. We examined whether routine use of exenatide at the time of primary percutaneous coronary intervention would reduce infarct size in patients with ST-segment-elevation myocardial infarction. APPROACH AND RESULTS: Fifty-eight patients with ST-segment-elevation myocardial infarction and thrombolysis in myocardial infarction flow 0 were enrolled in the study and randomly assigned to receive either exenatide or placebo (saline) subcutaneously. Infarct size was assessed by measuring the release of creatine kinase-MB and troponin I during 72 hours and by performing cardiac magnetic resonance imaging at 1 month after infarction. Routine and speckle tracking echocardiography was performed at initial presentation and at 3 days and 6 months after primary percutaneous coronary intervention. The exenatide and control groups had similar results with respect to ischemia time, demographic characteristics, and ejection fraction before primary percutaneous coronary intervention. The releases of creatine kinase-MB and troponin I were significantly reduced in the exenatide group. In 58 patients evaluated with cardiac magnetic resonance, the absolute mass of delayed hyperenhancement was significantly reduced in the exenatide group as compared with the control group (12.8±11.7 versus 26.4±11.6 g; P<0.01). At 6 months, the exenatide group showed a significantly lower value of E/E' with improved strain parameters. No significant adverse effects of exenatide administration were detected. CONCLUSIONS: In patients with ST-segment-elevation myocardial infarction, adjunctive exenatide therapy with primary percutaneous coronary intervention was associated with reduction of infarct size and improvement of subclinical left ventricular function.

Non-lipid effects of rosuvastatin-fenofibrate combination therapy in high-risk Asian patients with mixed hyperlipidemia.

OBJECTIVE: The aim of this study is to compare the non-lipid effects of rosuvastatin-fenofibrate combination therapy with rosuvastatin monotherapy in high-risk Asian patients with mixed hyperlipidemia. METHODS: A total of 236 patients were initially screened. After six weeks of diet and life style changes, 180 of these patients were randomly assigned to receive one of two regimens: rosuvastatin 10 mg plus fenofibrate 160 mg or rosuvastatin 10 mg. The primary outcome variables were the incidences of muscle or liver enzyme elevation. The patients were followed for 24 weeks during drug treatment and for an additional four weeks after drug discontinuation. RESULTS: The rates of the primary outcome variables were similar between the two groups (2.8% and 3.9% in the combination and the rosuvastatin groups, respectively, p=1.00). The combination group had more, but not significantly, common treatment-related adverse events (AEs) (13.3% and 5.6%, respectively) and drug discontinuation due to AEs (10.0% and 3.3%, respectively) than the rosouvastatin group. Combination therapy was associated with higher elevations in homocysteine, blood urea nitrogen, and serum creatinine, whereas elevation in alanine aminotransferase was greater in the rosuvastatin group. Leukocyte count and hemoglobin level decreased to a greater extent in the combination group. The combination group showed greater reductions in TG and elevation in HDL-cholesterol. CONCLUSION: In our study population, the rosuvastatin-fenofibrate combination resulted in comparable incidences of myo- or hepatotoxicity as rosuvastatin monotherapy. However, this combination may need to be used with caution in individuals with underlying pathologies such as renal dysfunction (NCT01414803).

Preventive effects of exenatide on endothelial dysfunction induced by ischemia-reperfusion injury via KATP channels.

OBJECTIVE: The purpose of this study was to evaluate whether exenatide administration can prevent impairment in endothelium-dependent vasodilatation induced by ischemia-reperfusion (IR) injury and whether this effect is mediated by K(ATP) channel opening. METHODS AND RESULTS: In a double-blind, placebo-controlled, crossover design, 20 volunteers were randomly assigned to 2 groups: subcutaneous exenatide (10 µg) or placebo administration. At 30 minutes after the study drug administration, endothelium-dependent flow-mediated dilatation (FMD) of the radial artery was measured before and after IR (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion) injury. Seven days later, both groups were crossed over and received the other treatment (ie, placebo or exenatide) and underwent the same protocol. Pre-IR radial artery diameter, FMD, and baseline radial artery diameter after IR injury were similar between 2 groups (P=no significant difference). After placebo administration, IR significantly blunted FMD (before IR: 12.0±6.23%; after IR: 4.6±3.57%, P=0.02). Exenatide prevented this impairment (FMD before IR: 15.0±7.14%; FMD after IR: 15.0±5.96%, P=no significant difference; P<0.001 compared with placebo). In a separate protocol, this protective effect was completely abolished by pretreatment with glibenclamide (glyburide, 5 mg), a blocker of K(ATP) channels (n=7; FMD before IR: 12.0±2.2%; after IR: 3.2±2.1%, P<0.001). CONCLUSIONS: The present study demonstrates that subcutaneous exenatide protects IR-induced endothelial dysfunction through opening of K(ATP) channels in human IR injury model.