Dong-Hyun Choi

Stroke prediction using mean platelet volume in patients with atrial fibrillation.

Platelet size, measured as mean platelet volume (MPV), is associated with platelet reactivity. MPV has been identified as an independent risk factor for future stroke and myocardial infarction. The aim of this study was to determine the association of MPV with the development of stoke in patients with atrial fibrillation (AF). MPV, N-terminal pro B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hsCRP) were analysed in 200 patients with AF (mean age 69 years; 56% male). The primary endpoint was ischaemic stroke event. The mean MPV was 8.5 ± 1.0 fL and the median NT-proBNP was 1916.5 (IQR 810–4427) pg/mL. The median hsCRP was 0.47 (IQR 0.32–2.46) mg/dL. There were 14 stroke events during a mean of 15.1 months of follow up. Kaplan-Meier analysis revealed that the higher tertile MPV group (≥8.9 fL) had a significantly higher stroke rate compared to the lower tertile MPV group (<8.0 fL) (14.7% vs. 3.1%, log-rank: P = 0.01). A higher MPV was an independent predictor of stroke risk after adjusting for age, gender, and other CHADS2 (congestive heart failure, hypertension, diabetes, and previous stroke or transient ischemic attack (TIA) history) score components (hazard ratio: 5.03, 95% CI 1.05–24.05, P = 0.043) in Cox proportional hazard analysis. When the MPV cut-off level was set to 8.85 fL using the receiver operating characteristic curve, the sensitivity was 71% and the specificity was 69% for differentiating between the group with stroke and the group without stroke. This value was more useful in patients with a low to intermediate traditional thromboembolic risk (CHADS2 score <2). Furthermore, AF patients with an MPV over 8.85 fL had high stroke risk without anticoagulation, especially in the low thromboembolic risk group (Log-Rank <0.0001). The results of this study show that MPV was a predictive marker for stroke; its predictive power for stroke was independent of age, gender, and other CHADS2 score components in patients with AF. These findings suggest that anticoagulation may be needed in patients with a high MPV, even if they have low to intermediate traditional thromboembolic risk (CHADS2 score <2).

Stroke or coronary artery disease prediction from mean platelet volume in patients with type 2 diabetes mellitus

The aim of this study was to determine the association of mean platelet volume (MPV) with the development of stroke or coronary artery disease (CAD) in diabetes mellitus (DM). MPV was analyzed in 200 Korean patients with DM. The primary endpoint was composite of ischemic stroke/CAD events. The mean MPV was 7.6 ± 0.8 fl. There were 14 ischemic stroke events and 8 CAD events during a mean of 28.4 months of follow-up. The Kaplan–Meier analysis revealed that the higher tertile MPV group (≥7.9 fl) had a significantly higher stroke/CAD rate compared to the lower tertile MPV group (≤7.3 fl) (29.9% vs. 2.8%, log-rank: p < 0.001). Higher MPV was an independent predictor of stroke/CAD risk after adjusting for 10-year risk ≥10%, hypertension, dyslipidemia, and previous stroke or transient ischemic attack history (hazard ratio: 11.92, 95% confidence interval 2.68–52.92, p = 0.001) in the Cox proportional hazard analysis. When the MPV cut-off level was set to 7.95 fl using the receiver operating characteristic curve, the sensitivity was 91% and the specificity was 80% for differentiating between the group with stroke/CAD and the group without stroke/CAD. This value was more useful in patients with hypertension. The results of this study show that MPV is a predictive marker for stroke/CAD; its predictive power for stroke/CAD is independent of age, gender, hypertension, and hemoglobin A1C.

Effects of oral epigallocatechin gallate on the oral pharmacokinetics of verapamil in rats

Verapamil is known to be a P-glycoprotein (P-gp) substrate and norverapamil is formed via hepatic cytochrome P450 (CYP 3A) in the rat. Epigallocatechin gallate (EGCG), a flavonoid, was reported to be an inhibitor of both P-gp and CYP3A. Hence, it could be expected that EGCG could alter the pharmacokinetics of verapamil. In this study, 9 mg/kg verapamil was administered orally to Sprague-Dawley rats 30 min after the oral administration of 2 and 10 mg/kg of oral EGCG. Compared with the controls, the AUC values of both verapamil (74.3% and 111% increase for 2 and 10 mg/kg EGCG, respectively) and norverapamil (51.5% and 87.2% increase for 2 and 10 mg/kg EGCG, respectively) were significantly greater in the presence of EGCG. However, compared with the controls, both the AUC and the relative bioavailability of verapamil were significantly (p<0.01) increased by 74.3-111% in the presence of EGCG. The likely explanation is inhibition of P-gp. Inhibition of CYP3A would increase the AUC of verapamil but decrease the AUC of norverampil. However, inhibition of P-gp would lead to an increase of AUC of both verapamil and norverapamil.

Effects of myricetin, an antioxidant, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats: possible role of cytochrome P450 3A4, cytochrome P450 2C9 and P-glycoprotein inhibition by myricetin

Objectives  The effects of myricetin, a natural flavonoid, on the pharmacokinetics of losartan and its active metabolite, EXP‐3174, were investigated in rats. Losartan and myricetin interact with cytochrome P450 (CYP) enzymes and P‐glycoprotein, and the increase in the use of health supplements may result in myricetin being taken concomitantly with losartan as a combination therapy to treat or prevent cardiovascular diseases.

Effects of HMG-CoA Reductase Inhibitors on the Pharmacokinetics of Losartan and Its Main Metabolite EXP-3174 in Rats: Possible Role of CYP3A4 and P-gp Inhibition by HMG-CoA Reductase Inhibitors

The present study was designed to investigate the effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (atorvastatin, pravastatin, simvastatin) on the pharmacokinetics of losartan and its active metabolite EXP-3174 in rats. Pharmacokinetic parameters of losartan and EXP-3174 in rats were determined after oral and intravenous administration of losartan (9 mg/kg) without and with HMG-CoA reductase inhibitors (1 mg/kg). The effect of HMG-CoA reductase inhibitors on P-gp and cytochrome (CYP) 3A4 activity were also evaluated. Atorvastatin, pravastatin and simvastatin inhibited CYP3A4 activities with IC50 values of 48.0, 14.1 and 3.10 µmol/l, respectively. Simvastatin (1–10 µmol/l) enhanced the cellular uptake of rhodamine-123 in a concentration-dependent manner. The area under the plasma concentration-time curve (AUC0–∞) and the peak plasma concentration of losartan were significantly (p < 0.05) increased by 59.6 and 45.8%, respectively, by simvastatin compared to those of control. The total body clearance (CL/F) of losartan after oral administration with simvastatin was significantly decreased (by 34.8%) compared to that of controls. Consequently, the absolute bioavailability (F) of losartan after oral administration with simvastatin was significantly increased by 59.4% compared to that of control. The metabolite-parent AUC ratio was significantly decreased by 25.7%, suggesting that metabolism of losartan was inhibited by simvastatin. In conclusion, the enhanced bioavailability of losartan might be mainly due to inhibition of P-gp in the small intestine and CYP3A subfamily-mediated metabolism of losartan in the small intestine and/or liver and to reduction of the CL/F of losartan by simvastatin.

Effects of Resveratrol on the Pharmacokinetics of Diltiazem and Its Major Metabolite, Desacetyldiltiazem, in Rats

The purpose of this study was to investigate the effects of resveratrol, an antioxidant, on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. The pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined after an oral administration of diltiazem (15 mg/kg) to rats in the presence and absence of resveratrol (0.5, 2.5, and 10 mg/kg). Compared to the control group, the presence of resveratrol significantly (P < 0.05) increased the area under the plasma concentration-time curve (AUC) of diltiazem, except for resveratrol 0.5 mg/kg. Consequently, the absolute bioavailability (AB) of diltiazem in the presence of resveratrol (2.5 and 10 mg/kg) was significantly (P < 0.05) higher (10.2-11.1%) than that of the control (6.9%). The relative bioavailability (RB) of diltiazem in the presence of resveratrol (2.5 and 10 mg/kg) was increased by 1.48- to 1.60-fold. Resveratrol did not alter absorption rate constant (K(a)) and the time to reach the peak concentration (T(max)) of diltiazem. The AUC of desacetyldiltiazem was increased significantly (P < 0.05) in the presence of 10 mg/kg of resveratrol. The metabolite-parent AUC ratio (MR) in the presence of resveratrol was decreased but did not show significant change. In conclusion, resveratrol significantly increased the bioavailability of diltiazem due to the inhibition of both the cytochrome P450 (CYP) 3A4-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or liver. Based on these results, if these results would be confirmed in clinical experiments, the dosage of diltiazem should be readjusted when diltiazem is used concomitantly with resveratrol.

Usefulness of mean platelet volume as a biomarker for long-term clinical outcomes after percutaneous coronary intervention in Korean cohort: A comparable and additive predictive value to high-sensitivity cardiac troponin T and N-terminal pro-B type natriuretic peptide

Abstract The aim of this study was to determine the associations of the mean platelet volume (MPV) high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B type natriuretic peptide (NT-proBNP) with the development of adverse outcomes after percutaneous coronary intervention (PCI). MPV hs-cTnT and NT-proBNP were analyzed in 372 patients who underwent PCI. The primary endpoint was cardiac death. The secondary endpoint analyzed was cardiovascular events (CVE): the composite of cardiac death, myocardial infarction (MI), target vessel revascularization (TVR), ischemic stroke and stent thrombosis (ST). The median MPV hs-cTnT and NT-proBNP levels were 8.20 (IQR 7.70–8.70) fL, 0.291 (IQR 0.015–3.785) ng/mL, and 105.25 (IQR 50.84–1128.5) pg/mL, respectively. There were 21 events of cardiac death, 10 MI (including 4 events of ST), 7 ischemic strokes and 29 TVR during a mean of 25.8 months of follow-up. The Kaplan–Meier analysis revealed that the higher MPV group (>8.20 fL, median) had a significantly higher cardiac death rate than the lower MPV group (≤8.20 fL; 9.4% vs. 2.1%, log-rank: p = 0.0026). When the MPV cut-off level was set to 8.20 fL using the receiver operating characteristic curve, the sensitivity was 81% and the specificity was 53.3% for differentiating between the group with cardiac death and the group without cardiac death. This value was more useful in patients with myocardial injury (hs-cTnT ≥ 0.1 ng/mL) or heart failure (NT-proBNP ≥ 450 pg/mL). The results of this study show that MPV is a predictive marker for cardiac death after PCI; its predictive power for cardiac death is more useful in patients with myocardial injury or heart failure.

Clinical outcome prediction from mean platelet volume in patients undergoing percutaneous coronary intervention in Korean cohort: Implications of more simple and useful test than platelet function testing

Abstract The aim of this study was to determine the associations of the mean platelet volume (MPV) with the development of adverse outcomes after percutaneous coronary intervention (PCI) and platelet reactivity. MPV and platelet function testing were analysed in 208 patients who underwent PCI. The primary endpoint was cardiac death. The secondary endpoint analysed was cardiovascular events (CVE): the composite of myocardial infarction (MI), target vessel revascularization (TVR), and stent thrombosis (ST). The median MPV level, aspirin reaction unit (ARU), P2Y12 reaction units (PRU) and P2Y12% inhibition (PI%) of clopidogrel were 8.55 (IQR 8.00–9.18) fl, 401.0 (IQR 389.3–442.0) ARU, 222.0 (IQR 169.0–272.3) PRU and 22 (IQR 9–38) %, respectively. We observed that high values of MPV were associated with elevated ARU (r = 0.165, p = 0.017) and decreased PI% (r = −0.167, p = 0.016). There were 10 events of cardiac death, 3 MI (including 1 event of ST), and 8 TVR during a mean of 7.6 months of follow-up. The Kaplan–Meier analysis revealed that the higher MPV group (≥8.55 fl, median) had a significantly higher cardiac death rate compared to the lower MPV group (<8.55 fl) (7.7% vs. 1.9%, log-rank: p = 0.035). However, aspirin or clopidogrel resistance (>550 ARU, <40 PI%, respectively) did not predict cardiac death. When the MPV cut-off level was set to 8.55 fl using the receiver operating characteristic curve, the sensitivity was 80% and the specificity was 51.5% for differentiating between the group with cardiac death and the group without cardiac death. This value was more useful in patients with clinical diagnosis of acute coronary syndrome (ACS). Furthermore, ACS patients with an MPV over 8.55 fl had high cardiac death and CVE risk without atorvastatin loading before PCI (Log-Rank = 0.0031, 0.0023, respectively). The results of this study show that MPV was a predictive marker for cardiac death after PCI; its predictive power for cardiac death was more useful in patients with ACS.

Mean platelet volume: a potential biomarker of the risk and prognosis of heart disease.

Platelets are essential for progression of atherosclerotic lesions, plaque destabilization, and thrombosis. They secrete and express many substances that are crucial mediators of coagulation, inflammation, and atherosclerosis. Mean platelet volume (MPV) is a precise measure of platelet size, and is routinely reported during complete blood count analysis. Emerging evidence supports the use of MPV as a biomarker predicting the risk of ischemic stroke in patients with atrial fibrillation, and as a guide for prescription of anticoagulation and rhythm-control therapy. In addition, MPV may predict the clinical outcome of percutaneous coronary intervention (PCI) in patients with coronary artery disease and indicate whether additional adjunctive therapy is needed to improve clinical outcomes. This review focuses on the current evidence that MPV may be a biomarker of the risk and prognosis of common heart diseases, particularly atrial fibrillation and coronary artery disease treated via PCI.

Effects of matrix metalloproteinase 13 on vascular smooth muscle cells migration via Akt–ERK dependent pathway

Migration of vascular smooth muscle cells (VSMCs) is an early event of atherosclerosis, which is mediated mainly by matrix metalloproteinase (MMP) 2 and 9. Because MMP13 is associated with tumor cells migration, we hypothesized that MMP13 participates in VSMC migration induced by certain stimuli such as platelet-derived growth factor (PDGF) and angiotensin II (Ang II). We found that the mRNA level of MMP13 in rat aortic smooth muscle cells (RAoSMCs) was increased by both PDGF and Ang II. We observed the significant decrease of migration in PDGF- or Ang II-treated RAoSMCs by MMP13 specific inhibitor treatment. Silencing of MMP13 by a specific small interfering RNA (siRNA) significantly decreased expression of the active form of MMP13, which is followed by the decreased migration of PDGF- or Ang II-treated RAoSMCs. Interestingly, we observed synergistic inhibitory effects on migration by treatment with MMP2 and 13 or MMP9 and 13 inhibitors compared with that in single treatments. Moreover, we found that cordycepin, a known inhibitor of VSMC migration, caused significant downregulation of MMP2, 9, and 13 expression in PDGF-treated RAoSMCs. We further show that the expression level of MMP13 was significantly decreased by the treatment of Akt or ERK specific inhibitor in PDGF-treated RAoSMCs. Together, our data strongly suggest that MMP13 involves VSMCs migration via an Akt and ERK-dependent regulation [corrected].