Heesang Song

Crucial role of calbindin-D28k in the pathogenesis of Alzheimer's disease mouse model.

Calbindin-D28k (CB), one of the major calcium-binding and buffering proteins, has a critical role in preventing a neuronal death as well as maintaining calcium homeostasis. Although marked reductions of CB expression have been observed in the brains of mice and humans with Alzheimer disease (AD), it is unknown whether these changes contribute to AD-related dysfunction. To determine the pathogenic importance of CB depletions in AD models, we crossed 5 familial AD mutations (5XFAD; Tg) mice with CB knock-out (CBKO) mice and generated a novel line CBKO·5XFAD (CBKOTg) mice. We first identified the change of signaling pathways and differentially expressed proteins globally by removing CB in Tg mice using mass spectrometry and antibody microarray. Immunohistochemistry showed that CBKOTg mice had significant neuronal loss in the subiculum area without changing the magnitude (number) of amyloid β-peptide (Aβ) plaques deposition and elicited significant apoptotic features and mitochondrial dysfunction compared with Tg mice. Moreover, CBKOTg mice reduced levels of phosphorylated mitogen-activated protein kinase (extracellular signal-regulated kinase) 1/2 and cAMP response element-binding protein at Ser-133 and synaptic molecules such as N-methyl-D-aspartate receptor 1 (NMDA receptor 1), NMDA receptor 2A, PSD-95 and synaptophysin in the subiculum compared with Tg mice. Importantly, this is the first experimental evidence that removal of CB from amyloid precursor protein/presenilin transgenic mice aggravates AD pathogenesis, suggesting that CB has a critical role in AD pathogenesis.

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.

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.

Implanted bone marrow-derived mesenchymal stem cells fail to metabolically stabilize or recover electromechanical function in infarcted hearts.

Mesenchymal stem cells (MSCs) have been used with success in several clinical applications for clinical treatment of ischemic hearts. However, the reported effects of MSC-based therapy on myocardial infarction (MI) are inconsistent. In particular, the preventive effects of MSC-based therapy on arrhythmic sudden death and metabolic disorders after infarction remain controversial. Here, we investigated the effects of MSCs on reverse remodeling in an infarcted myocardium, and found that MSC-therapy failed to achieve the complete regeneration of infarcted myocardium. Histological analyses showed that although infarct size and interstitial fibrosis induced by MI recovered significantly after MSC treatment, these improvements were marginal, indicating that a significant amount of damaged tissue was still present. Furthermore, transplanted MSCs had slight anti-apoptotic and anti-inflammatory effects in MSC-implanted regions and no significant improvements in cardiac function were observed, suggesting that naïve MSCs might not be the right cell type to treat myocardial infarction. Furthermore, small ion profiling using ToF-SIMS revealed that the metabolic stabilization provided by the MSCs implantation was not significant compared to the sham group. Together, these results indicate that pretreatment of MSCs is needed to enhance the benefits of MSCs, particularly when MSCs are used to treat arrhythmogenicity and metabolically stabilize infarcted myocardium.

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].

High-sensitivity C-reactive protein and mean platelet volume as predictive values after percutaneous coronary intervention for long-term clinical outcomes: a comparable and additive study.

This study was designed to establish the relationship of high-sensitivity C-reactive protein (hsCRP) and mean platelet volume (MPV) with the development of adverse outcomes after percutaneous coronary intervention (PCI). hsCRP levels and MPV were analysed in 372 patients who underwent PCI, with the primary endpoint as major adverse cardiac and cerebrovascular events (MACCE): a composite of cardiac death, myocardial infarction (MI), target vessel revascularization (TVR), ischemic stroke and stent thrombosis. During the follow-up period (mean, 25.8 months), there were 21 cardiac deaths, 10 MIs including four stent thrombosis events, seven ischemic strokes and 29 TVRs. The hsCRP cut-off level was set at 0.31 mg/dl using the receiver operating characteristic curve to differentiate between the groups with and without MACCE. The MPV cut-off level was set at 8.00 fl by the receiver operating characteristic curve to differentiate between the groups with and without MACCE. A Kaplan–Meier analysis revealed that the high hsCRP group (≥0.31 mg/dl) had a significantly higher cardiac death and MACCE rate than the low hsCRP group (<0.31 mg/dl), and the high MPV group (>8.00 fl) had a significantly higher cardiac death and MACCE rate than the low MPV group (⩽8.00 fl). Furthermore, the high hsCRP and MPV groups were significantly associated with an increased risk of MACCE. These results show that hsCRP and MPV are predictive markers after PCI for MACCE; they are also additively associated with a higher risk of MACCE.

Prediction of Long-Term Mortality Based on Neutrophil-Lymphocyte Ratio After Percutaneous Coronary Intervention

Background: The preprocedural neutrophil‐lymphocyte ratio (NLR) is related to adverse outcomes in patients with coronary artery disease. We hypothesized that high NLR is a predictor of cardiac death after percutaneous coronary intervention (PCI). The objective of this investigation was to assess the associations of NLR, high‐sensitivity cardiac troponin T (hs‐cTnT) and N‐terminal pro‐B type natriuretic peptide (NT‐proBNP) with the occurrence of cardiac death after PCI. Materials and Methods: The NLR, hs‐cTnT and NT‐proBNP were analyzed in 372 patients who underwent PCI. The primary end point was cardiac death. Results: The median NLR was 2.3 (interquartile range: 1.5–4.1). There were 21 cardiac death events during a mean follow‐up duration of 25.8 months. With the NLR cutoff level set to 3.3 using the receiver‐operating characteristic curve, the sensitivity and specificity for differentiating between the group with cardiac death and the group without cardiac death were 85.7% and 59.3%, respectively. Kaplan‐Meier analysis revealed that the higher NLR group (≥3.3) had a significantly higher cardiac death rate than the lower NLR group (<3.3) (11.1% versus 1.4%, log‐rank: P < 0.0001). This value was more useful in patients with heart failure (NT‐proBNP ≥ 300 ng/L) or myocardial injury (hs‐cTnT ≥ 100 ng/L). Conclusions: The outcomes of the current study demonstrate that high NLR is a predictor of cardiac death after PCI, especially in patients with heart failure or myocardial injury.

Predictive value of brachial-ankle pulse wave velocity for long-term clinical outcomes after percutaneous coronary intervention in a Korean cohort.

OBJECTIVE The aim of this study was to determine the associations of brachial-ankle pulse wave velocity (baPWV), 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). METHODS The baPWV, hs-cTnT and NT-proBNP were analyzed in 372 patients who underwent PCI. The primary endpoint was cardiac death. RESULTS There were 21 events of cardiac death during a mean of 25.8 months of follow-up. When the baPWV cut-off level was set to 1672 cm/s using the receiver operating characteristic curve, the sensitivity was 85.7% and the specificity was 60.1% for differentiating between the group with cardiac death and the group without cardiac death. Kaplan-Meier analysis revealed that the higher baPWV group (≥1672 cm/s) had a significantly higher cardiac death rate than the lower baPWV group (<1672 cm/s) (11.4% vs. 1.4%, log-rank: P<0.0001). This value was more useful in patients with myocardial injury (hs-cTnT≥0.1 ng/mL) or heart failure (NT-proBNP≥450 pg/mL). CONCLUSIONS The results of this study show that high baPWV is a predictive marker for cardiac death after PCI.

Relation of Triiodothyronine to Subclinical Myocardial Injury in Patients With Chest Pain

Heart dysfunctions have been shown to be associated with altered concentrations of thyroid hormones. However, the relation between thyroid hormones and subclinical myocardial injury in those without clinically apparent coronary heart disease is not well-established. We examined the correlation between altered levels of thyrotropin, free thyroxine, and triiodothyronine (T3) and high-sensitivity cardiac troponin T (hs-cTnT) in 250 patients (mean age 60 years; 42% men) with chest pain, who were free of coronary heart disease and heart failure. These patients were examined in the emergency room or outpatient department of the cardiovascular center of Chosun University Hospital. Multivariate logistic regression models were used for statistical analysis. The baseline values of T3 were associated with elevated hs-cTnT levels (r = -0.428, p <0.001), a significantly negative correlation. We did not observe any significant correlation between the thyrotropin or free thyroxine and hs-cTnT levels. When the T3 cutoff was set at 74.6 ng/dl using the receiver operating characteristic curve, the sensitivity and specificity was 70% and 69%, respectively, for differentiating between groups with and without myocardial injury. After adjusting for traditional risk factors, the odds ratio for an elevated hs-cTnT level (≥0.014 ng/ml) for patients with T3 <74.6 ng/dl was 6.95 (95% confidence interval 3.09 to 15.66) compared to patients with T3 ≥74.6 ng/dl. In conclusion, the T3 levels were negatively related to hs-cTnT levels among patients without clinically obvious coronary heart disease.

Combination of Mean Platelet Volume and Neutrophil to Lymphocyte Ratio Predicts Long-Term Major Adverse Cardiovascular Events After Percutaneous Coronary Intervention

We hypothesized that the combination of a high neutrophil to lymphocyte ratio (NLR) and mean platelet volume (MPV) would be a stronger predictor of future cardiovascular events after percutaneous coronary intervention (PCI). Both NLR and MPV were measured in 364 consecutive patients undergoing PCI. The primary end point was the incidence of major adverse cardiovascular events (MACEs), including cardiac death, nonfatal myocardial infarction, and stent thrombosis. The median values of NLR and MPV were 2.8 and 8.2 fL, respectively. There were 26 MACEs during a median follow-up duration of 29.3 months. Kaplan-Meier analysis revealed that the higher NLR group had a significantly higher MACE rate than the lower NLR group and that the higher MPV group had a significantly higher MACE rate than the lower MPV group (log-rank: P = .0064 and P = .0004, respectively). The cumulative MACE-free survival can be further stratified by the combination of NLR and MPV. This value was especially useful in patients with acute coronary syndrome (ACS). By multivariate Cox proportional hazards model, the combination of high NLR and high MPV was independently associated with MACE (P = .026). The combination of a high NLR and high MPV is an independent predictor of MACE after PCI, especially in patients with ACS.