• Molecules and Cells
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• v.37 no.3
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• pp.196-201
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• 2014

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by the vascular remodeling of the pulmonary arterioles, including formation of plexiform and concentric lesions comprised of proliferative vascular cells. Clinically, PAH leads to increased pulmonary arterial pressure and subsequent right ventricular failure. Existing therapies have improved the outcome but mortality still remains exceedingly high. There is emerging evidence that the seven-transmembrane G-protein coupled receptor APJ and its cognate endogenous ligand apelin are important in the maintenance of pulmonary vascular homeostasis through the targeting of critical mediators, such as Kr$\ddot{u}$ppel-like factor 2 (KLF2), endothelial nitric oxide synthase (eNOS), and microRNAs (miRNAs). Disruption of this pathway plays a major part in the pathogenesis of PAH. Given its role in the maintenance of pulmonary vascular homeostasis, the apelin-APJ pathway is a potential target for PAH therapy. This review highlights the current state in the understanding of the apelin-APJ axis related to PAH and discusses the therapeutic potential of this signaling pathway as a novel paradigm of PAH therapy.

• Korean Journal of Radiology
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• v.24 no.5
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• pp.395-405
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• 2023

Objective: This study aimed to develop and validate models using radiomics features on a native T1 map from cardiac magnetic resonance (CMR) to predict left ventricular reverse remodeling (LVRR) in patients with nonischemic dilated cardiomyopathy (NIDCM). Materials and Methods: Data from 274 patients with NIDCM who underwent CMR imaging with T1 mapping at Severance Hospital between April 2012 and December 2018 were retrospectively reviewed. Radiomic features were extracted from the native T1 maps. LVRR was determined using echocardiography performed ≥ 180 days after the CMR. The radiomics score was generated using the least absolute shrinkage and selection operator logistic regression models. Clinical, clinical + late gadolinium enhancement (LGE), clinical + radiomics, and clinical + LGE + radiomics models were built using a logistic regression method to predict LVRR. For internal validation of the result, bootstrap validation with 1000 resampling iterations was performed, and the optimism-corrected area under the receiver operating characteristic curve (AUC) with 95% confidence interval (CI) was computed. Model performance was compared using AUC with the DeLong test and bootstrap. Results: Among 274 patients, 123 (44.9%) were classified as LVRR-positive and 151 (55.1%) as LVRR-negative. The optimism-corrected AUC of the radiomics model in internal validation with bootstrapping was 0.753 (95% CI, 0.698-0.813). The clinical + radiomics model revealed a higher optimism-corrected AUC than that of the clinical + LGE model (0.794 vs. 0.716; difference, 0.078 [99% CI, 0.003-0.151]). The clinical + LGE + radiomics model significantly improved the prediction of LVRR compared with the clinical + LGE model (optimism-corrected AUC of 0.811 vs. 0.716; difference, 0.095 [99% CI, 0.022-0.139]). Conclusion: The radiomic characteristics extracted from a non-enhanced T1 map may improve the prediction of LVRR and offer added value over traditional LGE in patients with NIDCM. Additional external validation research is required.

• Journal of Chest Surgery
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• v.37 no.9
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• pp.755-761
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• 2004

We evaluated the efficacy of Dor procedure in patients with ischemic left ventricular dysfunction. Material and Method: Between April 1998 and December 2002, 45 patients underwent the Dor procedure con-comitant with coronary artery bypass grafting (CABG). Left ventricular ejection fraction (LVEF) and left ventricular end-diastolic/end-systolic volumes (LVEDV/LVESV) were measured by echocardiography, myocardial SPECT, and cardiac catheterization and angiography performed at the sequence of preoperative, early postoperative, and one year postoperative stage. Result: Cardiopulmonary bypass and aortic clamp times were mean 141$\pm$64, 69$\pm$24 minutes, respectively. Intraaortic balloon pump (IABP) therapy was required in 19 patients (42%; 7 preoperatively, 9 intraoperatively, 3 postoperatively). Operative mortality rate was 2.2% (1/45). Postoperative morbidities were low cardiac output syndrome (12), atrial fibrillation (5), acute renal failure (4), and postoperative bleeding (4). Functional class (NYHA) was improved from classes 2.8 to 1.1 (p < 0,01). When we compared between the preoperative and early postoperative values, LVEF was improved from 32$\pm$9% to 52$\pm$11% (p<0.01). The asynergy portion decreased from 57$\pm$12% to 22$\pm$9%, and LVEDV/LVESV indexes improved from 125$\pm$39 mL/$m^2$, 85$\pm$30 mL/$m^2$ to 66$\pm$23 mL/$m^2$, 32$\pm$16 mL/$m^2$ (p<0.01). Although these changes in volumes were relatively preserved at postoperative one year, the left ventricular volumes showed a tendency to increase. Conclusion: After the Dor procedure for ischemic left ventricular dysfunction, LVEF improvement and left ventricular volume reduction were maintained till postoperative one year. The tendency for left ventricular volume to increase at postoperative one year suggested the requirement of strict medical management.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.4
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• pp.447-456
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• 2018

Angiotensin-(1-9) [Ang-(1-9)], generated from Ang I by Ang II converting enzyme 2, has been reported to have protective effects on cardiac and vascular remodeling. However, there is no report about the effect of Ang-(1-9) on pulmonary hypertension. The aim of the present study is to investigate whether Ang-(1-9) improves pulmonary vascular remodeling in monocrotaline (MCT)-induced pulmonary hypertensive rats. Sprague-Dawley rats received Ang-(1-9) ($576{\mu}g/kg/day$) or saline via osmotic mini-pumps for 3 weeks. Three days after implantation of osmotic mini-pumps, 50 mg/kg MCT or vehicle were subcutaneously injected. MCT caused increases in right ventricular weight and systolic pressure, which were reduced by co-administration of Ang-(1-9). Ang-(1-9) also attenuated endothelial damage and medial hypertrophy of pulmonary arterioles as well as pulmonary fibrosis induced by MCT. The protective effects of Ang-(1-9) against pulmonary hypertension were inhibited by Ang type 2 receptor ($AT_2R$) blocker, but not by Mas receptor blocker. Additionally, the levels of LDH and inflammatory cytokines, such as $TNF-{\alpha}$, MCP-1, $IL-1{\beta}$, and IL-6, in plasma were lower in Ang-(1-9) co-treated MCT group than in vehicle-treated MCT group. Changes in expressions of apoptosis-related proteins such as Bax, Bcl2, Caspase-3 and -9 in the lung tissue of MCT rats were attenuated by the treatment with Ang-(1-9). These results indicate that Ang-(1-9) improves MCT-induced pulmonary hypertension by decreasing apoptosis and inflammatory reaction via $AT_2R$.

• Endocrinology and Metabolism
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• v.33 no.4
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• pp.485-492
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• 2018

Background: Increasing evidence supports interplay between aldosterone and parathyroid hormone (PTH), which may aggravate cardiovascular complications in various heart diseases. Negative structural cardiovascular remodeling by primary aldosteronism (PA) is also suspected to be associated with changes in calcium levels. However, to date, few clinical studies have examined how changes in calcium and PTH levels influence cardiovascular outcomes in PA patients. Therefore, we investigated the impact of altered calcium homeostasis caused by excessive aldosterone on cardiovascular parameters in patients with PA. Methods: Forty-two patients (mean age $48.8{\pm}10.9$ years; 1:1, male:female) whose plasma aldosterone concentration/plasma renin activity ratio was more than 30 were selected among those who had visited Severance Hospital from 2010 to 2014. All patients underwent adrenal venous sampling with complete access to both adrenal veins. Results: The prevalence of unilateral adrenal adenoma (54.8%) was similar to that of bilateral adrenal hyperplasia. Mean serum corrected calcium level was $8.9{\pm}0.3mg/dL$ (range, 8.3 to 9.9). The corrected calcium level had a negative linear correlation with left ventricular end-diastolic diameter (LVEDD, ${\rho}=-0.424$, P=0.031). Moreover, multivariable regression analysis showed that the corrected calcium level was marginally associated with the LVEDD and corrected QT (QTc) interval (${\beta}=-0.366$, P=0.068 and ${\beta}=-0.252$, P=0.070, respectively). Conclusion: Aldosterone-mediated hypercalciuria and subsequent hypocalcemia may be partly involved in the development of cardiac remodeling as well as a prolonged QTc interval, in subjects with PA, thereby triggering deleterious effects on target organs additively.

• Journal of Veterinary Clinics
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• v.27 no.6
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• pp.735-739
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• 2010

An 8 month old female Maltese (body weight 3.6 kg) was referred with primary complaints of dyspnea and exercise intolerance. Diagnostic imaging studies revealed marked cardiomegaly and prominent main pulmonary trunk dilation on thoracic radiography, abnormally arisen aortic roots (toward right ventricle) with left-to right shunted perimembraneous ventricular septal defect located underneath of aortic root, aortic root was located to predominantly to the right ventricle and pulmonary regurgitation (peak velocity 4.7 m/s, pressure gradient ~88 mmHg) from pulmonary over-circulation and hypertension on echocardiography, indicating double outlet right ventricle (DORV). The dog was treated with furosemide (1 mg/kg, BID) for reducing volume overload at right ventricle, spironolatcone (1 mg/kg) and enalapril (0.5 mg/kg) for minimizing deleterious cardiac remodeling, and sildenafil (1 mg/kg) for lessening pulmonary over-circulation and hypertension. The clinical condition of this dog was improved after 1 week of medical treatment. The dog is currently survived and regularly monitored.

• Journal of Ginseng Research
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• v.40 no.3
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• pp.285-291
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• 2016

Background: Ginsenosides have been shown to exert beneficial pharmacological effects on the central nervous, cardiovascular, and endocrine systems. We sought to determine whether total ginsenosides (TG) inhibit monocrotaline (MCT)-induced pulmonary hypertension and to elucidate the underlying mechanism. Methods: MCT-intoxicated rats were treated with gradient doses of TG, with or without $N^G$-nitro-$\small{L}$-arginine methyl ester. The levels of molecules involving the regulation of nitric oxide and mitogen-activated protein kinase pathways were determined. Results: TG ameliorated MCT-induced pulmonary hypertension in a dose-dependent manner, as assessed by the right ventricular systolic pressure, the right ventricular hypertrophy index, and pulmonary arterial remodeling. Furthermore, TG increased the levels of pulmonary nitric oxide, endothelial nitric oxide synthase, and cyclic guanosine monophosphate. Lastly, TG increased mitogen-activated protein kinase phosphatase-1 expression and promoted the dephosphorylation of extracellular signal-regulated protein kinases 1/2, p38 mitogen-activated protein kinase, and c-Jun NH2-terminal kinase 1/2. Conclusion: TG attenuates MCT-induced pulmonary hypertension, which may involve in part the regulation of nitric oxide and mitogen-activated protein kinase pathways.

• The Korean Journal of Physiology and Pharmacology
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• v.26 no.2
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• pp.87-94
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• 2022

Myocardial infarction promotes cardiac remodeling and myocardial fibrosis, thus leading to cardiac dysfunction or heart failure. Peiminine has been regarded as a traditional anti-fibrotic Chinese medicine in pulmonary fibrosis. However, the role of peiminine in myocardial infarction-induced myocardial injury and fibrosis remained elusive. Firstly, rat model of myocardial infarction was established using ligation of the left coronary artery, which were then intraperitoneally injected with 2 or 5 mg/kg peiminine once a day for 4 weeks. Echocardiography and haemodynamic evaluation results showed that peiminine treatment reduced left ventricular end-diastolic pressure, and enhanced maximum rate of increase/decrease of left ventricle pressure (± dP/dt max) and left ventricular systolic pressure, which ameliorate the cardiac function. Secondly, myocardial infarction-induced myocardial injury and infarct size were also attenuated by peiminine. Moreover, peiminine inhibited myocardial infarction-induced increase of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α production, as well as the myocardial cell apoptosis, in the rats. Thirdly, peiminine also decreased the myocardial fibrosis related protein expression including collagen I and collagen III. Lastly, peiminine reduced the expression of p38 and phosphorylation of extracellular signal-regulated kinase 1/2 in rat model of myocardial infarction. In conclusion, peiminine has a cardioprotective effect against myocardial infarction-induced myocardial injury and fibrosis, which can be attributed to the inactivation of mitogen-activated protein kinase pathway.

• Molecules and Cells
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• v.40 no.1
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• pp.66-72
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• 2017

Pathological hypertrophy of the heart is closely associated with endoplasmic reticulum stress (ERS), leading to maladaptations such as myocardial fibrosis, induction of apoptosis, and cardiac dysfunctions. Salubrinal is a known selective inhibitor of protein phosphatase 1 (PP1) complex involving dephosphorylation of phospho-eukaryotic translation initiation factor 2 subunit $(p-eIF2)-{\alpha}$, the key signaling process in the ERS pathway. In this study, the effects of salubrinal were examined on cardiac hypertrophy using the mouse model of transverse aortic constriction (TAC) and cell model of neonatal rat ventricular myocytes (NRVMs). Treatment of TAC-induced mice with salubrinal ($0.5mg{\cdot}kg^{-1}{\cdot}day^{-1}$) alleviated cardiac hypertrophy and tissue fibrosis. Salubrinal also alleviated hypertrophic growth in endothelin 1 (ET1)-treated NRVMs. Therefore, the present results suggest that salubrinal may be a potentially efficacious drug for treating pathological cardiac remodeling.

• Tuberculosis and Respiratory Diseases
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• v.60 no.6
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• pp.625-630
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• 2006

Background: Pulmonary hypertension in COPD patients is the result of a direct effect of tobacco smoke on the intrapulmonary vessels with the abnormal production of the mediators that control vasoconstriction, vasodilatation, and vascular cell proliferation, which ultimately lead to aberrant vascular remodeling and physiology. COPD patients are prone to the developmint of an acute and chronic thromboembolism with an elevation of the plasma procoagulant and fibrinolytic markers However, the roles of the coagulation and fibrinolysis system on the right ventricular dysfunction in COPD patients are not well defined. We examined the alteration of the coagulation and fibrinolysis system in COPD patients according to the right ventricular function measured using cardiac multidetector computed tomography (MDCT). Methods: The right ventricular ejection fraction (RVEF) was measured using cardiac MDCT in 26 patients who were diagnosed with COPD according to the definition of the GOLD guideline. The plasma level of thrombin antithrombin (TAT) and plasminogen activator inhibitor (PAI)-1 were measured using an enzyme linked immunoassay. Results: The plasma TAT was markedly elevated in COPD patients ($10.5{\pm}19.8{\mu}g/L$) compared with those of the control ($3.4{\pm}2.5{\mu}g/L$) (p<0.01). However, the plasma PAI-1 in COPD patients ($29.6{\pm}20.7ng/mL$) was similar to that in the controls. The plasma TAT showed a significant inverse relationship with the RVEF measured by the cardiac MDCT in COPD patients (r=-0.645, p<0.01). However, the plasma PAI-1 did not show a relationship with the RVEF (r=0.022, p=0.92). Conclusion: These results suggest that the coagulation system in COPD patients is markedly activated, and that the plasma level of TAT might be a marker of a right ventricular dysfunction in COPD patients.