The Efficacy and Tolerability of Irbesartan/Amlodipine Combination Therapy in Patients With Essential Hypertension Whose Blood Pressure Were not Controlled by Irbesartan Monotherapy.

PURPOSE: This study aimed to evaluate the efficacy and tolerability of irbesartan (IRB) and amlodipine (AML) combination therapy in patients with essential hypertension whose blood pressure (BP) was not controlled by IRB monotherapy. METHODS: Two multicenter, randomized, double-blind, placebo-controlled, phase III studies were conducted in Korea (the I-DUO 301 study and the I-DUO 302 study). After a 4-week run-in period with either 150 mg IRB (I-DUO 301 study) or 300 mg IRB (I-DUO 302 study), patients with uncontrolled BP (ie, mean sitting systolic BP [MSSBP] ≥140 mmHg to <180 mmHg and mean sitting diastolic BP <110 mmHg) were randomized to the placebo, AML 5 mg, or AML 10 mg group. A total of 428 participants were enrolled in the 2 I-DUO studies. In the I-DUO 301 study, 271 participants were randomized in a 1:1:1 ratio to receive either IRB/AML 150/5 mg, IRB/AML 150/10 mg, or IRB 150 mg/placebo. In the I-DUO 302 study, 157 participants were randomized in a 1:1 ratio to receive IRB/AML 300/5 mg or IRB 300 mg/placebo. The primary endpoint was the change in MSSBP from baseline to week 8. Tolerability was assessed according to the development of treatment-emergent adverse events (TEAEs) and clinically significant changes in physical examination, laboratory tests, pulse, and 12-lead electrocardiography. FINDINGS: In I-DUO 301, the mean (SD) changes of MSSBP at week 8 from baseline were -14.78 (12.35) mmHg, -21.47 (12.78) mmHg, and -8.61 (12.19) mmHg in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively. In I-DUO 302, the mean (SD) changes of MSSBP at week 8 from baseline were -13.30 (12.47) mmHg and -7.19 (15.37) mmHg in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively. In both studies, all combination groups showed a significantly higher reduction in MSSBP than the IRB monotherapy groups (P < 0.001 for both). TEAEs occurred in 10.00%, 10.99%, and 12.22% of participants in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively, in I-DUO 301 and in 6.33% and 10.67% of participants in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively, in I-DUO 302, with no significant between-group differences. Overall, there was one serious adverse event throughout I-DUO study. IMPLICATIONS: The combination of IRB and AML has superior antihypertensive effects compared with IRB alone over an 8-week treatment period, with placebo-like tolerability. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05476354 (I-DUO 301), NCT05475665 (I-DUO 302).

Low-density lipoprotein receptor-related protein 6 ablation in macrophages differentially inhibits lung injury-mediated inflammation and metastasis.

Low-density lipoprotein receptor-related protein 6 (LRP6) is a receptor protein for Wnt ligands. Yet, their role in immune cell regulation remains elusive. Here we demonstrated that genetic deletion of LRP6 in macrophages using LysM-cre Lrp6fl/fl (Lrp6MKO) mice showed differential inhibition of inflammation in the bleomycin (BLM)-induced lung injury model and B16F10 melanoma lung metastasis model. Lrp6MKO mice showed normal immune cell populations in the lung and circulating blood in homeostatic conditions. In the BLM-induced lung injury model, Lrp6MKO mice showed a decreased number of monocyte-derived alveolar macrophages, reduced collagen deposition and alpha-smooth muscle actin (αSMA) protein levels in the lung. In B16F10 lung metastasis model, Lrp6MKO mice reduced lung tumor foci. Monocytic and granulocytic-derived myeloid-derived suppressor cells (M-MDSCs and G-MDSCs) were increased in the lung. In G-MDSCs, hypoxia-inducible factor 1α (HIF1α)+ PDL1+ population was markedly decreased but not in M-MDSCs. Taken together, our results show that the role of LRP6 in macrophages is differential depending on the inflammation microenvironment in the lung.

Heavy metal concentration according to shrimp species and organ specificity: Monitoring and human risk assessment.

This study assessed heavy metal levels (lead (Pb), cadmium (Cd), total arsenic (tAs), arsenite (As (III)), arsenate (As (V)), monomethyl arsenic acid (MMA), dimethylarsinic acid (DMA), total mercury (tHg), and methylmercury (MeHg)) in six organs (total portion, head, body, shell, muscle, and intestine) of 11 shrimp species distributed in Korea. Shrimp exhibited significant variability in heavy metal accumulation, with Alaskan pink and dried shrimp (Lesser glass, Southern rough, and Chinese ditch prawn) showing the highest metal concentrations. Notably, the intestine having the highest overall metal content, while Cd was most prominent in the head, tHg was highest in the muscle. The Hazard Quotient values of 11 shrimp species in South Korea were below the European Food Safety Authority's allowable limits for heavy metals. This study illuminates the heavy metal profiles of distributed shrimp in Korea and emphasizes the ongoing need for monitoring heavy metals on seafood to ensure consumer safety.

Long-term clinical outcomes for patients with uncrossable patent foramen ovale.

Introduction: Patent foramen ovale (PFO) closure is performed in selected patients with cryptogenic stroke to prevent recurrence. The prognosis of patients with uncrossable PFO after failed guidewire or catheter passage during the procedure remains unknown. We compared the long-term prognosis between uncrossable PFO and successful PFO closure in patients with high-grade PFO shunts. Methods: We analyzed patients who underwent PFO closure for stroke or transient ischemic attack (TIA) prevention at Gachon University Gil Medical Center between April 2010 and March 2022. The primary outcome was a composite of recurrent stroke or TIA. Secondary outcomes included stroke, TIA, all-cause death, and a composite of stroke, TIA, and all-cause death. Results: Of 286 patients, 245 were included in the analysis after excluding those with transseptal puncture technique usage or concurrent atrial septal defect. Among them, 82 had uncrossable PFO, and 163 underwent successful PFO closure. Large shunts were more prevalent in the PFO closure group compared to the uncrossable PFO group (62.0% vs. 34.1%, P < 0.001), and resting shunts were also more common in the PFO closure group (17.8% vs. 2.4%, P < 0.001). Stroke or TIA occurred in 2 patients (2.4%) in the uncrossable PFO group and 8 patients (4.9%) in the PFO closure group (hazard ratio, 1.44; 95% confidence interval, 0.30-6.81; P = 0.647). Additionally, no disparities in the occurrence of stroke or TIA were found in subgroups divided by baseline characteristics, RoPE score, or shunt grade. Conclusion: Clinical outcomes for patients with uncrossable PFO seem similar to those with successful PFO closure.

Improved intra-atrial conduction delay after successful ablation for atrial fibrillation by scar homogenization in right atrium.

Atrial fibrosis in the right atrium (RA) presenting as a low-voltage zone might be the mechanism of atrial fibrillation (AF) and intra-atrial conduction delay. The impact of scar homogenization in RA on intra-atrial conduction delay is unknown. We describe a patient with paroxysmal AF and significant intra-atrial conduction delay with repetitive atrial flutter, triggered from the lateral free wall in the RA between the significant low-voltage zone and slow conduction area after pulmonary vein isolation. Linear ablation along the trabeculated lateral free wall in the RA to homogenize the scar was successfully performed, and the intra-atrial conduction delay improved ultimately.

Korean Society of Heart Failure Guidelines for the Management of Heart Failure: Advanced and Acute Heart Failure.

The Korean Society of Heart Failure (KSHF) Guidelines provide evidence-based recommendations based on Korean and international data to guide adequate diagnosis and management of heart failure (HF). Since introduction of 2017 edition of the guidelines, management of advanced HF has considerably improved, especially with advances in mechanical circulatory support and devices. The current guidelines addressed these improvements. In addition, we have included recently updated evidence-based recommendations regarding acute HF in these guidelines. In summary, Part IV of the KSHF Guidelines covers the appropriate diagnosis and optimized management of advanced and acute HF.

Korean Society of Heart Failure Guidelines for the Management of Heart Failure: Management of the Underlying Etiologies and Comorbidities of Heart Failure.

Most patients with heart failure (HF) have multiple comorbidities, which impact their quality of life, aggravate HF, and increase mortality. Cardiovascular comorbidities include systemic and pulmonary hypertension, ischemic and valvular heart diseases, and atrial fibrillation. Non-cardiovascular comorbidities include diabetes mellitus (DM), chronic kidney and pulmonary diseases, iron deficiency and anemia, and sleep apnea. In patients with HF with hypertension and left ventricular hypertrophy, renin-angiotensin system inhibitors combined with calcium channel blockers and/or diuretics is an effective treatment regimen. Measurement of pulmonary vascular resistance via right heart catheterization is recommended for patients with HF considered suitable for implantation of mechanical circulatory support devices or as heart transplantation candidates. Coronary angiography remains the gold standard for the diagnosis and reperfusion in patients with HF and angina pectoris refractory to antianginal medications. In patients with HF and atrial fibrillation, long-term anticoagulants are recommended according to the CHA2DS2-VASc scores. Valvular heart diseases should be treated medically and/or surgically. In patients with HF and DM, metformin is relatively safer; thiazolidinediones cause fluid retention and should be avoided in patients with HF and dyspnea. In renal insufficiency, both volume status and cardiac performance are important for therapy guidance. In patients with HF and pulmonary disease, beta-blockers are underused, which may be related to increased mortality. In patients with HF and anemia, iron supplementation can help improve symptoms. In obstructive sleep apnea, continuous positive airway pressure therapy helps avoid severe nocturnal hypoxia. Appropriate management of comorbidities is important for improving clinical outcomes in patients with HF.

Korean Society of Heart Failure Guidelines for the Management of Heart Failure: Advanced and Acute Heart Failure.

The Korean Society of Heart Failure (KSHF) Guidelines provide evidence-based recommendations based on Korean and international data to guide adequate diagnosis and management of heart failure (HF). Since introduction of 2017 edition of the guidelines, management of advanced HF has considerably improved, especially with advances in mechanical circulatory support and devices. The current guidelines addressed these improvements. In addition, we have included recently updated evidence-based recommendations regarding acute HF in these guidelines. In summary, Part IV of the KSHF Guidelines covers the appropriate diagnosis and optimized management of advanced and acute HF.

Korean Society of Heart Failure Guidelines for the Management of Heart Failure: Management of the Underlying Etiologies and Comorbidities of Heart Failure.

Most patients with heart failure (HF) have multiple comorbidities, which impact their quality of life, aggravate HF, and increase mortality. Cardiovascular comorbidities include systemic and pulmonary hypertension, ischemic and valvular heart diseases, and atrial fibrillation. Non-cardiovascular comorbidities include diabetes mellitus (DM), chronic kidney and pulmonary diseases, iron deficiency and anemia, and sleep apnea. In patients with HF with hypertension and left ventricular hypertrophy, renin-angiotensin system inhibitors combined with calcium channel blockers and/or diuretics is an effective treatment regimen. Measurement of pulmonary vascular resistance via right heart catheterization is recommended for patients with HF considered suitable for implantation of mechanical circulatory support devices or as heart transplantation candidates. Coronary angiography remains the gold standard for the diagnosis and reperfusion in patients with HF and angina pectoris refractory to antianginal medications. In patients with HF and atrial fibrillation, long-term anticoagulants are recommended according to the CHA2DS2-VASc scores. Valvular heart diseases should be treated medically and/or surgically. In patients with HF and DM, metformin is relatively safer; thiazolidinediones cause fluid retention and should be avoided in patients with HF and dyspnea. In renal insufficiency, both volume status and cardiac performance are important for therapy guidance. In patients with HF and pulmonary disease, beta-blockers are underused, which may be related to increased mortality. In patients with HF and anemia, iron supplementation can help improve symptoms. In obstructive sleep apnea, continuous positive airway pressure therapy helps avoid severe nocturnal hypoxia. Appropriate management of comorbidities is important for improving clinical outcomes in patients with HF.

Dickkopf1 Promotes Pulmonary Fibrosis upon Bleomycin-Induced Lung Injury.

Orchestration of inflammation and tissue repair processes is critical to maintaining homeostasis upon tissue injury. Tissue fibrosis is a pathological process characterized by aberrant accumulation of extracellular matrix proteins, such as collagen, upon injury. Dickkopf1 (DKK1) is a quintessential Wnt antagonist. The role of DKK1 in bleomycin (BLM)-induced lung injury and fibrosis model remains elusive. This study shows that BLM-induced lung injury markedly elevated DKK1 protein expressions in the lungs in mice, consistent with human pulmonary fibrosis patient lung tissues. The elevated DKK1 levels coincided with immune cell infiltration and collagen deposition. Notably, the reduced expression of DKK1 in Dkk1 hypomorphic doubleridge (Dkk1d/d) mice abrogated BLM-induced lung inflammation and fibrosis. Immune cell infiltration, collagen deposition, expression of profibrotic cytokine transforming growth factor ß1 (TGF-ß1), and extracellular matrix protein-producing myofibroblast marker α-smooth muscle actin (α-SMA) were reduced in Dkk1d/d mice. Consistent with these results, local DKK1 antibody administration after BLM-induced lung injury substantially decreased lung inflammation and fibrosis phenotypes. Taken together, these results demonstrate that DKK1 is a proinflammatory and profibrotic ligand that promotes inflammation and fibrosis upon BLM-induced lung injury, placing it as an attractive molecular target for dysregulated pulmonary inflammation and tissue repair.

Korean Society of Heart Failure Guidelines for the Management of Heart Failure: Definition and Diagnosis.

The Korean Society of Heart Failure guidelines aim to provide physicians with evidence-based recommendations for diagnosing and managing patients with heart failure (HF). In Korea, the prevalence of HF has been rapidly increasing in the last 10 years. HF has recently been classified into HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (EF), and HF with preserved EF (HFpEF). Moreover, the availability of newer therapeutic agents has led to an increased emphasis on the appropriate diagnosis of HFpEF. Accordingly, this part of the guidelines will mainly cover the definition, epidemiology, and diagnosis of HF.

Korean Society of Heart Failure Guidelines for the Management of Heart Failure: Treatment.

The Korean Society of Heart Failure (KSHF) guidelines aim to provide physicians with evidence-based recommendations for the management of patients with heart failure (HF). After the first introduction of the KSHF guidelines in 2016, newer therapies for HF with reduced ejection fraction, HF with mildly reduced ejection fraction, and HF with preserved ejection fraction have since emerged. The current version has been updated based on international guidelines and research data on Korean patients with HF. Herein, we present Part II of these guidelines, which comprises treatment strategies to improve the outcomes of patients with HF.

Korean Society of Heart Failure Guidelines for the Management of Heart Failure: Definition and Diagnosis.

The Korean Society of Heart Failure guidelines aim to provide physicians with evidence-based recommendations for diagnosing and managing patients with heart failure (HF). In Korea, the prevalence of HF has been rapidly increasing in the last 10 years. HF has recently been classified into HF with reduced ejection fraction (EF), HF with mildly reduced EF, and HF with preserved EF (HFpEF). Moreover, the availability of newer therapeutic agents has led to an increased emphasis on the appropriate diagnosis of HFpEF. Accordingly, this part of the guidelines will mainly cover the definition, epidemiology, and diagnosis of HF.

Korean Society of Heart Failure Guidelines for the Management of Heart Failure: Treatment.

The Korean Society of Heart Failure (KSHF) guidelines aim to provide physicians with evidence-based recommendations for the management of patients with heart failure (HF). After the first introduction of the KSHF guidelines in 2016, newer therapies for HF with reduced ejection fraction, HF with mildly reduced ejection fraction, and HF with preserved ejection fraction have since emerged. The current version has been updated based on international guidelines and research data on Korean patients with HF. Herein, we present Part II of these guidelines, which comprises treatment strategies to improve the outcomes of patients with HF.

Epidemiology of PAH in Korea: An Analysis of the National Health Insurance Data, 2002-2018.

BACKGROUND AND OBJECTIVES: Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Recent advances in PAH-specific drugs have improved its outcomes, although the healthcare burden of novel therapeutics may lead to a discrepancy in outcomes between developing and developed countries. We analyzed how the epidemiology and clinical features of PAH has changed through the rapidly advancing healthcare infrastructure in South Korea. METHODS: PAH was defined according to a newly devised 3-component algorithm. Using a nationwide health insurance claims database, we delineated annual trends in the prevalence, incidence, medication prescription pattern, and 5-year survival of PAH in Korea. Cumulative survival and potential predictors of mortality were also assessed among 2,151 incident PAH cases. RESULTS: Between 2002 or 2004 and 2018, the prevalence and incidence of PAH increased 75-fold (0.4 to 29.9 per million people) and 12-fold (0.5 to 6.3 per million person-years), respectively. The proportion of patients on combination PAH-specific drug therapy has also steadily increased up to 29.0% in 2018. Among 2,151 incident PAH cases (median [interquartile range] age, 50 [37-62] years; 67.2% female), the 5-year survival rate and median survival duration were 71.8% and 13.1 years, respectively. Independent predictors of mortality were age, sex, etiology of PAH, diabetes, dyslipidemia, and chronic kidney disease. CONCLUSIONS: This nationwide study delineated that the prevalence and incidence of PAH have grown rapidly in Korea since the early 2000s. The use of combination therapy has also increased, and the 5-year survival rate of PAH in Korea was similar to those in western countries.

Chemical Constituents from the Roots of Angelica reflexa That Improve Glucose-Stimulated Insulin Secretion by Regulating Pancreatic ß-Cell Metabolism.

The aim of this study was to discover bioactive constituents of Angelica reflexa that improve glucose-stimulated insulin secretion (GSIS) in pancreatic ß-cells. Herein, three new compounds, namely, koseonolin A (1), koseonolin B (2), and isohydroxylomatin (3), along with 28 compounds (4-31) were isolated from the roots of A. reflexa by chromatographic methods. The chemical structures of new compounds (1-3) were elucidated through spectroscopic/spectrometric methods such as NMR and HRESIMS. In particular, the absolute configuration of the new compounds (1 and 3) was performed by electronic circular dichroism (ECD) studies. The effects of the root extract of A. reflexa (KH2E) and isolated compounds (1-31) on GSIS were detected by GSIS assay, ADP/ATP ratio assay, and Western blot assay. We observed that KH2E enhanced GSIS. Among the compounds 1-31, isohydroxylomatin (3), (-)-marmesin (17), and marmesinin (19) increased GSIS. In particular, marmesinin (19) was the most effective; this effect was superior to treatment with gliclazide. GSI values were: 13.21 ± 0.12 and 7.02 ± 0.32 for marmesinin (19) and gliclazide at a same concentration of 10 µM, respectively. Gliclazide is often performed in patients with type 2 diabetes (T2D). KH2E and marmesinin (19) enhanced the protein expressions associated with pancreatic ß-cell metabolism such as peroxisome proliferator-activated receptor γ, pancreatic and duodenal homeobox 1, and insulin receptor substrate-2. The effect of marmesinin (19) on GSIS was improved by an L-type Ca2+ channel agonist and K+ channel blocker and was inhibited by an L-type Ca2+ channel blocker and K+ channel activator. Marmesinin (19) may improve hyperglycemia by enhancing GSIS in pancreatic ß-cells. Thus, marmesinin (19) may have potential use in developing novel anti-T2D therapy. These findings promote the potential application of marmesinin (19) toward the management of hyperglycemia in T2D.

Gender disparities in prevalence by diagnostic criteria, treatment and mortality of newly diagnosed acute myocardial infarction in Korean adults.

Acute myocardial infarction (AMI) is highly prevalent and remains the leading cause of mortality. Particularly in women, under-recognition and management of AMI have been raised. The aim of this study was to investigate the long-term trends of prevalence, treatment methodologies, and mortality of AMI by gender. The subjects of this study were patients hospitalized for AMI according to the Korean National Health Insurance Claims Database from 2002 to 2018. Total 633,097 AMI patients were hospitalized, 40% women. The incidence of AMI has been increasing since 2011, with a lower incidence in women. Overall, 53.1% of patients underwent CAG, with a lower tendency in women than in men (39.8% vs. 62.3%). Furthermore, fewer women underwent PCI than men (77.5% vs. 85.8% in 2018, p < 0.0001). Of the 336,463 AMI patients undergoing CAG, women were undertreated with a lower prescription rate of beta-blockers or statins at discharge. When adjusted for age, women showed higher 7-day mortality but lower 1-year mortality relative to men. According to the Korean National Health Insurance Claims Database, women with AMI have been under-recognized, underdiagnosed, and undertreated in terms of revascularization or medical therapy for years suggesting that efforts to close the gender gap are necessary.

In vitro propagation of Codonopsis pilosula (Franch.) Nannf. using apical shoot segments and phytochemical assessments of the maternal and regenerated plants.

BACKGROUND: Codonopsis pilosula (Franch.) Nannf. is a medicinal plant traditionally used in China, Korea, and Japan to treat many diseases including poor gastrointestinal function, low immunity, gastric ulcers, and chronic gastritis. The increasing therapeutic and preventive use of C. pilosula has subsequently led to depletion of the natural populations of this species thus necessitating propagation of this important medicinal plant. Here, we developed an efficient and effective in vitro propagation protocol for C. pilosula using apical shoot segments. We tested various plant tissue culture media for the growth of C. pilosula and evaluated the effects of plant growth regulators on the shoot proliferation and rooting of regenerated C. pilosula plants. Furthermore, the tissues (roots and shoots) of maternal and in vitro-regenerated C. pilosula plants were subjected to Fourier-transform near-infrared (FT-NIR) spectrometry, Gas chromatography-mass spectrometry (GC-MS), and their total flavonoids, phenolics, and antioxidant capacity were determined and compared. RESULTS: Full-strength Murashige and Skoog (MS) medium augmented with vitamins and benzylaminopurine (1.5 mg·L-1) regenerated the highest shoot number (12 ± 0.46) per explant. MS medium augmented with indole-3-acetic acid (1.0 mg·L-1) produced the highest root number (9 ± 0.89) and maximum root length (20.88 ± 1.48 mm) from regenerated C. pilosula shoots. The survival rate of in vitro-regenerated C. pilosula plants was 94.00% after acclimatization. The maternal and in vitro-regenerated C. pilosula plant tissues showed similar FT-NIR spectra, total phenolics, total flavonoids, phytochemical composition, and antioxidant activity. Randomly amplified polymorphic DNA (RAPD) test confirmed the genetic fidelity of regenerated C. pilosula plants. CONCLUSIONS: The proposed in vitro propagation protocol may be useful for the rapid mass multiplication and production of high quality C. pilosula as well as for germplasm preservation to ensure sustainable supply amidst the ever-increasing demand.