Development and Validation of 3-Year Atrial Fibrillation Prediction Models Using Electronic Health Record With or Without Standardized Electrocardiogram Diagnosis and a Performance Comparison Among Models.

Background Improved prediction of atrial fibrillation (AF) may allow for earlier interventions for stroke prevention, as well as mortality and morbidity from other AF-related complications. We developed a clinically feasible and accurate AF prediction model using electronic health records and computerized ECG interpretation. Methods and Results A total of 671 318 patients were screened from 3 tertiary hospitals. After careful exclusion of cases with missing values and a prior AF diagnosis, AF prediction models were developed from the derivation cohort of 25 584 patients without AF at baseline. In the internal/external validation cohort of 117 523 patients, the model using 6 clinical features and 5 ECG diagnoses showed the highest performance for 3-year new-onset AF prediction (C-statistic, 0.796 [95% CI, 0.785-0.806]). A more simplified model using age, sex, and 5 ECG diagnoses (atrioventricular block, fusion beats, marked sinus arrhythmia, supraventricular premature complex, and wide QRS complex) had comparable predictive power (C-statistic, 0.777 [95% CI, 0.766-0.788]). The simplified model showed a similar or better predictive performance than the previous models. In the subgroup analysis, the models performed relatively better in patients without risk factors. Specifically, the predictive power was lower in patients with heart failure or decreased renal function. Conclusions Although the 3-year AF prediction model using both clinical and ECG variables showed the highest performance, the simplified model using age, sex, and 5 ECG diagnoses also had a comparable prediction power with broad applicability for incident AF

Clinical effectiveness and safety of amlodipine/losartan‐based single‐pill combination therapy in patients with hypertension: Findings from real‐world, multicenter observational databases

Abstract Various single‐pill combinations (SPCs) have been introduced to improve drug compliance and clinical efficacy. However, there is a lack of real‐world evidence regarding the effectiveness of these SPCs for hypertension. This study evaluated the real‐world clinical efficacy and safety of amlodipine/losartan‐based SPC therapies in patients with hypertension in a real‐world setting. A total of 15 538 patients treated with amlodipine/losartan‐based SPCs [amlodipine + losartan (AL), amlodipine + losartan + rosuvastatin (ALR), and amlodipine + losartan + chlorthalidone (ALC)] were selected from the database of three tertiary hospitals in Korea. The efficacy endpoints were target blood pressure (BP) and low‐density lipoprotein cholesterol (LDL‐C) achievement rates. Safety was evaluated based on laboratory parameters. Drug adherence was defined as the proportion of medication days covered (PDC). The target BP attainment rate was above 90% and was similar among the three groups. Although many patients in the AL and ALC groups took statins, the target LDL‐C attainment rate was significantly higher in the ALR group than in the AL and ALC groups. Safety endpoints were not significantly different among the groups, except serum uric acid level and incidence rate of new‐onset hyperuricemia, which were significantly lower in the AL and ALR groups than in the ALC group. The PDC was > 90% in all groups. In the real‐world hypertensive patients, amlodipine/losartan‐based SPC therapy demonstrated good target BP achievement rates. Especially, rosuvastatin‐combination SPC showed better target LDL‐C goal achievement rate compared to the other SPCs. All three amlodipine/losartan‐based SPC had excellent drug adherence

Prevalence and Clinical Impact of Electrocardiographic Abnormalities in Patients with Chronic Kidney Disease

Chronic kidney disease (CKD) is a strong risk factor for cardiovascular disease. An electrocardiogram (ECG) is a basic test for screening cardiovascular disease. However, the impact of ECG abnormalities on cardiovascular prognosis in patients with CKD is largely unknown. A total of 2442 patients with CKD (stages 3–5) who underwent ECG between 2013 and 2015 were selected from the electronic health record database of the Korea University Anam Hospital. ECG abnormalities were defined using the Minnesota classification. The five-year major adverse cerebrocardiovascular event (MACCE), the composite of death, myocardial infarction (MI), and stroke were analyzed. The five-year incidences for MACCE were 27.7%, 20.8%, and 17.2% in patients with no, minor, and major ECG abnormality (p < 0.01). Kaplan–Meier curves also showed the highest incidence of MI, death, and MACCE in patients with major ECG abnormality. Multivariable Cox regression analysis revealed age, sex, diabetes, CKD stage, hsCRP, antipsychotic use, and major ECG abnormality as independent risk predictors for MACCE (adjusted HR of major ECG abnormality: 1.39, 95% CI: 1.09–1.76, p < 01). Among the detailed ECG diagnoses, sinus tachycardia, myocardial ischemia, atrial premature complex, and right axis deviation were proposed as important ECG diagnoses. The accuracy of cardiovascular risk stratification was improved when the ECG results were added to the conventional SCORE model (net reclassification index 0.07). ECG helps to predict future cerebrocardiovascular events in CKD patients. ECG diagnosis can be useful for cardiovascular risk evaluation in CKD patients when applied in addition to the conventional risk stratification model

Minoxidil Induction of VEGF Is Mediated by Inhibition of HIF-Prolyl Hydroxylase

The topical application of minoxidil may achieve millimolar concentrations in the skin. We investigated whether millimolar minoxidil could induce vascular endothelial growth factor (VEGF), a possible effector for minoxidil-mediated hair growth, and how it occurred at the molecular level. Cell-based experiments were performed to investigate a molecular mechanism underlying the millimolar minoxidil induction of VEGF. The inhibitory effect of minoxidil on hypoxia-inducible factor (HIF) prolyl hydroxylase-2 (PHD-2) was tested by an in vitro von Hippel–Lindau protein (VHL) binding assay. To examine the angiogenic potential of millimolar minoxidil, a chorioallantoic membrane (CAM) assay was used. In human keratinocytes and dermal papilla cells, millimolar minoxidil increased the secretion of VEGF, which was not attenuated by a specific adenosine receptor antagonist that inhibits the micromolar minoxidil induction of VEGF. Millimolar minoxidil induced hypoxia-inducible factor-1α (HIF-1α), and the induction of VEGF was dependent on HIF-1. Moreover, minoxidil applied to the dorsal area of mice increased HIF-1α and VEGF in the skin. In an in vitro VHL binding assay, minoxidil directly inhibited PHD-2, thus preventing the hydroxylation of cellular HIF-1α and VHL-dependent proteasome degradation and resulting in the stabilization of HIF-1α protein. Minoxidil inhibition of PHD-2 was reversed by ascorbate, a cofactor of PHD-2, and the minoxidil induction of cellular HIF-1α was abrogated by the cofactor. Millimolar minoxidil promoted angiogenesis in the CAM assay, an in vivo angiogenic test, and this was nullified by the specific inhibition of VEGF. Our data demonstrate that PHD may be the molecular target for millimolar minoxidil-mediated VEGF induction via HIF-1

Colon-Targeted Cell-Permeable NFκB Inhibitory Peptide Is Orally Active against Experimental Colitis

For the purpose of development of orally active peptide therapeutics targeting NFκB for treatment of inflammatory bowel disease (IBD), two major barriers in oral delivery of therapeutic peptides, metabolic lability and tissue impermeability, were circumvented by introduction of a colon-targeted delivery system and cell permeable peptides (CPP) to NFκB inhibitory peptides (NIP). Suppression of NFκB activation was compared following treatment with various CPP conjugated NIPs (CPP–NIP). The most potent CPP–NIP was loaded in a capsule coated with a colon specific polymer, which was administered orally to colitic rats. The anti-inflammatory activity of the colon-targeted CPP–NIP was evaluated by measuring inflammatory indices in the inflamed colonic tissue. For confirmation of the local action of the CPP–NIP, the same experiment was done after rectal administration. Tissue permeability of the CPP–NIP was examined microscopically and spectrophotometrically using FITC-labeled CPP–NIP (CPP–NIP-FITC). NEMO binding domain peptide (NBD, TALDWSWLQTE) fused with a cell permeable peptide CTP (YGRRARRRARR), CTP-NBD, was most potent in inhibiting NFκB activity in cells. Colon-targeted CTP-NBD, but not colon-targeted NBD and CTP-NBD in an enteric capsule, ameliorated the colonic injury, which was in parallel with decrease in MPO activity and the levels of inflammatory mediators. Intracolonic treatment with CTP-NBD alleviated rat colitis and improved all the inflammatory indicators. CTP-NBD-FITC was detected at much greater level in the inflamed tissue than was NBD-FITC. Taken together, introduction of cell permeability and colon targetability to NIP may be a feasible strategy for an orally active peptide therapy for treatment of IBD

Colon-Targeted Cell-Permeable NFκB Inhibitory Peptide Is Orally Active against Experimental Colitis

For the purpose of development of orally active peptide therapeutics targeting NFκB for treatment of inflammatory bowel disease (IBD), two major barriers in oral delivery of therapeutic peptides, metabolic lability and tissue impermeability, were circumvented by introduction of a colon-targeted delivery system and cell permeable peptides (CPP) to NFκB inhibitory peptides (NIP). Suppression of NFκB activation was compared following treatment with various CPP conjugated NIPs (CPP–NIP). The most potent CPP–NIP was loaded in a capsule coated with a colon specific polymer, which was administered orally to colitic rats. The anti-inflammatory activity of the colon-targeted CPP–NIP was evaluated by measuring inflammatory indices in the inflamed colonic tissue. For confirmation of the local action of the CPP–NIP, the same experiment was done after rectal administration. Tissue permeability of the CPP–NIP was examined microscopically and spectrophotometrically using FITC-labeled CPP–NIP (CPP–NIP-FITC). NEMO binding domain peptide (NBD, TALDWSWLQTE) fused with a cell permeable peptide CTP (YGRRARRRARR), CTP-NBD, was most potent in inhibiting NFκB activity in cells. Colon-targeted CTP-NBD, but not colon-targeted NBD and CTP-NBD in an enteric capsule, ameliorated the colonic injury, which was in parallel with decrease in MPO activity and the levels of inflammatory mediators. Intracolonic treatment with CTP-NBD alleviated rat colitis and improved all the inflammatory indicators. CTP-NBD-FITC was detected at much greater level in the inflamed tissue than was NBD-FITC. Taken together, introduction of cell permeability and colon targetability to NIP may be a feasible strategy for an orally active peptide therapy for treatment of IBD

Colon-Targeted Cell-Permeable NFκB Inhibitory Peptide Is Orally Active against Experimental Colitis

For the purpose of development of orally active peptide therapeutics targeting NFκB for treatment of inflammatory bowel disease (IBD), two major barriers in oral delivery of therapeutic peptides, metabolic lability and tissue impermeability, were circumvented by introduction of a colon-targeted delivery system and cell permeable peptides (CPP) to NFκB inhibitory peptides (NIP). Suppression of NFκB activation was compared following treatment with various CPP conjugated NIPs (CPP–NIP). The most potent CPP–NIP was loaded in a capsule coated with a colon specific polymer, which was administered orally to colitic rats. The anti-inflammatory activity of the colon-targeted CPP–NIP was evaluated by measuring inflammatory indices in the inflamed colonic tissue. For confirmation of the local action of the CPP–NIP, the same experiment was done after rectal administration. Tissue permeability of the CPP–NIP was examined microscopically and spectrophotometrically using FITC-labeled CPP–NIP (CPP–NIP-FITC). NEMO binding domain peptide (NBD, TALDWSWLQTE) fused with a cell permeable peptide CTP (YGRRARRRARR), CTP-NBD, was most potent in inhibiting NFκB activity in cells. Colon-targeted CTP-NBD, but not colon-targeted NBD and CTP-NBD in an enteric capsule, ameliorated the colonic injury, which was in parallel with decrease in MPO activity and the levels of inflammatory mediators. Intracolonic treatment with CTP-NBD alleviated rat colitis and improved all the inflammatory indicators. CTP-NBD-FITC was detected at much greater level in the inflamed tissue than was NBD-FITC. Taken together, introduction of cell permeability and colon targetability to NIP may be a feasible strategy for an orally active peptide therapy for treatment of IBD

Colon-Targeted Cell-Permeable NFκB Inhibitory Peptide Is Orally Active against Experimental Colitis

For the purpose of development of orally active peptide therapeutics targeting NFκB for treatment of inflammatory bowel disease (IBD), two major barriers in oral delivery of therapeutic peptides, metabolic lability and tissue impermeability, were circumvented by introduction of a colon-targeted delivery system and cell permeable peptides (CPP) to NFκB inhibitory peptides (NIP). Suppression of NFκB activation was compared following treatment with various CPP conjugated NIPs (CPP–NIP). The most potent CPP–NIP was loaded in a capsule coated with a colon specific polymer, which was administered orally to colitic rats. The anti-inflammatory activity of the colon-targeted CPP–NIP was evaluated by measuring inflammatory indices in the inflamed colonic tissue. For confirmation of the local action of the CPP–NIP, the same experiment was done after rectal administration. Tissue permeability of the CPP–NIP was examined microscopically and spectrophotometrically using FITC-labeled CPP–NIP (CPP–NIP-FITC). NEMO binding domain peptide (NBD, TALDWSWLQTE) fused with a cell permeable peptide CTP (YGRRARRRARR), CTP-NBD, was most potent in inhibiting NFκB activity in cells. Colon-targeted CTP-NBD, but not colon-targeted NBD and CTP-NBD in an enteric capsule, ameliorated the colonic injury, which was in parallel with decrease in MPO activity and the levels of inflammatory mediators. Intracolonic treatment with CTP-NBD alleviated rat colitis and improved all the inflammatory indicators. CTP-NBD-FITC was detected at much greater level in the inflamed tissue than was NBD-FITC. Taken together, introduction of cell permeability and colon targetability to NIP may be a feasible strategy for an orally active peptide therapy for treatment of IBD

Colon-Targeted Cell-Permeable NFκB Inhibitory Peptide Is Orally Active against Experimental Colitis

For the purpose of development of orally active peptide therapeutics targeting NFκB for treatment of inflammatory bowel disease (IBD), two major barriers in oral delivery of therapeutic peptides, metabolic lability and tissue impermeability, were circumvented by introduction of a colon-targeted delivery system and cell permeable peptides (CPP) to NFκB inhibitory peptides (NIP). Suppression of NFκB activation was compared following treatment with various CPP conjugated NIPs (CPP–NIP). The most potent CPP–NIP was loaded in a capsule coated with a colon specific polymer, which was administered orally to colitic rats. The anti-inflammatory activity of the colon-targeted CPP–NIP was evaluated by measuring inflammatory indices in the inflamed colonic tissue. For confirmation of the local action of the CPP–NIP, the same experiment was done after rectal administration. Tissue permeability of the CPP–NIP was examined microscopically and spectrophotometrically using FITC-labeled CPP–NIP (CPP–NIP-FITC). NEMO binding domain peptide (NBD, TALDWSWLQTE) fused with a cell permeable peptide CTP (YGRRARRRARR), CTP-NBD, was most potent in inhibiting NFκB activity in cells. Colon-targeted CTP-NBD, but not colon-targeted NBD and CTP-NBD in an enteric capsule, ameliorated the colonic injury, which was in parallel with decrease in MPO activity and the levels of inflammatory mediators. Intracolonic treatment with CTP-NBD alleviated rat colitis and improved all the inflammatory indicators. CTP-NBD-FITC was detected at much greater level in the inflamed tissue than was NBD-FITC. Taken together, introduction of cell permeability and colon targetability to NIP may be a feasible strategy for an orally active peptide therapy for treatment of IBD

Colon-Targeted Cell-Permeable NFκB Inhibitory Peptide Is Orally Active against Experimental Colitis

For the purpose of development of orally active peptide therapeutics targeting NFκB for treatment of inflammatory bowel disease (IBD), two major barriers in oral delivery of therapeutic peptides, metabolic lability and tissue impermeability, were circumvented by introduction of a colon-targeted delivery system and cell permeable peptides (CPP) to NFκB inhibitory peptides (NIP). Suppression of NFκB activation was compared following treatment with various CPP conjugated NIPs (CPP–NIP). The most potent CPP–NIP was loaded in a capsule coated with a colon specific polymer, which was administered orally to colitic rats. The anti-inflammatory activity of the colon-targeted CPP–NIP was evaluated by measuring inflammatory indices in the inflamed colonic tissue. For confirmation of the local action of the CPP–NIP, the same experiment was done after rectal administration. Tissue permeability of the CPP–NIP was examined microscopically and spectrophotometrically using FITC-labeled CPP–NIP (CPP–NIP-FITC). NEMO binding domain peptide (NBD, TALDWSWLQTE) fused with a cell permeable peptide CTP (YGRRARRRARR), CTP-NBD, was most potent in inhibiting NFκB activity in cells. Colon-targeted CTP-NBD, but not colon-targeted NBD and CTP-NBD in an enteric capsule, ameliorated the colonic injury, which was in parallel with decrease in MPO activity and the levels of inflammatory mediators. Intracolonic treatment with CTP-NBD alleviated rat colitis and improved all the inflammatory indicators. CTP-NBD-FITC was detected at much greater level in the inflamed tissue than was NBD-FITC. Taken together, introduction of cell permeability and colon targetability to NIP may be a feasible strategy for an orally active peptide therapy for treatment of IBD