Artificial Intelligence-Based Electrocardiographic Biomarker for Outcome Prediction in Patients With Acute Heart Failure: Prospective Cohort Study.

BACKGROUND: Although several biomarkers exist for patients with heart failure (HF), their use in routine clinical practice is often constrained by high costs and limited availability. OBJECTIVE: We examined the utility of an artificial intelligence (AI) algorithm that analyzes printed electrocardiograms (ECGs) for outcome prediction in patients with acute HF. METHODS: We retrospectively analyzed prospectively collected data of patients with acute HF at two tertiary centers in Korea. Baseline ECGs were analyzed using a deep-learning system called Quantitative ECG (QCG), which was trained to detect several urgent clinical conditions, including shock, cardiac arrest, and reduced left ventricular ejection fraction (LVEF). RESULTS: Among the 1254 patients enrolled, in-hospital cardiac death occurred in 53 (4.2%) patients, and the QCG score for critical events (QCG-Critical) was significantly higher in these patients than in survivors (mean 0.57, SD 0.23 vs mean 0.29, SD 0.20; P<.001). The QCG-Critical score was an independent predictor of in-hospital cardiac death after adjustment for age, sex, comorbidities, HF etiology/type, atrial fibrillation, and QRS widening (adjusted odds ratio [OR] 1.68, 95% CI 1.47-1.92 per 0.1 increase; P<.001), and remained a significant predictor after additional adjustments for echocardiographic LVEF and N-terminal prohormone of brain natriuretic peptide level (adjusted OR 1.59, 95% CI 1.36-1.87 per 0.1 increase; P<.001). During long-term follow-up, patients with higher QCG-Critical scores (>0.5) had higher mortality rates than those with low QCG-Critical scores (<0.25) (adjusted hazard ratio 2.69, 95% CI 2.14-3.38; P<.001). CONCLUSIONS: Predicting outcomes in patients with acute HF using the QCG-Critical score is feasible, indicating that this AI-based ECG score may be a novel biomarker for these patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01389843; https://clinicaltrials.gov/study/NCT01389843.

Blood pressure and heart failure: focused on treatment.

Heart failure (HF) remains a significant global health burden, and hypertension is known to be the primary contributor to its development. Although aggressive hypertension treatment can prevent heart changes in at-risk patients, determining the optimal blood pressure (BP) targets in cases diagnosed with HF is challenging owing to insufficient evidence. Notably, hypertension is more strongly associated with HF with preserved ejection fraction than with HF with reduced ejection fraction. Patients with acute hypertensive HF exhibit sudden symptoms of acute HF, especially those manifested with severely high BP; however, no specific vasodilator therapy has proven beneficial for this type of acute HF. Since the majority of medications used to treat HF contribute to lowering BP, and BP remains one of the most important hemodynamic markers, targeted BP management is very concerned in treatment strategies. However, no concrete guidelines exist, prompting a trend towards optimizing therapies to within tolerable ranges, rather than setting explicit BP goals. This review discusses the connection between BP and HF, explores its pathophysiology through clinical studies, and addresses its clinical significance and treatment targets.

Chemotherapy-related cardiotoxicity and its symptoms in patients with breast cancer: a scoping review.

BACKGROUND: Chemotherapy-related cardiotoxicity is a significant concern because it is a major cause of morbidity. This study aimed to provide in-depth information on the symptoms of chemotherapy-related cardiotoxicity (CRCT) by exploring literature that concurrently reports the types and symptoms of CRCT in patients with breast cancer. METHODS: A scoping review was performed according to an a priori protocol using the Joanna Briggs Institute's guidelines. The participants were patients with breast cancer. The concept was the literature of specifically reported symptoms directly matched with CRCT and the literature, in English, from 2010, and the context was open. The search strategy included four keywords: "breast cancer," "chemotherapy," "cardiotoxicity," and "symptoms." All types of research designs were included; however, studies involving patients with other cancer types, animal subjects, and symptoms not directly related to CRCT were excluded. Data were extracted and presented including tables and figures. RESULTS: A total of 29 articles were included in the study, consisting of 23 case reports, 4 retrospective studies, and 2 prospective studies. There were no restrictions on the participants' sex; however, all of them were women, except for one case report. The most used chemotherapy regimens were trastuzumab, capecitabine, and doxorubicin or epirubicin. The primary CRCT identified were myocardial dysfunction and heart failure, followed by coronary artery disease, pulmonary hypertension, and other conditions. Major tests used to diagnose CRCT include echocardiography, electrocardiography, serum cardiac enzymes, coronary angiography, computed tomography, and magnetic resonance imaging. In all case reports, CRCT was diagnosed through an incidental checkup according to the patient's symptom presentation; however, only 10 of these studies showed a baseline checkup before chemotherapy. The five most common CRCT symptoms were dyspnea, chest pain, peripheral edema, fatigue, and palpitations, which were assessed by patient-reported symptom presentation rather than using a symptom assessment tool. Dyspnea with trastuzumab treatment and chest pain with capecitabine treatment were particularly characteristic. The time for first symptom onset after chemotherapy ranged from 1 hour to 300 days, with anthracycline-based regimens requiring 3-55 days, trastuzumab requiring 60-300 days, and capecitabine requiring 1-7 days. CONCLUSIONS: This scoping review allowed data mapping according to the study design and chemotherapy regimens. Cardiac assessments for CRCT diagnosis were performed according to the patient's symptoms. There were approximately five types of typical CRCT symptoms, and the timing of symptom occurrence varied. Therefore, developing and applying a CRCT-specific and user-friendly symptom assessment tool are expected to help healthcare providers and patients manage CRCT symptoms effectively.

Generation of an induced pluripotent stem cell line from a patient with arrhythmogenic right ventricular cardiomyopathy harboring a TMEM43 splice-site variant.

Arrhythmogenic cardiomyopathy (ACM) is a cardiomyopathy that is predominantly inherited and characterized by cardiac arrhythmias and structural abnormalities. TMEM43 (transmembrane protein 43) is one of the well-known genetic culprits behind ACM. In this study, we successfully generated an induced pluripotent stem cell (iPSC) line, YCMi010-A, derived from a male patient diagnosed with ACM. Although these iPSCs harbored a heterozygous intronic splice variant, TMEM43 c.443-2A > G, they still displayed normal cellular morphology and were confirmed to express pluripotency markers. YCMi010-A iPSC line is a promising model for investigating the pathomechanisms associated with ACM and exploring potential therapeutic strategies.

The Third Nationwide Korean Heart Failure III Registry (KorHF III): The Study Design Paper.

With advancements in both pharmacologic and non-pharmacologic treatments, significant changes have occurred in heart failure (HF) management. The previous Korean HF registries, namely the Korea Heart Failure Registry (KorHF-registry) and Korean Acute Heart Failure Registry (KorAHF-registry), no longer accurately reflect contemporary acute heart failure (AHF) patients. Our objective is to assess contemporary AHF patients through a nationwide registry encompassing various aspects, such as clinical characteristics, management approaches, hospital course, and long-term outcomes of individuals hospitalized for AHF in Korea. This prospective observational multicenter cohort study (KorHF III) is organized by the Korean Society of Heart Failure. We aim to prospectively enroll 7,000 or more patients hospitalized for AHF at 47 tertiary hospitals in Korea starting from March 2018. Eligible patients exhibit signs and symptoms of HF and demonstrate either lung congestion or objective evidence of structural or functional cardiac abnormalities in echocardiography, or isolated right-sided HF. Patients will be followed up for up to 5 years after enrollment in the registry to evaluate long-term clinical outcomes. KorHF III represents the nationwide AHF registry that will elucidate the clinical characteristics, management strategies, and outcomes of contemporary AHF patients in Korea. Trial Registration: ClinicalTrials.gov Identifier: NCT04329234.

Heart Failure Statistics 2024 Update: A Report From the Korean Society of Heart Failure.

Background and Objectives: The number of people with heart failure (HF) is increasing worldwide, and the social burden is increasing as HF has high mortality and morbidity. We aimed to provide updated trends on the epidemiology of HF in Korea to shape future social measures against HF. Methods: We used the National Health Information Database of the National Health Insurance Service to determine the prevalence, incidence, hospitalization rate, mortality rate, comorbidities, in-hospital mortality, and healthcare cost of patients with HF from 2002 to 2020 in Korea. Results: The prevalence of HF in the total Korean population rose from 0.77% in 2002 to 2.58% (1,326,886 people) in 2020. Although the age-standardized incidence of HF decreased over the past 18 years, the age-standardized prevalence increased. In 2020, the hospitalization rate for any cause in patients with HF was 1,166 per 100,000 persons, with a steady increase from 2002. In 2002, the HF mortality was 3.0 per 100,000 persons, which rose to 15.6 per 100,000 persons in 2020. While hospitalization rates and in-hospital mortality for patients with HF increased, the mortality rate for patients with HF did not (5.8% in 2020), and the one-year survival rate from the first diagnosis of HF improved. The total healthcare costs for patients with HF were approximately $2.4 billion in 2020, a 16-fold increase over the $0.15 billion in 2002. Conclusions: The study's results underscore the growing socioeconomic burden of HF in Korea, driven by an aging population and increasing HF prevalence.

Inhibition of TBL1 cleavage alleviates doxorubicin-induced cardiomyocytes death by regulating the Wnt/ß-catenin signal pathway.

AIMS: Doxorubicin (DOX) is a widely used anthracycline anticancer agent; however, its irreversible effects on the heart can result in DOX-induced cardiotoxicity (DICT) after cancer treatment. Unfortunately, the pathophysiology of DICT has not yet been fully elucidated, and there are no effective strategies for its prevention or treatment. In this investigation, the novel role of transducin beta-like protein 1 (TBL1) in developing and regulating DICT was explored. METHODS AND RESULTS: We observed a reduction in TBL1 protein expression levels as well as cleavage events in the transplanted cardiac tissues of patients diagnosed with Dilated Cardiomyopathy (DCM) and DICT. It was revealed that DOX selectively induces TBL1 cleavage at caspase-3 preferred sites-D125, D136, and D215. Interestingly, overexpression of the uncleaved TBL1 mutant (TBL1uclv) variant reduced apoptosis, effectively preventing DOX-induced cell death. We confirmed that cleaved TBL1 cannot form a complex with ß-catenin. As a result, Wnt reporter activity, and Wnt target gene expression collectively indicate a decrease in Wnt/ß-catenin signaling, leading to DICT progression. Furthermore, the cleaved TBL1 triggered DOX-induced abnormal electrophysiological features and disrupted calcium homeostasis. However, these effects were improved in TBL1uclv-overexpressing human-induced pluripotent stem cell-derived cardiomyocytes. Finally, in a DICT mouse model, TBL1uclv overexpression inhibited the DICT-induced reduction of cardiac contractility and collagen accumulation, ultimately protecting cardiomyocytes from cell death. CONCLUSIONS: Our findings reveal that the inhibition of TBL1 cleavage not only mitigates apoptosis but also enhances cardiomyocyte function, even in the context of DOX administration. Consequently, this study's results suggest that inhibiting TBL1 cleavage may be a novel strategy to ameliorate DICT.

Feasibility of the Threshold-Based Quantification of Myocardial Fibrosis on Cardiac CT as a Prognostic Marker in Nonischemic Dilated Cardiomyopathy.

OBJECTIVE: This study investigated the feasibility and prognostic relevance of threshold-based quantification of myocardial delayed enhancement (MDE) on CT in patients with nonischemic dilated cardiomyopathy (NIDCM). MATERIALS AND METHODS: Forty-three patients with NIDCM (59.3 ± 17.1 years; 21 male) were included in the study and underwent cardiac CT and MRI. MDE was quantified manually and with a threshold-based quantification method using cutoffs of 2, 3, and 4 standard deviations (SDs) on three sets of CT images (100 kVp, 120 kVp, and 70 keV). Interobserver agreement in MDE quantification was assessed using the intraclass correlation coefficient (ICC). Agreement between CT and MRI was evaluated using the Bland-Altman method and the concordance correlation coefficient (CCC). Patients were followed up for the subsequent occurrence of the primary composite outcome, including cardiac death, heart transplantation, heart failure hospitalization, or appropriate use of an implantable cardioverter-defibrillator. The Kaplan-Meier method was used to estimate event-free survival according to MDE levels. RESULTS: Late gadolinium enhancement (LGE) was observed in 29 patients (67%, 29/43), and the mean LGE found with the 5-SD threshold was 4.1% ± 3.6%. The 4-SD threshold on 70-keV CT showed excellent interobserver agreement (ICC = 0.810) and the highest concordance with MRI (CCC = 0.803). This method also yielded the smallest bias with the narrowest range of 95% limits of agreement compared to MRI (bias, -0.119%; 95% limits of agreement, -4.216% to 3.978%). During a median follow-up of 1625 days (interquartile range, 712-1430 days), 10 patients (23%, 10/43) experienced the primary composite outcome. Event-free survival significantly differed between risk subgroups divided by the optimal MDE cutoff of 4.3% (log-rank P = 0.005). CONCLUSION: The 4-SD threshold on 70-keV monochromatic CT yielded results comparable to those of MRI for quantifying MDE as a marker of myocardial fibrosis, which showed prognostic value in patients with NIDCM.

Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

Impacts of Pre-transplant Panel-Reactive Antibody on Post-transplantation Outcomes: A Study of Nationwide Heart Transplant Registry Data.

BACKGROUND AND OBJECTIVES: The number of sensitized heart failure patients on waiting lists for heart transplantation (HTx) is increasing. Using the Korean Organ Transplantation Registry (KOTRY), a nationwide multicenter database, we investigated the prevalence and clinical impact of calculated panel-reactive antibody (cPRA) in patients undergoing HTx. METHODS: We retrospectively reviewed 813 patients who underwent HTx between 2014 and 2021. Patients were grouped according to peak PRA level as group A: patients with cPRA ≤10% (n= 492); group B: patients with cPRA >10%, <50% (n=160); group C patients with cPRA ≥50% (n=161). Post-HTx outcomes were freedom from antibody-mediated rejection (AMR), acute cellular rejection, coronary allograft vasculopathy, and all-cause mortality. RESULTS: The median follow-up duration was 44 (19-72) months. Female sex, re-transplantation, and pre-HTx renal replacement therapy were independently associated with an increased risk of sensitization (cPRA ≥50%). Group C patients were more likely to have longer hospital stays and to use anti-thymocyte globulin as an induction agent compared to groups A and B. Significantly more patients in group C had positive flow cytometric crossmatch and had a higher incidence of preformed donor-specific antibody (DSA) compared to groups A and B. During follow-up, group C had a significantly higher rate of AMR, but the overall survival rate was comparable to that of groups A and B. In a subgroup analysis of group C, post-transplant survival was comparable despite higher preformed DSA in a desensitized group compared to the non-desensitized group. CONCLUSIONS: Patients with cPRA ≥50% had significantly higher incidence of preformed DSA and lower freedom from AMR, but post-HTx survival rates were similar to those with cPRA <50%. Our findings suggest that sensitized patients can attain comparable post-transplant survival to non-sensitized patients when treated with optimal desensitization treatment and therapeutic intervention.

Ertugliflozin for Functional Mitral Regurgitation Associated With Heart Failure: EFFORT Trial.

BACKGROUND: The morbidity and mortality rates of patients with heart failure (HF) and functional mitral regurgitation (MR) remain substantial despite guideline-directed medical therapy for HF. We evaluated the efficacy of ertugliflozin for reduction of functional MR associated with HF with mild to moderately reduced ejection fraction. METHODS: The EFFORT trial (Ertugliflozin for Functional Mitral Regurgitation) was a multicenter, double-blind, randomized trial to examine the hypothesis that the sodium-glucose cotransporter 2 inhibitor ertugliflozin is effective for improving MR in patients with HF with New York Heart Association functional class II or III, 35%≤ejection fraction<50%, and effective regurgitant orifice area of chronic functional MR >0.1 cm2 on baseline echocardiography. We randomly assigned 128 patients to receive either ertugliflozin or placebo in addition to guideline-directed medical therapy for HF. The primary end point was change in effective regurgitant orifice area of functional MR from baseline to the 12-month follow-up. Secondary end points included changes in regurgitant volume, left ventricular (LV) volume indices, left atrial volume index, LV global longitudinal strain, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS: The treatment groups were generally well-balanced with regard to baseline characteristics: mean age, 66±11 years; 61% men; 13% diabetes; 51% atrial fibrillation; 43% use of angiotensin receptor-neprilysin inhibitor; ejection fraction, 42±8%; and effective regurgitant orifice area, 0.20±0.12 cm2. The decrease in effective regurgitant orifice area was significantly greater in the ertugliflozin group than in the placebo group (-0.05±0.06 versus 0.03±0.12 cm2; P<0.001). Compared with placebo, ertugliflozin significantly reduced regurgitant volume by 11.2 mL (95% CI, -16.1 to -6.3; P=0.009), left atrial volume index by 6.0 mL/m2 (95% CI, -12.16 to 0.15; P=0.005), and LV global longitudinal strain by 1.44% (95% CI, -2.42% to -0.46%; P=0.004). There were no significant between-group differences regarding changes in LV volume indices, ejection fraction, or NT-proBNP levels. Serious adverse events occurred in one patient (1.6%) in the ertugliflozin group and 6 (9.2%) in the placebo group (P=0.12). CONCLUSIONS: Among patients with functional MR associated with HF, ertugliflozin significantly improved LV global longitudinal strain and left atrial remodeling, and reduced functional MR. Sodium-glucose cotransporter 2 inhibitors may be considered for patients with functional MR. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04231331.

Impact of Everolimus Initiation and Corticosteroid Weaning During Acute Phase After Heart Transplantation on Clinical Outcome: Data from the Korean Organ Transplant Registry (KOTRY).

The effect of changes in immunosuppressive therapy during the acute phase post-heart transplantation (HTx) on clinical outcomes remains unclear. This study aimed to investigate the effects of changes in immunosuppressive therapy by corticosteroid (CS) weaning and everolimus (EVR) initiation during the first year post-HTx on clinical outcomes. We analyzed 622 recipients registered in the Korean Organ Transplant Registry (KOTRY) between January 2014 and December 2021. The median age at HTx was 56 years (interquartile range [IQR], 45-62), and the median follow-up time was 3.9 years (IQR 2.0-5.1). The early EVR initiation within the first year post-HTx and maintenance during the follow-up is associated with reduced the risk of primary composite outcome (all-cause mortality or re-transplantation) (HR, 0.24; 95% CI 0.09-0.68; p < 0.001) and cardiac allograft vasculopathy (CAV) (HR, 0.39; 95% CI 0.19-0.79; p = 0.009) compared with EVR-free or EVR intermittent treatment regimen, regardless of CS weaning. However, the early EVR initiation tends to increase the risk of acute allograft rejection compared with EVR-free or EVR intermittent treatment.

Eligibility and Cost-Utility Analysis of Dapagliflozin in Patients with Heart Failure Across the Whole Spectrum of Ejection Fraction in South Korea.

BACKGROUND: The DAPA-HF and DELIVER trials demonstrated the clinical benefits of dapagliflozin in heart failure (HF) patients across the entire ejection fraction (EF) spectrum. However, further investigation is needed for the real-world application of dapagliflozin in HF patients. This study examines the proportion of real-world HF patients eligible for dapagliflozin and evaluates the cost-effectiveness of adding dapagliflozin to current HF therapy. METHODS: Data from the nationwide prospective registry, the Korean Acute Heart Failure (KorAHF) registry, were used to determine dapagliflozin eligibility based on the enrollment criteria of the DAPA-HF/DELIVER trials. A cost-utility analysis was conducted using a Markov model to assess the cost-effectiveness of dapagliflozin by comparing it to the standard of care. RESULTS: Out of 5178 KorAHF patients, 48.7% met the enrollment criteria of the DAPA-HF/DELIVER trials, while 89.5% met the label criteria (US Food and Drug Administration, European Medicines Agency, and Korean Ministry of Food and Drug Safety). Eligibility was highest among HF patients with preserved EF (55.3% vs. HF with mildly reduced EF and HF with reduced EF 46.4%). Dapagliflozin proved to be cost-effective, with an incremental cost-effectiveness ratio (ICER) of 4557 US dollar (US$) per quality-adjusted life year, which falls below the US$18,182 willingness-to-pay threshold. The cost-effectiveness benefit was more pronounced in patients with a left ventricular EF (LVEF) ≤ 40% (ICER US$3279 for LVEF ≤ 40% vs. US$8383 for LVEF > 40%). CONCLUSIONS: Discrepancies in dapagliflozin eligibility were observed between real-world data and clinical trial results. The addition of dapagliflozin to HF therapy proved to be highly cost-effective across the entire EF spectrum.

Efficacy and safety of combination therapy with telmisartan, rosuvastatin, and ezetimibe in patients with dyslipidemia and hypertension: A randomized, double-blind, multicenter, therapeutic confirmatory, phase III clinical trial.

This study aimed to compare and evaluate the efficacy of the blood pressure (BP) control and cholesterol-lowering effects and safety of combination therapy with telmisartan, rosuvastatin, and ezetimibe versus rosuvastatin and ezetimibe double therapy or telmisartan single therapy in dyslipidemia patients with hypertension. After a wash-out/therapeutic lifestyle change period of ≥4 weeks, a total of 100 eligible patients were randomized and received one of three treatments for 8 weeks: (1) telmisartan 80 mg/rosuvastatin 20 mg/ezetimibe 10 mg (TRE), (2) rosuvastatin 20 mg/ezetimibe 10 mg (RE), or (3) telmisartan 80 mg (T). The primary endpoint was the efficacy evaluation of TRE by comparing changes in mean sitting systolic blood pressure (msSBP) and mean percentage change in low-density lipoprotein-C (LDL-C) from baseline after 8 weeks of treatment. The least square (LS) mean (SE) changes in msSBP at 8 weeks compared with baseline were -23.02 (3.04) versus -7.18 (3.09) mmHg in the TRE and RE groups, respectively (p < .0001), and -25.80 (2.74) versus -14.92 (2.65) mmHg in the TRE and T groups, respectively (p = .0005). The percentage changes in the mean (SD) LDL-C at 8 weeks compared with baseline were -54.97% (3.49%) versus -0.17% (3.23%) in the TRE and T groups, respectively (p < .0001). No serious adverse events occurred, and no statistically significant differences in the incidence of overall AEs and adverse drug reactions occurred among the three groups. TRE therapy significantly decreased msSBP and LDL-C compared to RE or T therapy with comparable safety and tolerability profiles.

A Detailed Protocol for Constructing a Human Single-Chain Variable Fragment (scFv) Library and Downstream Screening via Phage Display.

The development of monoclonal antibodies (mAbs) represents a significant milestone in both basic research and clinical applications due to their target specificity and versatility in therapeutic and diagnostic applications. The innovative strategy of mAb screening, utilizing phage display, facilitates the in vitro screening of antibodies with high affinity to target antigens. The single-chain variable fragment (scFv) is a subset of mAb derivatives, known for its high binding affinity and smaller size-just one-third of that of human IgG. This report outlines a detailed and comprehensive procedure for constructing a scFv phagemid library derived from human patients, followed by screening via phage display affinity selection. The protocol utilizes 348 primer combinations spanning the entire human antibody repertoire to minimize sequence bias and maintain library diversity during polymerase chain reaction (PCR) for scFv generation, resulting in a library size greater than 1 × 108. Furthermore, we describe a high-throughput phage display screening protocol using enzyme-linked immunosorbent assay (ELISA) to evaluate more than 1200 scFv candidates. The generation of a highly diverse scFv library, coupled with the implementation of a phage display screening methodology, is expected to provide a valuable resource for researchers in pursuit of scFvs with high affinity for target antigens, thus advancing both research and clinical endeavors.

Efficacy and Safety of Triple Therapy of Telmisartan/Amlodipine/Rosuvastatin in Patients with Dyslipidemia and Hypertension: A Multicenter Randomized Clinical Trial.

Background: Hypertension and dyslipidemia significantly contribute to cardiovascular disease development. Their coexistence poses challenges in managing multiple medications, influencing treatment adherence. Objective: This study aimed to assess the efficacy and safety of a combined treatment approach using a fixed-dose combination therapy. Methods: This multicenter, 8-week, randomized, double-blind, Phase IV trial was named Telmisartan/Amlodipine/Rosuvastatin from Samjin Pharmaceuticals and evaluated the efficacy and safety of fixed-dose combination treatment in patients with essential hypertension and dyslipidemia. They were randomly assigned to 2 fixed-dose combination therapy groups, telmisartan 40 mg/amlodipine 5 mg/rosuvastatin 10 mg (TEL/ALD/RSV) or amlodipine 5 mg/atorvastatin 10 mg (ALD/ATV) after washout/run-in period. The primary outcomes were the change in mean sitting systolic blood pressure and the percentage change of LDL-C after 8 weeks of medical treatment. Adverse drug reactions and events were assessed. Results: Of a total of 304 patients who underwent screening, 252 were randomized to the TEL/ALD/RSV group (125 patients) and the ALD/ATV group (127 patients). The mean (SD) ages of the TEL/ALD/RSV group and the ALD/ATV group were 67.4 (11.3) and 68.2 (10.6) years, respectively (P = 0.563). The least-squares mean (SE) in mean sitting systolic blood pressure changes between the 2 groups were -16.27 (0.93) mm Hg in the TEL/ALD/RSV group, -6.85 (0.92) mm Hg in the ALD/ATV group (LSM difference = -9.42 mm Hg; 95% CI, -11.99 to -6.84; P < .001). For LDL-C level changes, a significant difference was noted between the 2 groups: -50.03% (1.18%) in the TEL/ALD/RSV group, -39.60% (1.17%) in the ALD/ATV group (LSM difference = -10.43%; 95% CI, -13.70 to -7.16; P < .001). No severe adverse events were observed. Conclusions: TEL/ALD/RSV proved to be more efficient than ALD/ATV in lowering blood pressure and reducing LDL-C levels among patients with hypertension and dyslipidemia, with no notable safety concerns. (Curr Ther Res Clin Exp. 2024; XX:XXX-XXX). ClinicalTrials.gov identifier: NCT03860220.

Real-World Eligibility and Cost-Effectiveness Analysis of Empagliflozin for Heart Failure in Korea.

BACKGROUND: The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved empagliflozin for reducing cardiovascular mortality and heart failure (HF) hospitalization in patients with both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). However, limited data are available on the generalizability of empagliflozin to clinical practice. Therefore, we evaluated real-world eligibility and potential cost-effectiveness based on a nationwide prospective HF registry. METHODS: A total of 3,108 HFrEF and 2,070 HFpEF patients from the Korean Acute Heart Failure (KorAHF) registry were analyzed. Eligibility was estimated by inclusion and exclusion criteria of EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) and EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved) trials and by FDA & EMA label criteria. The cost-utility analysis was done using a Markov model to project the lifetime medical cost and quality-adjusted life year (QALY). RESULTS: Among the KorAHF patients, 91.4% met FDA & EMA label criteria, while 44.7% met the clinical trial criteria. The incremental cost-effectiveness ratio of empagliflozin was calculated at US$6,764 per QALY in the overall population, which is far below a threshold of US$18,182 per QALY. The cost-effectiveness benefit was more evident in patients with HFrEF (US$5,012 per QALY) than HFpEF (US$8,971 per QALY). CONCLUSION: There is a large discrepancy in real-world eligibility for empagliflozin between FDA & EMA labels and clinical trial criteria. Empagliflozin is cost-effective in HF patients regardless of ejection fraction in South Korea health care setting. The efficacy and safety of empagliflozin in real-world HF patients should be further investigated for a broader range of clinical applications. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01389843.