Triphenylphosphonium conjugation to a TRAP1 inhibitor, 2-amino-6-chloro-7,9-dihydro-8H-purin-8-one increases antiproliferative activity.

Tumor-necrosis-factor-receptor associated protein 1 (TRAP1), a mitochondrial paralog of heat shock protein 90 family proteins, is overexpressed in many cancer cells and supports tumorigenesis by rewiring vital metabolic and cell death pathways. The triphenylphosphonium moiety is used to deliver therapeutic cargo to increase drug uptake into mitochondria. Various aryl- or alkyl-substituted phosphonium analogs were conjugated with TRAP1-selective inhibitors 4a-c to optimize anticancer activity. Among these various phosphonium-conjugated compounds, (6-(2-amino-9-(4-bromo-2-fluorobenzyl)-6-chloro-8-oxo-8,9-dihydro-7H-purin-7-yl)hexyl)triphenylphosphornium (6a) was identified as a potential anticancer agent. Compound 6a had IC50 values of 0.30-3.24 µM in seven different cancer cell lines and potently suppressed tumor growth without any noticeable in vivo toxicity in a nude mouse model xenografted with PC3 prostate cancer cells.

Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site.

Heat shock protein 90 (Hsp90) family proteins are molecular chaperones that modulate the functions of various substrate proteins (clients) implicated in pro-tumorigenic pathways. In this study, the mitochondria-targeted antioxidant mitoquinone (MitoQ) was identified as a potent inhibitor of mitochondrial Hsp90, known as a tumor necrosis factor receptor-associated protein 1 (TRAP1). Structural analyses revealed an asymmetric bipartite interaction between MitoQ and the previously unrecognized drug binding sites located in the middle domain of TRAP1, believed to be a client binding region. MitoQ effectively competed with TRAP1 clients, and MitoQ treatment facilitated the identification of 103 TRAP1-interacting mitochondrial proteins in cancer cells. MitoQ and its redox-crippled SB-U014/SB-U015 exhibited more potent anticancer activity in vitro and in vivo than previously reported mitochondria-targeted TRAP1 inhibitors. The findings indicate that targeting the client binding site of Hsp90 family proteins offers a novel strategy for the development of potent anticancer drugs.

Effective production of human growth factors in Escherichia coli by fusing with small protein 6HFh8.

BACKGROUND: Growth factors (GFs) are signaling proteins that affect cellular processes such as growth, proliferation, and differentiation. GFs are used as cosmeceuticals, exerting anti-wrinkle, anti-aging, and whitening effects, and also as pharmaceuticals to treat wounds, growth failure, and oral mucositis. However, in mammalian and bacterial cells, low productivity and expression in inclusion bodies, respectively, of GFs does not satisfy the consumer demand. Here, we aimed to develop a bacterial expression system that produces high yields of soluble GFs that can be purified in their native forms. RESULTS: We present Fh8, an 8-kDa peptide from Fasciola hepatica with an N-terminal hexa-histidine (6HFh8), as a fusion partner for enhanced human GF production in recombinant Escherichia coli. The fusion partner harboring a tobacco etch virus (TEV) protease cleavage site was fused to the N-terminus of 10 human GFs: acidic and basic fibroblast growth factors (aFGF and bFGF, respectively), epidermal growth factor (EGF), human growth hormone (hGH), insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor 165 (VEGF165), keratinocyte growth factor 1 (KGF-1), placental growth factor (PGF), stem cell factor (SCF), and tissue inhibitor of metalloproteinase 1 (TIMP-1). The fusion proteins were expressed in E. coli under the control of T7 promoter at three temperatures (25 °C, 30 °C, and 37 °C). All individual fusion proteins, except for SCF and TIMP-1, were successfully overexpressed in cytoplasmic soluble form at more than one temperature. Further, the original aFGF, IGF-1, EGF, and VEGF165 proteins were cleaved from the fusion partner by TEV protease. Five-liter fed-batch fermentation approaches for the 6HFh8-aFGF (lacking disulfide bonds) and 6HFh8-VEGF165 (a cysteine-rich protein) were devised to obtain the target protein at concentrations of 9.7 g/l and 3.4 g/l, respectively. The two GFs were successfully highly purified (> 99% purity). Furthermore, they exerted similar cell proliferative effects as those of their commercial equivalents. CONCLUSIONS: We demonstrated that 6HFh8-GF fusion proteins could be overexpressed on a g/l scale in the cytoplasm of E. coli, with the GFs subsequently highly purified and maintaining their biological activity. Hence, the small protein 6HFh8 can be used for efficient mass-production of various GFs.

Discovery of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl)acetates as potent Hsp90 inhibitors with selectivity over TRAP1.

As the most abundant heat shock protein (HSP), Hsp90 is actively involved in tumor cell growth and various responses to anti-carcinogenic stress. Hsp90 has thus emerged as a potential drug target. A structure-based drug design approach was applied to develop novel resorcinolyltriazole derivatives as Hsp90 inhibitors. Structure-activity relationships (SARs) and molecular docking were investigated to provide a rationale for binding affinity and paralog selectivity. Click chemistry between iodoethynylresorcinol and an azido derivative was used to synthesize a new family of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl) acetates that exhibited Hsp90 binding affinities of 40-100 nM (IC50). Among the synthesized molecules, the triazole alkyl acetates displayed the highest Hsp90 binding affinities. Their potency against Hsp90 was over 100-fold stronger than against TRAP1 and 1-3-fold stronger than against Grp94. In particular, compounds 18, 19, and 30 had Hsp90 inhibitory activities of ~45 nM (IC50) and they displayed over 350-fold selectivity for Hsp90 over TRAP1.

Development of pyrazolo[3,4-d]pyrimidine-6-amine-based TRAP1 inhibitors that demonstrate in vivo anticancer activity in mouse xenograft models.

TNF Receptor Associated Protein 1 (TRAP1) is a mitochondrial paralog of Hsp90 related to the promotion of tumorigenesis in various cancers via maintaining mitochondrial integrity, reducing the production of reactive oxygen species, and reprogramming cellular metabolism. Consequently, Hsp90 and TRAP1 have been targeted to develop cancer therapeutics. Herein, we report a series of pyrazolo[3,4-d]pyrimidine derivatives that are mitochondria-permeable TRAP1 inhibitors. Structure-based drug design guided the optimization of potency, leading to the identification of compounds 47 and 48 as potent TRAP1 and Hsp90 inhibitors with good metabolic and plasma stability as well as acceptable CYP and hERG inhibition. X-ray co-crystallization studies confirmed both 47 and 48 interact with the ATP binding pocket in the TRAP1 protein. Compounds 47 and 48 demonstrated excellent anticancer efficiency in various cancer cells, with limited toxicity over normal hepatocyte and prostate cells. Mouse PC3 xenograft studies showed 47 and 48 significantly reduced tumor growth.

Identification of novel immunogenic proteins against Streptococcus parauberis in a zebrafish model by reverse vaccinology.

Streptococcus parauberis is the major infectious agent of streptococcosis in the olive flounder (Paralichthys olivaceus), causing serious economic damage. In this study, we identified potential vaccine candidates against S. parauberis by reverse vaccinology. In total, the 2 out of 21 proteins were identified as vaccine candidates from two available S. parauberis genomes. The membrane-anchored protein SEC10/PgrA and the metal ABC transporter substrate-binding lipoprotein mtsA were potent antigenic proteins based on western blotting with mouse-derived antiserum against whole bacteria of S. parauberis serotypes I and II. In particular, metal ABC transporter substrate-binding lipoprotein (mtsA) showed similar protective immunity to that of whole-cell bacterins against S. parauberis in a zebrafish model. These results suggest that mtsA may be considered as a novel candidate in the development of vaccines against S. parauberis.

Surgical treatment of glioblastoma in the elderly: the impact of complications.

The diagnosis of glioblastoma (GBM) often carries a dismal prognosis, with a median survival of 14.6 months. A particular challenge is the diagnosis of GBM in the elderly population (age > 75 years), who have significant comorbidities, present with worse functional status, and are at higher risk with surgical treatments. We sought to evaluate the impact of current GBM treatment, specifically in the elderly population. The authors undertook a retrospective review of all patients aged 75 or older who underwent treatment for GBM from 1997 to 2016. Patient outcomes were evaluated with regards to demographics, surgical variables, postoperative treatment, and complications. A total of 82 patients (mean age 80.5 ± 3.8 years) were seen. Most patients presented with confusion (57.3%) and associated comorbidities, and prior anticoagulation use was common in this age group. Extent of resection (EOR) included no surgery (9.8%), biopsy (22.0%), subtotal resection (40.2%), and gross-total resection (23.2%). Postoperative adjuvant therapy included temozolomide (36.1%), radiation (52.5%), and bevacizumab (11.9%). A mean overall survival of 6.3 ± 1.2 months was observed. There were 34 complications in 23 patients. Improved survival was seen with increased EOR only for patients without postoperative complications. A multivariate Cox proportional hazards model showed that complications (HR = 5.43, 95% CI 1.73, 17.04, p = 0.004) predicted poor outcome. Long-term survivors (> 12 months survival) and short-term survivors had similar median preoperative Karnofsky Performance Scale (KPS) score (80 vs. 80, p = 0.43), but long-term survivors had unchanged postoperative KPS (80 vs. 60, p = 0.02) and no complications (0/9 vs. 23/72, p = 0.04). The benefit of glioblastoma treatment in our series was limited by the postoperative complications and KPS. Presence of a complication served as an independent risk factor for worsened overall survival in this age group. It is likely that decreased patient function limits postoperative adjuvant therapy and predisposes to higher morbidity especially in this age group.

Surgical repair of sciatic nerve traumatic rupture: technical considerations and approaches.

Traumatic proximal sciatic nerve rupture poses surgical repair dilemmas. Disruption often causes a large nerve gap after proximal neuroma and distal scar removal. Also, autologous graft material to bridge the segmental defect may be insufficient, given the sciatic nerve diameter. The authors utilized knee flexion to allow single neurorrhaphy repair of a large sciatic nerve defect, bringing healthy proximal stump to healthy distal segment. To avoid aberrant regeneration, the authors split the sciatic nerve into common peroneal and tibial divisions. After 3 months, the patient can fully extend the knee and has evidence of distal regeneration and nerve continuity without substantial injury. The video can be found here: https://youtu.be/lsezRT5I8MU .

Preoperative embolization of skull base meningiomas: current indications, techniques, and pearls for complication avoidance.

Skull base meningiomas are technically challenging tumors to treat because of their deep vascular supply that can preclude early devascularization during resection. Preoperative embolization of these arterial feeders is thought to decrease blood loss and facilitate resection; however, given the complex and varied anatomy of these skull base lesions, preoperative embolization is not without risk. It is essential for both endovascular and skull base neurosurgeons to understand these risks in light of the potential benefits. The authors review the vascular anatomy of skull base meningiomas, indications for preoperative devascularization, endovascular techniques, and published results regarding embolization of these lesions.

Predictors of Left Ventricular Functional Recovery and Their Impact on Clinical Outcomes in Patients With Newly Diagnosed Dilated Cardiomyopathy and Heart Failure.

BACKGROUND: To identify the predictors of left ventricular functional recovery (LVFR) and its impacts on clinical outcomes in acute heart failure (AHF) patients with newly diagnosed dilated cardiomyopathy (DCM). METHODS: A total of 175 consecutive patients with newly diagnosed DCM and AHF were divided into two groups according to LVFR on FU echocardiography; the recovered group (n=54, 54.3±18.5years, 31 males) vs. the non-recovered group (n=121, 60.5±15.1years, 79 males). Clinical, laboratory, and echocardiographic findings were compared, and major adverse cardiac and cerebrovascular events (MACCE) including death, rehospitalisation, and stroke were analysed. RESULTS: Left ventricular function (LV) was normalised in 54 patients (30.8%) on follow-up echocardiography. The change in the level of N-terminal pro-B-type natriuretic peptide (ΔNT-proBNP) between initial presentation and discharge >1633.5pg/mL was an independent predictor of LVFR, whereas diabetes and LV end-systolic diameter >50mm were negative predictors of LVFR on multivariate analysis. During five years of clinical follow-up, MACCE developed in 91 patients: 58 deaths, 29 rehospitalisations, and 4 strokes. On multivariate analysis, baseline LVEF <30% and no LVFR were independent predictors of MACCE. CONCLUSION: Left ventricular functional recovery was not uncommon in newly diagnosed DCM with AHF. The changes in NT-proBNP level during hospitalisation, diabetes, and larger initial LV size were independent predictors of LVFR, and LVFR was an independent predictor of future MACCE. Serial monitoring of NT-proBNP and LV function would be useful in the risk stratification of newly diagnosed DCM with AHF.

Optimal dose of dabigatran for the prevention of thromboembolism with minimal bleeding risk in Korean patients with atrial fibrillation.

AIMS: We aim to determine the optimal dose of dabigatran in Korean patients with atrial fibrillation (AF). METHODS AND RESULTS: We analysed 1834 patients with non-valvular AF, classified into a warfarin group (n = 990), dabigatran 150 mg group (D150, n = 294), and 110 mg group (D110, n = 550). The D110 group was further classified into patients concordant (co-D110, n = 367) and patients discordant (di-D110, n = 183) with guidelines to dose reduction. Propensity-matched 1-year clinical outcomes were then compared. Efficacy outcomes were defined as thromboembolism composed of new-onset stroke or systemic embolism. Safety outcomes were major bleeding. Both D150 and D110 had comparable efficacies as warfarin. However, only D110 significantly lowered the risk of major bleeding [hazard ratio (HR) 0.19, 95% confidence interval (CI) 0.07-0.55, P = 0.002]. In a subgroup analysis according to guideline-concordant indications for dose reduction, both co-D110 and di-D110 displayed a comparable efficacy as warfarin. Both co-D110 (HR 0.22, 95% CI 0.06-0.76, P = 0.017) and di-D110 (HR 0.11, 95% CI 0.02-0.81, P = 0.030) significantly lowered incidences of major bleeding. There were no differences in the efficacy and safety between di-D110 and D150, and net clinical outcomes were similar. CONCLUSION: Although D150 and D110 had a comparable efficacy, only D110 lowered the risk of major bleeding in Korean AF patients compared with warfarin. Even the guideline-discordant use of dabigatran 110 mg demonstrated a similar efficacy and safety compared with D150. However, further prospective randomized trials are needed in order to comprehensively evaluate whether D150 or D110 is the optimal dosage in Asian patients with AF.

Stent technology in ischemic stroke.

Atherosclerotic disease of the cerebral vasculature is a major cause of stroke worldwide. Atherosclerosis that is refractory to best medical management may require revascularization. In these instances, endovascular treatment provides a popular and safe alternative to open surgical techniques. The authors provide an overview of stent technology in the treatment of ischemic stroke, discussing the major studies evaluating stenting for extracranial carotid artery, vertebral artery, and intracranial atherosclerotic disease. The authors describe the commonly used stents with respect to their individual characteristics and technical limitations. Current and future developments in stent technology are also discussed, with areas for further innovation and clinical research.

Flow diversion of tandem cerebral aneurysms: a multi-institutional retrospective study.

OBJECTIVE Flow diversion has proven to be an efficacious means of treating cerebral aneurysms that are refractory to other therapeutic means. Patients with tandem aneurysms treated with flow diversion have been included in larger, previously reported series; however, there are no dedicated reports on using this technique during a single session to treat this unique subset of patients. Therefore, the authors analyzed the outcomes of patients who had undergone single-session flow diversion for the treatment of tandem aneurysms. METHODS The authors conducted a retrospective review of flow diversion with the Pipeline embolization device (PED) for the treatment of tandem aneurysms in a single session at 2 participating medical centers: University of Utah, Salt Lake City, Utah, and Barrow Neurological Institute, Phoenix, Arizona. Patient demographic data, aneurysm characteristics, treatment strategy and results, complications, and follow-up data were collected from the medical record and analyzed. RESULTS Between January 2011 and December 2015, 17 patients (12 female, 5 male) with a total of 38 aneurysms (mean size 4.7 ± 2.7 mm, mean ± SD) were treated. Sixteen patients had aneurysms in the anterior circulation, and 1 patient had tandem aneurysms in the posterior circulation. Twelve patients underwent only placement of a PED, whereas 5 underwent adjunctive coil embolization of at least 1 aneurysm. One PED was used in each of 9 patients, and 2 PEDs were required in each of 8 patients. There were 2 intraprocedural complications; however, in both instances, the patients were asymptomatic at the last follow-up. The follow-up imaging studies were available for 15 patients at a mean of 7 months after treatment (216 days, range 0-540 days). The mean initial Raymond score after treatment was 2.7 ± 0.7, and the mean final score was 1.3 ± 0.7. CONCLUSIONS In this series, the use of flow diversion for the treatment of tandem cerebral aneurysms had an acceptable safety profile, indicating that it should be considered as an effective therapy for this complicated subset of patients. Further prospective studies must be performed before more definitive conclusions can be made.

Synthesis of Fe3O4@nickel-silicate core-shell nanoparticles for His-tagged enzyme immobilizing agents.

Immobilizing enzymes on artificially fabricated carriers for their efficient use and easy removal from reactants has attracted enormous interest for decades. Specifically, binding platforms using inorganic nanoparticles have been widely explored because of the benefits of their large surface area, easy surface modification, and high stability in various pH and temperatures. Herein, we fabricated Fe3O4 encapsulated 'sea-urchin' shaped nickel-silicate nanoparticles with a facile synthetic route. The enzymes were then rapidly and easily immobilized with poly-histidine tags (His-tags) and nickel ion affinity. Porous nickel silicate covered nanoparticles achieved a high immobilization capacity (85 µg mg-1) of His-tagged tobacco etch virus (TEV) protease. To investigate immobilized TEV protease enzymatic activity, we analyzed the cleaved quantity of maltose binding protein-exendin-fused immunoglobulin fusion protein, which connected with the TEV protease-specific cleavage peptide sequence. Moreover, TEV protease immobilized nanocomplexes conveniently removed and recollected from the reactant by applying an external magnetic field, maintained their enzymatic activity after reuse. Therefore, our newly developed nanoplatform for His-tagged enzyme immobilization provides advantageous features for biotechnological industries including recombinant protein processing.

Comparison of non-vitamin K antagonist oral anticoagulants and warfarin on clinical outcomes in atrial fibrillation patients with renal dysfunction.

AIMS: We aimed to compare the efficacy and safety between non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in atrial fibrillation (AF) patients according to renal dysfunction. METHODS AND RESULTS: We analysed 1319 patients who had been taken oral anticoagulants. They were classified into patients taking NOACs (n = 326) and warfarin (n = 993). Renal dysfunction was defined as the estimated glomerular filtration rate <60 mL/min by using the Chronic Kidney Disease Epidemiology Collaboration equation. The composite clinical outcomes were defined as the composite of death, hospitalization, and new-onset strokes. Safety outcomes were composed of major and minor bleeding. Subgroup analyses for clinical and safety outcomes were performed according to renal dysfunction during median 596 (506-612) follow-up days. The prevalence of renal dysfunction was similar between the two groups. The incidences of death, hospitalization, and strokes were not different between the two groups. However, the incidences of major bleeding was significantly higher in patients taking warfarin. In the subgroup analysis with renal dysfunction, the use of NOACs significantly improved the composite clinical outcomes (adjusted hazard ratio, HR, 0.30, 95% confidence interval, CI, 0.11-0.77, interaction P = 0.018) and major bleeding (adjusted HR 0.18, 95% CI 0.07-0.45, interaction P = 0.199) even after the covariate adjustment. However, in patients without renal dysfunction, there were no differences in the incidences of the composite clinical outcomes between the two groups. CONCLUSIONS: The benefit of NOACs was more prominent in AF patients with renal dysfunction than without renal dysfunction. These results suggest that NOACs as the first choice oral anticoagulant in AF patients with renal dysfunction.

Red cell distribution width as a novel predictor for clinical outcomes in patients with paroxysmal atrial fibrillation.

AIMS: Elevated red cell distribution width (RDW) has been known to be associated with adverse long-term outcomes in patients with cardiovascular diseases. We aimed to evaluate relationship between RDW values and clinical outcomes in patients with paroxysmal atrial fibrillation (AF). METHODS AND RESULTS: We analysed 567 patients who were newly diagnosed as paroxysmal AF. Clinical outcomes were analysed after median 4.8 (3.4-6.9) years follow-up. The composite clinical outcomes were defined as the composite of death, hospitalization due to heart failure, and new-onset stroke. Bleeding events were composed of major and minor bleeding. The relationship of RDW with clinical outcomes was assessed using continuous or categorical variables as quartiles: <12.8, 12.8-13.2, 13.3-13.8, and ≥13.9%. Patients with the highest RDW quartile were the oldest and had more frequent history of heart failure. CHA2DS2-VASc score was increased along with increasing RDW quartiles (1.75 ± 1.48 vs. 1.77 ± 1.63 vs. 1.87 ± 1.61 vs. 2.33 ± 1.65, P = 0.008). Incidence of new-onset stroke (log-rank P = 0.032), the composite clinical outcomes (log-rank P = 0.014), and bleeding events (log-rank P = 0.001) were increased as increasing RDW quartiles. Multivariate analysis identified that RDW was a significant predictor for new-onset stroke [adjusted hazard ratio (HR) 1.32, 95% confidence interval (CI) 1.06-1.65, P = 0.015], the composite clinical outcomes (adjusted HR 1.21, 95% CI 1.03-1.41, P = 0.017), and bleeding events (adjusted HR 1.36, 95% CI 1.13-1.64, P = 0.001). CONCLUSIONS: RDW can be a new, useful, novel predictor of clinical and safety outcomes in patients with paroxysmal AF.

Cardioprotective effect of fimasartan, a new angiotensin receptor blocker, in a porcine model of acute myocardial infarction.

Cardioprotective effect of fimasartan, a new angiotensin receptor blocker (ARB), was evaluated in a porcine model of acute myocardial infarction (MI). Fifty swine were randomized to group 1 (sham, n=10), group 2 (no angiotensin-converting enzyme inhibitor [ACEI] or ARB, n=10), group 3 (perindopril 2 mg daily, n=10), group 4 (valsartan 40 mg daily, n=10), or group 5 (fimasartan 30 mg daily, n=10). Acute MI was induced by occlusion of the left anterior descending artery for 50 min. Echocardiography, single photon emission computed tomography (SPECT), and F-18 fluorodeoxyglucose cardiac positron emission tomography (PET) were performed at baseline, 1 week, and 4 weeks. Iodine-123 meta-iodobenzylguanidine (MIBG) scan was done at 6 weeks for visualization of cardiac sympathetic activity. Left ventricular function and volumes at 4 weeks were similar between the 5 groups. No difference was observed in groups 2 to 5 in SPECT perfusion defect, matched and mismatched segments between SPECT and PET at 1 week and 4 weeks. MIBG scan showed similar uptake between the 5 groups. Pathologic analysis showed similar infarct size in groups 2 to 5. Infarct size reduction was not observed with use of fimasartan as well as other ACEI and ARB in a porcine model of acute MI.

Characteristics, in-hospital and long-term clinical outcomes of nonagenarian compared with octogenarian acute myocardial infarction patients.

We compared clinical characteristics, management, and clinical outcomes of nonagenarian acute myocardial infarction (AMI) patients (n=270, 92.3 ± 2.3 yr old) with octogenarian AMI patients (n=2,145, 83.5 ± 2.7 yr old) enrolled in Korean AMI Registry (KAMIR). Nonagenarians were less likely to have hypertension, diabetes and less likely to be prescribed with beta-blockers, statins, and glycoprotein IIb/IIIa inhibitors compared with octogenarians. Although percutaneous coronary intervention (PCI) was preferred in octogenarians than nonagenarians, the success rate of PCI between the two groups was comparable. In-hospital mortality, the composite of in-hospital adverse outcomes and one year mortality were higher in nonagenarians than in octogenarians. However, the composite of the one year major adverse cardiac events (MACEs) was comparable between the two groups without differences in MI or re-PCI rate. PCI improved 1-yr mortality (adjusted hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.36-0.69, P<0.001) and MACEs (adjusted HR, 0.47; 95% CI, 0.37-0.61, P<0.001) without significant complications both in nonagenarians and octogenarians. In conclusion, nonagenarians had similar 1-yr MACEs rates despite of higher in-hospital and 1-yr mortality compared with octogenarian AMI patients. PCI in nonagenarian AMI patients was associated to better 1-yr clinical outcomes.

Modified application of SAMe-TT2R2 scoring system in Asian patients with atrial fibrillation for the selection of oral anticoagulants.

BACKGROUND/AIMS: The SAMe-TT2R2 score is used for assessing anticoagulation control (AC) quality with warfarin. However, it is hard to apply SAMe-TT2R2 score in Asian patients with atrial fibrillation (AF), because it has not been proven in those populations. This study aimed to validate the SAMe-TT2R2 score in Asian patients with AF and suggest a modified SAMe- TT2R2 score for this population. METHODS: We analyzed 710 Korean patients with AF who were using warfarin. The AC quality was assessed as the mean time in therapeutic range (TTR). Each component of SAMe-TT2R2 score was evaluated for the relationship with AC. Further clinical factors that predict AC were analyzed. Identified factors were re-assorted and constructed as SA2Me-TTR scoring system. RESULTS: Of the components of the SAMe-TT2R2 score, female, age, and rhythm control were associated with AC. Heart failure and renal insufficiency were newly identified factors associated with AC. The modified SA2Me-TTR score was reconstructed with the relevant risk factors (S, female gender, 1 point; A, age < 60 yr, 2 points; Me, medical history of heart failure, 1 point; T, treatment for rhythm control, 1 point; T, history of stroke or transient ischemic attack, 1 point; R, renal insufficiency, 1 point). The modified SA2Me-TTR score demonstrated an excellent relationship with the grading of AC. The modified SA2Me-TTR score ≤ 1 identified patients with good AC (hazard ratio 2.46, 95% CI 1.75-3.47). CONCLUSION: The modified SA2Me-TTR score was useful for guiding oral anticoagulants selection in Asian patients with AF.