RESUMO
Furosemide is a diuretic and is used for the treatment of patients with heart failure (HF). It has been found that in some HF patients, the drug does not treat patients efficiently. This condition is named as furosemide resistance. In this study, it is aimed to investigate the relationship between UDP-glucuronosyltransferase 1 (UGT1A1) and interleukine-6 (IL-6) variations with furosemide resistance in HF patients. Sixty HF patients using furosemide (patient group) and 30 healthy individuals (control group) were enrolled in this study. Patients were divided into two subgroups as non-responders (furosemide resistant) group (n = 30) and the responders (non-resistant) group (n = 30) according to the presence of furosemide resistance (n = 30). Variations in the first exon of UGT1A1 and rs1800795 and rs1800796 variations in IL-6 were analyzed by direct sequencing and real-time polymerase chain reaction (RT-PCR), respectively. The effects of newly detected mutations on 3-D protein structure were analyzed by in silico analysis. At the end of the study, 11 variations were detected in UGT1A1, of which nine of them are novel and eight of them cause amino acid change. Also, rs1800795 and rs1800796 variations were detected in all the groups. When patient and control groups were compared with each other, rs1800796 mutation in IL-6 was found statistically high in the patient group (p = 0.027). When the three groups were compared with each other, similarly, rs1800796 mutation in IL-6 was found statistically high in the non-responders group (p = 0.043). When allele distributions were compared between the patient and control groups, the C allele of rs1800795 mutation in IL-6 was found statistically high in the patient group (p = 0.032). When allele distributions were compared between the three groups, 55T-insertion in UGT1A1 was found statistically high in the non-responders group (p = 0.017). According to in silico analysis results, two variations were found deleterious and six variations were detected as probably damaging to protein functions. Our study may contribute to the elucidation of pharmacogenetic features (drug response-gene relationship) and the development of individual-specific treatment strategies in HF patients using furosemide.
Assuntos
Furosemida , Insuficiência Cardíaca , Humanos , Furosemida/farmacologia , Furosemida/uso terapêutico , Interleucina-6/genética , Glucuronosiltransferase/genética , Glucuronosiltransferase/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Diuréticos/farmacologia , Diuréticos/uso terapêuticoRESUMO
BACKGROUND: Livedoid vasculopathy (LV) is a rare, disabling disease characterized by painful ulcers, livedo reticularis and atrophy blanche. Hypercoagulation, endothelial, and microcirculatory dysfunction are believed to be responsible for the pathogenesis of this difficult-to-treat disease. OBJECTIVES: This study sought to investigate the frequency of endothelial dysfunction, hypercoagulability, and nailfold capillaroscopic features in LV patients to shed light on its etiology. METHODS: This case-control study included 16 patients with LV, 24 with systemic sclerosis (SSc), and 23 control subjects. Serum markers of endothelial dysfunction soluble endoglin, endocan, endothelin-1, lipoprotein a, plasminogen activator inhibitor-1 (PAI-1), soluble thrombomodulin, and von Willebrand factor were measured using enzyme-linked immunosorbent assays. Flow-mediated dilation and carotid intima-media thickness were examined as markers of endothelial dysfunction, and microcirculation was assessed with nailfold capillaroscopy. Thrombophilia-related parameters, including gene polymorphisms of factor V Leiden, prothrombin, PAI-1 genes, methylenetetrahydrofolate reductase (MTHFR) and factor XIII mutation and serum levels of protein C, protein S, antithrombin, homocysteine, D-dimer and antiphospholipid antibodies were investigated in LV patients. RESULTS: Plasminogen activator inhibitor-1 and soluble thrombomodulin levels were significantly higher in LV patients compared to control subjects (2.3 [2.05-2.79] ng/ml vs. 1.89 [1.43-2.33] ng/ml, p = 0.007; 1.15 [0.88-1.4] ng/ml vs. 0.76 [0.56-0.9] ng/ml, p = 0.004, respectively). Flow-mediated dilation was 25.4 % lower in the LV patients compared to the control group (14.77 % [11.26-18.26] vs. 19.80 % [16.47-24.88], p = 0.034). Capillaroscopic features, including ramifications (75 % vs. 8.7 %, p < 0.001), avascular areas (25 % vs. 0 %, p = 0.011) and dilatations (33.2 % vs. 0 %, p = 0.016), were significantly higher in LV patients than in controls. LV patients had multiple biochemical or genetic abnormalities related to thrombophilia, including heterozygous factor V Leiden mutations (6.3 %), MTHFR (C677T) mutations (heterozygous 43.8 %, homozygous 18.8 %), MTHFR (A1298C) mutations (heterozygous 37.5 %, homozygous 12.5 %), factor XIII heterozygous mutation (12.5 %), antithrombin deficiency (31.3 %), protein S deficiency (12.5 %), hyperhomocysteinemia (31.3 %), D-dimer elevation (25 %), anti-ß2-glycoprotein I (12.5 %), lupus anticoagulant antibodies (6.3 %), and anticardiolipin antibodies (6.3 %). CONCLUSIONS: In conclusion, LV patients were characterized by an increased presence of thrombophilia-related parameters, and also exhibited vascular endothelial and microcirculatory dysfunction, resembling SSc. These findings support the complex interaction of thrombophilia, endothelial dysfunction, and microcirculation dysregulation in the pathogenesis of LV. Thus, the treatment of LV patients should be individualized, based on the identification of the predominant pathological pathways.
Assuntos
Livedo Reticular , Vasculopatia Livedoide , Trombofilia , Humanos , Inibidor 1 de Ativador de Plasminogênio , Trombomodulina , Estudos de Casos e Controles , Fator XIII , Espessura Intima-Media Carotídea , Microcirculação , Angioscopia Microscópica , Trombofilia/diagnóstico , AntitrombinasRESUMO
OBJECTIVE: Chronic total occlusions (CTOs) are complex lesions that usually require stenting of long segments, and, therefore more prone to restenosis and/or thrombosis. Polymer-free stents to avoid chronic inflammatory response in the vessel wall are a potential solution to reduce target lesion revascularization. We, therefore, investigated the clinical outcomes following successful amphilimus-eluting polymer-free stent implantation in long CTOs. PATIENTS AND METHODS: A total of 77 consecutive patients who underwent successful revascularization for long CTOs (lesion length ≥30 mm) using Cre8 stents were included. Baseline demographics, periprocedural characteristics, in-hospital events, and post-discharge long-term cardiovascular events were retrospectively screened for all patients. RESULTS: The Japanese CTO score was 1.58 ± 0.96, and the lesion length was 54.0 ± 9.89 mm. All cases were technically successful (n = 77, 100%), while procedural success was obtained in 74 patients (96.1%). Periprocedural complications were contrast-induced nephropathy (n = 4, 5.2%), coronary perforation (n = 3, 3.8%), residual dissection (n = 1, 1.3%), and femoral artery pseudoaneurysm (n = 1, 1.3%). Three patients (3.9%) presented periprocedural myocardial infarction requiring repeat percutaneous coronary intervention. At 25.0 ± 15.8 months follow-up, major adverse cardiac and cerebrovascular events were observed in 14 patients (18.1%). CONCLUSIONS: The Cre8 polymer-free drug- eluting stents seems safe and effective for percutaneous revascularization of long CTO lesions with a high success and low adverse event rate.