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Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the urinary albumin-to-creatinine ratio (UACR) in patients with elevated levels of albuminuria in the presence or absence of heart failure (HF) or type 2 diabetes mellitus (T2D). However, these effects have not yet been reported in the presence of both HF and T2D. This lack of evidence prompted us to conduct a clinical trial on the effects of dapagliflozin on UACR in patients with HF and T2D. Methods: DAPPER is a multicentre, randomised, open-labeled, parallel-group, standard treatment-controlled trial that enrolled patients at 18 medical facilities in Japan. Eligible participants with both HF and T2D and aged between 20 and 85 years were randomly assigned to a dapagliflozin or control (anti-diabetic drugs other than SGLT 2 inhibitors) group with a 1:1 allocation. The primary outcome was changes in UACR from baseline after a two-year observation, and secondary endpoints were cardiovascular (CV) events and parameters related to HF. This trial was registered with the UMIN-CTR registry, UMIN000025102 and the Japan Registry of Clinical Trials, jRCTs051180135. Findings: Between 12 May 2017 and 31 March 2020, 294 patients were randomly assigned to the dapagliflozin group (n = 146) or control group (n = 148). The mean age of patients was 72.1 years and 29% were female. The mean glycated hemoglobin value was 6.9%, mean NT-proBNP was 429.1 pg/mL, mean estimated GFR was 65.7 mL/min/1.73 m2, and median UACR was 25.0 (8.8-74.6) mg/g Cr in the dapagliflozin group and 25.6 (8.2-95.0) mg/g Cr in the control group. Of the 146 patients in the dapagliflozin group, 122 completed the study, and 107 (87.7%) were taking 5 mg of dapagliflozin daily at the end of the observation period. The primary outcome did not significantly differ between the dapagliflozin and control groups. Among the secondary endpoints, the mean decrease in left ventricular end-diastolic dimensions as one of the echocardiographic parameters was larger in the dapagliflozin group than in the control group. The composite endpoint, defined as CV death or hospitalisation for CV events, hospitalisation for HF events, hospitalisation for all causes, and an additional change in prescriptions for heart failure in a two-year observation, was less frequent in the dapagliflozin group than in the control group. Interpretation: Although dapagliflozin at a dose of 5 mg daily did not reduce urinary albumin excretion in patients with HF and T2D from that in the controls, our findings suggest that dapagliflozin decreased CV events and suppressed left ventricular remodeling. Funding: AstraZeneca KK, Ono Pharmaceutical Co., Ltd.
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BACKGROUND: B-type natriuretic peptide (BNP) is a risk factor for stroke and cardiac death in patients with atrial fibrillation. We hypothesized the prognostic outcomes of very elderly non-valvular atrial fibrillation patients ineligible for standard anticoagulation treatment would vary according to BNP stratification. METHODS: In this subanalysis of the ELDERCARE-AF trial, patients were stratified by BNP levels at enrollment, and clinical outcomes compared among BNP subgroups. Hazard ratios were adjusted for age, atrial fibrillation type, body mass index, creatine clearance, congestive heart failure, and D-dimer. BNP levels were measured using chemiluminescence enzyme immunoassays. RESULTS: In total, 984 patients (average age: 86.6 years) not considered eligible for oral anticoagulant therapy at approved doses for stroke prevention were included. The BNP levels at enrollment were <200 (low), 200 to <400 (moderate), and ≥400 (high) pg/mL in 428, 300, and 256 patients, respectively. The number (%) of patients with stroke or systemic embolism (SSE) was 7 (1.2%), 24 (5.9%), and 28 (8.6%) in the low, moderate, and high BNP subgroups, respectively (adjusted hazard ratio 3.82, P = .0025 for low vs moderate BNP and 4.76, P = .0007 for low vs high BNP). There was no significant difference in major bleeding incidence between the BNP subgroups. Edoxaban 15 mg was associated with a consistent reduction in SSE vs placebo in all BNP subgroups. CONCLUSIONS: Stratification by BNP level was associated with the incidence of SSE for very elderly non-valvular atrial fibrillation patients ineligible for standard anticoagulation treatment, and the effect of edoxaban 15 mg was consistent across BNP levels.
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Fibrilação Atrial , Embolia , Acidente Vascular Cerebral , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Embolia/prevenção & controle , Humanos , Peptídeo Natriurético Encefálico , Prognóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controleAssuntos
Cardiomiopatias/diagnóstico por imagem , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos , Sarcoidose/diagnóstico por imagem , Tionucleosídeos , Timidina/análogos & derivados , Adulto , Idoso , Radioisótopos de Carbono , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Ambulatory and home blood pressure (BP) monitoring parameters are better predictors of cardiovascular events than are office BP monitoring parameters, but there is a lack of robust data and little information on heart failure (HF) risk. The JAMP study (Japan Ambulatory Blood Pressure Monitoring Prospective) used the same ambulatory BP monitoring device, measurement schedule, and diary-based approach to data processing across all study centers and determined the association between both nocturnal hypertension and nighttime BP dipping patterns and the occurrence of cardiovascular events, including HF, in patients with hypertension. METHODS: This practitioner-based, nationwide, multicenter, prospective, observational study included patients with at least 1 cardiovascular risk factor, mostly hypertension, and free of symptomatic cardiovascular disease at baseline. All patients underwent 24-hour ambulatory BP monitoring at baseline. Patients were followed annually to determine the occurrence of primary end point cardiovascular events (atherosclerotic cardiovascular disease and HF). RESULTS: A total of 6,359 patients (68.6±11.7 years of age, 48% men) were included in the final analysis. During a mean±SD follow-up of 4.5±2.4 years, there were 306 cardiovascular events (119 stroke, 99 coronary artery disease, 88 HF). Nighttime systolic BP was significantly associated with the risk of atherosclerotic cardiovascular disease and HF (hazard ratio adjusted for demographic and clinical risk factors per 20-mm Hg increase: 1.18 [95% CI, 1.02-1.37], P=0.029; and 1.25 [95% CI, 1.00-1.55], P=0.048, respectively). Disrupted circadian BP rhythm (riser pattern, nighttime BP higher than daytime BP) was significantly associated with higher overall cardiovascular disease risk (1.48 [95% CI, 1.05-2.08]; P=0.024), and especially HF (2.45 [95% CI, 1.34-4.48]; P=0.004) compared with normal circadian rhythm. CONCLUSIONS: Nighttime BP levels and a riser pattern were independently associated with the total cardiovascular event rate, in particular for HF. These findings suggest the importance of antihypertensive strategies targeting nighttime systolic BP. Registration: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000020377.
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Monitorização Ambulatorial da Pressão Arterial , Ritmo Circadiano , Hipertensão/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Humanos , Hipertensão/epidemiologia , Japão/epidemiologia , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
Amyloidosis and sarcoidosis are systemic diseases that affect multiple organ systems. Accurate diagnosis of cardiac amyloidosis and sarcoidosis is particularly important because cardiac involvement can be fatal. Amyloidosis is characterized by the deposition of amyloid fibrils, and cardiac amyloidosis is classified into amyloid immunoglobulin light chain (AL) and amyloid transthyretin (ATTR) types. Radionuclide tracers for amyloidosis include (a) bone tracers, (b) amyloid-directed molecules, and (c) PET amyloid agents. Bone tracers are particularly sensitive in detection of ATTR type amyloidosis, whereas PET amyloid agents show a higher affinity for the AL type. In sarcoidosis, gallium 67 (67Ga) citrate scintigraphy and fluorine 18 (18F) fluorodeoxyglucose (FDG) PET are pivotal to diagnosis of cardiac sarcoidosis, and 18F-FDG PET/CT has particularly high efficacy in detection of sarcoidosis and monitoring of response to therapy. A major limitation of 18F-FDG is physiologic uptake in the myocardium, which can remain in approximately 20% of patients even after elaborate preparation (eg, prolonged fasting >12-18 hours, modification to a high-fat and low-carbohydrate diet, and injection of unfractionated heparin). This limitation has led to a search for potential new tracers. Recently introduced tracers that show promise include those used in somatostatin receptor imaging and cellular proliferation imaging, which provide detectability as high as that for 18F-FDG without requiring dietary restrictions and have potential for monitoring disease activity. ©RSNA, 2020.
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Amiloidose/diagnóstico por imagem , Cardiomiopatias/diagnóstico por imagem , Cintilografia , Sarcoidose/diagnóstico por imagem , Humanos , Compostos RadiofarmacêuticosRESUMO
BACKGROUND: Implementation of appropriate oral anticoagulant treatment for the prevention of stroke in very elderly patients with atrial fibrillation is challenging because of concerns regarding bleeding. METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven trial to compare a once-daily 15-mg dose of edoxaban with placebo in elderly Japanese patients (≥80 years of age) with nonvalvular atrial fibrillation who were not considered to be appropriate candidates for oral anticoagulant therapy at doses approved for stroke prevention. The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding according to the definition of the International Society on Thrombosis and Haemostasis. RESULTS: A total of 984 patients were randomly assigned in a 1:1 ratio to receive a daily dose of 15 mg of edoxaban (492 patients) or placebo (492 patients). A total of 681 patients completed the trial, and 303 discontinued (158 withdrew, 135 died, and 10 had other reasons); the numbers of patients who discontinued the trial were similar in the two groups. The annualized rate of stroke or systemic embolism was 2.3% in the edoxaban group and 6.7% in the placebo group (hazard ratio, 0.34; 95% confidence interval [CI], 0.19 to 0.61; P<0.001), and the annualized rate of major bleeding was 3.3% in the edoxaban group and 1.8% in the placebo group (hazard ratio, 1.87; 95% CI, 0.90 to 3.89; P = 0.09). There were substantially more events of gastrointestinal bleeding in the edoxaban group than in the placebo group. There was no substantial between-group difference in death from any cause (9.9% in the edoxaban group and 10.2% in the placebo group; hazard ratio, 0.97; 95% CI, 0.69 to 1.36). CONCLUSIONS: In very elderly Japanese patients with nonvalvular atrial fibrillation who were not appropriate candidates for standard doses of oral anticoagulants, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo. (Funded by Daiichi Sankyo; ELDERCARE-AF ClinicalTrials.gov number, NCT02801669.).
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Fibrilação Atrial/tratamento farmacológico , Embolia/prevenção & controle , Inibidores do Fator Xa/administração & dosagem , Piridinas/administração & dosagem , Acidente Vascular Cerebral/prevenção & controle , Tiazóis/administração & dosagem , Idoso de 80 Anos ou mais , Fibrilação Atrial/complicações , Fibrilação Atrial/mortalidade , Método Duplo-Cego , Embolia/etiologia , Inibidores do Fator Xa/efeitos adversos , Feminino , Seguimentos , Hemorragia/induzido quimicamente , Humanos , Incidência , Masculino , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Piridinas/efeitos adversos , Acidente Vascular Cerebral/etiologia , Tiazóis/efeitos adversosRESUMO
BACKGROUND: Selexipag is an oral prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. This study examined its efficacy and safety in Japanese patients with non-operated or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH).MethodsâandâResults:This Phase II study was a randomized, double-blind, placebo-controlled parallel-group comparison. The primary endpoint was a change in pulmonary vascular resistance (PVR) from baseline to week 17. The main analysis involved a per-protocol set group of 28 subjects. The change in PVR (mean±SD) after 17 weeks of treatment in the selexipag group was -104±191 dyn·s/cm5, whereas that in the placebo group was 26±180 dyn·s/cm5. Thus, the treatment effect after 17 weeks of selexipag treatment was calculated as -130±189 dyn·s/cm5(P=0.1553). Although the primary endpoint was not met, for the group not concomitantly using a pulmonary vasodilator the PVR in the selexipag group was significantly decreased compared with placebo group (P=0.0364). The selexipag group also showed improvement in total pulmonary resistance and cardiac index. CONCLUSIONS: Selexipag treatment improved pulmonary hemodynamics in Japanese patients with CTEPH, but PVR did not show a significant difference between the selexipag and placebo groups. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111667]).
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Acetamidas/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/tratamento farmacológico , Embolia Pulmonar/complicações , Embolia Pulmonar/tratamento farmacológico , Pirazinas/efeitos adversos , Adulto , Idoso , Doença Crônica , Método Duplo-Cego , Feminino , Humanos , Hipertensão Pulmonar/epidemiologia , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Embolia Pulmonar/epidemiologia , Receptores de Epoprostenol/agonistas , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacosRESUMO
This prospective study was conducted according to the principles outlined within the Declaration of Helsinki, and approved by the Ethics Review Board of National Center for Global Health and Medicine (NCGM-G-00839-01, NCGM-G-00839-02).
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BACKGROUND: This study was to investigate the significance of 11C-Pittsburgh B (PIB) PET/CT in patients with suspected cardiac amyloidosis compared with 99mTc-aprotinin scintigraphy. METHODS: Thirteen consecutive patients with suspected cardiac amyloidosis were considered for enrolment in this prospective pilot study. Participants were scheduled to undergo a series of 11C-PIB PET/CT and 99mTc-aprotinin within a 2-month period. Finally, we evaluated nine cases who underwent both imaging modalities, and compared imaging results with clinical and pathological results and prognosis. RESULTS: Six of the 9 patients who underwent both imaging modalities were diagnosed with amyloidosis, of whom 3 patients were diagnosed with cardiac amyloidosis from endomyocardial biopsy. These 3 patients with positive 11C-PIB uptake at the left ventricle wall showed worsening of cardiac function progressing in the short term or death caused by acute exacerbation of chronic heart failure. Six of 8 patients with positive uptake on 99mTc-aprotinin presented with amyloid deposition in the left ventricle wall, but symptoms remained stable if results of 11C-PIB were not positive. CONCLUSION: In a small sample of subjects, the present study showed that 11C-PIB accumulation in myocardium indicated cardiac amyloidosis with poor prognosis. Uptake of 11C-PIB may be related to progressive amyloid deposition to the heart and can predict patient prognosis.
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Amiloidose/diagnóstico por imagem , Compostos de Anilina , Aprotinina , Radioisótopos de Carbono , Cardiopatias/diagnóstico por imagem , Compostos de Organotecnécio , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tiazóis , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , Estudos ProspectivosAssuntos
Atorvastatina/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Estenose Coronária/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Placa Aterosclerótica , Idoso , Biomarcadores/sangue , LDL-Colesterol/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/patologia , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/patologia , Dislipidemias/sangue , Dislipidemias/diagnóstico , Humanos , Masculino , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Light chain (AL) cardiac amyloidosis is associated with a poor prognosis. Diagnosing at an early stage is critical for treatment and the management of cardiac complication. PURPOSE: We aimed to evaluate the diagnostic performance of 99mTc-aprotinin images in patients with AL cardiac amyloidosis. METHODS AND RESULTS: 99mTc-aprotinin scintigraphy and endomyocardial biopsy were performed in 10 patients with suspected amyloidosis. Endomyocardial biopsy showed amyloid deposits in 5 of 10 patients. 99mTc-aprotinin (planer image) was positive in 4 of 5 patients who had amyloid deposits in endomyocardial biopsy. On the other hand, all 5 patients without amyloid deposits were negative in planer image. 99mTc-aprotinin (SPECT/CT image) was positive in all 5 patients who had amyloid deposits. CONCLUSIONS: 99mTc-aprotinin scintigraphy is valuable for the non-invasive diagnosis of AL cardiac amyloidosis.
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Aprotinina/farmacocinética , Biópsia , Cardiomiopatias/diagnóstico por imagem , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico por imagem , Miocárdio/patologia , Compostos de Organotecnécio/farmacocinética , Adulto , Idoso , Cardiomiopatias/patologia , Desfibriladores Implantáveis , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Estudos Prospectivos , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
A 50-year-old man with a dual-chamber pacemaker was admitted to our hospital complaining of chest pain. Anterior ST segment elevation myocardial infarction (STEMI) was diagnosed. Emergency coronary angiography revealed total occlusion of the proximal left anterior descending artery (LAD), and primary percutaneous coronary intervention was performed. Angiograms showed that the LAD was wrapped around the apex of both ventricles. On day 8, ventricular fibrillation and cardiopulmonary arrest occurred due to elevation of the pacing threshold because of pacemaker malfunction. The pacemaker was upgraded to an implantable cardioverter-defibrillator and the lead was inserted into the right ventricular septum. Myocardial scintigraphy with thallium-201 and technetium-99m pyrophosphate located the infarct zone around the apex of both ventricles. We conclude that pacing failure of the right ventricular lead occurred in this case of LAD occlusion due to a LAD supplying the right ventricular apex. Clinicians should be aware of the possibility of pacemaker failure in patients presenting with anterior STEMI due to a wrap-around LAD.
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The differences in the morbidity and mortality of cardiovascular diseases between Sri Lankan and Japanese populations might be explained by the differences in their diet, especially fat. To test the hypothesis that the fatty acid (FA) compositions differ between Sri Lankan and Japanese populations and that high concentrations of n-3 polyunsaturated FAs and linoleic acid are associated with a low level of arteriosclerosis, the authors compared the circulating FA compositions between Sri Lankan and Japanese populations and examined the association of the circulating FA composition with arterial stiffness in each population. The study participants were patients with diabetes, dyslipidemia, or hypertension in Sri Lanka (n = 100) or Japan (n = 236). Serum FA compositions were measured by gas chromatography. Arterial stiffness was measured using the cardio-ankle vascular index (CAVI). Analysis of covariance was used to compare the FA compositions between the populations. Multiple regression was used to assess the association between each FA and CAVI levels. The concentrations of myristic, γ-linolenic, dihomo-γ-linolenic, and arachidonic acids were higher in the Sri Lankan patients than in the Japanese patients. In contrast, the concentrations of linoleic, α-linolenic, and eicosapentaenoic acids were higher in the Japanese patients than in the Sri Lankan patients. Although no associations of n-3 polyunsaturated FAs and linoleic acid with CAVI were observed in both patient populations, odd-chain saturated FAs (pentadecanoic and heptadecanoic acids) were significantly inversely associated with CAVI levels in the Sri Lankan (P for trend = .03) but not the Japanese patients. The odd-chain saturated FAs might be inversely associated with atherosclerosis in this Sri Lankan population.
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Arteriosclerose/sangue , Diabetes Mellitus , Dieta/etnologia , Dislipidemias , Ácidos Graxos/sangue , Hipertensão , Rigidez Vascular , Idoso , Arteriosclerose/etnologia , Arteriosclerose/prevenção & controle , Povo Asiático , Diabetes Mellitus/sangue , Diabetes Mellitus/etnologia , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/sangue , Dislipidemias/sangue , Dislipidemias/etnologia , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-6/sangue , Feminino , Humanos , Hipertensão/sangue , Hipertensão/etnologia , Japão , Masculino , Pessoa de Meia-Idade , Sri LankaRESUMO
BACKGROUND: Selexipag is an orally available prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. In this open-label Phase II trial, the efficacy and safety of selexipag in Japanese patients with pulmonary arterial hypertension (PAH) is examined.MethodsâandâResults:Selexipag was administered at 200 µg twice daily and titrated up to 1,600 µg by increments of 200 µg in 37 subjects to reach the individual maximum tolerated dose. At 16 weeks, in 33 patients comprising the per-protocol set, the pulmonary vascular resistance (PVR; primary endpoint) decreased from 683.2±237.3 to 560.3±238.7 dyn·s/cm5(P<0.0001). For the secondary endpoint, the 6-min walk distance (6MWD) increased from 445.0±102.2 to 459.1±112.8 m (P=0.0324); World Health Organization functional class improved in 4 patients (12.1%), and was maintained in 29 patients (87.9%). A decrease in PVR was also shown in patients treated with selexipag, on top of a phosphodiesterase inhibitor and endothelin receptor antagonist. Most of the commonly reported adverse events were consistent with those reported for other PGI2formulations. Thirty-four patients attained the individual maximum tolerated dose (maintenance dose). CONCLUSIONS: The efficacy and tolerability of selexipag in Japanese PAH patients was confirmed by improvement in pulmonary hemodynamics, exercise capacity, symptoms. Selexipag is an efficacious treatment option for Japanese PAH patients. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111532].).
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Acetamidas/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar , Pulmão , Pirazinas/administração & dosagem , Receptores de Epoprostenol/agonistas , Acetamidas/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Pulmão/irrigação sanguínea , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pirazinas/efeitos adversosRESUMO
It has long been thought that there is a close association between hypertension and atrial fibrillation (AF). However, the efficacy of an angiotensin II receptor blocker for the prevention of organ damage in hypertensive individuals with AF is still controversial. The present study was a multicentered, prospective, randomized, open-label clinical trial investigating the differences in the effect of treatment with telmisartan/amlodipine combination tablets on blood pressure (BP) levels and BP variability between morning and bedtime administration in hypertensive patients with paroxysmal AF, using ambulatory BP monitoring (ABPM) and home BP. With this treatment, the patients' 24-hour BP, nighttime BP, preawake BP, and morning BP shown by ABPM were significantly reduced, and the antihypertensive effects were similar regardless of the timing of the drug administration. The standard deviation of day-by-day home systolic BP and the maximum home systolic BP were also significantly reduced, and these effects were similar regardless of the treatment timing. The N-terminal pro-brain natriuretic peptide level was significantly decreased only in the bedtime administration group. A larger study will demonstrate whether the bedtime administration of telmisartan/amlodipine combination tablets maximizes the risk-lowering effect against AF recurrence in paroxysmal AF hypertensive patients.
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Anlodipino/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Fibrilação Atrial/prevenção & controle , Benzimidazóis/administração & dosagem , Benzoatos/administração & dosagem , Hipertensão/tratamento farmacológico , Fibrilação Atrial/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Monitorização Ambulatorial da Pressão Arterial , Bloqueadores dos Canais de Cálcio/administração & dosagem , Ritmo Circadiano , Combinação de Medicamentos , Feminino , Humanos , Hipertensão/metabolismo , Masculino , Peptídeo Natriurético Encefálico/metabolismo , Estudos Prospectivos , Telmisartan , Resultado do TratamentoRESUMO
Promising biomarkers were identified in adult male Crl:CD (SD) rats for the screening of new chemical entities for their potential to cause liver injury. We examined the serum biochemistry, liver histopathology, and bile acid profiles by LC-MS/MS, and the mRNA expression of transporters and CYPs by an RT-PCR after the following treatments to male Crl:CD (SD) rats: (a) bile duct ligation (BDL); (b) a single oral dose of 150 mg/kg α-naphthylisothiocyanate (ANIT); and (c) repeated oral doses of a novel pyrrolidinecarboxylic acid derivative (abbreviated as PCA) at 30, 300, and 1000 mg/kg. The serum total bile acid levels and bilirubin concentrations were found to be elevated in all of the groups. However, the bile acid component profiles of the PCA group differed significantly from BDL and ANIT models: deoxycholic acid, lithocholic acid, and sulfated bile acids were upregulated in a dose-dependent manner only in the PCA group. In addition, the PCA group demonstrated high levels of hepatic heme oxygenase-1 expression, whereas the profiles of the mRNA levels of the hepatic transporters and CYPs of all groups were found to be similar. The histopathological findings, for both the BDL and ANIT groups, were of bile duct hyperplasia, hepatocyte degeneration and necrosis. In contrast, only bile duct hyperplasia and hepatocyte degeneration were observed in the PCA group, even at a lethal dose. These results indicated that PCA induced a cholestatic condition and the increase of oxidative stress markers implies that this will also lead hepatocellular injury. In conclusion, the serum bile acid components and sulfated bile acid levels, and the expression of oxidative stress markers could provide information that aids in the diagnosis of liver injury type and helps to elucidate the mechanisms of hepatotoxicity. These findings can be extrapolated into our clinical investigation. The analysis of these crucial biomarkers is likely to be a useful screening tool in the lead optimization phase of drug discovery.
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1-Naftilisotiocianato/toxicidade , Ácidos e Sais Biliares/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Fígado/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ácido Pirrolidonocarboxílico/toxicidade , 1-Naftilisotiocianato/administração & dosagem , Animais , Ácidos e Sais Biliares/sangue , Biomarcadores/análise , Biomarcadores/sangue , Biomarcadores/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Colestase/sangue , Colestase/induzido quimicamente , Colestase/genética , Colestase/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Avaliação Pré-Clínica de Medicamentos/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Ácido Pirrolidonocarboxílico/administração & dosagem , Ácido Pirrolidonocarboxílico/análogos & derivados , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: The purpose of this study was to evaluate the cardiac sarcoidosis (CS) activity according to the classified visual uptake pattern using (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and assess the uptake pattern based on the free fatty acid (FFA) levels. METHODS: Nineteen CS subjects who underwent (18)F-FDG PET/CT examinations with heparin loading (HL) were recruited to evaluate their CS activity. The (18)F-FDG uptake in the heart was classified into five categories ("none," "diffuse" and "diffuse at base," regarded as stable CS, and "focal" and "focal on diffuse," regarded as de novo or worsening CS). The subject data were compared with the (18)F-FDG PET/CT findings in 13 healthy volunteers. The FFA serum levels were assessed in 10 patients with CS and all volunteers. RESULTS: The sensitivity and specificity of (18)F-FDG PET/CT with HL were 75% (6/8) and 73% (8/11), respectively. The major pattern of cardiac (18)F-FDG uptake was "diffuse at base." Ten of the 32 subjects, including the control group, exhibited this pattern. The FFA serum levels before heparin administration were statistically significantly different between the patients with the "none" pattern and those with the "diffuse" and "diffuse at base" patterns. There were no significant correlations between the FFA serum levels after heparin administration and the (18)F-FDG uptake patterns. CONCLUSION: "Diffuse at base" is the major (18)F-FDG uptake pattern associated with inadequate physiologic (18)F-FDG suppression. This pattern should be carefully interpreted when examining the (18)F-FDG PET/CT images of CS patients. Additionally, increased FFAs levels associated with HL may not completely suppress the physiologic myocardial FDG uptake.
Assuntos
Cardiomiopatias/diagnóstico , Fluordesoxiglucose F18 , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons/métodos , Sarcoidose/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
BACKGROUND: F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a promising modality for detecting active lesions of cardiac sarcoidosis (CS). However, determining whether 18F-FDG uptake in the myocardium is physiological is challenging due to metabolic shift in myocardial cells. Although methods for inhibiting physiological myocardial 18F-FDG uptake have been proposed, no standard methods exist. This study therefore aimed to compare the effect of an 18-h fast (long fasting (LF)) with heparin loading plus a 12-h fast (HEP) before 18F-FDG PET scan. METHODS: We analyzed the effects of LF and HEP on the inhibition of physiological myocardial 18F-FDG uptake in healthy subjects (18 in HEP and 19 in LF) and in patients with known or suspected CS (96 in HEP and 69 in LF). In CS, the lower uptake of 18F-FDG in the myocardium was evaluated. A visual four-point scale was used to assess myocardial 18F-FDG uptake in comparison with hepatic uptake (1 lower, 2 similar, 3 somewhat higher, 4 noticeably higher). RESULTS: Myocardial 18F-FDG uptake was 1.68 ± 1.06 in LF and 3.17 ± 1.16 in HEP in healthy subjects (p < 0.0001), whereas it was 1.48 ± 0.99 in LF and 2.48 ± 1.33 in HEP in CS patients (p < 0.0001). Logistic regression and regression trees revealed the LF was the most effective in inhibiting myocardial 18F-FDG uptake. In addition, serum free fatty acid levels on intravenous 18F-FDG injection were a possible biomarker. CONCLUSIONS: LF is effective in inhibiting myocardial 18F-FDG uptake, and consequently, it could be useful for evaluating active lesions of CS in 18F-FDG PET images.
RESUMO
BACKGROUND: The prevalence of gestational diabetes mellitus (GDM) has important health complications for both mother and child and is increasing all over the world. Although prevalence estimates for GDM are not new in developed and many developing countries, data are lacking for many low-income countries like Bangladesh. OBJECTIVE: To evaluate the prevalence of GDM in Bangladesh. RESEARCH DESIGN AND METHODS: This cross-sectional study included 3447 women who consecutively visited the antenatal clinics with an average gestation age of 26 weeks. GDM was defined according to WHO criteria (fasting plasma glucose [FPG] ≥7.0 mmol/L or 2-h ≥7.8 mmol/L) and the new ADA criteria (FPG ≥5.3 mmol/L or 2-h ≥8.6 mmol/L OGTT). We also calculated overt diabetes as FPG ≥7.0 mmol/L. RESULTS: Prevalence of GDM was 9.7% according to the WHO criteria and 12.9% according to the ADA criteria in this study population. Prevalence of overt diabetes was 1.8%. Women with GDM were older, higher educated, had higher household income, higher parity, parental history of diabetes, and more hypertensive, compared with non-GDM women. CONCLUSION: This study demonstrates a high prevalence of GDM in Bangladesh. These estimates for GDM may help to formulate new policies to prevent and manage diabetes.