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1.
Angiology ; 72(1): 62-69, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32815383

RESUMO

The optimal strategy for assessing the ischemic significance of intermediate coronary stenoses with adenosine-induced fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) is still debated. Few studies have previously assessed the impact of age on FFR and iFR, which was the aim of our study. Patients undergoing FFR and iFR evaluation for intermediate (40%-70%) coronary lesions were included and divided according to age. Fractional flow reserve was performed by intracoronary boluses of adenosine (60-1440 µg). Instantaneous wave-free ratio was automatically calculated. Among 148 patients undergoing FFR measurement of 166 lesions, 45.3% were ≥70 years. Elderly patients had higher minimal lumen diameter (P = .03). We also observed a linear relationship between iFR and FFR independently of age. Fractional flow reserve values were higher in the elderly patients, whereas iFR was not related to age. A total of 33 lesions had a positive iFR with no difference for age (17.3% vs 22%, P = .56), while FFR <0.80 was more infrequent in the elderly patients (17.1% vs 34.8%, P = .02). In intermediate coronary stenoses, iFR and FFR correlation is unaffected by age. Fractional flow reserve is higher in the elderly patients, whereas iFR is less affected by age. Future large-scale studies are needed to define whether iFR should be the preferred choice in elderly patients.


Assuntos
Envelhecimento/fisiologia , Estenose Coronária/fisiopatologia , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Adenosina/administração & dosagem , Idoso , Angiografia Coronária , Estenose Coronária/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Vasodilatadores/administração & dosagem
2.
PLoS One ; 15(10): e0239692, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33031409

RESUMO

BACKGROUND: SARS-Cov2 infection may trigger lung inflammation and acute-respiratory-distress-syndrome (ARDS) that requires active ventilation and may have fatal outcome. Considering the severity of the disease and the lack of active treatments, 14 patients with Covid-19 and severe lung inflammation received inhaled adenosine in the attempt to therapeutically compensate for the oxygen-related loss of the endogenous adenosine→A2A adenosine receptor (A2AR)-mediated mitigation of the lung-destructing inflammatory damage. This off label-treatment was based on preclinical studies in mice with LPS-induced ARDS, where inhaled adenosine/A2AR agonists protected oxygenated lungs from the deadly inflammatory damage. The treatment was allowed, considering that adenosine has several clinical applications. PATIENTS AND TREATMENT: Fourteen consecutively enrolled patients with Covid19-related interstitial pneumonitis and PaO2/FiO2 ratio<300 received off-label-treatment with 9 mg inhaled adenosine every 12 hours in the first 24 hours and subsequently, every 24 days for the next 4 days. Fifty-two patients with analogue features and hospitalized between February and April 2020, who did not receive adenosine, were considered as a historical control group. Patients monitoring also included hemodynamic/hematochemical studies, CTscans, and SARS-CoV2-tests. RESULTS: The treatment was well tolerated with no hemodynamic change and one case of moderate bronchospasm. A significant increase (> 30%) in the PaO2/FiO2-ratio was reported in 13 out of 14 patients treated with adenosine compared with that observed in 7 out of52 patients in the control within 15 days. Additionally, we recorded a mean PaO2/FiO2-ratio increase (215 ± 45 vs. 464 ± 136, P = 0.0002) in patients receiving adenosine and no change in the control group (210±75 vs. 250±85 at 120 hours, P>0.05). A radiological response was demonstrated in 7 patients who received adenosine, while SARS-CoV-2 RNA load rapidly decreased in 13 cases within 7 days while no changes were recorded in the control group within 15 days. There was one Covid-19 related death in the experimental group and 11in the control group. CONCLUSION: Our short-term analysis suggests the overall safety and beneficial therapeutic effect of inhaled adenosine in patients with Covid-19-inflammatory lung disease suggesting further investigation in controlled clinical trials.


Assuntos
Adenosina/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Adenosina/administração & dosagem , Administração por Inalação , Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/fisiopatologia , Feminino , Hospitalização , Humanos , Pulmão/patologia , Pulmão/virologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/virologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologia , Estudos Retrospectivos
3.
Medicine (Baltimore) ; 99(31): e21482, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756175

RESUMO

RATIONALE: In absence of conduction over the accessory pathway (AP) during the electrophysiological study, mapping and ablation is impossible. Various techniques can be used to activate absent conduction. In this presentation we describe the first case of latent AP ablation performed under continuous infusion of adenosine. PATIENT CONCERNS: A 65-year-old man, presented to emergency department with atrial fibrillation and antegrade conduction through a left lateral AP. He had palpitations and lightheadedness that occurred every 2 to 3 weeks. DIAGNOSIS: The electrophysiological study confirmed a latent left-side AP. INTERVENTIONS: Catheter ablation could not be performed because of absent conduction through AP. Therefore, a continuous infusion of adenosine was used to activate AP. Ablation was performed at the left lateral mitral ring. OUTCOMES: After catheter ablation and a new adenosine bolus there was no conduction through AP. LESSONS: In case of a latent AP when ablation is difficult to perform because of absent conduction at the time of electrophysiological study, adenosine can be used in doses of 1.5 mg/kg over 5 minutes continuous infusion.


Assuntos
Feixe Acessório Atrioventricular/cirurgia , Adenosina/administração & dosagem , Antiarrítmicos/administração & dosagem , Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Feixe Acessório Atrioventricular/complicações , Idoso , Fibrilação Atrial/complicações , Humanos , Infusões Intra-Arteriais , Masculino
4.
Sci Adv ; 6(23): eaaz5466, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32548259

RESUMO

Uncontrolled inflammatory processes are at the root of numerous pathologies. Most recently, studies on confirmed COVID-19 cases have suggested that mortality might be due to virally induced hyperinflammation. Uncontrolled pro-inflammatory states are often driven by continuous positive feedback loops between pro-inflammatory signaling and oxidative stress, which cannot be resolved in a targeted manner. Here, we report on the development of multidrug nanoparticles for the mitigation of uncontrolled inflammation. The nanoparticles are made by conjugating squalene, a natural lipid, to adenosine, an endogenous immunomodulator, and then encapsulating α-tocopherol, as antioxidant. This resulted in high drug loading, biocompatible, multidrug nanoparticles. By exploiting the endothelial dysfunction at sites of acute inflammation, these multidrug nanoparticles delivered the therapeutic agents in a targeted manner, conferring survival advantage to treated animals in models of endotoxemia. Selectively delivering adenosine and antioxidants together could serve as a novel therapeutic approach for safe treatment of acute paradoxal inflammation.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Endotoxemia/tratamento farmacológico , Nanopartículas/química , Esqualeno/química , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Adenosina/administração & dosagem , Adenosina/química , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Endotoxemia/induzido quimicamente , Feminino , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/química , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Esqualeno/administração & dosagem , Síndrome de Resposta Inflamatória Sistêmica/induzido quimicamente , Resultado do Tratamento , alfa-Tocoferol/administração & dosagem , alfa-Tocoferol/química
5.
Circ Cardiovasc Interv ; 13(6): e009019, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32519879

RESUMO

BACKGROUND: Among patients with angina and nonobstructive coronary artery disease, those with coronary microvascular dysfunction have a poor outcome. Coronary microvascular dysfunction is usually diagnosed by assessing flow reserve with an endothelium-independent vasodilator like adenosine, but the optimal diagnostic threshold is unclear. Furthermore, the incremental value of testing endothelial function has never been assessed before. We sought to determine what pharmacological thresholds correspond to exercise pathophysiology and myocardial ischemia in patients with coronary microvascular dysfunction. METHODS: Patients with angina and nonobstructive coronary artery disease underwent simultaneous acquisition of coronary pressure and flow during rest, supine bicycle exercise, and pharmacological vasodilatation with adenosine and acetylcholine. Adenosine and acetylcholine coronary flow reserve were calculated as vasodilator/resting coronary blood flow (CFR and AchFR, respectively). Coronary wave intensity analysis was used to quantify the proportion of accelerating wave energy; a normal exercise response was defined as an increase in accelerating wave energy from rest to peak exercise. Ischemia was assessed by quantitative 3-Tesla stress perfusion cardiac magnetic resonance imaging and dichotomously defined by a hyperemic endo-epicardial gradient <1.0. RESULTS: Ninety patients were enrolled (58±10 years, 77% female). Area under the curve using receiver-operating characteristic analysis demonstrated optimal CFR and AchFR thresholds for identifying exercise pathophysiology and ischemia as 2.6 and 1.5, with positive and negative predictive values of 91% and 86%, respectively. Fifty-eight percent had an abnormal CFR (of which 96% also had an abnormal AchFR). Of those with a normal CFR, 53% had an abnormal AchFR, and 47% had a normal AchFR; ischemia rates were 83%, 63%, and 14%, respectively. CONCLUSIONS: The optimal CFR and AchFR diagnostic thresholds are 2.6 and 1.5, with high-positive and negative predictive values, respectively. A normal CFR value should prompt the measurement of AchFR. A stepwise algorithm incorporating both vasodilators can accurately identify an ischemic cause in patients with nonobstructive coronary artery disease.


Assuntos
Acetilcolina/administração & dosagem , Adenosina/administração & dosagem , Cateterismo Cardíaco , Circulação Coronária , Hemodinâmica , Microcirculação , Angina Microvascular/diagnóstico , Vasodilatadores/administração & dosagem , Acetilcolina/efeitos adversos , Adenosina/efeitos adversos , Idoso , Teste de Esforço , Feminino , Humanos , Masculino , Angina Microvascular/fisiopatologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Vasodilatadores/efeitos adversos
6.
J Cardiovasc Magn Reson ; 22(1): 43, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32507107

RESUMO

BACKGROUND: Identifying coronary artery disease (CAD) in patients with end-stage renal disease (ESRD) is challenging. Adenosine stress native T1 mapping with cardiovascular magnetic resonance (CMR) may accurately detect obstructive CAD and microvascular dysfunction in the general population. This study assessed the feasibility and reliability of adenosine stress native T1 mapping in patients on haemodialysis. METHODS: The feasibility of undertaking rest and adenosine stress native T1 mapping using the single-shot Modified Look-Locker inversion recovery (MOLLI) sequence was assessed in 58 patients on maintenance haemodialysis using 3 T CMR. Ten patients underwent repeat stress CMR within 2 weeks for assessment of test-retest reliability of native T1, stress T1 and delta T1 (ΔT1). Interrater and intrarater agreement were assessed in 10 patients. Exploratory analyses were undertaken to assess associations between clinical variables and native T1 values in 51 patients on haemodialysis. RESULTS: Mean age of participants was 55 ± 15 years, 46 (79%) were male, and median dialysis vintage was 21 (8; 48) months. All patients completed the scan without complications. Mean native T1 rest, stress and ΔT1 were 1261 ± 57 ms, 1297 ± 50 ms and 2.9 ± 2.5%, respectively. Interrater and intrarater agreement of rest T1, stress T1 and ΔT1 were excellent, with intraclass correlation coefficients (ICC) > 0.9 for all. Test-retest reliability of rest and stress native T1 were excellent or good (CoV 1.2 and 1.5%; ICC, 0.79 and 0.69, respectively). Test-retest reliability of ΔT1 was moderate to poor (CoV 27.4%, ICC 0.55). On multivariate analysis, CAD, diabetes mellitus and resting native T1 time were independent determinants of ΔT1 (ß = - 0.275, p = 0.019; ß = - 0.297, p = 0.013; ß = - 0.455; p < 0.001, respectively). CONCLUSIONS: Rest and adenosine stress native T1 mapping is feasible and well-tolerated amongst patients with ESRD on haemodialysis. Although rater agreement of the technique is excellent, test-retest reliability of ΔT1 is moderate to poor. Prospective studies should evaluate the relationship between this technique and established methods of CAD assessment and association with outcomes.


Assuntos
Adenosina/administração & dosagem , Doença da Artéria Coronariana/diagnóstico por imagem , Falência Renal Crônica/terapia , Imagem por Ressonância Magnética , Diálise Renal , Vasodilatadores/administração & dosagem , Adulto , Idoso , Doença da Artéria Coronariana/fisiopatologia , Estudos Transversais , Estudos de Viabilidade , Feminino , Humanos , Falência Renal Crônica/diagnóstico , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Valor Preditivo dos Testes , Reprodutibilidade dos Testes
7.
J Cardiovasc Magn Reson ; 22(1): 30, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366254

RESUMO

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is thought to be associated with microvascular dysfunction. Adenosine stress-perfusion cardiovascular magnetic resonance imaging (CMR) is a sensitive method for assessing microvascular perfusion abnormalities. We evaluated the prevalence and clinical characteristics of HCM patients with adenosine-induced perfusion defects on CMR. METHODS: Among 189 consecutive patients with HCM who underwent adenosine-stress perfusion CMR, 115 patients who had clinical, echocardiography, 24-h Holter monitoring and treadmill exercise test data were analyzed. We calculated myocardial perfusion ratio index from the intensity-over-time curve to quantify perfusion defects. The presence and extent of the stress-induced perfusion defect were compared with clinical characteristics, presence and extent of late gadolinium enhancement (LGE), left ventricular (LV) mass index and volume, presence of non-sustained ventricular tachycardia (NSVT) and results of treadmill exercise test. RESULTS: The mean age of enrolled patients was 51.8 ± 11.3 years. Most patients were asymptomatic except 25 subjects presented with New York Heart Association Class II dyspnea and 16 patients with atypical non-exertional chest discomfort. LGE was present in 103 (89.6%) subjects. Adenosine stress-induced perfusion defects were present in 48 (42%) subjects. None of the perfusion defects corresponded with a single or multiple coronary artery territories, showing a multiple patchy pattern in 24 (50.0%), a concentric subendocardial pattern in 20 subjects (41.7%), and as a single blot-like defect in the remaining 4 (8.3%). A perfusion defect was associated with NSVT, LV apical aneurysm, higher LV mass index, and higher LGE volume on univariate analysis. Multivariate analysis revealed female gender (P = 0.008), presence of apical aneurysm and NSVT (P = 0.036 and 0.047, respectively), and LV mass index (P = 0.022) to be independently associated with adenosine stress-induced perfusion defects. CONCLUSIONS: In patients with HCM, adenosine-stress perfusion defects on CMR are present in more than 40% of subjects. This perfusion defect is associated with NSVT, higher LV mass index, and apical aneurysms. The prognostic value of this finding needs further elucidation.


Assuntos
Adenosina/administração & dosagem , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Circulação Coronária , Imagem Cinética por Ressonância Magnética , Microcirculação , Imagem de Perfusão do Miocárdio/métodos , Vasodilatadores/administração & dosagem , Cardiomiopatia Hipertrófica/epidemiologia , Cardiomiopatia Hipertrófica/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Estudos Prospectivos , Fatores de Risco , Seul/epidemiologia , Função Ventricular Esquerda , Remodelação Ventricular
8.
J Surg Res ; 253: 127-138, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32353638

RESUMO

BACKGROUND: Noncompressible hemorrhage is the leading cause of preventable death in military and civilian trauma. Our aim was to examine the effect of adenosine, lidocaine, and magnesium (Mg2+; ALM) on cardiovascular and cerebral function in a porcine hepatic hemorrhage model. MATERIALS AND METHODS: Pigs (59.1 ± 0.34 kg) were anesthetized, instrumented, and randomly assigned into sham (n = 6), saline controls (n = 10) or ALM (n = 10) groups before laparoscopic liver resection. After 30 min, groups received 4 mL/kg 3% NaCl ± ALM bolus (Phase 1) followed 60 min later with 3 mL/kg/h 0.9% NaCl ± ALM drip (4 h; Phase 2), then transfusion. Hemodynamics, carotid artery flow, and intracranial pressure were measured continuously. Microdialysis samples were analyzed for metabolites. RESULTS: Saline controls had 20% mortality (mean survival time: 307 ± 38 min) with no ALM deaths over 6 h. Bolus administration increased mean arterial pressure (MAP) in both groups, and drip led to further increases to 62 ± 10 mmHg in controls compared with a steady fall to 47 ± 8 mmHg in ALM group at 240 min. The lower MAP was associated with a dramatic fall in systemic vascular resistance and improved oxygen delivery. ALM drip significantly increased cardiac output and stroke volume with lower dP/dtMin, indicating a less stiff heart. ALM drip also significantly decreased cerebral perfusion pressure, reduced cerebral oxygen consumption (28%), and reduced brain glycerol (60%), lactate (47%), and relative expression of hypoxia-inducible factor (38%) compared with saline controls. CONCLUSIONS: ALM therapy improved cardiac function and oxygen delivery by lowering systemic vascular resistance after noncompressible hemorrhage. ALM also appeared to protect the brain at hypotensive MAPs with significantly lower cerebral perfusion pressure, lower O2 consumption, and significantly lower cortical lactate and glycerol levels compared to saline controls.


Assuntos
Hidratação/métodos , Hipotensão/terapia , Hipóxia Encefálica/prevenção & controle , Ressuscitação/métodos , Choque Hemorrágico/terapia , Adenosina/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Modelos Animais de Doenças , Esquema de Medicação , Quimioterapia Combinada/métodos , Feminino , Glicerol/análise , Humanos , Hipotensão/etiologia , Hipóxia Encefálica/etiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Infusões Intravenosas/métodos , Injeções Intravenosas/métodos , Ácido Láctico/análise , Lidocaína/administração & dosagem , Fígado/irrigação sanguínea , Fígado/lesões , Magnésio/administração & dosagem , Oxigênio/metabolismo , Choque Hemorrágico/etiologia , Volume Sistólico/efeitos dos fármacos , Sus scrofa , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
9.
Am J Emerg Med ; 38(7): 1541.e3-1541.e4, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32278568

RESUMO

Paroxysmal supraventricular tachycardia (PSVT) is one of the more common arrhythmias requiring treatment in the emergency department. Intravenous adenosine is recommended as the initial medication of choice for treatment of PSVT, given in escalating doses up to a maximum of 12 mg. With a serum half-life of less than 10 s, adenosine must be given rapidly to allow for adequate time for it to reach the heart via venous return. In over 10% of adult patients, PSVT will not be terminated with maximum doses of adenosine. We report a case of a patient requiring a higher-than recommended dose of adenosine for termination of PSVT. The patient had a history of pulmonary hypertension with resultant right heart failure at the time of presentation. We believe the higher dose of adenosine was necessary in this patient because of the impaired venous return to her right heart. This case indicates that patients with impaired venous return to the right heart may require higher-than-recommended doses of adenosine for effective termination of PSVT.


Assuntos
Adenosina/administração & dosagem , Antiarrítmicos/administração & dosagem , Taquicardia Paroxística/tratamento farmacológico , Taquicardia Supraventricular/tratamento farmacológico , Relação Dose-Resposta a Droga , Eletrocardiografia , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Hipertensão Pulmonar/complicações , Pessoa de Meia-Idade
10.
Cardiovasc Diabetol ; 19(1): 42, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32234045

RESUMO

BACKGROUND: Stress cardiovascular magnetic resonance (CMR) to screen for silent myocardial ischaemia in asymptomatic high risk patients with type 2 diabetes mellitus (DM) has never been performed, and its effectiveness is unknown. Our aim was to determine the feasibility of a screening programme using stress CMR by obtaining preliminary data on the prevalence of silent ischaemia caused by obstructive coronary artery disease (CAD) and quantify myocardial perfusion in asymptomatic high risk patients with type 2 diabetes. METHODS: In this prospective cohort study, we recruited 63 asymptomatic DM patients (mean age 66 years ± 4.4 years; 77.8% male); with Framingham risk score ≥ 20% from 3 sites from June 2017 to August 2018. Normal volunteers were recruited to determine normal global myocardial perfusion reserve index (MPRI). Adenosine stress CMR and global MPRI was performed and measured in all subjects. Positive stress CMR cases were referred for catheter coronary angiography (CCA) with/without fractional flow reserve (FFR) measurements. Positive CCA was defined as an FFR ≤ 0.8 or coronary narrowing ≥ 70%. Patients were followed up for major adverse cardiovascular events. Prevalence is presented as patient numbers and percentage. Mann-Whitney U test was used to compare global MPRI between patients and normal volunteers. RESULTS: 13 patients had positive stress CMR with positive CCA (20.6% of patient population), while 9 patients with positive stress CMR examinations had a negative CCA. 5 patients (7.9%) had infarcts detected of which 2 patients had no stress perfusion defects. 12 patients had coronary artery stents inserted, whilst 1 patient declined stent placement. DM patients had lower global MPRI than normal volunteers (n = 7) (1.43 ± 0.27 vs 1.83 ± 0.31 respectively; p < 0.01). After a median follow-up of 653 days, there was no death, heart failure, acute coronary syndrome hospitalisation or stroke. CONCLUSION: 20.6% of asymptomatic DM patients (with Framingham risk ≥ 20%) had silent obstructive CAD. Furthermore, asymptomatic patients have reduced global MPRI than normal volunteers. TRIAL REGISTRATION: ClinicalTrials.gov Registration Number: NCT03263728 on 28th August 2017; https://clinicaltrials.gov/ct2/show/NCT03263728.


Assuntos
Doença da Artéria Coronariana/diagnóstico por imagem , Circulação Coronária , Diabetes Mellitus Tipo 2/epidemiologia , Imagem Cinética por Ressonância Magnética , Infarto do Miocárdio/diagnóstico por imagem , Imagem de Perfusão do Miocárdio/métodos , Adenosina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas , Estudos de Casos e Controles , Angiografia Coronária , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/terapia , Diabetes Mellitus Tipo 2/diagnóstico , Estudos de Viabilidade , Feminino , Hong Kong/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea/instrumentação , Projetos Piloto , Valor Preditivo dos Testes , Prevalência , Estudos Prospectivos , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Stents , Fatores de Tempo , Resultado do Tratamento , Vasodilatadores/administração & dosagem
11.
Circ J ; 84(3): 404-410, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32023574

RESUMO

BACKGROUND: We recently demonstrated that the acute reconnection rate detected with adenosine provocation test (APT) was significantly lower after pulmonary vein isolation (PVI) with visually guided laser balloon ablation (VGLB) than with RF ablation (RF). We evaluated the recurrence rate of atrial arrhythmias at 12 months after VGLB vs. RF and the significance of APT results for the outcome.Methods and Results:Fifty patients with paroxysmal AF were randomized to either RF or VGLB ablation in a 1 : 1 fashion. After PVI each PV underwent an APT. All patients underwent a 3-day Holter and clinical follow-up every 3 months. Significantly less PVs reconnected during APT in the VGLB-arm (10 PV (10.8%) vs. 29 PV (30.9%); P=0.001). Significantly less patients had a recurrence of atrial arrhythmia in the VGLB-arm (3 vs. 9; P=0.047). In the VGLB-arm no recurrence was seen in those patients with a negative APT (negative predictive value (NPV)=100%). Only 3 of the 8 patients with a positive APT in the VGLB-arm had a recurrence (positive PV (PPV)=37%). Recurrences in the RF-arm were seen in 3 patients with positive APT as well as in 6 patients with negative APT (PPV=18% and NPV=33%). CONCLUSIONS: There was significantly less recurrence of atrial arrhythmias at 12 months after PVI with VGLB. A negative APT after PVI with VGBL predicted freedom from AF with a very high NPV meaning that the high acute efficiency of the VGLB persisted long term.


Assuntos
Adenosina/administração & dosagem , Fibrilação Atrial/cirurgia , Ablação por Cateter , Técnicas Eletrofisiológicas Cardíacas , Frequência Cardíaca , Terapia a Laser , Veias Pulmonares/cirurgia , Potenciais de Ação , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Ablação por Cateter/efeitos adversos , Eletrocardiografia Ambulatorial , Feminino , Alemanha , Humanos , Terapia a Laser/efeitos adversos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Veias Pulmonares/fisiopatologia , Recidiva , Reoperação , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
12.
J Cardiovasc Magn Reson ; 22(1): 14, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32028980

RESUMO

BACKGROUND: Myocardial perfusion with cardiovascular magnetic resonance (CMR) imaging is an established diagnostic test for evaluation of myocardial ischaemia. For quantification purposes, the 16 segment American Heart Association (AHA) model poses limitations in terms of extracting relevant information on the extent/severity of ischaemia as perfusion deficits will not always fall within an individual segment, which reduces its diagnostic value, and makes an accurate assessment of outcome data or a result comparison across various studies difficult. We hypothesised that division of the myocardial segments into epi- and endocardial layers and a further circumferential subdivision, resulting in a total of 96 segments, would improve the accuracy of detecting myocardial hypoperfusion. Higher (sub-)subsegmental recording of perfusion abnormalities, which are defined relatively to the normal reference using the subsegment with the highest value, may improve the spatial encoding of myocardial blood flow, based on a single stress perfusion acquisition. OBJECTIVE: A proof of concept comparison study of subsegmentation approaches based on transmural segments (16 AHA and 48 segments) vs. subdivision into epi- and endocardial (32) subsegments vs. further circumferential subdivision into 96 (sub-)subsegments for diagnostic accuracy against invasively defined obstructive coronary artery disease (CAD). METHODS: Thirty patients with obstructive CAD and 20 healthy controls underwent perfusion stress CMR imaging at 3 T during maximal adenosine vasodilation and a dual bolus injection of 0.1 mmol/kg gadobutrol. Using Fermi deconvolution for blood flow estimation, (sub-)subsegmental values were expressed relative to the (sub-)subsegment with the highest flow. In addition, endo-/epicardial flow ratios were calculated based on 32 and 96 (sub-)subsegments. A receiver operating characteristics (ROC) curve analysis was performed to compare the diagnostic performance of discrimination between patients with CAD and healthy controls. Observer reproducibility was assessed using Bland-Altman approaches. RESULTS: Subdivision into more and smaller segments revealed greater accuracy for #32, #48 and # 96 compared to the standard #16 approach (area under the curve (AUC): 0.937, 0.973 and 0.993 vs 0.820, p < 0.05). The #96-based endo-/epicardial ratio was superior to the #32 endo-/epicardial ratio (AUC 0.979, vs. 0.932, p < 0.05). Measurements for the #16 model showed marginally better reproducibility compared to #32, #48 and #96 (mean difference ± standard deviation: 2.0 ± 3.6 vs. 2.3 ± 4.0 vs 2.5 ± 4.4 vs. 4.1 ± 5.6). CONCLUSIONS: Subsegmentation of the myocardium improves diagnostic accuracy and facilitates an objective cut-off-based description of hypoperfusion, and facilitates an objective description of hypoperfusion, including the extent and severity of myocardial ischaemia. Quantification based on a single (stress-only) pass reduces the overall amount of gadolinium contrast agent required and the length of the overall diagnostic study.


Assuntos
Adenosina/administração & dosagem , Doença da Artéria Coronariana/diagnóstico por imagem , Circulação Coronária , Estenose Coronária/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador , Imagem Cinética por Ressonância Magnética , Imagem de Perfusão do Miocárdio/métodos , Adulto , Idoso , Estudos de Casos e Controles , Meios de Contraste/administração & dosagem , Doença da Artéria Coronariana/fisiopatologia , Estenose Coronária/fisiopatologia , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organometálicos/administração & dosagem , Valor Preditivo dos Testes , Estudo de Prova de Conceito , Estudos Prospectivos , Reprodutibilidade dos Testes , Vasodilatadores/administração & dosagem
13.
Circ Cardiovasc Imaging ; 13(1): e009407, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31959009

RESUMO

BACKGROUND: We previously proposed a technique for quantitative measurement of rest and stress absolute myocardial blood flow (MBF) using a 2-injection single-scan imaging session. Recently, we validated the method in a pig model for the long-lived radiotracer 18F-Flurpiridaz with adenosine as a pharmacological stressor. The aim of the present work is to validate our technique for 13NH3. METHODS: Nine studies were performed in 6 pigs; 5 studies were done in the native state and 4 after infarction of the left anterior descending artery. Each study consisted of 3 dynamic scans: a 2-injection rest-rest single-scan acquisition (scan A), a 2-injection rest/stress single-scan acquisition (scan B), and a conventional 1-injection stress acquisition (scan C). Variable doses of adenosine combined with dobutamine were administered to induce a wide range of MBF. The 2-injection single-scan measurements were fitted with our nonstationary kinetic model (MGH2). In 4 studies, 13NH3 injections were paired with microsphere injections. MBF estimates obtained with our method were compared with those obtained with the standard method and with microspheres. We used a model-based method to generate separate rest and stress perfusion images. RESULTS: In the absence of stress (scan A), the MBF values estimated by MGH2 were nearly the same for the 2-radiotracer injections (mean difference: 0.067±0.070 mL·min-1·cc-1, limits of agreement: [-0.070 to 0.204] mL·min-1·cc-1), showing good repeatability. Bland-Altman analyses demonstrated very good agreement with the conventional method for both rest (mean difference: -0.034±0.035 mL·min-1·cc-1, limits of agreement: [-0.103 to 0.035] mL·min-1·cc-1) and stress (mean difference: 0.057±0.361 mL·min-1·cc-1, limits of agreement: [-0.651 to 0.765] mL·min-1·cc-1) MBF measurements. Positron emission tomography and microsphere MBF measurements correlated closely. Very good quality perfusion images were obtained. CONCLUSIONS: This study provides in vivo validation of our single-scan rest-stress method for 13NH3 measurements. The 13NH3 rest/stress myocardial perfusion imaging procedure can be compressed into a single positron emission tomography scan session lasting less than 15 minutes.


Assuntos
Vasos Coronários/diagnóstico por imagem , Imagem de Perfusão do Miocárdio/métodos , Tomografia por Emissão de Pósitrons/métodos , Adenosina/administração & dosagem , Amônia , Animais , Circulação Coronária , Processamento de Imagem Assistida por Computador , Microesferas , Isótopos de Nitrogênio , Compostos Radiofarmacêuticos , Fluxo Sanguíneo Regional , Reprodutibilidade dos Testes , Suínos
14.
Int J Cardiovasc Imaging ; 36(3): 521-532, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31728679

RESUMO

In this study, we sought to investigate the impact of baseline calibration, which is used in quantitative cardiac MRI perfusion analysis to correct for surface coil inhomogeneity and noise, on myocardial perfusion reserve index (MPRI) and its contribution to previously reported paradoxical low MPRI < 1.0 in patients with unobstructed coronary arteries. Semiquantitative perfusion analysis was performed in 20 patients with unobstructed coronary arteries undergoing stress/rest perfusion CMR and in ten patients undergoing paired rest perfusion CMR. The following baseline calibration settings were compared: (1) baseline division, (2) baseline subtraction and (3) no baseline calibration. In uncalibrated analysis, we observed ~ 20% segmental dispersion of signal intensity (SI)-over-time curves. Both baseline subtraction and baseline division reduced relative dispersion of t0-SI (p < 0.001), but only baseline division corrected for dispersion of peak-SI and maximum upslope also (p < 0.001). In the assessment of perfusion indices, however, baseline division resulted in paradoxical low MPRI (1.01 ± 0.23 vs. 1.63 ± 0.38, p < 0.001) and rest perfusion index (RPI 0.54 ± 0.07 vs. 0.94 ± 0.12, p < 0.001), respectively. This was due to a reversed ratio of blood-pool and myocardial baseline-SI before the second perfusion study caused by circulating contrast agent from the first injection. In conclusion, baseline division reliably corrects for inhomogeneity of the surface coil sensitivity profile facilitating comparisons of regional myocardial perfusion during hyperemia or at rest. However, in the assessment of MPRI, baseline division can lead to paradoxical low results (even MPRI < 1.0 in patients with unobstructed coronary arteries) potentially mimicking severely impaired perfusion reserve. Thus, in the assessment of MPRI we propose to waive baseline calibration.


Assuntos
Adenosina/administração & dosagem , Angina Pectoris/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Imagem de Perfusão do Miocárdio/métodos , Miocardite/diagnóstico por imagem , Vasodilatadores/administração & dosagem , Adulto , Idoso , Angina Pectoris/fisiopatologia , Calibragem , Circulação Coronária , Feminino , Humanos , Imagem Cinética por Ressonância Magnética/normas , Masculino , Pessoa de Meia-Idade , Imagem de Perfusão do Miocárdio/normas , Miocardite/fisiopatologia , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Função Ventricular Esquerda
15.
Int J Oncol ; 56(1): 283-300, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746375

RESUMO

Current treatment against glioblastoma consists of surgical resection followed by temozolomide, with or without combined radiotherapy. Glioblastoma frequently acquires resistance to chemotherapy and/or radiotherapy. Novel therapeutic approaches are thus required. The inhibition of enhancer of zeste homolog 2 (EZH2; a histone methylase) and histone deacetylases (HDACs) are possible epigenetic treatments. Temozolomide, 3­deazaneplanocin A (DZ­Nep; an EZH2 inhibitor) and panobinostat (an HDAC inhibitor) were tested in regular and temozolomide­resistant glioblastoma cells to confirm whether the compounds could behave in a synergistic, additive or antagonistic manner. A total of six commercial cell lines, two temozolomide­induced resistant cell lines and two primary cultures derived from glioblastoma samples were used. Cell lines were exposed to single treatments of the drugs in addition to all possible two­ and three­drug combinations. Colony formation assays, synergistic assays and reverse transcription­quantitative PCR analysis of apoptosis­associated genes were performed. The highest synergistic combination was DZ­Nep + panobinostat. Triple treatment was also synergistic. Reduced clonogenicity and increased apoptosis were both induced. It was concluded that the therapeutic potential of the combination of these three drugs in glioblastoma was evident and should be further explored.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Glioblastoma/patologia , Adenosina/administração & dosagem , Adenosina/análogos & derivados , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Panobinostat/administração & dosagem , Temozolomida/administração & dosagem , Células Tumorais Cultivadas
16.
Eur Heart J Acute Cardiovasc Care ; 9(1): 90-95, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30124050

RESUMO

OBJECTIVES: To investigate the role of endothelial function in patients with previous spontaneous coronary artery dissection. BACKGROUND: Mechanisms underlying spontaneous coronary artery dissection, including a possible contribution from endothelial dysfunction, remain poorly understood. METHODS: This was a single center, retrospective study of patients with a prior spontaneous coronary artery dissection episode who underwent invasive endothelial function testing in the cardiac catheterization laboratory for evaluation of recurrent chest pain. Coronary epicardial and microvascular responses to acetylcholine, adenosine, and nitroglycerine were assessed. Findings were compared to a reference group of normal controls (n=232). RESULTS: A total of 10 patients with prior angiographically confirmed spontaneous coronary artery dissection were referred for coronary endothelial function testing. The median coronary flow reserve was 2.8 (interquartile range (IQR) 2.3, 3.6). The median change in coronary diameter with acetylcholine was -0.9% (IQR -23.9, 4.2). The median increase in peak coronary blood flow following acetylcholine administration was 91.4% (IQR 9.1, 105.7), which was similar to the response observed in a reference group of patients (median age 51 years, 96% women) from our laboratory with normal microvascular responses to acetylcholine: 107.4% (IQR 75.5, 165.7; P=0.20). Four patients (40%) had an abnormal microvascular response to acetylcholine, with less than a 50% increase in coronary blood flow, and all but one patient had left anterior descending artery or multivessel spontaneous coronary artery dissection. CONCLUSION: Coronary epicardial and microvascular vasomotor dysfunction is not a predominant feature of spontaneous coronary artery dissection. Endothelial dysfunction is not implicated as the principal underlying mechanism.


Assuntos
Circulação Coronária/fisiologia , Anomalias dos Vasos Coronários/fisiopatologia , Vasos Coronários/fisiopatologia , Células Endoteliais/fisiologia , Doenças Vasculares/congênito , Acetilcolina/administração & dosagem , Acetilcolina/farmacologia , Adenosina/administração & dosagem , Adenosina/farmacologia , Adulto , Idoso , Velocidade do Fluxo Sanguíneo/fisiologia , Estudos de Casos e Controles , Dor no Peito/diagnóstico , Dor no Peito/etiologia , Angiografia Coronária/métodos , Anomalias dos Vasos Coronários/diagnóstico , Feminino , Humanos , Masculino , Microcirculação/efeitos dos fármacos , Microcirculação/fisiologia , Pessoa de Meia-Idade , Nitroglicerina/administração & dosagem , Nitroglicerina/farmacologia , Estudos Retrospectivos , Doenças Vasculares/diagnóstico , Doenças Vasculares/fisiopatologia
17.
JACC Cardiovasc Imaging ; 13(3): 732-742, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31422127

RESUMO

OBJECTIVES: The goal of this study was to assess the diagnostic performance of coronary computed tomography angiography (CTA) alone, adenosine-stress myocardial perfusion assessed by computed tomography (CTP) alone, and coronary CTA + CTP by using a 16-cm Z-axis coverage scanner versus invasive coronary angiography (ICA) and fractional flow reserve (FFR) as the clinical standard. BACKGROUND: Diagnostic performance of coronary CTA for in-stent restenosis detection is still challenging. Recently, CTP showed additional diagnostic power over coronary CTA in patients with suspected coronary artery disease. However, few data are available on CTP performance in patients with previous stent implantation. METHODS: Consecutive stable patients with previous coronary stenting referred for ICA were enrolled. All patients underwent stress myocardial CTP and rest CTP + coronary CTA. Invasive FFR was performed during ICA when clinically indicated. The diagnostic rate and diagnostic accuracy of coronary CTA, CTP, and coronary CTA + CTP were evaluated in stent-, territory-, and patient-based analyses. RESULTS: In the 150 enrolled patients (132 men; mean age 65.1 ± 9.1 years), the CTP diagnostic rate was significantly higher than that of coronary CTA in all analyses (territory based [96.7% vs. 91.1%; p < 0.0001] and patient based [96% vs. 68%; p < 0.0001]). When ICA was used as gold standard, CTP diagnostic accuracy was significantly higher than that of coronary CTA in all analyses (territory based [92.1% vs. 85.5%, p < 0.03] and patient based [86.7% vs. 76.7%, p < 0.03]). The concordant coronary CTA + CTP assessment exhibited the highest diagnostic accuracy values versus ICA (95.8% in the territory-based analysis). The diagnostic accuracy of CTP was significantly higher than that of coronary CTA (75% vs. 30.5%; p < 0.001). The radiation exposure of coronary CTA + CTP was 4.15 ± 1.5 mSv. CONCLUSIONS: In patients with coronary stents, CTP significantly improved the diagnostic rate and accuracy of coronary CTA alone compared with both ICA and invasive FFR as gold standard.


Assuntos
Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/terapia , Reestenose Coronária/diagnóstico por imagem , Tomografia Computadorizada Multidetectores , Imagem de Perfusão do Miocárdio , Intervenção Coronária Percutânea/instrumentação , Stents , Adenosina/administração & dosagem , Idoso , Doença da Artéria Coronariana/fisiopatologia , Reestenose Coronária/fisiopatologia , Progressão da Doença , Feminino , Reserva Fracionada de Fluxo Miocárdico , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Valor Preditivo dos Testes , Estudos Prospectivos , Resultado do Tratamento , Vasodilatadores/administração & dosagem
18.
JACC Cardiovasc Imaging ; 13(3): 746-756, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31422133

RESUMO

OBJECTIVES: The current substudy of the PACIFIC (Prospective Comparison of Cardiac PET/CT, SPECT/CT Perfusion Imaging and CT Coronary Angiography With Invasive Coronary Angiography) trial explores the impact of computed tomography (CT)-derived unfavorable plaque features on both hyperemic and non-hyperemic flow indices. BACKGROUND: Next to lesion severity, plaque vulnerability as assessed using coronary CT angiography affects fractional flow reserve (FFR), which is associated with imminent acute coronary syndromes. Instantaneous wave-free ratio (iFR) has recently emerged as an alternative for FFR to interrogate coronary lesions for ischemia. It is, however, unknown whether vasodilator-free assessment with iFR is associated with plaque stability similarly as FFR. METHODS: Of 120 patients (62% men, age 58.3 ± 8.6 years) with suspected coronary artery disease, 257 vessels were prospectively evaluated. Each patient underwent 256-slice coronary CT angiography to assess stenosis severity and plaque features (positive remodeling [PR], low attenuation plaque [LAP], spotty calcification [SC], and napkin ring sign [NRS]), as well as intracoronary pressure measurements (FFR, iFR, Pd/Pa, and pressure ratio during adenosine within the wave-free period [iFRa]). CT-derived plaque characteristics were related to these invasive pressure measurements. RESULTS: Atherosclerotic plaques were present in 170 (66%) coronary arteries. On a per-vessel basis, luminal stenosis severity was significantly associated with impaired FFR, iFR, Pd/Pa, and iFRa. Multivariable analysis revealed that FFR and iFR were independently related to ≥70% stenosis (-0.10, p < 0.001 and -0.09, p = 0.003, respectively) and plaque volume (-0.02, p = 0.020 and -0.02, p = 0.030, respectively). Additionally, PR and SC were also independent predictors of an impaired FFR (-0.10, p < 0.001 and -0.07, p = 0.021, respectively), but adverse plaque characteristics were not independently related to the vasodilator-free iFR. CONCLUSIONS: CT-derived vulnerable plaque characteristics are independently associated with hyperemic flow indices as assessed with FFR and iFRa, but not with non-hyperemic indices such as iFR and Pd/Pa. These findings suggest that the effects of hyperemia on pressure-derived indices might depend not only on hemodynamic stenosis severity but also on plaque characteristics.


Assuntos
Adenosina/administração & dosagem , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Estenose Coronária/diagnóstico por imagem , Reserva Fracionada de Fluxo Miocárdico , Hiperemia/fisiopatologia , Tomografia Computadorizada Multidetectores , Placa Aterosclerótica , Vasodilatadores/administração & dosagem , Idoso , Doença da Artéria Coronariana/fisiopatologia , Estenose Coronária/fisiopatologia , Feminino , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Índice de Gravidade de Doença
19.
Circ Cardiovasc Interv ; 13(1): e007893, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31870178

RESUMO

BACKGROUND: Intravenous infusion of adenosine is considered standard practice for fractional flow reserve (FFR) assessment but is associated with adverse side-effects and is time-consuming. Intracoronary bolus injection of adenosine is better tolerated by patients, cheaper, and less time-consuming. However, current literature remains fragmented and modestly sized regarding the equivalence of intracoronary versus intravenous adenosine. We aim to investigate the relationship between intracoronary adenosine and intravenous adenosine to determine FFR. METHODS: We performed a lesion-level meta-analysis to compare intracoronary adenosine with intravenous adenosine (140 µg/kg per minute) for FFR assessment. The search was conducted in accordance to the Preferred Reporting for Systematic Reviews and Meta-Analysis statement. Lesion-level data were obtained by contacting the respective authors or by digitization of scatterplots using custom-made software. Intracoronary adenosine dose was defined as; low: <40 µg, intermediate: 40 to 99 µg, and high: ≥100 µg. RESULTS: We collected 1972 FFR measurements (1413 lesions) comparing intracoronary with intravenous adenosine from 16 studies. There was a strong correlation (correlation coefficient =0.915; P<0.001) between intracoronary-FFR and intravenous-FFR. Mean FFR was 0.81±0.11 for intracoronary adenosine and 0.81±0.11 for intravenous adenosine (P<0.001). We documented a nonclinically relevant mean difference of 0.006 (limits of agreement: -0.066 to 0.078) between the methods. When stratified by the intracoronary adenosine dose, mean differences between intracoronary and intravenous-FFR amounted to 0.004, 0.011, or 0.000 FFR units for low-dose, intermediate-dose, and high-dose intracoronary adenosine, respectively. CONCLUSIONS: The present study documents clinically irrelevant differences in FFR values obtained with intracoronary versus intravenous adenosine. Intracoronary adenosine hence confers a practical and patient-friendly alternative for intravenous adenosine for FFR assessment.


Assuntos
Adenosina/administração & dosagem , Cateterismo Cardíaco , Doença da Artéria Coronariana/diagnóstico , Reserva Fracionada de Fluxo Miocárdico , Vasodilatadores/administração & dosagem , Adenosina/efeitos adversos , Doença da Artéria Coronariana/fisiopatologia , Humanos , Infusões Intravenosas , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Vasodilatadores/efeitos adversos
20.
Respir Res ; 20(1): 288, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856838

RESUMO

BACKGROUND: Although allergic asthma is a complex area with many interacting factors involved, the 'hygiene hypothesis' proposes that a lack of exposure to infection during childhood may polarise the immune system towards allergen-reactive Th2-type responses in genetically susceptible individuals. Toll-like receptors (TLRs) play a key role within the innate immune system and TLR7 agonists have previously been shown to up-regulate Th1 responses and down-regulate Th2 responses to allergens in murine models of allergic or chronic asthma. This study aimed to examine the efficacy and safety of the novel TRL7 agonist AZD8848, which has been developed as an antedrug. METHODS: In this double-blind, randomised, parallel-group study, AZD8848 60 µg or placebo was administered intranasally once-weekly for 8 weeks in patients with mild-to-moderate allergic asthma (NCT00999466). Efficacy assessments were performed at 1 and 4 weeks after the last dose. The primary outcome was the late asthmatic response (LAR) fall in forced expiratory volume in 1 s (FEV1) after allergen challenge at 1-week post-treatment. RESULTS: AZD8848 significantly reduced average LAR fall in FEV1 by 27% vs. placebo at 1 week after treatment (p = 0.035). This effect was sustained at 4 weeks post-treatment; however, it did not reach clinical significance. AZD8848 reduced post-allergen challenge methacholine-induced airway hyper-responsiveness (AHR) vs. placebo at 1 week post-dosing (treatment ratio: 2.20, p = 0.024), with no effect at 4 weeks. There was no significant difference between the two groups in plasma cytokine, sputum Th2 cytokine or eosinophil responses post-allergen challenge at 1 week after treatment. The incidence of adverse events was similar in the two groups. AZD8848 was generally well tolerated. CONCLUSIONS AND CLINICAL RELEVANCE: In patients with allergic asthma, TLR7 agonists could potentially reduce allergen responsiveness by stimulating Type 1 interferon responses to down-regulate the dominant Th2 responses. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT00999466.


Assuntos
Adenosina/análogos & derivados , Alérgenos/efeitos adversos , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Testes de Provocação Brônquica/métodos , Fenilacetatos/administração & dosagem , Receptor 7 Toll-Like/agonistas , Adenosina/administração & dosagem , Administração Intranasal , Adolescente , Adulto , Asma/induzido quimicamente , Asma/metabolismo , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
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