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1.
Artigo em Inglês | MEDLINE | ID: mdl-33093771

RESUMO

Background: Pulmonary hypertension (PH) is a known complication of pulmonary sarcoidosis and is associated with higher morbidity and mortality. Currently, there are no approved PH-targeted therapies for sarcoidosis-associated pulmonary hypertension (SAPH). Macitentan is frequently used as treatment for pulmonary arterial hypertension, but no results are known in the SAPH population. Objective: We investigated the safety and effect of macitentan as treatment for SAPH. Methods: We retrospectively reviewed our patient database for all SAPH patients receiving macitentan as treatment, with a minimum follow-up of twelve months for monitoring safety. Safety outcomes included reported side-effects, hospitalisations and mortality. Furthermore, six-minutes walking distance, New York Heart Association functional class and NT-proBNP levels were collected. Results: Six cases (three men) with a median age of 64 years (range 52-74 years) were identified. During macitentan treatment, one patient experienced side effects and aborted therapy after five days of treatment and died 16 months later. Three patients were hospitalised during treatment for congestive heart failure. Four patients showed improvement of their functional class and three patients in exercise capacity after 12 months of therapy. Conclusion: Macitentan was well tolerated in five out of six cases with severe pulmonary sarcoidosis and PH. Functional capacity improved in four cases. Prospective controlled trials are warranted before therapeutic recommendations can be made. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 74-78).


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Antagonistas dos Receptores de Endotelina/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Pirimidinas/uso terapêutico , Sarcoidose Pulmonar/complicações , Sulfonamidas/uso terapêutico , Idoso , Anti-Hipertensivos/efeitos adversos , Bases de Dados Factuais , Antagonistas dos Receptores de Endotelina/efeitos adversos , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/fisiopatologia , Recuperação de Função Fisiológica , Estudos Retrospectivos , Sarcoidose Pulmonar/diagnóstico , Fatores de Tempo , Resultado do Tratamento
2.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 184-191, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093782

RESUMO

Sarcoidosis-Associated Pulmonary Hypertension (SAPH) is a common finding in patients with chronic sarcoidosis and is associated with increased mortality. The optimal treatment for SAPH is not known; however, therapies approved for Group 1 pulmonary hypertension have improved hemodynamics and functional status. Prostanoids, including epoprostenol, have been therapeutic in short-term studies of SAPH, but long-term efficacy is unknown. In this study, we evaluated the long-term effect of epoprostenol therapy in 12 patients with SAPH. Hemodynamic assessment after an average of 4.1 years of epoprostenol therapy demonstrated significant improvement in mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output; furthermore, patients demonstrated improved NYHA functional class. To evaluate further the long-term effect of epoprostenol, we compared survival of SAPH patients to a cohort of hemodynamically matched patients from the same center treated with epoprostenol for Idiopathic Pulmonary Arterial Hypertension (IPAH). Interestingly, there was no difference in survival, despite the additional systemic disease burden of the SAPH subjects. Subgroup analysis by Scadding stage demonstrated that Scadding stages 1-3 had improved survival compared to Scadding stage 4. These observations suggest that epoprostenol is an effective long-term therapy for patients with SAPH; it improves hemodynamics, functional class, and provides survival similar to that seen in a hemodynamically-matched cohort of IPAH patients. Furthermore, we identify a subgroup of SAPH patients (nonfibrotic lung disease Scadding 1-3) who may derive significant benefit from prostanoid therapy. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 184-191).


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Epoprostenol/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Sarcoidose/complicações , Adulto , Anti-Hipertensivos/efeitos adversos , Débito Cardíaco/efeitos dos fármacos , Doença Crônica , Epoprostenol/efeitos adversos , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/fisiopatologia , Estudos Retrospectivos , Sarcoidose/diagnóstico , Sarcoidose/tratamento farmacológico , Fatores de Tempo , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos
3.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 234-238, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093789

RESUMO

Sarcoid Associated Pulmonary Hypertension (SAPH) is a common complication of sarcoidosis and is associated with poor prognosis. SAPH can be due to multiple synergistic mechanisms and current therapeutic strategies treat systemic sarcoidosis and pulmonary hypertension separately. Several studies have been performed to develop an effective therapy for SAPH but have been met with mixed results. The AMBITION trial successfully treated incident patients with pulmonary arterial hypertension (PAH) with the upfront combination of ambrisentan and tadalafil; however combination therapy has not yet been studied in patients with SAPH. Here we report a cohort of patients with newly diagnosed SAPH who were treated with upfront combination therapy per the AMBITION study protocol. We report three subjects with newly diagnosed SAPH who were treated with combination ambrisentan and tadalafil. Baseline hemodynamics were compared with those from surveillance right heart catheterization while on therapy. Mean follow up period was 17 months. Each subject demonstrated clinical and hemodynamic improvement with combination therapy. This series is the first to evaluate upfront combination ambrisentan and tadalafil therapy for treatment of newly diagnosed SAPH. Despite the impressive clinical and hemodynamic improvement, the study is limited by its small size and retrospective nature. While these initial results are promising, further work is needed to fully evaluate this regimen for treatment of SAPH. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 234-238).


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Antagonistas do Receptor de Endotelina A/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Fenilpropionatos/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Piridazinas/uso terapêutico , Sarcoidose Pulmonar/complicações , Tadalafila/uso terapêutico , Adulto , Idoso , Quimioterapia Combinada , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/fisiopatologia , Estudos Retrospectivos , Sarcoidose Pulmonar/diagnóstico , Resultado do Tratamento
4.
Hipertens. riesgo vasc ; 37(3): 133-136, jul.-sept. 2020. ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-193522

RESUMO

La disfunción autonómica es una enfermedad muy frecuente en las alfa-sinucleoinopatías (enfermedad de Parkinson, demencia por cuerpos de Lewy, atrofia multisistémica). A nivel cardiovascular puede producir síntomas como hipotensión ortostática, hipertensión supina o disminución de la respuesta de la frecuencia cardiaca a estímulos. Para el diagnóstico es fundamental una sospecha clínica y una exploración física minuciosa, tomando la presión arterial tanto en posición de decúbito supino como en bipedestación. El electrocardiograma puede mostrar un alargamiento de los intervalos PR y QT, mientras que la monitorización ambulatoria de presión arterial de 24 h aporta información sobre los patrones de presión arterial. La confirmación de la disfunción simpática cardiaca puede realizarse con una gammagrafía miocárdica de inervación con 123-I-metilbencilguanidina (123-I-MIBG), ya que refleja la captación noradrenérgica neuronal específica. A continuación presentamos el caso de un varón con enfermedad de Parkinson que tras un completo estudio fue diagnosticado de disfunción autonómica cardiovascular


Autonomic dysfunction is a common condition in the alpha-synucleinopathies (Parkinson's disease, dementia with Lewy bodies, multiple system atrophy). Cardiovascular symptoms may include orthostatic hypotension, supine hypertension or decreased heart rate response. A clinical suspicion and physical examination are essential for diagnosis, taking blood pressure in supine and standing positions. The electrocardiogram may show a prolongation of the PR and QT intervals, while 24-hour ambulatory blood pressure monitoring provides information on blood pressure patterns. Cardiac sympathetic dysfunction can be confirmed by an innervation myocardial scintigraphy with 123-I-methylbenzylguanidine (123-I-MIBG). This can reflect specific neuronal noradrenergic uptake.We present the case of a man with Parkinson's disease who was diagnosed with cardiovascular autonomic dysfunction after a complete study


Assuntos
Humanos , Masculino , Idoso de 80 Anos ou mais , Doenças do Sistema Nervoso Autônomo/complicações , Doenças do Sistema Nervoso Autônomo/diagnóstico por imagem , Doenças Neurodegenerativas/complicações , Pressão Arterial/efeitos dos fármacos , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Índice de Gravidade de Doença , Eletrocardiografia , Frequência Cardíaca , Captopril , Síndrome do QT Longo/diagnóstico
5.
Medicine (Baltimore) ; 99(36): e21864, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899016

RESUMO

Spinal anesthesia (SpA) for elective caesarean section (CS) is often accompanied by clinically relevant arterial hypotension. The Bezold-Jarisch reflex, causing postspinal hypotension, has been shown to be antagonized by serotonin type 3 (5-HT3) blockade. Our aim was to assess if routine prophylactic administration of the 5-HT3 antagonist ondansetron (ODS) attenuates postspinal change in maternal blood pressure.Elective CS under SpA were retrospectively analyzed. Eighty parturients having routinely received 8 mg ODS prior to SpA were compared with 80 patients having not (control group).Mean arterial blood pressure significantly decreased from baseline to the postspinal period (P < .0001) without differences in blood pressure decreases between the 2 groups. This also applied to the heart rate. Overall use of cafedrine/theodrenaline was higher in the ODS group (0.8 (0.4-1.6) mL vs 0.8 (0-1.0) mL in the control group, P = .01). APGAR values showed a presumably clinically irrelevant decrease in control group compared with the ODS group.Our results suggest that routine administration of ODS in a dosage of 8 mg does not effectively attenuate postspinal change in maternal blood pressure during CS in our setting. Given the wide variability of anesthetic techniques, only large prospective and randomized multicenter trials will ultimately serve to elucidate this issue.


Assuntos
Anestesia Obstétrica/métodos , Raquianestesia/métodos , Cesárea/métodos , Ondansetron/administração & dosagem , Antagonistas do Receptor 5-HT3 de Serotonina/administração & dosagem , Adulto , Índice de Apgar , Pressão Arterial/efeitos dos fármacos , Estudos de Casos e Controles , Cesárea/efeitos adversos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Recém-Nascido , Gravidez , Estudos Retrospectivos
6.
Cardiovasc Ther ; 2020: 4349612, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983258

RESUMO

Background: Central aortic blood pressure (CABP) indices, central hemodynamics, and arterial stiffness are better predictors of cardiovascular events as compared with brachial cuff pressure measurements alone. The present study is aimed at assessing the effects of different antihypertensive drug combination regimens involving renin-angiotensin-aldosterone system (RAAS) inhibitors on CABP indices in Indian patients with hypertension. Methods: This was a cross-sectional, single-center study conducted in patients treated for hypertension for >6 weeks using different treatment regimens involving the combination of RAAS inhibitors with drugs from other classes. CABP indices, vascular age, arterial stiffness, and central hemodynamics were measured in patients using the noninvasive Agedio B900 device (IEM, Stolberg, Germany) and compared between different treatment regimens. Results: A total of 199 patients with a mean age of 54.22 ± 10.15 years were enrolled, where 68.8% had hypertension for over three years and 50.25% had their systolic blood pressure (SBP) < 140 mmHg. Combination treatment with angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) was given to 77.9% and to 20.1% patients, respectively. The mean vascular age was higher than the actual age (58.13 ± 12.43 vs. 54.22 ± 10.15, p = 0.001). The SBP and diastolic blood pressure (DBP) levels in patients treated with ACEI-based combinations were lower than those in patients treated with ARB-based combinations (p < 0.05). The mean central pulse pressure amplification, augmentation pressure, and augmentation index were lower in patients treated with ACEI-based combinations than those treated with other treatments (p = 0.001). In a subgroup analysis, patients given perindopril and calcium channel blockers (CCBs) or diuretics had significantly lower CABP and pulse wave velocity than those given other treatments (p < 0.05). A total of 6.5% patients experienced any side effects. Conclusion: The majority of central hemodynamic parameters, including vascular age, were found to improve more effectively in patients treated with ACEIs than with ARBs. Our results indicate a gap between routine clinical practice and evidence-based guidelines in Indian settings and identify a need to reevaluate the current antihypertensive prescription strategy.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Adulto , Idoso , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Estudos Transversais , Quimioterapia Combinada , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Índia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
7.
Br J Anaesth ; 125(4): 622-628, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32739045

RESUMO

BACKGROUND: Arterial pressure lability is common during the process of replacing syringes used for norepinephrine infusions in critically ill patients. It is unclear if there is an optimal approach to minimise arterial pressure instability during this procedures. We investigated whether 'double pumping' changeover (DPC) or automated changeover (AC) reduced blood pressure lability in critically ill adults compared with quick syringe changeover (QC). METHODS: Patients requiring a norepinephrine infusion syringe change were randomised in a non-blinded trial undertaken in six ICUs. Randomisation was minimised by norepinephrine flow rate at inclusion and centre. The primary outcome was the frequency of increased/decreased mean arterial pressure (defined by 15 mm Hg from baseline measurements) within 15 min of switching the syringe compared with QC. RESULTS: Patients (mean age: 64 (range:18-88)) yr were randomly assigned to QC (n=95), DPC (n=95), or AC (n=96). Increased MAP was the commonest consequence of syringe changeovers. MAP variability was most frequent after DPC (89/224 changeovers; 39.7%) compared with 57/223 (25.6%) changeovers after quick syringe switch and 46/181 (25.4%) in patients randomised to receive automated changeover (P=0.001). Fewer events occurred with QC compared with DPC (P=0.002). Sensitivity analysis based on mixed models showed that performing several changeovers on a single patient had no impact. Both type of changeover and norepinephrine dose before syringe changeover were independently associated with MAP variations >15 mm Hg. CONCLUSIONS: Quick changeover of norepinephrine syringes was associated with less blood pressure lability compared with DPC. The prevalence of MAP variations was the same between AC and QC. CLINICAL TRIAL REGISTRATION: NCT02304939.


Assuntos
Pressão Arterial/efeitos dos fármacos , Cuidados Críticos , Norepinefrina/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Seringas , Adulto Jovem
8.
Ecotoxicol Environ Saf ; 204: 111036, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32784013

RESUMO

Human exposure to methylmercury (MeHg) due to contaminated fish intake as part of a high-fat (HFD), high-carbohydrate diets is a reality today for many populations. HFD is associated with hypertension and hyperlipidemia, primary cardiovascular disease (CVD) risk factors. Some studies suggest that MeHg induces those risk factors. We evaluated the effect of MeHg exposure in mice fed with HFD or control diet for eight weeks. In the last experimental 15 days, the half group received a MeHg solution (20 mg/L) replacing water. Blood pressure (BP), heart rate, lipoprotein concentrations, and paraoxonase activity were evaluated. Liver cholesterol, triacylglycerol, and IBA-1+ cells, as well as transcriptional levels of genes related to lipid metabolism and inflammatory response, were also assessed. HFD and both MeHg groups presented increased BP and total cholesterol (TC). In the liver, HFD but not MeHg was related to an increase in TC. Also, MeHg intoxication reduced paraoxonase activity regardless of diet. MeHg intoxication and HFD increased steatosis and the number of IBA-1+ cells and modified some gene transcripts associated with lipid metabolism. In conclusion, we demonstrated that MeHg effects on CVD risk factors resemble those caused by HFD.


Assuntos
Pressão Arterial/efeitos dos fármacos , Aterosclerose/epidemiologia , Dieta Hiperlipídica/efeitos adversos , Poluentes Ambientais/efeitos adversos , Fígado/efeitos dos fármacos , Compostos de Metilmercúrio/efeitos adversos , Estado Nutricional , Animais , Aterosclerose/induzido quimicamente , Fígado Gorduroso/metabolismo , Feminino , Inflamação/induzido quimicamente , Inflamação/fisiopatologia , Lipoproteínas/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Risco
9.
J Cardiovasc Magn Reson ; 22(1): 50, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32698897

RESUMO

BACKGROUND: Bronchopulmonary dysplasia (BPD) associated with pulmonary hypertension (PH) is a significant source of morbidity and mortality in premature infants. Recent advances have allowed the use of cardiovascular magnetic resonance (CMR) in the assessment of respiratory and cardiac disease in infants with BPD. In adults and older pediatric patients, decreased CMR interventricular septal curvature correlates with increased mean pulmonary artery pressure and pulmonary vascular resistance. The current study sought to determine the relationship of CMR derived septal curvature in neonates with BPD and BPD-PH with a need for PH therapy. METHODS: Forty moderate or severe BPD and 12 mild BPD or control infants were imaged without contrast between 38 and 47 weeks post-menstrual age on a neonatal-sized, neonatal intensive care unit-sited 1.5 T CMR scanner. CMR indices including eccentricity index (CMR-EI) and septal curvature were measured and compared to BPD severity and clinical outcomes including hospital length of stay (LOS), duration of respiratory support, respiratory support level at discharge and PH therapy. RESULTS: CMR-EI was directly associated and septal curvature was inversely associated with BPD severity. In a univariate analysis, CMR-EI and septal curvature were associated with increased hospital LOS, duration of respiratory support, respiratory support at hospital discharge, and need for PH therapy. In multivariable analysis CMR-EI was associated with hospital LOS and duration of respiratory support and septal curvature was associated with respiratory support at hospital discharge. Septal curvature was the only clinical or CMR variable associated with need for PH therapy (R2 = 0.66, p = 0.0014) in multivariable analysis demonstrating improved discrimination beyond CMR-EI. CONCLUSIONS: CMR derived septal curvature correlates significantly with clinical outcomes including hospital LOS, duration of respiratory support, respiratory support level at hospital discharge, and PH therapy in neonates with BPD and BPD-PH. Further, CMR derived septal curvature demonstrated improved discrimination of need for PH therapy and respiratory support at discharge compared to clinical variables and other CMR indices, supporting septal curvature as a non-invasive marker of PH in this population with potential to guide management strategies.


Assuntos
Pressão Arterial , Displasia Broncopulmonar/diagnóstico por imagem , Hipertensão Pulmonar/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Artéria Pulmonar/fisiopatologia , Resistência Vascular , Septo Interventricular/diagnóstico por imagem , Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/fisiopatologia , Displasia Broncopulmonar/terapia , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , Recém-Nascido , Tempo de Internação , Masculino , Valor Preditivo dos Testes , Artéria Pulmonar/efeitos dos fármacos , Terapia Respiratória , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos , Septo Interventricular/efeitos dos fármacos , Septo Interventricular/fisiopatologia
10.
Br J Anaesth ; 125(4): 539-547, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32718724

RESUMO

BACKGROUND: Patients undergoing cerebral bypass surgery are prone to cerebral hypoperfusion. Currently, arterial blood pressure is often increased with vasopressors to prevent cerebral ischaemia. However, this might cause vasoconstriction of the graft and cerebral vasculature and decrease perfusion. We hypothesised that cardiac output, rather than arterial blood pressure, is essential for adequate perfusion and aimed to determine whether dobutamine administration resulted in greater graft perfusion than phenylephrine administration. METHODS: This randomised crossover study included 10 adult patients undergoing cerebral bypass surgery. Intraoperatively, patients randomly and sequentially received dobutamine to increase cardiac index or phenylephrine to increase mean arterial pressure (MAP). An increase of >10% in cardiac index or >10% in MAP was targeted, respectively. Before both interventions, a reference phase was implemented. The primary outcome was the absolute difference in graft flow between the reference and intervention phase. We compared the absolute flow difference between each intervention and constructed a random-effect linear regression model to explore treatment and carry-over effects. RESULTS: Graft flow increased with a median of 4.1 (inter-quartile range [IQR], 1.7-12.0] ml min-1) after dobutamine administration and 3.6 [IQR, 1.3-7.8] ml min-1 after phenylephrine administration (difference -0.6 ml min-1; 95% confidence interval [CI], -14.5 to 5.3; P=0.441). There was no treatment effect (0.9 ml min-1; 95% CI, 0.0-20.1; P=0.944) and no carry-over effect. CONCLUSIONS: Both dobutamine and phenylephrine increased graft flow during cerebral bypass surgery, without a preference for one method over the other. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register, NL7077 (https://www.trialregister.nl/trial/7077).


Assuntos
Revascularização Cerebral/métodos , Circulação Cerebrovascular/efeitos dos fármacos , Dobutamina/farmacologia , Fenilefrina/farmacologia , Adulto , Pressão Arterial/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
Am J Physiol Heart Circ Physiol ; 319(2): H456-H467, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32706261

RESUMO

Peripheral artery disease (PAD) is a manifestation of atherosclerosis in the leg arteries, which causes claudication. This may be in part due to vascular mitochondrial dysfunction and excessive reactive oxygen species (ROS) production. A mitochondrial-targeted antioxidant (MitoQ) has been shown to improve vascular mitochondrial function that, in turn, led to improved vascular function in older adults and animal models. However, the roles of vascular mitochondria in vascular function including endothelial function and arterial stiffness in patients with PAD are unknown; therefore, with the use of acute MitoQ intake, this study examined the roles of vascular mitochondria in endothelial function, arterial stiffness, exercise tolerance, and skeletal muscle function in patients with PAD. Eleven patients with PAD received either MitoQ or placebo in a randomized crossover design. At each visit, blood samples, brachial and popliteal artery flow-mediated dilation (FMD), peripheral and central pulse-wave velocity (PWV), blood pressure (BP), maximal walking capacity, time to claudication (COT), and oxygen utility capacity were measured pre- and-post-MitoQ and placebo. There were significant group by time interactions (P < 0.05) for brachial and popliteal FMD that both increased by Δ2.6 and Δ3.3%, respectively, and increases superoxide dismutase (Δ0.03 U/mL), maximal walking time (Δ73.8 s), maximal walking distance (Δ49.3 m), and COT (Δ44.2 s). There were no changes in resting heart rate, BP, malondialdehyde, total antioxidant capacity, PWV, or oxygen utility capacity (P > 0.05). MitoQ intake may be an effective strategy for targeting the vascular mitochondrial environment, which may be useful for restoring endothelial function, leg pain, and walking time in patients with PAD.NEW & NOTEWORTHY The results of this study reveal for the first time that acute oral intake of mitochondrial-targeted antioxidant (MitoQ, 80 mg) is effective for improving vascular endothelial function and superoxide dismutase in patients with peripheral artery disease (PAD). Acute MitoQ intake is also effective for improving maximal walking capacity and delaying the onset of claudication in patients with PAD. These findings suggest that the acute oral intake of MitoQ-mediated improvements in vascular mitochondria play a pivotal role for improving endothelial function, the redox environment, and skeletal muscle performance in PAD.


Assuntos
Antioxidantes/uso terapêutico , Artéria Braquial/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Tolerância ao Exercício/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Claudicação Intermitente/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Compostos Organofosforados/uso terapêutico , Doença Arterial Periférica/tratamento farmacológico , Artéria Poplítea/efeitos dos fármacos , Ubiquinona/análogos & derivados , Idoso , Antioxidantes/metabolismo , Pressão Arterial/efeitos dos fármacos , Artéria Braquial/metabolismo , Artéria Braquial/fisiopatologia , Estudos Cross-Over , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Claudicação Intermitente/diagnóstico , Claudicação Intermitente/metabolismo , Claudicação Intermitente/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Contração Muscular/efeitos dos fármacos , Nebraska , Compostos Organofosforados/metabolismo , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/metabolismo , Doença Arterial Periférica/fisiopatologia , Artéria Poplítea/metabolismo , Artéria Poplítea/fisiopatologia , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento , Ubiquinona/metabolismo , Ubiquinona/uso terapêutico , Rigidez Vascular/efeitos dos fármacos , Caminhada
12.
Rev Cardiovasc Med ; 21(2): 163-179, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32706206

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive and fatal lung disease of multifactorial etiology. Most of the available drugs and FDA-approved therapies for treating pulmonary hypertension attempt to overcome the imbalance between vasoactive and vasodilator mediators, and restore the endothelial cell function. Traditional medications for treating PAH include the prostacyclin analogs and receptor agonists, phosphodiesterase 5 inhibitors, endothelin-receptor antagonists, and cGMP activators. While the current FDA-approved drugs showed improvements in quality of life and hemodynamic parameters, they have shown only very limited beneficial effects on survival and disease progression. None of them offers a cure against PAH, and the median survival rate remains less than three years from diagnosis. Extensive research efforts have led to the emergence of innovative therapeutic approaches in the area of PAH. In this review, we provide an overview of the current FDA-approved therapies in PAH and discuss the associated clinical trials and reported-side effects. As recent studies have led to the emergence of innovative therapeutic approaches in the area of PAH, we also focus on the latest promising therapies in preclinical studies such as stem cell-based therapies, gene transfer, and epigenetic therapies.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Hipertensão Arterial Pulmonar/terapia , Artéria Pulmonar/efeitos dos fármacos , Animais , Terapia Genética , Humanos , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/mortalidade , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Transplante de Células-Tronco , Resultado do Tratamento
13.
PLoS One ; 15(7): e0235635, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614897

RESUMO

BACKGROUND: Normothermic ex vivo liver perfusion (NEVLP) is a promising strategy to increase the donor pool in liver transplantation. Small animal models are essential to further investigate questions regarding organ preservation and reconditioning by NEVLP. A dual vessel small animal NEVLP (dNEVLP) model was developed using metamizole as a vasodilator and compared to conventional portovenous single vessel NEVLP (sNEVLP). METHODS: Livers of male Wistar rats were perfused with erythrocyte-supplemented culture medium for six hours by either dNEVLP via hepatic artery and portal vein or portovenous sNEVLP. dNEVLP was performed either with or without metamizole treatment. Perfusion pressure and flow rates were constantly monitored. Transaminase levels were determined in the perfusate at the start and after three and six hours of perfusion. Bile secretion was monitored and bile LDH and GGT levels were measured hourly. Histopathological analysis was performed using liver and bile duct tissue samples after perfusion. RESULTS: Hepatic artery pressure was significantly lower in dNEVLP with metamizole administration. Compared to sNEVLP, dNEVLP with metamizole treatment showed higher bile production, lower levels of transaminases during and after perfusion as well as significantly lower necrosis in liver and bile duct tissue. Biochemical markers of bile duct injury showed the same trend. CONCLUSION: Our miniaturized dNEVLP system enables normothermic dual vessel rat liver perfusion. The administration of metamizole effectively ameliorates arterial vasospasm allowing for six hours of dNEVLP, with superior outcome compared to sNEVLP.


Assuntos
Dipirona/farmacologia , Transplante de Fígado , Preservação de Órgãos/métodos , Vasodilatação/efeitos dos fármacos , Animais , Pressão Arterial/efeitos dos fármacos , Bile/metabolismo , Ductos Biliares/patologia , Artéria Hepática/patologia , Fígado/irrigação sanguínea , Fígado/patologia , Testes de Função Hepática , Masculino , Ratos , Ratos Wistar
16.
High Blood Press Cardiovasc Prev ; 27(4): 299-308, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32572706

RESUMO

Large conductive arteries undergo to structural modifications by aging, eventually leading to increased vascular stiffness. As consequence, cardiovascular hemodynamic changes by increasing central blood pressure which may be also associated to the remodelling of peripheral resistance arteries that contribute to increase further the central vascular stiffness and blood pressure. These modifications resemble the ones that has been shown in essential hypertension, thus a condition of "early vascular aging" has been described in hypertensive patients. Since hypertension related target organs, particularly the heart, face aortic blood pressure rather than brachial blood pressure, it has been recently suggested that central blood pressure and other parameters of large arteries' stiffness, including pulse wave velocity (PWV), may better correlate with subclinical organ damage and might be useful to assess the cardiovascular risk of patients beyond the traditional risk factors. Different devices have been validated to measure central blood pressure and PWV, and are currently available for clinical use. The increasing application of these tools in clinical practice could improve the management of hypertensive patients by better defining the cardiovascular risk and address the antihypertensive therapy.


Assuntos
Envelhecimento , Aorta/fisiopatologia , Pressão Arterial , Hipertensão/fisiopatologia , Remodelação Vascular , Rigidez Vascular , Fatores Etários , Animais , Anti-Hipertensivos/uso terapêutico , Aorta/efeitos dos fármacos , Pressão Arterial/efeitos dos fármacos , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Prognóstico , Medição de Risco , Fatores de Risco , Fatores de Tempo , Remodelação Vascular/efeitos dos fármacos , Rigidez Vascular/efeitos dos fármacos
17.
Life Sci ; 256: 117915, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504752

RESUMO

AIMS: Autonomic dysfunction in arterial hypertension affects cardiorespiratory control and gastric motility and has been characterized by increased sympathetic and reduced parasympathetic activity. In the present work we investigated the effects of anticholinesterase drugs [donepezil (DON) or pyridostigmine (PYR)] on cardiovascular, autonomic, and gastric parameters in L-NAME-induced hypertensive rats. MATERIALS AND METHODS: Daily oral gavage of L-NAME (70 mg/kg/day) was performed over 14 days in male Wistar rats (180-220 g), whereas daily oral gavage of DON or PYR (1.6 and 22 mg/kg/day, respectively) started 2 days after the L-NAME treatment initiation and lasted 12 days. The development of hypertension was verified by tail plethysmography technique. After the end of treatments, the animals were subjected to experimental protocols (6-12 animals per group; total number of animals used: 78). KEY FINDINGS: L-NAME hypertensive animals had no alterations in heart rate (HR) and intrinsic HR, but showed reduction in baroreflex sensitivity, parasympathetic tone, and gastric motility; and the sympathetic tone, chemoreflex sensitivity, and the LF (low frequency) band of systolic arterial pressure (SAP) variability were increased. DON or PYR attenuated the increase in mean arterial pressure (MAP) induced by L-NAME. Both anticholinesterase drugs were effective in preventing the decrease in baroreflex sensitivity, parasympathetic tone and gastric motility, and also prevented the increases in peripheral chemoreflex response and cardiac sympathetic tone. SIGNIFICANCE: Acetylcholinesterase inhibition with DON or PYR is a promising pharmacological approach to increase parasympathetic function, thus preventing the hypertension-induced alterations in the cardiovascular, gastrointestinal and autonomic systems.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Hipertensão/prevenção & controle , NG-Nitroarginina Metil Éster/efeitos adversos , Substâncias Protetoras/farmacologia , Brometo de Piridostigmina/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Modelos Animais de Doenças , Donepezila/metabolismo , Donepezila/farmacologia , Frequência Cardíaca , Hipertensão/metabolismo , Masculino , Substâncias Protetoras/metabolismo , Brometo de Piridostigmina/metabolismo , Ratos , Ratos Wistar , Estômago/efeitos dos fármacos , Volume Sistólico
18.
J Cardiovasc Pharmacol ; 75(5): 421-425, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32379109

RESUMO

Pulmonary arterial hypertension is a quite rare, but problematic disease in everyday cardiologists' practice. Prostanoids are the most important group of drugs used in this disease. One of the biggest problems encountered during treatment with analogs of prostacyclin is thrombocytopenia. Based on hematological guidelines we suggest common therapeutic schemes depending on the number of platelets or the severity of bleeding conducting the therapy.


Assuntos
Anti-Hipertensivos/efeitos adversos , Pressão Arterial/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Prostaglandinas I/efeitos adversos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Trombocitopenia/induzido quimicamente , Animais , Humanos , Contagem de Plaquetas , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Fatores de Risco , Trombocitopenia/sangue , Resultado do Tratamento
19.
Am J Physiol Regul Integr Comp Physiol ; 318(6): R1036-R1046, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32320265

RESUMO

T-helper (TH)17s, IL-17, and cytolytic natural killer cells (cNKs) are increased in preeclampsia and contribute to the hypertension, inflammation, and fetal growth restriction that occurs in response to placental ischemia in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. As IL-17 stimulates NK cytotoxicity in vitro, we tested the hypothesis that IL-17 inhibition in RUPP rats would decrease cNK activation as a mechanism to improve maternal and fetal outcomes. On gestation day (GD) 14, rats undergoing RUPP received a miniosmotic pump infusing IL-17RC (100 pg/day), a soluble IL-17 receptor (RUPP + IL-17RC). On GD19, mean arterial pressure (MAP) was measured in normal pregnant (NP), RUPP, and RUPP + IL-17RC rats (n = 10-12/group), animals were euthanized, and blood and tissues were collected for analysis. MAP was 30% higher in RUPP compared with NP (P < 0.0001) and was 12% lower in RUPP + IL-17RC (P = 0.0007 vs. RUPP). Placental cytolytic NK cells were 132% higher in RUPP than in NP (P = 0.04 vs. NP) and were normalized in RUPP + IL-17RC (P = 0.03 vs. RUPP). Placental levels of TNF-α, a cNK-secreted cytokine, and macrophage inflammatory protein-3α (MIP-3α), a cNK chemokine, were higher in RUPP vs. NP and lower after IL-17 blockade. Placental VEGF was lower in RUPP vs. NP and was normalized in RUPP + IL-17RC. In vitro cytolytic activity of RUPP placental NKs was higher compared with NP and was blunted in RUPP + IL-17RC NKs. Finally, both fetal weight and placental weight were lower in RUPP compared with NP, and were improved in RUPP + IL-17RC. These data identify IL-17 as a mediator of cNK activation in response to placental ischemia during pregnancy.


Assuntos
Interleucina-17/metabolismo , Isquemia/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Placenta/irrigação sanguínea , Receptores de Interleucina-17/administração & dosagem , Animais , Pressão Arterial/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Mediadores da Inflamação/metabolismo , Isquemia/metabolismo , Placenta/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo
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