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1.
Adv Ther ; 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35917059

RESUMO

INTRODUCTION: Evaluating overall survival in randomized controlled trials (RCTs) can often be confounded by bias introduced by treatment switching. SERAPHIN was a large RCT that evaluated the effects of long-term treatment with the endothelin receptor antagonist macitentan in patients with pulmonary arterial hypertension. In an intent-to-treat (ITT) analysis, a non-significant decrease in the risk of all-cause mortality up to study closure was reported with macitentan 10 mg versus placebo. As patients could switch treatment when experiencing symptoms of disease progression, this analysis attempts to adjust for the confounding effects on overall survival. METHODS: The inverse probability of censoring weighted (IPCW) and rank-preserving structural failure time (RPSFT) models were used to estimate the treatment effect on overall mortality had there been no treatment switching in SERAPHIN. Time to all-cause death was evaluated up to study closure. Treatment switching was defined as patients in the placebo group switching to open-label macitentan 10 mg, and patients in the macitentan 10 mg group prematurely discontinuing macitentan. RESULTS: By study closure, 73.2% (183/250) of patients in the placebo group had switched to macitentan 10 mg. Among these patients, exposure time to macitentan 10 mg represented 28.2% of total study treatment exposure (cumulative exposure 134.6 patient-years). At study closure, 24.8% (60/242) of patients in the macitentan 10 mg group were not receiving open-label macitentan; mean time not receiving macitentan was 44.3 weeks. The adjusted hazard ratios (HR) for overall survival using the IPCW and RPSFT methods were lower (HR 0.42, 95% confidence interval [CI] 0.22, 0.81; p = 0.009, and HR 0.33, 95% CI 0.04, 2.83, respectively) than the ITT unadjusted HR (0.80, 95% CI 0.51, 1.24). CONCLUSION: These results from the current analyses indicate that in SERAPHIN, the standard ITT analysis was confounded by treatment switching resulting in an underestimation of the benefit of macitentan 10 mg on overall survival. By adjusting for switching, the IPCW and RPSFT models estimated a 58% and 67% reduction in risk of mortality, respectively, with macitentan 10 mg versus placebo. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00660179.

2.
Front Microbiol ; 13: 929752, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35910623

RESUMO

Pulmonary arterial hypertension (PAH) is a severe clinical condition that is characterized pathologically by perivascular inflammation and pulmonary vascular remodeling that ultimately leads to right heart failure. However, current treatments focus on controlling vasoconstriction and have little effect on pulmonary vascular remodeling. Better therapies of PAH require a better understanding of its pathogenesis. With advances in sequencing technology, researchers have begun to focus on the role of the human microbiota in disease. Recent studies have shown that the gut and airway microbiota and their metabolites play an important role in the pathogenesis of PAH. In this review, we summarize the current literature on the relationship between the gut and airway microbiota and PAH. We further discuss the key crosstalk between the gut microbiota and the lung associated with PAH, and the potential link between the gut and airway microbiota in the pathogenesis of PAH. In addition, we discuss the potential of using the microbiota as a new target for PAH therapy.

3.
J Cardiol Cases ; 26(1): 42-45, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35923524

RESUMO

Some patients with pulmonary arterial hypertension (PAH) might undergo transition to parenteral prostacyclin analogs due to inadequate response to oral combination therapy. However, there is no consensus on how transition from oral selexipag to subcutaneous treprostinil should be performed. Herein, we report a 56-year-old woman diagnosed with idiopathic PAH that was treated with initial combination therapy (10 mg of macitentan, 40 mg of tadalafil, and 3.2 mg of selexipag daily). Mean pulmonary arterial pressure (PAP) improved from 63 to 39 mm Hg. Transition to parenteral prostacyclin analog was required because cardiac index was below 2.5 L/min/m2. The selexipag was tapered off while subcutaneous treprostinil was titrated up to 30 ng/kg/min over 19 days. Hemodynamic parameters were slightly better than those before the transition. The mean PAP improved to 32 mm Hg by further gradual increases of subcutaneous treprostinil up to 60 ng/kg/min. Therefore, the patient having idiopathic PAH with inadequate response to oral triple combination therapy experienced successful transition from selexipag to subcutaneous treprostinil. Hemodynamic parameters were slightly more improved at a dose of 30 ng/kg/min of subcutaneous treprostinil than at a dose of 3200 µg daily of selexipag in the midst of disease progression. Learning objectives: There is limited evidence for transition of pulmonary vasodilators, especially from oral selexipag to subcutaneous treprostinil. Detailed change in hemodynamic parameters before and after transition and the way of performing transition in patients with idiopathic pulmonary arterial hypertension with exacerbations despite treatment with oral triple combination therapy may provide useful information for better management in the clinical setting.

4.
Pulm Pharmacol Ther ; : 102144, 2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-35918025

RESUMO

BACKGROUND: Previous meta-analyses of pulmonary arterial hypertension (PAH) combination therapy pooled sequential and initial combination together, which might threaten their authenticity and clinical significance for the difference between two strategies. METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) that compared sequential combination therapy (SCT) with background therapy (BT) in PAH patients. Raw data were extracted to calculate risk ratio (RR) or weighted mean difference (WMD) for predefined efficacy and safety outcomes. Mantel-Haenszel fixed or random effects model was used based on heterogeneity. RESULTS: 17 RCTs involving 4343 patients (97.2% of patients with WHO-FC II-III) were included. SCT decreased clinical worsening (RR 0.66, 95% CI 0.58 to 0.76), nonfatal clinical worsening (RR 0.61, 95% CI 0.52 to 0.71), functional class (decrease of 28% in the portion of patients with WHO-FC worsening and increase of 33% in the portion of patients with WHO-FC improvement), and increased 6-min walk distance (WMD 17.68 m, 95% CI 10.16 to 25.20), but didn't reduce mortality, lung transplantation, admission to hospital, and treatment escalation compared with BT. Although any adverse event and serious adverse event were similar between SCT and BT, SCT increased all-cause treatment discontinuation (RR 1.49, 95% CI 1.30 to 1.71) and drug-related treatment discontinuation (RR 2.30, 95% CI 1.86 to 2.84) with higher incidence of headache, flushing, nausea, diarrhoea and jaw pain. CONCLUSIONS: For WHO-FC II-III PAH patients who have established BT, our study reinforced the recommendation of SCT to improve clinical worsening, functional status, and exercise capacity, although with higher incidence of side-effects and withdrawal.

5.
J Crit Care ; 72: 154120, 2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35914371

RESUMO

PURPOSE: Bilateral lung transplantation for end-stage pulmonary arterial hypertension (PAH) is traditionally associated with higher early post-transplant mortality when compared with other indications. Changes in perioperative management, including the growing use of perioperative extracorporeal membrane oxygenation (ECMO) and an increased awareness of postoperative left ventricular dysfunction (LVD), have resulted in outcomes that are uncertain. MATERIALS AND METHODS: We conducted a single-center, retrospective observational study at a lung transplantation center in Melbourne, Australia, from 2006 to 2019. ECMO use was categorized as preoperative, prophylactic, or rescue. Postoperative LVD was defined as a reduction in left ventricular function on echocardiography or using strict clinical criteria. RESULTS: 50 patients underwent lung transplantation for PAH. 12-month survival was 48/50 (96%). ECMO was used in 26 (52%) patients, and the use of prophylactic VA-ECMO increased over the study period. Postoperative LVD was diagnosed in 21 (42%) patients. 12-month survival and left ventricular function was no different between LVD and non-LVD groups. CONCLUSIONS: This study showed that high survival rates can be achieved following lung transplantation for PAH. We found that ECMO utilization was common, and indications have changed over time. LVD was common but did not impact 12-month survival.

6.
An. Fac. Cienc. Méd. (Asunción) ; 55(2): 18-24, 20220801.
Artigo em Espanhol | LILACS | ID: biblio-1380292

RESUMO

Introducción: Las enfermedades cardiovasculares son la primera causa de muerte. El accidente cerebrovascular isquémico es un problema de salud pública. Objetivos: Determinar las características clínicas de los pacientes con accidente cerebrovascular de tipo isquémico admitidos durante el periodo de ventana terapéutica en el Servicio de Urgencias del Hospital de Clínicas en el periodo 2018 - 2020. Materiales y métodos: Estudio observacional, descriptivo, retrospectivo, transversal. Los sujetos fueron los pacientes de sexo masculino y femenino, mayores de 18 años admitidos en la Unidad de Ictus del Servicio de Urgencias del Hospital de Clínicas en el periodo de ventana terapéutica comprendido entre junio del año 2018 y septiembre del año 2020. Resultados: Se incluyó en el estudio 512 pacientes. La media de edad fue 65 ± 12,1 años. El sexo más frecuente fue el masculino con (58,7%) y la mayoría proceden del Departamento Central (61,3%). Los factores de riesgo más frecuentes fueron la hipertensión arterial (83,3%), el sobrepeso (34,7%) y la diabetes mellitus tipo 2 (27,3%). Presentaron infarto moderado (41,8%) y la trombólisis fue realizada en el (16%) de los pacientes. Conclusión: Los pacientes que presentaron accidente cerebrovascular de tipo isquémico admitidos en el periodo de ventana terapéutica fueron en su mayoría del sexo masculino, edad media de 65 años, los factores de riesgo cardiovasculares más frecuentes fueron la hipertensión arterial, el sobrepeso y la diabetes mellitus tipo 2, el infarto moderado fue la más frecuente y escasa cantidad recibieron trombólisis.


Introduction: Cardiovascular diseases are the leading cause of death. Ischemic stroke is a public health problem. Objectives: To determine the clinical characteristics of patients with ischemic stroke admitted during the therapeutic window period in the Emergency Department of the Hospital de Clínicas in the period 2018 - 2020. Materials and methods: Observational, descriptive, retrospective, cross-sectional study. The subjects were male and female patients, over 18 years of age admitted to the Stroke Unit of the Emergency Service of the Hospital de Clínicas in the therapeutic window period between June 2018 and September 2020. Results: Included 512 patients in the study. The mean age was 65 ± 12,1 years. The most frequent sex was male with (58.7%), most of them come from the central department (61.3%). The most frequent risk factors were arterial hypertension (83.3%), overweight (34.7%) and type 2 diabetes mellitus (27.3%). They presented moderate infarction (41,8%). Thrombolysis was performed in (16%) of the patients. Conclusion: The patients who presented ischemic stroke admitted in the therapeutic window period were mostly male, mean age 65 years, the most frequent cardiovascular risk factors were arterial hypertension, overweight and mellitus diabetes type 2, moderate infarction was the most frequent and few received thrombolysis.


Assuntos
Diabetes Mellitus Tipo 2 , Sobrepeso , AVC Isquêmico , Hipertensão , Doenças Cardiovasculares , Saúde Pública , Fatores de Risco , Causas de Morte , Acidente Vascular Cerebral
7.
Pulm Circ ; 12(3): e12120, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35911181

RESUMO

Outcomes of patients with pulmonary arterial hypertension (PAH) may be associated with social determinants of health (SDOH) and other baseline patient characteristics. At present, there is no prognostic model to predict important patient outcomes in PAH based on SDOH. Utilizing information from the Pulmonary Hypertension Association Registry (PHAR), we derive a model (PHAR Evaluation or PHARE) to predict an important composite patient outcomes based on SDOH and other patient characteristics. Baseline data regarding SDOH from adult patients with PAH enrolled in the PHAR between 2015 and March 23, 2020, were included for analysis. We performed repeated measures logistic regression modeling with dichotomous outcome data (0 for no events, 1 for one or more events) to derive the PHARE. Here, 1275 consecutive adult patients enrolled in the PHAR from 47 participating centers were included. Variables included in our model are race, gender, ethnicity, household income, level of education, age, body mass index, drug use, alcohol use, marital status, and type of health insurance. Interaction effect between variables was analyzed and several interactions were also included in the PHARE. The PHARE shows a c-statistic of 0.608 (p < 0.0001) with 95% confidence intervals (0.583, 0.632). Using SDOH and baseline characteristics from the PHAR, the PHARE correlates with our composite patient outcome. Further work evaluating the role of SDOH in prognostic modeling of PAH is indicated.

8.
Pulm Circ ; 12(3): e12107, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35911183

RESUMO

Pulmonary arterial hypertension (PAH) is a fatal vasculopathy that ultimately leads to elevated pulmonary pressure and death by right ventricular (RV) failure, which occurs in part due to decreased fatty acid oxidation and cytotoxic lipid accumulation. In this study, we tested the hypothesis that decreased fatty acid oxidation and increased lipid accumulation in the failing RV is driven, in part, by a relative carnitine deficiency. We then tested whether supplementation of l-carnitine can reverse lipotoxic RV failure through augmentation of fatty acid oxidation. In vivo in transgenic mice harboring a human BMPR2 mutation, l-carnitine supplementation reversed RV failure by increasing RV cardiac output, improving RV ejection fraction, and decreasing RV lipid accumulation through increased PPARγ expression and augmented fatty acid oxidation of long chain fatty acids. These findings were confirmed in a second model of pulmonary artery banding-induced RV dysfunction. In vitro, l-carnitine supplementation selectively increased fatty acid oxidation in mitochondria and decreased lipid accumulation through a Cpt1-dependent pathway. l-Carnitine supplementation improves right ventricular contractility in the stressed RV through augmentation of fatty acid oxidation and decreases lipid accumulation. Correction of carnitine deficiency through l-carnitine supplementation in PAH may reverse RV failure.

9.
Front Cardiovasc Med ; 9: 924873, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911521

RESUMO

Pulmonary arterial hypertension (PAH), also known as Group 1 Pulmonary Hypertension (PH), is a PH subset characterized by pulmonary vascular remodeling and pulmonary arterial obstruction. PAH has an estimated incidence of 15-50 people per million in the United States and Europe, and is associated with high mortality and morbidity, with patients' survival time after diagnosis being only 2.8 years. According to current guidelines, right heart catheterization is the gold standard for diagnostic and prognostic evaluation of PAH patients. However, this technique is highly invasive, so it is not used in routine clinical practice or patient follow-up. Thereby, it is essential to find new non-invasive strategies for evaluating disease progression. Biomarkers can be an effective solution for determining PAH patient prognosis and response to therapy, and aiding in diagnostic efforts, so long as their detection is non-invasive, easy, and objective. This review aims to clarify and describe some of the potential new candidates as circulating biomarkers of PAH.

10.
Anesth Pain Med (Seoul) ; 17(3): 291-297, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35918862

RESUMO

BACKGROUND: Pulmonary hypertension in pregnancy is rare and leads to high maternal morbidity and mortality. CASE: A 27-year-old parturient woman with a 31-week gestational age underwent cesarean delivery under combined spinal-epidural anesthesia. She had systemic lupus erythematosus associated with severe pulmonary arterial hypertension. The operation was done in the cardiac theatre along with meticulous invasive monitoring. Insertion of femoral artery and femoral vein catheters for veno-arterial extracorporeal membrane oxygenation was done before delivery as preparation for the potential emergency of a life-threatening form of decompensated cardiac failure. During the delivery, the patient suddenly developed increased pulmonary arterial pressure. This was controlled by the continuous infusion of intravenous milrinone. CONCLUSIONS: We report the successful management of this patient in the perioperative period. For cases such as that reported here, we recommend multidisciplinary team collaboration coupled with invasive cardiovascular monitoring and scrupulous anesthetic management.

12.
Front Pharmacol ; 13: 881084, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35784689

RESUMO

Introduction: Quantitative information on disposition of maternal medicines in human milk remains a major knowledge gap. This case report presents the clinical and pharmacokinetic data of a single mother-infant pair exposed to bosentan and sildenafil for the treatment of pulmonary arterial hypertension (PAH) during lactation. Case presentation: A 43-year old mother was treated with sildenafil (20 mg, 3x/day) and bosentan (125 mg, 2x/day) for PAH. Her 21-months old infant received breastfeeding in combination with adequate complementary foods. Milk samples were collected over 24 h, at day 637 and 651 after delivery. The observed average steady-state concentrations of sildenafil (2.84 µg/L) and bosentan (49.0 µg/L) in human milk were low. The Daily Infant Dosage ingested by the nursing infant through human milk was 0.02 µg/kg/day for sildenafil and 0.29 µg/kg/day for bosentan at day 637, and 0.03 µg/kg/day and 0.60 µg/kg/day at day 651. The Relative Infant Dose calculated for an exclusively breastfed infant with an estimated milk intake of 150 ml/kg/day, was 0.06% for sildenafil and 0.24% for bosentan. General health outcome of the infant, reported by the mother, was uneventful until the sampling days. Conclusion: Low medicine concentrations were found in human milk expressed 21 months after delivery after maternal intake of 20 mg sildenafil three times daily and 125 mg bosentan twice daily. General health of the nursing infant until sampling was reported as optimal by the mother.

13.
BMC Pulm Med ; 22(1): 264, 2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35790938

RESUMO

BACKGROUNDS: The EmPHasis-10 questionnaire is a disease-specific quality of life (QoL) measurement in patients with pulmonary hypertension. We report the results of cross-cultural validation of the Chinese version of the EmPHasis-10 and its relationship with risk stratification in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). METHODS: The Emphasis-10 was administered to 75 CTD-PAH patients along with the 36-item Medical Outcomes Study Short Form Survey (SF-36) and EuroQol five dimensions questionnaire (EQ-5D). The diagnosis of PAH was confirmed by right heart catheterization. Demographic and clinical data were obtained. Multivariable logistic regression was conducted based on the low risk profile assessed by a 4-strata risk assessment model (COMPERA 2.0) at follow-up. RESULTS: Date from 75 patients with CTD-PAH were analysed. The EmPHasis-10 demonstrated satisfactory reliability (Cronbach α = 0.95) and convergent validity showed by the significant relationship with WHO Functional Class (P = 0.003), SF-36 (P < 0.001) and EQ-5D (P = 0.002). EmPHasis-10 was significantly associated with achieving the low risk profile at 12 months of follow-up (Odds ratio: 0.928, P = 0.029) after adjusting for WHO Functional Class. CONCLUSION: EmPHasis-10 has acceptable reliability and validity in CTD-PAH patients and may serve as an additional parameter in risk stratification.


Assuntos
Doenças do Tecido Conjuntivo , Hipertensão Arterial Pulmonar , China , Doenças do Tecido Conjuntivo/complicações , Comparação Transcultural , Hipertensão Pulmonar Primária Familiar , Humanos , Hipertensão Arterial Pulmonar/diagnóstico , Qualidade de Vida , Reprodutibilidade dos Testes , Medição de Risco , Inquéritos e Questionários
14.
Pulm Circ ; 12(3): e12089, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35795255

RESUMO

The outbreak of novel coronavirus-19 disease (COVID-19) was classified as a global pandemic thanks to the rapid viral spread, and restrictive policy measures of infection containment, including "lockdown" periods and self-isolation, were first instituted in Belgium from March to June 2020. The consequent reduction in physical activity could have a negative impact on exercise capacity, especially in frail patients with pre-existing chronic diseases, such as pulmonary arterial hypertension (PAH). With the aim to define the impact of COVID-19 lockdown on functional status, we included in our observational analysis clinically stable PAH patients, who had performed at least four consecutive 6-min walking tests (6MWT) during 2019-2020, to compare their exercise performance before and after the lockdown. In the 63 patients included, a comparison between the distance covered at 6MWT after the lockdown period and the pooled mean of the previous three 6MWTs showed a mean reduction of 14 m after the lockdown (p = 0.004). Moreover, the mean distance covered at 6MWT went from 447 m in March 2020 to 434 m in June 2020, with a significant average loss of 13 m (p = 0.024). Our results showed that PAH patients were less performing at 6MWT after 3 months of reduced physical activity, despite constant clinical stability and the absence of signs of disease progression, suggesting that this confounding factor should be kept in mind when evaluating changes in 6MWT during or after COVID-19 pandemic.

15.
Pulm Circ ; 12(2): e12073, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35795489

RESUMO

Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension (PH) arising from pulmonary vascular obstruction at varying levels within the pulmonary vascular bed, due to chronic pulmonary emboli. The cornerstone of treatment for CTEPH is pulmonary thromboendarterectomy (PTE), a specialized surgery to remove the chronic vascular obstruction. At experienced centers, PTE leads to marked hemodynamic improvement and, in many cases, normalization of cardiopulmonary hemodynamics. However, increasing evidence supports the fact that a significant percentage of patients will have persistent PH after PTE. No consensus exists on the optimal approach to post-PTE patient assessment, and often the most experienced CTEPH centers have little experience in the direct follow-up care of the CTEPH patient post PTE. In this article, we will discuss a practical approach to patient assessment after PTE to help guide clinicians on how to recognize significant PH following PTE. In doing so, we identify the true phenotype of persistent PH post PTE so that appropriate patients can be further helped with the evolving therapies for the management of CTEPH.

16.
Pulm Circ ; 12(2): e12075, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35795494

RESUMO

Protein kinase inhibitors (PKIs) have been implicated in pulmonary vascular toxicities including risk factors for at least three of the five World Health Organization groups of pulmonary hypertension (PH). These toxicities include direct drug-induced pulmonary arterial hypertension, an increase in cardiomyopathies, and an increase in interstitial lung disease. On- and off-target toxicities are common within multitargeted PKIs leading to cardiopulmonary toxicities. This review highlights the incidence, possible mechanisms, and management strategies for each group of possible PKI-induced PH. Future identification and clarification of protein kinase pathways for both mechanisms of toxicity and pathophysiology for PH could lead to improvements in patient care in oncology and pulmonary vascular diseases.

17.
Pulm Circ ; 12(2): e12090, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35795495

RESUMO

Treatment for pulmonary arterial hypertension (PAH) has evolved over the past decade, including approval of new medications and growing evidence to support earlier use of combination therapy. Despite these changes, few studies have assessed real-world treatment patterns, healthcare resource utilization (HCRU), and costs among people with PAH using recent data. We conducted a retrospective cohort study using administrative claims from the HealthCore Integrated Research Database®. Adult members with claims for a PAH diagnosis, right heart catheterization, and who initiated PAH treatment (index date) between October 1, 2015 and November 30, 2020 were identified. Members had to be continuously enrolled in the health plan for 6 months before the index date (baseline) and ≥30 days after. Treatment patterns, HCRU, and costs were described. A total of 843 members with PAH (mean age 62.3 years, 64.2% female) were included. Only 21.0% of members received combination therapy as their first-line treatment, while most members (54.6%) received combination therapy as second-line treatment. All-cause HCRU remained high after treatment initiation with 58.0% of members having ≥1 hospitalization and 41.3% with ≥1 emergency room visit. Total all-cause costs declined from $15,117 per patient per month at baseline to $14,201 after treatment initiation, with decreased medical costs ($14,208 vs. $6,349) more than offsetting increased pharmacy costs ($909 vs. $7,852). In summary, despite growing evidence supporting combination therapy, most members with PAH initiated treatment with monotherapy. Total costs decreased following treatment, driven by a reduction in medical costs even with increases in pharmacy costs.

18.
Arch Med Sci ; 18(4): 1088-1094, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35832696

RESUMO

Introduction: The present study aimed to determine whether the presence of cardiac hypertrophy due to arterial hypertension is associated with a change in the activity of the oxytocinergic system in cardiomyocytes. Material and methods: The experiments were performed on male, spontaneously hypertensive rats (SHR, n = 10) and normotensive Wistar-Kyoto rats (WKY, n = 12). Blood samples were collected from both SHR and WKY animals to asses plasma oxytocin (OT) concentration; the rats were sacrificed by decapitation. Samples of the left and right ventricles were harvested for the analysis of the OT and oxytocin receptor (OTR) protein by ELISA, and OT and OTR mRNA expression by RT-PCR. Immunohistopathological studies were performed to confirm the presence of OTR receptors in the cardiac muscle of the ventricles. Results: Plasma OT concentration did not differ between SHR and WKY rats. In the SHR rats, the expression of OT mRNA and the OT protein level was higher in the left and the right ventricle, while OTR mRNA expression was significantly lower in both the left and the right ventricle. However, the level of OTR protein was higher only in the left ventricle of the SHR rats. The presence of OTR receptors was confirmed by immunohistochemical analysis in the muscle of the right and left ventricle. Conclusions: The presence of arterial hypertension is associated with increased activity of the oxytocinergic system in the heart, especially in the area of the left ventricle. These findings support the important role of this system in the maintenance of cardiovascular homeostasis.

19.
Chest ; 2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35841932

RESUMO

The management of pulmonary arterial hypertension (PAH) has become more complex in recent years due to increased pharmacotherapy options and longer patient survival with increasing numbers of comorbidities. As such, there are more opportunities for drug-drug interactions between PAH-targeted medications and medications potentially used to treat comorbid conditions. In this review, we provide an overview of pharmaceutical metabolism by cytochrome P450 and discuss important drug-drug interactions for the 14 FDA-approved medications for PAH in the nitric oxide, endothelin, and prostacyclin pathways. Among the targets in the NO pathway (sildenafil, tadalafil, and riociguat), important interactions with nitrates, protease inhibitors, and other phosphodiesterase inhibitors can cause profound hypotension. In the endothelin pathway, bosentan is associated with more drug interactions via CYP3A4 inhibition; macitentan and ambrisentan have less interactions of note. While the parenteral therapies in the prostacyclin pathway bypass significant liver metabolism and avoid drug interactions, selexipag and oral treprostinil may exhibit interactions with CYP2C8 inhibitors such as gemfibrozil and clopidogrel, which can raise drug levels. Finally, we provide a framework for identifying potential drug-drug interactions and avoiding errors.

20.
Histochem Cell Biol ; 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35849202

RESUMO

Zinc homeostasis is vital to immune and other organ system functions, yet over a quarter of the world's population is zinc deficient. Abnormal zinc transport or storage protein expression has been linked to diseases, such as cancer and chronic obstructive pulmonary disorder. Although recent studies indicate a role for zinc regulation in vascular functions and diseases, detailed knowledge of the mechanisms involved remains unknown. This study aimed to assess protein expression and localization of zinc transporters of the SLC39A/ZIP family (ZIPs) and metallothioneins (MTs) in human subcutaneous microvessels and to relate them to morphological features and expression of function-related molecules in the microvasculature. Microvessels in paraffin biopsies of subcutaneous adipose tissues from 14 patients undergoing hernia reconstruction surgery were analysed for 9 ZIPs and 3 MT proteins by MQCM (multifluorescence quantitative confocal microscopy). Zinc regulation proteins detected in human microvasculature included ZIP1, ZIP2, ZIP8, ZIP10, ZIP12, ZIP14 and MT1-3, which showed differential localization among endothelial and smooth muscle cells. ZIP1, ZIP2, ZIP12 and MT3 showed significantly (p < 0.05) increased immunoreactivities, in association with increased microvascular muscularization, and upregulated ET-1, α-SMA and the active form of p38 MAPK (Thr180/Tyr182 phosphorylated, p38 MAPK-P). These findings support roles of the zinc regulation system in microvascular physiology and diseases.

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