Imaging-based clusters in current smokers of the COPD cohort associate with clinical characteristics: The SubPopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) 11 Medical and Health Sciences 1102 Cardiorespiratory Medicine and Haematology

Background: Classification of COPD is usually based on the severity of airflow, which may not sensitively differentiate subpopulations. Using a multiscale imaging-based cluster analysis (MICA), we aim to identify subpopulations for current smokers with COPD. Methods: Among the SPIROMICS subjects, we analyzed computed tomography images at total lung capacity (TLC) and residual volume (RV) of 284 current smokers. Functional variables were derived from registration of TLC and RV images, e.g. functional small airways disease (fSAD%). Structural variables were assessed at TLC images, e.g. emphysema and airway wall thickness and diameter. We employed an unsupervised method for clustering. Results: Four clusters were identified. Cluster 1 had relatively normal airway structures; Cluster 2 had an increase of fSAD% and wall thickness; Cluster 3 exhibited a further increase of fSAD% but a decrease of wall thickness and airway diameter; Cluster 4 had a significant increase of fSAD% and emphysema. Clinically, Cluster 1 showed normal FEV1/FVC and low exacerbations. Cluster 4 showed relatively low FEV1/FVC and high exacerbations. While Cluster 2 and Cluster 3 showed similar exacerbations, Cluster 2 had the highest BMI among all clusters. Conclusions: Association of imaging-based clusters with existing clinical metrics suggests the sensitivity of MICA in differentiating subpopulations

The role of cardiac magnetic resonance imaging in the assessment of heart failure with preserved ejection fraction

Heart failure (HF) is a major cause of morbidity and mortality worldwide. Current classifications of HF categorize patients with a left ventricular ejection fraction of 50% or greater as HF with preserved ejection fraction or HFpEF. Echocardiography is the first line imaging modality in assessing diastolic function given its practicality, low cost and the utilization of Doppler imaging. However, the last decade has seen cardiac magnetic resonance (CMR) emerge as a valuable test for the sometimes challenging diagnosis of HFpEF. The unique ability of CMR for myocardial tissue characterization coupled with high resolution imaging provides additional information to echocardiography that may help in phenotyping HFpEF and provide prognostication for patients with HF. The precision and accuracy of CMR underlies its use in clinical trials for the assessment of novel and repurposed drugs in HFpEF. Importantly, CMR has powerful diagnostic utility in differentiating acquired and inherited heart muscle diseases presenting as HFpEF such as Fabry disease and amyloidosis with specific treatment options to reverse or halt disease progression. This state of the art review will outline established CMR techniques such as transmitral velocities and strain imaging of the left ventricle and left atrium in assessing diastolic function and their clinical application to HFpEF. Furthermore, it will include a discussion on novel methods and future developments such as stress CMR and MR spectroscopy to assess myocardial energetics, which show promise in unraveling the mechanisms behind HFpEF that may provide targets for much needed therapeutic interventions

The influence of menstrual cycle and oral contraceptive pill phases on the vascular response to hypoxia and sympathetic activation in healthy young women

INTRODUCTION: Hypoxia elicits peripheral vasodilation to preserve blood flow to metabolically active tissue and is accompanied by an increase in muscle sympathetic nervous system activity (MSNA). Prior data predominantly in male subjects, demonstrated the vasoconstrictive effects of MSNA are preserved in the setting of hypoxia. Because women are better able to attenuate or ignore the vasoconstrictive effects of MSNA at rest, we hypothesized women would exhibit greater hypoxic vasodilation (Aim 1). We further hypothesized women would attenuate the vasoconstrictive effects of sympathetic activation during both normoxia (Aim 2) and in the setting of hypoxia (Aim 3). The female sex hormone, estrogen, has been purported to be responsible for mediating the attenuated vasoconstriction to MSNA. As synthetic estrogen found in oral contraceptives is more biologically potent, we further hypothesized women taking oral contraceptives (OCPs) will better attenuate vasoconstriction relative to naturally cycling (NC) women during normoxia and hypoxia and this will be greatest during the high hormone phase of the pill or menstrual cycle. METHODS: Ten NC women, (25[plus or minus]1 yrs, 23[plus or minus]1 kg/m2) and ten women on OCPs, (24[plus or minus]1 yrs, 21[plus or minus]1 kg/m2) participated (N=20). Women were studied twice, once during the low hormone of the menstrual or pill cycle (menstrual cycle day, NC: 3.1[plus or minus]0.4; pill cycle day: OCP: 5.2[plus or minus]0.4) and once during the high hormone phase of the menstrual or pill cycle (menstrual cycle day, NC: 14.9[plus or minus]0.9; pill cycle day OCP: 16.6[plus or minus]0.6). Heart rate (ECG), blood pressure (finger photoplethysmography), forearm blood flow (venous occlusion plethysmography) and systemic blood flow (Modelflow) were continuously measured across three trials: 1) steady state hypoxia (80 percent SpO2); 2) sympathetic activation via two-minute cold pressor test (CPT); and 3) concomitant steady-state hypoxia and sympathetic activation via two-minute CPT. Forearm and systemic blood flow were normalized for blood pressure and expressed as forearm vascular conductance (FVC) and total vascular conductance (TVC), respectively. Data are reported from the last one minute of each trial. RESULTS: Hypoxia elicited a relative increase in FVC ( percent change from baseline) that was greater during the high hormone phase of the menstrual or pill cycle compared to the low hormone phase in both NC and women taking OCPs (p[less than]0.01). Sympathetic activation via CPT caused paradoxical local vasodilation in women taking OCPs, whereas NC women exhibited local vasoconstriction (p[less than]0.01). Concomitant hypoxia and sympathetic activation via CPT resulted in less systemic vasoconstriction compared to normoxia that was not different between groups or hormone phases (p=0.71). CONCLUSION: The hypoxic vasodilatory response is augmented during the high hormone phase of the menstrual or pill cycle. Exogenous estrogen found in OCPs may cause paradoxical vasodilation to sympathetic activation, whereas sympathetic activation in NC women with endogenous hormones elicits vasoconstriction. We observed a hypoxia-mediated attenuation of the systemic vasoconstrictor response to sympathetic activation in both NC women and women taking OCPs across all hormone phases. These data demonstrate the vascular response to autonomic and environmental stressors are influenced by female sex hormones and menstrual/pill cycle phase.Includes bibliographical references

Strategies used through new technologies to improve adherence to positive pressure devices in adult patients with obstructive sleep apnea. Systematic review of the literature and recommendations based on evidence synthesis

La apnea obstructiva del sueño (AOS) es una patología de alta prevalencia alrededor del mundo(1). El tratamiento está guiado por un abordaje multidisciplinar que permita corregir los eventos respiratorios, siendo necesario en una buena proporción de los casos el uso de dispositivos de presión positiva para tal fin (2). La terapia con presión positiva (PAP) ha demostrado beneficios en relación con mejoría de los síntomas de la enfermedad como la somnolencia diurna(3) y en mejoría de desenlaces clínicos como control de hipertensión arterial en poblaciones específicas (4), mejoría en la condición hemodinámica en pacientes con falla cardiaca(5), así como mayor éxito en el control de la fibrilación auricular (6). A pesar de los beneficios descritos es difícil lograr la adherencia adecuada al uso de la terapia PAP (7). Con el objetivo de mejorar esta adherencia las guías internacionales para el manejo de pacientes con apnea obstructiva del sueño recomiendan el uso de estrategias de educación, intervenciones comportamentales y apoyo basado en resolución de problemas que deben ser brindadas al paciente al inicio del tratamiento y durante el seguimiento (8,9). En los últimos años se han introducido nuevas tecnologías en el proceso de adaptación de los pacientes con AOS(10), siendo mayor el uso después del inicio de la pandemia de COVID19. Se desconoce la utilidad de estas herramientas para lograr una buena adherencia de los pacientes con AOS a los dispositivos de presión positiva.1. Título 4 2. Resumen 4 3. Abstract 6 4. Planteamiento del problema 8 5. Marco teórico 9 6. Estado del arte 15 7. Objetivo General 17 8. Objetivos Específicos 18 9. Metodología 19 9.1 Formulación de las preguntas clínicas 19 9.2 Desarrollo de preguntas PICO 19 9.3 Fuentes de información 21 9.4 Criterios de selección 21 9.5 Estrategias de búsqueda de la literatura 22 9.6 Proceso de selección de los estudios y recolección de datos 22 9.7 Evaluación del riesgo de sesgos 23 9.8 Análisis y síntesis 23 10.Resultados 24 10.1 Selección del cuerpo de la evidencia 24 10.2 Extracción de datos 26 10.3 Evaluación de riesgo de sesgos 34 10.4 Efectos de las intervenciones 35 11. Evaluación del cuerpo de la evidencia y generación de 43 recomendaciones 12. Bibliografía 50 13. Anexos 57MaestríaObstructive sleep apnea (OSA) is a highly prevalent pathology around the world (1). The treatment is guided by a multidisciplinary approach that allows correcting respiratory events, being necessary in many cases the use of devices of positive pressure for this purpose (2). Positive pressure therapy (PAP) has shown benefits in relation to improvement of disease symptoms such as daytime sleepiness (3) and improvement of clinical outcomes such as control of arterial hypertension in specific populations (4), improvement in the condition hemodynamics in patients with heart failure (5), as well as greater success in the control of atrial fibrillation (6). Despite the benefits described, it is difficult to achieve adequate adherence to the use of PAP therapy (7). With the aim of improving this adherence, the international guidelines for the management of patients with obstructive sleep apnea recommend the use of educational strategies, behavioral interventions and support based on problem solving that should be provided to the patient at the beginning of treatment and during follow-up (8,9). In recent years, new technologies have been introduced in the adaptation process of patients with OSA (10), with greater use after the onset of the COVID19 pandemic. The usefulness of these tools in achieving good adherence of OSA patients to positive pressure devices is unknown

Caracterização da função cardiovascular em modelo murino de Mucopolissacaridose tipo II

A mucopolissacaridose tipo II (MPS II) ou síndrome de Hunter é uma doença genética ligada ao X, causada por mutações no gene IDS que codifica a enzima Iduronato-2-sulfatase (IDS). A enzima IDS é responsável pela degradação dos glicosaminoglicanos (GAGs) lisossomais, heparan sulfato (HS) e dermatan sulfato (DS). A deficiência da enzima leva ao acúmulo progressivo de GAGs nos diversos tipos celulares, afetando a estrutura e a função de múltiplos órgãos e tecidos. Os desfechos cardiovasculares são comumente observados em pacientes com MPS II, sendo uma das principais causas de morbimortalidade entre estes pacientes. Tendo em vista as várias alterações cardíacas apresentadas e o fato de que as terapias existentes possuem baixa eficácia sobre os danos resultantes da doença no sistema cardiovascular, a caracterização dessas modificações em modelos animais tem grande relevância. O modelo animal murino de MPS II reproduz o fenótipo mais grave da doença, o que corresponde à forma neuronopata da MPS II. Os camundongos MPS II (knockout para enzima IDS) têm sido amplamente utilizados para avaliar a ocorrência de distúrbios em órgãos e tecidos afetados pela deficiência da enzima, como doenças neurológicas e esqueléticas. Entretanto, as alterações cardiovasculares e sua progressão, nestes animais, não são totalmente conhecidas. Portanto, o objetivo deste trabalho foi caracterizar as alterações cardiovasculares presentes no modelo animal de MPS II em diferentes momentos, explorando possíveis mecanismos fisiopatológicos. Para tanto, foram realizadas análises bioquímicas, histológicas e funcionais do músculo cardíaco e principais valvas e artérias. Foram encontradas anormalidades funcionais nos tempos avaliados, 6, 8 e 10 meses de idade que incluíram dilatação cardíaca e aórtica e também redução do débito cardíaco e da Fração de Ejeção. Análises histológicas mostraram quebra de elastina na artéria aorta, desarranjo das fibras musculares e presença de vacúolos no tecido cardíaco. As análises bioquímicas mostraram ainda que a atividade de catepsina B, uma protease lisossomal, bem como outras catepsinas, estavam aumentadas no tecido cardíaco. Os resultados deste trabalho levaram a conclusão de que os desfechos cardiovasculares da MPS II podem ser observados a partir dos 6 meses de idade e são progressivos. Além disso, o modelo mimetiza os desfechos cardiovasculares da MPS II, semelhantes ao observado em seres humanos portadores da doença.Mucopolysaccharidosis type II (MPS II), or Hunter syndrome is an X-linked genetic disorder caused by mutations in the IDS gene, that codifies the Iduronate-2-sulfatase enzyme (IDS). The cause of MPS II is the IDS enzyme deficiency, involved in the degradation of glycosaminoglycans (GAGs) heparan and dermatan sulfate. This deficiency leads to progressive GAGs accumulation in different cell types, affecting multiple organs and tissues. Cardiovascular outcomes are commonly observed in patients with MPS II, being one of the main causes of morbidity and mortality in adults. In view of the various cardiac alterations presented in MPS II and the fact that existing therapies have low efficacy on the damage resulting from the disease in the cardiovascular system, the characterization of these modifications in animal models is of great relevance. MPS II (IDS knockout) mice have been widely used to assess the occurrence of disorders in organs and tissues affected by IDS enzyme deficiency, such as neurological and skeletal diseases, however, the follow up of the cardiovascular manifestations progression in these animals still is not fully known. Therefore, the goal of this study was to characterize the cardiovascular abnormalities in the MPS II mouse model at different time points. Biochemical, histological, and functional analyzes of the cardiac muscle and main valves and arteries were performed. Functional abnormalities were found at 6, 8 and 10 months of age in MPS II mice, which included cardiac and aortic dilatation, reduced cardiac output, and decreased ejection fraction. Histological analyzes showed a breakdown of elastin in the aorta artery, disarrangement of fibers and presence of vacuoles in the cardiac tissue. Biochemical analyzes showed that cathepsin B, a lysosomal protease, was increased in the cytosolic compartment outside cardiomyocyte lysosomes. In conclusion, we have demonstrated that the deleterious cardiovascular outcomes can be observed from 6 months of age and are progressive. In addition, the animal model used was mimetic to the effects and outcomes of MPS II observed in humans with regard to cardiovascular changes

Regenerative Pharmacology for COPD

Regenerative pharmacology for COPDXinhui Wu investigated novel therapeutic targets for chronic obstructive pulmonary disease (COPD). COPD is one of the most common lung diseases worldwide. It is characterized by airflow obstruction in the lung that causes breathing difficulties, cough, mucus (sputum) production and wheezing. The main causes of COPD are tobacco smoke and air pollution. They key problem in COPD is defective tissue repair, causing chronic bronchitis and emphysema, which are the two most common conditions resulting from airway and/or alveolar abnormalities. However, the current treatments for COPD can only reduce the symptoms and do not reverse or slow down the progression of the disease. Ms. Wu focused her research on the mechanisms underlying cigarette smoke and air pollution-induced dysfunctional lung repair and discovered several potential regenerative drug targets beneficial to lung repair in COPD.By using novel tools, such as 3D organoids and the precision-cut-lung slices (PCLS), to model different pathological conditions, Ms. Wu identified that cigarette smoke and air pollution both cause defective lung repair, but with different mechanisms. Molecular pathways such WNT-5A/B signaling, TGF- signaling, growth factors related signaling, cell death related signaling and circadian clock signaling all appear to play fundamental roles in the defective functions of alveolar epithelial progenitors. Several pharmacological strategies, such as ROCK inhibitors; antioxidants such as NAC and MitoQ; the analogues of PGE2 and PGI2 were discovered as potential regenerative therapeutic targets in lung repair for COPD