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RATIONALE: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) cause right ventricular dysfunction which can impact other solid organs. However, the profiles and consequences of hepatic injury due to PAH and CTEPH have not been well-studied. OBJECTIVES: We aimed to identify underlying patterns of liver injury in a cohort of PAH and CTEPH patients enrolled in 15 randomized clinical trials conducted between 1998 and 2014. METHODS: We used unsupervised machine learning to identify liver injury clusters in 13 trials and validated the findings in two additional trials. We then determined whether these liver injury clusters were associated with clinical outcomes or treatment effect heterogeneity. MEASUREMENTS AND MAIN RESULTS: Our training dataset included 4,219 patients and our validation dataset included 1,756 patients with serum total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin data. Using k-means clustering, we identified phenotypes with no liver injury, hepatocellular injury, cholestatic injury, and combined injury patterns. Patients in the cholestatic injury liver cluster had the shortest time to clinical worsening and the highest risk of mortality. The cholestatic injury group also experienced the greatest placebo-corrected treatment effect on six-minute walk distance. Randomization to the experimental arm transitioned patients to a healthier liver status. CONCLUSIONS: Liver injury was associated with adverse outcomes in patients with PAH and CTEPH. Randomization to active treatment had beneficial effects on liver health compared to placebo. The role of liver disease (often subclinical) in determining outcomes warrants prospective studies.
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RATIONALE: Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models. OBJECTIVES: We aimed to determine whether anastrozole improved six-minute walk distance (6MWD) at six months in pulmonary arterial hypertension (PAH). METHODS: We performed a randomized, double-blind, placebo-controlled Phase II clinical trial of anastrozole in subjects with PAH at seven centers. Eighty-four post-menopausal women and men with PAH were randomized in a 1:1 ratio to receive anastrozole 1 mg or placebo by mouth daily, stratified by sex using permuted blocks of variable sizes. All subjects and study staff were masked. The primary outcome was the change from baseline in 6MWD at six months. Using intent-to-treat analysis, we estimated the treatment effect of anastrozole using linear regression models adjusted for sex and baseline 6MWD. Assuming 10% loss to follow-up, we anticipated having 80% power to detect a difference in the change in 6MWD of 22 meters. MEASUREMENTS AND MAIN RESULTS: Forty-one subjects were randomized to placebo and 43 to anastrozole and all received the allocated treatment. Three subjects in the placebo group and two in the anastrozole group discontinued study drug. There was no significant difference in the change in 6MWD at six months (placebo-corrected treatment effect -7.9 m, 95%CI -32.7 - 16.9, p = 0.53). There was no difference in adverse events between the groups. CONCLUSIONS: Anastrozole did not show a significant effect on 6MWD compared to placebo in post-menopausal women and men with PAH. Anastrozole was safe and did not show adverse effects. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT03229499.
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BACKGROUND AND AIMS: Effective therapies that target three main signalling pathways are approved to treat pulmonary arterial hypertension (PAH). However, there are few large patient-level studies that compare the effectiveness of these pathways. The aim of this analysis was to compare the effectiveness of the treatment pathways in PAH and to assess treatment heterogeneity. METHODS: A network meta-analysis was performed using individual participant data of 6811 PAH patients from 20 Phase III randomized clinical trials of therapy for PAH that were submitted to the US Food and Drug Administration. Individual drugs were grouped by the following treatment pathways: endothelin, nitric oxide, and prostacyclin pathways. RESULTS: The mean (±standard deviation) age of the sample was 49.2 (±15.4) years; 78.4% were female, 59.7% had idiopathic PAH, and 36.5% were on background PAH therapy. After covariate adjustment, targeting the endothelin + nitric oxide pathway {ß: 43.7â m [95% confidence interval (CI): 32.9, 54.4]}, nitric oxide pathway [ß: 29.4â m (95% CI: 22.6, 36.3)], endothelin pathway [ß: 25.3â m (95% CI: 19.8, 30.8)], and prostacyclin pathway [oral/inhaled ß: 19.1â m (95% CI: 14.2, 24.0), intravenous/subcutaneous ß: 24.4â m (95% CI: 15.1, 33.7)] significantly increased 6â min walk distance at 12 or 16 weeks compared with placebo. Treatments also significantly reduced the likelihood of having clinical worsening events. There was significant heterogeneity of treatment effects by age, body mass index, hypertension, diabetes, and coronary artery disease. CONCLUSIONS: Drugs targeting the three traditional treatment pathways significantly improve outcomes in PAH, with significant treatment heterogeneity in patients with some comorbidities. Randomized clinical trials are warranted to identify the most effective treatment strategies in a personalized approach.
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Antihipertensivos , Humanos , Antihipertensivos/uso terapéutico , Femenino , Persona de Mediana Edad , Epoprostenol/uso terapéutico , Metaanálisis en Red , Ensayos Clínicos Controlados Aleatorios como Asunto , Óxido Nítrico/metabolismo , Masculino , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Ensayos Clínicos Fase III como Asunto , Endotelinas/metabolismo , Hipertensión Pulmonar/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Rationale: The 6-minute-walk distance (6MWD) is an important clinical and research metric in pulmonary arterial hypertension (PAH); however, there is no consensus about what minimal change in 6MWD is clinically significant. Objectives: We aimed to determine the minimal clinically important difference in the 6MWD. Methods: We performed a meta-analysis using individual participant data from eight randomized clinical trials of therapy for PAH submitted to the U.S. Food and Drug Administration to derive minimal clinically important differences in the 6MWD. The estimates were externally validated using the Pulmonary Hypertension Association Registry. We anchored the change in 6MWD to the change in the Medical Outcomes Survey Short Form physical component score. Measurements and Main Results: The derivation (clinical trial) and validation (Pulmonary Hypertension Association Registry) samples were comprised of 2,404 and 537 adult patients with PAH, respectively. The mean ± standard deviation age of the derivation sample was 50.5 ± 15.2 years, and 1,849 (77%) were female, similar to the validation sample. The minimal clinically important difference in the derivation sample was 33 meters (95% confidence interval, 27-38), which was almost identical to that in the validation sample (36 m [95% confidence interval, 29-43]). The minimal clinically important difference did not differ by age, sex, race, pulmonary hypertension etiology, body mass index, use of background therapy, or World Health Organization functional class. Conclusions: We estimated a 6MWD minimal clinically important difference of approximately 33 meters for adults with PAH. Our findings can be applied to the design of clinical trials of therapies for PAH.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Adulto , Humanos , Femenino , Persona de Mediana Edad , Anciano , Masculino , Hipertensión Pulmonar/etiología , Hipertensión Arterial Pulmonar/complicaciones , Diferencia Mínima Clínicamente Importante , Hipertensión Pulmonar Primaria Familiar/complicaciones , CaminataRESUMEN
BACKGROUND: It is currently unknown if disease severity modifies response to therapy in pulmonary arterial hypertension (PAH). We aimed to explore if disease severity, as defined by established risk-prediction algorithms, modified response to therapy in randomised clinical trials in PAH. METHODS: We performed a meta-analysis using individual participant data from 18 randomised clinical trials of therapy for PAH submitted to the United States Food and Drug Administration to determine if predicted risk of 1-year mortality at randomisation modified the treatment effect on three outcomes: change in 6-min walk distance (6MWD), clinical worsening at 12â weeks and time to clinical worsening. RESULTS: Of 6561 patients with a baseline US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL 2.0) score, we found that individuals with higher baseline risk had higher probabilities of clinical worsening but no difference in change in 6MWD. We detected a significant interaction of REVEAL 2.0 risk and treatment assignment on change in 6MWD. For every 3-point increase in REVEAL 2.0 score, there was a 12.49â m (95% CI 5.86-19.12â m; p=0.001) greater treatment effect in change in 6MWD. We did not detect a significant risk by treatment interaction on clinical worsening with most of the risk-prediction algorithms. CONCLUSIONS: We found that predicted risk of 1-year mortality in PAH modified treatment effect as measured by 6MWD, but not clinical worsening. Our findings highlight the importance of identifying sources of treatment heterogeneity by predicted risk to tailor studies to patients most likely to have the greatest treatment response.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Humanos , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar Primaria Familiar/tratamiento farmacológico , Resultado del Tratamiento , Antihipertensivos/uso terapéuticoRESUMEN
The factors associated with persistent hypoxemia after pulmonary embolus (PE) are not well understood. Predicting the need for oxygen post discharge at the time of diagnosis using available CT imaging will enable better discharge planning. To examine the relationship between CT derived imaging markers (automated computation of arterial small vessel fraction, pulmonary artery diameter to aortic diameter ratio (PA:A), right to left ventricular diameter ratio (RV:LV) and new oxygen requirement at the time of discharge in patients diagnosed with acute intermediate-risk PE. CT measurements were obtained in a retrospective cohort of patients with acute-intermediate risk PE admitted to Brigham and Women's Hospital between 2009 and 2017. Twenty one patients without a history of lung disease requiring home oxygen and 682 patients without discharge oxygen requirements were identified. There was an increased median PA:A ratio (0.98 vs. 0.92, p = 0.02) and arterial small vessel fraction (0.32 vs. 0.39, p = 0.001) in the oxygen-requiring group], but no difference in the median RV:LV ratio (1.20 vs. 1.20, p = 0.74). Being in the upper quantile for the arterial small vessel fraction was associated with decreased odds of oxygen requirement (OR 0.30 [0.10-0.78], p = 0.02). Loss of arterial small vessel volume as measured by arterial small vessel fraction and an increase in the PA:A ratio at the time of diagnosis were associated with the presence of persistent hypoxemia on discharge in acute intermediate-risk PE.
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Embolia Pulmonar , Disfunción Ventricular Derecha , Humanos , Femenino , Tomografía Computarizada por Rayos X/métodos , Estudios Retrospectivos , Cuidados Posteriores , Valor Predictivo de las Pruebas , Alta del Paciente , Hipoxia , Oxígeno , Enfermedad AgudaRESUMEN
Exosomes are nanovesicles secreted by cells and contain various molecules including protein, lipid, and DNA/RNA. They are crucial mediators of the intercellular communication and serve as promising vehicles for drug delivery and gene therapy. Recently, accumulating evidence suggests that microRNAs (miRNAs) may serve as new and potentially powerful targets for therapeutic interventions against various human diseases. However, steadily and effectively delivering miRNA mimics or inhibitors to target cells remains a major obstacle. To enhance the efficacy of exosome-mediated delivery of miRNA molecules, it is crucial to develop a convenient and efficient method to enrich specific miRNAs or antisense oligos in isolated exosomes. Here we report a novel method to prepare specific miRNA molecule-loaded exosomes. Using a modified calcium chloride-mediated transfection method, we successfully enhanced the designated miRNA mimics or inhibitors in isolated exosomes directly, instead of transfecting their mother cells. We also compared this method with direct transfection of exosomes using electroporation. Both methods confirmed that exosomes can serve as cargos to deliver a robustly increased amount of selected miRNA mimic(s) or inhibitor(s) to the recipient cells. Delivery of these miRNA molecule enriched-exosomes subsequently results in highly efficient overexpression or deletion of the designated miRNAs in the recipient cells both in vivo and in vitro. Additionally, we confirmed that exosome-delivered miRNA mimics or inhibitors are functional in the recipient cells. Collectively, we developed a novel protocol to conveniently manipulate exosomal miRNAs with high efficiency and successfully deliver the exosomal miRNA molecules to recipient cells.
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Exosomas/genética , MicroARNs/genética , Animales , Secuencia de Bases , Electroporación , Femenino , Técnicas de Transferencia de Gen , Humanos , Macrófagos Alveolares/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Modelos Biológicos , Células RAW 264.7RESUMEN
OBJECTIVE: Prior work has described the relationship between pulmonary vascular pruning on computed tomography (CT) scans and metrics of right-sided heart dysfunction in smokers. In this analysis, we sought to look at pruning on a lobar level, as well as examine the effect of the arterial and venous circulation on this association. METHODS: Automated vessel segmentation applied to noncontrast CT scans from the COPDGene Study in 24 subjects with cardiac magnetic resonance imaging scans was used to create a blood volume distribution profile. These vessels were then manually tracked to their origin and characterized as artery or vein. RESULTS: Assessment of pruning on a lobar level revealed associations between pruning and right ventricular function previously not observed on a global level. The right ventricular mass index, the right ventricular end-systolic volume index, and pulmonary arterial-to-aorta ratio were associated with both arterial and venous pruning, whereas right ventricular ejection fraction was associated with only arterial pruning. CONCLUSIONS: Lobar assessment and segmentation of the parenchymal vasculature into arterial and venous components provide additional information about the relationship between loss of vasculature on CT scans and right ventricular dysfunction.
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Arteria Pulmonar/patología , Venas Pulmonares/patología , Fumar/epidemiología , Fumar/patología , Disfunción Ventricular Derecha/epidemiología , Disfunción Ventricular Derecha/patología , Boston/epidemiología , Femenino , Humanos , Imagen por Resonancia Cinemagnética/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Imagen Multimodal/métodos , Prevalencia , Arteria Pulmonar/diagnóstico por imagen , Venas Pulmonares/diagnóstico por imagen , Reproducibilidad de los Resultados , Factores de Riesgo , Sensibilidad y Especificidad , Disfunción Ventricular Derecha/diagnóstico por imagenRESUMEN
Rationale: Pulmonary arterial hypertension (PAH) is a progressive disease with manifestations including right atrial enlargement, right ventricular dysfunction, dilation, and hypertrophy. Electrocardiography (ECG) is a noninvasive, inexpensive test that is routinely performed in clinical settings. Prior studies have described separate abnormal findings in the electrocardiograms of patients with PAH. However, the role of composite ECG findings reflective of right heart disease (RHD) for risk stratification, clinical trial enrichment, and management of patients with PAH has not been explored. Objectives: To describe a pattern of RHD on ECG in patients with PAH and to investigate the association of this pattern with clinical measures of disease severity and outcomes. Methods: We harmonized individual participant data from 18 phase III randomized clinical trials of therapies for PAH (1998-2013) submitted to the U.S. Food and Drug Administration. RHD was defined as the presence of right ventricular hypertrophy, right axis deviation, right atrial enlargement, or right bundle branch block on ECG. Random effects linear regression, multilevel ordinal regression (cumulative link model), and Cox proportional hazards models were used to assess the association of RHD by ECG with 6-minute walk distance (6MWD), World Health Organization (WHO) functional class, and clinical worsening after a priori adjustment for age, sex, body mass index, and PAH etiology. Effect modification of treatment and ECG abnormalities was assessed by including an interaction term. Results: A total of 4,439 patients had baseline ECG, and 68% of patients had evidence of RHD. RHD on ECG was associated with higher pulmonary vascular resistance (P < 0.001) and higher mean pulmonary artery pressures (P < 0.001). Patients with RHD on ECG had 10 meters shorter 6MWD (P = 0.005) and worse WHO functional class (P < 0.001) at baseline. RHD on baseline ECG was associated with increased risk of clinical worsening (hazard ratio, 1.42; 95% confidence interval; 1.21, 1.67; P < 0.001). Patients with RHD had greater treatment effect in terms of 6MWD, WHO functional class, and time to clinical worsening than those without (P for interaction = 0.03, 0.001, and 0.03, respectively). Conclusions: RHD by ECG may be associated with worse outcomes and potentially greater treatment effect. Electrocardiograms could be an inexpensive, widely available noninvasive method to enrich clinical trial populations in PAH.
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Electrocardiografía , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Femenino , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Hipertrofia Ventricular Derecha/fisiopatología , Hipertrofia Ventricular Derecha/diagnóstico , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/diagnóstico , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/diagnóstico , Adulto , Anciano , Ensayos Clínicos Fase III como Asunto , Prueba de Paso , Atrios Cardíacos/fisiopatologíaRESUMEN
Knowledge of what outcomes are most meaningful to pulmonary arterial hypertension (PAH) stakeholders is limited. In this qualitative study, patients and clinicians endorsed personalized physical activity, symptoms, and psychosocial well-being as key outcomes to assess PAH treatment response, yet few are routinely measured in PAH clinical trials.
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Rationale: Sex-based differences in pulmonary arterial hypertension (PAH) are known, but the contribution to disease measures is understudied. Objectives: We examined whether sex was associated with baseline 6-minute-walk distance (6MWD), hemodynamics, and functional class. Methods: We conducted a secondary analysis of participant-level data from randomized clinical trials of investigational PAH therapies conducted between 1998 and 2014 and provided by the U.S. Food and Drug Administration. Outcomes were modeled as a function of an interaction between sex and age or sex and body mass index (BMI), respectively, with generalized mixed modeling. Results: We included a total of 6,633 participants from 18 randomized clinical trials. A total of 5,197 (78%) were female, with a mean age of 49.1 years and a mean BMI of 27.0 kg/m2. Among 1,436 males, the mean age was 49.7 years, and the mean BMI was 26.4 kg/m2. The most common etiology of PAH was idiopathic. Females had shorter 6MWD. For every 1 kg/m2 increase in BMI for females, 6MWD decreased 2.3 (1.6-3.0) meters (P < 0.001), whereas 6MWD did not significantly change with BMI in males (0.31 m [-0.30 to 0.92]; P = 0.32). Females had lower right atrial pressure (RAP) and mean pulmonary artery pressure, and higher cardiac index than males (all P < 0.03). Age significantly modified the sex by RAP and mean pulmonary artery pressure relationships. For every 10-year increase in age, RAP was lower in males (0.5 mm Hg [0.3-0.7]; P < 0.001), but not in females (0.13 [-0.03 to 0.28]; P = 0.10). There was a significant decrease in pulmonary vascular resistance (PVR) with increasing age regardless of sex (P < 0.001). For every 1 kg/m2 increase in BMI, there was a 3% decrease in PVR for males (P < 0.001), compared with a 2% decrease in PVR in females (P < 0.001). Conclusions: Sexual dimorphism in subjects enrolled in clinical trials extends to 6MWD and hemodynamics; these relationships are modified by age and BMI. Sex, age, and body size should be considered in the evaluation and interpretation of surrogate outcomes in PAH.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Humanos , Femenino , Masculino , Persona de Mediana Edad , Caracteres Sexuales , Ensayos Clínicos Controlados Aleatorios como Asunto , Hipertensión Pulmonar Primaria Familiar , HemodinámicaRESUMEN
Background: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are disorders of the pulmonary vasculature that cause right ventricular dysfunction. Systemic consequences of right ventricular dysfunction include damage to other solid organs, such as the liver. However, the profiles and consequences of hepatic injury due to PAH and CTEPH have not been well-studied. Methods: We aimed to identify underlying patterns of liver injury in a cohort of PAH and CTEPH patients enrolled in 15 randomized clinical trials conducted between 1998 and 2012. We used unsupervised machine learning to identify liver injury clusters in 13 trials and validated the findings in two additional trials. We then determined whether these liver injury clusters were associated with clinical outcomes or treatment effect heterogeneity. Results: Our training dataset included 4,219 patients and our validation dataset included 1,756 patients with complete liver laboratory panels (serum total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin). Using k-means clustering paired with factor analysis, we identified four unique liver phenotypes (no liver injury, hepatocellular injury, cholestatic injury, and combined injury patterns). Patients in the cholestatic injury liver cluster had the shortest time to clinical worsening and highest chance of worsening World Health Organization functional class. Randomization to the experimental arm was associated with a transition to healthier liver clusters compared to randomization to the control arm. The cholestatic injury group experienced the greatest placebo-corrected treatment benefit in terms of six-minute walk distance. Conclusions: Liver injury patterns were associated with adverse outcomes in patients with PAH and CTEPH. Randomization to active treatment of pulmonary hypertension in these clinical trials had beneficial effects on liver health compared to placebo. The independent role of liver disease (often subclinical) in determining outcomes warrants prospective studies of the clinical utility of liver phenotyping for PAH prognosis and contribution to clinical disease.
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Rationale: Limitation of physical activity is a common presenting complaint for patients with pulmonary arterial hypertension (PAH). Physical activity is thought to be determined by cardiopulmonary function, yet there are limited data that investigate this relationship. Objectives: We aimed to study the relationship between right ventricular function and daily activity and its impact on health-related quality of life (HRQoL) in PAH. Methods: Baseline data for 55 patients enrolled in PHANTOM (Pulmonary Hypertension and Anastrozole), an ongoing multicenter randomized controlled trial of anastrozole in PAH, were used. Postmenopausal women and men were eligible and underwent 6-minute walk testing and echocardiography and completed HRQoL questionnaires. Each patient wore an accelerometer for 7 days. Multivariable linear regression models were used to study the association between tricuspid annular plane systolic excursion (TAPSE) and vector magnitude counts, and between daily activity and HRQoL. Principal component analysis and K-means clustering were used to identify activity-based phenotypes. K-nearest neighbors classification was applied to an independent cross-sectional cohort from the University of Pennsylvania. Results: The mean age of patients in PHANTOM was 61 years. In total, 67% were women with idiopathic PAH as the most common etiology. A 0.4-cm increase in TAPSE was associated with an increase in daily vector magnitude counts (ß: 34,000; 95% confidence interval [CI], 900-67,000; P = 0.004) after adjustment for age, sex, body mass index, etiology of PAH, and wear time. A 1-SD increase in vector magnitude counts was associated with higher 6-minute walk distance (ß: 56.1 m; 95% CI, 28.6-83.7; P < 0.001) and lower emPHasis-10 scores (ß: -3.3; 95% CI, 0.3-6.4; P = 0.03). Three activity phenotypes, low, medium, and high, were identified. The most active phenotype had greater 6-minute walk distances (P = 0.001) and lower emPHasis-10 scores (P = 0.009) after adjustment for age, sex, body mass index, World Health Organization functional class, and parenteral prostacyclin use. Phenotypes of physical activity were reproduced in the second cohort and were independently associated with 6-minute walk distance. Conclusions: Better right ventricular systolic function was associated with increased levels of activity in PAH. Increased daily activity was associated with greater 6-minute walk distance and better HRQoL. Distinct activity-based phenotypes may be helpful in risk stratification of patients with PAH or provide novel endpoints for clinical trials.
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Hipertensión Arterial Pulmonar , Estudios Transversales , Ejercicio Físico , Femenino , Humanos , Evaluación de Resultado en la Atención de Salud , Calidad de VidaRESUMEN
Rationale: The population of patients with pulmonary arterial hypertension (PAH) has evolved over time from predominantly young White women to an older, more racially diverse and obese population. Whether these changes are reflected in clinical trials is not known. Objectives: To determine secular and regional trends among PAH trial participants. Methods: We performed a pooled cohort analysis using harmonized data from phase III clinical trials of PAH therapies submitted to the U.S. Food and Drug Administration. We used mixed-effects linear and logistic regression to assess regional differences in participant age, sex, body habitus, and hemodynamics over time. Results: A total of 6,599 participants were enrolled in 18 trials between 1998 and 2013; 78% were female. The mean age of participants in North America, Europe, and Latin America at the time of study start increased by 2.09 (95% confidence interval [CI], 0.67-3.51), 1.62 (95% CI, 0.24-3.00), and 4.75 (95% CI, 2.29-7.21) years per 5 years, respectively (P = 0.01). Body mass index at the time of study start increased by 0.72 kg/m2 per 5 years (95% CI, 0.44-0.99; P < 0.001) across all regions. Eighty-five percent of participants in early studies were non-Hispanic White, but this decreased over time to 70%. Ninety-seven percent of Asians and 74% of Hispanics in the sample were recruited from Asia and Latin America. Conclusions: Patients enrolled in more recent PAH therapy trials are older and more obese, mirroring the changing epidemiology of observational cohorts. However, these trends varied by geographic region. PAH cohorts remain predominantly female, presenting challenges for generalizability to male patients. Although the proportion of non-White participants increased over time, this was primarily through recruitment in Asia and Latin America.
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Hipertensión Arterial Pulmonar , Estudios de Cohortes , Europa (Continente)/epidemiología , Hipertensión Pulmonar Primaria Familiar , Femenino , Humanos , Masculino , Obesidad , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/epidemiología , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Obesity is increasingly prevalent in pulmonary arterial hypertension (PAH) but is associated with improved survival, creating an "obesity paradox" in PAH. It is unknown if the improved outcomes could be attributable to obese patients deriving a greater benefit from PAH therapies. RESEARCH QUESTION: Does BMI modify treatment effectiveness in PAH? STUDY DESIGN AND METHODS: Using individual participant data, a meta-analysis was conducted of phase III, randomized, placebo-controlled trials of treatments for PAH submitted for approval to the U.S. Food and Drug Administration from 2000 to 2015. Primary outcomes were change in 6-min walk distance (6MWD) and World Health Organization (WHO) functional class. RESULTS: A total of 5,440 participants from 17 trials were included. Patients with overweight and obesity had lower baseline 6MWD and were more likely to be WHO functional class III or IV. Treatment was associated with a 27.01-m increase in 6MWD (95% CI, 21.58-32.45; P < .001) and lower odds of worse WHO functional class (OR, 0.58; 95% CI, 0.48-0.70; P < .001). For every 1 kg/m2 increase in BMI, 6MWD was reduced by 0.66 m (P = .07); there was no significant effect modification of treatment response in 6MWD according to BMI (P for interaction = .34). Higher BMI was not associated with odds of WHO functional class at end of follow-up; however, higher BMI attenuated the treatment response such that every 1 kg/m2 increase in BMI increased odds of worse WHO functional class by 3% (OR, 1.03; P for interaction = .06). INTERPRETATION: Patients with overweight and obesity had lower baseline 6MWD and worse WHO functional class than patients with normal weight with PAH. Higher BMI did not modify the treatment response for change in 6MWD, but it attenuated the treatment response for WHO functional class. PAH trials should include participants representative of all weight groups to allow for assessment of treatment heterogeneity and mechanisms.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Antihipertensivos/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Hipertensión Pulmonar Primaria Familiar , Humanos , Obesidad/complicaciones , Obesidad/epidemiología , Sobrepeso , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
BACKGROUND: In acute pulmonary embolism, chest computed tomography angiography derived metrics, such as the right ventricle (RV): left ventricle ratio are routinely used for risk stratification. Paucity of intraparenchymal blood vessels has previously been described, but their association with clinical biomarkers and outcomes has not been studied. We sought to determine if small vascular volumes measured on computed tomography scans were associated with an abnormal RV on echocardiography and mortality. We hypothesized that decreased small venous volume would be associated with greater RV dysfunction and increased mortality. METHODS: A retrospective cohort of patients with intermediate risk pulmonary embolism admitted to Brigham and Women's Hospital between 2009 and 2017 was assembled, and clinical and radiographic data were obtained. We performed 3-dimensional reconstructions of vasculature to assess intraparenchymal vascular volumes. Statistical analyses were performed using multivariable regression and cox proportional hazards models, adjusting for age, sex, lung volume, and small arterial volume. RESULTS: Seven hundred twenty-two subjects were identified of whom 573 had documented echocardiography. A 50% reduction in small venous volume was associated with an increased risk of RV dilation (relative risk: 1.38 [95% CI, 1.18-1.63], P<0.001), RV dysfunction (relative risk: 1.62 [95% CI, 1.36-1.95], P<0.001), and RV strain (relative risk: 1.67 [95% CI, 1.37-2.04], P<0.001); increased cardiac biomarkers, and higher 30-day and 90-day mortality (hazard ratio: 2.50 [95% CI, 1.33-4.67], P=0.004 and hazard ratio: 1.84 [95% CI, 1.11-3.04], P=0.019, respectively). CONCLUSIONS: Loss of small venous volume quantified from computed tomography angiography is associated with increased risk of abnormal RV on echocardiography, abnormal cardiac biomarkers, and higher risk of 30- and 90-day mortality. Small venous volume may be a useful marker for assessing disease severity in acute pulmonary embolism.
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Ventrículos Cardíacos/diagnóstico por imagen , Arteria Pulmonar/diagnóstico por imagen , Embolia Pulmonar/mortalidad , Medición de Riesgo/métodos , Disfunción Ventricular Derecha/fisiopatología , Enfermedad Aguda , Anciano , Angiografía por Tomografía Computarizada , Ecocardiografía/métodos , Femenino , Estudios de Seguimiento , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Arteria Pulmonar/fisiopatología , Embolia Pulmonar/complicaciones , Embolia Pulmonar/fisiopatología , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Tasa de Supervivencia/tendencias , Estados Unidos/epidemiología , Disfunción Ventricular Derecha/diagnóstico , Disfunción Ventricular Derecha/etiologíaRESUMEN
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, morbid, potentially curable subtype of pulmonary hypertension that negatively impacts health-related quality of life (HRQoL). Little is known about differences in HRQoL and hospitalization between CTEPH patients and idiopathic pulmonary arterial hypertension (IPAH) patients. Using multivariable linear regression and mixed effects models, we examined differences in HRQoL assessed by emPHasis-10 (E10) and SF-12 between CTEPH and IPAH patients in the Pulmonary Hypertension Association Registry, a prospective multicenter cohort of patients newly evaluated at a Pulmonary Hypertension Care Center. Multivariable negative binomial regression models were used to estimate incidence rate ratios (IRR) for hospitalization amongst the two groups. We included 461 IPAH patients and 169 CTEPH patients. Twenty-one percent of CTEPH patients underwent pulmonary thromboendarterectomy (PTE) before the end of follow-up. At baseline, patients with CTEPH had significantly worse HRQoL (higher E10 scores) (ß 2.83, SE 1.11, p = 0.01); however, differences did not persist over time. CTEPH patients had higher rates of hospitalization (excluding the hospitalization for PTE) compared to IPAH patients after adjusting for age, sex, body mass index, WHO functional class and six-minute walk distance (IRR 1.66, 95%CI 1.04-2.65, p = 0.03). CTEPH patients who underwent PTE had improved HRQoL as compared to those who were medically managed, but patients who underwent PTE were younger, had higher cardiac outputs and greater six-minute walk distances. In this large, prospective, multicenter cohort, CTEPH patients had significantly worse baseline HRQoL and higher rates of hospitalizations than those with IPAH. CTEPH patients who underwent PTE had significant improvements in HRQoL.
RESUMEN
Imaging continues to be the modality of choice for the diagnosis of venous thromboembolic disease, particularly when incorporated into diagnostic algorithms. Improvement in imaging techniques as well as new imaging modalities and processing methods have improved diagnostic accuracy and additionally are being leveraged in prognostication and decision making for choice of intervention. In this article, we review the role of imaging in diagnosis and prognostication of venous thromboembolism. We also discuss emerging imaging approaches that may in the near future find clinical usefulness in improving diagnosis and prognostication as well as differentiating disease phenotypes.