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2.
Eur Respir J ; 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32108049

RESUMO

BACKGROUND: Individuals with idiopathic pulmonary arterial hypertension (PAH) display reduced oral glucose tolerance. This may involve defects in pancreatic function or insulin sensitivity, but this hypothesis has not been tested; moreover, fasting nutrient metabolism remains poorly described in PAH. Thus, we aimed to characterise fasting nutrient metabolism and investigated the metabolic response to hyperglycemia in PAH. METHODS: Twelve participants (6-PAH, 6-Controls) were administered a hyperglycemic clamp, while 52 (21-PAH, 31-Controls) underwent plasma metabolomic analysis. Glucose, insulin, C-peptide, free fatty acids and acylcarnitines were assessed from the clamp. Plasma metabolomics was conducted on fasting plasma samples. RESULTS: The clamp verified a reduced insulin response to hyperglycemia in PAH (-53% versus Control), but with similar pancreatic insulin secretion. Skeletal muscle insulin sensitivity was unexpectedly greater in PAH. Hepatic insulin extraction was elevated in PAH (+11% versus Control). Plasma metabolomics identified 862 metabolites: 213 elevated, 145 reduced in PAH (p<0.05). In both clamp and metabolomic cohorts, lipid oxidation and ketones were elevated in PAH. Insulin sensitivity, fatty acids, acylcarnitines and ketones correlated with PAH severity, while hepatic extraction and fatty acid:ketone ratio correlated with longer 6-minute walk distance. CONCLUSION: Poor glucose control in PAH could not be explained by pancreatic ß-cell function or skeletal muscle insulin sensitivity. Instead, elevated hepatic insulin extraction emerged as an underlying factor. In agreement, nutrient metabolism in PAH favors lipid and ketone metabolism at the expense of glucose control. Future research should investigate the therapeutic potential of reinforcing lipid and ketone metabolism on clinical outcomes in PAH.

3.
Pulm Circ ; 10(1): 2045894019890553, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110382

RESUMO

We aimed to characterize the plasma metabolome of chronic thromboembolic pulmonary hypertension patients using a high-throughput unbiased omics approach. We collected fasting plasma from a peripheral vein in 33 operable chronic thromboembolic pulmonary hypertension patients, 31 healthy controls, and 21 idiopathic pulmonary arterial hypertension patients matched for age, gender, and body mass index. Metabolomic analysis was performed using an untargeted approach (Metabolon Inc. Durham, NC). Of the total of 862 metabolites identified, 362 were different in chronic thromboembolic pulmonary hypertension compared to controls: 178 were higher and 184 were lower. Compared to idiopathic pulmonary arterial hypertension, 147 metabolites were different in chronic thromboembolic pulmonary hypertension: 45 were higher and 102 were lower. The plasma metabolome allowed us to distinguish subjects with chronic thromboembolic pulmonary hypertension and healthy controls with a predictive accuracy of 89%, and chronic thromboembolic pulmonary hypertension versus idiopathic pulmonary arterial hypertension with 80% accuracy. Compared to idiopathic pulmonary arterial hypertension and healthy controls, chronic thromboembolic pulmonary hypertension patients had higher fatty acids and glycerol; while acyl cholines and lysophospholipids were lower. Compared to healthy controls, both idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients had increased acyl carnitines, beta-hydroxybutyrate, amino sugars and modified amino acids and nucleosides. The plasma global metabolomic profile of chronic thromboembolic pulmonary hypertension suggests aberrant lipid metabolism characterized by increased lipolysis, fatty acid oxidation, and ketogenesis, concomitant with reduced acyl choline and phospholipid moieties. Future research should investigate the pathogenetic and therapeutic potential of modulating lipid metabolism in chronic thromboembolic pulmonary hypertension.

4.
Am J Cardiol ; 124(9): 1465-1469, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31495443

RESUMO

Treatment strategies for complex patients with pulmonary embolism (PE) are often debated given patient heterogeneity, multitude of available treatment modalities, and lack of consensus guidelines. Although multidisciplinary Pulmonary Embolism Response Teams (PERT) are emerging to address this lack of consensus, their impact on patient outcomes is not entirely clear. This analysis was conducted to compare outcomes of all patients with PE before and after PERT availability. We analyzed all adult patients admitted with acute PE diagnosed on computed tomography scans in the 18 months before and after the institution of PERT at a large tertiary care hospital. Among 769 consecutive inpatients with PE, PERT era patients had lower rates of major or clinically relevant nonmajor bleeding (17.0% vs 8.3%, p = 0.002), shorter time-to-therapeutic anticoagulation (16.3 hour vs 12.6 hour, p = 0.009) and decreased use of inferior vena cava filters (22.2% vs 16.4%, p = 0.004). There was an increase in the use of thrombolytics/catheter-based strategies, however, this did not achieve statistical significance (p = 0.07). There was a significant decrease in 30-day/inpatient mortality (8.5% vs 4.7%, p = 0.03). These differences in outcomes were more pronounced in intermediate and high-risk patients (mortality 10.0% vs 5.3%, p = 0.02). The availability of multidisciplinary PERT was associated with improved outcomes including 30-day mortality. Patients with higher severity of PE seemed to derive most benefit from PERT availability.

5.
Chest ; 156(1): 45-52, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30776364

RESUMO

BACKGROUND: Pulmonary edema may complicate the use of pulmonary arterial hypertension (PAH)-targeted therapies. We aimed to determine the proportion of patients who develop pulmonary edema after initiation of parenteral prostacyclin therapy, to identify its risk factors, and to assess its implications for hospital length of stay and mortality. METHODS: A retrospective cohort study of patients with PAH at the initiation of parenteral prostacyclin between 1997 and 2015 enrolled in the Cleveland Clinic PAH registry. Pulmonary edema was defined as at least one symptom or clinical sign and radiographic evidence of pulmonary edema. We determined patient characteristics predictive of pulmonary edema as well as the association between pulmonary edema and hospital length of stay (LOS) and 6-month mortality. RESULTS: One hundred and fifty-five patients were included (median age, 51 years; female, 72%; white, 85%; idiopathic, 64%; and connective tissue disease [CTD], 23%). Pulmonary edema developed in 33 of 155 patients (21%). Independent predictors of pulmonary edema were high right atrial pressure (RAP), CTD etiology, and the presence of three or more risk factors for left heart disease (LHD). Pulmonary edema was associated with a 4.5-day increase in hospital LOS (95% CI, 1.4-7.5 days; P < .001) and a 4-fold increase in 6-month mortality (OR, 4.3; 95% CI, 1.28-14.36; P = .031). CONCLUSIONS: Pulmonary edema occurred in 21% of patients with PAH initiated on parenteral prostacyclin. Three or more risk factors for LHD, CTD-PAH, and a high baseline RAP were independent predictors of pulmonary edema. Pulmonary edema was associated with a prolonged hospital LOS and increased 6-month mortality.

7.
J Thorac Imaging ; 34(6): 367-372, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30562223

RESUMO

PURPOSE: The purpose of this study was to evaluate patterns of vascular and lung parenchymal enhancement in patients with suspected chronic thromboembolic pulmonary hypertension (CTEPH) and in those with acute pulmonary embolism (PE) and compare those two groups. MATERIALS AND METHODS: We retrospectively studied 186 thoracic DECT studies referred for evaluation of CTEPH or pulmonary hypertension. A total of 80 of these patients had a negative scan (control group), 13 had acute PE, and 53 had chronic thromboembolic disease (CTED)/CTEPH. Five different DECT-based parameters were evaluated that highlight patterns of vascular kinetics. Specifically, total DECT-based parenchymal attenuation in Hounsfield Unit (HU) (LungHU), percentage of perfused blood volume (PBV), peak enhancement of main pulmonary artery (PApeak in HU), maximum enhancement corresponding to 100 (PAmax), and the ratio of PApeak to LungHU were calculated. RESULTS: Compared with patients with negative CT, patients with CTED/CTEPH tended to have lower LungHU (median: 27 vs. 38, P<0.001), lower PBV (median: 39 vs. 51, P=0.003), and higher PApeak/LungHU ratio (median: 17 vs. 13, P=0.003). Compared with patients with acute PE, patients with CTED/CTEPH tended to have lower LungHU (median: 27 vs. 39, P=0.006), lower PBV (median: 39 vs. 62, P=0.023), and higher PApeak/LungHU ratio (median: 17 vs. 11, P=0.023). No statistically significant differences were observed between patients with acute PE and those with negative CT. CONCLUSIONS: DECT-based vascular parameters offer the potential to differentiate patients with acute versus chronic PE. These various anatomic and functional vascular DECT-based parameters might be reflective of the state of the underlying vascular bed.

8.
Clin Appl Thromb Hemost ; : 1076029618812954, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30453745

RESUMO

Pulmonary embolism represents the third most common cause of cardiovascular death in the United States. Reperfusion therapeutic strategies such as systemic thrombolysis, catheter directed therapies, surgical pulmonary embolectomy, and cardiopulmonary support devices are currently available for patients with high- and intermediate-high-risk pulmonary embolism. However, deciding on optimal therapy may be challenging. Pulmonary embolism response teams have been designed to facilitate multidisciplinary decision-making with the goal to improve quality of care for complex cases with pulmonary embolism. Herein, we discuss the current role and strategies on how to leverage the strengths from pulmonary embolism response teams, its possible worldwide adoption, and implementation to improve survival and change the paradigm in the care of a potentially deadly disease.

9.
Cardiovasc Diagn Ther ; 8(4): 414-422, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30214856

RESUMO

Background: The purpose of this study was to compare the qualitative and quantitative assessment of perfusion on dual-energy CT (DECT) and planar and single photon emission computed tomography (SPECT)-CT V/Q scanning in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods: Nineteen patients with known CTEPH underwent both DECT and SPECT-CT V/Q scanning. Sixteen of these patients underwent planar V/Q imaging concurrently. Two readers independently graded DECT-perfused blood volume (PBV) defects on a four-point scale (0= normal, 1= mild <25%, 2= moderate 25-50%, 3= severe >50%). A grade was given for each lung lobe and for each of 18 lung segments. One reader graded the SPECT-CT images similarly. Quantitative measurements of lung perfusion were calculated with DECT and planar V/Q scanning for 16 of these patients. Results: The inter-reader agreement on DECT was strong with agreement in 85% (258/304) of segments (kappa =0.86) and 84% (80/95) of lobes (kappa =0.82). The inter-modality agreement between DECT and SPECT-CT was lower. Readers 1 and 3 agreed in only 34% (103/304) of segments (kappa =0.25) and 33% (31/94) of lobes (kappa =0.22). Agreement between readers 2 and 3 was similar. Correlation between quantitative measurements with DECT and planar V/Q imaging was poor and ranged from 0.01 to 0.45. Conclusions: Inter-observer agreement in subjective grading of PBV maps is excellent. However, inter-modality agreement between DECT and SPECT-CT is modest. Automated quantification values of PBV maps correlate poorly with established tools like planar V/Q imaging. These differences need to be kept in mind during clinical decision making.

10.
Clin Chest Med ; 39(3): 493-504, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30122174

RESUMO

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.


Assuntos
Imagem por Ressonância Magnética/métodos , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/diagnóstico , Tomografia Computadorizada de Emissão/métodos , Ultrassonografia/métodos , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/diagnóstico , Idoso , Humanos , Masculino
12.
JCI Insight ; 3(11)2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29875311

RESUMO

Pulmonary arterial hypertension (PAH) remains a disease with limited therapeutic options and dismal prognosis. Despite its etiologic heterogeneity, the underlying unifying pathophysiology is characterized by increased vascular tone and adverse remodeling of the pulmonary circulation. Myeloperoxidase (MPO), an enzyme abundantly expressed in neutrophils, has potent vasoconstrictive and profibrotic properties, thus qualifying as a potential contributor to this disease. Here, we sought to investigate whether MPO is causally linked to the pathophysiology of PAH. Investigation of 2 independent clinical cohorts revealed that MPO plasma levels were elevated in subjects with PAH and predicted adverse outcome. Experimental analyses showed that, upon hypoxia, right ventricular pressure was less increased in Mpo-/- than in WT mice. The hypoxia-induced activation of the Rho-kinase pathway, a critical subcellular signaling pathway yielding vasoconstriction and structural vascular remodeling, was blunted in Mpo-/- mice. Mice subjected to i.v. infusion of MPO revealed activation of Rho-kinase and increased right ventricular pressure, which was prevented by coinfusion of the Rho-kinase inhibitor Y-27632. In the Sugen5416/hypoxia rat model, PAH was attenuated by the MPO inhibitor AZM198. The current data demonstrate a tight mechanistic link between MPO, the activation of Rho-kinase, and adverse pulmonary vascular function, thus pointing toward a potentially novel avenue of treatment.


Assuntos
Hipertensão Pulmonar/patologia , Hipóxia/patologia , Peroxidase/metabolismo , Artéria Pulmonar/patologia , Quinases Associadas a rho/metabolismo , Adulto , Amidas/administração & dosagem , Animais , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/mortalidade , Hipertensão Pulmonar/fisiopatologia , Hipóxia/sangue , Hipóxia/etiologia , Infusões Intravenosas , Estimativa de Kaplan-Meier , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Peroxidase/administração & dosagem , Peroxidase/sangue , Artéria Pulmonar/fisiopatologia , Piridinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/sangue , Proteínas Recombinantes/metabolismo , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/fisiologia , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Quinases Associadas a rho/antagonistas & inibidores
13.
J Thromb Thrombolysis ; 46(2): 186-192, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29855780

RESUMO

Management of intermediate and high risk acute pulmonary embolism (PE) is challenging. The role of multidisciplinary teams for the care of these patients is emerging. Herein, we report our experience with a pulmonary embolism response team (PERT). We conducted a retrospective chart review on all patients admitted to the Cleveland Clinic main campus who required activation of the (PERT) from October 1, 2014 to September 1, 2016. We extracted data pertaining to clinical presentation, bleeding complications, and pre- and post-discharge imaging. Patients were classified as low, intermediate or high risk PE. Descriptive and continuous variables were collected and analyzed. There were 134 PERT activations. PE was confirmed by CT-PA in 118 patients. Fifteen (13%) patients were classified as low risk, 80 (68%) intermediate risk PE and 23 (19%) high risk PE. Fourteen (12%) patients were treated with catheter directed rtPA, 6 (5%) received full dose (100 mg rtPA), 16 (13%) received systemic half-dose (50 mg rtPA), 6 (5%) underwent a surgical embolectomy and 4 (3%) underwent mechanical thrombectomy. 65 (55%) patients received anticoagulation only, and 8 (7%) patients were managed conservatively without any anticoagulation or advanced therapy. 11 (9%) patients died while during the hospitalization. Fourteen patients had major bleeding events. There were no bleeding events among patients who received systemic low dose or full dose rtPA. A multidisciplinary approach to cases of intermediate risk and high risk PE can be implemented successfully. We saw a relatively low rate of bleeding events with use of rtPA.


Assuntos
Equipe de Assistência ao Paciente/normas , Embolia Pulmonar/terapia , Adulto , Idoso , Anticoagulantes/uso terapêutico , Gerenciamento Clínico , Embolectomia , Hemorragia/induzido quimicamente , Hemorragia/etiologia , Humanos , Pessoa de Meia-Idade , Embolia Pulmonar/complicações , Estudos Retrospectivos , Medição de Risco , Trombectomia , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/uso terapêutico
16.
PLoS One ; 13(5): e0197700, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29813091

RESUMO

BACKGROUND: High Density Lipoprotein Cholesterol (HDL-C) has various anti-inflammatory, anti-atherogenic, anti-oxidant and anti-coagulant properties that improve vascular function. The utility of HDL-C as a biomarker of severity and predictor of survival was described in patients with pulmonary arterial hypertension (PAH). No prior study has assessed the utility of HDL-C in patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH). OBJECTIVES: We aim to measure HDL-C levels in CTEPH patients and compare it to those in PAH patients and controls and determine HDL-C associations with markers of disease severity, hemodynamics and mortality in CTEPH. METHODS: We retrospectively included patients with CTEPH, identified from the Cleveland Clinic Pulmonary Hypertension Registry. All patients had right heart catheterization (RHC) and imaging studies consistent with CTEPH. We collected demographics, co-morbidities, baseline laboratory data including plasma HDL-C, six-minute walk test (6MWT), echocardiography and RHC. HDL-C levels were compared to a cohort of patients with cardiovascular risk factors and a previously published PAH cohort. RESULTS: HDL-C levels were available for 90 patients with CTEPH (age: 57.4±13.9 years; female 40%), 69 patients with PAH (age: 46.7±12.8 years; female 90%) and 254 control subjects (age: 56.7±13 years; female 48%). HDL-C levels in CTEPH patients were lower compared to controls and higher compared to PAH patients (median, IQR: CTEPH: 44, 34-57 mg/dl; PAH: 35.3, 29-39 mg/dl; Control: 49, 40-60 mg/dl; p < 0.01 for both pairwise comparisons). In CTEPH, higher HDL-C was associated with decreased prevalence of right ventricular dilation on echocardiography (p = 0.02). 57 patients with CTEPH underwent pulmonary thromboendarterectomy, higher HDL-C was associated with a larger decrement in postoperative pulmonary vascular resistance (PVR) (r = 0.37, p = 0.049). HDL-C was not associated with mortality or other markers of disease severity. CONCLUSIONS: HDL-C levels in CTEPH patients were lower compared to control subjects, but higher compared to PAH patients. Higher HDL-C in CTEPH was associated with less right ventricular dilation and greater decrement in postoperative PVR. These data suggest that HDL-C may be a useful marker of small vessel disease in CTEPH.


Assuntos
HDL-Colesterol/sangue , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/cirurgia , Embolia Pulmonar/metabolismo , Embolia Pulmonar/cirurgia , Adulto , Idoso , Biomarcadores/sangue , Cateterismo Cardíaco , Ecocardiografia , Endarterectomia , Feminino , Humanos , Hipertensão Pulmonar/sangue , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/sangue , Estudos Retrospectivos , Índice de Gravidade de Doença , Teste de Caminhada
18.
PLoS One ; 13(1): e0191869, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29377954

RESUMO

BACKGROUND: The prevalence and prognostic implications of hypoxemia either at rest or during six-minute walk test (6MWT) in patients with idiopathic or heritable pulmonary arterial hypertension (IPAH or HPAH) have not been systemically studied. OBJECTIVES: We sought to determine the prevalence, phenotypic and prognostic implications of hypoxemia in patients with IPAH and HPAH. METHODS: Patients with IPAH or HPAH were identified from the Cleveland Clinic Pulmonary Hypertension Registry. Pulse oximetry (SpO2) at rest and during 6MWT was used to define hypoxemia at rest or during activities when measurements were lower than 90%, respectively. RESULTS: A total of 292 patients (age 50.6 ± 18.0 years, 73% females) with IPAH (88%) and HPAH (12%) were included. Of them, 143 (49%) had SpO2 >90% at rest and during 6MWT, 89 (31%) subjects had hypoxemia during 6MWT and 60 (20%) had hypoxemia at rest. Patients with hypoxemia had older age, greater body mass index, higher prevalence of cardiovascular risk factors, worse functional capacity and pulmonary function tests but less severe pre-capillary pulmonary hypertension. Individuals with hypoxemia either at rest or during the initial 6MWT had worse long-term survival when compared to subjects without hypoxemia, even when adjusting for a great number of potential confounders. (HR: 2.5 (95% CI: 1.54-3.98)). CONCLUSIONS: Hypoxemia in patients with IPAH and HPAH is associated with more comorbidities, less severe pre-capillary pulmonary hypertension and worse survival.


Assuntos
Hipertensão Pulmonar/complicações , Hipóxia/complicações , Adulto , Idoso , Feminino , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Hipóxia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Oximetria , Testes de Função Respiratória , Estudos Retrospectivos , Análise de Sobrevida
19.
Pulm Circ ; 7(1): 256-260, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28680585

RESUMO

Venous malformations have static venous lakes that predispose to spontaneous venous thrombosis within the malformation due to its low-flow static state. Thrombi of varying sizes can then embolize continually into the pulmonary arterial circulation, and occlude and narrow elastic pulmonary arteries causing chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary thromboendarterectomy (PTE) is potentially curative in CTEPH, but has not been previously reported in the setting of mediastinal and chest wall venous malformations. We report the case of a 21-year-old female with such a large malformation treated successfully with PTE. The patient underwent complete endovascular reconstruction of her subclavian vein system from the axillary vein to the innominate vein stump with covered stent grafts to exclude the malformations from causing recurrent pulmonary emboli. This was followed by embolization of the malformation to allow for the surgical approach. The series of events in this case serves as a novel approach in managing such rare patients.

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