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1.
Am J Physiol Lung Cell Mol Physiol ; 327(2): L250-L257, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38810241

RESUMO

In the field of pulmonary hypertension (PH), a well-established protocol to induce severe angioproliferation in rats (SuHx) involves combining the VEGF-R inhibitor Sugen 5416 (SU5416) with 3 wk of hypoxia (Hx). In addition, injecting monocrotaline (MCT) into rats can induce inflammation and shear stress in the pulmonary vasculature, leading to neointima-like remodeling. However, the SuHx protocol in mice is still controversial, with some studies suggesting it yields higher and reversible PH than Hx alone, possibly due to species-dependent hypoxic responses. To establish an alternative rodent model of PH, we hypothesized mice would be more sensitive to hemodynamic changes secondary to shear stress compared with Hx. We attempted to induce severe and irreversible PH in mice by combining SU5416 or monocrotaline pyrrole (MCTP) injection with pneumonectomy (PNx). However, our experiments showed SU5416 administered to mice at various time points after PNx did not result in severe PH. Similarly, mice injected with MCTP after PNx (MPNx) showed no difference in right ventricular systolic pressure or exacerbated pulmonary vascular remodeling compared with PNx alone. These findings collectively demonstrate that C57/B6 mice do not develop severe and persistent PH when PNx is combined with either SU5416 or MCTP.NEW & NOTEWORTHY We attempted to establish a mouse model of severe and irreversible pulmonary hypertension by substituting hypoxia with pulmonary overcirculation. To do so, we treated mice with either SU5416 or monocrotaline pyrrole after pneumonectomy and performed hemodynamic evaluations for PH. Despite this "two-hit" protocol, mice did not exhibit signs of severe pulmonary hypertension or exacerbated pulmonary vascular remodeling compared with PNx alone.


Assuntos
Hipertensão Pulmonar , Indóis , Camundongos Endogâmicos C57BL , Monocrotalina , Pneumonectomia , Pirróis , Animais , Monocrotalina/análogos & derivados , Pirróis/farmacologia , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/induzido quimicamente , Indóis/farmacologia , Camundongos , Masculino , Modelos Animais de Doenças , Hipóxia/patologia , Remodelação Vascular/efeitos dos fármacos , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Hemodinâmica/efeitos dos fármacos
2.
Eur Respir J ; 63(6)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38575159

RESUMO

BACKGROUND: The consequences of tricuspid regurgitation (TR) for right ventricular (RV) function and prognosis in pulmonary arterial hypertension (PAH) are poorly described and effects of tricuspid valve repair on the RV are difficult to predict. METHODS: In 92 PAH patients with available cardiac magnetic resonance (CMR) studies, TR volume was calculated as the difference between RV stroke volume and forward stroke volume, i.e. pulmonary artery (PA) stroke volume. Survival was estimated from the time of the CMR scan to cardiopulmonary death or lung transplantation. In a subgroup, pressure-volume loop analysis including two-parallel elastances was applied to evaluate effective elastances, including net afterload (effective arterial elastance (E a)), forward afterload (effective pulmonary arterial elastance (E pa)) and backward afterload (effective tricuspid regurgitant elastance (E TR)). The effects of tricuspid valve repair were simulated using the online software package Harvi. RESULTS: 26% of PAH patients had a TR volume ≥30 mL. Greater TR volume was associated with increased N-terminal pro-brain natriuretic peptide (p=0.018), mean right atrial pressure (p<0.001) and RV end-systolic and -diastolic volume (both p<0.001). TR volume ≥30 mL was associated with a poor event-free survival (p=0.008). In comparison to E a, E pa correlated better with indices of RV dysfunction. Lower end-systolic elastance (E es) (p=0.002) and E TR (p=0.030), higher E pa (p=0.001) and reduced E es/E pa (p<0.001) were found in patients with a greater TR volume. Simulations predicted that tricuspid valve repair increases RV myocardial oxygen consumption in PAH patients with severe TR and low E es unless aggressive volume reduction is accomplished. CONCLUSIONS: In PAH, TR has prognostic significance and is associated with low RV contractility and RV-PA uncoupling. However, haemodynamic simulations showed detrimental consequences of tricuspid valve repair in PAH patients with low RV contractility.


Assuntos
Hipertensão Arterial Pulmonar , Insuficiência da Valva Tricúspide , Função Ventricular Direita , Humanos , Insuficiência da Valva Tricúspide/fisiopatologia , Insuficiência da Valva Tricúspide/complicações , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Hipertensão Arterial Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/complicações , Volume Sistólico , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Prognóstico , Idoso , Valva Tricúspide/fisiopatologia , Valva Tricúspide/diagnóstico por imagem , Disfunção Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/diagnóstico por imagem , Imageamento por Ressonância Magnética , Hipertensão Pulmonar/fisiopatologia , Peptídeo Natriurético Encefálico/sangue
3.
Eur Respir J ; 64(4)2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38991711

RESUMO

INTRODUCTION: Pathogenic variants in the gene encoding for BMPR2 are a major genetic risk factor for heritable pulmonary arterial hypertension. Owing to incomplete penetrance, deep phenotyping of unaffected carriers of a pathogenic BMPR2 variant through multimodality screening may aid in early diagnosis and identify susceptibility traits for future development of pulmonary arterial hypertension. METHODS: 28 unaffected carriers (44±16 years, 57% female) and 21 healthy controls (44±18 years, 48% female) underwent annual screening, including cardiac magnetic resonance imaging, transthoracic echocardiography, cardiopulmonary exercise testing and right heart catheterisation. Right ventricular pressure-volume loops were constructed to assess load-independent contractility and compared with a healthy control group. A transgenic Bmpr2Δ71Ex1/+ rat model was employed to validate findings from humans. RESULTS: Unaffected carriers had lower indexed right ventricular end-diastolic (79.5±17.6 mL·m-2 versus 62.7±15.3 mL·m-2; p=0.001), end-systolic (34.2±10.5 mL·m-2 versus 27.1±8.3 mL·m-2; p=0.014) and left ventricular end-diastolic (68.9±14.1 mL·m-2 versus 58.5±10.7 mL·m-2; p=0.007) volumes than control subjects. Bmpr2Δ71Ex1/+ rats were also observed to have smaller cardiac volumes than wild-type rats. Pressure-volume loop analysis showed that unaffected carriers had significantly higher afterload (arterial elastance 0.15±0.06 versus 0.27±0.08 mmHg·mL-1; p<0.001) and end-systolic elastance (0.28±0.07 versus 0.35±0.10 mmHg·mL-1; p=0.047) in addition to lower right ventricular pulmonary artery coupling (end-systolic elastance/arterial elastance 2.24±1.03 versus 1.36±0.37; p=0.006). During the 4-year follow-up period, two unaffected carriers developed pulmonary arterial hypertension, with normal N-terminal pro-brain natriuretic peptide and transthoracic echocardiography indices at diagnosis. CONCLUSION: Unaffected BMPR2 mutation carriers have an altered cardiac phenotype mimicked in Bmpr2Δ71Ex1/+ transgenic rats. Future efforts to establish an effective screening protocol for individuals at risk for developing pulmonary arterial hypertension warrant longer follow-up periods.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II , Ecocardiografia , Hipertensão Pulmonar , Adulto , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Cateterismo Cardíaco , Estudos de Casos e Controles , Modelos Animais de Doenças , Teste de Esforço , Predisposição Genética para Doença , Heterozigoto , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Imageamento por Ressonância Magnética , Fenótipo , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/fisiopatologia , Ratos Transgênicos
4.
Neth Heart J ; 32(3): 106-115, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38224411

RESUMO

Randomised clinical trials (RCTs) are vital for medical progress. Unfortunately, 'traditional' RCTs are expensive and inherently slow. Moreover, their generalisability has been questioned. There is considerable overlap in routine health care data (RHCD) and trial-specific data. Therefore, integration of RHCD in an RCT has great potential, as it would reduce the effort and costs required to collect data, thereby overcoming some of the major downsides of a traditional RCT. However, use of RHCD comes with other challenges, such as privacy issues, as well as technical and practical barriers. Here, we give a current overview of related initiatives on national cardiovascular registries (Netherlands Heart Registration, Heart4Data), showcasing the interrelationships between and the relevance of the different registries for the practicing physician. We then discuss the benefits and limitations of RHCD use in the setting of a pragmatic RCT from a cardiovascular perspective, illustrated by a case study in heart failure.

5.
Semin Respir Crit Care Med ; 44(6): 738-745, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37487527

RESUMO

The right ventricle plays a pivotal role in patients with pulmonary hypertension (PH). Its adaptation to pressure overload determines a patient's functional status as well as survival. In a healthy situation, the right ventricle is part of a low pressure, high compliance system. It is built to accommodate changes in preload, but not very well suited for dealing with pressure overload. In PH, right ventricular (RV) contractility must increase to maintain cardiac output. In other words, the balance between the degree of RV contractility and afterload determines stroke volume. Hypertrophy is one of the major hallmarks of RV adaptation, but it may cause stiffening of the ventricle in addition to intrinsic changes to the RV myocardium. Ventricular filling becomes more difficult for which the right atrium tries to compensate through increased stroke work. Interaction of RV diastolic stiffness and right atrial (RA) function determines RV filling, but also causes vena cava backflow. Assessment of RV and RA function is critical in the evaluation of patient status. In recent guidelines, this is acknowledged by incorporating additional RV parameters in the risk stratification in PH. Several conventional parameters of RV and RA function have been part of risk stratification for many years. Understanding the pathophysiology of RV failure and the interactions with the pulmonary circulation and right atrium requires consideration of the unique RV anatomy. This review will therefore describe normal RV structure and function and changes that occur during adaptation to increased afterload. Consequences of a failing right ventricle and its implications for RA function will be discussed. Subsequently, we will describe RV and RA assessment in clinical practice.


Assuntos
Insuficiência Cardíaca , Hipertensão Pulmonar , Disfunção Ventricular Direita , Humanos , Ventrículos do Coração , Circulação Pulmonar/fisiologia , Volume Sistólico , Função Ventricular Direita , Disfunção Ventricular Direita/etiologia
6.
Am J Respir Crit Care Med ; 205(7): 806-818, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35081007

RESUMO

Rationale: von Willebrand factor (vWF) mediates platelet adhesion during thrombosis. While chronic thromboembolic pulmonary hypertension (CTEPH) is associated with increased plasma levels of vWF, the role of this protein in CTEPH has remained enigmatic. Objectives: To identify the role of vWF in CTEPH. Methods: CTEPH-specific patient plasma and pulmonary endarterectomy material from patients with CTEPH were used to study the relationship between inflammation, vWF expression, and pulmonary thrombosis. Cell culture findings were validated in human tissue, and proteomics and chromatin immunoprecipitation were used to investigate the underlying mechanism of CTEPH. Measurements and Main Results: vWF is increased in plasma and the pulmonary endothelium of CTEPH patients. In vitro, the increase in vWF gene expression and the higher release of vWF protein upon endothelial activation resulted in elevated platelet adhesion to CTEPH endothelium. Proteomic analysis revealed that nuclear factor (NF)-κB2 was significantly increased in CTEPH. We demonstrate reduced histone tri-methylation and increased histone acetylation of the vWF promoter in CTEPH endothelium, facilitating binding of NF-κB2 to the vWF promoter and driving vWF transcription. Genetic interference of NFκB2 normalized the high vWF RNA expression levels and reversed the prothrombotic phenotype observed in CTEPH-pulmonary artery endothelial cells. Conclusions: Epigenetic regulation of the vWF promoter contributes to the creation of a local environment that favors in situ thrombosis in the pulmonary arteries. It reveals a direct molecular link between inflammatory pathways and platelet adhesion in the pulmonary vascular wall, emphasizing a possible role of in situ thrombosis in the development or progression of CTEPH.


Assuntos
Hipertensão Pulmonar , Fator de von Willebrand , Células Endoteliais/metabolismo , Endotélio Vascular , Epigênese Genética , Humanos , Agregação Plaquetária , Proteômica , Fator de von Willebrand/análise , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismo
7.
J Physiol ; 600(10): 2327-2344, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35421903

RESUMO

Right ventricular (RV) wall tension in pulmonary arterial hypertension (PAH) is determined not only by pressure, but also by RV volume. A larger volume at a given pressure generates more wall tension. Return of reflected waves early after the onset of contraction, when RV volume is larger, may augment RV load. We aimed to elucidate: (1) the distribution of arrival times of peak reflected waves in treatment-naïve PAH patients; (2) the relationship between time of arrival of reflected waves and RV morphology; and (3) the effect of PAH treatment on the arrival time of reflected waves. Wave separation analysis was conducted in 68 treatment-naïve PAH patients. In the treatment-naïve condition, 54% of patients had mid-systolic return of reflected waves (defined as 34-66% of systole). Despite similar pulmonary vascular resistance (PVR), patients with mid-systolic return had more pronounced RV hypertrophy compared to those with late-systolic or diastolic return (RV mass/body surface area; mid-systolic return 54.6 ± 12.6 g m-2 , late-systolic return 44.4 ± 10.1 g m-2 , diastolic return 42.8 ± 13.1 g m-2 ). Out of 68 patients, 43 patients were further examined after initial treatment. At follow-up, the stiffness of the proximal arteries, given as characteristic impedance, decreased from 0.12 to 0.08 mmHg s mL-1 . Wave speed was attenuated from 13.3 to 9.1 m s-1 , and the return of reflected waves was delayed from 64% to 71% of systole. In conclusion, reflected waves arrive at variable times in PAH. Early return of reflected waves was associated with more RV hypertrophy. PAH treatment not only decreased PVR, but also delayed the timing of reflected waves. KEY POINTS: Right ventricular (RV) wall tension in pulmonary arterial hypertension (PAH) is determined not only by pressure, but also by RV volume. Larger volume at a given pressure causes larger RV wall tension. Early return of reflected waves adds RV pressure in early systole, when RV volume is relatively large. Thus, early return of reflected waves may increase RV wall tension. Wave reflection can provide a description of RV load. In PAH, reflected waves arrive back at variable times. In over half of PAH patients, the RV is exposed to mid-systolic return of reflected waves. Mid-systolic return of reflected waves is related to RV hypertrophy. PAH treatment acts favourably on the RV not only by reducing resistance, but also by delaying the return of reflected waves. Arrival timing of reflected waves is an important parameter for understanding the relationship between RV load and its function in PAH.


Assuntos
Hipertensão Arterial Pulmonar , Disfunção Ventricular Direita , Ventrículos do Coração , Humanos , Hipertrofia , Disfunção Ventricular Direita/etiologia , Função Ventricular Direita , Pressão Ventricular
8.
Eur Respir J ; 59(6)2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34764180

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness. This study assessed the impact of RV diastolic stiffness on RA-RV interaction. METHODS: PAH patients with low or high end-diastolic elastance (Eed) (n=94) were compared with controls (n=31). Treatment response was evaluated in 62 patients. RV and RA longitudinal strain, RA emptying and RV filling were determined and diastole was divided into a passive and active phase. Vena cava backflow was calculated as RA active emptying-RV active filling and RA stroke work as RA active emptying×RV end-diastolic pressure. RESULTS: With increased Eed, RA and RV passive strain were reduced while active strain was preserved. In comparison to controls, patients had lower RV passive filling but higher RA active emptying and RA stroke work. RV active filling was lower in patients with high Eed, resulting in higher vena cava backflow. Upon treatment, Eed was reduced in ~50% of the patients with high Eed, which coincided with larger reductions in afterload, RV mass and vena cava backflow and greater improvements in RV active filling and stroke volume in comparison with patients in whom Eed remained high. CONCLUSIONS: In PAH, RA function is associated with changes in RV function. Despite increased RA stroke work, severe RV diastolic stiffness is associated with reduced RV active filling and increased vena cava backflow. In 50% of patients with high baseline Eed, diastolic stiffness remained high, despite treatment. A reduction in Eed coincided with a large reduction in afterload, increased RV active filling and decreased vena cava backflow.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Disfunção Ventricular Direita , Função do Átrio Direito , Diástole , Hipertensão Pulmonar Primária Familiar , Humanos , Função Ventricular Direita
9.
J Cardiovasc Pharmacol ; 80(6): 783-791, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-35976136

RESUMO

ABSTRACT: Although previous studies support the clinical benefit of imatinib regarding respiratory status in hospitalized patients with COVID-19, potential cardiotoxicity may limit its clinical application. This study aimed to investigate the cardiac safety of imatinib in COVID-19. In the CounterCOVID study, 385 hospitalized hypoxemic patients with COVID-19 were randomly assigned to receive 10 days of oral imatinib or placebo in a 1:1 ratio. Patients with a corrected QT interval (QTc) >500 ms or left ventricular ejection fraction <40% were excluded. Severe cardiac adverse events were monitored for 28 days or until death occurred. Electrocardiogram measurements and cardiac biomarkers were assessed repeatedly during the first 10 days. A total of 36 severe cardiac events occurred, with a similar incidence in both treatment groups. No differences were observed in the computer-generated Bazett, manually interpreted Bazett, or Fridericia-interpreted QTcs. No clinically relevant alterations in other electrocardiogram parameters or plasma high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentrations were observed. Similar findings were observed in a subgroup of 72 patients admitted to the intensive care unit. In the univariate and multivariable linear mixed models, treatment with imatinib was not significantly associated with QT interval duration, hs-cTnT, or NT-proBNP levels. In conclusion, imatinib treatment did not result in more cardiac events, QT interval prolongation, or altered hs-cTnT or NT-proBNP levels. This suggests that treatment with imatinib is safe in hospitalized patients with COVID-19 with a QTc duration of less than 500 ms and left ventricular ejection fraction >40%.


Assuntos
COVID-19 , Doenças Cardiovasculares , Humanos , Mesilato de Imatinib/efeitos adversos , Volume Sistólico , Função Ventricular Esquerda
10.
Am J Respir Cell Mol Biol ; 64(3): 331-343, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33264068

RESUMO

Monoamine oxidases (MAOs), a class of enzymes bound to the outer mitochondrial membrane, are important sources of reactive oxygen species. Increased MAO-A activity in endothelial cells and cardiomyocytes contributes to vascular dysfunction and progression of left heart failure. We hypothesized that inhibition of MAO-A can be used to treat pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. MAO-A levels in lung and RV samples from patients with PAH were compared with levels in samples from donors without PAH. Experimental PAH was induced in male Sprague-Dawley rats by using Sugen 5416 and hypoxia (SuHx), and RV failure was induced in male Wistar rats by using pulmonary trunk banding (PTB). Animals were randomized to receive either saline or the MAO-A inhibitor clorgyline at 10 mg/kg. Echocardiography and RV catheterization were performed, and heart and lung tissues were collected for further analysis. We found increased MAO-A expression in the pulmonary vasculature of patients with PAH and in experimental experimental PAH induced by SuHx. Cardiac MAO-A expression and activity was increased in SuHx- and PTB-induced RV failure. Clorgyline treatment reduced RV afterload and pulmonary vascular remodeling in SuHx rats through reduced pulmonary vascular proliferation and oxidative stress. Moreover, clorgyline improved RV stiffness and relaxation and reversed RV hypertrophy in SuHx rats. In PTB rats, clorgyline had no direct clorgyline had no direct effect on the right ventricle effect. Our study reveals the role of MAO-A in the progression of PAH. Collectively, these findings indicated that MAO-A may be involved in pulmonary vascular remodeling and consecutive RV failure.


Assuntos
Progressão da Doença , Monoaminoxidase/metabolismo , Hipertensão Arterial Pulmonar/enzimologia , Animais , Clorgilina/farmacologia , Clorgilina/uso terapêutico , Modelos Animais de Doenças , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/enzimologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Direita/complicações , Hipertrofia Ventricular Direita/fisiopatologia , Indóis , Estresse Oxidativo/efeitos dos fármacos , Hipertensão Arterial Pulmonar/induzido quimicamente , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/enzimologia , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Pirróis , Ratos , Remodelação Vascular/efeitos dos fármacos , Rigidez Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
11.
Eur Respir J ; 58(4)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33766951

RESUMO

Pulmonary hypertension is a fatal condition of elevated pulmonary pressures, complicated by right heart failure. Pulmonary hypertension appears in various forms; one of those is pulmonary arterial hypertension (PAH) and is particularly characterised by progressive remodelling and obstruction of the smaller pulmonary vessels. Neurohormonal imbalance in PAH patients is associated with worse prognosis and survival. In this back-to-basics article on neurohormonal modulation in PAH, we provide an overview of the pharmacological and nonpharmacological strategies that have been tested pre-clinically and clinically. The benefit of neurohormonal modulation strategies in PAH patients has been limited by lack of insight into how the neurohormonal system is changed throughout the disease and difficulties in translation from animal models to human trials. We propose that longitudinal and individual assessments of neurohormonal status are required to improve the timing and specificity of neurohormonal modulation strategies. Ongoing developments in imaging techniques such as positron emission tomography may become helpful to determine neurohormonal status in PAH patients in different disease stages and optimise individual treatment responses.


Assuntos
Insuficiência Cardíaca , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Animais , Hipertensão Pulmonar Primária Familiar , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Prognóstico
12.
Eur Respir J ; 58(6)2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34112733

RESUMO

INTRODUCTION: The pulmonary arterial morphology of patients with pulmonary embolism (PE) is diverse and it is unclear how the different vascular lesions evolve after initiation of anticoagulant treatment. A better understanding of the evolution of computed tomography pulmonary angiography (CTPA) findings after the start of anticoagulant treatment may help to better identify those PE patients prone to develop chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to assess the evolution of various thromboembolic lesions on CTPA over time after the initiation of adequate anticoagulant treatment in individual acute PE patients with and without an ultimate diagnosis of CTEPH. METHODS: We analysed CTPA at diagnosis of acute PE (baseline) and at follow-up in 41 patients with CTEPH and 124 patients without an ultimate diagnosis of CTEPH, all receiving anticoagulant treatment. Central and segmental pulmonary arteries were scored by expert chest radiologists as normal or affected. Lesions were further subclassified as 1) central thrombus, 2) total thrombotic occlusion, 3) mural thrombus, 4) web or 5) tapered pulmonary artery. RESULTS: Central thrombi resolved after anticoagulant treatment, while mural thrombi and total thrombotic occlusions either resolved or evolved into webs or tapered pulmonary arteries. Only patients with an ultimate diagnosis of CTEPH exhibited webs and tapered pulmonary arteries on the baseline scan. Moreover, such lesions always persisted after follow-up. CONCLUSIONS: Webs and tapered pulmonary arteries at the time of PE diagnosis strongly indicate a state of chronic PE and should raise awareness for possible CTEPH, particularly in patients with persistent dyspnoea after anticoagulant treatment for acute PE.


Assuntos
Hipertensão Pulmonar , Embolia Pulmonar , Anticoagulantes/uso terapêutico , Doença Crônica , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/tratamento farmacológico , Artéria Pulmonar/diagnóstico por imagem , Embolia Pulmonar/complicações , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/tratamento farmacológico , Tomografia Computadorizada por Raios X
13.
Circulation ; 139(2): 269-285, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30615500

RESUMO

The role of right ventricular (RV) fibrosis in pulmonary hypertension (PH) remains a subject of ongoing discussion. Alterations of the collagen network of the extracellular matrix may help prevent ventricular dilatation in the pressure-overloaded RV. At the same time, fibrosis impairs cardiac function, and a growing body of experimental data suggests that fibrosis plays a crucial role in the development of RV failure. In idiopathic pulmonary arterial hypertension and chronic thromboembolic PH, the RV is exposed to a ≈5 times increased afterload, which makes these conditions excellent models for studying the impact of pressure overload on RV structure. With this review, we present clinical evidence of RV fibrosis in idiopathic pulmonary arterial hypertension and chronic thromboembolic PH, explore the correlation between fibrosis and RV function, and discuss the clinical relevance of RV fibrosis in patients with PH. We postulate that RV fibrosis has a dual role in patients with pressure-overloaded RVs of idiopathic pulmonary arterial hypertension and chronic thromboembolic PH: as part of an adaptive response to prevent cardiomyocyte overstretch and to maintain RV shape for optimal function, and as part of a maladaptive response that increases diastolic stiffness, perturbs cardiomyocyte excitation-contraction coupling, and disrupts the coordination of myocardial contraction. Finally, we discuss potential novel therapeutic strategies and describe more sensitive techniques to quantify RV fibrosis, which may be used to clarify the causal relation between RV fibrosis and RV function in future research.


Assuntos
Insuficiência Cardíaca/etiologia , Ventrículos do Coração/fisiopatologia , Hipertensão Pulmonar/complicações , Hipertrofia Ventricular Direita/etiologia , Artéria Pulmonar/fisiopatologia , Disfunção Ventricular Direita/etiologia , Função Ventricular Direita , Remodelação Ventricular , Adaptação Fisiológica , Animais , Pressão Arterial , Matriz Extracelular/patologia , Fibrose , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Ventrículos do Coração/patologia , Humanos , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/fisiopatologia , Hipertrofia Ventricular Direita/terapia , Miocárdio/patologia , Prognóstico , Disfunção Ventricular Direita/patologia , Disfunção Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/terapia
14.
Am J Physiol Heart Circ Physiol ; 319(6): H1438-H1450, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33035435

RESUMO

Pulmonary vascular resistance (PVR) and compliance are comparable in proximal and distal chronic thromboembolic pulmonary hypertension (CTEPH). However, proximal CTEPH is associated with inferior right ventricular (RV) adaptation. Early wave reflection in proximal CTEPH may be responsible for altered RV function. The aims of the study are as follows: 1) to investigate whether reflected pressure returns sooner in proximal than in distal CTEPH and 2) to elucidate whether the timing of reflected pressure is related to RV dimensions, ejection fraction (RVEF), hypertrophy, and wall stress. Right heart catheterization and cardiac MRI were performed in 17 patients with proximal CTEPH and 17 patients with distal CTEPH. In addition to the determination of PVR, compliance, and characteristic impedance, wave separation analysis was performed to determine the magnitude and timing of the peak reflected pressure (as %systole). Findings were related to RV dimensions and time-resolved RV wall stress. Proximal CTEPH was characterized by higher RV volumes, mass, and wall stress, and lower RVEF. While PVR, compliance, and characteristic impedance were similar, proximal CTEPH was related to an earlier return of reflected pressure than distal CTEPH (proximal 53 ± 8% vs. distal 63 ± 15%, P < 0.05). The magnitude of the reflected pressure waves did not differ. RV volumes, RVEF, RV mass, and wall stress were all related to the timing of peak reflected pressure. Poor RV function in patients with proximal CTEPH is related to an early return of reflected pressure wave. PVR, compliance, and characteristic impedance do not explain the differences in RV function between proximal and distal CTEPH.NEW & NOTEWORTHY In chronic thromboembolic pulmonary hypertension (CTEPH), proximal localization of vessel obstructions is associated with poor right ventricular (RV) function compared with distal localization, though pulmonary vascular resistance, vascular compliance, characteristic impedance, and the magnitude of wave reflection are similar. In proximal CTEPH, the RV is exposed to an earlier return of the reflected wave. Early wave reflection may increase RV wall stress and compromise RV function.


Assuntos
Pressão Arterial , Hipertensão Pulmonar/etiologia , Hipertrofia Ventricular Direita/etiologia , Artéria Pulmonar/fisiopatologia , Embolia Pulmonar/complicações , Disfunção Ventricular Direita/etiologia , Função Ventricular Direita , Idoso , Cateterismo de Swan-Ganz , Doença Crônica , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/fisiopatologia , Estudos Retrospectivos , Volume Sistólico , Fatores de Tempo , Resistência Vascular , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/fisiopatologia , Remodelação Ventricular
15.
Eur Respir J ; 55(6)2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32366481

RESUMO

AIM: Haemodynamic normalisation is the ultimate goal of pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH). However, whether normalisation of haemodynamics translates into normalisation of exercise capacity is unknown. The incidence, determinants and clinical implications of exercise intolerance after PEA are unknown. We performed a prospective analysis to determine the incidence of exercise intolerance after PEA, assess the relationship between exercise capacity and (resting) haemodynamics and search for preoperative predictors of exercise intolerance after PEA. METHODS: According to clinical protocol all patients underwent cardiopulmonary exercise testing (CPET), right heart catheterisation and cardiac magnetic resonance (CMR) imaging before and 6 months after PEA. Exercise intolerance was defined as a peak oxygen consumption (V'O2 ) <80% predicted. CPET parameters were judged to determine the cause of exercise limitation. Relationships were analysed between exercise intolerance and resting haemodynamics and CMR-derived right ventricular function. Potential preoperative predictors of exercise intolerance were analysed using logistic regression analysis. RESULTS: 68 patients were included in the final analysis. 45 (66%) patients had exercise intolerance 6 months after PEA; in 20 patients this was primarily caused by a cardiovascular limitation. The incidence of residual pulmonary hypertension was significantly higher in patients with persistent exercise intolerance (p=0.001). However, 27 out of 45 patients with persistent exercise intolerance had no residual pulmonary hypertension. In the multivariate analysis, preoperative transfer factor of the lung for carbon monoxide (T LCO) was the only predictor of exercise intolerance after PEA. CONCLUSIONS: The majority of CTEPH patients have exercise intolerance after PEA, often despite normalisation of resting haemodynamics. Not all exercise intolerance after PEA is explained by the presence of residual pulmonary hypertension, and lower preoperative T LCO was a strong predictor of exercise intolerance 6 months after PEA.


Assuntos
Endarterectomia , Hipertensão Pulmonar , Embolia Pulmonar , Doença Crônica , Tolerância ao Exercício , Humanos , Hipertensão Pulmonar/cirurgia , Pulmão , Estudos Prospectivos , Artéria Pulmonar/cirurgia , Embolia Pulmonar/complicações , Resultado do Tratamento
16.
J Card Fail ; 26(1): 26-34, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31394199

RESUMO

BACKGROUND: Drugs approved for pulmonary arterial hypertension have been considered for patients with heart failure with preserved ejection fraction and combined post- and precapillary pulmonary hypertension (Cpc-PH). We aimed to study changes in cardiac volumes, cardiac load and left ventricular (LV) filling pressures in patients with heart failure with preserved ejection fraction and Cpc-PH in response to pulmonary arterial hypertension-specific treatment. METHODS AND RESULTS: In this prospective study, 23 patients with heart failure with preserved ejection fraction and Cpc-PH underwent right-heart catheterization, including acute provocation testing (fluid loading and inhaled nitric oxide) and cardiac MRI at baseline. Right-heart catheterization and cardiac MRI were repeated after 4 months of treatment. At baseline, acutely increasing preload by fluid loading resulted in a significant increase in pulmonary arterial wedge pressure (PAWP), whereas reducing right ventricular (RV) afterload and increasing LV distensability by acute administration of inhaled nitric oxide had no effect on PAWP. After 4 months of treatment, we observed a significant reduction in RV and LV afterload and increased RV and LV stroke volume, but PAWP significantly increased. CONCLUSIONS: In patients with heart failure with preserved ejection fraction and Cpc-PH, 4 months of pulmonary arterial hypertension-specific treatment increased RV and LV stroke volume at the expense of increased PAWP. This increase in PAWP was similarly observed acutely after fluid loading.


Assuntos
Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/tratamento farmacológico , Hemodinâmica/fisiologia , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/tratamento farmacológico , Volume Sistólico/fisiologia , Antagonistas Adrenérgicos beta/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Capilares/fisiopatologia , Estudos de Coortes , Diuréticos/administração & dosagem , Quimioterapia Combinada , Feminino , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/fisiopatologia , Imagem Cinética por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento
18.
Circulation ; 137(9): 910-924, 2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29167228

RESUMO

BACKGROUND: The beneficial effects of parasympathetic stimulation have been reported in left heart failure, but whether it would be beneficial for pulmonary arterial hypertension (PAH) remains to be explored. Here, we investigated the relationship between parasympathetic activity and right ventricular (RV) function in patients with PAH, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase inhibition, in experimental pulmonary hypertension (PH). METHODS: Heart rate recovery after a maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity. RV ejection fraction was assessed in 112 patients with PAH. Expression of nicotinic (α-7 nicotinic acetylcholine receptor) and muscarinic (muscarinic acetylcholine type 2 receptor) receptors, and acetylcholinesterase activity were evaluated in RV (n=11) and lungs (n=7) from patients with PAH undergoing heart/lung transplantation and compared with tissue obtained from controls. In addition, we investigated the effects of PYR (40 mg/kg per day) in experimental PH. PH was induced in male rats by SU5416 (25 mg/kg subcutaneously) injection followed by 4 weeks of hypoxia. In a subgroup, sympathetic/parasympathetic modulation was assessed by power spectral analysis. At week 6, PH status was confirmed by echocardiography, and rats were randomly assigned to vehicle or treatment (both n=12). At the end of the study, echocardiography was repeated, with additional RV pressure-volume measurements, along with lung, RV histological, and protein analyses. RESULTS: Patients with PAH with lower RV ejection fraction (<41%) had a significantly reduced heart rate recovery in comparison with patients with higher RV ejection fraction. In PAH RV samples, α-7 nicotinic acetylcholine receptor was increased and acetylcholinesterase activity was reduced versus controls. No difference in muscarinic acetylcholine type 2 receptor expression was observed. Chronic PYR treatment in PH rats normalized the cardiovascular autonomic function, demonstrated by an increase in parasympathetic activity and baroreflex sensitivity. PYR improved survival, increased RV contractility, and reduced RV stiffness, RV hypertrophy, RV fibrosis, RV inflammation, and RV α-7 nicotinic acetylcholine receptor and muscarinic acetylcholine type 2 receptor expression, as well. Furthermore, PYR reduced pulmonary vascular resistance, RV afterload, and pulmonary vascular remodeling, which was associated with reduced local and systemic inflammation. CONCLUSIONS: RV dysfunction is associated with reduced systemic parasympathetic activity in patients with PAH, with an inadequate adaptive response of the cholinergic system in the RV. Enhancing parasympathetic activity by PYR improved survival, RV function, and pulmonary vascular remodeling in experimental PH.


Assuntos
Inibidores da Colinesterase/uso terapêutico , Endotélio Vascular/patologia , Hipertensão Pulmonar/metabolismo , Sistema Nervoso Parassimpático , Artéria Pulmonar/patologia , Brometo de Piridostigmina/uso terapêutico , Disfunção Ventricular Direita/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Remodelação Vascular , Disfunção Ventricular Direita/tratamento farmacológico , Função Ventricular Direita
19.
Eur Respir J ; 54(4)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31320456

RESUMO

Vena cava backflow is a well-recognised clinical hallmark of right ventricular failure in pulmonary arterial hypertension (PAH). Backflow may result from tricuspid regurgitation during right ventricular systole or from impaired right ventricular diastolic filling during atrial contraction. Our aim was to quantify the forward and backward flow in the vena cava and to establish the main cause in PAH.In 62 PAH patients, cardiac magnetic resonance measurements provided volumetric flows (mL·s-1) in the superior and inferior vena cava; time integration of flow gave volume. The "backward fraction" was defined as the ratio of the backward and forward volumes in the vena cava, expressed as a percentage. Time of maximum vena cava backflow was expressed as a percentage of the cardiac cycle. Right ventricular volumes and aortic stroke volume were determined. Right heart catheterisation gave right ventricular and right atrial pressures. Right ventricular end-diastolic stiffness was determined with the single-beat method.The median (interquartile range) backward fraction was 12% (3-24%) and it was >20% in 21 patients. Maximum backflow occurred at near 90% of the cardiac cycle, coinciding with atrial contraction. The backward fraction was associated with maximal right atrial pressure (Spearman's r=0.77), right ventricular end-diastolic stiffness (r=0.65) and right ventricular end-diastolic pressure (r=0.77), and was negatively associated with stroke volume (r= -0.61) (all p<0.001).Significant backward flow in the vena cava was observed in a large group of PAH patients and occurred mostly during atrial contraction as a consequence of impaired right ventricular filling due to right ventricular diastolic stiffness. The backward flow due to tricuspid regurgitation was of significance in only a small minority of patients.


Assuntos
Função do Átrio Direito , Ventrículos do Coração/diagnóstico por imagem , Hipertensão Arterial Pulmonar/diagnóstico por imagem , Veia Cava Inferior/diagnóstico por imagem , Veia Cava Superior/diagnóstico por imagem , Disfunção Ventricular Direita/diagnóstico por imagem , Pressão Ventricular , Adulto , Idoso , Diástole , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Hipertensão Arterial Pulmonar/fisiopatologia , Volume Sistólico , Insuficiência da Valva Tricúspide/diagnóstico por imagem , Insuficiência da Valva Tricúspide/fisiopatologia , Veia Cava Inferior/fisiopatologia , Veia Cava Superior/fisiopatologia , Disfunção Ventricular Direita/fisiopatologia
20.
Eur Respir J ; 54(3)2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31273046

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterised by abnormal remodelling of pulmonary vessels, leading to increased vascular resistance and right ventricle failure. This abnormal vascular remodelling is associated with endothelial cell dysfunction, increased proliferation of smooth muscle cells, inflammation and impaired bone morphogenetic protein (BMP) signalling. Orphan nuclear receptor Nur77 is a key regulator of proliferation and inflammation in vascular cells, but its role in impaired BMP signalling and vascular remodelling in PAH is unknown.We hypothesised that activation of Nur77 by 6-mercaptopurine (6-MP) would improve PAH by inhibiting endothelial cell dysfunction and vascular remodelling.Nur77 expression is decreased in cultured pulmonary microvascular endothelial cells (MVECs) and lungs of PAH patients. Nur77 significantly increased BMP signalling and strongly decreased proliferation and inflammation in MVECs. In addition, conditioned medium from PAH MVECs overexpressing Nur77 inhibited the growth of healthy smooth muscle cells. Pharmacological activation of Nur77 by 6-MP markedly restored MVEC function by normalising proliferation, inflammation and BMP signalling. Finally, 6-MP prevented and reversed abnormal vascular remodelling and right ventricle hypertrophy in the Sugen/hypoxia rat model of severe angioproliferative PAH.Our data demonstrate that Nur77 is a critical modulator in PAH by inhibiting vascular remodelling and increasing BMP signalling, and activation of Nur77 could be a promising option for the treatment of PAH.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Hipertensão Pulmonar/tratamento farmacológico , Mercaptopurina/farmacologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/agonistas , Animais , Proliferação de Células , Meios de Cultivo Condicionados , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais/efeitos dos fármacos , Células HEK293 , Humanos , Inflamação , Pulmão/efeitos dos fármacos , Masculino , Microcirculação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Remodelação Vascular
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