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Journal of the American Heart... Aug 2019
Review
Topics: Bosentan; Disease Progression; Endothelin Receptor Antagonists; Enzyme Activators; Humans; Hypertension, Pulmonary; Hypoxia; Idiopathic Pulmonary Fibrosis; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Pulmonary Circulation; Pulmonary Diffusing Capacity; Pulmonary Ventilation; Pyrazoles; Pyrimidines; Sildenafil Citrate; Treatment Failure; Vascular Remodeling; Vasoconstriction
PubMed: 31423872
DOI: 10.1161/JAHA.119.013310 -
American Journal of Respiratory and... Jun 2021Data on the molecular mechanisms that regulate platelet-pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic...
Data on the molecular mechanisms that regulate platelet-pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications. To identify a hypoxia-sensitive, modifiable mediator of platelet-pulmonary artery endothelial cell adhesion and thrombotic remodeling. Network medicine was used to profile protein-protein interactions in hypoxia-treated human pulmonary artery endothelial cells. Data from liquid chromatography-mass spectrometry and microscale thermophoresis informed the development of a novel antibody (Ab) to inhibit platelet-endothelial adhesion, which was tested in cells from patients with chronic thromboembolic pulmonary hypertension (CTEPH) and three animal models . The protein NEDD9 was identified in the hypoxia thrombosome network . Compared with normoxia, hypoxia (0.2% O) for 24 hours increased HIF-1α (hypoxia-inducible factor-1α)-dependent NEDD9 upregulation . Increased NEDD9 was localized to the plasma-membrane surface of cells from control donors and patients with CTEPH. In endarterectomy specimens, NEDD9 colocalized with the platelet surface adhesion molecule P-selectin. Our custom-made anti-NEDD9 Ab targeted the NEDD9-P-selectin interaction and inhibited the adhesion of activated platelets to pulmonary artery endothelial cells from control donors and from patients with CTEPH . Compared with control mice, platelet-pulmonary endothelial aggregates and pulmonary hypertension induced by ADP were decreased in NEDD9 mice or wild-type mice treated with the anti-NEDD9 Ab, which also decreased chronic pulmonary thromboembolic remodeling . The NEDD9-P-selectin protein-protein interaction is a modifiable target with which to inhibit platelet-pulmonary endothelial adhesion and thromboembolic vascular remodeling, with potential therapeutic implications for patients with disorders of increased hypoxia signaling pathways, including CTEPH.
Topics: Adaptor Proteins, Signal Transducing; Animals; Blood Platelets; Cell Adhesion; Cells, Cultured; Endothelial Cells; Female; Humans; Hypoxia; Male; Mice; Middle Aged; Models, Animal; Pulmonary Circulation; Pulmonary Embolism; Signal Transduction
PubMed: 33523764
DOI: 10.1164/rccm.202003-0719OC -
Therapeutic Advances in Respiratory... Dec 2015Acute respiratory distress syndrome (ARDS) is a syndrome of acute lung injury that is characterized by noncardiogenic pulmonary edema and severe hypoxemia second to a... (Review)
Review
Acute respiratory distress syndrome (ARDS) is a syndrome of acute lung injury that is characterized by noncardiogenic pulmonary edema and severe hypoxemia second to a pathogenic impairment of gas exchange. Despite significant advances in the area, mortality remains high among ARDS patients. High mortality and a limited spectrum of therapeutic options have left clinicians searching for alternatives, spiking interest in selective pulmonary vasodilators (SPVs). Despite the lack of robust evidence, SPVs are commonly employed for their therapeutic role in improving oxygenation in patients who have developed refractory hypoxemia in ARDS. While inhaled epoprostenol (iEPO) also impacts arterial oxygenation by decreasing ventilation-perfusion (V/Q) mismatching and pulmonary shunt flow, this effect is not different from inhaled nitric oxide (iNO). The most effective and safest dose for yielding a clinically significant increase in PaO2 and reduction in pulmonary artery pressure (PAP) appears to be 20-30 ng/kg/min in adults and 30 ng/kg/min in pediatric patients. iEPO appears to have a ceiling effect above these doses in which no additional benefit may be derived. iNO and iEPO have shown similar efficacy profiles; however, they differ with respect to cost and ease of therapeutic administration. The most beneficial effects of iEPO have been seen in adult patients with secondary ARDS as compared with primary ARDS, most likely due to the difference in etiology of the two disease states, and in patients suffering from baseline right ventricular heart failure. Although iEPO has demonstrated improvements in hemodynamic parameters and oxygenation in ARDS patients, due to the limited number of randomized clinical trials and the lack of studies investigating mortality, the use of iEPO cannot be recommended as standard of care in ARDS. iEPO should be reserved for those refractory to traditional therapies.
Topics: Administration, Inhalation; Age Factors; Cost-Benefit Analysis; Drug Administration Schedule; Drug Costs; Drug Dosage Calculations; Epoprostenol; Humans; Lung; Pulmonary Circulation; Recovery of Function; Respiratory Distress Syndrome; Respiratory System Agents; Treatment Outcome; Vasodilation; Vasodilator Agents
PubMed: 26294418
DOI: 10.1177/1753465815599345 -
Methods in Molecular Biology (Clifton,... 2017Chronic pulmonary hypertension (PH) is associated with right ventricular failure and high mortality regardless of the underlying disease. Currently, therapies can...
Chronic pulmonary hypertension (PH) is associated with right ventricular failure and high mortality regardless of the underlying disease. Currently, therapies can improve clinical outcomes in specific subsets of patients, but have little impact on the progression of pulmonary vascular remodeling. Upon new advances in vector development and delivery techniques, gene therapy is a novel strategy in this field with the potential of overcoming the main limitations of approved drug therapies: modulation of novel anti-remodeling targets and selective pulmonary vasculature targeting with minimal systemic effects. In the recent years, several reports have shown that gene transfer to the pulmonary vascular system is feasible in rodent models of PH. Our group has focused on the translation of airway delivery of viral vectors in small and large animals. Here, we describe a procedure to achieve vector transduction at the distal vasculature in animal models of PH and the methods to evaluate the outcomes of this intervention as a promising new approach in pulmonary vascular diseases.
Topics: Administration, Inhalation; Animals; Disease Models, Animal; Electrocardiography; Gene Transfer Techniques; Heart Ventricles; Hemodynamics; Pulmonary Circulation; Swine; Transduction, Genetic
PubMed: 27910061
DOI: 10.1007/978-1-4939-6588-5_24 -
The European Respiratory Journal Oct 2015Right ventricular adaptation to the increased pulmonary arterial load is a key determinant of outcomes in pulmonary hypertension (PH). Pulmonary vascular resistance...
Right ventricular adaptation to the increased pulmonary arterial load is a key determinant of outcomes in pulmonary hypertension (PH). Pulmonary vascular resistance (PVR) and total arterial compliance (C) quantify resistive and elastic properties of pulmonary arteries that modulate the steady and pulsatile components of pulmonary arterial load, respectively. PVR is commonly calculated as transpulmonary pressure gradient over pulmonary flow and total arterial compliance as stroke volume over pulmonary arterial pulse pressure (SV/PApp). Assuming that there is an inverse, hyperbolic relationship between PVR and C, recent studies have popularised the concept that their product (RC-time of the pulmonary circulation, in seconds) is "constant" in health and diseases. However, emerging evidence suggests that this concept should be challenged, with shortened RC-times documented in post-capillary PH and normotensive subjects. Furthermore, reported RC-times in the literature have consistently demonstrated significant scatter around the mean. In precapillary PH, the true PVR can be overestimated if one uses the standard PVR equation because the zero-flow pressure may be significantly higher than pulmonary arterial wedge pressure. Furthermore, SV/PApp may also overestimate true C. Further studies are needed to clarify some of the inconsistencies of pulmonary RC-time, as this has major implications for our understanding of the arterial load in diseases of the pulmonary circulation.
Topics: Blood Pressure; Elasticity; Heart Ventricles; Humans; Hypertension, Pulmonary; Lung; Prognosis; Pulmonary Artery; Pulmonary Circulation; Pulmonary Medicine; Pulmonary Wedge Pressure; Reference Values; Reproducibility of Results; Stroke Volume; Systole; Vascular Resistance; Ventricular Dysfunction, Right
PubMed: 26341990
DOI: 10.1183/13993003.00741-2015 -
European Respiratory Review : An... Sep 2021Cardiopulmonary exercise testing (CPET) is a frequently used tool in the differential diagnosis of dyspnoea. Ventilatory inefficiency, defined as high minute ventilation...
Cardiopulmonary exercise testing (CPET) is a frequently used tool in the differential diagnosis of dyspnoea. Ventilatory inefficiency, defined as high minute ventilation ( ) relative to carbon dioxide output ( ), is a hallmark characteristic of pulmonary vascular diseases, which contributes to exercise intolerance and disability in these patients. The mechanisms of ventilatory inefficiency are multiple and include high physiologic dead space, abnormal chemosensitivity and an altered carbon dioxide (CO) set-point. A normal / makes a pulmonary vascular disease such as pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) unlikely. The finding of high without an alternative explanation should prompt further diagnostic testing to exclude PAH or CTEPH, particularly in patients with risk factors, such as prior venous thromboembolism, systemic sclerosis or a family history of PAH. In patients with established PAH or CTEPH, the / may improve with interventions and is a prognostic marker. However, further studies are needed to clarify the added value of assessing ventilatory inefficiency in the longitudinal follow-up of patients.
Topics: Exercise Test; Humans; Hypertension, Pulmonary; Lung; Pulmonary Arterial Hypertension; Pulmonary Circulation
PubMed: 34289981
DOI: 10.1183/16000617.0214-2020 -
Experimental Physiology Dec 2020What is the topic of this review? This review concerns the negative impact of pulmonary hypertension (PH) on the pulmonary haemodynamic and gas exchange responses to... (Review)
Review
NEW FINDINGS
What is the topic of this review? This review concerns the negative impact of pulmonary hypertension (PH) on the pulmonary haemodynamic and gas exchange responses to exercise, considering the mechanisms by which PH plays a role in exercise intolerance in heart failure (HF) patients. What advances does it highlight? The hallmark limited pulmonary vascular 'reserve' and impaired pulmonary gas exchange responses to exercise in HF are worsened by the development of PH; these are key determinants of exercise intolerance. Even HF patients who present with 'normal' pulmonary vascular function experience exercise-induced PH, which plays a role in exercise intolerance.
ABSTRACT
Patients with heart failure universally complain of exertional intolerance, but the underlying cause(s) of this intolerance may differ between patients with different disease phenotypes. Exercise introduces an impressive stress to the lungs, where elevations in venous return and cardiac output engender substantial increases in pulmonary blood volume and flow. Relative to healthy individuals, the pulmonary vascular reserve to accept this increase in pulmonary perfusion is compromised in heart failure, with a growing body of evidence suggesting that the development of pulmonary hypertension (PH), and in particular a precapillary component of PH, worsens the pulmonary haemodynamic response to exercise in these patients. Characterized by an exaggerated increase in pulmonary arterial pressure and an elevation in pulmonary vascular resistance, this dysfunctional pulmonary haemodynamic response plays a role in exercise intolerance, probably through an impairment of right ventricular function, underperfusion of the pulmonary circulation and a subsequent reduction in systemic blood flow and oxygen delivery. The hallmark abnormalities in ventilatory and pulmonary gas exchange that accompany heart failure, including a greater ventilatory equivalent for carbon dioxide, are also worsened by the development of PH. This raises the possibility that measures of exercise pulmonary gas exchange might help to 'describe' underlying PH in heart failure; however, several fundamental issues and questions need to be addressed before such gas exchange measures could truly be considered efficacious measures used to differentiate the type of PH and track the severity of PH in heart failure. exercise intolerance, heart failure, pulmonary gas exchange, pulmonary haemodynamics, pulmonary hypertension.
Topics: Exercise; Exercise Tolerance; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Pulmonary Artery; Pulmonary Circulation; Pulmonary Gas Exchange
PubMed: 32092200
DOI: 10.1113/EP088105 -
Journal of Cardiovascular Magnetic... Nov 2019Body position can be optimized for pulmonary ventilation/perfusion matching during surgery and intensive care. However, positional effects upon distribution of pulmonary... (Comparative Study)
Comparative Study
BACKGROUND
Body position can be optimized for pulmonary ventilation/perfusion matching during surgery and intensive care. However, positional effects upon distribution of pulmonary blood flow and vascular distensibility measured as the pulmonary blood volume variation have not been quantitatively characterized. In order to explore the potential clinical utility of body position as a modulator of pulmonary hemodynamics, we aimed to characterize gravitational effects upon distribution of pulmonary blood flow, pulmonary vascular distension, and pulmonary vascular distensibility.
METHODS
Healthy subjects (n = 10) underwent phase contrast cardiovascular magnetic resonance (CMR) pulmonary artery and vein flow measurements in the supine, prone, and right/left lateral decubitus positions. For each lung, blood volume variation was calculated by subtracting venous from arterial flow per time frame.
RESULTS
Body position did not change cardiac output (p = 0.84). There was no difference in blood flow between the superior and inferior pulmonary veins in the supine (p = 0.92) or prone body positions (p = 0.43). Compared to supine, pulmonary blood flow increased to the dependent lung in the lateral positions (16-33%, p = 0.002 for both). Venous but not arterial cross-sectional vessel area increased in both lungs when dependent compared to when non-dependent in the lateral positions (22-27%, p ≤ 0.01 for both). In contrast, compared to supine, distensibility increased in the non-dependent lung in the lateral positions (68-113%, p = 0.002 for both).
CONCLUSIONS
CMR demonstrates that in the lateral position, there is a shift in blood flow distribution, and venous but not arterial blood volume, from the non-dependent to the dependent lung. The non-dependent lung has a sizable pulmonary vascular distensibility reserve, possibly related to left atrial pressure. These results support the physiological basis for positioning patients with unilateral pulmonary pathology with the "good lung down" in the context of intensive care. Future studies are warranted to evaluate the diagnostic potential of these physiological insights into pulmonary hemodynamics, particularly in the context of non-invasively characterizing pulmonary hypertension.
Topics: Adult; Female; Gravitation; Healthy Volunteers; Hemodynamics; Humans; Magnetic Resonance Angiography; Magnetic Resonance Imaging, Cine; Male; Patient Positioning; Prone Position; Prospective Studies; Pulmonary Artery; Pulmonary Circulation; Pulmonary Veins; Supine Position; Young Adult
PubMed: 31707989
DOI: 10.1186/s12968-019-0577-9 -
Paediatric Respiratory Reviews Jun 2015The newborn's transition from fetal to neonatal life includes aeration of the lungs, establishment of pulmonary gas exchange and changing the fetal circulation into the... (Review)
Review
The newborn's transition from fetal to neonatal life includes aeration of the lungs, establishment of pulmonary gas exchange and changing the fetal circulation into the adult phenotype. This review summarizes the latest research findings, which show that lung aeration, airway liquid clearance and cardiovascular changes are directly interconnected at birth. The mechanisms of airway liquid clearance at birth are reviewed and the particular importance of the transpulmonary pressure gradient during lung aeration is discussed. Further, we summarize research findings which prove that lung aeration triggers the increase in pulmonary blood flow (PBF) at birth, and how the increase in PBF secures the preload for left ventricular output. Consequently, we review animal experiments which suggest that delaying umbilical cord clamping until breathing commences facilitates hemodynamic stability during transition. These data are reviewed with respect to the clinical applicability: As lung aeration is the key to successful transition to newborn life, providing adequate respiratory support at birth must be the primary objective of neonatal staff attending to the newborn infant. Clinical studies are needed to demonstrate whether the obvious benefits of delaying cord clamping until breathing commences hold true in human babies.
Topics: Animals; Constriction; Hemodynamics; Humans; Infant, Newborn; Lung; Pulmonary Circulation; Pulmonary Gas Exchange; Respiration; Umbilical Cord
PubMed: 25870083
DOI: 10.1016/j.prrv.2015.03.003 -
International Journal of Cardiology Nov 2018Elevation in central venous pressure (CVP) plays a fundamental pathophysiologic role in Fontan circulation. Because there is no sub-pulmonary ventricle in this system,...
BACKGROUND
Elevation in central venous pressure (CVP) plays a fundamental pathophysiologic role in Fontan circulation. Because there is no sub-pulmonary ventricle in this system, CVP also provides the driving force for pulmonary blood flow. We hypothesized that this would make Fontan patients more susceptible to even low-level elevation in pulmonary vascular resistance index (PVRI), resulting in greater systemic venous congestion and adverse outcomes.
METHODS
Adult Fontan patients and controls without congenital heart disease undergoing clinical evaluation that included cardiac catheterization and echocardiography were examined retrospectively. Outcomes including all-cause mortality and the development of Fontan associated diseases (FAD, defined as protein losing enteropathy, cirrhosis, heart failure hospitalization, arrhythmia, or thromboembolism) were assessed from longitudinal assessment.
RESULTS
As compared to controls (n = 82), Fontan patients (n = 164) were younger (36 vs 45 years, p < 0.001), more likely to be on anticoagulation or antiplatelet therapy, and more likely to have atrial arrhythmia or cirrhosis. There was a strong correlation between CVP and PVRI in the Fontan group (r = 0.79, p < 0.001), but there was no such relationship in controls. Elevated PVRI identified patients at increased risk for FAD (HR 1.92, 95% CI 1.39-2.41, p = 0.01), and composite endpoint of FAD and/or death (HR 1.89, 95% CI 1.32-2.53, p = 0.01) per 1 WU∗m increment.
CONCLUSIONS
Systemic venous congestion, which is the primary factor in the pathogenesis of FAD and death, is related to even low-level abnormalities in pulmonary vascular function. Multicenter studies are needed to determine whether interventions targeting pulmonary vascular structure and function can improve outcomes in the Fontan population.
Topics: Adult; Central Venous Pressure; Cohort Studies; Cross-Sectional Studies; Female; Fontan Procedure; Humans; Hyperemia; Male; Middle Aged; Prognosis; Pulmonary Circulation; Retrospective Studies; Treatment Outcome
PubMed: 30223363
DOI: 10.1016/j.ijcard.2018.05.039