Pulmonary Vascular Dysfunctions in Cystic Fibrosis.

Cystic fibrosis (CF) is an inherited disorder caused by a deleterious mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Given that the CFTR protein is a chloride channel expressed on a variety of cells throughout the human body, mutations in this gene impact several organs, particularly the lungs. For this very reason, research regarding CF disease and CFTR function has historically focused on the lung airway epithelium. Nevertheless, it was discovered more than two decades ago that CFTR is also expressed and functional on endothelial cells. Despite the great strides that have been made in understanding the role of CFTR in the airway epithelium, the role of CFTR in the endothelium remains unclear. Considering that the airway epithelium and endothelium work in tandem to allow gas exchange, it becomes very crucial to understand how a defective CFTR protein can impact the pulmonary vasculature and overall lung function. Fortunately, more recent research has been dedicated to elucidating the role of CFTR in the endothelium. As a result, several vascular dysfunctions associated with CF disease have come to light. Here, we summarize the current knowledge on pulmonary vascular dysfunctions in CF and discuss applicable therapies.

Physiologic Effects of Extracorporeal Membrane Oxygenation in Patients with Severe Acute Respiratory Distress Syndrome.

Rationale: Blood flow rate affects mixed venous oxygenation (SvO2) during venovenous extracorporeal membrane oxygenation (ECMO), with possible effects on the pulmonary circulation and the right heart function. Objectives: To describe the physiologic effects of different levels of SvO2 obtained by changing ECMO blood flow in patients with severe acute respiratory distress syndrome receiving ECMO and controlled mechanical ventilation. Methods: Low (SvO2 target, 70-75%), intermediate (SvO2 target, 75-80%), and high (SvO2 target, >80%) ECMO blood flows were applied for 30 minutes in random order in 20 patients. Mechanical ventilation settings were left unchanged. The hemodynamic and pulmonary effects were assessed with pulmonary artery catheter and electrical impedance tomography. Measurements and Main Results: Cardiac output decreased from low to intermediate and to high blood flow/SvO2 (9.2 [6.2-10.9] vs. 8.3 [5.9-9.8] vs. 7.9 [6.5-9.1] L/min; P = 0.014), as well as mean pulmonary artery pressure (34 ± 6 vs. 31 ± 6 vs. 30 ± 5 mm Hg; P < 0.001) and right ventricular stroke work index (14.2 ± 4.4 vs. 12.2 ± 3.6 vs. 11.4 ± 3.2 g × m/beat/m2; P = 0.002). Cardiac output was inversely correlated with mixed venous and arterial Po2 values (R2 = 0.257; P = 0.031; and R2 = 0.324; P = 0.05). Pulmonary artery pressure was correlated with decreasing mixed venous Po2 (R2 = 0.29; P < 0.001) and with increasing cardiac output (R2 = 0.378; P < 0.007). Measures of [Formula: see text]/[Formula: see text] mismatch did not differ between the three steps. Conclusions: In patients with severe acute respiratory distress syndrome, increased ECMO blood flow rate resulting in higher SvO2 decreases pulmonary artery pressure, cardiac output, and right heart workload.

Quantitative texture analysis using machine learning for predicting interpretable pulmonary perfusion from non-contrast computed tomography in pulmonary embolism patients.

BACKGROUND: Pulmonary embolism (PE) is life-threatening and requires timely and accurate diagnosis, yet current imaging methods, like computed tomography pulmonary angiography, present limitations, particularly for patients with contraindications to iodinated contrast agents. We aimed to develop a quantitative texture analysis pipeline using machine learning (ML) based on non-contrast thoracic computed tomography (CT) scans to discover intensity and textural features correlated with regional lung perfusion (Q) physiology and pathology and synthesize voxel-wise Q surrogates to assist in PE diagnosis. METHODS: We retrospectively collected 99mTc-labeled macroaggregated albumin Q-SPECT/CT scans from patients suspected of PE, including an internal dataset of 76 patients (64 for training, 12 for testing) and an external testing dataset of 49 patients. Quantitative CT features were extracted from segmented lung subregions and underwent a two-stage feature selection pipeline. The prior-knowledge-driven preselection stage screened for robust and non-redundant perfusion-correlated features, while the data-driven selection stage further filtered features by fitting ML models for classification. The final classification model, trained with the highest-performing PE-associated feature combination, was evaluated in the testing cohorts based on the Area Under the Curve (AUC) for subregion-level predictability. The voxel-wise Q surrogate was then synthesized using the final selected feature maps (FMs) and model score maps (MSMs) to investigate spatial distributions. The Spearman correlation coefficient (SCC) and Dice similarity coefficient (DSC) were used to assess the spatial consistency between FMs or MSMs and Q-SPECT scans. RESULTS: The optimal model performance achieved an AUC of 0.863 during internal testing and 0.828 on the external testing cohort. The model identified a combination containing 14 intensity and textural features that were non-redundant, robust, and capable of distinguishing between high- and low-functional lung regions. Spatial consistency assessment in the internal testing cohort showed moderate-to-high agreement between MSMs and reference Q-SPECT scans, with median SCC of 0.66, median DSCs of 0.86 and 0.64 for high- and low-functional regions, respectively. CONCLUSIONS: This study validated the feasibility of using quantitative texture analysis and a data-driven ML pipeline to generate voxel-wise lung perfusion surrogates, providing a radiation-free, widely accessible alternative to functional lung imaging in managing pulmonary vascular diseases. CLINICAL TRIAL NUMBER: Not applicable.

Effects of Positive End-expiratory Pressure on Pulmonary Perfusion Distribution and Intrapulmonary Shunt during One-lung Ventilation in Pigs: A Randomized Crossover Study.

BACKGROUND: During one-lung ventilation (OLV), positive end-expiratory pressure (PEEP) can improve lung aeration but might overdistend lung units and increase intrapulmonary shunt. The authors hypothesized that higher PEEP shifts pulmonary perfusion from the ventilated to the nonventilated lung, resulting in a U-shaped relationship with intrapulmonary shunt during OLV. METHODS: In nine anesthetized female pigs, a thoracotomy was performed and intravenous lipopolysaccharide infused to mimic the inflammatory response of thoracic surgery. Animals underwent OLV in supine position with PEEP of 0 cm H2O, 5 cm H2O, titrated to best respiratory system compliance, and 15 cm H2O (PEEP0, PEEP5, PEEPtitr, and PEEP15, respectively, 45 min each, Latin square sequence). Respiratory, hemodynamic, and gas exchange variables were measured. The distributions of perfusion and ventilation were determined by IV fluorescent microspheres and computed tomography, respectively. RESULTS: Compared to two-lung ventilation, the driving pressure increased with OLV, irrespective of the PEEP level. During OLV, cardiac output was lower at PEEP15 (5.5 ± 1.5 l/min) than PEEP0 (7.6 ± 3 l/min) and PEEP5 (7.4 ± 2.9 l/min; P = 0.004), while the intrapulmonary shunt was highest at PEEP0 (PEEP0: 48.1% ± 14.4%; PEEP5: 42.4% ± 14.8%; PEEPtitr: 37.8% ± 11.0%; PEEP15: 39.0% ± 10.7%; P = 0.027). The relative perfusion of the ventilated lung did not differ among PEEP levels (PEEP0: 65.0% ± 10.6%; PEEP5: 68.7% ± 8.7%; PEEPtitr: 68.2% ± 10.5%; PEEP15: 58.4% ± 12.8%; P = 0.096), but the centers of relative perfusion and ventilation in the ventilated lung shifted from ventral to dorsal and from cranial to caudal zones with increasing PEEP. CONCLUSIONS: In this experimental model of thoracic surgery, higher PEEP during OLV did not shift the perfusion from the ventilated to the nonventilated lung, thus not increasing intrapulmonary shunt.

The relevance of vascular adjustments to hemodynamic control in the face of temperature change in Crotalus durissus.

The presence of cardiac shunts in ectothermic tetrapods is thought to be consistent with active vascular modulations for proper hemodynamic support. Local control of blood flow modulates tissue perfusion and thus systemic conductance (Gsys) is assumed to increase with body temperature (Tb) to accommodate higher aerobic demand. However, the general increase of Gsys presses for a higher right-to-left (R-L) shunt, which reduces arterial oxygen concentration. In contrast, Tb reduction leads to a Gsys decrease and a left-to-right shunt, which purportedly increases pulmonary perfusion and plasma filtration in the respiratory area. This investigation addressed the role of compensatory vascular adjustments in the face of the metabolic alterations caused by Tb change in the South American rattlesnake (Crotalus durissus). Cardiovascular recordings were performed in decerebrated rattlesnake preparations at 10, 20 and 30°C. The rise in Tb increased metabolic demand, and correlated with an augmentation in heart rate. Although cardiac output increased, systemic stroke volume reduced while pulmonary stroke volume remained stable. Although that resulted in a proportionally higher increase in pulmonary blood flow, the R-L shunt was maintained. While the systemic compliance of large arteries was the most relevant factor in regulating arterial systemic blood pressure, peripheral conductance of pulmonary circulation was the major factor influencing the final cardiac shunt. Such dynamic adjustment of systemic compliance and pulmonary resistance for shunt modulation has not been demonstrated before and contrasts with previous knowledge on shunt control.

Novel interventions on the tricuspid valve: how to consider the pulmonary circulation?

PURPOSE OF REVIEW: This review addresses treatment options for moderate to severe tricuspid valve regurgitation and the importance of right ventricular function and the pulmonary circulation. RECENT FINDINGS: Several interventional treatment options for severe tricuspid regurgitation have been developed including transcatheter edge-to-edge repair, annuloplasty and valve replacement. So far, transcatheter edge-to-edge repair is most frequently used with procedural success rates of more than 95% and improvements in functional and quality of life parameters for up to 2 years. Right ventricular function as well as pulmonary artery pressure and resistance levels are important outcome predictors. Mean pulmonary artery pressure more than 30 mmHg, transpulmonary gradient more than 17 mmHg and right ventricular to pulmonary artery coupling ratio less than 0.406 indicate poor outcome. SUMMARY: Despite the remarkable safety of interventional treatment of severe tricuspid regurgitation right ventricular dysfunction and abnormal pulmonary hemodynamics are important determinants of procedural success and clinical outcome.Complete hemodynamic work-up should be an integral part of prerepair assessment although validated data predicting outcome are limited.

Evaluation of the Relationship Between Pulmonary Perfusion Via Chest Digital Dynamic Radiography System and Diffusing Capacity Test.

Non-invasive, visual, and quantitative in vivo evaluation of pulmonary blood flow is helpful in assessing gas exchange at the alveolar level. A chest digital dynamic radiography system (CDDR) has the potential to visually and quantitatively express pulmonary haemodynamics using temporal changes in radiographic transparency synchronised with the heartbeat. The lung-diffusing capacity (DLCO) test involves membranous factors comprising the alveolar membrane, interstitium, and vascular walls. Additionally, DLCO includes pulmonary blood flow factors defined by pulmonary capillary blood flow and haemoglobin levels. In individuals lacking an alveolar septum, interstitial abnormalities or anaemia leading to changes in DLCO may reflect changes in the pulmonary blood flow. Here, we investigated the usefulness of CDDR in evaluating pulmonary blood flow by comparing it with DLCO.For pulmonary blood flow, we extracted and visualised signal changes in the lung field synchronised with heart rate during CDDR imaging and created a maximum intensity projection (MIP). The DLCO was measured using the single-breath method. Among the patients who underwent CDDR, 10 with FEV/FVC (FEV1.0%) > 70% and 16 with COPD (FEV1.0% < 70%) without noticeable interstitial changes were included, with a cutoff = 70%/predicted value. MIP was compared as a pulmonary blood flow evaluation method in the DLCO≥70% group (control group: n = 15) and the DLCO<70% group (decreased DLCO group: n = 11). The mean and median values of MIP in the reduced group were lower than those in the control group (p < 0.05).Pulmonary blood flow evaluated using CDDR may be able to assess pulmonary circulatory disturbances visually and quantitatively, as indicated by decreased pulmonary diffusion capacity in patients with negligible pulmonary interstitial changes and anaemia.

Utility of Balloon Occlusion Testing in Determining Fontan Suitability Among Patients with Elevated Pulmonary Artery Pressure and Additional Antegrade Pulmonary Blood Flow.

In individuals with a single ventricle undergoing evaluation before Fontan surgery, the presence of excessive pulmonary blood flow can contribute to increased pulmonary artery pressure, notably in those who had a Glenn procedure with antegrade pulmonary flow. 28 patients who had previously undergone Glenn anastomosis with antegrade pulmonary blood flow (APBF) and with elevated mean pulmonary artery (mPAP) pressure > 15 mmHg in diagnostic catheter angiography were included in the study. After addressing other anatomical factors that could affect pulmonary artery pressure, APBF was occluded with semi-compliant, Wedge or sizing balloons to measure pulmonary artery pressure accurately. 23 patients (82% of the cohort) advanced to Fontan completion. In this group, median mPAP dropped from 20.5 (IQR 19-22) mmHg to 13 (IQR 12-14) mmHg post-test (p < 0.001). Median PVR post-test was 1.8 (IQR 1.5-2.1) WU m2. SpO2 levels decreased from a median of 88% (IQR 86%-93%) pre-test to 80% (IQR 75%-84%) post-test (p < 0.001). In five patients, elevated mPAP post-test occlusion on diagnostic catheter angiography led to non-completion of Fontan circulation. In this group, median pre- and post-test mPAP were 23 mmHg (IQR 21.5-23.5) and 19 mmHg (IQR 18.5-20), respectively (p = 0.038). Median post-test PVR was 3.8 (IQR 3.6-4.5) WU m2. SpO2 levels decreased from a median of 79% (IQR 76%-81%) pre-test to 77% (IQR 73.5%-80%) post-test (p = 0.039). Our study presents a specialized approach for patients initially deemed unsuitable for Fontan due to elevated pulmonary artery pressures. We were able to successfully complete the Fontan procedure in the majority of these high-risk cases after temporary balloon occlusion test.

Teaching the distribution of pulmonary blood flow using a Starling resistor model and turbine flowmeters.

The distribution of pulmonary blood flow is uneven and can be described as a three-zone model, the West zones: zone 1 occurs whenever alveolar pressure exceeds arterial pressure; zone 2 when the arterial pressure is greater than alveolar but the alveolar pressure exceeds the venous pressure; and finally zone 3 when both arterial and venous pressures exceed alveolar pressure. Consequently, the blood flow is almost determined by the difference between the arterial and venous pressures in zone 3 and between arterial and alveolar pressures in zone 2 and ceases in zone 1. The understanding of this subject may be difficult to some medical students. Therefore, to improve the learning of this topic in our physiology course, we used a didactic model to demonstrate the core concept of flow down gradients and its application to pulmonary blood flow. We modeled a Starling resistor by placing a collapsible tube inside a hermetic chamber of variable pressure. Transparent turbine flowmeters were connected to the upstream and downstream extremities of the Starling resistor, and we generated a constant airflow with a brushless motor. By maintaining the input (arterial) pressure constant and varying the chamber (alveolar) pressure, we could simulate the three zones and demonstrate the resulting flow through the turbines. In conclusion, our demonstration using a Starling resistor model combined with visible turbine flowmeters can be used to facilitate comprehension of important concepts in physiology involving flow down gradients, such as pulmonary blood flow.NEW & NOTEWORTHY The understanding of respiratory physiology is a challenge to medical students. To improve the learning of pulmonary blood flow distribution through lung vessels in our physiology course, we modeled a Starling resistor model combined with visible turbine flowmeters. Our model can significantly improve the core concept of flow down gradients teaching and its application to West zones.

Pulmonary Transit Time Assessment by CEUS in Healthy Rabbits: Feasibility, and the Effects of UCAs Dilution Concentration.

To evaluate the inter-observer variability and the intra-observer repeatability of pulmonary transit time (PTT) measurement using contrast-enhanced ultrasound (CEUS) in healthy rabbits, and assess the effects of dilution concentration of ultrasound contrast agents (UCAs) on PTT. Thirteen healthy rabbits were selected, and five concentrations UCAs of 1:200, 1:100, 1:50, 1:10, and 1:1 were injected into the right ear vein. Five digital loops were obtained from the apical 4-chamber view. Four sonographers obtained PTT by plotting the TIC of right atrium (RA) and left atrium (LA) at two time points (T1 and T2). The frame counts of the first appearance of UCAs in RA and LA had excellent inter-observer agreement, with intra-class correlations (ICC) of 0.996, 0.988, respectively. The agreement of PTT among four observers was all good at five different concentrations, with an ICC of 0.758-0.873. The reproducibility of PTT obtained by four observers at T1 and T2 was performed well, with ICC of 0.888-0.961. The median inter-observer variability across 13 rabbits was 6.5% and the median variability within 14 days for 4 observers was 1.9%, 1.7%, 2.2%, 1.9%, respectively; The PTT of 13 healthy rabbits is 1.01 ± 0.18 second. The difference of PTT between five concentrations is statistically significant. The PTT obtained by a concentration of 1:200 and 1:100 were higher than that of 1:1, while there were no significantly differences in PTT of a concentration of 1:1, 1:10, and 1:50. PTT measured by CEUS in rabbits is feasible, with excellent inter-observer and intra-observer reliability and reproducibility, and dilution concentration of UCAs influences PTT results.

Hyperoxia-induced stepwise reduction in blood flow through intrapulmonary, but not intracardiac, shunt during exercise.

Blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) (QIPAVA) increases during exercise breathing air, but it has been proposed that QIPAVA is reduced during exercise while breathing a fraction of inspired oxygen ([Formula: see text]) of 1.00. It has been argued that the reduction in saline contrast bubbles through IPAVA is due to altered in vivo microbubble dynamics with hyperoxia reducing bubble stability, rather than closure of IPAVA. To definitively determine whether breathing hyperoxia decreases saline contrast bubble stability in vivo, the present study included individuals with and without patent foramen ovale (PFO) to determine if hyperoxia also eliminates left heart contrast in people with an intracardiac right-to-left shunt. Thirty-two participants consisted of 16 without a PFO; 8 females, 8 with a PFO; 4 females, and 8 with late-appearing left-sided contrast (4 females) completed five, 4-min bouts of constant-load cycle ergometer exercise (males: 250 W, females: 175 W), breathing an [Formula: see text] = 0.21, 0.40, 0.60, 0.80, and 1.00 in a balanced Latin Squares design. QIPAVA was assessed at rest and 3 min into each exercise bout via transthoracic saline contrast echocardiography and our previously used bubble scoring system. Bubble scores at [Formula: see text]= 0.21, 0.40, and 0.60 were unchanged and significantly greater than at [Formula: see text]= 0.80 and 1.00 in those without a PFO. Participants with a PFO had greater bubble scores at [Formula: see text]= 1.00 than those without a PFO. These data suggest that hyperoxia-induced decreases in QIPAVA during exercise occur when [Formula: see text] ≥ 0.80 and is not a result of altered in vivo microbubble dynamics supporting the idea that hyperoxia closes QIPAVA.

The Pulmonary Vasculature.

The pulmonary circulation is a low-pressure, low-resistance circuit whose primary function is to deliver deoxygenated blood to, and oxygenated blood from, the pulmonary capillary bed enabling gas exchange. The distribution of pulmonary blood flow is regulated by several factors including effects of vascular branching structure, large-scale forces related to gravity, and finer scale factors related to local control. Hypoxic pulmonary vasoconstriction is one such important regulatory mechanism. In the face of local hypoxia, vascular smooth muscle constriction of precapillary arterioles increases local resistance by up to 250%. This has the effect of diverting blood toward better oxygenated regions of the lung and optimizing ventilation-perfusion matching. However, in the face of global hypoxia, the net effect is an increase in pulmonary arterial pressure and vascular resistance. Pulmonary vascular resistance describes the flow-resistive properties of the pulmonary circulation and arises from both precapillary and postcapillary resistances. The pulmonary circulation is also distensible in response to an increase in transmural pressure and this distention, in addition to recruitment, moderates pulmonary arterial pressure and vascular resistance. This article reviews the physiology of the pulmonary vasculature and briefly discusses how this physiology is altered by common circumstances.

The Right Ventricle in Pulmonary Hypertension.

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.

Mechanisms of Acute Right Ventricular Injury in Cardiothoracic Surgical and Critical Care Settings: Part 2.

The right ventricle (RV) is intricately linked in the clinical presentation of critical illness; however, the basis of this is not well-understood and has not been studied as extensively as the left ventricle. There has been an increased awareness of the need to understand how the RV is affected in different critical illness states. In addition, the increased use of point-of-care echocardiography in the critical care setting has allowed for earlier identification and monitoring of the RV in a patient who is critically ill. The first part of this review describes and characterizes the RV in different perioperative states. This second part of the review discusses and analyzes the complex pathophysiologic relationships between the RV and different critical care states. There is a lack of a universal RV injury definition because it represents a range of abnormal RV biomechanics and phenotypes. The term "RV injury" (RVI) has been used to describe a spectrum of presentations, which includes diastolic dysfunction (early injury), when the RV retains the ability to compensate, to RV failure (late or advanced injury). Understanding the mechanisms leading to functional 'uncoupling' between the RV and the pulmonary circulation may enable perioperative physicians, intensivists, and researchers to identify clinical phenotypes of RVI. This, consequently, may provide the opportunity to test RV-centric hypotheses and potentially individualize therapies.

Comparison of phase contrast magnetic resonance imaging and scintigraphy for determination of split pulmonary blood flow in children and young adults with congenital heart disease.

BACKGROUND: Measurement of differential blood flow to the lungs is important to understanding flow dynamics in the setting of congenital heart disease. Split blood flow via the pulmonary arteries guides and demonstrates the effect of interventions. Minimally invasive imaging of pulmonary blood flow can be achieved with scintigraphy or magnetic resonance imaging (MRI). OBJECTIVE: To assess agreement of pulmonary blood flow measurements obtained by scintigraphy and MRI in children and young adults. MATERIALS AND METHODS: We performed a retrospective review of patients < 21 years of age who had undergone both nuclear medicine pulmonary perfusion scans (Tc-99 m MAA) and cardiac MRI examinations from January 2012 to August 2021 at our tertiary pediatric hospital. Patient demographics, medical/surgical information, and estimates of split blood flow by both modalities were recorded. Pearson's correlation coefficient was used to determine the relationship between split blood flow measured by the two examinations. Agreement was calculated using interclass correlation coefficient (ICC) for absolute agreement and Bland-Altman difference analysis. RESULTS: Correlation between split blood flow measured by scintigraphy and MRI using net flow was 0.90 (95% CI: 0.83-0.94, P < 0.001) and the ICC for agreement on split blood flow was 0.90 (95% CI: 0.84-0.94). Mean difference in split blood flow by Bland-Altman analysis was 0.79% with 95% limits of agreement (-11.2 to 12.8%). CONCLUSION: There is excellent agreement between Tc-99 m scintigraphy and phase contrast MRI for quantification of split pulmonary blood flow in children and young adults with congenital heart disease.

Cardiac MRI for Fontan candidates after intrapulmonary-artery septation.

Intrapulmonary-artery septoplasty may be effective for establishing two-lung Fontan circulation in patients with unilateral pulmonary circulation. However, evaluation of the function of each lung by conventional modalities can be challenging in these patients due to differing sources of blood flow to the left and right lungs following intrapulmonary-artery septation. Herein, we report a case in which two-lung Fontan circulation was successfully achieved after using cardiac MRI along with conventional modalities to evaluate pulmonary circulation.

Quantification of systemic-to-pulmonary collateral flow in univentricular physiology with 4D flow MRI.

PURPOSE: Systemic-to-pulmonary collateral flow is a well-recognised phenomenon in patients with single ventricle physiology, but remains difficult to quantify. The aim was to compare the reported formula's that have been used for calculation of systemic-to-pulmonary-collateral flow to assess their consistency and to quantify systemic-to-pulmonary collateral flow in patients with a Glenn and/or Fontan circulation using four-dimensional flow MRI (4D flow MR). METHODS: Retrospective case-control study of Glenn and Fontan patients who had a 4D flow MR study. Flows were measured at the ascending aorta, left and right pulmonary arteries, left and right pulmonary veins, and both caval veins. Systemic-to-pulmonary collateral flow was calculated using two formulas: 1) pulmonary veins - pulmonary arteries and 2) ascending aorta - caval veins. Anatomical identification of collaterals was performed using the 4D MR image set. RESULTS: Fourteen patients (n = 11 Fontan, n = 3 Glenn) were included (age 26 [22-30] years). Systemic-to-pulmonary collateral flow was significantly higher in the patients than the controls (n = 10, age 31.2 [15.1-38.4] years) with both formulas: 0.28 [0.09-0.5] versus 0.04 [-0.66-0.21] l/min/m2 (p = 0.036, formula 1) and 0.67 [0.24-0.88] versus -0.07 [-0.16-0.08] l/min/m2 (p < 0.001, formula 2). In patients, systemic-to-pulmonary collateral flow differed significantly between formulas 1 and 2 (13% versus 26% of aortic flow, p = 0.038). In seven patients, veno-venous collaterals were detected and no aortopulmonary collaterals were visualised. CONCLUSION: 4D flow MR is able to detect increased systemic-to-pulmonary collateral flow and visualise collaterals vessels in Glenn and Fontan patients. However, the amount of systemic-to-pulmonary collateral flow varies with the formula employed. Therefore, further research is necessary before it could be applied in clinical care.

Pulmonary Hypertension in Left Heart Diseases: Pathophysiology, Hemodynamic Assessment and Therapeutic Management.

Pulmonary hypertension (PH) associated with left heart diseases (PH-LHD), also termed group 2 PH, represents the most common form of PH. It develops through the passive backward transmission of elevated left heart pressures in the setting of heart failure, either with preserved (HFpEF) or reduced (HFrEF) ejection fraction, which increases the pulsatile afterload of the right ventricle (RV) by reducing pulmonary artery (PA) compliance. In a subset of patients, progressive remodeling of the pulmonary circulation resulted in a pre-capillary phenotype of PH, with elevated pulmonary vascular resistance (PVR) further increasing the RV afterload, eventually leading to RV-PA uncoupling and RV failure. The primary therapeutic objective in PH-LHD is to reduce left-sided pressures through the appropriate use of diuretics and guideline-directed medical therapies for heart failure. When pulmonary vascular remodeling is established, targeted therapies aiming to reduce PVR are theoretically appealing. So far, such targeted therapies have mostly failed to show significant positive effects in patients with PH-LHD, in contrast to their proven efficacy in other forms of pre-capillary PH. Whether such therapies may benefit some specific subgroups of patients (HFrEF, HFpEF) with specific hemodynamic phenotypes (post- or pre-capillary PH) and various degrees of RV dysfunction still needs to be addressed.

Hypoxic pulmonary vasoconstriction as a regulator of alveolar-capillary oxygen flux: A computational model of ventilation-perfusion matching.

The relationship between regional variabilities in airflow (ventilation) and blood flow (perfusion) is a critical determinant of gas exchange efficiency in the lungs. Hypoxic pulmonary vasoconstriction is understood to be the primary active regulator of ventilation-perfusion matching, where upstream arterioles constrict to direct blood flow away from areas that have low oxygen supply. However, it is not understood how the integrated action of hypoxic pulmonary vasoconstriction affects oxygen transport at the system level. In this study we develop, and make functional predictions with a multi-scale multi-physics model of ventilation-perfusion matching governed by the mechanism of hypoxic pulmonary vasoconstriction. Our model consists of (a) morphometrically realistic 2D pulmonary vascular networks to the level of large arterioles and venules; (b) a tileable lumped-parameter model of vascular fluid and wall mechanics that accounts for the influence of alveolar pressure; (c) oxygen transport accounting for oxygen bound to hemoglobin and dissolved in plasma; and (d) a novel empirical model of hypoxic pulmonary vasoconstriction. Our model simulations predict that under the artificial test condition of a uniform ventilation distribution (1) hypoxic pulmonary vasoconstriction matches perfusion to ventilation; (2) hypoxic pulmonary vasoconstriction homogenizes regional alveolar-capillary oxygen flux; and (3) hypoxic pulmonary vasoconstriction increases whole-lobe oxygen uptake by improving ventilation-perfusion matching.

NEDD9 Is a Novel and Modifiable Mediator of Platelet-Endothelial Adhesion in the Pulmonary Circulation.

Rationale: Data on the molecular mechanisms that regulate platelet-pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications. Objectives: To identify a hypoxia-sensitive, modifiable mediator of platelet-pulmonary artery endothelial cell adhesion and thrombotic remodeling. Methods: 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 in vivo. Measurements and Main Results: The protein NEDD9 was identified in the hypoxia thrombosome network in silico. Compared with normoxia, hypoxia (0.2% O2) for 24 hours increased HIF-1α (hypoxia-inducible factor-1α)-dependent NEDD9 upregulation in vitro. 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 in vitro and from patients with CTEPH ex vivo. 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 in vivo. Conclusions: 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.