Transpulmonary Gradient Research Articles

Transpulmonary proteome gradients identify inflammatory pathways involved in the development of pulmonary vasculopathy in heart failure

Abstract Background Some, but not all, patients with heart failure (HF) develop pulmonary vascular disease (PVD), which contributes to poor prognosis. Mechanisms leading to PVD in HF are poorly understood. Unbiased analysis of transpulmonary gradients may identify not only markers but also mediators of PVD by identifying proteins that may be consumed or elaborated across the lungs. Purpose Examine hemodynamics and transpulmonary proteome gradients in HFrEF and controls. Methods 21 non-HF controls and 160 patients with advanced HFrEF underwent pulmonary artery (PA) catheterization with blood sampling from the PA catheter in the wedged position (02sat > 90%, indicating pulmonary venous blood) and the un-wedged position to obtain transpulmonary proteome gradients. Samples from controls and HF from the highest quartile (Q4, n=40) and lowest quartile (Q1, n=40) of pulmonary vascular resistance (PVR) were analyzed using proteomic PEA assay of 275 proteins (Olink Target 96, panels CVII, CVIII, Inflammation). Pulmonary artery concentrations ("markers") or transpulmonary fold-change gradients (i.e. putative "mediators") of normalized protein expression (NPX) were plotted against significance; Benjamini–Hochberg FDR<0.05 considered as significant. Results Patients displayed typical characteristics of HFrEF (age 56±8y, NYHA 3.0 ±0.6, 87% males, LVEF 24±9.6%), Controls had similar anthropometrics, gender and age. Comparing all HF to Con, 38 markers of HF were identified (NPX fold-change>2), including 33 up (top 5: NTproBNP, BNP, GDF15, FGF23, IL8) and 5 down. HF patients in Q1 had median PVR 1.5 (IQR: 0.3-1.7) WU and those in Q4 had PVR 5.4 (4.3-6.6) WU. Comparison of Q1 and Q4 identified 3 protein markers of high PVR in PA blood from HF: chemokine CCL3, TNFRSF13B and surfactant protein-D (PSP-D). Examination of protein gradients from HF lungs (Figure) showed significant uptake of 14 protein mediators, most of which were associated with inflammatory responses (top 5: OSM, MMP9, CCL19, BNP, TR), and release of 8 mediators (top 4: IL-6, IL33, CCL4, CXCL10). In contrast, protein gradients were negligible in controls. Patients in Q4 PVR group were characterized by the highest pulmonary uptake of OSM (Oncostatin-M), lymphatic chemokine CCL19, BNP, MMP9, and had more significant transpulmonary release of IL6 and IL33. Across all patients, OSM lung uptake was the strongest correlate of transpulmonary pressure gradient (r=-0.3, p<0.001). Conclusions Lungs of patients with HF, and particularly those with high PVR, display abnormal uptake and release of proinflammatory CC and CXC chemokines and cytokines from IL1 and IL6 family, along with increased pulmonary uptake of IL6-type cytokine Oncostatin-M, a known mediator of lung inflammation and fibrosis, that acts via gp130/JAK/STAT, suggesting a novel role in PVD due to HF.Transpulmonary proteome in HF patients

Magnetic resonance lymphangiography abnormalities as extracardiac biomarkers of pulmonary hypertension and functional phenotype in Fontan-Kreutzer univentricular circulation.

Lymphatic abnormalities have been documented on magnetic resonance lymphangiography in patients with functionally univentricular circulation. The aim of this study is to evaluate associations between findings on magnetic resonance lymphangiography, cardiac catheterisation and functional phenotype in patients with Fontan-Kreutzer circulation. Between January 2017 and October 2019, seven patients with Fontan-Kreutzer circulation (16.57 ± 7.10 years) were enrolled following ethical committee approval and attainment of informed consent. Clinical data, consecutive magnetic resonance imaging and cardiac catheterisation findings were reviewed. Qualitative lymphatic abnormality types were defined as: 1 - Little or none; 2 - Localised to the supraclavicular region; 3 - Extending into the mediastinum; and 4 - Extending into the lung. Pulmonary hypertension was defined as a transpulmonary gradient > 6 mmHg. Quantitative data were assessed using Mann-Whitney U tests, and p < 0.05 was considered statistically significant. Patients with lymphatic abnormalities categorised type 1 or 2 and transpulmonary gradient ≤ 6 mmHg had a normal functional phenotype, while those with type 3 or 4 and transpulmonary gradient > 6 mmHg had a failing functional phenotype. Magnetic resonance lymphangiography in patients with Fontan-Kreutzer circulation and pulmonary hypertension revealed lymphatic abnormalities types 3-4, indicative of a failing functional phenotype compared to patients without pulmonary hypertension. If validated in larger studies, these results suggest the potential utility of this extracardiac biomarker for improving risk stratification. Integration of lymphangiography and transpulmonary gradient with functional class, atrioventricular valve function, and ejection fraction allowed for the categorisation of three distinct functional phenotypes, which may be valuable for future analyses.

Improvement of endorgan function following tricuspid edge-to-edge repair

Abstract Background/Introduction Subjects with severe tricuspid regurgitation (TR) often suffer from impaired endorgan function. The potential to improve endorgan function is an important goal of treatment. Purpose To assess baseline endorgan function and changes in organ function following transcatheter edge-to-edge repair with the TriClip device in subjects with severe TR from the TRILUMINATE Pivotal randomized controlled trial. Methods Right heart catheterization was required prior to enrollment; medication history was collected. Changes in biomarkers, including MELD-XI, GGT, eGFR, BUN, and TR and KCCQ overall summary score were assessed at baseline and 12-month follow-up for all enrolled subjects. A 15% improvement in biomarker levels was considered clinically relevant. The odds of achieving a 15% improvement in biomarkers between baseline and 12-month follow-up was compared between the Device and Control groups (presented as OR [95% CI]). Results A total of 572 subjects were enrolled and randomized. At baseline, subjects had elevated levels of GGT (83.0±87.7 U/L) and MELD-XI score (10.3±5.2), low eGFR (56.7±21.0 mL/min/1.73m2), and elevated BUN (29.5±16.7 mg/dL). Nearly 90% of subjects were on loop diuretics, with approximately 50% taking these in combination with a thiazide or potassium-sparing diuretic. The average diuretic dosage was 71 mg (furosemide equivalent). Most subjects had normal left ventricle ejection fraction (only 5% with LVEF &amp;lt;40%). Subjects had well-managed blood pressure (systolic: 122±13 mmHg, diastolic: 69±10), slightly elevated central venous pressures (12±6 mmHg), systolic pulmonary artery pressures (40±10 mmHg) and pulmonary capillary wedge pressures (15±4 mmHg), and normal transpulmonary gradients (11±4 mmHg). The odds of achieving a 15% improvement in liver and renal function was higher in TriClip patients compared to control: MELD-XI score (1.79 [1.22, 2.63]), GGT (1.83 [1.21, 2.77]), and eGFR (1.81 [1.18, 2.77]) - Fig 1. The favorable changes in organ function observed were also reflected when stratifying subjects by residual TR severity: The odds of a 15% biomarker improvement favored subjects with moderate or less residual TR for MELD-XI score (2.05 [1.39, 3.00]), GGT (1.91 [1.26, 2.90]), and eGFR (1.83 [1.20, 2.80]) compared with subjects who had severe or worse residual TR. Lastly, improvement in these biomarkers also favored subjects with a 15-point or greater improvement in KCCQ compared with subjects with less than a 15-point KCCQ improvement. Conclusions Use of TriClip in subjects with severe tricuspid regurgitation was associated with improvement in kidney and liver function, and this improvement was associated with reduction in the severity of TR. These data provide the first objective evidence of the physiologic impact of TR reduction obtained in a randomized clinical trial.

Outcomes in patients with light chain cardiac amyloidosis undergoing heart transplantation: a single centre UK study

Abstract Background Light chain cardiac amyloidosis (AL-CA) results in restrictive cardiomyopathy associated with progressive heart failure and poor survival. Traditionally, outcomes following heart transplantation in patients with AL-CA have been worse than in other heart failure cohorts and consequently, many centres do not offer this population transplantation. Purpose and Methods This was a retrospective observational study of 18 patients with AL-CA (age 52.7years +/- 8.3, male 66%) referred to our centre in the UK for assessment for heart transplantation from 2008 to 2023. Seven patients (39%) were listed for transplant, and all received orthotopic heart transplantation (OHT). This study compared pre-transplantation characteristics in those offered cardiac transplantation with those not transplanted. We also examined post-transplantation outcomes in this group (n=7) compared with the overall heart transplantation population (n=95) at our centre. Results Patients with AL-CA who were not offered transplantation (n=11) were older (mean age 54.3 vs 50.3 years), were more likely male (72% vs 57%) but had similar baseline renal function to those transplanted (median eGFR 60.4 vs 54.2ml/min). Reasons against offering OHT included extensive multisystem or renal amyloid deposition (n=4), insufficient haematological response (n=2), heart failure not advanced enough for OHT (n=1) and malignancy (n=1). Pre-transplant right heart catheterisation of patients undergoing OHT demonstrated a mean transpulmonary gradient of 7.8mmHg (+/- 1.9) and cardiac output of 2.94/min (+/- 0.3). Five patients (71%) had a complete and two (29%) a partial haematological response to clonally directed chemotherapy. Three patients were bridged to transplant with biventricular assist devices for 9, 10 and 51 days, respectively. Five patients developed episodes of histologically confirmed rejection of grade 2R that resolved with medical management. One patient experienced first degree atrioventricular block and had a pulseless electrical activity arrest 19 days after transplantation before being fitted with a permanent pacemaker. Two patients went on to receive autologous stem cell transplantation. Patients with AL-CA undergoing OHT had a lower mortality rate compared with non-transplanted patients over a median follow up of 9 months (HR 0.3, 95%CI 0.07-1.3, p = 0.10). Two patients with AL-CA died at 42 days and 7.7 years after OHT. Five patients (71%) are alive under follow up at 4, 7.5, 9, 10 months and 7.7 years post OHT. There was no difference in survival between patients who underwent heart transplantation for AL-CA and patients who underwent heart transplantation for all other indications (HR 1.94, 95%CI 0.3 – 12, p=0.45). Conclusions In selected patients with AL-CA, OHT offers favourable outcomes. After clonally directed therapy to control the underlying plasma cell dyscrasia, heart transplantation should be considered in the absence of widespread systemic disease.

Prognosis of different hemodynamic classifications in patients with pulmonary hypertension due to left heart disease

Objective: To compare the prognostic values of different classification by using transpulmonary pressure gradient (TPG), diastolic pressure gradient (DPG) and pulmonary vascular resistance (PVR) in patients with pulmonary hypertension due to left heart disease (PH-LHD), and investigated hemodynamic and clinical factors associated with mortality in patients with PH-LHD. Methods: This was a single-center prospective cohort study. In-hospital patients diagnosed with PH-LHD via right heart catheterization at the Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, from September 2013 to December 2019 were enrolled. Patients were divided according to TPG (cutoff value 12 mmHg; 1 mmHg=0.133 kPa), DPG (cutoff value 7 mmHg), PVR (cutoff value 3 Wood Units), and the combination of TPG and PVR. Baseline characteristic was recorded. All patients were followed up until the occurrence of endpoint event, defined as all-cause death that occurred during the follow-up period, or until April 18, 2022. Receiver operating characteristic curves were used to compare the predictive value of 3 classification methods for all-cause death in PH-LHD patients. The optimal cutoff values were calculated using Jorden index. Survival analysis was performed using Kaplan-Meier analysis, and log-rank test was used to compare the predictive efficacy of classification methods based on optimal cutoff values or guidance-recommended thresholds for the survival of PH-LHD patients. Variables showing statistical significance in the univariate analysis were incorporated into multivariate Cox regression model to analyze the independent risk factors for all-cause mortality. Results: A total of 243 patients were enrolled, aged (54.9±12.7) years old, including 169 (69.5%) males. During a median follow-up of 57 months, there were 101 (41.6%) deaths occurred. Grouping results were as follows: (1) TPG: TPG≤12 mmHg group 115 patients, TPG>12 mmHg group 128 patients; (2) DPG: DPG<7 mmHg group 193 patients, DPG≥7 mmHg group 50 patients; (3) PVR: PVR≤3 Wood Units group 108 patients, PVR>3 Wood Units group 135 patients; (4) TPG and PVR: TPG≤12 mmHg and PVR≤3 Wood Units group 89 patients, TPG>12 mmHg and PVR>3 Wood Units group 109 patients. PVR (AUC=0. 698,95%CI:0.631-0.766) had better predictive value for all-cause mortality than TPG (AUC=0.596, 95%CI: 0.523-0.669) and DPG (AUC=0.526, 95%CI: 0.452-0.601) (all P<0.05). The optimal cutoff values for TPG, DPG, and PVR were13.9 mmHg, 2.8 mmHg, and 3.8 Wood Units, respectively. Kaplan-Meier analysis based on the optimal cutoff values or guidance-recommended thresholds showed that PVR and TPG were the predictors of survival (P<0.05), while DPG did not showed significance (P>0.05). Multivariate Cox regression analysis showed that age, PVR and log2N-terminal pro-B-type natriuretic peptide were independent risk factors for all-cause mortality in PH-LHD patients (all P<0.05). Conclusion: Classification according to PVR was most valuable in predicting all-cause death in PH-LHD patients, while TPG showed moderate predictive ability and DPG had no predictive value.

Comparison of Echocardiographically-Calculated Fontan Fenestration Gradient and Catheter-Based Measurement.

Patients born with single ventricle anatomy typically undergo surgical palliation in three stages, culminating in the Fontan procedure. Assessment of flow across a Fontan fenestration by Doppler ultrasound theoretically allows for non-invasive estimation of the transpulmonary gradient (TPG). Our objective was to determine the relationship between Doppler-derived mean fenestration gradient (mFG) and direct catheter-based measurements of TPG in patients with fenestrated Fontans. We performed a single-center retrospective cohort study of 59 patients with fenestrated Fontans completed between 2000 and 2022. The primary outcome was catheter-based measurement of TPG and the primary predictor was mFG from echo performed within 6 months of the catheterization. Linear regression and R2 were used to determine the relationship between predictors and outcomes. Catheter-based measurements of TPG and mFG were weakly correlated (R2 = 0.382, p < 0.001); the regression coefficient was 0.550, with a standard error of 0.09 for every increase in mFG (Cath TPG = 0.55 [mFG] + 1.92). mFG had a slightly better predictive relationship with cath-derived TPG in patients with systemic left ventricles with R2 of 0.47, p < 0.004. mFG accounts for approximately 38% of the variance in catheter-derived TPG. Although mFG is non-invasive and intuitive, mFG in Fontan patients should be interpreted with caution and direct measurement by cardiac catheterization should be considered.

Agreement of echocardiographic and catheterization-based methods of transpulmonary pressure gradient measurement in dogs

Introduction/ObjectivesDoppler echocardiographic estimation of transpulmonary pressure gradient (PG) is widely used to determine severity of pulmonary valve stenosis and indication for transcatheter intervention. The objective of this study was to describe agreement between Doppler echocardiographic methods of transpulmonary PG estimation and direct peak-to-peak pressure gradient at catheterization (PGcath) in dogs. We hypothesized that with reference to PGcath, mean echocardiographic PG (PGecho-mean) would have less bias than peak modal instantaneous echocardiographic PG (PGecho-peak). AnimalsClient-owned dogs with congenital pulmonary valve stenosis that underwent balloon pulmonary valvuloplasty at one of two veterinary teaching hospitals between June 2012 and May 2022 were included in this study. Materials and MethodsCases that underwent transthoracic echocardiography and subsequent balloon pulmonary valvuloplasty separated by 30 or fewer days were retrospectively identified. For each echocardiogram, average PGecho-mean (mmHg) and average PGecho-peak (mmHg) were calculated from stored spectral Doppler recordings. Peak right ventricular-to-peak pulmonary artery PG data (mmHg) were obtained from catheterization reports. Bland–Altman analysis was used to assess agreement between echocardiographic and catheterization data. ResultsData from 209 dogs (n = 215 instances) were evaluated. Proportional bias, greater at higher gradients, was observed for PGecho-mean versus PGcath (P<0.001). A constant bias of −38.12 mmHg was observed for PGecho-peak versus PGcath (P=0.62). Bias for both echocardiographic variables had wide limits of agreement that increased with PG. ConclusionsPGecho-mean and PGecho-peak underestimated and overestimated PGcath, respectively, preventing their interchangeability with PGcath.

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

This review addresses treatment options for moderate to severe tricuspid valve regurgitation and the importance of right ventricular function and the pulmonary circulation. 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. 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.

Impact of veno-venous collaterals on outcome after the total cavopulmonary connection

ObjectiveTo evaluate the prevalence of veno-venous collaterals (VVCs) after total cavopulmonary connection (TCPC) and analyze their impact on outcomes. MethodsPatients undergoing TCPC between 1994 and 2022 were evaluated. VVCs were identified using angiograms of cardiac catheterizations and their impact on outcomes was analyzed. ResultsA total of 635 patients were included. Median age at TCPC was 2.3 (interquartile ranges (IQR): 1.8–3.3) years. The most frequent diagnosis was hypoplastic left heart syndrome in 173 (27.2%) patients. Prior bidirectional cavopulmonary shunt was performed in 586 (92.3%) patients at a median age of 5.3 (3.6–9.9) months. VVCs were found in 94 (14.8%) patients at a median of 2.8 (0.1–11.8) years postoperatively. The prevalence of VVCs was similar between the dominant right and left ventricle (14.7 vs. 14.9%, p = 0.967). Mean pulmonary artery pressure (16.2 vs. 16.0 mmHg, p = 0.902), left atrial pressure (5.5 vs. 5.7 mmHg, p = 0.480), transpulmonary gradient (4.0 vs. 3.8 mmHg, p = 0.554) and oxygen saturation (81.4 vs. 82.6%, p = 0.103) before TCPC were similar between patients with and without VVCs. The development of VVCs did not affect survival after TCPC (p = 0.161). Nevertheless, VVCs were a risk for the development of plastic bronchitis (PB, p < 0.001). Interventional closure of VVCs was performed in 60 (9.4%) patients at a median of 8.9 (0.6–15.1) years after TCPC, and improvement of oxygen saturation was observed in 66% of the patients. ConclusionsThe prevalence of VVCs after TCPC was 15%. VVCs had no impact on survival following TCPC but were associated with a high prevalence of PB.

Invasive haemodynamics predict outcomes in paediatric pulmonary artery hypertension.

Invasive haemodynamics are often performed for initiating and guiding pulmonary artery hypertension therapy. Little is known about the predictive value of invasive haemodynamic indices for long-term outcomes in children with pulmonary artery hypertension. We aimed to evaluate invasive haemodynamic data to help predict outcomes in paediatric pulmonary artery hypertension. Patients with pulmonary artery hypertension who underwent cardiac catheterisation (2006-2019) at a single centre were included. Invasive haemodynamic data from the first cardiac catheterisation and clinical outcomes were reviewed. The combined adverse outcome was defined as pericardial effusion (due to right ventricle failure), creation of a shunt for pulmonary artery hypertension (atrial septal defect or reverse Pott's shunt), lung transplant, or death. Among 46 patients with a median [interquartile range (IQR)] age of 13.2 [4.1-44.7] months, 76% had CHD. Median mean pulmonary artery pressure was 37 [28-52] mmHg and indexed pulmonary vascular resistance was 6.2 [3.6-10] Woods units × m2. Median pulmonary artery pulsatility index was 4.0 [3.0-4.7] and right ventricular stroke work index was 915 [715-1734] mmHg mL/m2. After a median follow-up of 2.4 years, nine patients had a combined adverse outcome (two had a pericardial effusion, one underwent atrial level shunt, one underwent reverse Pott's shunt, and six died). Patients with an adverse outcome had higher systolic and mean pulmonary artery pressures, higher diastolic and transpulmonary pressure gradients, higher indexed pulmonary vascular resistance, higher pulmonary artery elastance, and higher right ventricular stroke work index (p < 0.05 each). Invasive haemodynamics (especially mean pulmonary artery pressure and diastolic pressure gradient) obtained at first cardiac catheterisation in children with pulmonary artery hypertension predicts outcomes.

Impact of pulmonary hypertension on outcomes after TEER in patients suffering from mitral regurgitation.

Data on associations of invasively determined hemodynamic parameters with procedural success and outcomes in patients suffering from mitral regurgitation (MR) undergoing transcatheter edge-to-edge repair of the mitral valve (M-TEER) is limited. We enrolled 239 patients with symptomatic MR of grade 2 + , who received M-TEER. All patients underwent extensive pre-interventional invasive hemodynamic measurements via right heart catheterization (mean pulmonary arterial pressure (mPAP), systolic- (PAPsys) and diastolic pulmonary arterial pressure (PAPdia), pulmonary arterial wedge pressure (PAWP), a-wave, v-wave, pulmonary vascular resistance (PVR), transpulmonary pressure gradient (TPG), cardiac index (CI), stroke volume index (SVI)). mPAP and PAWP at baseline were neither associated with procedural success, immediate reduction of MR, nor residual MR after 6months of follow-up. The composite outcome (All-cause mortality (ACM) and/or heart failure induced rehospitalization (HFH)) and HFH differed significantly after M-TEER when stratified according to mPAP, PAWP, PAPdia, a-wave and v-wave. ACM was not associated with the afore mentioned parameters. Neither PVR, TPG, CI nor SVI were associated with the composite outcome and HFH, respectively. In multivariable analyses, PAWP was independently associated with the composite outcome and HFH. PVR and SVI were not associated with outcomes. PAWP at baseline was significantly and independently associated with HFH and might serve as a valuable parameter for identifying patients at high risk for HFH after M-TEER. ACM and procedural success were not affected by pulmonary arterial pressure before M-TEER. We suggest that the post-capillary component of PH serves as the driving force behind the risk of HFH.

In vitro hemodynamic performance of a blood pump for self-powered venous assist in univentricular hearts

Univentricular heart anomalies represent a group of severe congenital heart defects necessitating early surgical intervention in infancy. The Fontan procedure, the final stage of single-ventricle palliation, establishes a serial connection between systemic and pulmonary circulation by channeling venous return to the lungs. The absence of the subpulmonary ventricle in this peculiar circulation progressively eventuates in failure, primarily due to chronic elevation in inferior vena cava (IVC) pressure. This study experimentally validates the effectiveness of an intracorporeally-powered venous ejector pump (VEP) in reducing IVC pressure in Fontan patients. The VEP exploits a fraction of aortic flow to create a jet-venturi effect for the IVC, negating the external power requirement and driveline infections. An invitro Fontan mock-up circulation loop is developed and the impact of VEP design parameters and physiological conditions is assessed using both idealized and patient-specific total cavopulmonary connection (TCPC) phantoms. The VEP performance in reducing IVC pressure exhibited an inverse relationship with the cardiac output and extra-cardiac conduit (ECC) size and a proportional relationship with the transpulmonary pressure gradient (TPG) and mean arterial pressure (MAP). The ideal VEP with fail-safe features provided an IVC pressure drop of 1.82 ± 0.49, 2.45 ± 0.54, and 3.12 ± 0.43 mm Hg for TPG values of 6, 8, and 10 mm Hg, respectively, averaged over all ECC sizes and cardiac outputs. Furthermore, the arterial oxygen saturation was consistently maintained above 85% during full-assist mode. These results emphasize the potential utility of the VEP to mitigate elevated venous pressure in Fontan patients.

Limiting Overdistention or Collapse When Mechanically Ventilating Injured Lungs: A Randomized Study in a Porcine Model.

Rationale: It is unknown whether preventing overdistention or collapse is more important when titrating positive end-expiratory pressure (PEEP) in acute respiratory distress syndrome (ARDS). Objectives: To compare PEEP targeting minimal overdistention or minimal collapse or using a compromise between collapse and overdistention in a randomized trial and to assess the impact on respiratory mechanics, gas exchange, inflammation, and hemodynamics. Methods: In a porcine model of ARDS, lung collapse and overdistention were estimated using electrical impedance tomography during a decremental PEEP titration. Pigs were randomized to three groups and ventilated for 12 hours: PEEP set at ⩽3% of overdistention (low overdistention), ⩽3% of collapse (low collapse), and the crossing point of collapse and overdistention. Measurements and Main Results: Thirty-six pigs (12 per group) were included. Median (interquartile range) values of PEEP were 7 (6-8), 11 (10-11), and 15 (12-16) cm H2O in the three groups (P < 0.001). With low overdistension, 6 (50%) pigs died, whereas survival was 100% in both other groups. Cause of death was hemodynamic in nature, with high transpulmonary vascular gradient and high epinephrine requirements. Compared with the other groups, pigs surviving with low overdistension had worse respiratory mechanics and gas exchange during the entire protocol. Minimal differences existed between crossing-point and low-collapse animals in physiological parameters, but postmortem alveolar density was more homogeneous in the crossing-point group. Inflammatory markers were not significantly different. Conclusions: PEEP to minimize overdistention resulted in high mortality in an animal model of ARDS. Minimizing collapse or choosing a compromise between collapse and overdistention may result in less lung injury, with potential benefits of the compromise approach.

Fatty acid metabolism promotes TRPV4 activity in lung microvascular endothelial cells in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a morbid disease characterized by significant lung endothelial cell (EC) dysfunction. Prior work has shown that microvascular endothelial cells (MVECs) isolated from animals with experimental PAH and patients with PAH exhibit significant abnormalities in metabolism and calcium signaling. With regards to metabolism, we and others have shown evidence of increased aerobic glycolysis and evidence of increased utilization of alternate fuel sources (such as fatty acids) in PAH EC. In the realm of calcium signaling, our prior work linked increased activity of the transient receptor potential vanilloid-4 (TRPV4) channel to increased proliferation of MVECs isolated from the Sugen/Hypoxia rat model of PAH (SuHx-MVECs). However, the relationship between metabolic shifts and calcium abnormalities was not clear. Specifically, whether shifts in metabolism were responsible for increasing TRPV4 channel activity in SuHx-MVECs was not known. In this study, using human data, serum samples from SuHx rats, and SuHx-MVECs, we describe the consequences of increased MVEC fatty acid oxidation in PAH. In human samples, we observed an increase in long-chain fatty acid levels that was associated with PAH severity. Next, using SuHx rats and SuHx-MVECs, we observed increased intracellular levels of lipids. We also show that increasing intracellular lipid content increases TRPV4 activity, whereas inhibiting fatty acid oxidation normalizes basal calcium levels in SuHx-MVECs. By exploring the fate of fatty acid-derived carbons, we observed that the metabolite linking increased intracellular lipids to TRPV4 activity was β-hydroxybutyrate (BOHB), a product of fatty acid oxidation. Finally, we show that BOHB supplementation alone is sufficient to sensitize the TRPV4 channel in rat and mouse MVECs. Returning to humans, we observe a transpulmonary BOHB gradient in human patients with PAH. Thus, we establish a link between fatty acid oxidation, BOHB production, and TRPV4 activity in MVECs in PAH. These data provide new insight into metabolic regulation of calcium signaling in lung MVECs in PAH.NEW & NOTEWORTHY In this paper, we explore the link between metabolism and intracellular calcium levels in microvascular endothelial cells (MVECs) in pulmonary arterial hypertension (PAH). We show that fatty acid oxidation promotes sensitivity of the transient receptor potential vanilloid-4 (TRPV4) calcium channel in MVECs isolated from a rodent model of PAH.

Effect of Acute Vasodilator Testing Using Oxygen in Pulmonary Hypertension Due to Left Heart Disease.

Pulmonary vasodilators, including oxygen, have not shown consistent beneficial effects on pulmonary hypertension due to valvular heart disease (PH-VHD). Therefore, the study aimed to assess the effect of 100% fractional inspiration of oxygen (FiO2) on pulmonary and systemic hemodynamics in patients with combined pre- and post-capillary pulmonary hypertension (CpcPH) and isolated post-capillary pulmonary hypertension (IpcPH) due to PH-VHD. This prospective study was conducted among patients with PH-VHD undergoing mitral or aortic valve replacement or repair. The study was conducted after induction of anesthesia and pulmonary artery catheterization. Cardiac output was obtained using thermodilution and all direct, and derived hemodynamic variables were obtained at 30% and 100% FiO2. The patients were stratified a priori into responders {(≥10mmHg fall in mean pulmonary artery pressure (MPAP)} and non-responders. Fifty-seven patients completed the acute vasodilator test. The mean age and body mass index of the study population was 41.8 ± 14.1years and 21.4 ± 4.6kg/m2, respectively. There was a significant decrease in MPAP (40.77 ± 12.07mmHg vs 36.74 ± 13.3mmHg; P < .001) and pulmonary vascular resistance (PVR) {(median; Interquartile range (IQR); 388; 371 vs 323; 362dynes sec.cm-5; P < .001) at 100% FiO2. Transpulmonary gradient (TPG) and diastolic pulmonary gradient (DPG) also decreased significantly (P < .001 and P < .001). Cardiac output did not change significantly. The magnitude of decrease in MPAP, PVR, TPG, DPG, and pulmonary artery compliance (PAC) between CpcPH and IpcPH was comparable. Responders did not show a significantly greater fall in MPAP, PVR, TPG, DPG, and PAC after surgery. Hyperoxia may lead to reduction in MPAP and PVR in both hemodynamic phenotypes of PH-VHD. A larger sample size is required to support or refute the findings of this study.

Impact of diastolic pulmonary gradient and pulmonary vascular remodeling on survival after left ventricular assist device implantation and heart transplantation

BackgroundThe left ventricular assist devices (LVADs) are increasingly used for advanced heart failure as a bridge to heart transplantation or as a destination therapy. The aim of this study was to investigate the changes of diastolic pulmonary gradient (DPG), pulmonary vascular resistance (PVR) and transpulmonary gradient (TPG) after LVAD implantation and their impact on survival after LVAD and heart transplantation.ResultsA total of 73 patients who underwent LVAD (HeartMate III) implantation between 2016 and 2022 were retrospectively studied. According to pre-LVAD catheterization, 49 (67.1%) patients had DPG < 7 mmHg and 24 (32.9%) patients had DPG ≥ 7 mmHg. The patients with a pre-VAD DPG ≥ 7 mmHg had higher frequencies of right ventricular (RV) failure (p < 0.001), RVAD insertion (p < 0.001), need for renal replacement therapy (p = 0.002), total mortality (p = 0.036) and on-VAD mortality (p = 0.04) with a longer ICU stay (p = 0.001) compared to the patients with DPG < 7 mmHg. During the follow-up period of 38 (12–60) months, 24 (32.9%) patients died. Pre-LVAD DPG ≥ 7 mmHg (adjusted HR 1.83, 95% CI 1.21–6.341, p = 0.039) and post-LVAD DPG ≥ 7 mmHg (adjusted HR 3.824, 95% CI 1.482–14.648, p = 0.002) were associated with increased risks of mortality. Neither pre-LVAD TPG ≥ 12 (p = 0.505) nor post-LVAD TPG ≥ 12 mmHg (p = 0.122) was associated with an increased risk of death. Pre-LVAD PVR ≥ 3 WU had a statistically insignificant risk of mortality (HR 2.35, 95% CI 0.803–6.848, p = 0.119) while post-LVAD PVR ≥ 3 WU had an increased risk of death (adjusted HR 2.37, 95% CI 1.241–7.254, p = 0.038). For post-transplantation mortality, post-LVAD DPG ≥ 7 mmHg (p = 0.55), post-LVAD TPG ≥ 12 mmHg (p = 0.85) and PVR ≥ 3 WU (p = 0.54) did not have statistically increased risks. The logistic multivariable regression showed that post-LVAD PVR ≥ 3 WU (p = 0.013), post-LVAD DPG ≥ 7 mmHg (p = 0.026) and RVF (p = 0.018) were the predictors of mortality after LVAD implantation. Pre-LVAD DPG ≥ 7 mmHg (p < 0.001) and pre-LVAD PVR ≥ 3 WU (p = 0.036) were the predictors of RVF after LVAD implantation.ConclusionsPersistently high DPG was associated with right ventricular failure and mortality after LVAD implantation rather than after heart transplantation. DPG is a better predictor of pulmonary vascular remodeling compared to TPG and PVR. Further larger prospective studies are required in this field due to the growing numbers of patients with advanced heart failure, as possible candidates for LVAD implantation, and limitations of heart transplantation.

Five-year follow-up after percutaneous pulmonary valve implantation using the Venus P-valve system for patients with pulmonary regurgitation and an enlarged native right ventricular outflow tract.

Percutaneous pulmonary valve implantation (PPVI) with the self-expandable Venus P-valve system is a promising treatment for patients with pulmonary regurgitation (PR) and a native right ventricular outflow tract (RVOT). However, limited data is available regarding its midterm outcomes. This study assessed the midterm clinical and echocardiographic outcomes following Venus P-valve implantation. From 2013 to 2018, 55 patients with moderate or severe PR after surgical RVOT repair with a transannular or RVOT patch were consecutively enrolled from six hospitals in China. Five-year clinical and echocardiographic outcomes were collected and evaluated. The primary endpoint was a freedom from all-cause mortality and reintervention. At 5 years, the primary endpoint was met for 96% of patients, corresponding to a freedom from all-cause mortality of 96% (95% confidence interval [CI]: 86%-99%) and freedom from reintervention of 98% (95% CI: 87%-100%). Endocarditis was reported in five patients (four patients within 1 year and one patient at 5 years) following PPVI. Transpulmonary gradient and stent orifice diameter remained stable compared to at discharge (p＞0.05). No paravalvular leak was reported while only 1 patient gradually increased to moderate PR during follow-up. Significant improvement of RV diameter and LVEF(p＜0.001) sustained over the 5-year follow-up, in consistent with remarked improved New York Heart Association(NYHA) functional class (p＜0.001). The 5-year results of the China VenusP Study demonstrated the midterm benefits of Venus P-valve implantation in the management of patients with severe PR with an enlarged native RVOT by providing sustained symptomatic and hemodynamic improvement.

Intraoperative transit-time flow measurement of caval veins before and after bidirectional cavopulmonary anastomosis.

Haemodynamic changes in caval venous flow distribution occurring during bidirectional cavopulmonary anastomosis operation are still largely unknown. Transit time flow measurements were performed in 15 cavopulmonary anastomosis operations. Superior and inferior caval vein flows were measured before and after the cavopulmonary anastomosis. Ratio of superior caval vein to overall caval veins flow was calculated. Mean superior caval vein flow ratio before cavopulmonary anastomosis was higher than previously reported for healthy children. Superior caval vein flow ratio decreased in 14/15 patients after cavopulmonary anastomosis: mean 0.63 ± 0.12 before versus 0.43 ± 0.14 after. No linear correlation between intraoperative superior caval vein pressure and superior caval vein flow after cavopulmonary anastomosis was found. Neither Nakata index nor pulmonary vascular resistance measured at preoperative cardiac catheterisation correlated with intraoperative flows. None of patients died or required a take down. The higher mean superior caval vein flow ratio before cavopulmonary anastomosis compared to healthy children suggests flow redistribution in univentricular physiology to protect brain and neurodevelopment. The decrease of superior caval vein flow ratio after cavopulmonary anastomosis may reflect the flow redistribution related to trans-pulmonary gradient. The lack of correlation between superior caval vein pressure and superior caval vein flow could be explained by limited sample size and multifactorial determinants of caval veins flow, although pressure remain essential. Larger sample of measurements are needed to find flow range potentially predictive for clinical failure. To authors' knowledge, this is the first intraoperative flow measurement of both caval veins during cavopulmonary operations.

Cochlear Implantation with Fontan Circulation: A Rare Case of Non-Cardiac Pediatric Surgery

Background: Fontan circulation is a cardiac circulation following the Fontan procedure in patients with a single ventricle congenital heart defect. This circulation depends on the difference in pressure between pulmonary capillaries and central venous pressure to achieve optimal cardiac output. This case report aims to discuss intraoperative anesthesia management in a patient with Fontan circulation undergoing a non-cardiac surgical operation.&#x0D; Case presentation: The patient is a 7-year-old male with a history of congenital heart disease who has undergone the Fontan circulation procedure and is now undergoing Cochlear implantation surgery. The patient was managed with general anesthesia - endotracheal intubation and controlled ventilation during the operation, following the principle of minimizing intrathoracic positive pressure, low PEEP, and low tidal volume with a target peripheral saturation &gt; 95%. Cardiac output monitoring during the intraoperative period is done using intra-arterial blood pressure. After 5 hours of surgery, the patient was extubated with stable hemodynamics. &#x0D; Conclusion: The primary goal of intraoperative anesthesia management in patients with Fontan circulation is to maintain an optimal transpulmonary gradient by ensuring optimal transpulmonary blood flow, thus preserving cardiac output.

Revisiting Pulmonary Hypertension in the Era of Temporary Mechanical Circulatory Support – Literature Review and Case-Based Discussion

Pulmonary arterial hypertension (PAH) is characterized by persistently increased pressure in the pulmonary arteries. New defining criteria for the different hemodynamic types of pulmonary hypertension (PH) that occur with left heart disease have been proposed by the task force on PH. After consideration of the changes in the general definition of PH in left heart disease, the proposed hemodynamic definition was: (1) isolated postcapillary PH: pulmonary artery wedge pressure >15 mm Hg and mean pulmonary arterial pressure (mPAP) >20 mm Hg and pulmonary vascular resistance (PVR) <3 Woods units (WU); and (2) combined post- and precapillary PH: pulmonary artery wedge pressure >15 mm Hg, mPAP >20 mm Hg, and PVR ≥3 WU. Secondary PH is initially reversible, but eventually, it can become fixed because of the remodeling process of the pulmonary vascular system. Limitations in defining both the time for and amount of reversibility lack clarity. We discuss a case of PH as a framework to better understand these key principles in addressing patients' candidacy for heart or heart-lung transplantation. We performed a literature search for all available contemporary data with the following terms: "pulmonary hypertension," "reversal," "Impella 5.5," "temporary mechanical support," and "LVAD" using the National Library of Medicine - PubMed and PubMed Central between 2019 and 2023. A total of 14 published papers were found with these search. From these, 3 addressed the issue of PH and reversibility in the setting of LHD after durable LVAD placement. No papers were found using Impella 5.5 and PH during this timeframe. Given the paucity of data in the field regarding temporary mechanical circulatory support and pulmonary hypertension, we present a case-based discussion to guide the reader in understanding the potential impact of this method in patients with WHO Class 2 Pulmonary hypertension. A 49-year-old woman with a medical history of acute on chronic biventricular systolic and diastolic heart failure, American College of Cardiology stage D, Stevenson profile C, New York Heart Association class IV (ejection fraction 18%) secondary to nonischemic cardiomyopathy after cardiac resynchronization therapy, pulmonary hypertension, bilateral deep vein thrombosis, and segmental pulmonary embolism presented for heart transplant evaluation. Her cardiac output and central hemodynamics were measured, and she was found to have a pulmonary artery (PA) pressure of 78/38 with a mean PA pressure of 51, pulmonary capillary wedge pressure (PCWP) 30, transpulmonary pressure gradient (TPG) 21, thermodilution cardiac output (CO) 3.35 L/min, and cardiac input (CI) 1.75 L/min/m2. Her PVR was 6.2 WU. Provocative pharmacologic testing for reversibility of PH was performed using sodium nitroprusside, which resulted in a blood pressure of 83/57 (92), heart rate 92/min, and PA pressure of 71/31, with a mean PA pressure of 44 PCWP 22, TPG 22, CO 4.8 L/min, and CI of 2.48 L/min/m2 with a PVR of 4.5 WU. Following this, the patient underwent Impella 5.5 placement through the right axillary artery to optimize afterload reduction and improve end-organ perfusion. Post-Impella hemodynamics on milrinone 0.5 mcg/kg/min demonstrated the following: blood pressure 90/66 (74), heart rate 53/min, and PA pressure of 56/29, with a mean PA pressure of 38, PCWP 24, TPG 14, CO 6 L/min, and CI of 2.9 L/min/m2 with a PVR of 2.3 WU. Left ventricular assist device support with Impella 5.5 is associated with a reduction in mPAP and PVR over weeks to months and thus plays a crucial role as a bridge to transplant. Our case and this review highlights the characteristics of PH resulting from heart failure with reduced ejection fraction and discusses the important clinical issues related to the treatment of these patients. We have shown that left ventricular assist device therapy with Impella 5.5 can effectively reduce left-sided filling pressures and lead to PH improvement. We demonstrate the potential benefits of Impella 5.5 in the management of patients with WHO 2 PH and cardiogenic shock with impaired hemodynamics.