A Metabolic Basis for Endothelial-to-Mesenchymal Transition.

Endothelial-to-mesenchymal transition (EndoMT) is a cellular process often initiated by the transforming growth factor ß (TGF-ß) family of ligands. Although required for normal heart valve development, deregulated EndoMT is linked to a wide range of pathological conditions. Here, we demonstrate that endothelial fatty acid oxidation (FAO) is a critical in vitro and in vivo regulator of EndoMT. We further show that this FAO-dependent metabolic regulation of EndoMT occurs through alterations in intracellular acetyl-CoA levels. Disruption of FAO via conditional deletion of endothelial carnitine palmitoyltransferase II (Cpt2E-KO) augments the magnitude of embryonic EndoMT, resulting in thickening of cardiac valves. Consistent with the known pathological effects of EndoMT, adult Cpt2E-KO mice demonstrate increased permeability in multiple vascular beds. Taken together, these results demonstrate that endothelial FAO is required to maintain endothelial cell fate and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions.

Wearable Devices in Cardiovascular Medicine.

Wearable devices, such as smartwatches and activity trackers, are commonly used by patients in their everyday lives to manage their health and well-being. These devices collect and analyze long-term continuous data on measures of behavioral or physiologic function, which may provide clinicians with a more comprehensive view of a patients' health compared with the traditional sporadic measures captured by office visits and hospitalizations. Wearable devices have a wide range of potential clinical applications ranging from arrhythmia screening of high-risk individuals to remote management of chronic conditions such as heart failure or peripheral artery disease. As the use of wearable devices continues to grow, we must adopt a multifaceted approach with collaboration among all key stakeholders to effectively and safely integrate these technologies into routine clinical practice. In this Review, we summarize the features of wearable devices and associated machine learning techniques. We describe key research studies that illustrate the role of wearable devices in the screening and management of cardiovascular conditions and identify directions for future research. Last, we highlight the challenges that are currently hindering the widespread use of wearable devices in cardiovascular medicine and provide short- and long-term solutions to promote increased use of wearable devices in clinical care.

Physical Activity Over the Lifecourse and Cardiovascular Disease.

Despite improvements in cardiovascular care in recent decades, cardiovascular disease (CVD) remains a leading cause of death worldwide. At its core, CVD is a largely preventable disease with diligent risk factor management and early detection. As highlighted in the American Heart Association's Life's Essential 8, physical activity plays a central role in CVD prevention at an individual and population level. Despite pervasive knowledge of the numerous cardiovascular and noncardiovascular health benefits of physical activity, physical activity has steadily decreased over time and unfavorable changes in physical activity occur throughout people's lives. Here, we use a lifecourse framework to examine the evidence reporting on the association of physical activity with CVD. From in utero to older adults, we review and discuss the evidence detailing how physical activity may prevent incident CVD and mitigate CVD-related morbidity and death across all life stages.

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 ß-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.

An electrocardiogram-based AI algorithm for early detection of pulmonary hypertension.

BACKGROUND: Early diagnosis of pulmonary hypertension (PH) is critical for effective treatment and management. We aimed to develop and externally validate an artificial intelligence algorithm that could serve as a PH screening tool, based on analysis of a standard 12-lead electrocardiogram (ECG). METHODS: The PH Early Detection Algorithm (PH-EDA) is a convolutional neural network developed using retrospective ECG voltage-time data, with patients classified as "PH-likely" or "PH-unlikely" (controls) based on right heart catheterisation or echocardiography. In total, 39 823 PH-likely patients and 219 404 control patients from Mayo Clinic were randomly split into training (48%), validation (12%), and test (40%) sets. ECGs taken within 1 month of PH diagnosis (diagnostic dataset) were used to train the PH-EDA at Mayo Clinic. Performance was tested on diagnostic ECGs within the test sets from Mayo Clinic (n=16 175/87 998 PH-likely/controls) and Vanderbilt University Medical Center (VUMC; n=6045/24 256 PH-likely/controls). Performance was also tested on ECGs taken 6-18 months (pre-emptive dataset), and up to 5 years prior to a PH diagnosis at both sites. RESULTS: Performance testing yielded an area under the receiver operating characteristic curve (AUC) of 0.92 and 0.88 in the diagnostic test set at Mayo Clinic and VUMC, respectively, and 0.86 and 0.81, respectively, in the pre-emptive test set. The AUC remained a minimum of 0.79 at Mayo Clinic and 0.73 at VUMC up to 5 years before diagnosis. CONCLUSION: The PH-EDA can detect PH at diagnosis and 6-18 months prior, demonstrating the potential to accelerate diagnosis and management of this debilitating disease.

Elevated Pulmonary Arterial Compliance Is Associated with Survival in Pulmonary Hypertension: Results from a Novel Network Medicine Analysis.

Rationale: Predictors of adverse outcome in pulmonary hypertension (PH) are well established; however, data that inform survival are lacking. Objectives: We aim to identify clinical markers and therapeutic targets that inform the survival in PH. Methods: We included data from patients with elevated mean pulmonary artery pressure (mPAP) diagnosed by right heart catheterization in the U.S. Veterans Affairs system (October 1, 2006-September 30, 2018). Network medicine framework was used to subgroup patients when considering an N of 79 variables per patient. The results informed outcome analyses in the discovery cohort and a sex-balanced validation right heart catheterization cohort from Vanderbilt University (September 24, 1998-December 20, 2013). Measurements and Main Results: From an N of 4,737 complete case patients with mPAP of 19-24 mm Hg, there were 21 distinct subgroups (network modules) (all-cause mortality range = 15.9-61.2% per module). Pulmonary arterial compliance (PAC) drove patient assignment to modules characterized by increased survival. When modeled continuously in patients with mPAP ⩾19 mm Hg (N = 37,744; age, 67.2 yr [range = 61.7-73.8 yr]; 96.7% male; median follow-up time, 1,236 d [range = 570-1,971 d]), the adjusted all-cause mortality hazard ratio was <1.0 beginning at PAC ⩾3.0 ml/mm Hg and decreased progressively to ∼7 ml/mm Hg. A protective association between PAC ⩾3.0 ml/mm Hg and mortality was also observed in the validation cohort (N = 1,514; age, 60.2 yr [range = 49.2-69.1 yr]; 48.0% male; median follow-up time, 2,485 d [range = 671-3,580 d]). The association was strongest in patients with precapillary PH at the time of catheterization, in whom 41% (95% confidence interval, 0.55-0.62; P < 0.001) and 49% (95% confidence interval, 0.38-0.69; P < 0.001) improvements in survival were observed for PAC ⩾3.0 versus <3.0 ml/mm Hg in the discovery and validation cohorts, respectively. Conclusions: These data identify elevated PAC as an important parameter associated with survival in PH. Prospective studies are warranted that consider PAC ⩾3.0 ml/mm Hg as a therapeutic target to achieve through proven interventions.

Heart failure subtype after acute kidney injury.

INTRODUCTION: Acute kidney injury (AKI) is associated with increased risk of heart failure (HF). Determining the type of HF experienced by AKI survivors (heart failure with preserved or reduced ejection fraction, HFpEF or HFrEF) could suggest potential mechanisms underlying the association and opportunities for improving post-AKI care. METHODS: In this retrospective study of adults within the Vanderbilt University health system with a diagnosis of HF, we tested whether AKI events in the two years preceding incident HF associated more with HFpEF or HFrEF while controlling for known predictors. HF outcomes were defined by administrative codes and classified as HFpEF or HFrEF by echocardiogram data. We used multivariable logistic regression models to estimate the effects of AKI on the odds of incident HFpEF versus HFrEF. RESULTS: AKI (all stages) trended towards a preferential association with HFpEF in adjusted analyses (adjusted OR 0.80, 95% CI 0.63 - 1.01). Stage 1 AKI was associated with higher odds of HFpEF that was statistically significant (adjusted OR 0.62, 95% CI 0.43 - 0.88), whereas stages 2-3 AKI showed a trend toward HFrEF that did not reach statistical significance (adjusted OR 1.11, 95% CI 0.76 - 1.63). CONCLUSIONS: AKI as a binary outcome trended towards a preferential association with HFpEF. Stage 1 AKI was associated with higher odds of HFpEF, whereas stage 2-3 trended towards an association with HFrEF that did not meet statistical significance. Different mechanisms may predominate in incident HF following mild versus more severe AKI. Close follow-up with particular attention to volume status and cardiac function after discharge is warranted after even mild AKI.

Elucidating the Clinical Implications and Pathophysiology of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction: A Call to Action: A Science Advisory From the American Heart Association.

This science advisory focuses on the need to better understand the epidemiology, pathophysiology, and treatment of pulmonary hypertension in patients with heart failure with preserved ejection fraction. This clinical phenotype is important because it is common, is strongly associated with adverse outcomes, and lacks evidence-based therapies. Our goal is to clarify key knowledge gaps in pulmonary hypertension attributable to heart failure with preserved ejection fraction and to suggest specific, actionable scientific directions for addressing such gaps. Areas in need of additional investigation include refined disease definitions and interpretation of hemodynamics, as well as greater insights into noncardiac contributors to pulmonary hypertension risk, optimized animal models, and further molecular studies in patients with combined precapillary and postcapillary pulmonary hypertension. We highlight translational approaches that may provide important biological insight into pathophysiology and reveal new therapeutic targets. Last, we discuss the current and future landscape of potential therapies for patients with heart failure with preserved ejection fraction and pulmonary vascular dysfunction, including considerations of precision medicine, novel trial design, and device-based therapies, among other considerations. This science advisory provides a synthesis of important knowledge gaps, culminating in a collection of specific research priorities that we argue warrant investment from the scientific community.

Cirrhotic cardiomyopathy: Appraisal of the original and revised criteria in predicting posttransplant cardiac outcomes.

Cardiovascular disease (CVD) significantly contributes to morbidity and mortality after liver transplantation (LT). Cirrhotic cardiomyopathy (CCM) is a risk factor for CVD after transplant. CCM criteria were originally introduced in 2005 with a revision proposed in 2020 reflecting echocardiographic technology advancements. This study assesses the two criteria sets in predicting major adverse cardiac events (MACE) after transplant. This single-center retrospective study reviewed adult LT recipients between January 1, 2009, and December 31, 2018. Patients with insufficient pre-LT echocardiographic data, prior ischemic heart disease, portopulmonary hypertension, or longitudinal care elsewhere were excluded. The primary composite outcome was MACE (arrhythmia, heart failure, cardiac arrest, and/or cardiac death) after transplant. Of 1165 patients, 210 met the eligibility criteria. CCM was present in 162 patients (77%) per the original criteria and 64 patients (30%) per the revised criteria. There were 44 MACE and 31 deaths in the study period. Of the deaths, 38.7% occurred secondary to CVD. CCM defined by the original criteria was not associated with MACE after LT (p = 0.21), but the revised definition was significantly associated with MACE (hazard ratio [HR], 1.93; 95% confidence interval, 1.05-3.56; p = 0.04) on multivariable analysis. Echocardiographic variable analysis demonstrated low septal e' as the most predictive variable for MACE after LT (HR, 3.45; p < 0.001). CCM, only when defined by the revised criteria, was associated with increased risk for MACE after LT, validating the recently revised CCM definition. Abnormal septal e', reflecting impaired relaxation, appears to be the most predictive echocardiographic criterion for MACE after LT.

An algorithm to identify cases of pulmonary arterial hypertension from the electronic medical record.

BACKGROUND: Study of pulmonary arterial hypertension (PAH) in claims-based (CB) cohorts may facilitate understanding of disease epidemiology, however previous CB algorithms to identify PAH have had limited test characteristics. We hypothesized that machine learning algorithms (MLA) could accurately identify PAH in an CB cohort. METHODS: ICD-9/10 codes, CPT codes or PAH medications were used to screen an electronic medical record (EMR) for possible PAH. A subset (Development Cohort) was manually reviewed and adjudicated as PAH or "not PAH" and used to train and test MLAs. A second subset (Refinement Cohort) was manually reviewed and combined with the Development Cohort to make The Final Cohort, again divided into training and testing sets, with MLA characteristics defined on test set. The MLA was validated using an independent EMR cohort. RESULTS: 194 PAH and 786 "not PAH" in the Development Cohort trained and tested the initial MLA. In the Final Cohort test set, the final MLA sensitivity was 0.88, specificity was 0.93, positive predictive value was 0.89, and negative predictive value was 0.92. Persistence and strength of PAH medication use and CPT code for right heart catheterization were principal MLA features. Applying the MLA to the EMR cohort using a split cohort internal validation approach, we found 265 additional non-confirmed cases of suspected PAH that exhibited typical PAH demographics, comorbidities, hemodynamics. CONCLUSIONS: We developed and validated a MLA using only CB features that identified PAH in the EMR with strong test characteristics. When deployed across an entire EMR, the MLA identified cases with known features of PAH.

Mendelian randomisation analysis of red cell distribution width in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare disease that leads to premature death from right heart failure. It is strongly associated with elevated red cell distribution width (RDW), a correlate of several iron status biomarkers. High RDW values can signal early-stage iron deficiency or iron deficiency anaemia. This study investigated whether elevated RDW is causally associated with PAH.A two-sample Mendelian randomisation (MR) approach was applied to investigate whether genetic predisposition to higher levels of RDW increases the odds of developing PAH. Primary and secondary MR analyses were performed using all available genome-wide significant RDW variants (n=179) and five genome-wide significant RDW variants that act via systemic iron status, respectively.We confirmed the observed association between RDW and PAH (OR 1.90, 95% CI 1.80-2.01) in a multicentre case-control study (cases n=642, disease controls n=15 889). The primary MR analysis was adequately powered to detect a causal effect (odds ratio) between 1.25 and 1.52 or greater based on estimates reported in the RDW genome-wide association study or from our own data. There was no evidence for a causal association between RDW and PAH in either the primary (ORcausal 1.07, 95% CI 0.92-1.24) or the secondary (ORcausal 1.09, 95% CI 0.77-1.54) MR analysis.The results suggest that at least some of the observed association of RDW with PAH is secondary to disease progression. Results of iron therapeutic trials in PAH should be interpreted with caution, as any improvements observed may not be mechanistically linked to the development of PAH.

Bone Marrow-Derived Proangiogenic Cells Mediate Pulmonary Arteriole Stiffening via Serotonin 2B Receptor Dependent Mechanism.

RATIONALE: Pulmonary arterial hypertension is a deadly disease of the pulmonary vasculature for which no disease-modifying therapies exist. Small-vessel stiffening and remodeling are fundamental pathological features of pulmonary arterial hypertension that occur early and drive further endovascular cell dysfunction. Bone marrow (BM)-derived proangiogenic cells (PACs), a specialized heterogeneous subpopulation of myeloid lineage cells, are thought to play an important role in pathogenesis. OBJECTIVE: To determine whether BM-derived PACs directly contributed to experimental pulmonary hypertension (PH) by promoting small-vessel stiffening through 5-HT2B (serotonin 2B receptor)-mediated signaling. METHODS AND RESULTS: We performed BM transplants using transgenic donor animals expressing diphtheria toxin secondary to activation of an endothelial-specific tamoxifen-inducible Cre and induced experimental PH using hypoxia with SU5416 to enhance endovascular injury and ablated BM-derived PACs, after which we measured right ventricular systolic pressures in a closed-chest procedure. BM-derived PAC lineage tracing was accomplished by transplanting BM from transgenic donor animals with fluorescently labeled hematopoietic cells and treating mice with a 5-HT2B antagonist. BM-derived PAC ablation both prevented and reversed experimental PH with SU5416-enhanced endovascular injury, reducing the number of muscularized pulmonary arterioles and normalizing arteriole stiffness as measured by atomic force microscopy. Similarly, treatment with a pharmacological antagonist of 5-HT2B also prevented experimental PH, reducing the number and stiffness of muscularized pulmonary arterioles. PACs accelerated pulmonary microvascular endothelial cell injury response in vitro, and the presence of BM-derived PACs significantly correlated with stiffer pulmonary arterioles in pulmonary arterial hypertension patients and mice with experimental PH. RNA sequencing of BM-derived PACs showed that 5-HT2B antagonism significantly altered biologic pathways regulating cell proliferation, locomotion and migration, and cytokine production and response to cytokine stimulus. CONCLUSIONS: Together, our findings illustrate that BM-derived PACs directly contribute to experimental PH with SU5416-enhanced endovascular injury by mediating small-vessel stiffening and remodeling in a 5-HT2B signaling-dependent manner.

Biomarker-specific differences between transpulmonary and peripheral arterial-venous blood sampling in patients with pulmonary hypertension.

Purpose: Transpulmonary biomarkers may provide insight into pulmonary hypertension (PH) pathophysiology, but require cardiac catheterization. We investigated whether the peripheral arterial-venous ratio (PR) could substitute for the transpulmonary ratio (TPR).Materials and methods: Blood from the pulmonary artery (PA), pulmonary arterial wedge (PAW), peripheral venous, and peripheral arterial positions was analysed for ET-1, NT-pro-BNP and cAMP levels in subjects with no PH (n = 18) and PH due to left heart disease (PH-LHD), which included combined pre- and post-capillary PH (Cpc-PH; n = 7) and isolated post-capillary PH (Ipc-PH; n = 9). Bland-Altman comparisons were made between peripheral venous and PA samples and between peripheral arterial and PAW samples. TPR was defined as [PAW]/[PA].Results: For ET-1, Bland-Altman analysis indicated negative bias (-24%) in peripheral arterial compared to PAW concentration and positive bias (23%) in peripheral venous compared to PA concentration. There was <10% absolute bias for NT-pro-BNP and cAMP. For ET-1, there was no difference in PR between Cpc-PH and Ipc-PH (0.87 ± 0.4 vs. 0.94 ± 0.6, p = 0.8), whereas there was a difference in TPR (2.2 ± 1.1 vs. 1.1 ± 0.2, p < 0.05).Conclusions: In PH-LHD, peripheral samples may be inadequate surrogates for transpulmonary samples, particularly when measuring mediators with prominent pulmonary secretion or clearance, such as ET-1.

Increased Echocardiographic Pulmonary Pressure in HIV-infected and -uninfected Individuals in the Veterans Aging Cohort Study.

RATIONALE: The epidemiology and prognostic impact of increased pulmonary pressure among HIV-infected individuals in the antiretroviral therapy era is not well described. OBJECTIVES: To examine the prevalence, clinical features, and outcomes of increased echocardiographic pulmonary pressure in HIV-infected and -uninfected individuals. METHODS: This study evaluated 8,296 veterans referred for echocardiography with reported pulmonary artery systolic pressure (PASP) estimates from the Veterans Aging Cohort study, an observational cohort of HIV-infected and -uninfected veterans matched by age, sex, race/ethnicity, and clinical site. The primary outcome was adjusted mortality by HIV status. MEASUREMENTS AND MAIN RESULTS: PASP was reported in 2,831 HIV-infected and 5,465 HIV-uninfected veterans (follow-up [mean ± SD], 3.8 ± 2.6 yr). As compared with uninfected veterans, HIV-infected veterans with HIV viral load greater than 500 copies/ml (odds ratio, 1.27; 95% confidence interval [CI], 1.05-1.54) and those with CD4 cell count less than 200 cells/µl (odds ratio, 1.28; 95% CI, 1.02-1.60) had a higher prevalence of PASP greater than or equal to 40 mm Hg. As compared with uninfected veterans with a PASP less than 40 mm Hg, HIV-infected veterans with a PASP greater than or equal to 40 mm Hg had an increased risk of death (adjusted hazard ratio, 1.78; 95% CI, 1.57-2.01). This risk persisted even among participants without prevalent comorbidities (adjusted hazard ratio, 3.61; 95% CI, 2.17-6.01). The adjusted risk of mortality in HIV-infected veterans was higher at all PASP values than in uninfected veterans, including at values currently considered to be normal. CONCLUSIONS: HIV-infected people with high HIV viral loads or low CD4 cell counts have a higher prevalence of increased PASP than uninfected people. Mortality risk in HIV-infected veterans increases at lower values of PASP than previously recognized and is present even among those without prevalent comorbidities. These findings may inform clinical decision-making regarding screening and surveillance of pulmonary hypertension in HIV-infected individuals.

Pulmonary transit time from contrast echocardiography and cardiac magnetic resonance imaging: Comparison between modalities and the impact of region of interest characteristics.

INTRODUCTION: The degree of correlation of pulmonary transit time (PTT) between contrast echocardiography and cardiac magnetic resonance imaging (MRI) across the spectrum of cardiac disease has not been quantified. In addition, the degree to which PTT estimates are affected by variation in location and size of regions of interest (ROI) is unknown. METHODS: Pulmonary transit time was obtained using an inflection point technique from individuals that underwent contrast echocardiography and cardiac MRI. Right ventricular, left atrial, and left ventricular ROIs were evaluated, and two sizes for each ROI were used. The Spearman correlation coefficient and Bland-Altman analysis were used for comparisons between modalities. Bland-Altman plots were also used to measure the impact of ROI size and location on transit times. RESULTS: Fourteen participants (age: 27-64 years; LV ejection fraction: 30%-60%) underwent both studies a median of 1 week apart. The correlation between modalities was significant for PTT (r = 0.65; P = 0.01) and normalized PTT (r = 0.80; P = 0.001). Cardiac MRI yielded transit times consistently higher than contrast echocardiography (bias ~ 1.4 seconds), but the discordance was not dependent on transit time magnitude. Low bias was observed for comparisons of ROI size and location (<0.5 seconds). CONCLUSIONS: Contrast echocardiography underestimates transit time measurements obtained by cardiac MRI, although the discrepancy was systematic and may have been contributed to by the interval between imaging studies. ROI location and size did not impact transit time values, suggesting that ROIs could be placed without intensive training, a step toward incorporation of real-time PTT measurement into echocardiographic laboratory workflow.

A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg-1 intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.

The relationship between pulmonary artery wedge pressure and pulmonary blood volume derived from contrast echocardiography: A proof-of-concept study.

BACKGROUND: Pulmonary transit time (PTT) obtained from contrast echocardiography is a marker of global cardiopulmonary function. Pulmonary blood volume (PBV), derived from PTT, may be a noninvasive surrogate for left-sided filling pressures, such as pulmonary artery wedge pressure (PAWP). We sought to assess the relationship between PBV obtained from contrast echocardiography and PAWP. METHODS: Participants were adult survivors of childhood cancer that had contrast echocardiography performed nearly simultaneously with right-heart catheterization. PTT was derived from time-intensity curves of contrast passage through the right ventricle (RV) and left atrium (LA). PBV relative to overall stroke volume (rPBV) was estimated from the product of PTT and heart rate during RV-LA transit. PAWP was obtained during standard right-heart catheterization. The Spearman correlation coefficient was used to assess the relationship between rPBV and PAWP. RESULTS: The study population consisted of 7 individuals who had contrast echocardiography and right-heart catheterization within 3 hours of each other. There was a wide range of right atrial (1-17 mm Hg), mean pulmonary artery (18-42 mm Hg), and PAW pressures (4-26 mm Hg) as well as pulmonary vascular resistance (<1-6 Wood Units). We observed a statistically significant correlation between rPBV and PAWP (r = .85; P = .02). CONCLUSION: Relative PBV derived from contrast echocardiography correlates with PAWP. If validated in larger studies, rPBV could potentially be used as an alternative to invasively determine left-sided filling pressure.