Explore the vast range of titles available.

Hematocrit was much higher in Andeans, but hematocrit-corrected total PVR was not. [...]contrary to current belief (17), different adaptations to permanent life at high altitude in South American versus Himalayan populations may not clearly include intrinsic differences in the pulmonary circulation. With a PAWP of 15 mm Hg, which is more realistic as high CO in anemia tends to be associated with increased PAWP, a hematocrit-corrected PVR becomes 4.9 WU (Figure 1). [...]in cases of a higherthan-normal PAWP, PVR even lower than 2 WU may or may not reflect abnormal pulmonary vascular tone and structure suggestive of pulmonary vascular disease in patients with SCD. [...]the PVR equation can be improved by incorporation of a resistive vessel distensibility coefficient a, which defines the percentage increase in vessel diameter per mm Hg: ... Pulmonary vascular disease even at the earliest stages is associated with a loss of pulmonary resistive vessel distensibility, and a decreases to values equal or close to 0%/mm Hg (26, 27). [...]in patients with anemia or polycythemia with borderline pulmonary hypertension (that is, with mPAP or PVR at the upper limit of normal or slightly above), or with established pulmonary hypertension hematocrit corrections of PVR, would follow tightly the predictions of the diagrams presented in Figures 1 and 2.

Dysregulation of vascular stiffness and cellular metabolism occurs early in pulmonary hypertension (PH). However, the mechanisms by which biophysical properties of the vascular extracellular matrix (ECM) relate to metabolic processes important in PH remain undefined. In this work, we examined cultured pulmonary vascular cells and various types of PH-diseased lung tissue and determined that ECM stiffening resulted in mechanoactivation of the transcriptional coactivators YAP and TAZ (WWTR1). YAP/TAZ activation modulated metabolic enzymes, including glutaminase (GLS1), to coordinate glutaminolysis and glycolysis. Glutaminolysis, an anaplerotic pathway, replenished aspartate for anabolic biosynthesis, which was critical for sustaining proliferation and migration within stiff ECM. In vitro, GLS1 inhibition blocked aspartate production and reprogrammed cellular proliferation pathways, while application of aspartate restored proliferation. In the monocrotaline rat model of PH, pharmacologic modulation of pulmonary vascular stiffness and YAP-dependent mechanotransduction altered glutaminolysis, pulmonary vascular proliferation, and manifestations of PH. Additionally, pharmacologic targeting of GLS1 in this model ameliorated disease progression. Notably, evaluation of simian immunodeficiency virus-infected nonhuman primates and HIV-infected subjects revealed a correlation between YAP/TAZ-GLS activation and PH. These results indicate that ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis and anaplerosis, and thereby link mechanical stimuli to dysregulated vascular metabolism. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in PH.

Objective Prognosis in pulmonary hypertension (PH) is largely determined by RV function. However, uncertainty remains about what metrics of RV function might be most clinically relevant. The purpose of this study was to assess the clinical relevance of metrics of RV functional adaptation to increased afterload. Methods Patients referred for PH underwent right heart catheterisation and RV volumetric assessment within 48 h. A RV maximum pressure (Pmax) was calculated from the RV pressure curve. The adequacy of RV systolic functional adaptation to increased afterload was estimated either by a stroke volume (SV)/end-systolic volume (ESV) ratio, a Pmax/mean pulmonary artery pressure (mPAP) ratio, or by EF (RVEF). Diastolic function of the RV was estimated by a diastolic elastance coefficient β. Survival analysis was via Cox proportional HR, and Kaplan–Meier with the primary outcome of time to death or lung transplant. Results Patients (n=50; age 58±13 yrs) covered a range of mPAP (13–79 mm Hg) with an average RVEF of 39±17% and ESV of 143±89 mL. Average estimates of the ratio of end-systolic ventricular to arterial elastance were 0.79±0.67 (SV/ESV) and 2.3±0.65 (Pmax/mPAP-1). Transplantation-free survival was predicted by right atrial pressure, mPAP, pulmonary vascular resistance, β, SV, ESV, SV/ESV and RVEF, but after controlling for right atrial pressure, mPAP, and SV, SV/ESV was the only independent predictor. Conclusions The adequacy of RV functional adaptation to afterload predicts survival in patients referred for PH. Whether this can simply be evaluated using RV volumetric imaging will require additional confirmation.

People living with human immunodeficiency virus (PLWH) are at risk of developing pulmonary hypertension (PH) and right ventricular (RV) dysfunction, but understanding of the relationship of RV function to afterload (RV-PA coupling) is limited. We evaluated the clinical and hemodynamic characteristics of human immunodeficiency virus (HIV)-associated PH. We performed a retrospective review of patients with a diagnosis of HIV undergoing right heart catheterization (RHC) from 2000-2016 in a tertiary care center. Inclusion criteria were diagnosis of HIV, age ≥ 18 years and availability of RHC data. PH was classified as either pulmonary arterial hypertension (PAH; mean pulmonary arterial pressure [mPAP] ≥ 25mmHg with pulmonary artery wedge pressure [PAWP] ≤ 15mmHg) or pulmonary venous hypertension (PVH; mPAP ≥ 25mmHg with PAWP > 15). We collected demographics, CD4 cell count, HIV viral load, RHC and echocardiographic data. The single beat method was used to calculate RV-PA coupling from RHC. Sixty-two PLWH with a clinical likelihood for PH underwent RHC. Thirty-two (52%) met PH criteria (15 with PAH, 17 with PVH). Average time from diagnosis of HIV to diagnosis of PH was 11 years. Eleven of 15 individuals with PAH were on antiretroviral therapy (ART) while all 17 patients with PVH were on ART. Compared to PLWH without PH, those with PH had an increased likelihood of having a detectable HIV viral load and lower CD4 cell counts. PLWH with PAH or PVH had increased RV afterload with normal RV contractility, and preserved RV-PA coupling. PLWH with PH (PAH or PVH) were more likely to have a detectable HIV viral load and lower CD4 count at the time of RHC. PLWH with PAH or PVH had increased RV afterload, normal RV contractility, with preserved RV-PA coupling suggestive of an early onset, mild, and compensated form of PH. These results should be confirmed in larger studies.

Pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (PH-HFpEF; World Health Organization Group II) secondary to left ventricular (LV) diastolic dysfunction is the most frequent cause of PH. It is an increasingly recognized clinical complication of the metabolic syndrome. To date, no effective treatment has been identified, and no genetically modifiable mouse model is available for advancing our understanding for PH-HFpEF. To develop a mouse model of PH-HFpEF, we exposed 36 mouse strains to 20 weeks of high-fat diet (HFD), followed by systematic evaluation of right ventricular (RV) and LV pressure-volume analysis. The HFD induces obesity, glucose intolerance, insulin resistance, hyperlipidemia, as well as PH, in susceptible strains. We observed that certain mouse strains, such as AKR/J, NON/shiLtJ, and WSB/EiJ, developed hemodynamic signs of PH-HFpEF. Of the strains that develop PH-HFpEF, we selected AKR/J for further model validation, as it is known to be prone to HFD-induced metabolic syndrome and had low variability in hemodynamics. HFD-treated AKR/J mice demonstrate reproducibly higher RV systolic pressure compared with mice fed with regular diet, along with increased LV end-diastolic pressure, both RV and LV hypertrophy, glucose intolerance, and elevated HbA1c levels. Time course assessments showed that HFD significantly increased body weight, RV systolic pressure, LV end-diastolic pressure, biventricular hypertrophy, and HbA1c throughout the treatment period. Moreover, we also identified and validated 129S1/SvlmJ as a resistant mouse strain to HFD-induced PH-HFpEF. These studies validate an HFD/AKR/J mouse model of PH-HFpEF, which may offer a new avenue for testing potential mechanisms and treatments for this disease.

Each year the American Thoracic Society (ATS) Conference brings together scientists who conduct basic, translational and clinical research to present on the recent advances in the field of respirology. Due to the Coronavirus Disease of 2019 (COVID-19) pandemic, the ATS2020 Conference was held online in a series of virtual meetings. In this review, we focus on the breakthroughs in pulmonary hypertension research. We have selected 11 of the best basic science abstracts which were presented at the ATS2020 Assembly on Pulmonary Circulation mini-symposium “What’s New in Pulmonary Arterial Hypertension (PAH) and Right Ventricular (RV) Signaling: Lessons from the Best Abstracts,” reflecting the current state of the art and associated challenges in PH. Particular emphasis is placed on understanding the mechanisms underlying RV failure, the regulation of inflammation, and the novel therapeutic targets that emerged from preclinical research. The pathologic interactions between pulmonary hypertension, right ventricular function and COVID-19 are also discussed.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, increased pulmonary artery (PA) pressure, right-heart afterload and death. Mechanistic target of rapamycin (mTOR) promotes smooth muscle cell proliferation, survival, and pulmonary vascular remodeling via two functionally distinct mTOR complexes (mTORCs)-1 (supports cell growth) and -2 (promotes cell survival), and dual mTORC1/mTORC2 inhibition selectively induces pulmonary arterial hypertension PA vascular smooth muscle cell apoptosis and reverses pulmonary vascular remodeling. The consequences of mTOR inhibition on right ventricle (RV) morphology and function are not known. Using SU5416/hypoxia rat model of pulmonary hypertension (PH), we report that, in contrast to activation of both mTORC1 and mTORC2 pathways in small remodeled PAs, RV tissues had predominant up-regulation of mTORC1 signaling accompanied by cardiomyocyte and RV hypertrophy, increased RV wall thickness, RV/left ventricle end-diastolic area ratio, RV contractility and afterload (arterial elastance), and shorter RV acceleration time compared with controls. Treatment with mTOR kinase inhibitor, PP242, at Weeks 6-8 after PH induction suppressed both mTORC1 and mTORC2 in small PAs, but only mTORC1 signaling in RV, preserving basal mTORC2-Akt levels. Vehicle-treated rats showed further PH and RV worsening and profound RV fibrosis. PP242 reversed pulmonary vascular remodeling and prevented neointimal occlusion of small PAs, significantly reduced PA pressure and pulmonary vascular resistance, reversed cardiomyocyte hypertrophy and RV remodeling, improved max RV contractility, arterial elastance, and RV acceleration time, and prevented development of RV fibrosis. Collectively, these data show a predominant role of mTORC1 versus mTORC2 in RV pathology, and suggest potential attractiveness of mTOR inhibition to simultaneously target pulmonary vascular remodeling and RV dysfunction in established PH.

Because PH-HFpEF shares many pathophysiological characteristics with PAH, and many patients with PAH exhibit signs of insulin resistance and glucose intolerance in the absence of obesity and diabetes (3, 4), we evaluated metformin in the treatment of group 1 PH. Restoration of SIRT3 in skeletal muscle with nitrite and metformin improved insulin sensitivity and reduced pulmonary pressures (2). Because insulin resistance and exercise intolerance are key features of PAH (3, 4, 10), we next assessed the activation levels of skeletal muscle SIRT3 in SuHx rats. [...]our data suggest that metformin treatment may be preferentially beneficial in the treatment of PH-HFpEF, with limited efficacy for PAH. ? SIRT3-AMP-activated protein kinase activation by nitrite and metformin improves hyperglycemia and normalizes pulmonary hypertension associated with heart failure with preserved ejection fraction.

Prostacyclin analogs are among the most effective and widely used therapies for pulmonary arterial hypertension (PAH). However, it is unknown whether they also confer protection through right ventricle (RV) myocardio-specific mechanisms. Moreover, the use of prostacyclin analogs in severe models of PAH has not been adequately tested. To further identify underlying responses to prostacyclin, a prostacyclin analogue, treprostinil, was used in a preclinical rat Sugen-chronic hypoxia (SuCH) model of severe PAH that closely resembles the human disease. Male Sprague–Dawley rats were implanted with osmotic pumps containing vehicle or treprostinil, injected concurrently with a bolus of Sugen (SU5416) and exposed to 3-week hypoxia followed by 3-week normoxia. RV function was assessed using pressure–volume loops and hypertrophy by weight assessed. To identify altered mechanisms within the RV, tissue samples were used to perform a custom RNA array analysis, histological staining, and protein and transcript level confirmatory analyses. Treprostinil significantly reduced SuCH-associated RV hypertrophy and decreased the rise in RV systolic pressure, mean pulmonary arterial (mPAP), and right atrial (RAP) pressure. Prostacyclin treatment was associated with improvements in RV stroke work, maximum rate of ventricular pressure change (max dP/dt) and the contractile index, and almost a complete reversal of SuCH-associated increase in RV end-systolic elastance, suggesting the involvement of load-independent improvements in intrinsic RV systolic contractility by prostacyclin treatment. An analysis of the RV tissues showed no changes in cardiac mitochondrial respiration and ATP generation. However, custom RNA array analysis revealed amelioration of SuCH-associated increases in newly identified TBX20 as well as the fibrotic markers collagen1α1 and collagen 3α1 upon treprostinil treatment. Taken together, our data support decreased afterload and load-independent improvements in RV function following prostacyclin administration in severe PAH, and these changes appear to associate with improvements in RV fibrotic responses.