Publications by authors named "Rebecca R Vanderpool"

44 Publications

The Right Ventricular-Pulmonary Arterial Coupling and Diastolic Function Response to Therapy in Pulmonary Arterial Hypertension.

Chest 2021 Oct 9. Epub 2021 Oct 9.

Department of Medicine, University of Arizona, Tucson, AZ; Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, University of Arizona, Tucson, AZ. Electronic address:

Background: Multiparametric risk assessment is used in pulmonary arterial hypertension (PAH) to target therapy. However, this strategy is imperfect as most patients remain in intermediate or high risk after initial treatment with low risk being the goal. Metrics of right ventricular (RV) adaptation are promising tools that may help refine our therapeutic strategy.

Research Question: Does RV adaptation predict therapeutic response over time?

Study Design And Methods: We evaluated 52 incident treatment naïve patients with advanced PAH by catheterization and cardiac imaging longitudinally at baseline, follow-up 1 (∼3 mo.) and follow-up 2 (∼18 mo.). All patients were placed on goal-directed therapy with parenteral treprostinil and/or combination therapy with treatment escalation if functional class I-II was not achieved. Therapeutic response was evaluated at follow-up 1 as non-responders (died) or responders and again at follow-up 2 as super-responders (low risk) or partial-responders (high/intermediate risk). Multiparametric risk was based on a simplified ERS/ESC guideline score. RV adaptation was evaluated with the single-beat coupling ratio (Ees/Ea) and diastolic function with diastolic elastance (Eed). Data are expressed as mean±SD or odds ratio [95%CI].

Results: Nine patients (17%) were non-responders. PAH-directed therapy improved ERS low risk from 1 (2%) at baseline to 23 (55%) at follow-up 2. Ees/Ea at presentation was non-significantly higher in responders (0.9±0.4) versus non-responders (0.6±0.4, p=0.09) but was unable to predict super-responder status at follow-up 2 (odds ratio 1.40 [0.28-7.0], p=0.84). Baseline RVEF and change in Eed successfully predicted super-responder status at follow-up 2 (odds ratio 1.15 [1.0-1.27], p=0.009 and 0.29 [0.86-0.96], p=0.04, respectively).

Interpretation: In patients with advanced PAH, RV-PA coupling could not discriminate irreversible RV failure (non-responders) at presentation but showed a late trend to improvement by follow-up 2. Early change in Eed and baseline RVEF were the best predictors of therapeutic response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2021.09.040DOI Listing
October 2021

Recent advancements in pulmonary arterial hypertension and right heart failure research: overview of selected abstracts from ATS2020 and emerging COVID-19 research.

Pulm Circ 2021 Jul-Sep;11(3):20458940211037274. Epub 2021 Aug 19.

Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/20458940211037274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381443PMC
August 2021

Relaxin Inhibits Ventricular Arrhythmia and Asystole in Rats With Pulmonary Arterial Hypertension.

Front Cardiovasc Med 2021 6;8:668222. Epub 2021 Jul 6.

Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.

Pulmonary arterial hypertension (PAH) leads to right ventricular cardiomyopathy and cardiac dysfunctions where in the clinical setting, cardiac arrest is the likely cause of death, in ~70% of PAH patients. We investigated the cardiac phenotype of PAH hearts and tested the hypothesis that the insulin-like hormone, Relaxin could prevent maladaptive cardiac remodeling and protect against cardiac dysfunctions in a PAH animal model. PAH was induced in rats with sugen (20 mg/kg), hypoxia then normoxia (3-weeks/each); relaxin (RLX = 0, 30 or 400 μg/kg/day, ≥ 6/group) was delivered subcutaneously (6-weeks) with implanted osmotic mini-pumps. Right ventricle (RV) hemodynamics and Doppler-flow measurements were followed by cardiac isolation, optical mapping, and arrhythmia phenotype. Sugen-hypoxia (SuHx) treated rats developed PAH characterized by higher RV systolic pressures (50 ± 19 vs. 22 ± 5 mmHg), hypertrophy, reduced stroke volume, ventricular fibrillation (VF) ( = 6/11) and bradycardia/arrest ( = 5/11); both cardiac phenotypes were suppressed with dithiothreitol (DTT = 1 mM) ( = 0/2/group) or RLX (low or high dose, = 0/6/group). PAH hearts developed increased fibrosis that was reversed by RLX-HD, but not RLX-LD. Relaxin decreased Nrf2 and glutathione transferases but not glutathione-reductase. High-dose RLX improved pulmonary arterial compliance (measured by Doppler flow), suppressed VF even after burst-pacing, = 2/6). Relaxin suppressed VF and asystole through electrical remodeling and by reversing thiol oxidative stress. For the first time, we showed two cardiac phenotypes in PAH animals and their prevention by RLX. Relaxin may modulate maladaptive cardiac remodeling in PAH and protect against arrhythmia and cardiac arrest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcvm.2021.668222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290063PMC
July 2021

NHLBI-CMREF Workshop Report on Pulmonary Vascular Disease Classification: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 04;77(16):2040-2052

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

The National Heart, Lung, and Blood Institute and the Cardiovascular Medical Research and Education Fund held a workshop on the application of pulmonary vascular disease omics data to the understanding, prevention, and treatment of pulmonary vascular disease. Experts in pulmonary vascular disease, omics, and data analytics met to identify knowledge gaps and formulate ideas for future research priorities in pulmonary vascular disease in line with National Heart, Lung, and Blood Institute Strategic Vision goals. The group identified opportunities to develop analytic approaches to multiomic datasets, to identify molecular pathways in pulmonary vascular disease pathobiology, and to link novel phenotypes to meaningful clinical outcomes. The committee suggested support for interdisciplinary research teams to develop and validate analytic methods, a national effort to coordinate biosamples and data, a consortium of preclinical investigators to expedite target evaluation and drug development, longitudinal assessment of molecular biomarkers in clinical trials, and a task force to develop a master clinical trials protocol for pulmonary vascular disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2021.02.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065203PMC
April 2021

Right ventricular load and contractility in HIV-associated pulmonary hypertension.

PLoS One 2021 23;16(2):e0243274. Epub 2021 Feb 23.

Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States of America.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243274PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901734PMC
July 2021

Transcriptomic profiles in pulmonary arterial hypertension associate with disease severity and identify novel candidate genes.

Pulm Circ 2020 Oct-Dec;10(4):2045894020968531. Epub 2020 Dec 7.

Department of Medicine, College of Medicine, The University of Arizona, Tucson, AZ, USA.

Using RNAseq, we identified a 61 gene-based circulating transcriptomic profile most correlated with four indices of pulmonary arterial hypertension severity. In an independent dataset, 13/61 (21%) genes were differentially expressed in lung tissues of pulmonary arterial hypertension cases versus controls, highlighting potentially novel candidate genes involved in pulmonary arterial hypertension development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2045894020968531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727059PMC
December 2020

Treatment With Treprostinil and Metformin Normalizes Hyperglycemia and Improves Cardiac Function in Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction.

Arterioscler Thromb Vasc Biol 2020 06 9;40(6):1543-1558. Epub 2020 Apr 9.

Division of Pulmonary, Critical Care, Sleep and Occupational Medicine (G.H., A.F., T.C., Y.B., R.F.M., Y.-C.L.), Indiana University School of Medicine, Indianapolis.

Objective: Pulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle.

Conclusions: Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.119.313883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255946PMC
June 2020

Comprehensive Diagnostic Evaluation of Cardiovascular Physiology in Patients With Pulmonary Vascular Disease: Insights From the PVDOMICS Program.

Circ Heart Fail 2020 03 24;13(3):e006363. Epub 2020 Feb 24.

Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Department of Medicine (F.P.R.).

Background: Invasive hemodynamic evaluation through right heart catheterization plays an essential role in the diagnosis, categorization, and risk stratification of patients with pulmonary hypertension.

Methods: Subjects enrolled in the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) program undergo an extensive invasive hemodynamic evaluation that includes repeated measurements at rest and during several provocative physiological challenges. It is a National Institutes of Health/National Heart, Lung, and Blood Institute initiative to reclassify pulmonary hypertension groups based on clustered phenotypic and phenomic characteristics. At a subset of centers, participants also undergo an invasive cardiopulmonary exercise test to assess changes in hemodynamics and gas exchange during exercise.

Conclusions: When coupled with other physiological testing and blood -omic analyses involved in the PVDOMICS study, the comprehensive right heart catheterization protocol described here holds promise to clarify the diagnosis and clustering of pulmonary hypertension patients into cohorts beyond the traditional 5 World Symposium on Pulmonary Hypertension groups. This article will describe the methods applied for invasive hemodynamic characterization in the PVDOMICS program. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02980887.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046052PMC
March 2020

Tetramethylpyrazine: A promising drug for the treatment of pulmonary hypertension.

Br J Pharmacol 2020 06 27;177(12):2743-2764. Epub 2020 Apr 27.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Background And Purpose: Tetramethylpyrazine (TMP) was originally isolated from the traditional Chinese herb ligusticum and the fermented Japanese food natto and has since been synthesized. TMP has a long history of beneficial effects in the treatment of many cardiovascular diseases. Here we have evaluated the therapeutic effects of TMP on pulmonary hypertension (PH) in animal models and in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH).

Experimental Approach: Three well-defined models of PH -chronic hypoxia (10% O )-induced PH (HPH), monocrotaline-induced PH (MCT-PH) and Sugen 5416/hypoxia-induced PH (SuHx-PH) - were used in Sprague-Dawley rats, and assessed by echocardiography, along with haemodynamic and histological techniques. Primary cultures of rat distal pulmonary arterial smooth muscle cells (PASMCs) were used to study intracellular calcium levels. Western blots and RT-qPCR assays were also used. In the clinical cohort, patients with PAH or CTEPH were recruited. The effects of TMP were evaluated in all systems.

Key Results: TMP (100 mg·kg ·day ) prevented rats from developing experimental PH and ameliorated three models of established PH: HPH, MCT-PH and SuHx-PH. The therapeutic effects of TMP were accompanied by inhibition of intracellular calcium homeostasis in PASMCs. In a small cohort of patients with PAH or CTEPH, oral administration of TMP (100 mg, t.i.d. for 16 weeks) increased the 6-min walk distance and improved the 1-min heart rate recovery.

Conclusion And Implications: Our results suggest that TMP is a novel and inexpensive medication for treatment of PH. Clinical trial is registered with www.chictr.org.cn (ChiCTR-IPR-14005379).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.15000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236078PMC
June 2020

Looking backwards: is it time to assess veno-atrial interactions in pulmonary arterial hypertension?

Eur Respir J 2019 10 17;54(4). Epub 2019 Oct 17.

Division of Translational and Regenerative Medicine, University of Arizona, Tucson, AZ, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.01598-2019DOI Listing
October 2019

MicroRNA-mediated downregulation of K channels in pulmonary arterial hypertension.

Am J Physiol Lung Cell Mol Physiol 2020 01 25;318(1):L10-L26. Epub 2019 Sep 25.

Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California.

Downregulated expression of K channels and decreased K currents in pulmonary artery smooth muscle cells (PASMC) have been implicated in the development of sustained pulmonary vasoconstriction and vascular remodeling in patients with idiopathic pulmonary arterial hypertension (IPAH). However, it is unclear exactly how K channels are downregulated in IPAH-PASMC. MicroRNAs (miRNAs) are small non-coding RNAs that are capable of posttranscriptionally regulating gene expression by binding to the 3'-untranslated regions of their targeted mRNAs. Here, we report that specific miRNAs are responsible for the decreased K channel expression and function in IPAH-PASMC. We identified 3 miRNAs (miR-29b, miR-138, and miR-222) that were highly expressed in IPAH-PASMC in comparison to normal PASMC (>2.5-fold difference). Selectively upregulated miRNAs are correlated with the decreased expression and attenuated activity of K channels. Overexpression of miR-29b, miR-138, or miR-222 in normal PASMC significantly decreased whole cell K currents and downregulated voltage-gated K channel 1.5 (K1.5/KCNA5) in normal PASMC. Inhibition of miR-29b in IPAH-PASMC completely recovered K channel function and K1.5 expression, while miR-138 and miR-222 had a partial or no effect. Luciferase assays further revealed that K1.5 is a direct target of miR-29b. Additionally, overexpression of miR-29b in normal PASMC decreased large-conductance Ca-activated K (BK) channel currents and downregulated BK channel β1 subunit (BKβ1 or KCNMB1) expression, while inhibition of miR-29b in IPAH-PASMC increased BK channel activity and BKβ1 levels. These data indicate upregulated miR-29b contributes at least partially to the attenuated function and expression of K and BK channels in PASMC from patients with IPAH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajplung.00010.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985878PMC
January 2020

Dynamic right ventricular-pulmonary arterial uncoupling during maximum incremental exercise in exercise pulmonary hypertension and pulmonary arterial hypertension.

Pulm Circ 2019 Jul-Sep;9(3):2045894019862435

2 Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Despite recent advances, the prognosis of pulmonary hypertension (PH) remains poor. While the initial insult in PH implicates the pulmonary vasculature, the functional state, exercise capacity, and survival of such patients are closely linked to right ventricular (RV) function. In the current study, we sought to investigate the effects of maximum incremental exercise on the matching of RV contractility and afterload (i.e. right ventricular-pulmonary arterial [RV-PA] coupling) in patients with exercise PH (ePH) and pulmonary arterial hypertension (PAH). End-systolic elastance (Ees), pulmonary arterial elastance (Ea), and RV-PA coupling (Ees/Ea) were determined using single-beat pressure-volume loop analysis in 40 patients that underwent maximum invasive cardiopulmonary exercise testing. Eleven patients had ePH, nine had PAH, and 20 were age-matched controls. During exercise, the impaired exertional contractile reserve in PAH was associated with blunted stroke volume index (SVI) augmentation and reduced peak oxygen consumption (peak VO %predicted). Compared to PAH, ePH demonstrated increased RV contractility in response to increasing RV afterload during exercise; however, this was insufficient and resulted in reduced peak RV-PA coupling. The dynamic RV-PA uncoupling in ePH was associated with similarly blunted SVI augmentation and peak VO as PAH. In conclusion, dynamic rest-to-peak exercise RV-PA uncoupling during maximum exercise blunts SV increase and reduces exercise capacity in exercise PH and PAH. In ePH, the insufficient increase in RV contractility to compensate for increasing RV afterload during maximum exercise leads to deterioration of RV-PA coupling. These data provide evidence that even in the early stages of PH, RV function is compromised.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2045894019862435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643191PMC
June 2019

Longitudinal Evaluation of Pulmonary Arterial Hypertension in a Rhesus Macaque () Model of HIV Infection.

Comp Med 2018 12 12;68(6):461-473. Epub 2018 Dec 12.

Center for Vaccine and Immunology, University of Georgia, Athens, Georgia, USA.

Pulmonary arterial hypertension (PAH) is a life-threatening disease with higher incidence in HIV-infected compared with noninfected patients. SIV-infected NHP develop clinical manifestations of HIV infection, including PAH. To understand the pathogenesis of PAH and determine the relationship between hemodynamic changes and clinical characteristics associated with SIV infection, we performed right heart catheterization and echocardiographic imaging of 21 rhesus macaques before and after SIV infection. Between 6 and 12 mo after infection, 11 of the 21 animals had elevated mean pulmonary arterial pressure (mPAP; greater than 25 mm Hg). RV involvement was evident as increased RV glucose uptake in PAH macaques on positron emission tomography-coupled CT compared with uninfected animals. RV and pulmonary vascular collagen deposition were elevated in PAH animals. At 12 mo after infection, 6 of the 21 macaques (28.6%) exhibited continued increase in mPAP (progressive PAH), whereas 5 animals (23.8%) had reduced pressure (transient PAH). SIV infection of rhesus macaques led to 3 distinct outcomes with regard to hemodynamic function. Hemodynamic alterations correlated with specific inflammatory profiles and increased RV and pulmonary arterial fibrosis but not with viral load, sex, or CD4 T-cell levels. This model of a natural cause of PAH provides insight into disease pathways that are important for the development of novel therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.30802/AALAS-CM-18-000012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310202PMC
December 2018

Right ventricular afterload predicts long-term transition from parenteral to oral treprostinil in pulmonary arterial hypertension.

Pulm Circ 2018 Oct-Dec;8(4):2045894018797270. Epub 2018 Aug 20.

2 Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, University of Arizona, Tucson, AZ, USA.

Despite the increasing trends, reports on long-term follow-up are limited on transitioning from parenteral to oral treprostinil therapy in patients with pulmonary arterial hypertension (PAH). We investigated both the effectiveness of parenteral to oral treprostinil transition and the characteristics associated with transition failure over a duration of two years. The study included 37 Group I functional class I and II patients with PAH on combination therapy. Patients were excluded if cardiac index ≤2.2 L/min/m, right atrial pressure ≥11 mmHg, or 6-min walk distance ≤250 m. Patients were categorized as successful (Transition) or unsuccessful (Transition) transition based on clinical stability, or a parenteral comparator (Parenteral) if they remained on parenteral therapy (no transition). All patients underwent two right heart catheterizations, one at enrollment and a second post transition. Of 24 total transition patients, 46% were classified as Transition. Transition occurred on average 577 days post transition. Both Transition and Transition had similar hemodynamics at diagnosis and treprostinil dose before and after transition. Before transition, the pulmonary vascular resistance (PVR) was significantly higher in the Transition (6.7 ± 2 WU) vs. Transition group (3.5 ± 1.5 WU). At follow-up catheterization, the Transition group demonstrated further increases in PVR, greater than the Parenteral group, without recovery despite "rescue" therapy in the Transition group. A pre-transition PVR of 4.16 WU discriminated the Transition from the Transition group. While a subset of PAH patients on combination therapy may be safely transitioned from parenteral to oral treprostinil, caution should be exercised in patients with elevated baseline PVR to avoid irreversible destabilization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2045894018797270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122247PMC
August 2018

What Causes Pulmonary Arterial Hypertension in Down Syndrome With Congenital Heart Disease?

Circ J 2018 05 12;82(6):1513-1514. Epub 2018 May 12.

Department of Pediatrics, Tokyo Medical and Dental University.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1253/circj.CJ-18-0471DOI Listing
May 2018

Association Between Hemodynamic Markers of Pulmonary Hypertension and Outcomes in Heart Failure With Preserved Ejection Fraction.

JAMA Cardiol 2018 04;3(4):298-306

Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, Pittsburgh, Pennsylvania.

Importance: Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, yet there are no specific therapies, possibly due to phenotypic heterogeneity. The development of pulmonary hypertension (PH) in patients with HFpEF is considered a high-risk phenotype in need of targeted therapies, but there have been limited hemodynamic and outcomes data.

Objective: To identify the hemodynamic characteristics and outcomes of PH-HFpEF.

Design, Setting, And Participants: Cohort study of participants who had a right heart catheterization from January 2005 to September 2012 (median [interquartile range] follow-up time, 1578 [554-2513] days) were analyzed. Hemodynamic catheterization data was linked to the clinical data repository of all inpatient and outpatient encounters across a health system. Single tertiary referral center for heart failure and PH within a large health care network using a common clinical data repository was studied. There were 19 262 procedures in 10 023 participants.

Exposures: Participants were classified as having no PH, precapillary PH, or PH in the setting of left heart disease (reduced or preserved ejection fraction). Pulmonary hypertension associated with HFpEF was defined as mean pulmonary artery pressure of 25 mm Hg or more, pulmonary artery wedge pressure of 15 mm Hg or more, and left ventricular ejection fraction of 45% or more. Pulmonary hypertension severity was quantified by the hemodynamic parameters transpulmonary gradient, pulmonary vascular resistance, and diastolic pulmonary gradient.

Main Outcomes And Measures: The primary outcome was time to all-cause mortality. Secondary outcomes were time to acute hospitalization and cardiovascular hospitalization.

Results: The mean (SD) of all study individuals was 65 (38) years. Of 10 023 individuals, 2587 (25.8%) had PH-HFpEF. Mortality was 23.6% at 1 year and 48.2% at 5 years. Cardiac hospitalizations occurred in 28.1% at 1 year and 47.4% at 5 years. The frequency of precapillary PH using clinically defined cut-offs for transpulmonary gradient (>12 mm Hg), pulmonary vascular resistance (3 Woods units), and diastolic pulmonary gradient (≥7 mm Hg) were 12.6%, 8.8%, and 3.5%, respectively. Transpulmonary gradient, pulmonary vascular resistance, and diastolic pressure gradient were predictive of mortality and cardiac hospitalizations.

Conclusions And Relevance: In a large cohort referred for invasive hemodynamic assessment, PH-HFpEF was common. Transpulmonary gradient, pulmonary vascular resistance, and diastolic pulmonary gradient are all associated with mortality and cardiac hospitalizations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamacardio.2018.0128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875307PMC
April 2018

Hematocrit-corrected Pulmonary Vascular Resistance.

Am J Respir Crit Care Med 2018 08;198(3):305-309

2 Department of Cardiology, Erasmus University Hospital, Brussels, Belgium.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201801-0081PPDOI Listing
August 2018

Diabetes Mellitus Associates with Increased Right Ventricular Afterload and Remodeling in Pulmonary Arterial Hypertension.

Am J Med 2018 06 5;131(6):702.e7-702.e13. Epub 2018 Feb 5.

The University of Arizona Health Sciences, The University of Arizona, Tucson. Electronic address:

Background: Diabetes mellitus is associated with left ventricular hypertrophy and dysfunction. Parallel studies have also reported associations between diabetes mellitus and right ventricular dysfunction and reduced survival in patients with pulmonary arterial hypertension. However, the impact of diabetes mellitus on the pulmonary vasculature has not been well characterized. We hypothesized that diabetes mellitus and hyperglycemia could specifically influence right ventricular afterload and remodeling in patients with Group I pulmonary arterial hypertension, providing a link to their known susceptibility to right ventricular dysfunction.

Methods: Using an adjusted model for age, sex, pulmonary vascular resistance, and medication use, associations of fasting blood glucose, glycated hemoglobin, and the presence of diabetes mellitus were evaluated with markers of disease severity in 162 patients with pulmonary arterial hypertension.

Results: A surrogate measure of increased pulmonary artery stiffness, elevated pulmonary arterial elastance (P = .012), along with reduced log(pulmonary artery capacitance) (P = .006) were significantly associated with the presence of diabetes mellitus in patients with pulmonary arterial hypertension in a fully adjusted model. Similar associations between pulmonary arterial elastance and capacitance were noted with both fasting blood glucose and glycated hemoglobin. Furthermore, right ventricular wall thickness on echocardiography was greater in pulmonary arterial hypertension patients with diabetes, supporting the link between right ventricular remodeling and diabetes.

Conclusion: Cumulatively, these data demonstrate that an increase in right ventricular afterload, beyond pulmonary vascular resistance alone, may influence right ventricular remodeling and provide a mechanistic link between the susceptibility to right ventricular dysfunction in patients with both diabetes mellitus and pulmonary arterial hypertension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amjmed.2017.12.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963998PMC
June 2018

Nitric Oxide-Independent Soluble Guanylate Cyclase Activation Improves Vascular Function and Cardiac Remodeling in Sickle Cell Disease.

Am J Respir Cell Mol Biol 2018 05;58(5):636-647

2 Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine.

Sickle cell disease (SCD) is associated with intravascular hemolysis and oxidative inhibition of nitric oxide (NO) signaling. BAY 54-6544 is a small-molecule activator of oxidized soluble guanylate cyclase (sGC), which, unlike endogenous NO and the sGC stimulator, BAY 41-8543, preferentially binds and activates heme-free, NO-insensitive sGC to restore enzymatic cGMP production. We tested orally delivered sGC activator, BAY 54-6544 (17 mg/kg/d), sGC stimulator, BAY 41-8543, sildenafil, and placebo for 4-12 weeks in the Berkeley transgenic mouse model of SCD (BERK-SCD) and their hemizygous (Hemi) littermate controls (BERK-Hemi). Right ventricular (RV) maximum systolic pressure (RVmaxSP) was measured using micro right-heart catheterization. RV hypertrophy (RVH) was determined using Fulton's index and RV corrected weight (ratio of RV to tibia). Pulmonary artery vasoreactivity was tested for endothelium-dependent and -independent vessel relaxation. Right-heart catheterization revealed higher RVmaxSP and RVH in BERK-SCD versus BERK-Hemi, which worsened with age. Treatment with the sGC activator more effectively lowered RVmaxSP and RVH, with 90-day treatment delivering superior results, when compared with other treatments and placebo groups. In myography experiments, acetylcholine-induced (endothelium-dependent) and sodium-nitroprusside-induced (endothelium-independent NO donor) relaxation of the pulmonary artery harvested from placebo-treated BERK-SCD was impaired relative to BERK-Hemi but improved after therapy with sGC activator. By contrast, no significant effect for sGC stimulator or sildenafil was observed in BERK-SCD. These findings suggest that sGC is oxidized in the pulmonary arteries of transgenic SCD mice, leading to blunted responses to NO, and that the sGC activator, BAY 54-6544, may represent a novel therapy for SCD-associated pulmonary arterial hypertension and cardiac remodeling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1165/rcmb.2017-0292OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946331PMC
May 2018

Biomechanical and Hemodynamic Measures of Right Ventricular Diastolic Function: Translating Tissue Biomechanics to Clinical Relevance.

J Am Heart Assoc 2017 Sep 12;6(9). Epub 2017 Sep 12.

School of Medicine, University of Pittsburgh, PA

Background: Right ventricular (RV) diastolic function has been associated with outcomes for patients with pulmonary hypertension; however, the relationship between biomechanics and hemodynamics in the right ventricle has not been studied.

Methods And Results: Rat models of RV pressure overload were obtained via pulmonary artery banding (PAB; control, n=7; PAB, n=5). At 3 weeks after banding, RV hemodynamics were measured using a conductance catheter. Biaxial mechanical properties of the RV free wall myocardium were obtained to extrapolate longitudinal and circumferential elastic modulus in low and high strain regions (E and E, respectively). Hemodynamic analysis revealed significantly increased end-diastolic elastance (E) in PAB (control: 55.1 mm Hg/mL [interquartile range: 44.7-85.4 mm Hg/mL]; PAB: 146.6 mm Hg/mL [interquartile range: 105.8-155.0 mm Hg/mL]; =0.010). Longitudinal E was increased in PAB (control: 7.2 kPa [interquartile range: 6.7-18.1 kPa]; PAB: 34.2 kPa [interquartile range: 18.1-44.6 kPa]; =0.018), whereas there were no significant changes in longitudinal E or circumferential E and E. Last, wall stress was calculated from hemodynamic data by modeling the right ventricle as a sphere: stress=Pressure×radius2×thickness.

Conclusions: RV pressure overload in PAB rats resulted in an increase in diastolic myocardial stiffness reflected both hemodynamically, by an increase in E, and biomechanically, by an increase in longitudinal E. Modest increases in tissue biomechanical stiffness are associated with large increases in E. Hemodynamic measurements of RV diastolic function can be used to predict biomechanical changes in the myocardium.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.117.006084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634275PMC
September 2017

Targeting L-arginine-nitric oxide-cGMP pathway in pulmonary arterial hypertension.

Pulm Circ 2017 Jul-Sep;7(3):569-571

Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona College of Medicine, Tucson, AZ, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2045893217728261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841892PMC
September 2017

Development of a Mouse Model of Metabolic Syndrome, Pulmonary Hypertension, and Heart Failure with Preserved Ejection Fraction.

Am J Respir Cell Mol Biol 2017 04;56(4):497-505

1 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1165/rcmb.2016-0177OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449511PMC
April 2017

Mouse Genome-Wide Association Study of Preclinical Group II Pulmonary Hypertension Identifies Epidermal Growth Factor Receptor.

Am J Respir Cell Mol Biol 2017 04;56(4):488-496

1 Department of Medicine.

Pulmonary hypertension (PH) is associated with features of obesity and metabolic syndrome that translate to the induction of PH by chronic high-fat diet (HFD) in some inbred mouse strains. We conducted a genome-wide association study (GWAS) to identify candidate genes associated with susceptibility to HFD-induced PH. Mice from 36 inbred and wild-derived strains were fed with regular diet or HFD for 20 weeks beginning at 6-12 weeks of age, after which right ventricular (RV) and left ventricular (LV) end-systolic pressure (ESP) and maximum pressure (MaxP) were measured by cardiac catheterization. We tested for association of RV MaxP and RV ESP and identified genomic regions enriched with nominal associations to both of these phenotypes. We excluded genomic regions if they were also associated with LV MaxP, LV ESP, or body weight. Genes within significant regions were scored based on the shortest-path betweenness centrality, a measure of network connectivity, of their human orthologs in a gene interaction network of human PH-related genes. WSB/EiJ, NON/ShiLtJ, and AKR/J mice had the largest increases in RV MaxP after high-fat feeding. Network-based scoring of GWAS candidates identified epidermal growth factor receptor (Egfr) as having the highest shortest-path betweenness centrality of GWAS candidates. Expression studies of lung homogenate showed that EGFR expression is increased in the AKR/J strain, which developed a significant increase in RV MaxP after high-fat feeding as compared with C57BL/6J, which did not. Our combined GWAS and network-based approach adds evidence for a role for Egfr in murine PH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1165/rcmb.2016-0176OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449510PMC
April 2017

Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction.

JCI Insight 2016 11 3;1(18):e89620. Epub 2016 Nov 3.

Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute.

Background: Pulmonary hypertension (PH) is associated with poor outcomes, yet specific treatments only exist for a small subset of patients. The most common form of PH is that associated with left heart disease (Group 2), for which there is no approved therapy. Nitrite has shown efficacy in preclinical animal models of Group 1 and 2 PH, as well as in patients with left heart failure with preserved ejection fraction (HFpEF). We evaluated the safety and efficacy of a potentially novel inhaled formulation of nitrite in PH-HFpEF patients as compared with Group 1 and 3 PH.

Methods: Cardiopulmonary hemodynamics were recorded after acute administration of inhaled nitrite at 2 doses, 45 and 90 mg. Safety endpoints included change in systemic blood pressure and methemoglobin levels. Responses were also compared with those administered inhaled nitric oxide.

Results: Thirty-six patients were enrolled (10 PH-HFpEF, 20 Group 1 pulmonary arterial hypertension patients on background PH-specific therapy, and 6 Group 3 PH). Drug administration was well tolerated. Nitrite inhalation significantly lowered pulmonary, right atrial, and pulmonary capillary wedge pressures, most pronounced in patients with PH-HFpEF. There was a modest decrease in cardiac output and systemic blood pressure. Pulmonary vascular resistance decreased only in Group 3 PH patients. There was substantial increase in pulmonary artery compliance, most pronounced in patients with PH-HFpEF.

Conclusions: Inhaled nitrite is safe in PH patients and may be efficacious in PH-HFpEF and Group 3 PH primarily via improvements in left and right ventricular filling pressures and pulmonary artery compliance. The lack of change in pulmonary vascular resistance likely may limit efficacy for Group 1 patients.

Trial Registration: ClinicalTrials.gov NCT01431313 FUNDING. This work was supported in part by the NIH grants P01HL103455 (to MAS and MTG), R01HL098032 (to MTG), and R01HL096973 (to MTG), and Mast Therapeutics, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.89620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085611PMC
November 2016

TSP1-CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction.

Cardiovasc Res 2017 01 13;113(1):15-29. Epub 2016 Oct 13.

Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA

Aims: Thrombospondin-1 (TSP1) is a ligand for CD47 and TSP1 mice are protected from pulmonary hypertension (PH). We hypothesized the TSP1-CD47 axis is upregulated in human PH and promotes pulmonary arterial vasculopathy.

Methods And Results: We analyzed the molecular signature and functional response of lung tissue and distal pulmonary arteries (PAs) from individuals with (n = 23) and without (n = 16) PH. Compared with controls, lungs and distal PAs from PH patients showed induction of TSP1-CD47 and endothelin-1/endothelin A receptor (ET-1/ETA) protein and mRNA. In control PAs, treatment with exogenous TSP1 inhibited vasodilation and potentiated vasoconstriction to ET-1. Treatment of diseased PAs from PH patients with a CD47 blocking antibody improved sensitivity to vasodilators. Hypoxic wild type (WT) mice developed PH and displayed upregulation of pulmonary TSP1, CD47, and ET-1/ETA concurrent with down regulation of the transcription factor cell homolog of the v-myc oncogene (cMyc). In contrast, PH was attenuated in hypoxic CD47 mice while pulmonary TSP1 and ET-1/ETA were unchanged and cMyc was overexpressed. In CD47 pulmonary endothelial cells cMyc was increased and ET-1 decreased. In CD47cells, forced induction of cMyc suppressed ET-1 transcript, whereas suppression of cMyc increased ET-1 signaling. Furthermore, disrupting TSP1-CD47 signaling in pulmonary smooth muscle cells abrogated ET-1-stimulated hypertrophy. Finally, a CD47 antibody given 2 weeks after monocrotaline challenge in rats upregulated pulmonary cMyc and improved aberrations in PH-associated cardiopulmonary parameters.

Conclusions: In pre-clinical models of PH CD47 targets cMyc to increase ET-1 signaling. In clinical PH TSP1-CD47 is upregulated, and in both, contributes to pulmonary arterial vasculopathy and dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvw218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220673PMC
January 2017
-->