- Assistant Professor, Medicine - (Research Scholar Track)
- Research Assistant Professor, Biomedical Engineering
My research focuses on quantifying right ventricular-vascular coupling and pulmonary vascular stiffness in patients and animal models with pulmonary vascular disease. During my postdoctoral training in Belgium with Dr. Robert Naeije, MD, PhD, I established upper limit of normal of the increase in pulmonary artery pressure with exercise in normal patients. In collaboration with another group, we were able to show that subjects with pulmonary vascular disease will have decreased distensibility of the resistance vessels and an increase of pulmonary artery pressure outside of the limits of normal. During my postdoctoral training at the University of Pittsburgh in the Vascular Medicine Institute, my research focused on quantifying the interaction between the right ventricle and pulmonary circulation using the ratio of stroke volume to end-systolic volume in the right ventricle. We were the first to investigate the association between RV-PA coupling and mortality and transplant in pulmonary hypertension patients. Through collaborations in the Vascular Medicine Institute, I quantified right ventricular function in animal models of pulmonary arterial hypertension and pulmonary hypertension in the setting of left heart disease. As a new investigator at the University of Arizona, I am continuing the clinical research to quantify right ventricular function in patients with pulmonary vascular disease and investigate the effect of therapy on right ventricular function, RV-PA coupling, and pulmonary vascular stiffness in patients with pulmonary arterial hypertension.
- Ph.D. Biomedical Engineering
- University of Wisconsin-Madison, Madison, Wisconsin, United States
- B.S. Biomedical Engineering
- University of Wisconsin - Madison, Madison, Wisconsin, United States
- University of Pittsburgh, Pittsburgh, Pennsylvania (2013 - 2016)
- Free University of Brussels (ULB) (2011 - 2013)
- University of Wisconsin - Madison, Madison, Wisconsin (2005 - 2010)
- University of Wisconsin - Madison, Madison, Wisconsin (2004 - 2006)
- Max Harry Weil Award for Resuscitation Science
- American Heart Association - Sponsored by the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation (3CPR), Fall 2018
- Early Career Research Achievement Award
- American Thoracic Society - Assembly on Pulmonary Circulation, Spring 2018
- Abstract Scholarship
- American Thoracic Society, Spring 2017
- Certificate of Achievement in 2016
- PVRI - Committee for Young Clinicians and Scientists, Spring 2017
- PVRI Best Clinical Abstract
- Pulmonary Vascular Research Institue, Spring 2017
Pulmonary Hypertension, Right Ventricular Function, Pulmonary Vascular Mechanics, andExercise Physiology
Directed ResearchBIOC 492 (Spring 2018)
Honors Independent StudyPSIO 399H (Spring 2018)
- Babicheva, A., Ayon, R. J., Zhao, T., Ek Vitorin, J. F., Pohl, N. M., Yamamura, A., Yamamura, H., Quinton, B. A., Ba, M., Wu, L., Ravellette, K. S., Rahimi, S., Balistrieri, F., Harrington, A., Vanderpool, R. R., Thistlethwaite, P. A., Makino, A., & Yuan, J. X. (2020). MicroRNA-mediated downregulation of K channels in pulmonary arterial hypertension. American journal of physiology. Lung cellular and molecular physiology, 318(1), L10-L26.More infoDownregulated 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.
- Karnes, J. H., Wiener, H. W., Schwantes-An, T. H., Natarajan, B., Sweatt, A. J., Chaturvedi, A., Arora, A., Batai, K., Nair, V., Steiner, H. E., Giles, J. B., Yu, J., Hosseini, M., Pauciulo, M. W., Lutz, K. A., Coleman, A. W., Feldman, J., Vanderpool, R., Tang, H., , Garcia, J. G., et al. (2020). Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine.More infoLimited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH).
- Richter, M. J., Fortuni, F., Wiegand, M. A., Dalmer, A., Vanderpool, R., Ghofrani, H. A., Naeije, R., Roller, F., Seeger, W., Sommer, N., Gall, H., Ghio, S., & Tello, K. (2020). Association of right atrial conduit phase with right ventricular lusitropic function in pulmonary hypertension. The international journal of cardiovascular imaging.More infoAlterations of right atrial (RA) function have emerged as determinants of outcome in pulmonary hypertension (PH). We aimed to clarify the pathophysiological associations of impaired RA conduit function with right ventricular (RV) function in PH. In 51 patients with PH (48 with pulmonary arterial hypertension), RA conduit function was assessed as echocardiographic peak early diastolic strain rate (PEDSR). PEDSR and cardiac magnetic resonance parameters were measured within 24 h of right heart catheterization and generation of pressure-volume loops to assess RV diastolic (RV end-diastolic pressure [EDP] and relaxation [Tau]) and systolic function. Spearman rho correlation and linear regression analysis were used to determine the association of PEDSR with RV function. The impact of PEDSR on time to clinical worsening was assessed using Kaplan-Meier and Cox regression analyses. Median (interquartile range) PEDSR was - 0.56 s - (- 1.08 to - 0.37). Impaired PEDSR was significantly correlated with RV diastolic stiffness [EDP (rho = 0.570; p
- Singh, I., Rahaghi, F. N., Naeije, R., Oliveira, R. K., Vanderpool, R. R., Waxman, A. B., & Systrom, D. M. (2020). Dynamic right ventricular-pulmonary arterial uncoupling during maximum incremental exercise in exercise pulmonary hypertension and pulmonary arterial hypertension. Pulmonary circulation, 9(3), 2045894019862435.More infoDespite 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.
- Tello, K., Dalmer, A., Vanderpool, R., Ghofrani, H. A., Naeije, R., Roller, F., Seeger, W., Wiegand, M., Gall, H., & Richter, M. J. (2020). Right ventricular function correlates of right atrial strain in pulmonary hypertension: a combined cardiac magnetic resonance and conductance catheter study. American journal of physiology. Heart and circulatory physiology, 318(1), H156-H164.More infoThe functional relevance of right atrial (RA) function in pulmonary hypertension (PH) remains incompletely understood. The purpose of this study was to explore the correlation of cardiac magnetic resonance (CMR) feature tracking-derived RA phasic function with invasively measured pressure-volume (P-V) loop-derived right ventricular (RV) end-diastolic elastance () and RV-arterial coupling [ratio of end-systolic elastance to arterial elastance (/)]. In 54 patients with severe PH, CMR was performed within 24 h of diagnostic right heart catheterization and P-V measurements. RA phasic function was assessed by CMR imaging of RA reservoir, passive, and active strain. The association of RA phasic function with indexes of RV function was evaluated by Spearman's rank correlation and linear regression analyses. Median [interquartile range] RA reservoir strain, passive strain, and active strain were 19.5% [11.0-24.5], 7.0% [4.0-12.0], and 13.0% [7.0-18.5], respectively. / was 0.73 [0.48-1.08], and was 0.14 mmHg/mL [0.05-0.22]. RV diastolic impairment [RV end-diastolic pressure (EDP) and ] was correlated with RA phasic function, but and were not. In addition, RA phasic function was correlated with inferior vena cava diameter. In multivariate linear regression analysis, adjusting for key P-V loop indexes, and EDP remained significantly associated with RA phasic function. We conclude that RA phasic function is altered in relation to impaired diastolic function of the chronically overloaded right ventricle and contributes to backward venous flow and systemic congestion. These results call for more attention to RA function in the management of patients with PH. There is growing awareness of the importance of the right atrial (RA)-right ventricular (RV) axis in pulmonary hypertension (PH). Our results uncover alterations in RA phasic function that are related to depressed RV lusitropic function and contribute to backward venous return and systemic congestion in chronic RV overload. Assessment of RA function should be part of the management and follow-up of patients with PH.
- Kiely, D. G., Levin, D., Hassoun, P., Ivy, D. D., Jone, P. N., Bwika, J., Kawut, S. M., Lordan, J., Lungu, A., Mazurek, J., Moledina, S., Olschewski, H., Peacock, A., Puri, G. D., Rahaghi, F., Schafer, M., Schiebler, M., Screaton, N., Tawhai, M., , Van Beek, E. J., et al. (2019). EXPRESS: Statement on imaging and pulmonary hypertension from the Pulmonary Vascular Research Institute (PVRI). Pulmonary circulation, 2045894019841990.
- Maestas, T., Hansen, L. M., Vanderpool, R. R., Desai, A. A., Airhart, S., Knapp, S. M., Cohen, A., Feldman, J., & Rischard, F. P. (2019). Right ventricular afterload predicts long-term transition from parenteral to oral treprostinil in pulmonary arterial hypertension. Pulmonary circulation, 8(4), 2045894018797270.More infoDespite 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.
- Pugliese, S., & Vanderpool, R. R. (2019). Looking backwards: is it time to assess veno-atrial interactions in pulmonary arterial hypertension?. The European respiratory journal, 54(4).
- Tello, K., Dalmer, A., Axmann, J., Vanderpool, R., Ghofrani, H. A., Naeije, R., Roller, F., Seeger, W., Sommer, N., Wilhelm, J., Gall, H., & Richter, M. J. (2019). Reserve of Right Ventricular-Arterial Coupling in the Setting of Chronic Overload. Circulation. Heart failure, 12(1), e005512.More infoRight ventricular (RV) maladaptation and failure determine outcome in pulmonary hypertension. The adaptation of RV function to loading (RV-pulmonary arterial coupling) is defined by a ratio of end-systolic to arterial elastances (Ees/Ea). How RV-pulmonary arterial coupling relates to pulmonary hypertension severity and onset of RV failure (defined by excessive volume increase and ejection fraction [EF] decrease) is not exactly known.
- Tello, K., Dalmer, A., Vanderpool, R., Ghofrani, H. A., Naeije, R., Roller, F., Seeger, W., Dumitrescu, D., Sommer, N., Brunst, A., Gall, H., & Richter, M. J. (2019). Impaired right ventricular lusitropy is associated with ventilatory inefficiency in pulmonary arterial hypertension. The European respiratory journal, 54(5).More infoCardiopulmonary exercise testing (CPET) is an important tool for assessing functional capacity and prognosis in pulmonary arterial hypertension (PAH). However, the associations of CPET parameters with the adaptation of right ventricular (RV) function to afterload remain incompletely understood.In this study, 37 patients with PAH (idiopathic in 31 cases) underwent single-beat pressure-volume loop measurements of RV end-systolic elastance (Ees), arterial elastance (Ea) and diastolic elastance (Eed). Pulmonary arterial stiffness was assessed by magnetic resonance imaging. The results were correlated to CPET variables. The predictive relevance of RV function parameters for clinically relevant ventilatory inefficiency, defined as minute ventilation/carbon dioxide production (/ ) slope >48, was evaluated using logistic regression analysis.The median (interquartile range) of the / slope was 42 (32-52) and the / nadir was 40 (31-44). The mean±sd of peak end-tidal carbon dioxide tension ( ) was 23±8 mmHg. Ea, Eed and parameters reflecting pulmonary arterial stiffness (capacitance and distensibility) correlated with the / slope, / nadir, and peak oxygen pulse. RV Ees and RV-arterial coupling as assessed by the Ees/Ea ratio showed no correlations with CPET parameters. Ea (univariate OR 7.28, 95% CI 1.20-44.04) and Eed (univariate OR 2.21, 95% CI 0.93-5.26) were significantly associated with ventilatory inefficiency (p
- Tello, K., Dalmer, A., Vanderpool, R., Ghofrani, H. A., Naeije, R., Roller, F., Seeger, W., Wilhelm, J., Gall, H., & Richter, M. J. (2019). Cardiac Magnetic Resonance Imaging-Based Right Ventricular Strain Analysis for Assessment of Coupling and Diastolic Function in Pulmonary Hypertension. JACC. Cardiovascular imaging, 12(11 Pt 1), 2155-2164.More infoThis study sought to compare cardiac magnetic resonance (CMR) imaging-derived right ventricular (RV) strain and invasively measured pressure-volume loop-derived RV contractility, stiffness, and afterload and RV-arterial coupling in pulmonary hypertension (PH).
- Tello, K., Seeger, W., Naeije, R., Vanderpool, R., Ghofrani, H. A., Richter, M., Tedford, R. J., & Bogaard, H. J. (2019). Right heart failure in pulmonary hypertension: Diagnosis and new perspectives on vascular and direct right ventricular treatment. British journal of pharmacology.More infoAdaptation of right ventricular (RV) function to increased afterload-known as RV-arterial coupling-is a key determinant of prognosis in pulmonary hypertension. However, measurement of RV-arterial coupling is a complex, invasive process involving analysis of the RV pressure-volume relationship during preload reduction over multiple cardiac cycles. Simplified methods have therefore been proposed, including echocardiographic and cardiac MRI approaches. This review describes the available methods for assessment of RV function and RV-arterial coupling and the effects of pharmacotherapy on these variables. Overall, pharmacotherapies for pulmonary hypertension have shown beneficial effects on various measures of RV function, but it is often unclear if these are direct RV effects or indirect results of afterload reduction. Studies of the effects of pharmacotherapies on RV-arterial coupling are limited and mostly restricted to experimental models. Simplified methods to assess RV-arterial coupling should be validated and incorporated into routine clinical follow-up and future clinical trials.
- Tello, K., Wan, J., Dalmer, A., Vanderpool, R., Ghofrani, H. A., Naeije, R., Roller, F., Mohajerani, E., Seeger, W., Herberg, U., Sommer, N., Gall, H., & Richter, M. J. (2019). Validation of the Tricuspid Annular Plane Systolic Excursion/Systolic Pulmonary Artery Pressure Ratio for the Assessment of Right Ventricular-Arterial Coupling in Severe Pulmonary Hypertension. Circulation. Cardiovascular imaging, 12(9), e009047.More infoThe ratios of tricuspid annular plane systolic excursion (TAPSE)/echocardiographically measured systolic pulmonary artery pressure (PASP), fractional area change/invasively measured mean pulmonary artery pressure, right ventricular (RV) area change/end-systolic area, TAPSE/pulmonary artery acceleration time, and stroke volume/end-systolic area have been proposed as surrogates of RV-arterial coupling. The relationship of these surrogates with the gold standard measure of RV-arterial coupling (invasive pressure-volume loop-derived end-systolic/arterial elastance [Ees/Ea] ratio) and RV diastolic stiffness (end-diastolic elastance) in pulmonary hypertension remains incompletely understood. We evaluated the relationship of these surrogates with invasive pressure-volume loop-derived Ees/Ea and end-diastolic elastance in pulmonary hypertension.
- Vanderpool, R. R., Puri, R., Osorio, A., Wickstrom, K., Desai, A., Black, S., Garcia, J. G., Yuan, J., & Rischard, F. (2019). EXPRESS: Surfing the Right Ventricular Pressure Waveform: Methods to assess Global, Systolic and Diastolic RV Function from a Clinical Right Heart Catheterization. Pulmonary circulation, 2045894019850993.
- Goncharov, D. A., Goncharova, E. A., Tofovic, S. P., Hu, J., Baust, J. J., Pena, A. Z., Ray, A., Rode, A., Vanderpool, R. R., Mora, A. L., Gladwin, M. T., & Lai, Y. C. (2018). Metformin Therapy for Pulmonary Hypertension Associated with HFpEF versus PAH. American journal of respiratory and critical care medicine.
- Hosokawa, S., Vanderpool, R. R., Ishii, T., Nishiyama, M., & Doi, S. (2018). What Causes Pulmonary Arterial Hypertension in Down Syndrome With Congenital Heart Disease?. Circulation journal : official journal of the Japanese Circulation Society, 82(6), 1513-1514.
- Naeije, R., Vanderpool, R., Peacock, A., & Badagliacca, R. (2018). The Right Heart-Pulmonary Circulation Unit: Physiopathology. Heart failure clinics, 14(3), 237-245.More infoThe most common cause of right heart failure is increased afterload caused by pulmonary hypertension. Right ventricular function adaptation to increased afterload is basically systolic, with secondary increase in dimensions and systemic congestion. Increased right ventricular dimensions and decreased ejection fraction are associated with a decreased survival in severe pulmonary hypertension. Targeted therapies titrated to reverse the right ventricular remodeling dimensions improve survival in severe pulmonary hypertension.
- Tang, H., Wu, K., Wang, J., Vinjamuri, S., Gu, Y., Song, S., Wang, Z., Zhang, Q., Balistrieri, A., Ayon, R. J., Rischard, F., Vanderpool, R., Chen, J., Zhou, G., Desai, A. A., Black, S. M., Garcia, J. G., Yuan, J. X., & Makino, A. (2018). Pathogenic Role of mTORC1 and mTORC2 in Pulmonary Hypertension. JACC. Basic to translational science, 3(6), 744-762.More infoConcentric lung vascular wall thickening due to enhanced proliferation of pulmonary arterial smooth muscle cells is an important pathological cause for the elevated pulmonary vascular resistance reported in patients with pulmonary arterial hypertension. We identified a differential role of mammalian target of rapamycin (mTOR) complex 1 and complex 2, two functionally distinct mTOR complexes, in the development of pulmonary hypertension (PH). Inhibition of mTOR complex 1 attenuated the development of PH; however, inhibition of mTOR complex 2 caused spontaneous PH, potentially due to up-regulation of platelet-derived growth factor receptors in pulmonary arterial smooth muscle cells, and compromised the therapeutic effect of the mTOR inhibitors on PH. In addition, we describe a promising therapeutic strategy using combination treatment with the mTOR inhibitors and the platelet-derived growth factor receptor inhibitors on PH and right ventricular hypertrophy. The data from this study provide an important mechanism-based perspective for developing novel therapies for patients with pulmonary arterial hypertension and right heart failure.
- Tarantelli, R. A., Schweitzer, F., Simon, M. A., Vanderpool, R. R., Christman, I., Rayens, E., Kling, H. M., Zullo, T., Carney, J. P., Lopresti, B. J., Bertero, T., Chan, S. Y., & Norris, K. A. (2018). Longitudinal Evaluation of Pulmonary Arterial Hypertension in a Rhesus Macaque (Macaca mulatta) Model of HIV Infection. Comparative medicine.More infoPulmonary arterial hypertension (PAH) is a life-threatening disease with higher incidence in HIV-infected compared withnoninfected patients. SIV-infected NHP develop clinical manifestations of HIV infection, including PAH. To understand thepathogenesis of PAH and determine the relationship between hemodynamic changes and clinical characteristics associatedwith SIV infection, we performed right heart catheterization and echocardiographic imaging of 21 rhesus macaques before andafter 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 positronemission tomography-coupled CT compared with uninfected animals. RV and pulmonary vascular collagen depositionwere 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 to3 distinct outcomes with regard to hemodynamic function. Hemodynamic alterations correlated with specific inflammatoryprofiles and increased RV and pulmonary arterial fibrosis but not with viral load, sex, or CD4+ T-cell levels. This model of anatural cause of PAH provides insight into disease pathways that are important for the development of novel therapeutic targets.
- Vanderpool, R. R., & Naeije, R. (2018). Hematocrit-corrected Pulmonary Vascular Resistance. American journal of respiratory and critical care medicine, 198(3), 305-309.
- Vanderpool, R. R., & Naeije, R. (2018). Hematocrit-corrected pulmonary vascular resistance. Americna Journal of Respiratory and Critical Care Medicine.
- Vanderpool, R. R., Saul, M., Nouraie, M., Gladwin, M. T., & Simon, M. A. (2018). Association Between Hemodynamic Markers of Pulmonary Hypertension and Outcomes in Heart Failure With Preserved Ejection Fraction. JAMA cardiology, 3(4), 298-306.More infoHeart 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.
- Whitaker, M. E., Nair, V., Sinari, S., Dherange, P. A., Natarajan, B., Trutter, L., Brittain, E. L., Hemnes, A. R., Austin, E. D., Patel, K., Black, S. M., Garcia, J. G., Yuan Md PhD, J. X., Vanderpool, R. R., Rischard, F., Makino, A., Bedrick, E. J., & Desai, A. A. (2018). Diabetes Mellitus Associates with Increased Right Ventricular Afterload and Remodeling in Pulmonary Arterial Hypertension. The American journal of medicine, 131(6), 702.e7-702.e13.More infoDiabetes 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.
- Bellofiore, A., Vanderpool, R. R., Brewis, M. J., Peacock, A. J., & Chesler, N. C. (2017). A novel single-beat approach to assess right ventricular systolic function. Journal of applied physiology (Bethesda, Md. : 1985), jap.00258.2017.More infoClinical assessment of right ventricular (RV) contractility in diseases such as pulmonary arterial hypertension (PAH) has been hindered by the lack of a robust methodology. Here, a novel clinically-viable single-beat method was developed to assess end-systolic elastance (Ees), a measure of RV contractility. We hypothesized that this novel approach reduces uncertainty and interobserver variability in the estimation of the maximum isovolumic pressure (Piso), the key step in single-beat methods. The new method was designed to include a larger portion of the RV pressure data and minimize subjective adjustments by the operator. Data were obtained from right heart catheterization of PAH patients in a multicenter prospective study (Dataset 1) and a single-center retrospective study (Dataset 2). To obtain Piso, three independent observers used an established single-beat method (based on the first derivative of the pressure waveform) and the novel method (based on the second derivative). Interobserver variability analysis included paired t-test, one-way ANOVA, inter-class correlation (ICC) analysis and a modified Bland-Altman analysis. The Piso values obtained from two methods were linearly correlated for both Dataset 1 (R(2) = 0.74) and Dataset 2 (R(2) = 0.91). Compared to the established method, the novel method resulted in smaller interobserver variability (p
- Jang, S., Vanderpool, R. R., Avazmohammadi, R., Lapshin, E., Bachman, T. N., Sacks, M., & Simon, M. A. (2017). Biomechanical and Hemodynamic Measures of Right Ventricular Diastolic Function: Translating Tissue Biomechanics to Clinical Relevance. Journal of the American Heart Association, 6(9).More infoRight 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.
- Kelly, N. J., Radder, J. E., Baust, J. J., Burton, C. L., Lai, Y. C., Potoka, K. C., Agostini, B. A., Wood, J. P., Bachman, T. N., Vanderpool, R. R., Dandachi, N., Leme, A. S., Gregory, A. D., Morris, A., Mora, A. L., Gladwin, M. T., & Shapiro, S. D. (2017). Mouse Genome-wide Association Study of Pre-clinical Group II Pulmonary Hypertension Identifies Egfr. American journal of respiratory cell and molecular biology.More infoPulmonary 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.
- Meng, Q., Lai, Y. C., Kelly, N. J., Bueno, M., Baust, J., Bachman, T., Goncharov, D., Vanderpool, R. R., Radder, J. E., Hu, J., Goncharova, E., Morris, A., Mora, A. L., Shapiro, S. D., & Gladwin, M. T. (2017). Development of a Mouse Model of Metabolic Syndrome, Pulmonary Hypertension, and Heart Failure with Preserved Ejection Fraction (PH-HFpEF). American journal of respiratory cell and molecular biology.More infoPulmonary hypertension associated with heart failure and preserved ejection fraction (PH-HFpEF; WHO Group II) secondary to left ventricular diastolic dysfunction is the most frequent cause of pulmonary hypertension. 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.
- Pena, A., Kobir, A., Goncharov, D., Goda, A., Kudryashova, T. V., Ray, A., Vanderpool, R., Baust, J., Chang, B., Mora, A. L., Gorcsan, J., & Goncharova, E. A. (2017). Pharmacological Inhibition of mTOR Kinase Reverses Right Ventricle Remodeling and Improves Right Ventricle Structure and Function in Rats. American journal of respiratory cell and molecular biology, 57(5), 615-625.More infoPulmonary 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.
- Potoka, K. P., Wood, K. C., Baust, J. J., Bueno, M., Hahn, S. A., Vanderpool, R. R., Bachman, T., Mallampalli, G. M., Osei-Hwedieh, D. O., Schrott, V., Sun, B., Bullock, G. C., Becker-Pelster, E. M., Wittwer, M., Stampfuss, J., Mathar, I., Stasch, J. P., Truebel, H., Sandner, P., , Mora, A. L., et al. (2017). NO-independent sGC Activation Improves Vascular Function and Cardiac Remodeling in Sickle Cell Disease. American journal of respiratory cell and molecular biology.More infoSickle 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 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, sGC stimulator BAY 41-8543, sildenafil, or placebo for 4-12 weeks in a transgenic mouse model of SCD (BERK-SCD) and their hemizygous littermate controls (BERK-Hemi). Right ventricular maximum systolic pressure (RVmaxSP) was measured using micro right heart catheterization. Right ventricle hypertrophy (RVH) was determined using Fulton's Index and right ventricle 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 to 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 following 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 PAH and cardiac remodeling.
- Rogers, N. M., Sharifi-Sanjani, M., Yao, M., Ghimire, K., Bienes-Martinez, R., Mutchler, S. M., Knupp, H. E., Baust, J., Novelli, E. M., Ross, M., St Croix, C., Kutten, J. C., Czajka, C. A., Sembrat, J. C., Rojas, M., Labrousse-Arias, D., Bachman, T. N., Vanderpool, R. R., Zuckerbraun, B. S., , Champion, H. C., et al. (2017). TSP1-CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction. Cardiovascular research, 113(1), 15-29.More infoThrombospondin-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.
- Tang, H., Vanderpool, R. R., Wang, J., & Yuan, J. X. (2017). Targeting L-arginine-nitric oxide-cGMP pathway in pulmonary arterial hypertension. Pulmonary circulation, 7(3), 569-571.
- Vanderpool, R. R., Desai, A. A., Knapp, S. M., Simon, M. A., Abidov, A., Yuan, J. X., Garcia, J. G., Hansen, L. M., Knoper, S. R., Naeije, R., & Rischard, F. P. (2017). How prostacyclin therapy improves right ventricular function in pulmonary arterial hypertension. The European respiratory journal, 50(2).
- Vanderpool, R. R., Tang, H., Rischard, F., & Yuan, J. X. (2017). Is p38 MAPK a Dark Force in Right Ventricular Hypertrophy and Failure in Pulmonary Arterial Hypertension?. American journal of respiratory cell and molecular biology, 57(5), 506-508.
- Bertero, T., Oldham, W. M., Cottrill, K. A., Pisano, S., Vanderpool, R. R., Yu, Q., Zhao, J., Tai, Y., Tang, Y., Zhang, Y. Y., Rehman, S., Sugahara, M., Qi, Z., Gorcsan, J., Vargas, S. O., Saggar, R., Saggar, R., Wallace, W. D., Ross, D. J., , Haley, K. J., et al. (2016). Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. The Journal of clinical investigation, 126(9), 3313-35.More infoDysregulation 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.
- Brewis, M. J., Bellofiore, A., Vanderpool, R. R., Chesler, N. C., Johnson, M. K., Naeije, R., & Peacock, A. J. (2016). Imaging right ventricular function to predict outcome in pulmonary arterial hypertension. International journal of cardiology, 218, 206-11.More infoRight ventricular (RV) function is a major determinant of outcome in pulmonary arterial hypertension (PAH). However, uncertainty persists about the optimal method of evaluation.
- Kudryashova, T. V., Goncharov, D. A., Pena, A., Kelly, N., Vanderpool, R., Baust, J., Kobir, A., Shufesky, W., Mora, A. L., Morelli, A. E., Zhao, J., Ihida-Stansbury, K., Chang, B., DeLisser, H., Tuder, R. M., Kawut, S. M., Silljé, H. H., Shapiro, S., Zhao, Y., & Goncharova, E. A. (2016). HIPPO-Integrin-linked Kinase Cross-Talk Controls Self-Sustaining Proliferation and Survival in Pulmonary Hypertension. American journal of respiratory and critical care medicine, 194(7), 866-877.More infoEnhanced proliferation and impaired apoptosis of pulmonary arterial vascular smooth muscle cells (PAVSMCs) are key pathophysiologic components of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH).
- Lai, Y. C., Tabima, D. M., Dube, J. J., Hughan, K. S., Vanderpool, R. R., Goncharov, D. A., St Croix, C. M., Garcia-Ocaña, A., Goncharova, E. A., Tofovic, S. P., Mora, A. L., & Gladwin, M. T. (2016). SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction. Circulation, 133(8), 717-31.More infoPulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF) is an increasingly recognized clinical complication of metabolic syndrome. No adequate animal model of PH-HFpEF is available, and no effective therapies have been identified to date. A recent study suggested that dietary nitrate improves insulin resistance in endothelial nitric oxide synthase null mice, and multiple studies have reported that both nitrate and its active metabolite, nitrite, have therapeutic activity in preclinical models of pulmonary hypertension.
- Simon, M. A., Vanderpool, R. R., Nouraie, M., Bachman, T. N., White, P. M., Sugahara, M., Gorcsan, J., Parsley, E. L., & Gladwin, M. T. (2016). Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction. JCI insight, 1(18), e89620.More infoPulmonary 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.
- Vanderpool, R. R., Rischard, F., Naeije, R., Hunter, K., & Simon, M. A. (2016). Simple functional imaging of the right ventricle in pulmonary hypertension: Can right ventricular ejection fraction be improved?. International journal of cardiology, 223, 93-94.
- Maestas, T., Hansen, L. M., Vanderpool, R. R., Desai, A. A., Airhart, S., Knapp, S. M., Cohen, A., Feldman, J., & Rischard, F. P. (2015). Right ventricular afterload predicts long-term transition from parenteral to oral treprostinil in pulmonary arterial hypertension. Pulmonary circulation, 8(4), 2045894018797270.More infoDespite 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.
- Rischard, F., Simon, M., Hansen, L., Knoper, S. R., Knapp, S. M., Desai, A., Abidov, A., Yuan, J., Garcia, J. G., Vanderpool, R., & Champion, H. C. (2017). Treprostinil decreases right ventricular contractility but improves ejection fraction and exercise capacity in pulmonary arterial hypertension. European Respiratory J.
- Rischard, F., Vanderpool, R., Jenkins, I., Dalabih, M., Colombo, J., Lax, D., & Seckeler, M. (2015). Selective pulmonary vasodilation improves ventriculovascular coupling and gas exchange in a patient with unrepaired single-ventricle physiology. Pulmonary circulation, 5(2), 407-11.More infoWe describe a 63-year-old patient with unrepaired tricuspid valve atresia and a hypoplastic right ventricle (single-ventricle physiology) who presented with progressive symptomatic hypoxia. Her anatomy resulted in parallel pulmonary and systemic circulations, pulmonary arterial hypertension, and uncoupling of the ventricle/pulmonary artery. Hemodynamic and coupling data were obtained before and after pulmonary vasoactive treatment, first inhaled nitric oxide and later inhaled treprostinil. The coupling ratio (ratio of ventricular to vascular elastance) shunt fractions and dead space ventilation were calculated before and after treatment. Treatment resulted in improvement of the coupling ratio between the ventricle and the vasculature with optimization of stroke work, equalization of pulmonary and systolic flows, a decrease in dead space ventilation from 75% to 55%, and a significant increase in 6-minute walk distance and improved hypoxia. Inhaled treprostinil significantly increased 6-minute walk distance and improved hypoxia. This is the first report to show that pulmonary vasoactive treatment can be used in a patient with unrepaired single-ventricle anatomy and describes the hemodynamic effects of inhaled therapy on ventriculovascular coupling and gas exchange in the pulmonary circulation in this unique physiology.
- Tang, H., Vanderpool, R. R., Wang, J., & Yuan, J. X. (2015). Targeting L-arginine-nitric oxide-cGMP pathway in pulmonary arterial hypertension. Pulmonary circulation, 7(3), 569-571.
- Vanderpool, R. R., & Naeije, R. (2015). Progress in Pulmonary Hypertension with Left Heart Failure. Beyond New Definitions and Acronyms. American journal of respiratory and critical care medicine, 192(10), 1152-4.
- Vanderpool, R. R., Pinsky, M. R., Naeije, R., Deible, C., Kosaraju, V., Bunner, C., Mathier, M. A., Lacomis, J., Champion, H. C., & Simon, M. A. (2015). RV-pulmonary arterial coupling predicts outcome in patients referred for pulmonary hypertension. Heart (British Cardiac Society), 101(1), 37-43.More infoPrognosis 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.
- Vriz, O., Argiento, P., D'Alto, M., Ferrara, F., Vanderpool, R., Naeije, R., & Bossone, E. (2015). Increased pulmonary vascular resistance in early stage systemic hypertension: a resting and exercise stress echocardiography study. The Canadian journal of cardiology, 31(4), 537-43.More infoIn early stage uncomplicated systemic hypertension (HT), increased pulmonary vascular resistance (PVR) has been reported at rest, but more rarely during exercise. Recently, limits of normal for stress echocardiography in the evaluation of the pulmonary circulation have been better defined. We therefore used this approach to assess the pulmonary circulation in early HT.
- Lau, E. M., Vanderpool, R. R., Choudhary, P., Simmons, L. R., Corte, T. J., Argiento, P., D'Alto, M., Naeije, R., & Celermajer, D. S. (2014). Dobutamine stress echocardiography for the assessment of pressure-flow relationships of the pulmonary circulation. Chest, 146(4), 959-66.More infoStress testing of the pulmonary circulation (via increasing pulmonary blood flow) can reveal abnormal mean pulmonary artery pressure-cardiac output (mPpa-Q) responses, which may facilitate early diagnosis of pulmonary vascular disease. We investigated the application of dobutamine stress echocardiography (DSE) for the noninvasive assessment of mPpa-Q relationships.
- Novelli, E. M., Hildesheim, M., Rosano, C., Vanderpool, R., Simon, M., Kato, G. J., & Gladwin, M. T. (2014). Elevated pulse pressure is associated with hemolysis, proteinuria and chronic kidney disease in sickle cell disease. PloS one, 9(12), e114309.More infoA seeming paradox of sickle cell disease is that patients do not suffer from a high prevalence of systemic hypertension in spite of endothelial dysfunction, chronic inflammation and vasculopathy. However, some patients do develop systolic hypertension and increased pulse pressure, an increasingly recognized major cardiovascular risk factor in other populations. Hence, we hypothesized that pulse pressure, unlike other blood pressure parameters, is independently associated with markers of hemolytic anemia and cardiovascular risk in sickle cell disease. We analyzed the correlates of pulse pressure in patients (n = 661) enrolled in a multicenter international sickle cell trial. Markers of hemolysis were analyzed as independent variables and as a previously validated hemolytic index that includes multiple variables. We found that pulse pressure, not systolic, diastolic or mean arterial pressure, independently correlated with high reticulocyte count (beta = 2.37, p = 0.02) and high hemolytic index (beta = 1.53, p = 0.002) in patients with homozygous sickle cell disease in two multiple linear regression models which include the markers of hemolysis as independent variables or the hemolytic index, respectively. Pulse pressure was also independently associated with elevated serum creatinine (beta = 3.21, p = 0.02), and with proteinuria (beta = 2.52, p = 0.04). These results from the largest sickle cell disease cohort to date since the Cooperative Study of Sickle Cell Disease show that pulse pressure is independently associated with hemolysis, proteinuria and chronic kidney disease. We propose that high pulse pressure may be a risk factor for clinical complications of vascular dysfunction in sickle cell disease. Longitudinal and mechanistic studies should be conducted to confirm these hypotheses.
- Pellegrini, P., Rossi, A., Pasotti, M., Raineri, C., Cicoira, M., Bonapace, S., Dini, F. L., Temporelli, P. L., Vassanelli, C., Vanderpool, R., Naeije, R., & Ghio, S. (2014). Prognostic relevance of pulmonary arterial compliance in patients with chronic heart failure. Chest, 145(5), 1064-70.More infoReduced pulmonary arterial compliance (Ca) is a marker of poor prognosis in idiopathic pulmonary arterial hypertension. We tested the hypothesis that pulmonary arterial Ca could be a predictor of outcome in patients with chronic heart failure (CHF).
- D'Alto, M., Romeo, E., Argiento, P., D'Andrea, A., Vanderpool, R., Correra, A., Bossone, E., Sarubbi, B., Calabrò, R., Russo, M. G., & Naeije, R. (2013). Accuracy and precision of echocardiography versus right heart catheterization for the assessment of pulmonary hypertension. International journal of cardiology, 168(4), 4058-62.More infoEchocardiographic studies have contributed to progress in the understanding of the pathophysiology of the pulmonary circulation and have been shown to be useful for screening for and prognostication of pulmonary hypertension, but are considered unreliable for the diagnosis of pulmonary hypertension. We explored this apparent paradox with rigorous Bland and Altman analysis of the accuracy and the precision of measurements collected in a large patient population.
- Pagnamenta, A., Vanderpool, R., Brimioulle, S., & Naeije, R. (2013). Proximal pulmonary arterial obstruction decreases the time constant of the pulmonary circulation and increases right ventricular afterload. Journal of applied physiology (Bethesda, Md. : 1985), 114(11), 1586-92.More infoThe time constant of the pulmonary circulation, or product of pulmonary vascular resistance (PVR) and compliance (Ca), called the RC-time, has been reported to remain constant over a wide range of pressures, etiologies of pulmonary hypertension, and treatments. We wondered if increased wave reflection on proximal pulmonary vascular obstruction, like in operable chronic thromboembolic pulmonary hypertension, might also decrease the RC-time and thereby increase pulse pressure and right ventricular afterload. Pulmonary hypertension of variable severity was induced either by proximal obstruction (pulmonary arterial ensnarement) or distal obstruction (microembolism) eight anesthetized dogs. Pulmonary arterial pressures (Ppa) were measured with high-fidelity micromanometer-tipped catheters, and pulmonary flow with transonic technology. Pulmonary ensnarement increased mean Ppa, PVR, and characteristic impedance, decreased Ca and the RC-time (from 0.46 ± 0.07 to 0.30 ± 0.03 s), and increased the oscillatory component of hydraulic load (Wosc/Wtot) from 25 ± 2 to 29 ± 2%. Pulmonary microembolism increased mean Ppa and PVR, with no significant change in Ca and characteristic impedance, increased RC-time from 0.53 ± 0.09 to 0.74 ± 0.05 s, and decreased Wosc/Wtot from 26 ± 2 to 13 ± 2%. Pulse pressure increased more after pulmonary ensnarement than after microembolism. Concomitant measurements with fluid-filled catheters showed the same functional differences between the two types of pulmonary hypertension, with, however, an underestimation of Wosc. We conclude that pulmonary hypertension caused by proximal vs. distal obstruction is associated with a decreased RC-time and increased pulsatile component of right ventricular hydraulic load.
- Vanderpool, R. R., El-Bizri, N., Rabinovitch, M., & Chesler, N. C. (2013). Patchy deletion of Bmpr1a potentiates proximal pulmonary artery remodeling in mice exposed to chronic hypoxia. Biomechanics and modeling in mechanobiology, 12(1), 33-42.More infoReduced vascular expression of bone morphogenetic protein type IA receptor (Bmpr1a) has been found in patients with pulmonary arterial hypertension. Our previous studies in mice with patchy deletion of Bmpr1a in vascular smooth muscle cells and cardiac myocytes showed decreased distal vascular remodeling despite a similar severity of hypoxic pulmonary hypertension (HPH). We speculate increased stiffness from ectopic deposition of collagen in proximal pulmonary arteries might account for HPH. Pulsatile pressure-flow relationships were measured in isolated, ventilated, perfused lungs of SM22α;TRE-Cre;R26R;Bmpr1a(flox/flox) (KO) mice and wild-type littermates, following 21 days (hypoxia) and 0 days (control) of chronic hypoxia. Pulmonary vascular impedance, which yields insight into proximal and distal arterial remodeling, was calculated. Reduced Bmpr1a expression had no effect on input impedance Z(0) (P = 0.52) or characteristic impedance Z(C) (P = 0.18) under control conditions; it also had no effect on the decrease in Z(0) via acute rho kinase inhibition. However, following chronic hypoxia, reduced Bmpr1a expression increased Z(C) (P < 0.001) without affecting Z(0) (P = 0.72). These results demonstrate that Bmpr1a deficiency does not significantly alter the hemodynamic function of the distal vasculature or its response to chronic hypoxia but larger, more proximal arteries are affected. In particular, reduced Bmpr1a expression likely decreased dilatation and increased stiffening in response to hypoxia, probably by collagen accumulation. Increased PA stiffness can have a significant impact on right ventricular function. This study illustrates for the first time how proximal pulmonary artery changes in the absence of distal pulmonary artery changes contribute to pulmonary arterial hypertension.
- Argiento, P., Vanderpool, R. R., Mulè, M., Russo, M. G., D'Alto, M., Bossone, E., Chesler, N. C., & Naeije, R. (2012). Exercise stress echocardiography of the pulmonary circulation: limits of normal and sex differences. Chest, 142(5), 1158-65.More infoExercise stress echocardiography has not been recommended in the diagnostic workup of pulmonary hypertension because of insufficient certainty about feasibility and limits of normal.
- Groepenhoff, H., Overbeek, M. J., Mulè, M., van der Plas, M., Argiento, P., Villafuerte, F. C., Beloka, S., Faoro, V., Macarlupu, J. L., Guenard, H., de Bisschop, C., Martinot, J. B., Vanderpool, R., Penaloza, D., & Naeije, R. (2012). Exercise pathophysiology in patients with chronic mountain sickness exercise in chronic mountain sickness. Chest, 142(4), 877-84.More infoChronic mountain sickness (CMS) is characterized by a combination of excessive erythrocytosis,severe hypoxemia, and pulmonary hypertension, all of which affect exercise capacity.
- Pavelescu, A., Vanderpool, R., Vachiéry, J. L., Grunig, E., & Naeije, R. (2012). Echocardiography of pulmonary vascular function in asymptomatic carriers of BMPR2 mutations. The European respiratory journal, 40(5), 1287-9.
- Vanderpool, R. R., & Chesler, N. C. (2011). Characterization of the isolated, ventilated, and instrumented mouse lung perfused with pulsatile flow. Journal of visualized experiments : JoVE.More infoThe isolated, ventilated and instrumented mouse lung preparation allows steady and pulsatile pulmonary vascular pressure-flow relationships to be measured with independent control over pulmonary arterial flow rate, flow rate waveform, airway pressure and left atrial pressure. Pulmonary vascular resistance is calculated based on multi-point, steady pressure-flow curves; pulmonary vascular impedance is calculated from pulsatile pressure-flow curves obtained at a range of frequencies. As now recognized clinically, impedance is a superior measure of right ventricular afterload than resistance because it includes the effects of vascular compliance, which are not negligible, especially in the pulmonary circulation. Three important metrics of impedance--the zero hertz impedance Z(0;), the characteristic impedance Z(C;), and the index of wave reflection R(W;)--provide insight into distal arterial cross-sectional area available for flow, proximal arterial stiffness and the upstream-downstream impedance mismatch, respectively. All results obtained in isolated, ventilated and perfused lungs are independent of sympathetic nervous system tone, volume status and the effects of anesthesia. We have used this technique to quantify the impact of pulmonary emboli and chronic hypoxia on resistance and impedance, and to differentiate between sites of action (i.e., proximal vs. distal) of vasoactive agents and disease using the pressure dependency of Z(C;). Furthermore, when these techniques are used with the lungs of genetically engineered strains of mice, the effects of molecular-level defects on pulmonary vascular structure and function can be determined.
- Vanderpool, R. R., Kim, A. R., Molthen, R., & Chesler, N. C. (2011). Effects of acute Rho kinase inhibition on chronic hypoxia-induced changes in proximal and distal pulmonary arterial structure and function. Journal of applied physiology (Bethesda, Md. : 1985), 110(1), 188-98.More infoHypoxic pulmonary hypertension (HPH) is initially a disease of the small pulmonary arteries. Its severity is usually quantified by pulmonary vascular resistance (PVR). Acute Rho kinase inhibition has been found to reduce PVR toward control values in animal models, suggesting that persistent pulmonary vasoconstriction is the dominant mechanism for increased PVR. However, HPH may also cause proximal arterial changes, which are relevant to right ventricular (RV) afterload. RV afterload can be quantified by pulmonary vascular impedance, which is obtained via spectral analysis of pulsatile pressure-flow relationships. To determine the effects of HPH independent of persistent pulmonary vasoconstriction in proximal and distal arteries, we quantified pulsatile pressure-flow relationships before and after acute Rho kinase inhibition and measured pulmonary arterial structure with microcomputed tomography. In control lungs, Rho kinase inhibition decreased 0 Hz impedance (Z₀), which is equivalent to PVR, from 2.1 ± 0.4 to 1.5 ± 0.2 mmHg·min·ml⁻¹ (P < 0.05) and tended to increase characteristic impedance (Z(C)) from 0.21 ± 0.01 to 0.22 ± 0.01 mmHg·min·ml⁻¹. In HPH lungs, Rho kinase inhibition decreased Z₀ (P < 0.05) without affecting Z(C). Microcomputed tomography measurements performed on lungs after acute Rho kinase inhibition demonstrated that HPH significantly decreased the unstressed diameter of the main pulmonary artery (760 ± 60 vs. 650 ± 80 μm; P < 0.05), decreased right pulmonary artery compliance, and reduced the frequency of arteries of diameter 50-100 μm (both P < 0.05). These results demonstrate that acute Rho kinase inhibition reverses many but not all HPH-induced changes in distal pulmonary arteries but does not affect HPH-induced changes in the conduit arteries that impact RV afterload.
- Vanderpool, R. R., Naeije, R., & Chesler, N. C. (2010). Impedance in isolated mouse lungs for the determination of site of action of vasoactive agents and disease. Annals of biomedical engineering, 38(5), 1854-61.More infoHypoxic pulmonary hypertension is a disease of the lung vasculature that is usually quantified by pulmonary vascular resistance (PVR). However, a more complete description of lung vascular function and right ventricular afterload is provided by pulmonary vascular impedance (PVZ) from spectral analysis of pulsatile pressure-flow relationships. We studied pulsatile pressure-flow relationships in isolated, perfused lungs of mice in normoxia, after induction of hypoxic pulmonary hypertension by 10 days of hypoxic exposure, and after the administration of the vasoactive agents sodium nitroprusside and serotonin in order to gain insight into the effects of disease and vasoactive agents on afterload. Chronic hypoxia exposure increased 0 Hz impedance (Z(0)) from 2.0 +/- 0.2 to 3.3 +/- 0.2 mmHg min/mL but decreased characteristic impedance (Z(C)) from 0.21 +/- 0.02 to 0.18 +/- 0.01 mmHg min/mL (both p < 0.05). Sodium nitroprusside only slightly decreased Z(0) but increased Z(C) in normal lungs (p < 0.05) and did not affect Z(C) and decreased Z(0) in hypertensive lungs (p < 0.05). Serotonin increased Z(C) in normal and hypertensive lungs but decreased Z(0) in hypertensive lungs (p < 0.05). There was an inverse correlation between mean pulmonary artery pressure and Z(C) in all circumstances. These findings demonstrate that vasoactive interventions can have different sites of action (i.e., proximal vs. distal segments) in the normal and chronically hypoxic pulmonary vasculature, and the pressure-dependency of Z(C) and R(W). The measurement of PVZ in isolated lungs allows for an improved understanding of the modes of action of drugs and hypoxia on the pulmonary circulation.
- Chesler, N. C., Argiento, P., Vanderpool, R., D'Alto, M., & Naeije, R. (2009). How to measure peripheral pulmonary vascular mechanics. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2009, 173-6.More infoPulmonary hypertension (PH) is initially a disease of the small, peripheral resistance arteries. Changes in these vessels are best assessed by measurement of pulmonary artery pressure at several levels of flow to generate multi-point pressure-flow curves. This approach is superior to the traditional single-point measurement of pulmonary vascular resistance (PVR) because it allows a flow-independent definition of the resistive properties of that portion of the pulmonary vascular bed and also provides information on its distensibility. In animal models, multi-point pressure-flow curves can be obtained using an isolated, ventilated, perfused lung system. Clinically, cardiopulmonary exercise testing (CPET) with non-invasive echocardiography is feasible and provides realistic values of the resistance and peripheral compliance. Together, these values can be used to better understand and screen for PH and exercise-induced PH.
- Chesler, N. C., Roldan, A., Vanderpool, R. R., & Naeije, R. (2009). How to measure pulmonary vascular and right ventricular function. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2009, 177-80.More infoLong-standing pulmonary hypertension causes significant peripheral and proximal arterial remodeling and right ventricular dysfunction. The clinical metric most often used to assess the progression of PH is the pulmonary vascular resistance (PVR). However, even when measured from multipoint pressure-flow curves, PVR provides information only on the peripheral arterial function, not the proximal arterial function and gives only an incomplete description of all the forces that oppose right ventricular (RV) flow output. Pulmonary vascular impedance spectra (PVZ) capture the impact of proximal and peripheral arterial structure and function on RV function. Analyses of ventricular-vascular coupling give insight into the efficiency of mechanical and metabolic interactions between the right ventricle and the pulmonary vasculature. Here we review techniques for measuring PVZ in humans and animal models and for determining RV function.
- Tuchscherer, H. A., Vanderpool, R. R., & Chesler, N. C. (2007). Pulmonary vascular remodeling in isolated mouse lungs: effects on pulsatile pressure-flow relationships. Journal of biomechanics, 40(5), 993-1001.More infoChronic hypoxia causes pulmonary vasoconstriction and pulmonary hypertension, which lead to pulmonary vascular remodeling and right ventricular hypertrophy. To determine the effects of hypoxia-induced pulmonary vascular remodeling on pulmonary vascular impedance, which is the right ventricular afterload, we exposed C57BL6 mice to 0 (control), 10 and 15 days of hypobaric hypoxia (n=6, each) and measured pulmonary vascular resistance (PVR) and impedance ex vivo. Chronic hypoxia led to increased pulmonary artery pressures for flow rates between 1 and 5ml/min (P
- Vanderpool, R. R. (2017, August). Diastolic Right Ventricular Function in Severe Pulmonary Arterial Hypertension. China Heart Congress (CHC) 2017. Beijing, China: Chinese Medical Association (CMA) and National Center for Cardiovascular Diseases of China (NCCD).
- Vanderpool, R., Knapp, S. M., Honkanen, I., Wickstrom, K., Desai, A., Bernardo, R., & Rischard, F. (2017, January). Feasibility of determining right ventricular diastolic stiffness from a standard right heart catheterization. Pulmonary Vascular Research Institute Annual Conference. MIami, FL: Pulmonary Vascular Research Institute.
- Vanderpool, R., Knapp, S. M., Honkanen, I., Wickstrom, K., Desai, A., Bernardo, R., & Rischard, F. (2017, May). Resting right ventricular diastolic function and pulmonary arterial compliance associate with right ventricular contractile reserve in patients with pulmonary arterial hypertension.. American Thoracic Society Conference. Washington, D.C.: American Thoracic Society.
- Servin, F., Rosado, J. A., Janardhanan, R., Yuan, J., Rischard, F., & Vanderpool, R. (2018, Summer). Assessment of Pulmonary Arterial Structure and its Association with Right Ventricular Function in Pulmonary Arterial Hypertension. Biomechanics, Bioengineering and Biotransport Conference. Seven Springs, PA.
- Bernardo, R., Bernardo, R., Wickstrom, K., Wickstrom, K., Desai, A., Desai, A., Nair, V., Nair, V., Vanderpool, R. R., Vanderpool, R., Rischard, F., & Rischard, F. (2017, September). Echocardiographic measures of right ventricular function poorly correlate with changes in contractility and coupling in treatment naïve patients with pulmonary artery hypertension before and after therapy.. European Respiratory Society Congress. Milan, Italy: European Respiratory Society.
- Rosado-Toro, J. A., Avery, R., Altbach, M. I., Rischard, F., & Vanderpool, R. R. (2017, November). Feasibility of MRI-RHC based pressure volume loops in control and PAH patients. AHA Annual Conference. Anahaim, CA: American Heart Association.
- Vanderpool, R. R., Desai, A., Yuan, J., & Rischard, F. (2018, January). RV diastolic stiffness as a novel marker of RV failure in idiopathic pulmonary arterial hypertension. PVRI Annual International Congress. Singapore: Pulmonary Vascular Research Institute.
- Vanderpool, R., Airhart, S., & Rischard, F. (2018, May). Simplified Pressure Volume Loops Overestimate RV Function In A Load Dependent Fashion In Patients With PAH. American Thoracic Society. San Diego.