Steven Hsu1, Brian A Houston1, Emmanouil Tampakakis1, Anita C Bacher1, Parker S Rhodes1, Stephen C Mathai1, Rachel L Damico1, Todd M Kolb1, Laura K Hummers1, Ami A Shah1, Zsuzsanna McMahan1, Celia P Corona-Villalobos1, Stefan L Zimmerman1, Fredrick M Wigley1, Paul M Hassoun1, David A Kass2, Ryan J Tedford2. 1. From Divisions of Cardiology (S.H., B.A.H., E.T., A.C.B., P.S.R., D.A.K., R.J.T.), Pulmonary and Critical Care (S.C.M., R.L.D., T.M.K., P.M.H.), and Rheumatology (L.K.H., A.A.S., Z.M., F.M.W.), Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD; and Departments of Radiology (C.P.C.-V., S.L.Z.) and Biomedical Engineering (D.A.K.), Johns Hopkins Medical Institutions, Baltimore, MD. 2. From Divisions of Cardiology (S.H., B.A.H., E.T., A.C.B., P.S.R., D.A.K., R.J.T.), Pulmonary and Critical Care (S.C.M., R.L.D., T.M.K., P.M.H.), and Rheumatology (L.K.H., A.A.S., Z.M., F.M.W.), Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD; and Departments of Radiology (C.P.C.-V., S.L.Z.) and Biomedical Engineering (D.A.K.), Johns Hopkins Medical Institutions, Baltimore, MD. ryan.tedford@jhmi.edu dkass@jhmi.edu.
Abstract
BACKGROUND: Right ventricular (RV) functional reserve affects functional capacity and prognosis in patients with pulmonary arterial hypertension (PAH). PAH associated with systemic sclerosis (SSc-PAH) has a substantially worse prognosis than idiopathic PAH (IPAH), even though many measures of resting RV function and pulmonary vascular load are similar. We therefore tested the hypothesis that RV functional reserve is depressed in SSc-PAH patients. METHODS AND RESULTS: RV pressure-volume relations were prospectively measured in IPAH (n=9) and SSc-PAH (n=15) patients at rest and during incremental atrial pacing or supine bicycle ergometry. Systolic and lusitropic function increased at faster heart rates in IPAH patients, but were markedly blunted in SSc-PAH. The recirculation fraction, which indexes intracellular calcium recycling, was also depressed in SSc-PAH (0.32±0.05 versus 0.50±0.05; P=0.039). At matched exercise (25 W), SSc-PAH patients did not augment contractility (end-systolic elastance) whereas IPAH did (P<0.001). RV afterload assessed by effective arterial elastance rose similarly in both groups; thus, ventricular-vascular coupling declined in SSc-PAH. Both end-systolic and end-diastolic RV volumes increased in SSc-PAH patients to offset contractile deficits, whereas chamber dilation was absent in IPAH (+37±10% versus +1±8%, P=0.004, and +19±4% versus -1±6%, P<0.001, respectively). Exercise-associated RV dilation also strongly correlated with resting ventricular-vascular coupling in a larger cohort. CONCLUSIONS: RV contractile reserve is depressed in SSc-PAH versus IPAH subjects, associated with reduced calcium recycling. During exercise, this results in ventricular-pulmonary vascular uncoupling and acute RV dilation. RV dilation during exercise can predict adverse ventricular-vascular coupling in PAH patients.
BACKGROUND: Right ventricular (RV) functional reserve affects functional capacity and prognosis in patients with pulmonary arterial hypertension (PAH). PAH associated with systemic sclerosis (SSc-PAH) has a substantially worse prognosis than idiopathic PAH (IPAH), even though many measures of resting RV function and pulmonary vascular load are similar. We therefore tested the hypothesis that RV functional reserve is depressed in SSc-PAHpatients. METHODS AND RESULTS: RV pressure-volume relations were prospectively measured in IPAH (n=9) and SSc-PAH (n=15) patients at rest and during incremental atrial pacing or supine bicycle ergometry. Systolic and lusitropic function increased at faster heart rates in IPAH patients, but were markedly blunted in SSc-PAH. The recirculation fraction, which indexes intracellular calcium recycling, was also depressed in SSc-PAH (0.32±0.05 versus 0.50±0.05; P=0.039). At matched exercise (25 W), SSc-PAHpatients did not augment contractility (end-systolic elastance) whereas IPAH did (P<0.001). RV afterload assessed by effective arterial elastance rose similarly in both groups; thus, ventricular-vascular coupling declined in SSc-PAH. Both end-systolic and end-diastolic RV volumes increased in SSc-PAHpatients to offset contractile deficits, whereas chamber dilation was absent in IPAH (+37±10% versus +1±8%, P=0.004, and +19±4% versus -1±6%, P<0.001, respectively). Exercise-associated RV dilation also strongly correlated with resting ventricular-vascular coupling in a larger cohort. CONCLUSIONS: RV contractile reserve is depressed in SSc-PAH versus IPAH subjects, associated with reduced calcium recycling. During exercise, this results in ventricular-pulmonary vascular uncoupling and acute RV dilation. RV dilation during exercise can predict adverse ventricular-vascular coupling in PAH patients.
Authors: Frank van den Hoogen; Dinesh Khanna; Jaap Fransen; Sindhu R Johnson; Murray Baron; Alan Tyndall; Marco Matucci-Cerinic; Raymond P Naden; Thomas A Medsger; Patricia E Carreira; Gabriela Riemekasten; Philip J Clements; Christopher P Denton; Oliver Distler; Yannick Allanore; Daniel E Furst; Armando Gabrielli; Maureen D Mayes; Jacob M van Laar; James R Seibold; Laszlo Czirjak; Virginia D Steen; Murat Inanc; Otylia Kowal-Bielecka; Ulf Müller-Ladner; Gabriele Valentini; Douglas J Veale; Madelon C Vonk; Ulrich A Walker; Lorinda Chung; David H Collier; Mary Ellen Csuka; Barri J Fessler; Serena Guiducci; Ariane Herrick; Vivien M Hsu; Sergio Jimenez; Bashar Kahaleh; Peter A Merkel; Stanislav Sierakowski; Richard M Silver; Robert W Simms; John Varga; Janet E Pope Journal: Arthritis Rheum Date: 2013-10-03
Authors: Ryan J Tedford; James O Mudd; Reda E Girgis; Stephen C Mathai; Ari L Zaiman; Traci Housten-Harris; Danielle Boyce; Benjamin W Kelemen; Anita C Bacher; Ami A Shah; Laura K Hummers; Fredrick M Wigley; Stuart D Russell; Rajeev Saggar; Rajan Saggar; W Lowell Maughan; Paul M Hassoun; David A Kass Journal: Circ Heart Fail Date: 2013-09-01 Impact factor: 8.790
Authors: Rebecca R Vanderpool; Michael R Pinsky; Robert Naeije; Christopher Deible; Vijaya Kosaraju; Cheryl Bunner; Michael A Mathier; Joan Lacomis; Hunter C Champion; Marc A Simon Journal: Heart Date: 2014-09-11 Impact factor: 5.994
Authors: Gregory D Lewis; Ravi V Shah; Paul P Pappagianopolas; David M Systrom; Marc J Semigran Journal: Circ Heart Fail Date: 2008-11 Impact factor: 8.790
Authors: Guido Claessen; Andre La Gerche; Steven Dymarkowski; Piet Claus; Marion Delcroix; Hein Heidbuchel Journal: J Am Heart Assoc Date: 2015-03-23 Impact factor: 5.501
Authors: Jennifer L Philip; Thomas M Murphy; David A Schreier; Sydney Stevens; Diana M Tabima; Margie Albrecht; Andrea L Frump; Timothy A Hacker; Tim Lahm; Naomi C Chesler Journal: Am J Physiol Heart Circ Physiol Date: 2019-02-15 Impact factor: 4.733
Authors: Evan L Brittain; Thennapan Thennapan; Bradley A Maron; Stephen Y Chan; Eric D Austin; Edda Spiekerkoetter; Harm J Bogaard; Christophe Guignabert; Roxane Paulin; Roberto F Machado; Paul B Yu Journal: Am J Respir Crit Care Med Date: 2018-07-01 Impact factor: 21.405
Authors: Steven Hsu; Kristen M Kokkonen-Simon; Jonathan A Kirk; Todd M Kolb; Rachel L Damico; Stephen C Mathai; Monica Mukherjee; Ami A Shah; Fredrick M Wigley; Kenneth B Margulies; Paul M Hassoun; Marc K Halushka; Ryan J Tedford; David A Kass Journal: Circulation Date: 2018-01-19 Impact factor: 29.690
Authors: George Hung; Valentina Mercurio; Steven Hsu; Stephen C Mathai; Ami A Shah; Monica Mukherjee Journal: Curr Rheumatol Rep Date: 2019-12-07 Impact factor: 4.592
Authors: Rahul G Argula; Abhijit Karwa; Abigail Lauer; David Gregg; Richard M Silver; Carol Feghali-Bostwick; Lynn M Schanpp; Kim Egbert; Bruce W Usher; Viswanathan Ramakrishnan; Paul M Hassoun; Charlie Strange Journal: Ann Am Thorac Soc Date: 2017-05
Authors: Tim Lahm; Ivor S Douglas; Stephen L Archer; Harm J Bogaard; Naomi C Chesler; Francois Haddad; Anna R Hemnes; Steven M Kawut; Jeffrey A Kline; Todd M Kolb; Stephen C Mathai; Olaf Mercier; Evangelos D Michelakis; Robert Naeije; Rubin M Tuder; Corey E Ventetuolo; Antoine Vieillard-Baron; Norbert F Voelkel; Anton Vonk-Noordegraaf; Paul M Hassoun Journal: Am J Respir Crit Care Med Date: 2018-08-15 Impact factor: 21.405