Bellofiore, Alessandro

Chesler, Naomi C.

Goss, Kara N.

Mulchrone, Ashley

English

SJSU ScholarWorks

San Jose State University SJSU ScholarWorks Faculty Research, Scholarly, and Creative Activity 4-15-2020 Reply to Tello et al.: Pending Right Heart Failure in Healthy Preterm-Born Subjects? Alessandro Bellofiore San Jose State University, alessandro.bellofiore@sjsu.edu Kara N. Goss University of Wisconsin-Madison Ashley Mulchrone University of Wisconsin-Madison Naomi C. Chesler University of Wisconsin-Madison Follow this and additional works at: https://scholarworks.sjsu.edu/faculty_rsca Recommended Citation Alessandro Bellofiore, Kara N. Goss, Ashley Mulchrone, and Naomi C. Chesler. "Reply to Tello et al.: Pending Right Heart Failure in Healthy Preterm-Born Subjects?" American Journal of Respiratory and Critical Care Medicine (2020): 1009-1010. https://doi.org/10.1164/RCCM.201912-2356LE This Article is brought to you for free and open access by SJSU ScholarWorks. It has been accepted for inclusion in Faculty Research, Scholarly, and Creative Activity by an authorized administrator of SJSU ScholarWorks. For more information, please contact scholarworks@sjsu.edu. from the pulmonary circulation by.50% is associated with increasedright heart dimensions and decreased ejection fractions (EFs) to>35%, heralding the transition from maladaptation to failure (4).The extraordinary RV–PA uncoupling in preterm-bornsubjects disclosed in the study by Mulchrone and colleagues isprobably methodological. The authors applied a recentlydeveloped automatic second derivation of rate of pressure rise(dP/dt) (5) instead of a single derivation of dP/dt with manualidentification of the end and onset of diastole, whichtraditionally has been used to determine the isovolumic portions ofthe RV pressure curve and extrapolate an estimation of Pmax (3, 4).As acknowledged by the authors, the second-derivative approach mayreduce variability (i.e., increase precision) but underestimates Pmaxby some 13% (5). This would obviously increase Pes, probably in asimilar proportion. Calculating the EF from the pressure-onlymethod as 1 2 Pes/Pmax with 13–15% corrections of the reportedPmax and Pes in the study by Mulchrone and colleagues would bringit back around the normal value of 60%.Mulchrone and colleagues claim that there was good agreementbetween the pressure- and volume-only methods, with a Pearsoncoefficient of R2 = 0.78 (P, 0.001) (1). However, as repeatedlyunderscored by Bland and Altman, correlation coefficients largelyreflect the variability of the subjects being measured, such that if onemeasurement is always twice as big as the other, they arehighly correlated but do not agree (6). The large differencesin the means of Ees/Ea obtained by different methods in thepreterm-born subjects indicate considerable biases, which wouldhave been disclosed by a correct Bland and Altman analysis.In conclusion, we believe that preterm-born healthy subjects canbe reassured that they are not in a state of pending right heart failure.This discussion also underscores how difficult it is to measure thegold-standard Ees/Ea ratio to assess RV–PA coupling, and theimportance of using a rigorous methodology, including the EF, asan indispensable internal control. nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Khodr Tello, M.D.Manuel J. Richter, M.D.University of GiessenGiessen, GermanyRobert Naeije, M.D.*Free University of BrusselsBrussels, Belgium*Corresponding author (e-mail: rnaeije@ulb.ac.be).References1. Mulchrone A, Bellofiore A, Douwes JM, Duong N, Beshish AG,Barton GP, et al. Impaired right ventricular–vascular coupling inyoung adults born preterm. Am J Respir Crit Care Med 2020;201:615–618.2. Sanz J, Sánchez-Quintana D, Bossone E, Bogaard HJ,Naeije R. Anatomy, function, and dysfunction of the right ventricle:JACC state-of-the-art review. J Am Coll Cardiol 2019;73:1463–1482.3. Richter MJ, Peters D, Ghofrani HA, Naeije R, Roller F, Sommer N, et al.Evaluation and prognostic relevance of right ventricular-arterialcoupling in pulmonary hypertension. Am J Respir Crit Care Med 2020;201:116–119.4. Tello K, Dalmer A, Axmann J, Vanderpool R, Ghofrani HA, Naeije R, et al.Reserve of right ventricular-arterial coupling in the setting of chronicoverload. Circ Heart Fail 2019;12: e005512.5. Bellofiore A, Vanderpool R, Brewis MJ, Peacock AJ, Chesler NC. A novelsingle-beat approach to assess right ventricular systolic function.J Appl Physiol (1985) 2018;124:283–290.6. Bland JM, Altman DG. Statistical methods for assessing agreementbetween two methods of clinical measurement. Lancet 1986;1:307–310.Copyright © 2020 by the American Thoracic SocietyReply to Tello et al.From the Authors:We appreciate the opportunity to further discuss cardiopulmonarydifferences between adults born preterm and adults born at term (1).Tello and colleagues raise two important points in their letter that wewill address here. First, the “extraordinary” right ventricular–pulmonary arterial (RV–PA) uncoupling in the preterm-bornsubjects we reported is not the result of our use of the second-derivative approach to the single-beat method (2), as they suggest.The first author of this letter, who is an experienced user ofboth first- and second-derivative approaches, reanalyzed thehemodynamic data reported by Mulchrone and colleagues andfound similar results (Figure 1) that led to a similar conclusion:preterm birth leads to a decrease in the RV–PA end-systolic elastance toarterial elastance ratio (Ees/Ea) that is clinically relevant. With eitherapproach, the decrease is not statistically significant, most likely becauseof the small sample size.Second, although data support that uncoupling of the rightventricle from the pulmonary circulation by more than 50%predicts RV failure in pulmonary hypertension (3), preterm birthcauses a fundamentally different cardiopulmonary pathology. Inparticular, preterm birth results in morphologically differentventricles with smaller biventricular chamber size and subtle leftventricular (LV) dysfunction (4, 5). Herein lies a critically importantmethodological consideration in using RV–PA Ees/Ea to predict RVfailure. As elegantly demonstrated decades ago (6, 7), although LVpump function is largely insensitive to RV pump function, thereverse is not true. As we recently showed in a mouse model ofpulmonary hypertension secondary to left heart failure, impaired LVfunction depresses RV–PA Ees/Ea even if the right ventricle itself is inan adaptive, not maladaptive, state of remodeling (8). We anticipatethat this is the case in our cohort of preterm-born subjects but mustawait invasive LV hemodynamic data to prove the point.This article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage andreprints, please contact Diane Gern (dgern@thoracic.org).Supported by NIH grants 1R01HL086939 and 1R01HL105598 (N.C.C.).K.N.G. is supported by the University of Wisconsin Clinical and TranslationalScience Award program through the NIH National Center for AdvancingTranslational Sciences, NIH grant UL1TR000427 (Principal Investigator MarcDrezner; 4KL2TR000428-10).Originally Published in Press as DOI: 10.1164/rccm.201912-2356LE onJanuary 7, 2020CORRESPONDENCECorrespondence 1009 In conclusion, we agree that preterm-born subjects are not in astate of pending right heart failure, but they do show significantRV–PA uncoupling due to a combination of ventricular dysfunctionand elevated RV afterload revealed by our analysis. We previouslydemonstrated the clinical relevance of this uncoupling by reportingreduced exercise tolerance in the subjects included in the currentanalysis (9). Furthermore, should these subjects follow the trajectoryof progressive RV dysfunction identified in our animal model (10,11), careful clinical monitoring is warranted. Finally, we urge users ofthe gold-standard multibeat Ees/Ea ratio, as well as various single-beat methods, to consider LV function in their physiological andclinical interpretations of RV–PA coupling. nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Alessandro Bellofiore, Ph.D.San José State UniversitySan José, CaliforniaKara N. Goss, M.D.Ashley Mulchrone, Ph.D.Naomi C. Chesler, Ph.D.*University of Wisconsin-MadisonMadison, WisconsinORCID ID: 0000-0002-7612-5796 (N.C.C.).*Corresponding author (e-mail: naomi.chesler@wisc.edu).References1. Mulchrone A, Bellofiore A, Douwes JM, Duong N, Beshish AG, Barton GP,et al. Impaired right ventricular–vascular coupling in young adults bornpreterm. Am J Respir Crit Care Med 2020;201:615–618.2. Bellofiore A, Vanderpool R, Brewis MJ, Peacock AJ, Chesler NC. A novelsingle-beat approach to assess right ventricular systolic function.J Appl Physiol (1985) 2018;124:283–290.3. Tello K, Dalmer A, Axmann J, Vanderpool R, Ghofrani HA, Naeije R, et al.Reserve of right ventricular-arterial coupling in the setting of chronicoverload. Circ Heart Fail 2019;12:e005512.4. Lewandowski AJ, Bradlow WM, Augustine D, Davis EF, Francis J,Singhal A, et al. Right ventricular systolic dysfunction in young adultsborn preterm. Circulation 2013;128:713–720.5. Lewandowski AJ, Augustine D, Lamata P, Davis EF, Lazdam M, FrancisJ, et al. Preterm heart in adult life: cardiovascular magnetic resonancereveals distinct differences in left ventricular mass, geometry, andfunction. Circulation 2013;127:197–206.6. Santamore WP, Lynch PR, Heckman JL, Bove AA, Meier GD. Leftventricular effects on right ventricular developed pressure. J ApplPhysiol 1976;41:925–930.7. Damiano RJ Jr, La Follette P Jr, Cox JL, Lowe JE, Santamore WP.Significant left ventricular contribution to right ventricular systolicfunction. Am J Physiol 1991;261:H1514–H1524.8. Philip JL, Murphy TM, Schreier DA, Stevens S, Tabima DM, Albrecht M,et al. Pulmonary vascular mechanical consequences of ischemic heartfailure and implications for right ventricular function. Am J PhysiolHeart Circ Physiol 2019;316:H1167–H1177.9. Goss KN, Beshish AG, Barton GP, Haraldsdottir K, Levin TS, Tetri LH,et al. Early pulmonary vascular disease in young adults born preterm.Am J Respir Crit Care Med 2018;198:1549–1558.10. Goss KN, Kumari S, Tetri LH, Barton G, Braun RK, Hacker TA, et al. Postnatalhyperoxia exposure durably impairs right ventricular function andmitochondrial biogenesis. Am J Respir Cell Mol Biol 2017;56:609–619.11. Kumari S, Braun RK, Tetri LH, Barton GP, Hacker TA, Goss KN.Bimodal right ventricular dysfunction after postnatal hyperoxiaexposure: implications for the preterm heart. Am J Physiol Heart CircPhysiol 2019;317:H1272–H1281.Copyright © 2020 by the American Thoracic SocietyThe American Thoracic Society/EuropeanRespiratory Society 2019 Spirometry Statementand Occupational Spirometry Testing in theUnited StatesTo the Editor:U.S. occupational settings, in which hundreds of thousandsof workers are tested each year, have scrupulously adheredto American Thoracic Society (ATS) statements since the2nd derivative1st derivative2nd derivative1st derivative2nd derivative1st derivative45403530252015Piso (mmHg)Term PretermPes (mmHg)Term Preterm2520151050Ees/EaTerm Preterm543210Figure 1. Maximum isovolumic pressure (Piso), end-systolic pressure (Pes), and right ventricular–pulmonary arterial end-systolic elastance to arterialelastance ratio (Ees/Ea) for term-born and preterm-born subjects obtained with the second-derivative single-beat method (as reported in Reference 1)compared with the first-derivative approach. Mean6SE is shown.This article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage andreprints, please contact Diane Gern (dgern@thoracic.org).Originally Published in Press as DOI: 10.1164/rccm.201911-2267LE onJanuary 13, 2020CORRESPONDENCE1010 American Journal of Respiratory and Critical Care Medicine Volume 201 Number 8 | April 15 2020 

Reply to Tello et al.: Pending Right Heart Failure in Healthy Preterm-Born Subjects?

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Reply to Tello et al.: Pending Right Heart Failure in Healthy Preterm-Born Subjects?

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