Skip to main content
Top
Published in: European Journal of Applied Physiology 7/2018

Open Access 01-07-2018 | Original Article

Right ventriculo–arterial uncoupling and impaired contractile reserve in obese patients with unexplained exercise intolerance

Authors: Colm McCabe, Rudolf K. F. Oliveira, Farbod Rahaghi, Mariana Faria-Urbina, Luke Howard, Richard G. Axell, Andrew N. Priest, Aaron B. Waxman, David M. Systrom

Published in: European Journal of Applied Physiology | Issue 7/2018

Login to get access

Abstract

Background

Right ventricular (RV) dysfunction and heart failure with preserved ejection fraction may contribute to exercise intolerance in obesity. To further define RV exercise responses, we investigated RV–arterial coupling in obesity with and without development of exercise pulmonary venous hypertension (ePVH).

Methods

RV–arterial coupling defined as RV end-systolic elastance/pulmonary artery elastance (Ees/Ea) was calculated from invasive cardiopulmonary exercise test data in 6 controls, 8 obese patients without ePVH (Obese−ePVH) and 8 obese patients with ePVH (Obese+ePVH) within a larger series. ePVH was defined as a resting pulmonary arterial wedge pressure < 15 mmHg but ≥ 20 mmHg on exercise. Exercise haemodynamics were further evaluated in 18 controls, 20 Obese−ePVH and 17 Obese+ePVH patients.

Results

Both Obese−ePVH and Obese+ePVH groups developed exercise RV–arterial uncoupling (peak Ees/Ea = 1.45 ± 0.26 vs 0.67 ± 0.18 vs 0.56 ± 0.11, p < 0.001, controls vs Obese−ePVH vs Obese+ePVH respectively) with higher peak afterload (peak Ea = 0.31 ± 0.07 vs 0.75 ± 0.32 vs 0.88 ± 0.62 mL/mmHg, p = 0.043) and similar peak contractility (peak Ees = 0.50 ± 0.16 vs 0.45 ± 0.22 vs 0.48 ± 0.17 mL/mmHg, p = 0.89). RV contractile reserve was highest in controls (ΔEes = 224 ± 80 vs 154 ± 39 vs 141 ± 34% of baseline respectively, p < 0.001). Peak Ees/Ea correlated with peak pulmonary vascular compliance (PVC, r = 0.53, p = 0.02) but not peak pulmonary vascular resistance (PVR, r = − 0.20, p = 0.46). In the larger cohort, Obese+ePVH patients on exercise demonstrated higher right atrial pressure, lower cardiac output and steeper pressure-flow responses. BMI correlated with peak PVC (r = − 0.35, p = 0.04) but not with peak PVR (r = 0.24, p = 0.25).

Conclusions

Exercise RV–arterial uncoupling and reduced RV contractile reserve further characterise obesity-related exercise intolerance. RV dysfunction in obesity may develop independent of exercise LV filling pressures.
Literature
go back to reference Alpert MA, Singh A, Terry BE, Kelly DL, el-Deane MS, Mukerji V, Villarreal D, Artis AK (1989) Effect of exercise and cavity size on right ventricular function in morbid obesity. Am J Cardiol 64:1361–1365CrossRefPubMed Alpert MA, Singh A, Terry BE, Kelly DL, el-Deane MS, Mukerji V, Villarreal D, Artis AK (1989) Effect of exercise and cavity size on right ventricular function in morbid obesity. Am J Cardiol 64:1361–1365CrossRefPubMed
go back to reference Alpert MA, Omran J, Mehra A, Ardhanari S (2014) Impact of obesity and weight loss on cardiac performance and morphology in adults. Prog Cardiovasc Dis 56:391–400CrossRefPubMed Alpert MA, Omran J, Mehra A, Ardhanari S (2014) Impact of obesity and weight loss on cardiac performance and morphology in adults. Prog Cardiovasc Dis 56:391–400CrossRefPubMed
go back to reference Boerrigter BG, Waxman AB, Westerhof N, Vonk-Noordegraaf A, Systrom DM (2014) Measuring central pulmonary pressures during exercise in COPD: how to cope with respiratory effects. Eur Respir J 43:1316–1325CrossRefPubMed Boerrigter BG, Waxman AB, Westerhof N, Vonk-Noordegraaf A, Systrom DM (2014) Measuring central pulmonary pressures during exercise in COPD: how to cope with respiratory effects. Eur Respir J 43:1316–1325CrossRefPubMed
go back to reference Borlaug BA, Obokata M (2017) Is it time to recognize a new phenotype? Heart failure with preserved ejection fraction with pulmonary vascular disease. Eur Heart J 38:2874–2878CrossRefPubMed Borlaug BA, Obokata M (2017) Is it time to recognize a new phenotype? Heart failure with preserved ejection fraction with pulmonary vascular disease. Eur Heart J 38:2874–2878CrossRefPubMed
go back to reference Borlaug BA, Kane GC, Melenovsky V, Olson TP (2016) Abnormal right ventricular–pulmonary artery coupling with exercise in heart failure with preserved ejection fraction. Eur Heart J 37(43):3293–3302CrossRefPubMed Borlaug BA, Kane GC, Melenovsky V, Olson TP (2016) Abnormal right ventricular–pulmonary artery coupling with exercise in heart failure with preserved ejection fraction. Eur Heart J 37(43):3293–3302CrossRefPubMed
go back to reference Brimioulle S, Wauthy P, Ewalenko P, Rondelet B, Vermeulen F, Kerbaul F, Naeije R (2003) Single-beat estimation of right ventricular end-systolic pressure–volume relationship. Am J Physiol Heart Circ Physiol 284:H1625–H1630CrossRef Brimioulle S, Wauthy P, Ewalenko P, Rondelet B, Vermeulen F, Kerbaul F, Naeije R (2003) Single-beat estimation of right ventricular end-systolic pressure–volume relationship. Am J Physiol Heart Circ Physiol 284:H1625–H1630CrossRef
go back to reference Chahal H, McClelland RL, Tandri H, Jain A, Turkbey EB, Hundley WG, Barr RG, Kizer J, Lima JAC, Bluemke DA, Kawut SM (2012) Obesity and right ventricular structure and function: the MESA-Right Ventricle Study. Chest 141:388–395CrossRefPubMed Chahal H, McClelland RL, Tandri H, Jain A, Turkbey EB, Hundley WG, Barr RG, Kizer J, Lima JAC, Bluemke DA, Kawut SM (2012) Obesity and right ventricular structure and function: the MESA-Right Ventricle Study. Chest 141:388–395CrossRefPubMed
go back to reference Chemla D, Hebert JL, Coirault C, Salmeron S, Zamani K, Lecarpentier Y (1996) Matching dicrotic notch and mean pulmonary artery pressures: implications for effective arterial elastance. Am J Physiol 271:H1287–H1295 Chemla D, Hebert JL, Coirault C, Salmeron S, Zamani K, Lecarpentier Y (1996) Matching dicrotic notch and mean pulmonary artery pressures: implications for effective arterial elastance. Am J Physiol 271:H1287–H1295
go back to reference Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M, Aboyans V, Vaz Carneiro A, Achenbach S, Agewall S, Allanore Y, Asteggiano R, Paolo Badano L, Albert Barbera J, Bouvaist H, Bueno H, Byrne RA, Carerj S, Castro G, Erol C, Falk V, Funck-Brentano C, Gorenflo M, Granton J, Iung B, Kiely DG, Kirchhof P, Kjellstrom B, Landmesser U, Lekakis J, Lionis C, Lip GY, Orfanos SE, Park MH, Piepoli MF, Ponikowski P, Revel MP, Rigau D, Rosenkranz S, Voller H, Luis Zamorano J (2016) 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37:67–119CrossRefPubMed Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M, Aboyans V, Vaz Carneiro A, Achenbach S, Agewall S, Allanore Y, Asteggiano R, Paolo Badano L, Albert Barbera J, Bouvaist H, Bueno H, Byrne RA, Carerj S, Castro G, Erol C, Falk V, Funck-Brentano C, Gorenflo M, Granton J, Iung B, Kiely DG, Kirchhof P, Kjellstrom B, Landmesser U, Lekakis J, Lionis C, Lip GY, Orfanos SE, Park MH, Piepoli MF, Ponikowski P, Revel MP, Rigau D, Rosenkranz S, Voller H, Luis Zamorano J (2016) 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37:67–119CrossRefPubMed
go back to reference Groves BM, Reeves JT, Sutton JR, Wagner PD, Cymerman A, Malconian MK, Rock PB, Young PM, Houston CS (1987) Operation Everest II: elevated high-altitude pulmonary resistance unresponsive to oxygen. J Appl Physiol 63:521–530CrossRefPubMed Groves BM, Reeves JT, Sutton JR, Wagner PD, Cymerman A, Malconian MK, Rock PB, Young PM, Houston CS (1987) Operation Everest II: elevated high-altitude pulmonary resistance unresponsive to oxygen. J Appl Physiol 63:521–530CrossRefPubMed
go back to reference Hansen JE, Sue DY, Wasserman K (1984) Predicted values for clinical exercise testing. Am Rev Respir Dis 129:S49–S55 Hansen JE, Sue DY, Wasserman K (1984) Predicted values for clinical exercise testing. Am Rev Respir Dis 129:S49–S55
go back to reference Hsu S, Houston BA, Tampakakis E, Bacher AC, Rhodes PS, Mathai SC, Damico RL, Kolb TM, Hummers LK, Shah AA, McMahan Z, Corona-Villalobos CP, Zimmerman SL, Wigley FM, Hassoun PM, Kass DA, Tedford RJ (2016) Right ventricular functional reserve in pulmonary arterial hypertension. Circulation 133:2413–2422CrossRefPubMedPubMedCentral Hsu S, Houston BA, Tampakakis E, Bacher AC, Rhodes PS, Mathai SC, Damico RL, Kolb TM, Hummers LK, Shah AA, McMahan Z, Corona-Villalobos CP, Zimmerman SL, Wigley FM, Hassoun PM, Kass DA, Tedford RJ (2016) Right ventricular functional reserve in pulmonary arterial hypertension. Circulation 133:2413–2422CrossRefPubMedPubMedCentral
go back to reference Hussain I, Mohammed SF, Forfia PR, Lewis GD, Borlaug BA, Gallup DS, Redfield MM (2016) Impaired right ventricular–pulmonary arterial coupling and effect of Sildenafil in heart failure with preserved ejection fraction: an ancillary analysis from the phosphodiesterase-5 inhibition to improve clinical status and exercise capacity in diastolic heart failure (RELAX) trial. Circ Heart Fail 9:e002729CrossRefPubMed Hussain I, Mohammed SF, Forfia PR, Lewis GD, Borlaug BA, Gallup DS, Redfield MM (2016) Impaired right ventricular–pulmonary arterial coupling and effect of Sildenafil in heart failure with preserved ejection fraction: an ancillary analysis from the phosphodiesterase-5 inhibition to improve clinical status and exercise capacity in diastolic heart failure (RELAX) trial. Circ Heart Fail 9:e002729CrossRefPubMed
go back to reference Kaltman AJ, Goldring RM (1976) Role of circulatory congestion in the cardiorespiratory failure of obesity. Am J Med 60:645–653CrossRefPubMed Kaltman AJ, Goldring RM (1976) Role of circulatory congestion in the cardiorespiratory failure of obesity. Am J Med 60:645–653CrossRefPubMed
go back to reference Ketabchi F, Egemnazarov B, Schermuly RT, Ghofrani HA, Seeger W, Grimminger F, Shid-Moosavi M, Dehghani GA, Weissmann N, Sommer N (2009) Effects of hypercapnia with and without acidosis on hypoxic pulmonary vasoconstriction. Am J Physiol Lung Cell Mol Physiol 297:L977–L983CrossRef Ketabchi F, Egemnazarov B, Schermuly RT, Ghofrani HA, Seeger W, Grimminger F, Shid-Moosavi M, Dehghani GA, Weissmann N, Sommer N (2009) Effects of hypercapnia with and without acidosis on hypoxic pulmonary vasoconstriction. Am J Physiol Lung Cell Mol Physiol 297:L977–L983CrossRef
go back to reference Kregenow DA, Swenson ER (2002) The lung and carbon dioxide: implications for permissive and therapeutic hypercapnia. Eur Respir J 20:6–11CrossRefPubMed Kregenow DA, Swenson ER (2002) The lung and carbon dioxide: implications for permissive and therapeutic hypercapnia. Eur Respir J 20:6–11CrossRefPubMed
go back to reference Lai YC, Tabima DM, Dube JJ, Hughan KS, Vanderpool RR, Goncharov DA, St Croix CM, Garcia-Ocana A, Goncharova EA, Tofovic SP, Mora AL, Gladwin MT (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 133:717–731PubMedPubMedCentral Lai YC, Tabima DM, Dube JJ, Hughan KS, Vanderpool RR, Goncharov DA, St Croix CM, Garcia-Ocana A, Goncharova EA, Tofovic SP, Mora AL, Gladwin MT (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 133:717–731PubMedPubMedCentral
go back to reference Lykidis CK, White MJ, Balanos GM (2008) The pulmonary vascular response to the sustained activation of the muscle metaboreflex in man. Exp Physiol 93:247–253CrossRefPubMed Lykidis CK, White MJ, Balanos GM (2008) The pulmonary vascular response to the sustained activation of the muscle metaboreflex in man. Exp Physiol 93:247–253CrossRefPubMed
go back to reference Maron BA, Cockrill BA, Waxman AB, Systrom DM (2013) The invasive cardiopulmonary exercise test. Circulation 127:1157–1164CrossRefPubMed Maron BA, Cockrill BA, Waxman AB, Systrom DM (2013) The invasive cardiopulmonary exercise test. Circulation 127:1157–1164CrossRefPubMed
go back to reference Metkus TS, Mullin CJ, Grandin EW, Rame JE, Tampakakis E, Hsu S, Kolb TM, Damico R, Hassoun PM, Kass DA, Mathai SC, Tedford RJ (2016) Heart rate dependence of the pulmonary resistance × compliance (RC) time and impact on right ventricular load. PLoS One 11:e0166463CrossRefPubMedPubMedCentral Metkus TS, Mullin CJ, Grandin EW, Rame JE, Tampakakis E, Hsu S, Kolb TM, Damico R, Hassoun PM, Kass DA, Mathai SC, Tedford RJ (2016) Heart rate dependence of the pulmonary resistance × compliance (RC) time and impact on right ventricular load. PLoS One 11:e0166463CrossRefPubMedPubMedCentral
go back to reference Nishio K, Suzuki Y, Takeshita K, Aoki T, Kudo H, Sato N, Naoki K, Miyao N, Ishii M, Yamaguchi K (2001) Effects of hypercapnia and hypocapnia on [Ca2+]i mobilization in human pulmonary artery endothelial cells. J Appl Physiol 90:2094–2100CrossRefPubMed Nishio K, Suzuki Y, Takeshita K, Aoki T, Kudo H, Sato N, Naoki K, Miyao N, Ishii M, Yamaguchi K (2001) Effects of hypercapnia and hypocapnia on [Ca2+]i mobilization in human pulmonary artery endothelial cells. J Appl Physiol 90:2094–2100CrossRefPubMed
go back to reference Noble WH, Kay JC, Fisher JA (1981) The effect of PCO2 on hypoxic pulmonary vasoconstriction. Can Anaesth Soc J 28:422–430CrossRefPubMed Noble WH, Kay JC, Fisher JA (1981) The effect of PCO2 on hypoxic pulmonary vasoconstriction. Can Anaesth Soc J 28:422–430CrossRefPubMed
go back to reference Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA (2017) Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation 136:6–19CrossRefPubMedPubMedCentral Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA (2017) Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation 136:6–19CrossRefPubMedPubMedCentral
go back to reference Oliveira RK, Agarwal M, Tracy JA, Karin AL, Opotowsky AR, Waxman AB, Systrom DM (2016) Age-related upper limits of normal for maximum upright exercise pulmonary haemodynamics. Eur Respir J 47:1179–1188CrossRefPubMed Oliveira RK, Agarwal M, Tracy JA, Karin AL, Opotowsky AR, Waxman AB, Systrom DM (2016) Age-related upper limits of normal for maximum upright exercise pulmonary haemodynamics. Eur Respir J 47:1179–1188CrossRefPubMed
go back to reference Parker JO, Thadani U (1979) Cardiac performance at rest and during exercise in normal subjects. Bull Europeen de Physiopathologie Respiratoire 15:935–949 Parker JO, Thadani U (1979) Cardiac performance at rest and during exercise in normal subjects. Bull Europeen de Physiopathologie Respiratoire 15:935–949
go back to reference Spruijt OA, de Man FS, Groepenhoff H, Oosterveer F, Westerhof N, Vonk-Noordegraaf A, Bogaard HJ (2015) The effects of exercise on right ventricular contractility and right ventricular–arterial coupling in pulmonary hypertension. Am J Respir Crit Care Med 191:1050–1057CrossRefPubMed Spruijt OA, de Man FS, Groepenhoff H, Oosterveer F, Westerhof N, Vonk-Noordegraaf A, Bogaard HJ (2015) The effects of exercise on right ventricular contractility and right ventricular–arterial coupling in pulmonary hypertension. Am J Respir Crit Care Med 191:1050–1057CrossRefPubMed
go back to reference Sweeney M, Beddy D, Honner V, Sinnott B, O’Regan RG, McLoughlin P (1998) Effects of changes in pH and CO2 on pulmonary arterial wall tension are not endothelium dependent. J Appl Physiol 85:2040–2046CrossRefPubMed Sweeney M, Beddy D, Honner V, Sinnott B, O’Regan RG, McLoughlin P (1998) Effects of changes in pH and CO2 on pulmonary arterial wall tension are not endothelium dependent. J Appl Physiol 85:2040–2046CrossRefPubMed
go back to reference Trip P, Kind T, van de Veerdonk MC, Marcus JT, de Man FS, Westerhof N, Vonk-Noordegraaf A (2013) Accurate assessment of load-independent right ventricular systolic function in patients with pulmonary hypertension. J Heart Lung Transpl Off Publ Int Soc Heart Transpl 32:50–55CrossRef Trip P, Kind T, van de Veerdonk MC, Marcus JT, de Man FS, Westerhof N, Vonk-Noordegraaf A (2013) Accurate assessment of load-independent right ventricular systolic function in patients with pulmonary hypertension. J Heart Lung Transpl Off Publ Int Soc Heart Transpl 32:50–55CrossRef
go back to reference Viitanen A, Salmenpera M, Heinonen J (1990) Right ventricular response to hypercarbia after cardiac surgery. Anesthesiology 73:393–400CrossRefPubMed Viitanen A, Salmenpera M, Heinonen J (1990) Right ventricular response to hypercarbia after cardiac surgery. Anesthesiology 73:393–400CrossRefPubMed
go back to reference Wagner PD, Gale GE, Moon RE, Torre-Bueno JR, Stolp BW, Saltzman HA (1986) Pulmonary gas exchange in humans exercising at sea level and simulated altitude. J Appl Physiol 61:260–270CrossRefPubMed Wagner PD, Gale GE, Moon RE, Torre-Bueno JR, Stolp BW, Saltzman HA (1986) Pulmonary gas exchange in humans exercising at sea level and simulated altitude. J Appl Physiol 61:260–270CrossRefPubMed
go back to reference Wong CY, O’Moore-Sullivan T, Leano R, Hukins C, Jenkins C, Marwick TH (2006) Association of subclinical right ventricular dysfunction with obesity. J Am Coll Cardiol 47:611–616CrossRefPubMed Wong CY, O’Moore-Sullivan T, Leano R, Hukins C, Jenkins C, Marwick TH (2006) Association of subclinical right ventricular dysfunction with obesity. J Am Coll Cardiol 47:611–616CrossRefPubMed
go back to reference Yudkin JS, Eringa E, Stehouwer CD (2005) “Vasocrine” signalling from perivascular fat: a mechanism linking insulin resistance to vascular disease. Lancet 365:1817–1820CrossRefPubMed Yudkin JS, Eringa E, Stehouwer CD (2005) “Vasocrine” signalling from perivascular fat: a mechanism linking insulin resistance to vascular disease. Lancet 365:1817–1820CrossRefPubMed
Metadata
Title
Right ventriculo–arterial uncoupling and impaired contractile reserve in obese patients with unexplained exercise intolerance
Authors
Colm McCabe
Rudolf K. F. Oliveira
Farbod Rahaghi
Mariana Faria-Urbina
Luke Howard
Richard G. Axell
Andrew N. Priest
Aaron B. Waxman
David M. Systrom
Publication date
01-07-2018
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Applied Physiology / Issue 7/2018
Print ISSN: 1439-6319
Electronic ISSN: 1439-6327
DOI
https://doi.org/10.1007/s00421-018-3873-4

Other articles of this Issue 7/2018

European Journal of Applied Physiology 7/2018 Go to the issue