Clinical Research Study| Volume 131, ISSUE 6, P702.e7-702.e13, June 2018

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

Published:February 05, 2018DOI:



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


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


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


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


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Desai A.A.
        • Machado R.F.
        Diagnostic and therapeutic algorithm for pulmonary arterial hypertension.
        Pulm Circ. 2011; 1: 122-124
        • Oudiz R.J.
        Classification of pulmonary hypertension.
        Cardiol Clin. 2016; 34: 359-361
        • Maron B.A.
        • Loscalzo J.
        Pulmonary hypertension: pathophysiology and signaling pathways.
        Handb Exp Pharmacol. 2013; 218: 31-58
        • Tuder R.M.
        Pulmonary vascular remodeling in pulmonary hypertension.
        Cell Tissue Res. 2017; 367: 643-649
        • Tuder R.M.
        • Abman S.H.
        • Braun T.
        • et al.
        Development and pathology of pulmonary hypertension.
        J Am Coll Cardiol. 2009; 54: S3-S9
        • Fritz J.S.
        • Smith K.A.
        The pulmonary hypertension consult: clinical and coding considerations.
        Chest. 2016; 150: 705-713
        • McLaughlin V.V.
        • Archer S.L.
        • Badesch D.B.
        • et al.
        ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association.
        J Am Coll Cardiol. 2009; 53: 1573-1619
        • Mehari A.
        • Valle O.
        • Gillum R.F.
        Trends in pulmonary hypertension mortality and morbidity.
        Pulm Med. 2014; 2014: 105864
        • Lazzeroni D.
        • Rimoldi O.
        • Camici P.G.
        From left ventricular hypertrophy to dysfunction and failure.
        Circ J. 2016; 80: 555-564
        • Sowers J.R.
        • Epstein M.
        • Frohlich E.D.
        Diabetes, hypertension, and cardiovascular disease: an update.
        Hypertension. 2001; 37: 1053-1059
        • Tabit C.E.
        • Chung W.B.
        • Hamburg N.M.
        • et al.
        Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications.
        Rev Endocr Metab Disord. 2010; 11: 61-74
        • Baldi J.C.
        • Wilson G.A.
        • Wilson L.C.
        • et al.
        The type 2 diabetic heart: its role in exercise intolerance and the challenge to find effective exercise interventions.
        Sports Med. 2016; 46: 1605-1617
        • Archer S.L.
        Mitochondrial fission and fusion in human diseases.
        N Engl J Med. 2014; 370: 1074
        • Gopal D.M.
        • Santhanakrishnan R.
        • Wang Y.C.
        • et al.
        Impaired right ventricular hemodynamics indicate preclinical pulmonary hypertension in patients with metabolic syndrome.
        J Am Heart Assoc. 2015; 4 (e001597)
        • Grinnan D.
        • Farr G.
        • Fox A.
        • et al.
        The role of hyperglycemia and insulin resistance in the development and progression of pulmonary arterial hypertension.
        J Diabetes Res. 2016; 2016 (e-pub 2016 Jun 8) (2481659)
        • Lai Y.C.
        • Tabima D.M.
        • Dube J.J.
        • et al.
        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. 2016; 133: 717-731
        • Marsboom G.
        • Wietholt C.
        • Haney C.R.
        • et al.
        Lung (1)(8)F-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring of pulmonary arterial hypertension.
        Am J Respir Crit Care Med. 2012; 185: 670-679
        • Pan M.
        • Han Y.
        • Si R.
        • et al.
        Hypoxia-induced pulmonary hypertension in type 2 diabetic mice.
        Pulm Circ. 2017; 7: 175-185
        • Pugh M.E.
        • Robbins I.M.
        • Rice T.W.
        • et al.
        Unrecognized glucose intolerance is common in pulmonary arterial hypertension.
        J Heart Lung Transplant. 2011; 30: 904-911
        • Ryan J.J.
        • Archer S.L.
        Emerging concepts in the molecular basis of pulmonary arterial hypertension: part I: metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension.
        Circulation. 2015; 131: 1691-1702
        • Talati M.
        • Hemnes A.
        Fatty acid metabolism in pulmonary arterial hypertension: role in right ventricular dysfunction and hypertrophy.
        Pulm Circ. 2015; 5: 269-278
        • Benson L.
        • Brittain E.L.
        • Pugh M.E.
        • et al.
        Impact of diabetes on survival and right ventricular compensation in pulmonary arterial hypertension.
        Pulm Circ. 2014; 4: 311-318
        • Tedford R.J.
        • Mudd J.O.
        • Girgis R.E.
        • et al.
        Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension.
        Circ Heart Fail. 2013; 6: 953-963
        • Lang R.M.
        • Badano L.P.
        • Mor-Avi V.
        • et al.
        Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
        Eur Heart J Cardiovasc Imaging. 2015; 16: 233-270
        • R Development Core Team
        R: A Language and Environment for Statistical Computing.
        R Foundation for Statistical Computing, Vienna, Austria2016
        • Wickham H.
        Ggplot2: Elegant Graphics for Data Analysis.
        Springer-Verlag, New York2009
        • Warnes G.R.
        • Bolker B.
        • Gorjanc G.
        • et al.
        Gdata: various R Programming tools for data manipulation.
        (Available at:)
        • Wickham H.
        Reshaping data with the reshape package.
        J Statist Softw. 2007; 21: 1-20
        • Wickham H.
        Gtable: arrange ‘Grobs’ in tables.
        (Available at:)
        • Hlavac M.
        Stargazer: well-formatted regression and summary statistics tables.
        (Available at:)
        • Saouti N.
        • Westerhof N.
        • Postmus P.E.
        • et al.
        The arterial load in pulmonary hypertension.
        Eur Respir Rev. 2010; 19: 197-203
        • Thenappan T.
        • Prins K.W.
        • Pritzker M.R.
        • et al.
        The critical role of pulmonary arterial compliance in pulmonary hypertension.
        Ann Am Thorac Soc. 2016; 13: 276-284
        • Mahapatra S.
        • Nishimura R.A.
        • Sorajja P.
        • et al.
        Relationship of pulmonary arterial capacitance and mortality in idiopathic pulmonary arterial hypertension.
        J Am Coll Cardiol. 2006; 47: 799-803
        • Stevens G.R.
        • Garcia-Alvarez A.
        • Sahni S.
        • et al.
        RV dysfunction in pulmonary hypertension is independently related to pulmonary artery stiffness.
        JACC Cardiovasc Imaging. 2012; 5: 378-387
        • Swift A.J.
        • Capener D.
        • Johns C.
        • et al.
        Magnetic Resonance Imaging in the prognostic evaluation of patients with pulmonary arterial hypertension.
        Am J Respir Crit Care Med. 2017; 196: 228-239
        • Chawla A.
        • Chawla R.
        • Jaggi S.
        Microvasular and macrovascular complications in diabetes mellitus: distinct or continuum?.
        Indian J Endocrinol Metab. 2016; 20: 546-551
        • Tooke J.E.
        Microvascular function in human diabetes. A physiological perspective.
        Diabetes. 1995; 44: 721-726