title: Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction.
abstract: BACKGROUND
  Exercise capacity as measured by peak oxygen uptake (Vo2) is similarly impaired in patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). However, characterization of how each component of Vo2 changes in response to incremental exercise in HFpEF versus HFrEF has not been previously defined. We hypothesized that abnormally low peripheral o2 extraction (arterio-mixed venous o2 content difference, [C(a-v)o2]) during exercise significantly contributes to impaired exercise capacity in HFpEF.
  
  
  RESULTS
  We performed maximum incremental cardiopulmonary exercise testing with invasive hemodynamic monitoring on 104 patients with symptomatic NYHA II to IV heart failure (HFpEF, n=48, peak Vo2=13.9±0.5 mL kg(-1) min(-1), mean±SEM, and HFrEF, n=56, peak Vo2=12.1±0.5 mL kg(-1) min(-1)) and 24 control subjects (peak Vo2 27.0±1.7 mL kg(-1) min(-1)). Peak exercise C(a-v)o2 was lower in HFpEF compared with HFrEF (11.5±0.27 versus 13.5±0.34 mL/dL, respectively, P<0.0001), despite no differences in age, hemoglobin level, peak respiratory exchange ratio, Cao2, or cardiac filling pressures. Peak C(a-v)o2 and peak heart rate emerged as the leading predictors of peak Vo2 in HFpEF. Impaired peripheral o2 extraction was the predominant limiting factor to exercise capacity in 40% of patients with HFpEF and was closely related to elevated systemic blood pressure during exercise (r=0.49, P=0.0005).
  
  
  CONCLUSIONS
  In the first study to directly measure C(a-v)o2 throughout exercise in HFpEF, HFrEF, and normals, we found that peak C(a-v)o2 was a major determinant of exercise capacity in HFpEF. The important functional limitation imposed by impaired o2 extraction may reflect intrinsic abnormalities in skeletal muscle or peripheral microvascular function, and represents a potential target for therapeutic intervention.
authors.affiliation: From the Cardiology Division (B.P.D., R.M., R.M.M., A.L.B., R.B.W., N.E.H., A.S.E, G.D.L.) and the Pulmonary and Critical Care Unit (P.P.P., S.S.H., G.D.L.), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Bishnu P
authors.initials: BP
authors.lastname: Dhakal
authors.affiliation: From the Cardiology Division (B.P.D., R.M., R.M.M., A.L.B., R.B.W., N.E.H., A.S.E, G.D.L.) and the Pulmonary and Critical Care Unit (P.P.P., S.S.H., G.D.L.), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Malhotra
authors.affiliation: From the Cardiology Division (B.P.D., R.M., R.M.M., A.L.B., R.B.W., N.E.H., A.S.E, G.D.L.) and the Pulmonary and Critical Care Unit (P.P.P., S.S.H., G.D.L.), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Murphy
authors.affiliation: From the Cardiology Division (B.P.D., R.M., R.M.M., A.L.B., R.B.W., N.E.H., A.S.E, G.D.L.) and the Pulmonary and Critical Care Unit (P.P.P., S.S.H., G.D.L.), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Pappagianopoulos
authors.affiliation: From the Cardiology Division (B.P.D., R.M., R.M.M., A.L.B., R.B.W., N.E.H., A.S.E, G.D.L.) and the Pulmonary and Critical Care Unit (P.P.P., S.S.H., G.D.L.), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Baggish
authors.affiliation: From the Cardiology Division (B.P.D., R.M., R.M.M., A.L.B., R.B.W., N.E.H., A.S.E, G.D.L.) and the Pulmonary and Critical Care Unit (P.P.P., S.S.H., G.D.L.), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Rory B
authors.initials: RB
authors.lastname: Weiner
authors.affiliation: From the Cardiology Division (B.P.D., R.M., R.M.M., A.L.B., R.B.W., N.E.H., A.S.E, G.D.L.) and the Pulmonary and Critical Care Unit (P.P.P., S.S.H., G.D.L.), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Houstis
authors.affiliation: From the Cardiology Division (B.P.D., R.M., R.M.M., A.L.B., R.B.W., N.E.H., A.S.E, G.D.L.) and the Pulmonary and Critical Care Unit (P.P.P., S.S.H., G.D.L.), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Eisman
authors.affiliation: From the Cardiology Division (B.P.D., R.M., R.M.M., A.L.B., R.B.W., N.E.H., A.S.E, G.D.L.) and the Pulmonary and Critical Care Unit (P.P.P., S.S.H., G.D.L.), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Stacyann S
authors.initials: SS
authors.lastname: Hough
authors.affiliation: From the Cardiology Division (B.P.D., R.M., R.M.M., A.L.B., R.B.W., N.E.H., A.S.E, G.D.L.) and the Pulmonary and Critical Care Unit (P.P.P., S.S.H., G.D.L.), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston. glewis@partners.org.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Lewis
mesh_terms: D000368:Aged; D015444:Exercise / Q000502:physiology; D017079:Exercise Tolerance / Q000502:physiology*; D005260:Female; D006333:Heart Failure / Q000503:physiopathology*; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000503:physiopathology; D010101:Oxygen Consumption / Q000502:physiology*; D011659:Pulmonary Gas Exchange / Q000502:physiology; D013318:Stroke Volume / Q000502:physiology
keywords: diastole; exercise; heart failure