title: Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction.
abstract: OBJECTIVE
  The purpose of this study was to investigate whether peripheral endothelial dysfunction could predict the occurrence of cardiovascular events in patients with heart failure (HF) with normal left ventricular ejection fraction (HFNEF).
  
  
  BACKGROUND
  Endothelial dysfunction plays an important role in HF, but the relation between peripheral endothelial dysfunction and prognosis in HFNEF remains unknown.
  
  
  METHODS
  We conducted a prospective cohort study of 321 patients with HFNEF. We evaluated cardiac function by echocardiography measuring the ratio of early transmitral flow velocity to tissue Doppler early diastolic mitral annular velocity (E/e'), noninvasively assessed peripheral endothelial function by reactive hyperemia-peripheral arterial tonometry (RH-PAT) as the RH-PAT index (RHI), and followed cardiovascular events.
  
  
  RESULTS
  A total of 59 patients had a cardiovascular event. Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in the low RHI group than in the high RHI group (mean follow-up: 20 months; log-rank test: p < 0.001). Multivariate Cox hazard analysis identified RHI (per 0.1) (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.67 to 0.94; p = 0.007), E/e' (Ln[E/e'] [per 0.1]) (HR: 1.15; 95% CI: 1.04 to 1.26; p = 0.006), and B-type natriuretic peptide (BNP) (Ln[BNP] [per picogram/milliliter]) (HR: 1.81; 95% CI: 1.44 to 2.28; p < 0.001) as independent predictors of cardiovascular events. The C-statistics for cardiovascular events substantially increased when the RHI was added to the HFNEF prognostic 5 factors (PF5)-age, diabetes, New York Heart Association classification, HF hospitalization history, and left ventricular ejection fraction-which were identified in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction Study) (PF5 alone: 0.671; PF5 + RHI: 0.712). The net reclassification index was significant after addition of the RHI (19.0%, p = 0.01).
  
  
  CONCLUSIONS
  Peripheral endothelial dysfunction independently correlated with future cardiovascular events, adding incremental clinical significance for risk stratification in patients with HFNEF. (Endothelial Dysfunction Assessed by Reactive Hyperemia Peripheral Arterial Tonometry and Heart Failure with Preserved Left Ventricular Ejection Fraction; UMIN000002640).
authors.affiliation: Department of Cardiovascular Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Akiyama
authors.forename: Seigo
authors.initials: S
authors.lastname: Sugiyama
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuzawa
authors.forename: Masaaki
authors.initials: M
authors.lastname: Konishi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Nozaki
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ohba
authors.forename: Junichi
authors.initials: J
authors.lastname: Matsubara
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Maeda
authors.forename: Yoko
authors.initials: Y
authors.lastname: Horibata
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Sugamura
authors.forename: Megumi
authors.initials: M
authors.lastname: Yamamuro
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sumida
authors.forename: Koichi
authors.initials: K
authors.lastname: Kaikita
authors.forename: Satomi
authors.initials: S
authors.lastname: Iwashita
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Matsui
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kimura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
authors.forename: Hisao
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D000368:Aged; D015331:Cohort Studies; D004452:Echocardiography / Q000379:methods; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000175:diagnosis* / Q000503:physiopathology*; D006352:Heart Ventricles; D006801:Humans; D008297:Male; D008365:Manometry / Q000379:methods; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012306:Risk; D013318:Stroke Volume