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CLINICAL RESEARCH: HEART FAILURE AND CARDIAC TRANSPLANT

Impaired Insulin Sensitivity as an Independent Risk Factor for Mortality in Patients With Stable Chronic Heart Failure

Wolfram Doehner, MD, PhD^_*,,_*, Mathias Rauchhaus, MD, PhD, Piotr Ponikowski, MD, PhD, Ian F. Godsland, PhD, Stephan von Haehling, MD^_*,,,, Darlington O. Okonko, BSc^_*, Francisco Leyva, MD^_*,, Anthony J. Proudler, PhD, Andrew J.S. Coats, DM^|| and Stefan D. Anker, MD, PhD^_*,

^_* Department of Clinical Cardiology, National Heart and Lung Institute, Imperial College, London, United Kingdom
Division of Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Klinikum, Berlin, Germany
Cardiology Department, Clinical Military Hospital, Wroclaw, Poland
Wynn Department of Metabolic Medicine, Division of Medicine, Imperial College, London, United Kingdom
^|| Faculty of Medicine, University of Sydney, Sydney, Australia.

Manuscript received December 1, 2004; revised manuscript received February 9, 2005, accepted February 14, 2005.

^_* Reprint requests and correspondence: Dr. Wolfram Doehner, Division of Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. (Email: wolfram.doehner{at}charite.de).

Impaired Insulin Sensitivity as an Independent Risk Factor for Mortality in Patients With Stable Chronic Heart Failure

Wolfram Doehner, Mathias Rauchhaus, Piotr Ponikowski, Ian F. Godsland, Stephan von Haehling, Darlington O. Okonko, Francisco Leyva, Anthony J. Proudler, Andrew J. S. Coats, Stefan D. Anker

In chronic hart failure (CHF), impaired insulin sensitivity (S_I) indicates abnormal energy metabolism and is related to decreased exercise capacity and muscle fatigue. The relationship between insulin resistance and survival in CHF has not been established. We prospectively studied 105 male patients with CHF during a mean follow-up period of 44 ± 4 months. Lower S_I relates to higher mortality, independent of body composition and established prognosticators implicating a pathophysiologic role for S_I in CHF. Therapeutically targeting impaired S_I may potentially be beneficial in patients with CHF.

OBJECTIVES: The aim of this study was to determine the significance of insulin resistance as an independent risk factor for impaired prognosis in patients with chronic heart failure (CHF).

BACKGROUND: In CHF, impaired insulin sensitivity (S_I) indicates abnormal energy metabolism and is related to decreased exercise capacity and muscle fatigue. The relationship between insulin resistance (i.e., low S_I) and survival in patients with CHF has not been established.

METHODS: We prospectively studied 105 male patients with CHF due to ischemic (63%) or non-ischemic (37%) etiology. All patients were in clinically stable condition (age 62 ± 1 year, New York Heart Association [NYHA] functional class 2.6 ± 0.1, left ventricular ejection fraction [LVEF] 28 ± 2%, peak oxygen uptake [VO₂] 18.2 ± 0.7 ml/kg/min). Insulin sensitivity was assessed from glucose and insulin dynamic profiles during an intravenous glucose tolerance test using the minimal model technique.

RESULTS: During a mean follow-up period of 44 ± 4 months, 53 patients (50%) died. Patients with S_I below the median value (median: 1.82 min^–1·µU·ml^–1·10⁴; n = 52) had worse survival (at two years 61% [range 47% to 74%]) than patients with S_I above the median value (n = 53; at two years 83% [range 73% to 93%]; risk ratio [RR] 0.38, 95% confidence interval [CI] 0.21 to 0.67; p = 0.001). Both patient groups were similar in terms of age, NYHA functional class, and body composition parameters (dual-energy X-ray absorptiometric scan; p > 0.2), but patients with a lower S_I had a lower LVEF (24 ± 2% vs. 33 ± 3%) and peak VO₂ (16.8 ± 1.0 ml/kg/min vs. 19.7 ± 1.0 ml/kg/min; both p < 0.05). On univariate Cox analysis, higher S_I predicted better survival (RR 0.56, 95% CI 0.35 to 0.89; p = 0.015). On stepwise multivariate analysis, S_I predicted mortality independently of other variables.

CONCLUSIONS: In patients with CHF, lower S_I relates to higher mortality, independent of body composition and established prognosticators. Impaired S_I may have implications in the pathophysiology of CHF disease progression. Therapeutically targeting impaired insulin sensitivity may potentially be beneficial in patients with CHF.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   BMI = body mass index   CHF = chronic heart failure   CI = confidence interval   DEXA = dual-energy X-ray absorptiometry   ivGTT = intravenous glucose tolerance test   LVEF = left ventricular ejection fraction   NYHA = New York Heart Association   RR = risk ratio   SI = insulin sensitivity   VO2 = oxygen uptake

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