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).
 |
Abstract
|
|---|
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 (SI) 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 SI relates to higher mortality, independent of body composition and established prognosticators implicating a pathophysiologic role for SI in CHF. Therapeutically targeting impaired SI 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 (SI) indicates abnormal energy metabolism and is related to decreased exercise capacity and muscle fatigue. The relationship between insulin resistance (i.e., low SI) 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 SI 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 SI 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 SI 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 SI predicted better survival (RR 0.56, 95% CI 0.35 to 0.89; p = 0.015). On stepwise multivariate analysis, SI predicted mortality independently of other variables.
CONCLUSIONS: In patients with CHF, lower SI relates to higher mortality, independent of body composition and established prognosticators. Impaired SI 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 |
|
Chronic heart failure (CHF) is a leading cause of both morbidity and mortality in Western society with increasing prevalence and health care costs. It has been shown that impaired whole-body insulin sensitivity (SI) commonly occurs in CHF, independent of ischemic etiology (1). As part of the metabolic syndrome, insulin resistance is associated with arteriosclerotic cardiovascular disease, including ischemic CHF. It has been shown, however, that also patients with a non-ischemic etiology of CHF have impaired SI (2,3) and the degree of insulin resistance correlates with the degree of heart failure (1). Increasing evidence suggests a relationship between impaired glucose metabolism and CHF. Diabetes mellitus has been shown to be a predisposing factor for development of CHF (4,5). In the Studies Of Left Ventricular Dysfunction (SOLVD), diabetes was an independent predictor of mortality and morbidity in CHF patients (6). In large heart failure trials, diabetes mellitus has a prevalence of 20% to 25% (7–10). The clinical significance of insulin resistance in CHF is not known. However, insulin resistance may occur prior to type 2 diabetes mellitus being diagnosed, so the prevalence of insulin resistance is likely much higher. If insulin resistance is pathophysiologically linked with CHF and progresses in parallel with the degree of CHF (1,11), one could hypothesize insulin resistance to be a prognostic factor.
The aim of present study was to investigate in a cohort of patients with CHF whether the presence of insulin resistance in CHF is an independent risk factor for impaired prognosis. Regional fat and lean tissue composition (important factors in insulin resistance) were also measured.
|
Methods
|
|---|
Study population.
We prospectively studied 105 male CHF patients with ischemic (63%) or non-ischemic (37%) etiology between May 1993 and February 2001. The diagnosis of CHF was based on clinical evidence of heart failure with shortness of breath, symptomatic exercise limitation, and peripheral edema with a disease history of at least six months. In all patients, evidence of left ventricular functional impairment by radionuclide ventriculography and/or echocardiography was present. All patients were treated as clinically indicated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists (85%), diuretics (87%), beta-blockers (20%), digitalis (33%), or aspirin and/or warfarin (75%). Patients were clinically stable at the time of SI assessment, with no clinical evidence of decompensated heart failure, such as raised jugular venous pressure, ascites, or hepatomegaly. At the time of the study, none of the patients were diagnosed with diabetes (according to World Health Organization criteria) or had antidiabetic treatment. Female patients were excluded from the study to prevent influences from gender and related factors such as hormone replacement therapy.
All patients gave written, informed consent, and the study was approved by our local ethics committees.
Assessment of SI.
All participants underwent intravenous glucose tolerance testing (ivGTT), as previously described (12). The ivGTT was performed under standardized conditions in a metabolic day ward starting in the morning between 8:00 AM and 9:00 AM following overnight fasting after at least 20 min of supine rest. A glucose bolus (50% solution) was administered intravenously at a dose of 0.5 g/kg body weight. All blood samples were immediately processed and stored at –80°C until analysis of glucose and insulin. From the glucose and insulin dynamic profiles, the SI index was calculated using the minimal model approach according to Bergman et al. (13). The relatively high glucose dose (0.5 vs. 0.3 g/kg) we use enables evaluation of SI by the minimal model, without the need for augmentation of plasma insulin concentrations by tolbutamide or insulin injection. We have validated SI estimates derived using this approach in patients with CHF against the euglycemic clamp reference method (14). Insulin sensitivity—the inverse of insulin resistance—is defined as the fraction of the glucose distribution space cleared per minute by insulin-dependent glucose disposal relative to the concentration of insulin and is expressed in min–1·µU·ml–1·104. Insulin concentrations during ivGTT were expressed as the incremental area under the concentration profile, calculated using the trapezium rule.
Body composition.
In all subjects, body mass index (BMI) was calculated as the ratio of weight (kg) and squared height (m2). For body composition assessment, dual-energy X-ray absorptiometry (DEXA) was performed in 89 of the patients by using a Lunar DPX (Lunar Corp., Madison, Wisconsin). Total body scans were analyzed to obtain total and regional (legs, arms, and trunk) measurements of fat and lean tissue. Precision of total and regional assessments was <2% for lean tissue and <5% for fat tissue (15). Fat mass of the trunk, termed as "central fat mass," includes both visceral and subcutaneous fat of this anatomic region. The sum of fat mass of the legs and arms was termed as "peripheral fat mass." The distribution of fat mass was calculated as the ratio of central fat mass/peripheral fat mass.
Exercise test and follow-up.
A maximal cardiopulmonary treadmill exercise test was performed for clinical characterization (modified Bruce protocol), using a respiratory mass spectrometer (Amis 2000, Odense, Denmark) and a standard inert gas dilution technique for assessment of peak oxygen uptake (VO2), as described previously (16).
All patients received follow-up by the Royal Brompton Hospital Heart Failure and Cardiomyopathy Clinic. Follow-up was by outpatient assessment and from information obtained by the Office of National Statistics, where all patients had been flagged for death. No patient was lost during follow-up.
Statistical analyses.
All results are presented as the mean value ± SEM. The unpaired Student t test was used to compare mean values between groups. Distributions for biochemical variables were evaluated for normality using the Kolmogorov-Smirnov test, and logarithmic transformation was applied where necessary to allow a parametric statistical approach. Insulin sensitivity was square-root transformed in accordance with our previous analysis of the distribution characteristics of model-derived variables (17). A probability value of <0.05 was considered statistically significant. Cox proportional hazards analysis was employed to assess the association of variables to survival. Stepwise multivariate analysis was performed with all parameters that had a p  0.1 in the univariate analysis. The risk ratio (RR) and 95% confidence interval (CI) for risk factors are given. A commercially available statistical software program was used (StatView version 4.5, Abacus Concepts Inc., Berkeley, California).
|
Results
|
|---|
Patient characteristics and follow-up.
We studied a total of 105 CHF patients. Patient characteristics at baseline are given in Table 1. The mean follow-up period in these patients was 44 ± 4 months. During this period, 53 patients (50%) died after 4 to 3,319 days (mean 775 ± 106 days, median 527 days). The mean follow-up period of the 52 survivors was 1,905 ± 153 days (range 396 to 3,719 days, median 1,474 days). The cumulative mortality of the patients was 22% at 12 months (95% CI 14% to 30%), 28% at 24 months (95% CI 19% to 36%), and 40% at 36 months (95% CI 30% to 50%).
View this table:
[in this window]
[in a new window]
|
Table 1. Clinical and Anthropometric Characteristics of 105 Patients With Chronic Heart Failure and Group Comparison Between Patients Who Died During the Follow-Up Period and Those Who Were Alive at the End of the Follow-Up Period
|
|
Patients who died during follow-up had a similar age, BMI, and left ventricular ejection fraction (LVEF) compared with patients who did not die. Patients who died had a smaller regional lean tissue mass at the arms and legs and a trend toward lower total fat mass. These patients had also a higher mean NYHA functional class (+0.5) and lower peak VO2 (–21%, both p = 0.004). Insulin sensitivity was lower in these patients compared with the surviving patients (–42%, p = 0.002). Detailed clinical and body composition characteristics of both groups are shown in Table 1.
In all patients, mean SI was 2.53 ± 0.26 min–1·µU·ml–1·104. According to median SI (1.82 min–1·µU·ml–1·104), we dichotomized the CHF patients into two subgroups. Patients with SI below the median value (n = 52) had a mean SI of 0.95 ± 0.07 min–1·µU·ml–1·104), and patients with SI above the median value (n = 53) had a mean SI of 4.08 ± 0.40 min–1·µU·ml–1·104. The main characteristics of both groups are shown in Table 2. Both subgroups were similar in terms of age and NYHA functional class and parameters of body composition (all p > 0.2, except for arm lean tissue [p = 0.08] and BMI [p = 0.06]), but patients with SI above the median value had a higher LVEF (p = 0.02) and peak VO2 (p = 0.03).
View this table:
[in this window]
[in a new window]
|
Table 2. Group Comparison Between Patients With Chronic Heart Failure Above and Below the Median Insulin Sensitivity Value (1.82 min–1·µU·ml–1·104)
|
|
A comparison of SI between NYHA functional classes in CHF patients and healthy control subjects is shown in Figure 1. Control values were obtained from healthy subjects (mean age 54.6 years [range 32 to 74 years]) who voluntarily underwent metabolic assessment in our research unit. There was a stepwise decrease of SI across NYHA functional classes, with the lowest values in class IV (p = 0.0007 by analysis of variance). In regression analysis, SI correlated with LVEF (r = 0.36), peak VO2 (r = 0.23), BMI (r = –0.22), and total (r = –0.23) and regional fat mass (r = –0.27; all p < 0.05). No correlation was found for SI versus age, mean arterial pressure, lean tissue mass, serum cholesterol, creatinine, uric acid, or hemoglobin (all p > 0.25).
View larger version (23K):
[in this window]
[in a new window]
|
Figure 1 Insulin sensitivity in patients with chronic heart failure according to New York Heart Association (NYHA) functional class, as compared with healthy control subjects. Box plot displaying the 10th, 25th, 50th, 75th, and 90th percentiles. The p values for the Fisher post-hoc test of mean square-root transformed insulin sensitivity. *p < 0.05 and **p < 0.005 vs. controls.
|
|
Insulin sensitivity was not significantly different between patients treated with beta-blockers and those without (p = 0.13). Similarly, no difference was found for SI between patients with and without ACE inhibitor (p = 0.38) and diuretic treatment (p = 0.49).
Predictors of mortality.
In univariate Cox proportional hazard analysis, a higher SI as a continuous variable significantly predicted lower mortality (RR 0.56, 95% CI 0.35 to 0.89; p = 0.015). Fasting glucose and insulin levels and incremental insulin area did not significantly predict mortality (all p > 0.3). Low SI also predicted impaired survival after adjustment for parameters of body composition, such as BMI, total amount of fat tissue, and regional fat distribution (p < 0.01; data not shown). When adjusted for the use of beta-blockers, ACE inhibitors, and diuretics, SI remained a significant predictor of mortality (p = 0.0080), with only diuretic treatment significantly contributing to prognosis (p = 0.018 vs. p > 0.3 for ACE inhibitors and beta-blockers). In addition, age, NYHA functional class, and peak VO2 as a continuous variable and as a dichotomized variable (peak VO2 <14 ml/kg/min), serum uric acid (all p < 0.01), hemoglobin (p = 0.018), fat tissue mass, and lean tissue mass (both p < 0.05) predicted mortality, but LVEF, BMI, and cholesterol did not (Table 3).
In multivariate analysis including SI and clinical parameters (age, NYHA functional class, peak VO2, mean arterial pressure, uric acid, hemoglobin, cholesterol, sodium, creatinine, total fat tissue mass, lean tissue mass, and diuretic treatment), SI remained a significant prognosticator, independent of all other parameters (RR 0.30, 95% CI 0.14 to 0.63; p = 0.0016). In stepwise Cox proportional hazards analysis in three multivariate cumulative models, SI was an independent predictor of impaired survival (Table 4). The year of recruitment did not contribute to prediction of survival in either univariate or multivariate analyses (data not shown).
By analyzing SI as a dichotomized variable, it was found that patients with SI above the median value had better survival than did patients with SI below the median value (RR 0.38, 95% CI 0.21 to 0.67; p = 0.001). At two years, survival of patients with SI above the median was 83% (range 73% to 93%), but in patients with SI below the median, it was 61% (range 47% to 74%). At three years, survival was 76% (range 64% to 88%) and 44% (range 30% to 58%), and at four years, survival was 73% (range 60% to 85%) and 37% (range 23% to 51%), respectively (Fig. 2). For illustrative purposes, the prognostic significance of the combination of SI and peak VO2 used as dichotomized variables in a two-risk factor model is shown in Figure 3.
View larger version (18K):
[in this window]
[in a new window]
|
Figure 2 Survival in stable, ambulatory chronic heart failure patients (n = 105), classified according to the degree of impairment of insulin sensitivity (SI) (i.e., above [n = 53] or below [n = 52] median SI of 1.82 min–1·µU·ml–1·104). Kaplan-Meier survival curve for four-year survival.
|
|
View larger version (22K):
[in this window]
[in a new window]
|
Figure 3 Survival in stable, ambulatory chronic heart failure patients in a two-risk factor model using insulin sensitivity (SI) and peak oxygen uptake (VO2) as dichotomized variables: interaction of impaired SI (below median of 1.82 min–1·µU·ml–1·104), with the presence of low peak VO2 (peak VO2 <14 ml/kg/min) (patients with no risk factor: n = 41, 6 deaths; one risk factor: n = 44, 23 deaths; two risk factors: n = 20, 15 deaths). Kaplan-Meier survival curve for four-year survival.
|
|
|
Discussion
|
|---|
This study shows that impaired SI in patients with CHF is independently associated with impaired prognosis. Insulin resistance provides additional prognostic information independent of well-established prognosticators, such as clinical status, age, LVEF, and exercise capacity, as well as body composition measures. It has previously been shown from our group (3) and others (2) that insulin resistance occurs in CHF independent of ischemic etiology and is associated with the severity of CHF in terms of reduced peak VO2 (1), NYHA functional class, or the 6-min walk test (11). In the present study, SI decreases in parallel with the severity of CHF, as indicated by a stepwise reduction with higher NYHA functional classes.
Insulin resistance is a key precursor and feature of type 2 diabetes. Therefore, information on type 2 diabetes and CHF may provide indirect information on the clinical significance of insulin resistance in CHF (although insulin deficiency may also be a factor in any association between type 2 diabetes and CHF). Diabetes mellitus is a major co-morbidity in patients with CHF, with a prevalence of 20% to 25% (7–10). The Framingham study was the first to show that diabetes mellitus is an independent risk factor for heart failure with a 2.4 times higher risk in men and a 5.1 times higher risk in women, as compared with those without diabetes (18). In more recent, large epidemiologic studies, this association has been confirmed (4,5). In CHF, diabetes independently predicts all-cause mortality in both symptomatic and asymptomatic heart failure patients (RR 1.29, p < 0.002), as well as hospitalization due to CHF (RR 1.52, p < 0.001) (6). A reciprocal relationship emerges between CHF and type 2 diabetes that suggests impaired SI being a significant pathophysiologic factor in the metabolic imbalance of the heart failure syndrome. Notably, type 2 diabetes mellitus is only the late consequence of insulin resistance, with the latter preceding frank diabetes for years if not decades (19). The prevalence of diabetes mellitus in CHF, therefore, provides only a minimum indicator of the true prevalence of insulin resistance in these patients. Accordingly, an analysis from the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study has shown that, based on fasting blood glucose criteria, 43% of patients had abnormal glucose metabolism (11).
The present study is in line with previous data by Paolisso et al. (20), who observed impaired SI as a prognostic marker in CHF. However, in their study, Paolisso at al. (20) excluded about 50% of deaths from their mortality analysis as non-cardiac events. This might have had the effect of underestimating true mortality in their cohort. Moreover, patients with BMI >28 kg/m2 were excluded from this study, which may restrict applicability for the general CHF population (21).
Impaired SI is commonly known to relate to increased BMI, as obesity is a common confounder of type 2 diabetes. Accordingly, we found a correlation between SI and BMI and fat tissue mass. In our study, however, CHF patients with lower versus higher SI were not significantly different in terms of body composition. Moreover, when comparing the patients who died with those who were alive at the end of the follow-up period, SI was 42% lower in the patients who died. These patients were not heavier than the patients who survived, neither did they have more fat or lean tissue. In fact, the surviving patients (i.e., those with a greater SI) had a tendency toward a higher fat tissue mass. This is consistent with a previous observation of high BMI being a survival advantage in CHF (22,23). In our study, low SI predicted impaired survival independent of parameters of body composition, such as weight, BMI, and total and regional fat, as well as lean tissue mass. This is in contrast to the expected association between insulin metabolism and body composition (see above). In CHF patients, impaired SI is not merely a function of adiposity and may indeed have implications in the pathophysiology of CHF disease progression. Our study confirms and extends previous data showing that the abnormalities in SI in CHF may occur secondary to heart failure itself (1). Our data also suggest that in CHF, factors causing impaired balance between metabolic pathways and body composition might supersede the physiologic feedback regulation between the aforementioned factors.
To establish the underlying mechanism(s) of insulin resistance in these patients is beyond the scope of this study. Likely, a number of factors, exerting a combined effect, may have contributed, such as reduced peripheral tissue perfusion, impaired oxidative metabolism, lower GLUT4 transport protein amount in skeletal muscle (24), and increased neuroendocrine and immune activation (20). Moreover, changes in diet and reduced physical exercise may be discussed. Beta-blocker treatment has previously been reported to worsen metabolic control, but recent evidence suggests a beneficial effect of carvedilol on SI in hypertensive type 2 diabetics (25). Data on the metabolic effects of carvedilol in CHF are, however, inconclusive, as studies with no effect on glucose utilization in CHF have been reported (26,27). In our study population, SI was not dependent on treatment with beta-blockers, diuretics, or ACE inhibitors. When adjusting the Cox model for treatment, SI remained a significant predictor of mortality. The use of beta-blockers in the present study was low, however, and more work is needed to evaluate the effect of medications such as carvedilol on SI in CHF. Although medical treatment standards have advanced during the prolonged recruitment period, the predictive value of SI on survival was not altered when adjusted for the year of recruitment. Whether more complete adherence to modern treatment standards may improve SI in CHF needs to be tested in the future. Insulin sensitivity is not commonly assessed in patients with CHF during the routine clinical outpatient follow-up and is recognized only when overt diabetes mellitus is diagnosed. The aim of the present study has not been to establish SI assessment by minimal modeling as another marker for prognostic evaluation in CHF, but to emphasize the importance of metabolic derangement contributing to CHF pathophysiology, which only recently has been gathering growing attention. The time-consuming assessment of SI by ivGTT may render this method unsuitable to large epidemiologic studies. Simple and easier to apply estimates of SI such as homeostasis model assessment (using a single time point assessment) may provide a reasonable estimate in large-scale studies. In the setting of smaller epidemiologic evaluations such as the current study, however, the dynamic assessment of SI within the physiologic range of glucose metabolism may provide a more thorough estimate of pathophysiologic processes.
From the present data, it seems promising to test in future studies whether early detection and therapeutic targeting of insulin resistance in CHF may improve the outcome in these patients. This is indirectly supported from data from long-term exercise studies that show a reduction of mortality in CHF (28,29). Arguably, the well-known beneficial effect of physical exercise on SI (30) may be involved in the physiologic mechanisms that underlie the beneficial effects of exercise in CHF patients. Whether drug therapy aimed at improved SI may have a comparable beneficial effect is not known. Thiazolidinediones are selective agonists of peroxisome proliferator-activated receptor-gamma modulating, on a transcriptional level, the insulin-mediated glucose utilization by the skeletal muscle. Insulin sensitizers are, however, controversial in patients with CHF, as they increase fluid retention and may contribute to increased edema in CHF. Interventional studies designed to test whether targeting impaired SI may be beneficial in patients with CHF are required but need to be done carefully and with great attention to potential adverse effects.
|
Footnotes
|
|---|
This work was supported by a grant from the Clinical Research Council of the Royal Brompton Hospital in London. Dr. Doehner was supported by the "Verein der Freunde und Förderer der Berliner Charité," Germany, and the National Heart and Lung Institute in London. Dr. Godsland is supported by the Heart Disease and Diabetes Research Trust. Dr. Anker is supported by a Vandervell Fellowship and a donation from Dr. Hubert Bailey. The Division of Applied Cachexia Research is supported by a grant from the Charité Medical School.
|
References
|
|---|
1. Swan JW, Anker SD, Walton C, et al. Insulin resistance in chronic heart failurerelation to severity and etiology of heart failure. J Am Coll Cardiol 1997;30:527-532.[Abstract]
2. Paolisso G, De Riu S, Marrazzo G, Verza M, Varricchio M, D’Onofrio F. Insulin resistance and hyperinsulinemia in patients with chronic congestive heart failure Metabolism 1991;40:972-977.[CrossRef][Web of Science][Medline]
3. Swan JW, Walton C, Godsland IF, Clark AL, Coats AJS, Oliver MF. Insulin resistance in chronic heart failure Eur Heart J 1994;15:1528-1532.[Abstract/Free Full Text]
4. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in U.S. men and womenNHANES I epidemiologic follow-up study. Arch Intern Med 2001;161:996-1002.[Abstract/Free Full Text]
5. Iribarren C, Karter AJ, Go AS, et al. Glycemic control and heart failure among adult patients with diabetes Circulation 2001;103:2668-2673.[Abstract/Free Full Text]
6. Shindler DM, Kostis JB, Yusuf S, et al. Diabetes mellitus, a predictor of morbidity and mortality in the Studies Of Left Ventricular Dysfunction (SOLVD) trials and registry Am J Cardiol 1996;77:1017-1020.[CrossRef][Web of Science][Medline]
7. The CONSENSUS Trial Study Group Effects of enalapril on mortality in severe congestive heart failureresults of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-1435.[Abstract]
8. The SOLVD Investigators Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure N Engl J Med 1991;325:293-302.[Abstract]
9. Packer M, Poole-Wilson PA, Armstrong PW, et al. ATLAS Study Group Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure Circulation 1999;100:2312-2318.[Abstract/Free Full Text]
10. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure N Engl J Med 1991;325:303-310.[Abstract]
11. Suskin N, McKelvie RS, Burns RJ, et al. Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure Eur Heart J 2000;21:1368-1375.[Abstract/Free Full Text]
12. Doehner W, Pflaum CD, Rauchhaus M, et al. Leptin, insulin sensitivity and growth hormone binding protein in chronic heart failure with and without cardiac cachexia Eur J Endocrinol 2001;145:727-735.[Abstract]
13. Bergman RN, Ider YZ, Bowden CR, Cobelli C. Quantitative estimation of insulin sensitivity Am J Physiol 1979;236:E667-E677.
14. Swan JW, Walton C, Godsland IF. Assessment of insulin sensitivity in mana comparison of minimal model and euglycaemic clamp derived measures in health and heart failure. Clin Sci 1994;86:317-322.[Medline]
15. Anker SD, Ponikowski PP, Clark AL, et al. Cytokines and neurohormones relating to body composition alterations in the wasting syndrome of chronic heart failure Eur Heart J 1999;20:683-693.[Abstract/Free Full Text]
16. Anker SD, Swan JW, Volterrani M, et al. The influence of muscle mass, strength, fatigability and blood flow on exercise capacity in cachectic and non-cachectic patients with chronic heart failure Eur Heart J 1997;18:259-269.[Abstract/Free Full Text]
17. Walton C, Godsland IF, Proudler AJ, Felton C, Wynn V. Evaluation of four mathematical models of glucose and insulin dynamics with analysis of effects of age and obesity Am J Physiol 1992;262:E755-E762.
18. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failurethe Framingham study. Am J Cardiol 1974;34:29-34.[CrossRef][Web of Science][Medline]
19. Beck-Nielsen H, Groop LC. Metabolic and genetic characterization of prediabetic statessequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 1994;94:1714-1721.[Web of Science][Medline]
20. Paolisso G, Tagliamonte MR, Rizzo MR, et al. Prognostic importance of insulin-mediated glucose uptake in aged patients with congestive heart failure secondary to mitral and/or aortic valve disease Am J Cardiol 1999;83:1338-1344.[CrossRef][Web of Science][Medline]
21. Doehner W, Anker SD. Insulin-mediated glucose uptake in congestive heart failure Am J Cardiol 1999;84:761-762.[CrossRef][Web of Science][Medline]
22. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Woo MA, Tillisch JH. The relationship between obesity and mortality in patients with heart failure J Am Coll Cardiol 2001;38:789-795.[Abstract/Free Full Text]
23. Davos CH, Doehner W, Rauchhaus M, et al. Body mass and survival in patients with chronic heart failure without cachexiathe importance of obesity. J Card Fail 2003;9:29-35.[CrossRef][Web of Science][Medline]
24. Doehner W, Gathercole DV, Cicoira M, et al. Glucose transport protein GLUT4 levels in skeletal muscle and its relationship to insulin resistance in chronic heart failure(abstr) Circulation 2002;101(Suppl II):II569.
25. Bakris GL, Fonseca V, Katholi RE, et al. GEMINI Investigators Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertensiona randomized controlled trial. JAMA 2004;292:2227-2236.[Abstract/Free Full Text]
26. Bottcher M, Refsgaard J, Gotzsche O, Andreasen F, Nielsen TT. Effect of carvedilol on microcirculatory and glucose metabolic regulation in patients with congestive heart failure secondary to ischemic cardiomyopathy Am J Cardiol 2002;89:1388-1393.[CrossRef][Web of Science][Medline]
27. Wallhaus TR, Taylor M, DeGrado TR, et al. Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure Circulation 2001;103:2441-2446.[Abstract/Free Full Text]
28. Belardinelli R, Georgiou D, Cianci G, Purcaro A. Randomized, controlled trial of long-term moderate exercise training in chronic heart failureeffects on functional capacity, quality of life, and clinical outcome. Circulation 1999;99:1173-1182.[Abstract/Free Full Text]
29. Piepoli MF, Davos C, Francis DP, Coats AJ, ExTraMATCH Collaborative Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH) BMJ 2004;328:189-196.[Abstract/Free Full Text]
30. Lund S, Holman GD, Schmitz O, Pedersen O. Contraction stimulates translocation of glucose transporter GLUT4 in skeletal muscle through a mechanism distinct from that of insulin Proc Natl Acad Sci U S A 1995;92:5817-5821.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
L. Sacca
Heart Failure as a Multiple Hormonal Deficiency Syndrome
Circ Heart Fail,
March 1, 2009;
2(2):
151 - 156.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Fazakerley, S. P. Lawrence, V. A. Lizunov, S. W. Cushman, and G. D. Holman
A common trafficking route for GLUT4 in cardiomyocytes in response to insulin, contraction and energy-status signalling
J. Cell Sci.,
March 1, 2009;
122(5):
727 - 734.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. T.F. Facundo and S. P. Jones
AMP-Dependent Protein Kinase Activators: Not Just for Diabetes?
Circ. Res.,
February 13, 2009;
104(3):
282 - 284.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. T. Zamanian, G. Hansmann, S. Snook, D. Lilienfeld, K. M. Rappaport, G. M. Reaven, M. Rabinovitch, and R. L. Doyle
Insulin resistance in pulmonary arterial hypertension
Eur. Respir. J.,
February 1, 2009;
33(2):
318 - 324.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Tuunanen, E. Engblom, A. Naum, K. Nagren, M. Scheinin, B. Hesse, K.E. Juhani Airaksinen, P. Nuutila, P. Iozzo, H. Ukkonen, et al.
Trimetazidine, a Metabolic Modulator, Has Cardiac and Extracardiac Benefits in Idiopathic Dilated Cardiomyopathy
Circulation,
September 16, 2008;
118(12):
1250 - 1258.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Doehner, S. von Haehling, and S. D. Anker
Insulin resistance in chronic heart failure.
J. Am. Coll. Cardiol.,
July 15, 2008;
52(3):
239 - 239.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. R. MacDonald, M. C. Petrie, N. M. Hawkins, J. R. Petrie, M. Fisher, R. McKelvie, D. Aguilar, H. Krum, and J. J.V. McMurray
Diabetes, left ventricular systolic dysfunction, and chronic heart failure
Eur. Heart J.,
May 2, 2008;
29(10):
1224 - 1240.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C Berry, M Brett, K Stevenson, J J V McMurray, and J Norrie
Nature and prognostic importance of abnormal glucose tolerance and diabetes in acute heart failure
Heart,
March 1, 2008;
94(3):
296 - 304.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. V. Leier and G. J. Haas
Diabetes and Heart Failure: The Role of Thiazolidinediones in Managing These Partners in Crime
J. Am. Coll. Cardiol.,
July 3, 2007;
50(1):
37 - 39.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. von Haehling, W. Doehner, and S. D Anker
Nutrition, metabolism, and the complex pathophysiology of cachexia in chronic heart failure
Cardiovasc Res,
January 15, 2007;
73(2):
298 - 309.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Lainscak, W. Doehner, and S. D. Anker
Metabolic disturbances in chronic heart failure: A case for the "macho" approach with testosterone?!
Eur J Heart Fail,
January 1, 2007;
9(1):
2 - 3.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. J. Malkin, T. H. Jones, and K. S. Channer
The effect of testosterone on insulin sensitivity in men with heart failure
Eur J Heart Fail,
January 1, 2007;
9(1):
44 - 50.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. Horowitz and J. A. Kennedy
Time to Address the Cardiac Metabolic "Triple Whammy": Ischemic Heart Failure in Diabetic Patients
J. Am. Coll. Cardiol.,
December 5, 2006;
48(11):
2232 - 2234.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Karhausen, M. Stockburger, W. Doehner, and S. D. Anker
Questions in Cardiac Resynchronization Therapy: Metabolic Implications
J. Am. Coll. Cardiol.,
August 1, 2006;
48(3):
591 - 592.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Murray, C. A. Lygate, M. A. Cole, C. A. Carr, G. K. Radda, S. Neubauer, and K. Clarke
Insulin resistance, abnormal energy metabolism and increased ischemic damage in the chronically infarcted rat heart
Cardiovasc Res,
July 1, 2006;
71(1):
149 - 157.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. von Haehling, W. Doehner, and S. D. Anker
Obesity and the Heart: A Weighty Issue
J. Am. Coll. Cardiol.,
June 6, 2006;
47(11):
2274 - 2276.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Yang and G. D. Holman
Long-Term Metformin Treatment Stimulates Cardiomyocyte Glucose Transport through an AMP-Activated Protein Kinase-Dependent Reduction in GLUT4 Endocytosis
Endocrinology,
June 1, 2006;
147(6):
2728 - 2736.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Liao, S. Takashima, H. Zhao, Y. Asano, Y. Shintani, T. Minamino, J. Kim, M. Fujita, M. Hori, and M. Kitakaze
Control of plasma glucose with alpha-glucosidase inhibitor attenuates oxidative stress and slows the progression of heart failure in mice
Cardiovasc Res,
April 1, 2006;
70(1):
107 - 116.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Butler
More Risk Factors Affecting Heart Failure Outcomes!: Time for Hope or Despair?
J. Am. Coll. Cardiol.,
September 20, 2005;
46(6):
1027 - 1028.
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods