doi: 10.1161/CIRCULATIONAHA.106.685214
(Circulation. 2007;115:1334-1335.)
© 2007 American Heart Association, Inc.
Editorial |
Dysglycemia and Heart Failure Hospitalization
What Is the Link?
From the Department of Cardiology, Glasgow Royal Infirmary (M.P.), and Department of Cardiology, Western Infirmary (J.J.V.M.), Glasgow, UK.
Correspondence to Professor John J.V. McMurray, Department of Cardiology, Western Infirmary, Glasgow, G11 6NT. E-mail j.mcmurray{at}bio.gla.ac.uk
Key Words: Editorials • diabetes mellitus • glucose • heart failure • risk factors
Large epidemiological studies, including the Framingham Heart Study, the National Health and Nutrition Examination Survey, and the Cardiovascular Health Study, have shown that diabetes mellitus is an independent risk factor for the development of heart failure.1–3 Overall, the risk is approximately doubled, but the relative increase may be greater in younger compared with older individuals (and in younger women compared with younger men).1–9 In diabetic individuals, the risk of developing heart failure is greatest in those with an elevated body mass index, poor glycemic control (as indicated by hemoglobin A1c level), nephropathy, retinopathy, and coronary heart disease.1–9
Article p 1371
In this issue of Circulation, Held and colleagues10 have shown that the association between dysglycemia and heart failure extends beyond diabetes mellitus. In a clinical trial cohort of 31 546 subjects with arterial disease, diabetes with end-organ damage, or both who were followed up for a mean of 2.4 years, these investigators found that elevated fasting plasma glucose was an independent predictor of hospitalization for heart failure even in nondiabetic individuals (but unfortunately did not report other cardiovascular outcomes for comparison). These observations support 2 earlier studies. In an investigation of 20 810 nondiabetic patients receiving care in Veterans Affairs medical centers, Nielson and Lange11 found that higher morning glucose was independently associated with a linear increase in risk of incident heart failure (clinic diagnosis or admission). Ingelsson and colleagues,12 in a study of 1187 Swedish men 
70 years of age, showed that 2-hour glucose during an oral glucose tolerance test (as well as fasting serum proinsulin concentration and clamp glucose disposal rate) was independently related to incident heart failure hospitalization.
These studies raise many questions. None describe the potential role of intercurrent events such as acute coronary syndromes (or even change in blood pressure) in explaining subsequent hospitalization for heart failure.13 Clearly, dysglycemia often is associated with a diffuse and aggressive form of coronary artery disease, which, in turn, could lead to myocardial injury and failure. Another potentially confounding issue is the known high prevalence of dysglycemia in patients with heart failure and even asymptomatic left ventricular systolic dysfunction (which was not an exclusion criterion in the present study).14 This issue raises the question of whether dysglycemia serves as a marker for preexisting (but unrecognized) ventricular dysfunction. Similarly, diabetes mellitus and dysglycemia are associated with worse symptoms and lesser functional capacity in patients with heart failure and left ventricular systolic dysfunction; therefore, dysglycemia may result in earlier presentation of patients.14 The role of the kidney also could be important because dysglycemia is associated with renal dysfunction. Whether serum creatinine concentration is an adequate measure of renal function (and therefore whether renal function has been adequately adjusted for) is open to debate. Concomitant therapies also could be important (eg, patients treated with a thiazide diuretic for hypertension might be at increased risk of both dysglycemia and heart failure).
Dysglycemia and heart failure may simply have common pathophysiological origins or drivers. For example, overactivity of the sympathetic nervous system has long been related to insulin resistance and is clearly important in heart failure.15,16 Similarly, that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers appear to prevent the development of heart failure and possibly diabetes mellitus suggests a role for the renin-angiotensin system in both conditions.15–17
On the other hand, dysglycemia may, in some way, be directly implicated in the pathophysiology of developing heart failure (as opposed to acting as a marker for preexisting ventricular dysfunction or promoting an intercurrent event leading to myocardial injury). Why might this be? The first point to make is, of course, that glucose per se might not be the culprit. Hyperinsulinemia could be important, perhaps by causing myocardial hypertrophy.15,16 The formation of advanced glycosylation end products may cause collagen cross-linking and reduce ventricular distensibility and vascular compliance. Thus, it is a pity that none of the aforementioned studies described whether the cases of heart failure had a low or preserved ejection fraction. That information might have given a clue to the pathophysiological basis of the association between dysglycemia and heart failure, especially in view of the speculation that diabetes mellitus is associated with accelerated myocardial fibrosis, hypertrophy, and diastolic dysfunction.15,16
Advanced glycosylation end products also have been proposed to cause modification of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a. Hyperglycemia also may be associated with oxidative stress, altered intracellular signaling, decreased production of vascular endothelial growth factor, and altered gene expression. Similarly, autonomic neuropathy and microangiography are recognized complications of diabetes mellitus but may develop in early stages of dysglycemia. Another important consideration is myocardial metabolism, which may become more dependent on free fatty acids in dysglycemic states, resulting in uncoupling of oxidative phosphorylation and potentially reduced contractility.15,16
The authors of the present report correctly point out that proof of the hypothesis that dysglycemia causes heart failure is a trial of blood glucose lowering. This notion is premature. As summarized above, the relationship between dysglycemia and heart failure remains an association without a clear mechanistic basis (which may not be direct). Of even greater and practical importance, the choice of blood glucose–lowering strategy would currently be problematic. Few would wish to use a thiazolidinedione for fear of precipitating heart failure.18 Metformin would have to be stopped after development of heart failure in view of its current (but probably unjustified) "black box" warning. Do we really want to start insulin in this population?
Held and colleagues10 have taken the field an important step forward and illustrated the importance of cardiovascular and diabetic physicians working together to better understand the relationship between dysglycemia and heart failure.
 |
Acknowledgments |
|---|
Disclosures
None.
|
Footnotes |
|---|
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
 Top References |
|---|
1. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974; 34: 29–34.[CrossRef][Medline] [Order article via Infotrieve]
2. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med. 2001; 161: 996–1002.
3. Gottdiener JS, Arnold AM, Aurigemma GP, Polak JF, Tracy RP, Kitzman DW, Gardin JM, Rutledge JE, Boineau RC. Predictors of congestive heart failure in the elderly: the Cardiovascular Health Study. J Am Coll Cardiol. 2000; 35: 1628–1637.
4. Nichols GA, Gullion CM, Koro CE, Ephross SA, Brown JB. The incidence of congestive heart failure in type 2 diabetes: an update. Diabetes Care. 2004; 27: 1879–1884.
5. Thrainsdottir IS, Aspelund T, Thorgeirsson G, Gudnason V, Hardarson T, Malmberg K, Sigurdsson G, Ryden L. The association between glucose abnormalities and heart failure in the population-based Reykjavik study. Diabetes Care. 2005; 28: 612–616.
6. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000; 321: 405–412.
7. Carr AA, Kowey PR, Devereux RB, Brenner BM, Dahlof B, Ibsen H, Lindholm LH, Lyle PA, Snapinn SM, Zhang Z. Hospitalizations for new heart failure among subjects with diabetes mellitus in the RENAAL and LIFE studies. Am J Cardiol. 2005; 96: 1530–1536.[CrossRef][Medline] [Order article via Infotrieve]
8. Wong TY, Rosamond W, Chang PP, Couper DJ, Sharrett AR, Hubbard LD, Folsom AR, Klein R. Retinopathy and risk of congestive heart failure. JAMA. 2005; 293: 63–69.
9. Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC Jr. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care. 2004; 27: 699–703.
10. Held C, Gerstein HC, Yusuf S, Zhao F, Hilbrich L, Anderson C, Sleight P, Teo K, for the ONTARGET/TRANSCEND Investigators. Glucose levels predict hospitalization for congestive heart failure in patients at high cardiovascular risk. Circulation. 2007; 115: 1371–1375.
11. Nielson C, Lange T. Blood glucose and heart failure in nondiabetic patients. Diabetes Care. 2005; 28: 607–611.
12. Ingelsson E, Sundstrom J, Arnlov J, Zethelius B, Lind L. Insulin resistance and risk of congestive heart failure. JAMA. 2005; 294: 334–341.
13. Yusuf S, Pepine CJ, Garces C, Pouleur H, Salem D, Kostis J, Benedict C, Rousseau M, Bourassa M, Pitt B. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet. 1992; 340: 1173–1178.[CrossRef][Medline] [Order article via Infotrieve]
14. Suskin N, McKelvie RS, Burns RJ, Latini R, Pericak D, Probstfield J, Rouleau JL, Sigouin C, Solymoss CB, Tsuyuki R, White M, Yusuf S. Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure. Eur Heart J. 2000; 21: 1368–1375.
15. Kostis JB, Sanders M. The association of heart failure with insulin resistance and the development of type 2 diabetes. Am J Hypertens. 2005; 18: 731–737.[CrossRef][Medline] [Order article via Infotrieve]
16. Srikanthan P, Hsueh W. Preventing heart failure in patients with diabetes. Med Clin North Am. 2004; 88: 1237–1256.[CrossRef][Medline] [Order article via Infotrieve]
17. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions: the SOLVD Investigators. N Engl J Med. 1992; 327: 685–691.[Abstract]
18. Rydén L, Thráinsdóttir I, Swedberg K. Adjudication of serious heart failure in patients from PROactive. Lancet. 2007; 369: 189–190.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  M. Kamalesh Diabetes and prognosis: are systolic and diastolic heart failure different? Heart, February 1, 2009; 95(3): 178 - 179. [Full Text] [PDF]
|
|
|
|
 |
|
 D. T Eurich, F. A McAlister, D. F Blackburn, S. R Majumdar, R. T Tsuyuki, J. Varney, and J. A Johnson Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review BMJ, September 8, 2007; 335(7618): 497 - 497. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Elevated Glucose Levels and Risk for Incident Heart Failure Journal Watch Cardiology, April 4, 2007; 2007(404): 4 - 4. [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||