Impaired fasting glucose and cardiogenic shock in patients with acute myocardial infarction

Marianne Zellera,*, Yves Cottina, Marie-Claude Brindisib, Gilles Dentanc, Yves Laurentd, Luc Janin-Manificate, Isabelle L'Huilliera, Jean-Claude Beera, Claude Touzerya, Hamid Makkif, Bruno Vergesb and Jean-Eric Wolfa on behalf of RICO survey working group

a Service de Cardiologie, CHU Bocage, Dijon, France
b Service d'Endocrinologie, CHU Bocage, Dijon, France
c Service de Cardiologie, Clinique de Fontaine, Fontaine les Dijon, France
d Service de Cardiologie, Centre Hospitalier, Semur en Auxois, France
e Service de Cardiologie, Centre Hospitalier, Beaune, France
f Service de Cardiologie, Centre Hospitalier, Châtillon sur Seine, France

Received November 21, 2003; revised December 19, 2003; accepted December 22, 2003 * Correspondence author. Tel: +33 3802933.11; Fax: +33 80293333
E-mail address: marianne.zeller{at}u-bourgogne.fr


    Abstract
 Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Objectives In-hospital outcome after acute myocardial infarction (MI) has not yet been evaluated with regard to the new category of Impaired Fasting Glucose level (IFG) patients defined by the American Diabetes Association (ADA).

Methods Nine hundred and ninety-nine patients with acute MI from the RICO survey were included in the study. Fasting blood glucose was measured after admission. Patients were grouped according to ADA definitions: Diabetes Mellitus (DM) (FG ≥7mmol/l or personal history of DM); IFG (FG 6.1 to 7mmol/l); NFG (normal FG <6.1mmol/l).

Results Three hundred and eighty-one patients (38%) had DM, 145 (15%) IFG and 473 (47%) NFG. Mortality in the IFG group was twice that of the NFG group (8% vs 4%, P=0.049). A significant increase in cardiogenic shock (12% vs 6%, P=0.011) and ventricular arrhythmia (15% vs 9%, P=0.035) was observed in the IFG vs NFG group. IFG, after adjustment for confounding factors (age, sex, anterior location, and LVEF), was a strong independent predictive factor for cardiogenic shock (P=0.005).

Conclusion MI patients with IFG had an overall worse outcome, characterized by a higher risk of developing cardiogenic shock during their hospital stay.

Key Words: Myocardial infarction • Cardiogenic shock • Diabetes mellitus • Glucose


    1. Background
 Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Diabetes mellitus (DM) is a well established risk factor for death and cardiac complications such as cardiogenic shock in acute myocardial infarction (MI).1,2Recent American Diabetes Association (ADA) guidelines introduced a new category of impaired fasting glucose (IFG) for glucose levels ranging from 6.1mmol/l to 7mmol/l (110mg/dl to 126mg/dl), below the threshold for diabetes mellitus (DM).3Results of large cohort studies indicate that IFG patients have a higher risk of cardiovascular disease, suggesting that a blood glucose concentration even <7mmol/l is associated with macrovascular complications and coronary artery disease (CAD).4However, the effects of such abnormal glucose metabolism during acute MI has been only poorly evaluated. Recent study by Muhlestein et al., suggested a high associated risk of mortality in a cohort of coronary artery disease patients undergoing percutaneous coronary intervention, thus emphasizing the importance of risk evaluation for this population in acute MI.5

The aim of our study was to ascertain the incidence of cardiac events and mortality in patients with IFG, compared to patients with normal fasting glucose, at the acute phase of MI.


    2. Methods
 Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Patients
From 1 January 2001 to 31 July 2003, the French regional RICO survey prospectively collected in-hospital data from patients hospitalized for acute MI in all public centres or privately funded hospitals of one eastern region of France. All patients with MI diagnosed according to ESC and ACC criteria were included in the study.6Patients whose fasting blood glucose concentration had not been measured were excluded from the study. The present study complied with the Declaration of Helsinki, was approved by the ethics committee of university hospital of Dijon and each patient gave written consent before participation.

2.2. Data collection
Demographic data, cardiovascular risk factors and history were collected as well as on-admission ECG data. Left ventricle ejection fraction (LVEF) was measured by echocardiography. The rate of reperfusion (lysis or primary percutaneous coronary intervention) was also determined. In-hospital adverse events were recorded, including death, ventricular arrhythmia (ventricular tachycardia (VT) or fibrillation (VF)), stroke, recurrent MI and cardiogenic shock. The primary endpoint for the study was in-hospital mortality. Cardiogenic shock was defined as systolic blood pressure <90mmHg, persisting for >1h despite fluid challenge, associated with clinical signs of hypoperfusion.7Fasting blood glucose was measured twice at days 4 and 5 after hospital admission, and HbA1cwas measured on the first morning after admission. Peak plasma level of creatine kinase (CK) during in-hospital stay was also evaluated. Baseline serum creatinine clearance rate was estimated by the Cockcroft–Gault formula.8

2.3. Group definition and analysis
DM and IFG were defined according to revised ADA definition: we classified patients as having DM if they had a history of diagnosed DM or if their mean fasting blood glucose ≥7.0mmol/l (126mg/l). IFG was defined as mean fasting glucose between 6.1mmol/l (110mg/l) and 7.0mmol/l (126mg/l), and normal FG as mean fasting glucose less than 6.1mmol/l.3All the analysis were performed on the non diabetic patients (IFG+NFG groups).

2.4. Statistical analysis
Continuous data were expressed as median and interquartile range values and dichotomous data as percentages. For continuous variables, a Kolmogorov–Smirnov analysis was performed to test for normality. Comparisons between the two groups were performed either by unpaired Student's t-test (age, BMI, fasting glycaemia, and HbA1c), or by non-parametric Mann–Whitney U-test (creatinine clearance) as appropriate. Categorical data were analysed by {chi}2-test. A multiple logistic regression model was chosen to assess the relationship between variables and the occurrence of adverse events. Model-building involved selecting the variables that were prognostic for adverse hospital outcome in multiple regression analyses. The first model (model 1) included in-hospital adverse events (VT/VF, cardiogenic shock, stroke, recurrent myocardial infarction) as predictors of cardiovascular death in a backward stepwise regression analysis. For model 2, baseline characteristics as known risk factors (e.g. hypertension, current smoking, history of MI, age >70, sex, anterior location, LVEF <45%) and IFG were tested as univariate predictors for adverse outcome. Age and LVEF has been dichotomized according to classical data from literature (age >70 years and LVEF <45%). In univariate analysis, only age >70, sex, anterior location, LVEF <45%, and IFG were predictors of events. The significance level required to be entered in multivariate analysis was 10%. Backward stepwise regression analyses were then performed to test for independent predictor of adverse events. In this analysis, an {alpha} value of 1% as significance level was required in order to take account of the increase in the overall type I error due to multiple testing. The Wald test was performed to test for significance. Results are expressed as odds ratio (OR) with 99% confidence intervals (CI). All tests were two-sided.


    3. Results
 Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
3.1. Characteristics and cardiac events
We enrolled 999 patients of whom 526 (53%) had abnormal glucose metabolism: 381 (38%) DM (with history of diagnosed DM or mean fasting blood glucose ≥7.0mmol/l), and 145 (15%) IFG (with fasting glucose between 6.1mmol/l (110mg/l) and 7.0mmol/l). The remaining 473 (47%) had NFG (fasting glucose less than 6.1mmol/l).

We analysed the data from the two non-diabetic groups (IFG and NFG). The average length of hospital stay was similar for the two groups (10±2 vs 10±3 days, P=0.532). Table 1shows the characteristics and outcome of patients. CK plasma levels and BMI were higher in the IFG group compared to the NFG group (respectively P=0.002 and P=0.018). We noted a significant two-fold increase in cardiogenic shock in the IFG group, compared to the NFG group (P=0.011) (Fig. 1). In-hospital mortality in the IFG group was double that of the NFG group (P=0.049). Moreover, FG levels were significantly higher in patients with cardiogenic shock than in those without (P=0.003) (Fig. 2).


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Table 1 Patients characteristics and outcome: n (%) or median (25th and 75th percentile)

 


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Fig. 1 Cardiogenic shock occurrence according to glycaemic category (P=0.011, {chi}2-test).

 


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Fig. 2 Levels of fasting glycaemi a according to the occurrence of cardiogenic shock (P<0.001, Student's t-test).

 
3.2. Predictors of mortality
Multivariate analysis showed that cardiogenic shock (P<0.0001) and ventricular arrhythmias (P=0.036) explained most in-hospital mortality (Table 2). Table 3describes the baseline characteristics as predictive factors for adverse events. LVEF was a strong predictive factor of in-hospital death, ventricular arrhythmia and shock. IFG was an independent predictive factor for cardiogenic shock (P=0.005), when adjusted for confounding factors (age >70, sex, anterior location, LVEF <45%). IFG failed to be an independent prognostic factor for in-hospital death and for ventricular arrhythmias.


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Table 2 Multivariate analysis of in-hospital adverse events as predictors of cardiovascular death

 

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Table 3 Multivariate analysis baseline characteristics as predictors of death, VT/VF or cardiogenic shock

 

    4. Discussion
 Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
The main findings of our work are that in our non-selected population of MI: (1) A large proportion of the MI population (53%) has abnormal fasting glycaemia (DM or IFG). (2) Patients with IFG had an overall worse outcome, characterized by a higher risk of developing cardiogenic shock during their hospital stay.

4.1. Prevalence of IFG
Using criteria recently defined by ADA, we observed 15% of IFG among our study population. This number is twice that of the latest data from a representative sample of 170.5 million healthy US adults from the NHANES III population, where IFG was found in 7%.9Interestingly, when adjusted for age, CAD was more prevalent in IFG compared to NFG (8.4% vs 5.7%, RR=1.47). The present study describes a high prevalence (53%) of overall dysglycaemia (IFG+DM) in unselected MI patients. A very recent study involving 1612 patients with CAD undergoing percutaneous coronary intervention, showed that abnormalities of fasting glycaemia are much more prevalent (61%) than expected. This phenomenon could be attributable to stress hyperglycaemia.5Therefore, our work agrees with and confirms these findings and extends this concept to patients with acute MI.

4.2. IFG and prognosis
In subjects with CAD, the all-cause mortality at long term follow up (7.7 years) has been shown to be strongly related to FG (20.1% in IFG patients vs 14.3% in NFG patients, P<0.001), even after adjustment for 13 clinical variables.10There is no clear evidence that mild hyperglycaemia per se promotes atherogenesis; however, diabetic hyperglycaemia has been shown to induce vascular disease involving endothelial dysfunction and abnormalities in vascular smooth muscle cells and in platelet function.11These abnormalities contribute to the cellular events that cause atherosclerosis and subsequently increase the long-term risk of cardiovascular mortality. During acute MI, the mortality rate for patients with non-diabetic hyperglycaemia and factors influencing that mortality are less clear. An overview of 15 studies including 1856 patients with hyperglycaemia without DM, has revealed a pooled relative risk of in-hospital mortality of 3.9 (95% CI 2.9–5.4) for hyperglycaemia.12However, in this overview, the threshold of hyperglycaemia varied according to each study (from 6.1mmol/l to 8mmol/l), and was heterogeneously evaluated by fasting or admission glycaemia. Our findings clearly showed that the IFG-related risk of in-hospital death was twice that of patients with normal FG, thus extending the clinical relevance of the new ADA defined abnormal blood glucose levels for acute MI. Recent findings from a large prospective randomized study suggested that intensive insulin therapy in critically ill patients to maintain blood glucose level at or below 6.1mmol/l reduces 1-year mortality by 42%.13These data strongly suggest that elevated blood glucose levels contribute to a worse outcome during conditions of acute stress. These findings also emphasize the necessity for the evaluation of specific therapeutic strategies at the acute phase of MI.

4.3. IFG and cardiogenic shock
IFG was not persistent as a predictive factor of mortality after adjustment for covariates. Moreover, we found a strong association between IFG and the occurrence of shock. A number of studies have reported an increased risk of severe pump failure in MI patients, but with a higher glucose threshold (>10mmol/l) and without adjusting for potential covariates.14,15Only one study suggested that, after adjustment for age, dysglycaemic patients without DM (cut-off at 8mmol/l) had a higher risk of congestive heart failure or cardiogenic shock.16

The mechanisms of the increased risk of shock in patients with IFG are not fully understood; a direct role of hyperglycaemia could be suspected, since increased glycaemia has been shown to be harmful for cardiomyocytes.17Hyperglycaemia is a reflection of relative insulin deficiency, associated with increased lipolysis and elevated circulating free fatty acids, which may damage cardiac cells.18Recent works have further investigated the role of insulin during critical illness, showing that insulin has a powerful anti-inflammatory effect, which is associated with improvements in morbidity and mortality.19Since IFG patients have a relative insulin deficiency, the potential anti-inflammatory effect of insulin could be reduced.

Another possible explanation exists for this association between IFG and severe pump failure: shock could be the cause of IFG, not the consequence. Therefore, elevated glucose levels could be related to the acute ischaemic stress due to severe pump failure, inducing a disturbed metabolic state, and in particular alteredglucose metabolism. In this hypothesis, extensive cardiac damage associated with cardiogenic shock may lead to a greater rise in stress hormones, thus promoting hyperglycaemia, and may therefore increase the risk of severe pump failure. However, stress hyperglycaemia is a minor marker of the extent of cardiac damage.20In our study, we cannot exclude that shock is the cause of hyperglycaemia. However, primary impaired fasting glycaemia is more likely to be responsible for shock, as HbA1clevels, which is a marker of preexisting glucose metabolism, is significantly higher in IFG, thus confirming the presence of chronic altered glucose metabolism even before the acute ischaemic event. Moreover, as well as stresshormones, many other factors, such as pancreatic control of insulin secretion, contribute to the regulation of glucose blood levels. Further investigations are needed to clarify these mechanisms.

4.4. Study limitations
In our study, we cannot exclude the possibility that hyperglycaemia may be the consequence of metabolic stress due to an acute ischaemic event. However, several arguments do not support this view. First, the prevalence of IFG among our study population (15%) is lower than the IFG rate (19%) obtained from patients with CAD but without acute coronary event.5Furthermore, HbA1clevels as a marker of preexisting glucose metabolism are significantly higher in IFG, a sign of chronic altered glucose metabolism even before the acute ischaemic event. Finally, previous studies in non-diabetic patients have shown that a strong correlation exists between fasting glucose levels at the acute phase and abnormal glucose tolerance at 3 months (P<0.0017).21Moreover, determination of serial glucose levels was stable at day 4 and was an independent predictor for abnormal glucose tolerance at 3 months (OR: 1.9, 95% CI: 1.05–3.69, P=0.044).21Therefore, these findings strongly suggest that raised blood values observed in our study are not only related to stress induced by an ischaemic event, but could be linked to chronically disturbed glucose metabolism.


    5. Conclusions
 Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Our data in an unselected population of MI patients indicate for the first time that ADA defined IFG is associated with a higher risk of developing cardiogenic shock during in-hospital stay. Malmberg and associates showed that metabolic control by the use of insulin-glucose therapy in hyperglycaemic MI patients resulted in a 30% relative risk reduction in 1 year mortality.22,23Therefore, our findings also emphasize the clinical relevance for the evaluation of specific therapeutic strategies at the acute phase of MI in new ADA defined dysglycaemic patients.


    Acknowledgments
 
This work was supported by the Association de Cardiologie de Bourgogne and by grants from University Hospital of Dijon.


    Footnotes
 
ADA, American Diabetes Association; CAD, Coronary Artery Disease; CK, Creatine Kinase; DM, Diabetes Mellitus; IFG, Impaired Fasting Glucose; LVEF, Left Ventricle Ejection Fraction; MI, Myocardial Infarcation; RICO, observatoire des inferctus de Cote-d’Or; VF, Ventricular Fibrillation; VT, Ventricular Tachycardia.


    References
 Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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