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European Journal of Heart Failure 2007 9(10):1051-1057; doi:10.1016/j.ejheart.2007.07.017
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© 2007 European Society of Cardiology

Increasing glucose levels and BMI predict future heart failure Experience from the Reykjavík Study

I.S. Thrainsdottira,*, T. Aspelundb, V. Gudnasonb, K. Malmberga, G. Sigurdssonb,c, G. Thorgeirssonb,c, T. Hardarsonc and L. Rydéna

a Department of Cardiology Karolinska University Hospital Solna 171 76 Stockholm, Sweden
b Icelandic Heart Association Reykjavík, Iceland
c Landspítalinn University Hospital Reykjavík, Iceland

* Corresponding author. Tel.: +46 8 517 71768; fax: +46 8 31 10 44. E-mail address: inga.thrainsdottir{at}ki.se (I.S Thrainsdottir).


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background: Heart failure is common in diabetes and ischaemic heart disease is the most likely link. Still, it has been suggested that the relation extends beyond such disease.

Methods: 7060 subjects with two or more visits in the Reykjavík Study were followed–during 30years from 1967. All underwent oral glucose tolerance tests. Disease status was defined according to the glycaemic level and presence of heart failure. The incidence and predictive factors for these diseases were determined.

Findings: Age and sex standardized incidence of heart failure was 5.3/1000/year, of diabetes 4.6/1000/year and abnormal glucose regulation 12.6/1000/year. Body mass index (BMI) and fasting glucose predicted the development of these conditions (p<0.001). Increasing fasting glucose by 1mmol/l increased the risk for heart failure by 14% (p=0.04) after adjusting for IHD, BMI and other risk factors for CVD. There was a strong association between diabetes and heart failure, OR 3.0 (2.3–4.0), and abnormal glucose regulation and heart failure, OR 1.8 (1.5–2.3). Diabetes and heart failure were, however, not independent predictors of each other.

Interpretation: There was an independent relationship between increases in fasting glucose and development of heart failure. BMI was a strong predictor of heart failure. Although fasting glucose and BMI were significant risk factors for glucose disturbances and heart failure the conditions themselves did not independently predict each other.

Key Words: Heart failure • Diabetes • Epidemiology • Incidence • Predictive factors

Received August 30, 2006; Revised May 23, 2007; Accepted July 18, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
People with diabetes have a poor prognosis that has traditionally been linked to their high propensity to develop atherosclerotic cardiovascular disease [1]. It seems that there may be links between abnormal glucose regulation and heart failure that cannot be fully explained by the presence of coronary artery disease and its consequences. Moreover, it has been suggested that people with diabetes develop diabetic cardiomyopathy which, in its early stages, may present as diastolic myocardial dysfunction [2,3]. Systolic heart failure is also common in diabetes [4,5]. Recent observations from the Reykjavík Study showed that the prevalence of heart failure was increased among subjects with impaired glucose tolerance [4]. Data from this study also demonstrated that the combination of a glucose abnormality and heart failure was linked to a more unfavourable prognosis than in subjects with heart failure alone. The presence of ischaemic heart disease did not add further to the unfavourable prognosis of a glucose abnormality and heart failure [6]. Indeed the Campania study, performed in an elderly Italian population, reported that heart failure was an independent risk factor for diabetes [7]. However, these potentially important observations were made in an age limited cohort and have not been further substantiated in other cohort studies.

The Reykjavík Study provides an opportunity to study the relation between glucose abnormalities and heart failure in a large and population based cohort study with a long period of follow up. The aim of the present report was to study the incidence of diabetes, abnormal glucose regulation and heart failure, and the relation between glucose abnormalities and the incidence of heart failure. It was hypothesized that there is a relation between these diseases beyond the presence of ischaemic heart disease.


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. The Reykjavík Study
The Reykjavík Study, which was conducted between 1967 and 1997, recruited 19,381 participants aged 33-84 years. Details of the study design have been reported elsewhere [4,8]. Of all the participants in the Reykjavík Study, 7060 attended for more than one study visit, with the first visit between 1967 and 1980 (Fig. 1). This cohort, of whom 3194 (45%) were females, compose the present study population.


Figure 01
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  		Fig. 1 Flow chart of the number of eligible participants for this study from the Reykjavík Study population.

 
Each participant underwent an oral glucose tolerance test (OGTT; 50 g glucose in 250 ml water) at each visit until 1990. Blood glucose (mg/dl) was determined before (fasting) and 1.5 h after the glucose load, initially by means of a chemical method but subsequently a hexokinase enzymatic method was used [9]. Following a protocol amendment in 1990, investigation of the glucometabolic state was assessed from fasting serum glucose only [10].

The variables recorded included age, height, weight, blood pressure, smoking, previous ischaemic heart disease, cholesterol, triglycerides and current medications. ECG and chest x-ray were performed at each visit [4]. Variables were defined as predictive if they existed before or were detected at the first study visit.

Permission to conduct the Reykjavík Study was received from the Icelandic Science Ethics Committee and the Icelandic Data Protection Authority.

2.2. Definitions
Heart failure (HF) was defined according to the European Society of Cardiology guidelines [11], as the combination of at least two symptoms, dyspnoea, tiredness or ankle oedema, and objective evidence of cardiac involvement on ECG (Q-wave myocardial infarction according to MONICA criteria [12], left bundle branch block, left ventricular hypertrophy) or chest x-ray (pulmonary congestion, cardiomegaly or left ventricular enlargement). In addition, 38 out of the 489 heart failure cases were found by screening hospital records for participants with symptoms of heart failure but without any signs in the Reykjavík Study database. If subjects were found to have heart failure as a clinical diagnosis and signs of heart involvement by echocardiography, chest x-ray or ECG, they were included as heart failure cases.

Glucometabolic abnormalities were categorized as type 2 diabetes mellitus; defined as fasting serum glucose ≥7.0 mmol/l (>126 mg/dl) or OGTT ≥11.1 mmol/l (≥200 mg/dl) or abnormal glucose regulation (newly diagnosed impaired glucose tolerance or impaired fasting glucose); defined as fasting serum glucose 6.1-6.9 mmol/l (110-126 mg/dl) or OGTT 7.8-11.0 mmol/l (140-200 mg/dl). These conditions were defined as based on information from the questionnaire or as newly diagnosed type 2 diabetes or abnormal glucose regulation based on whole blood OGTT or, from 1990, fasting serum glucose.

Ischaemic heart disease was defined as recognized or unrecognized myocardial infarction by the MONICA criteria [12], or as a previous coronary intervention (PCI or CABG) or angina according to the Rose questionnaire [13].

2.3. Study groups
To be included, participants had to be free from all of the following conditions; diabetes, abnormal glucose regulation or heart failure at their first study visit and attend the Reykjavík Study more than once. Participants in the case cohort had developed symptoms and signs according to the definitions of diabetes, abnormal glucose regulation and/or heart failure at one of the subsequent visits. The first analysis considered subjects disease free at entry and in order study the incidence, subjects were subsequently allocated into one of six groups depending on their glucometabolic state and presence or absence of heart failure as recorded during follow up: 1) Controls=free from any of these conditions; 2) abnormal glucose regulation; 3) type 2 diabetes mellitus; 4) heart failure; 5) abnormal glucose regulation and heart failure; and 6) type 2 diabetes mellitus and heart failure.

Another analysis was performed to study the influence of abnormal glucose metabolism and heart failure on the subsequent risk of developing the alternate condition. This comprised all participants with one of the three conditions (abnormal glucose regulation, diabetes or heart failure) at their first visit. The appearance of heart failure or a glucose abnormality during follow up lead to a redefinition of the disease status as newly detected cases of the combination of glucose abnormality and heart failure.

The third analysis studied the predictive value of glucose levels as a continuous variable on future disease status as previously defined.

2.4. Statistical analysis
The Cox proportional hazards model was used to estimate the predictive value of risk factors with the onset of a disease. Age was chosen as the time scale with left truncation to accommodate for different entry age into the study. The traditional approach using time in study as the time scale with age correction gave similar results. Population incidence was estimated using the person-years method. Overall incidence was computed as a weighted average using the age distribution of the Icelandic population in 1995. Associations between glucose abnormalities and heart failure, unrelated to time, were estimated with odds ratios from the Cochran-Mantel-Haenszel method adjusting for sex and 5-years age groups. SAS statistical software version 9.1 was used for the analysis [14-16].


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
The average duration of follow up was 13±8 years and did not differ significantly between the six groups. Pertinent clinical and biochemical characteristics are presented in Tables 1 and 2. There were no significant differences in biochemical parameters between the groups. Mean age at the diagnosis of abnormal glucose regulation was 63 and 61 years for women and men respectively. The corresponding ages for diabetes were 64 and 62 years and for heart failure 63 and 59 years, without any significant gender differences between the diagnosis of heart failure and glucose abnormalities. BMI and blood pressure were highest in participants with the combination of heart failure and a glucose abnormality; while blood lipids, creatinine and hemoglobin did not differ significantly.


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  		Table 1 Clinical characteristics in the six study groups presented as mean (SD)

 


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  		Table 2 Biochemical findings in the six study groups presented as mean (SD)

 
At study entry, 6260 of the participants were free from abnormal glucose tolerance. New onset abnormal glucose regulation was detected in 1018 individuals (16.3%). Out of 6875 participants originally free from diabetes 460 (6.7%) developed new onset diabetes and out of 6864 free from heart failure 489 (7.1%) were diagnosed with new onset heart failure during follow up. The incidence of abnormal glucose tolerance, diabetes and heart failure increased with age in both sexes (Fig. 2). Age and sex standardized incidence of abnormal glucose regulation was 12.6/1000/year, of diabetes was 4.6/1000/year and of heart failure was 5.3/1000/year.


Figure 02
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  		Fig. 2 Incidence of abnormal glucose regulation, diabetes, heart failure, abnormal glucose regulation and heart failure, and diabetes and heart failure expressed as number of incident cases/1000 person years among men (panel a) and women (panel b) in different age groups.

 
Predictive factors, derived from the multivariable statistical model, for the development of heart failure and glucose abnormalities are outlined in Table 3. A rise in body mass index independently predicted each of the three conditions abnormal glucose regulation, diabetes and heart failure. Hypertension and ischaemic heart disease were independent predictors for the development of heart failure, however, not of diabetes or abnormal glucose regulation. A rise in cholesterol was a negative predictor of glucose abnormalities, i.e. appeared protective. Estimated from an unadjusted analysis, the risk for heart failure was increased on average by 25% (p=0.0001) by 1 mmol/l increase in glucose level. After adjustment for systolic blood pressure and ischaemic heart disease such an increment in glucose level increased the risk for heart failure by 21% (p=0.002). After further adjusting for BMI, cholesterol and smoking there was still an increased risk for heart failure; Hazard Ratio 1.14 (Confidence Interval 1.00-1.29) for every 1 mmol/l increase in glucose. Similarly an increase in fasting glucose by 1 mmol/l increased the risk for diabetes; HR 3.24 (CI 2.67-3.95) and abnormal glucose regulation; HR 1.68 (CI 1.44-1.95). The 90 minute post load plasma glucose did not predict heart failure after adjustment for cardiovascular risk factors and ischaemic heart disease (HR 1.0, CI: 0.9-1.1).


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  		Table 3 Predictive factors for heart failure and glucose abnormalities

 
Body mass index was a major predictive factor for developing heart failure as seen in Table 4 where BMI is divided into categories. Glucose values increased significantly as the BMI value rose (p<0.0001). Even though BMI was a major contributor for developing heart failure, glucose remained an independent predictor for heart failure development, even after adjustment for BMI, IHD, hypertension, cholesterol and smoking.


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  		Table 4 The incidence and risk of heart failure during the study period according to BMI (kg/m2)

 
There was a strong association between the concomitant occurrence of diabetes and heart failure (sex adjusted OR 3.0; CI 2.3-4.0; p<0.001) and abnormal glucose regulation and heart failure (sex adjusted OR 1.8; CI 1.5-2.3; p<0.001). The baseline existence of heart failure, diabetes and abnormal glucose regulation considered as risk factors for these diseases did not significantly influence the risk of developing the alternate disease resulting in the combination of a glucose abnormality and heart failure later in life (Fig. 3). Even when abnormal glucose regulation and diabetes were combined they did not predict future heart failure (HR 1.2; CI 0.9-1.5; p=0.2).


Figure 03
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  		Fig. 3 The risk of developing a glucose abnormality or heart failure by primary condition (Hazard ratios (HR)). Cox regression, adjusted values on a logarithmic scale.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
In the present study the incidence of abnormal glucose regulation, diabetes and heart failure increased with age and was higher in men than in women. There was a strong association between glucose abnormalities and heart failure. Body mass index was a strong predictor of heart failure, as well as hypertension and ischaemic heart disease. After adjustment for these factors and other risk factors for cardiovascular disease, there was a linear association between an increase in fasting glucose not only as regards new diabetes or abnormal glucose regulation but for heart failure as well.

The main strength of this study was the large number of participants, who attended for repeated study visits during the period of follow up. All subjects were randomly selected from the Reykjavík area and should therefore be representative of the general Icelandic population. This population has been compared to other populations as regards risk profiles and was found to be similar to a low risk European area [17]. The Reykjavík Study was not primarily designed to study the incidence of specific diseases, which explains the somewhat irregular time intervals between study visits. One limitation was the lack of a prospective definition of heart failure; this may have resulted in possible incorrect diagnoses, with an underestimation of the true incidence as the most likely outcome. According to guidelines from the European Society of Cardiology the diagnosis of heart failure should be based on a combination of symptoms and signs [11]. Currently the most commonly used and accepted method for diagnosing myocardial dysfunction is echocardiography. However, the present study was designed in 1966, when neither echocardiography nor international guidelines on how to diagnose heart failure were available. The Reykjavík Study questionnaire, however, included many questions about tiredness, breathlessness and oedema, which together with ECG recordings and chest x-rays made it possible to define heart failure with reasonable accuracy. In addition, hospital records from all participants with symptoms resembling heart failure were screened in order to detect further cases. This could have made standardization of cases less optimal than if only the original database was used. However, it did add cases to the population and made it possible to apply a defined diagnostic algorithm which was standardized to present European recommendations as much as possible, including objective measures of compromised cardiac function such as echocardiography, ECG and chest x-ray [11]. It is therefore likely that the present cases truly represent diagnosed heart failure. Moreover, subjects who developed heart failure during follow up more often received digitalis and/or medications for oedema than those who did not (11.3% vs. 3.3%), which may serve as an indication of the accuracy of the present definition of heart failure.

The incidence of heart failure in the Reykjavík Study was similar to that in previous reports from 1989-1992 [18-20]. In a more recent population based epidemiological study from Rotterdam, the incidence of heart failure based on similar criteria was higher than in the present study. A possible reason may be the generally low risk profile of the Icelandic population, making them less prone to develop diseases such as heart failure [21].

The age-standardized incidence of diabetes appears to be similar in a number of European countries. In Swedish men and women an incidence of 4.1/1000 and 3.8/1000 person-years respectively, has been reported; the corresponding numbers from the Netherlands were 2.2/1000 and 2.3/1000 [22,23]. This is less than the incidence reported in our study of 4.6 per 1000 person-years. However, when looking at an elderly population, as in the Italian Campania study, the incidence of type 2 diabetes was higher at 61/1000 per year. This is in contrast to data from the Netherlands, where the incidence decreased in the oldest age-group [7,22].

To the best of our knowledge, the relation between diabetes and heart failure has not previously been reported in a general population. A Swedish prospective cohort study showed that insulin resistance and metabolic syndrome were predictors of heart failure in men. The primary aim of this study was, however, not to study the mutual relationship between fully established diabetes and heart failure as in the current study [24,25]. A retrospective cohort study including almost 10000 individuals from a US health centre showed an increased incidence of heart failure in patients with diabetes compared to those without [26]. In the cross-sectional study from Campania, which recruited 1339 participants above the age of 65 years, the prevalence of diabetes was 14.7% and of heart failure 9.5%. After only three years of follow up, the investigators noted that heart failure carried an independent risk for the development of diabetes [7]. This contrasts with the outcome of the present study which showed a strong association between heart failure and glucose abnormalities but without an independent predictive association. This discrepancy may be explained by differences in the populations studied, elderly patients [7] or patients from a health maintenance organization [26] vs. participants in a population based study. Another important difference may be a strikingly high incidence of new onset diabetes during the longitudinal part of the Campania study [7].

Previous reports from the Reykjavík Study have shown a prevalence of diabetes and heart failure of 3.7% and 3.8% respectively, with a strong association between these two diseases (Odds Ratio=2.7; CI 1.9-4.1). There was also a strong association between abnormal glucose regulation and heart failure (OR 1.6; CI 1.2-2.4) [4]. The strength of the association between these disorders was confirmed by the current data. Moreover, participants with a glucose abnormality and heart failure had a more unfavourable prognosis than other participants, especially if both conditions were present [6]. Despite the strong association between glucose abnormalities and heart failure, these conditions did not predict each other. Possible explanations are the low prevalence of these diseases in this population leading to relatively few cases and the fact that these conditions tend to appear at about the same age, making prospective analysis of the relation of these diseases in time difficult.

A causal relationship between different diseases cannot be proven by an epidemiological investigation. However, the Reykjavík study, which included a 30 year period of follow up, a standardized exploration of the glucometabolic state and a reasonably accurate diagnosis of heart failure, provided an opportunity to observe the time relationship between these disorders in a large population sample. The hypothesis that there may be a causal relationship between abnormal glucose tolerance and heart failure or vice versa was not supported by the current data. It is perhaps more likely that a common denominator exists between abnormal glucose regulation, diabetes and heart failure, disorders which tend to occur at a similar age. There is still an ongoing debate about the existence of a diabetic cardiomyopathy, as suggested by Lundbaeck in 1954 [3].

In the current study there was a strong association between dysglycaemia and heart failure even after adjusting for risk factors and ischaemic heart disease. Importantly a significant linear relation was found between continuously increasing levels of glucose with new onset heart failure. This finding persisted even after adjustment for BMI, which itself was a strong predictor of heart failure and glucose abnormalities, making alternative links between glucometabolic disturbances and myocardial dysfunction likely.

The present findings support the initiation of screening for glucose abnormalities in heart failure patients and for heart failure in people with diabetes or abnormal glucose regulation, at an early stage of the respective disorders. Although there is no conclusive data, implementation of appropriate therapy to optimise glucose levels seems important. In addition the treatment of myocardial dysfunction in order to improve the prognosis of these patients is also important [27]. Trials are certainly warranted to elucidate the potential of screening and medical intervention in these patients.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
There was a linear relationship between fasting glucose and heart failure, and a strong association between glucose abnormalities and heart failure.

The present findings indicate that there may be a common pathway between diabetes and heart failure which is not entirely explained by the presence of ischaemic heart disease.


   Acknowledgement
 
This study was supported by AFA Insurance, King Gustav the V and Queen Victoria's Foundation and in part the Swedish Heart and Lung Foundation.

The authors want to express their special thanks to Ingibjörg Stefánsdóttir for help in data collection and to staff of the Heart Preventive Clinic for assistance in performing this study.


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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