Summary
Type 2 diabetes mellitus is one of the most common chronic conditions and its prevalence has increased continuously over the past decades, primarily due to the obesity epidemic. Atrial fibrillation (AF) is the most frequent sustained cardiac arrhythmia in clinical practice and is associated with increased cardiovascular and cerebrovascular morbidity and mortality. Recent studies have shown that patients with diabetes have an increased risk of AF. However, the results about the relationship between diabetes and AF are still conflicting. Mechanisms that are responsible for an association between diabetes and AF, as well as the adequate treatment of AF in patients with diabetes, are still insufficiently studied. The aim of this review is to summarize the current knowledge of mechanisms that connect AF and diabetes, the clinical studies that include patients with both conditions, and the treatment options in modern pharmacology.
Résumé
Le diabète de type II est une des affections chroniques les plus fréquentes et sa prévalence a augmenté de façon régulière au cours des dernières décennies, essentiellement du fait de l’épidémie d’obésité. La fibrillation atriale est l’arythmie cardiaque la plus fréquente en pratique clinique et est associée avec une augmentation de la morbi-mortalité cardiovasculaire et cérébrovasculaire. Des études récentes ont montré que les patients diabétiques avaient un risque accru de fibrillation atriale. Cependant, ces résultats établissant la relation entre diabète et fibrillation atriale sont controversés. Les mécanismes responsables d’une telle association, ainsi que le traitement de la fibrillation atriale chez les diabétiques sont insuffisamment étudiés à ce jour. L’objectif de cette revue générale est de résumer les données actuelles des mécanismes liant la fibrillation atriale au diabète, ainsi que les études cliniques qui incluent les patients ayant un diabète et une fibrillation atriale ; les options thérapeutiques et l’apport de la pharmacologie moderne sont également discutés.
Introduction
Type 2 diabetes mellitus is one of the most common chronic conditions and its prevalence is increasing. In 2014, the number of patients with diabetes was estimated at 387 millions people worldwide, of whom around half were undiagnosed . The projection for 2035 is that the number of patients with diabetes will have risen to 592 millions . It is well known that cardiovascular and cerebrovascular diseases are substantially more frequent among patients with diabetes . However, the mechanisms of this influence are still not completely understood. It is not known whether permanent hyperglycaemia or wide fluctuations in glucose levels–from hypoglycaemia to hyperglycaemia, which is commonly seen in diabetes subjects, especially the treated ones–is most responsible for cardiovascular damage.
Atrial fibrillation (AF), the most frequent sustained cardiac arrhythmia, is associated with an increased risk of stroke, thromboembolism, heart failure and recurrent hospital admissions . The prevalence of AF is constantly increasing, and it affects about 2.2 million individuals in America and 4.5 millions in Europe .
Studies have shown that diabetes is frequently associated with AF . However, it is difficult to determine whether diabetes directly affects the atrial tissue or whether different pathways are involved, including hypertension, coronary artery disease and abnormal activity of the autonomic nervous system. The aim of this review is to summarize current knowledge of the relationships between diabetes and AF, from mechanisms to clinically relevant studies.
Mechanisms of the relationship between diabetes and AF
Diabetes is associated with numerous metabolic defects including insulin resistance, impaired glucose tolerance, proinflammatory mediators, abnormalities of haemostasis, fibrinolysis, angiogenesis and extracellular matrix turnover ( Fig. 1 ). All of these metabolic changes lead to endothelial dysfunction, abnormal activation of the renin-angiotensin-aldosterone system (RAAS) and acceleration of atherogenesis, which could be responsible for AF occurrence . Diabetes could also cause structural, electrical, electromechanical and autonomic remodelling .
Atrial structural remodelling
Most evidence obtained from animal studies has demonstrated that structural remodelling of the left atrium, primarily atrial dilatation and interstitial fibrosis is the major trigger of AF in patients with diabetes . Structural remodelling leads to ionic remodelling and increases atrial tissue vulnerability, which induces inter-atrial conduction delay and, subsequently, initiation and maintenance of AF .
Atrial fibrosis could be caused by inflammation (oxidative stress), increased production of advanced glycation end products, increased expression of transforming growth factor-β and expression changes of gap junction proteins .
Atrial electrical remodelling
The principal characters of atrial electrical remodelling involve atrial effective refractory period shortening and its dispersion, as well as impairment of its frequency adaptation and consequent inter-atrial conduction delay . Changes in left atrial diameter, atrial activation time and voltage in patients with diabetes have been associated with atrial structural remodelling, not only electrical, especially in patients with AF. Chao et al., for example, studied patients with abnormal glucose metabolism (diabetes and impaired glucose tolerance) who underwent radiofrequency ablation of paroxysmal AF for the first time, and revealed that right and left atria voltages in these patients were significantly decreased due to atrial electrical remodelling and atrial fibrosis .
Atrial electromechanical remodelling
Findings from our group show that left and right atrial reservoir and conduit function, assessed by emptying fractions and strain, are decreased among subjects with prediabetes and patients with diabetes compared with controls . On the other hand, left and right atrial pump function increased in the same direction. These results agree with previous studies . Furthermore, Ayhan et al. found similar results regarding left atrial function, and also revealed that inter- and intra-atrial electromechanical delays were significantly higher in patients with glucose intolerance than in controls . Studies have also shown that that inter- and intra-atrial electromechanical abnormalities are associated with fasting glucose level and AF occurrence in patients with diabetes .
Atrial autonomic remodelling
The influence of diabetes on the autonomic nervous system–sympathetic and parasympathetic–is well known . Studies have demonstrated that atrial tissue in patients with diabetes has a greater ability to uptake choline and release acetylcholine .
Otake et al. revealed that diabetic mice were more susceptible to AF development after sympathetic stimulation than were controls . The electrophysiological investigation demonstrated shortened atrial effective refractory period and increased dispersion. However, parasympathetic stimulation in diabetic mice did not affect the atrial effective refractory period or the occurrence of AF . These findings imply that neural remodelling could have an essential role in the development of AF in patients with diabetes.
Clinical studies about diabetes and AF
Clinical investigations do not completely agree about the influence of diabetes on AF occurrence. Actually, the findings of these studies are conflicting ( Table 1 ). Some authors found that diabetes increased the risk of AF occurrence , whereas other studies did not reveal statistically significant differences in the risk of AF development with diabetes . Interestingly, some authors investigated differences in AF occurrence between men and women with diabetes. Frost et al. did not find any difference in AF prevalence between men and women with diabetes , whereas Benjamin et al. and Nichols et al. revealed that DM increases the risk of AF to a greater extent in women than in men . A recently published study showed that a significant relationship between baseline diabetes and incident AF was the consequence of changes of other AF risk factors (age, hypertension, obesity) .
| Reference | Sample size and subjects included in the study | Main findings |
|---|---|---|
| Movahed et al. | 293,124 diabetic patients and 552,624 hypertensive patients | Diabetes was a strong, independent risk factor for the occurrence of AF and atrial flutter, heart failure, left ventricular hypertrophy and CAD |
| Manitoba Follow-Up Study | 3983 male air crew recruits observed continuously for 44 years; 299 developed AF | Diabetes was a significant risk factor for AF development |
| Dublin et al. | 1410 people with newly recognized AF | Diabetes was associated with AF occurrence; risk was higher with longer duration of treated diabetes and worse glycaemic control |
| Ruigomez et al. | 1035 confirmed incident cases of chronic AF and 5000 controls from the general population | Diabetes was not a risk factor of AF occurrence |
| Danish Diet, Cancer, and Health Study | 47,589 participants without pre-existing cardiovascular or endocrine disease | Intermediate occurrence of diabetes during follow-up did not increase the risk for AF development |
| Framingham Heart Study | 2090 men and 2641 women, no history of AF | Men had a 1.5 times greater risk of developing AF than women; diabetes was a more important risk factor for AF in women |
| Nichols et al. | 17,372 patients with diabetes and matched subjects without diabetes | Diabetes was an independent predictor of AF among women but not men |
| Schoen et al. | 34,720 female health professionals who were free of cardiovascular disease and AF at baseline | A significant relationship between baseline diabetes and incident AF could be mainly explained by other cardiovascular risk factors |
| Swedish community study | 1739 subjects of both genders | Diabetes was not associated with AF, whereas the combination of hypertension and diabetes was related to AF |
| ARIC study | 14,598 middle-aged people followed for 17.1 years | Diabetes could explain 3% of the overall risk for AF occurrence |
| Thacker et al. | 1385 patients with newly diagnosed AF whose initial AF terminated within 6 months and who had ≥ 6 months of subsequent follow-up | Diabetes, blood pressure and hypertension were not associated with permanent AF |
| CARAF | 757 patients with a baseline diagnosis of paroxysmal AF | Diabetes did not contribute to the progression from paroxysmal to chronic AF |
| Tsang et al. | 3248 with paroxysmal AF | Progression from paroxysmal to permanent AF was related to gradual BMI increase, but not diabetes |
| NAVIGATOR study | 8943 patients without AF at baseline | Impaired glucose tolerance, but not progression to diabetes, predicted risk of AF |
| Huxley et al. | Meta-analysis including 108,703 cases of AF in 1,686,097 subjects | Patients with diabetes had an approximate 40% greater risk of AF compared to unaffected patients; the population-attributable fraction of AF due to diabetes was 2.5% |
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