QJM Advance Access originally published online on January 17, 2008
QJM 2008 101(3):181-187; doi:10.1093/qjmed/hcm123
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Influence of diabetes on the maintenance of sinus rhythm after a successful direct current cardioversion in patients with atrial fibrillation
From the 1Department of Medicine, Central Manchester University Hospitals, 2Department of Diabetes and Endocrinology, South Manchester University Hospitals, Manchester, 3Department of Cardiology, 4Department of Diabetes and Endocrinology, Wirral Hospitals NHS trust, Wirral, Cheshire, and 5University Department of Medicine, University Hospital Aintree, Liverpool, UK
Address correspondence to Dr Handrean Soran, Consultant Physician, Department of Endocrinology, Central Manchester University Hospitals, Oxford road, Manchester, M13 9WL, UK. email: handrean.soran{at}cmmc.nhs.uk
Received 28 April 2007 and in revised form 9 August 2007
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Summary |
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Aim: To determine independent risk factors for recurrence of atrial fibrillation (AF) after a successful direct current (DC) cardioversion in patients with and without diabetes.
Design: We retrospectively analysed the outcome in patients recently diagnosed with persistent AF.
Methods: Of 364 patients included, 289 had a successful direct current (DC) cardioversion. We compared 42 (14.5%) patients known to have diabetes to 247 (85.5%) without. Patients were reviewed in outpatient clinic with assessment of heart rhythm clinically and by electrocardiogram. Median follow-up after DC cardioversion was 74 days [interquartile range (IQR) 69–78 days].
Results: When reviewed in outpatient clinic, only 63.7% (185 of 289) were still in sinus rhythm (SR). Of the group without diabetes, 66.8% (165 of 247) remained in SR vs. 45.2% (19 of 42) of the group with diabetes (P = 0.005). Binary logistic regression analysis showed duration of AF (P < 0.0001) and the presence of diabetes (P = 0.019) have been independent risk factors for recurrence of AF.
Discussion: Presence of diabetes and the longer duration of AF were independent risk factors for the recurrence of AF after a successful DC cardioversion.
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Introduction |
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Atrial fibrillation (AF) is the commonest sustained cardiac arrhythmia.1 Both mortality and morbidity are significantly increased in patients with AF.2,3 Landmark studies4,5 have compared outcomes from two treatment strategies for chronic AF, rate control vs. rhythm control. These studies demonstrated that quality of life, the risk of stroke and mortality were not affected by an attempt to maintain sinus rhythm (SR).4,5 However, there are a substantial proportion of patients who continue to have AF-related symptoms or uncontrolled heart failure.5 For this group, it is still reasonable to aim at achieving SR especially with younger patients with recent AF. Even though, there is a role for rhythm control in selected groups of patients with AF, a careful assignment of patients to this type of treatment is important.
Cardioversion of AF can be established either by pharmacological or electrical approach with a primary success rates of 
70% in the former and 90% with external electrical cardioversion.6–8 However, both treatment modalities carry a high risk of recurrence of AF within 1 year.6–8 Recurrence of AF can be determined by many clinical and electrocardiographic parameters. A number of studies have investigated potential risk factors of failure of cardioversion, but generally the number of patients included were relatively small and most previous studies did not evaluate all relevant factors that may influence the long-term outcome of AF.9–12 Specifically, diabetes has not been identified before as a significant risk factor for failure of direct current (DC) cardioversion previously.
To our knowledge, no study has examined the influence of diabetes on the recurrence of AF after a successful DC cardioversion. We examined the clinical and echocardiographic factors on the recurrence of AF after a successful DC cardioversion.
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Research design and methods |
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This was a retrospective study, the subjects were recruited from patients diagnosed with persistent AF attending the Cardiology Department for DC cardioversion in a large district general hospital in Wirral, UK, which represents a health authority with 420 000 inhabitants. From the hospital's electronic database we identified patients due to have DC cardioversion from October 2001 to February 2005 (n = 401) and data were collected from the medical records. Thirty-seven patients were excluded (10 had valvular heart disease, two had history of heart valve replacement, two had AF after coronary bypass graft, six reverted to SR before attempted DC cardioversion, two had AF secondary to thyrotoxicosis, five developed AF in the course of acute MI and 10 because of missing data), exclusion criteria mentioned below.
All patients were anti-coagulated for at least 6 weeks prior to cardioversion. International normalized ratio (INR) was checked at least weekly for the preceding 4 weeks prior to cardioversion and the dose of warfarin adjusted to maintain the INR between 2.0 and 3.0 (target INR 2.5). Patients attended a nurse-led pre-cardioversion clinic to check serum potassium (target >4.0 mmol/l, oral potassium supplements were prescribed if necessary) and INR. Digoxin was stopped in all patients 48 h before cardioversion and not recommenced in patients who had a successful DC cardioversion. Thyroid function tests, urea and electrolytes, full blood count and cholesterol were checked in all patients. If prescribed amiodarone, sotalol or flecainide treatment, patients were advised to continue until reviewed in clinic. All patients were reviewed 3 to 4 h after DC cardioversion (before discharge) and then in the outpatient clinic, median time from DC cardioversion was 74 days (IQR 69–78 days). Clinical examination and a 12-lead ECG were performed at each review.
Definitions
Successful DC cardioversion was defined as remaining in SR when assessed clinically and by ECG 3 h post-DC cardioversion. Persistent AF was defined as episodes that failed to self-terminate spontaneously and lasted for longer than 7 days but could be converted to SR with pharmacological or electrical cardioversion. Duration of AF was the period (in weeks) from ECG-documented AF to the day of DC cardioversion (we acknowledge that this may not reflect the true arrhythmia duration in all cases). In patients who had a successful cardioversion, the period (in days) from the day of DC cardioversion to the day of first outpatient follow-up was calculated to compare differences between the subgroups with and without diabetes. All patients with documented history of hypertension or three recent blood pressure readings above 160/90 mmHg were regarded as having hypertension. All patients on lipid-lowering treatment or with a total serum cholesterol of more than 5.2 mmol/l were regarded as having hyperlipidaemia. In patients with diabetes, HbA1c referred to the mean of the most recent three measurements. HbA1c values were measured by affinity chromatography using a commercial kit (BioRad,UK; non-diabetic range 4.2–5.8%). Echocardiograms were performed in the Department of Cardiology, Wirral Hospital NHS trust (using Philips-Sonos 5500 and Philips-Sonos 5400 echocardiogram machines). All echocardiogram operators have British Society of Echocardiography accreditation. Estimates of left ventricular ejection fraction (LVEF) were made by readings obtained automatically by the standard computer package with the machines. LVH was diagnosed by measurement of intra-ventricular septum and posterior wall thickness or by an eye-ball estimate if these measurements could not be accurately measured. Using antero-apical position, uniphasic DC cardioversion was performed on an elective basis with a Hewlett Packard device. One hundred joules was used initially.
Ethical consideration
The study was approved by the Wirral Research Ethical Committee.
Inclusion criteria
All patients with documented persistent AF who had a successful DC cardioversion from October 2001 to February 2005 were included. There was no upper age limit.
Exclusion criteria
Patients with cardiac valvular disease (other than mild mitral and tricuspid valve regurgitation), rheumatic heart disease, previous heart valve surgery, congenital heart disease, patients with AF in the course of acute MI or cardiac surgery, AF secondary to thyrotoxicosis, patients who reverted to SR before DC cardioversion and patients in whom important data was missing from the notes.
Statistical analysis
SPSS software version 13 was used to analyse the data. Data was expressed as frequency and percentage for categorical data and median and IQR for continuous data. We used recurrence of AF at the first outpatient follow-up as a dependent outcome. Chi square test was used to compare different characteristics and medications used in patients with and without diabetes. Binary logistic regression analysis was used to identify independent risk factors for recurrence of AF following successful DC cardioversion. A P-value of <0.05 was considered to be statistically significant.
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Results |
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In 289 patients, DC cardioversion was successful (Figure 1). Median age was 70 years (IQR, 63–76 years), 60% (174 of 289) were male, 14.5% (42 of 289) had diabetes (41 had type 2 diabetes); other characteristics are shown in Table 1. Basic characteristics of individuals with diabetes compared with those without are demonstrated in Table 2. Hypertension, dyslipidaemia and smoking were significantly more common among the patients with diabetes. Lipid-lowering treatment and angiotensin system blocking agents (ACE-I and ARBs) were prescribed more frequently in patients with diabetes. There were no significant differences in prescribing other medications including anti-arrhythmic drugs sotalol and amiodarone. Duration of AF was significantly longer among the group with diabetes. Mean IV septum thickness was significantly greater in patients with diabetes (Table 2).
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DC cardioversion was successful in 289 (79.4%) patients. Only 184 (63.7%) patients remained in SR when seen in the first outpatient follow-up. Among the 247 patients with no history of diabetes, 66.8% (165 of 289) remained in SR compared with 45.2% (19 of 42 patients) in the group with diabetes (P < 0.01) (Figure 1).
Independent risk factors for recurrence of AF in the 289 patients who initially had a successful DC cardioversion
Logistic regression analysis showed that duration of AF (P < 0.0001) (odds ratio 0.9, 95% CI 0.87–0.93) and history of diabetes (P = 0.019) (odd ratio 0.34, 95% CI 0.14–0.84) were the independent risk factors reducing the likelihood of maintenance of SR after a successful DC cardioversion (Table 3). None of the other clinical and echocardiographic parameters or medications used had a significant impact on outcome (Table 3).
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Conclusion |
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Diabetes is associated with increased risk of developing AF in both men and women,2,13,14 the risk is higher in those with both diabetes and hypertension.15 Diabetes may also enhance the progression from paroxysmal AF to persistent AF.16
Electrical cardioversion was introduced by Lown17 in 1962. It is reported to restore SR in up to 90% of patients with persistent AF,6,16 yet up to 60% of patients may revert to AF within 1 year.6,17 A number of studies have investigated potential risk factors of failure of DC cardioversion and recurrence of AF after a successful DC cardioversion, but generally the number of patients included was relatively small and most of the previous studies did not evaluate all the relevant factors that may influence the outcome of AF.10–12,18,19 Furthermore, diabetes was not identified as a statistically significant risk factor for failure of DC cardioversion previously. This could be related to the relatively small number of the patients included,11 or in some other studies diabetes was not scrutinized as a potential risk for recurrence of AF after a successful DC cardioversion.12,19 In three previous studies, duration of AF, left atrial size, LVEF have been found to be predictors of recurrence, while age, gender and aetiology of AF have not been found to be related.9,10,19 In another study, Van Gelder et al.12 have showed better pre-cardioversion functional status (according to New York Heart Association Classification) and presence of non-rheumatic mitral valve disease independently increased arrhythmia free period after successful DC cardioversion. Interestingly, in patients not on class I and III anti-arrhythmic drugs, absence of diabetes has been reported to predict spontaneous reversion to SR in patients who develop post-operative AF after cardiac surgery.20
This study included a relatively large number of patients. Multiple logistic regression analysis showed that diabetes and duration of AF prior to DC cardioversion were significant factors influencing recurrence of AF after a successful DC cardioversion (Table 3). This adverse effect of diabetes on the outcome of rhythm control with DC cardioversion in patients with AF is likely to be multi-factorial. Higher prevalence of hypertension, ischaemic heart disease (IHD), dyslipidaemia, PVD, larger left atrial size, lower left ventricular ejection fraction, thicker inter-ventricular septum (IVS) and longer duration of AF may have all played a role. However, many of these differences did not reach statistical significance (Table 2). This suggests presence of other diabetes related important factors.
Cardiac myocyte necrosis has been identified in diabetic heart;21 this results in increased deposition of collagen in a diffuse or scattered manner causing myocardial fibrosis.22–25 Evidence in vivo has shown that hyperglycaemia directly induces apoptotic cell death and myocyte necrosis in the myocardium.26 In diabetic subjects, other factors may contribute to increased myocardium fibrosis including connective tissue proliferation,27 impaired collagen degradation,28 up-regulation of the local rennin-angiotensin system,29,30 hyperglycaemia-induced up-regulation of indothelin-1,31 resistance to insulin growth factor-1 action30 and increased tissue growth factor beta-1.32,33 Recent findings suggested a mechanistic link between inflammatory process and development of AF and it is maintenance.34 Fibrosis and inflammation of atrial myocardium slows the inter-atrial conduction velocity and increases re-entrant waves,34–36 that could predispose to recurrence of AF after a successful DC cardioversion. Increased re-entry waves are likely to occur in the atria with structural abnormalities.36 Increased oxidative stress in diabetes has also been implicated in the pathophysiology of AF37 and may play a role in it is maintenance. Furthermore, autonomic neuropathy appears to play an important role in onset, maintenance and termination of AF.38 While radio-frequency ablation has provided us with a unique insight into the role of possible denervation in suppression of AF, the exact mechanisms involved are far from been completely understood.38
However, exaggerated ischaemia consequent to more severe and extensive coronary artery disease in diabetes as well as the presence of microvascular diseases28,39 may also play an important role, perhaps the most important, in increasing myocardium fibrosis and recurrence of AF.28,36,39 Hypoglycaemia-induced adreno-sympathetic axis activation in patients on insulin or oral hypoglycaemic agents are other possible contributing factors.40
This was a retrospective analysis with all the inherent limitations. We do acknowledge that there are some potential sources of bias. Duration of AF was longer in the diabetes group. Blood glucose was not a part of routine pre-DC cardioversion tests, therefore it is possible that a small number of patients with undiagnosed diabetes, impaired glucose tolerance or impaired fasting glycaemia were included in the in the group with no history of diabetes. This obviously may have diluted any possible effect of diabetes on the outcome of DC cardioversion. Furthermore, as expected, hypertension and dyslipidaemia were significantly more prevalent in the group with diabetes. Smoking was also more common among the patients with diabetes. As data were collected retrospectively it is inevitable that different physicians and echocardiogram technicians had to perform the DC cardioversion as well as echocardiogram and are subject to bias. Not all patients presenting with AF are listed for DC cardioverion; this depends on the physician's management plan resulting in selection bias.
On the other hand, amiodarone, ACE-I and ARB were significantly more widely prescribed in patients with diabetes. There is growing evidence that these agents reduce the risk of AF41 and the chance of recurrence of AF after cardioversion if co-prescribed with amiodarone,42,43 therefore making the results of this study in some ways more interesting.
Left atrial diameter did not have a significant effect in our study; higher rate of amiodarone prescription in patients with larger left atrial size (
4.5 cm) could have played an important role in this difference between this and previous studies.9,10,19
Our findings are different from the retrospective evaluation of patients in AFFIRM study by Raitt et al.,44 however there are important differences. In Raitt et al.'s study both chemical and electrical cardioversion were used; all patients were reviewed in 2 months after cardioversion compared with a median first follow-up of 74 days in our study. Interestingly, in Raitt et al.'s study more patients with diabetes needed two or more cardioversions during the first year of follow-up but this did not reach statistical significance (P = 0.6). In contrast to previous studies,9,10,19 in Raitt et al.'s study the duration of AF was not identified as an important risk factor of recurrence of AF.44
In conclusion, we have demonstrated that diabetes is an independent risk factor for recurrence of AF after a successful DC cardioversion. Rate control strategy might be more appropriate for patients with diabetes who develop AF provided their symptoms are controlled with this type of treatment. Further studies needed to confirm our findings.
Conflict of interest: None declared.
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