Abstract
Background: We aimed to determine the relationship between
HbA1c levels and the development of postoperative atrial fibrillation
(PoAF) .
Methods: 288 patients diagnosed with diabet and undergoing
on-pump coronary bypass were included in the study. Those with serum
HbA1c levels between 5.5-7.0% were defined as Group 1, those with serum
HbA1c levels between 7.1-8.9% were defined as group 2, while those with
serum HbA1c levels 9.0% and above formed Group 3. Data between groups
were compared. The predictive values of the independent variables for
the development of PoAF were measured.
Results: We did not found difference between groups in terms of
development PoAF (p=0.170). Presence of hypertension was determined as
an independent predictor for the development of PoAF (p=0.003) but not
HbA1c levels (p=0.134). There was 50.5% sensitivity and 61.1%
specificity for HbA1c values of 9.06% and above to predict PoAF (AUC:
0.571, p=0.049)
Conclusions: HbA1c levels were not an independent predictor of
PoAF development. However, we think that high HbA1c levels may be a risk
factor for the development of PoAF.
Key words: Diabetes mellitus, HbA1c, postoperative atrial
fibrillation, coronary artery bypass grafting
INTRODUCTION
Diabetes mellitus (DM) is a chronic condition with dysfunction in
insulin secretion that associated with systemic atherosclerosis, such as
stroke, ischemic heart disease, and lower extremity arterial
disease.1 In 2015, the International Diabetes
Federation reported that 8.8% of the world’s population suffers from
DM.2
Hyperglycemia could increase mortality by causing renal and lung adverse
events in diabetic patients undergoing cardiac surgery and may also
increase the incidence of postoperative atrial fibrillation
(PoAF).3 PoAF is the most common arrhythmic
complication of coronary artery bypass grafting (CABG) surgery. Various
studies have reported that the incidence of PoAF varies between 10% and
45%, depending on the type of cardiac
surgery.4,5 There are many risk factors for
the development of PoAF, such as advanced age, obesity, abnormal heart
rate, hyperglycemia, hypertension, increased left atrial size, statin
withdrawal, and the presence of atrial fibrillation
(AF).6 Diabetes-induced endothelial
dysfunction, abnormal renin-angiotensin-aldosterone system, acceleration
of atherogenesis, angiogenesis and abnormal hemostasis eventually lead
to atrial remodeling, one of the mechanisms that may be responsible for
the formation of AF.7-9 In other words,
diabetes can cause structural, electrical, electromechanical and
autonomic remodeling in the atrium.10However, it is not entirely known whether DM plays a role in the
development of AF by affecting only the atrial tissue or by involving
different pathways such as hypertension, coronary artery disease and
abnormal activity of the autonomic nervous system.
Hemoglobin A1c (HbA1c) reflects the average blood glucose level over the
previous 3 months for glycemic management in patients with diabetes and
has been a well-accepted biomarker over the past few
decades.11 There are studies showing that
high HbA1c levels are associated with increased cardiovascular risks,
such as myocardial infarction and AF, in patients with and without
diabetes.12 However, the data on the effect
of HbA1c, which is determined as a marker of preoperative glycemic
control and the degree of hyperglycemia, on the development of PoAF are
insufficient and its predictive value has not yet been understood.
The aim of this study was to investigate the relationship between
preoperative HbA1c and PoAF development in diabetic patients who
underwent isolated on-pump CABG in our center.
METHODS
The Patients
All procedures were performed in accordance with the Declaration of
Helsinki. This retrospective observational clinical study was conducted
on 447 consecutive patients over 18 years of age diagnosed with Diabetes
Mellitus who underwent on-pump CABG in the Department of Cardiovascular
Surgery of Bursa Yüksek İhtisas Training and Research Hospital between
January 2018 and December 2020. This study was approved by the local
institutional Ethical Committee of University of Health Sciences -
Turkey (Approval number: 2011- KAEK-25 2021/04-05). All procedures were
performed in accordance with the Declaration of Helsinki.
Patients who were randomized according to the exclusion criteria were
included in the study. All data to be analyzed were obtained from the
patients’ medical files. Preoperative clinical conditions such as atrial
fibrillation/flutter, heart valve disease, chronic obstructive pulmonary
disease, patients receiving hemodialysis for end-stage renal disease,
serum creatinine > 2.0 mg/dl, clinical conditions such as
combined surgery (CABG + carotid surgery, CABG + heart valve surgery,
CABG + aortic surgery), emergency coronary bypass, redo bypass,
preoperative inotropic or mechanical support, bleeding revision, and
prolonged (more than ten days) intensive care unit (ICU) stay were
accepted as exclusion criterias. After these exclusion criteria, 288
diabetic patients who underwent isolated on-pump CABG were included in
the study (Figure 1). The patients included in the study were divided
into three groups according to their serum HbA1c levels. Those with
serum HbA1c levels between 5.5-7.0% were defined as Group 1, those with
serum HbA1c levels between 7.1-8.9% were defined as group 2, while
those with serum HbA1c levels 9.0% and above formed Group 3.
All data including age, gender, history of hypertension, presence of
peripheral arterial disease, previous cerebrovascular accident,
preoperative drug use (beta-blockers, statins, ACE /ARB inhibitors,
antidiabetic treatment), ejection fraction, left atrial diameter (LAD),
body mass index (BMI), development of PoAF, number of anastomosis,
aortic X-clamp time, total cardiopulmonary bypass (CPB) time, duration
of intensive care unit (ICU) stay, and discharge time from hospital were
added to the records. Laboratory parameters were also studied from
venous blood sample before the surgery.
Anesthesia and Surgical Procedure
The same anesthesia and surgical method were applied to all patients.
Fentanyl (Talinat®; Vem, Istanbul, Turkey) 1-2 μg/kg and pentothal
(Pental® Sodium, Istanbul, Turkey) 5-7 mg/kg and rocuronium bromide
(Curon®, Mustafa Nevzat, Istanbul, Turkey) 0.6 mg/kg iv was used for
induction. Anesthesia was maintained with midazolam, fentanyl and
rocuronium.
For extracorporeal circulation, membrane oxygenator and non-pulsatile
roller pump were used ((Maquet, Getinge group, Restalt, Germany) and
mild hypothermia (32°C) was applied. The mean arterial blood pressure
was kept in the range of 60-80 mmHg. Following the completion of the
surgery, patients were taken to the cardiovascular surgery intensive
care unit. Standard postoperative care was given to all the patients.
Insulin management
Insulin infusion was initiated at blood glucose levels above 200 mg/dL
and blood glucose levels between 120-150 mg/dL were targeted. Insulin
infusion dose ”(Unit/hour) = (Blood sugar-60) × insulin sensitivity
coefficient (0.03-0.05)” was calculated according to the formula. Blood
glucose measurements were made every 20 minutes in the operating room,
every hour for the first 6 hours in the intensive care unit, and every 2
hours thereafter.
Diagnosis of PoAF
All patients were followed up in ICU by monitoring continuous heart
rhythm and invasive blood pressure. In addition, a 12-lead
electrocardiography (ECG) was also obtained daily during the ICU stay. A
12-lead ECG was taken when patients complained of palpitations,
shortness of breath or angina in the postoperative inpatient service. AF
was verified by a 12-lead ECG and diagnosed according to the guidelines
of the European Society of Cardiology. An AF episode that lasted longer
than 5 minutes was considered as PoAF. Standard medical cardioversion
therapy was performed with a 30-minute amiodarone (5 mg/kg) infusion
followed by a maintenance dose of 900 mg/day. AFs that developed until
the day the patients were discharged from the operation were recorded.
Statistical Analysis
For statistical analysis, SPSS (IBM SPSS 21.0, Chicago, IL, USA) was
used. Continuous variables were expressed as mean±standard deviation and
nominal variables were expressed as frequency and percentage.
Kolmogorov-Smirnov test was used to identify distribution of variables
for normality analysis. Pearson chi-square test was used to compare two
and three independent groups for nominal variables and in the event of
the minimum expected count is less than 5 Fisher’s Exact test was used.
One-way ANOVA test was used for continuous data with normal distribution
in independent more than two groups, while Kruskal Wallis test was used
for continuous data that without normal distribution. To determine which
group caused the statistical difference, Tukey HSD for One-way ANOVA and
Dunn’s -Bonferroni test for Kruskal Wallis test were used as post-hoc
analyses. To evaluate whether there is a correlation between the
development of PoAF and preoperative HbA1c levels , a Dual-Series
Correlation test was performed, which correlates a dichotomy data with a
continuously variable data. Preoperative and operative independent
variables that may affect PoAF development were included in the logistic
regression analysis for predictors of development of PoAF. Parameters
with a p value < 0.25 in univariate logistic regression
analysis were included in multivariate logistic regression analysis.
Receiver-operating characteristic (ROC) curve was applied for the
prediction of PoAF development in patients undergoing diabetic isolated
CABG and the area under the curve was calculated for HbA1c levels and by
measuring the cut-off value the sensitivity and specificity of the area
under curve (AUC). For all tests, p <0.05 was considered
statistically significant.
RESULTS
Based on exclusion criteria, 288 of 447 diabetic coronary bypass
patients were included in the study (Figure 1). The demographic findings
of the patients according to the groups are shown in Table 1. While
there was no statistical difference between the groups in terms of
demographic data in general, the rate of not using any anti-diabetic
drug in the group with high HbA1c was found to be statistically
significantly higher than the other groups. Likewise, it was an expected
finding that oral anti-diabetic drug use was less common in group 3 than
in other groups (Table 1).
Comparison of laboratory variables is also shown in Table 1. It was a
natural consequence of this study that HbA1c levels were different (p
< 0.001) between groups in terms of laboratory parameters. In
addition, although creatinine levels were within normal limits, they
were found to be significantly lower in group 1 compared to other groups
(p=0.010).
The perioperative and postoperative findings of the patients are
summarized in Table 2. While the X-clamp time was shorter in Group 1,
the length of stay in the ICU was longer in Group 2. These differences
were statistically significant (p=0.034, p=0.007, respectively) (Table
2). Except those, when the groups were compared, there was no
significant difference in terms of development of PoAF, mortality and
length of hospital stay (Table 2)( p=0.170, p=0.996, p=0.088,
respectively)
We found a weak correlation between HbA1c levels and the development of
PoAF in a Dual-Series Correlation analysis (r=-0.116, p=0.049,
Spearman’s correlation).
In this study, risk factors related with the development of PoAF were
included in the univariate logistic regression analysis. In univariate
logistic regression analysis, the PoAF was significantly correlated with
only the presence of hypertension (OR [Odds Ratio]= 2.566, 95% CI
[Confidence interval]: 1.388-4.742, p=0.003), but was not correlated
with age, ejection fraction, LAD, BMI, C-reactive protein (CRP),
creatinine, HbA1c levels and aortic X-clamp time (Table 3). Parameters
with a p value < 0.25 in univariate logistic regression
analysis were included in multivariate logistic regression analysis.
Only the presence of hypertension (OR= .397, 95% CI: .214- .738,
p=0.003) was identified as an independent predictor of PoAF development
after CABG surgery in multivariate analysis (Table 3).
ROC curve analysis demonstrated that HbA1c values of 9.06% or above
could predict development PoAF with 50.5% sensitivity and 61.1%
specificity (AUC: 0.571, 95% CI: 0.502-0.640, log rank p=0.049)(Figure
2).
DISCUSSION
In our study, we evaluated the effect of HbA1c levels on the development
of PoAF in patients diagnosed with diabetes mellitus and undergoing
isolated on-pump CABG. In univariate and multivariate logistic
regression analysis, we found that only the presence of hypertension was
an independent variable predicting the development of PoAF. We could not
find HbA1c levels as a predictor of PoAF development. But, we found that
there was a weak correlation between HbA1c levels and the development of
PoAF (r=-0.116, p=0.049, Spearman’s correlation). Also, in the ROC curve
analysis, we found that 9.06% or higher HbA1c values could predict the
development of PoAF with 50.5% sensitivity and 61.1% specificity (AUC:
0.571, 95% CI: 0.502-0.640, log rank p=0.049). (Figure 2).
In a recently published meta-analysis involving 352,325 patients, the
relationship between HbA1c and atrial fibrillation was investigated and
demonstrated that high serum HbA1c levels are associated with an
increased risk of AF in both diabetes and undiagnosed diabetes. It has
been stated that for every 1% increase in HbA1c level, the risk of AF
increases by 28%.13 However, in the same
meta-analysis, no relationship was found between HbA1c and PoAF in
patients who had undergone CABG. In another study by Iguchi et
al.14 the effect of HbA1c on AF was
investigated in 52,448 diabetic and non-diabetic patients and the
authors stated that HbA1c levels above 6.5% may be associated with the
prevalence of AF.
While no correlation was found between HbA1c and AF seen after coronary
bypass in two studies investigating the relationship between PoAF and
HbA1c.15,16 Surer et
al.17 reported that high HbA1c levels may be
a predictor of the development of PoAF in their study including off-pump
coronary bypass patients. In their study which investigated the effect
of glycosylated hemoglobin on outcomes after isolated CABG, Ramadan et
al.18 found more PoAF at HbA1c levels above
7%, but did not accept this as a predictor. Likewise, in a similar
study, Arslan et al.19 found statistically
significantly more PoAF in the group with HbA1c level above 7%.
Contrary to these studies, Halkos et al.20found statistically significantly less PoAF in the group with HbA1c of
7% and above. Likewise, Kinoshita et al.21reported that higher preoperative HbA1c levels were independently
associated with a lower risk of postoperative AF. They stated that the
reason for this situation is that patients with high HbA1c need more
insulin for postoperative blood sugar control and that these insulin
applications reduce the risk of postoperative AF. In addition, Matsuura
et al.22 also detected more PoAF in the group
with HbA1c below 6.5%.
Diabetes is associated with several metabolic defects including insulin
resistance, impaired glucose tolerance, proinflammatory mediators,
abnormalities of haemostasis, fibrinolysis, angiogenesis and
extracellular matrix turnover.23 With
increased duration of DM, exposure to these metabolic abnormalities and
hyperglycemia will be longer, and HbA1c is an indicator of this. In
addition, DM is a chronic inflammatory process that associated with
systemic atherosclerosis, including coronary artery disease. An
association between increased CRP levels and the prevalence of AF has
been reported.24 Hyperglycemia can regulate
markers of chronic inflammation and contribute to increased generation
of reactive oxygen species (ROS). Increased oxidative stress and
inflammation can lead to insulin resistance and impaired insulin
secretion.25 Inflammation due to oxidative
stress can cause atrial fibrosis. Animal studies have shown that
interstitial fibrosis of the left atrium is a major trigger of AF in
patients with diabetes by causing structural
remodeling.26 In a study, it was stated that
hyperglycemia prolongs atrial transmission durations and P wave
distribution in prediabetic patients.27 Chao
et al.28 demonstrated that right and left
atrial voltages were significantly reduced due to atrial electrical
remodeling and atrial fibrosis in patients with diabetes and impaired
glucose tolerance who underwent radiofrequency ablation for paroxysmal
AF. In the light of all these explanations, it can be stated that
inflammation, oxidative process, fibrosis, structural and electrical
atrial remodeling caused by DM may play a role in the development of AF.
Considering HbA1c as a measure of exposure to hyperglycemia, it can be
said that high HbA1c levels are associated with the development of
AF.13,14 On the other hand, the relationship
between the development of PoAF after CABG and high HbA1c levels is not
clear, and there are even publications stating that it is inversely
related.20-22 This can be explained by the
presence of many factors such as hypoxia, low EF, CPB duration, renal
dysfunction and valve disease that may affect the development of PoAF in
CABG patients. In addition, in the literature, AF has generally
evaluated at HbA1c levels above 6.5% and 7%. In our study, the cut-off
value of HbA1c was 9.06%, and in ROC analysis, 50.5% sensitivity and
61.1% specificity were found for this and higher levels (AUC: 0.571,
p=0.049) (Figure 2). In our study, we could not find high HbA1c levels
as an independent predictor for the development of PoAF in logistic
regression analysis, but the 9.06% cut-off HbA1c level in our study was
in the very high category, indicating mean blood glucose levels above
240 mg/dL. There is a risk of serious complications at these high blood
glucose levels and together with other factors, may lead to the
development of AF after coronary bypass surgery.
In recent studies, it has been stated that oral antidiabetic drugs such
as thiazolidinedione, dipeptidyl peptidase 4 inhibitor and dapagliflozin
reduce the risk of developing atrial fibrillation in type-2 diabetic
patients.29-31 They explained the possible
reason for this as its effects on inflammation, oxidative process and
fibrosis. In our study, similar to the literature, we found the rate of
development of PoAF to be lower in the group with a significantly higher
rate of oral antidiabetic drug use (group 1) (p=0.002). At the same
time, the rate of those who did not use any antidiabetic agent was
statistically significantly higher in group 3 with high HbA1c levels
(p=0.008). This finding explains the high HbA1c levels of patients in
this group. Therefore, it can be said that the patients in this group
have lower blood insulin levels. In addition, although it was not
statistically significant, the incidence of PoAF was found to be higher
in this group than in the other groups. In parallel with the statement
of Kinoshita et al.21 that adequate insulin
levels reduce the risk of PoAF, according to our study it can be said
that more PoAF was seen in the group exposed to less insulin before
surgery.
Hypertension is a known cause of the development of AF, and in parallel,
hypertension was detected as an independent predictor of the development
of PoAF in our study. Although there was no correlation in univariate
analysis, the age parameter was included in the multivariate analysis in
our study since the role of advanced age in the development of AF has
been shown in many studies.32,33 But, we
could not find age as an independent predictor for the development of
PoAF. This may be because the mean age of the patients in our study was
below 65 years of age and we did not evaluate the development of AF in
patients over 65 years of age.
STUDY LIMITATIONS
There were several limitations of our study. Firstly, the sample size
was relatively small and the study was retrospective and
single-centered. Secondly, lack of a control group of non-diabetic
patients in our study. Thirdly, our disregard for the doses of inotropes
used that may have affected the occurrence of AF.
CONCLUSSION
Although more PoAF was seen in the high HbA1c (>9.0%)
group in our study, we could not find HbA1c levels as an independent
predictor for the development of PoAF. However, high HbA1c levels are
indicative of high blood glucose levels. We think that this high
hyperglycemic exposure may contribute to the development of PoAF after
CABG by causing inflammation, oxidative process and metabolic disorders.
Thus, we think it may be a risk factor.