Abstract
OBJECTIVES:
The aim of our study was to evaluate the total atrial conduction time and its relationship to subclinical atherosclerosis, inflammation and echocardiographic parameters in patients with type 2 diabetes mellitus.
METHODS:
A total of 132 patients with type 2 diabetes mellitus (mean age 54.5±9.6 years; 57.6% male) and 80 age- and gender-matched controls were evaluated. The total atrial conduction time was measured by tissue-Doppler imaging and the carotid intima-media thickness was measured by B-mode ultrasonography.
RESULTS:
The total atrial conduction time was significantly longer in the patients with type 2 diabetes mellitus than in the control group (131.7±23.6 vs. 113.1±21.3, p<0.001). The patients with type 2 diabetes mellitus had significantly increased carotid intima-media thicknesses, neutrophil to lymphocyte ratios and high-sensitivity C-reactive protein levels than those of the controls. The total atrial conduction time was positively correlated with the high-sensitivity C-reactive protein level, neutrophil to lymphocyte ratio, carotid intima-media thickness and left atrial volume index and negatively correlated with the early diastolic velocity (Em), Em/late diastolic velocity (Am) ratio and global peak left atrial longitudinal strain. A multiple logistic regression analysis demonstrated that the neutrophil to lymphocyte ratio, carotid intima-media thickness and global peak left atrial longitudinal strain were independent predictors of the total atrial conduction time.
CONCLUSIONS:
We suggest that subclinical atherosclerosis and inflammation may represent a mechanism related to prolonged total atrial conduction time and that prolonged total atrial conduction time and impaired left atrial myocardial deformation may be represent early subclinical cardiac involvement in patients with type 2 diabetes mellitus.
Inflammation; Left Atrial Strain; Subclinical Atherosclerosis; Total Atrial Conduction Time
INTRODUCTION
Type 2 diabetes mellitus (T2DM) is a chronic multisystem disease associated with a high risk of cardiovascular disease (11 Ryden L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, et al. DESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J. 2013;34(39):3035-87.). In clinical practice, atrial fibrillation (AF) is the most frequently observed cardiac arrhythmia and is related to increased morbidity and mortality. Diabetes is significantly correlated with AF in both genders even after adjusting for age and other risk factors (22 Benjamin EJ, Levy D, Vaziri SM, D′Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA. 1994;271(11):840-4.). However, the pathological mechanisms related to the initiation and maintenance of AF in patients with diabetes mellitus have not been well described.
In patients with T2DM, the carotid intima media thickness (CIMT), which is a
well-established marker of subclinical atherosclerosis, is significantly greater
than that in non-diabetic subjects (33 Taniwaki H, Kawagishi T, Emoto M, Shoji T, Kanda H, Maekawa K, et
al. Correlation between the intima-media thickness of the carotid artery and
aortic pulse-wave velocity in patients with type diabetes. Vessel wall
properties in type 2 diabetes. Diabetes Care.
1999;22(11):1851-57.).
Subclinical chronic inflammation is widely known to play a key role in the
initiation, propagation and development of diabetes (44 Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory
disease. Nat Rev Immunol. 2011;11(2):98-107,
http://dx.doi.org/10.1038/nri2925.
http://dx.doi.org/10.1038/nri2925...
). Both laboratory and epidemiological studies have suggested that
subclinical atherosclerosis and inflammation can play a role in the development of
AF (55 Boos CJ, Anderson RA, Lip GY. Is atrial fibrillation an
inflammatory disorder? Eur Heart J.
2006;27(2):136-49.
6 Chen LY, Foo DC, Wong RC, Seow SC, Gong L, Benditt DG, et al.
Increased carotid-intima media thickness and arterial stiffness are associated
with lone atrial fibrillation. Int J Cardiol.
2013;168(3):3132-4.
7 Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Rooij FJ, Lip
GY, et al. Subclinical atherosclerosis and risk of atrial fibrillation: the
Rotterdam Study. Arch Intern Med. 2007;167(4):382-7,
http://dx.doi.org/10.1001/archinte.167.4.382.
http://dx.doi.org/10.1001/archinte.167.4...
8 Willeit K, Pechlaner R, Egger G, Weger S, Oberhollenzer M,
Willeit J, et al. Carotid atherosclerosis and incident atrial fibrillation.
Arterioscler Thromb Vasc Biol. 2013;33(11):2660-5,
http://dx.doi.org/10.1161/ATVBAHA.113.302272.
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-99 Liu T, Li G. Inflammation: Another potential mechanism between
diabetes mellitus and atrial fibrillation. Am J Cardiol.
2008;101(11):1681-2,
http://dx.doi.org/10.1016/j.amjcard.2008.04.006.
http://dx.doi.org/10.1016/j.amjcard.2008...
). However, there are not sufficient data in the literature regarding
the relationship between AF and subclinical atherosclerosis and inflammation in
diabetic patients.
Electrical and structural atrial remodeling, the shortening of the atrial refractory
period and the inhomogeneous propagation of sinus impulses are well-known
electrophysiological characteristics of fibrillation-prone atria. The total atrial
conduction time (TACT), measured via tissue Doppler imaging (PA-TDI Interval), is a
novel echocardiographic parameter used to identify the presence and the extent of
electrical and structural atrial remodeling (1010 Chao TF, Sung SH, Wang KL, Lin YJ, Chang SL, Lo LW, et al.
Association between the atrial electromechanical interval, atrial remodeling and
outcome of catheter ablation in paroxysmal atrial fibrillation. Heart.
2011;97(3):225-30, http://dx.doi.org/10.1136/hrt.2010.212373.
http://dx.doi.org/10.1136/hrt.2010.21237...
). Previous studies have shown that a prolonged TACT is a strong and
independent predictor of new-onset AF (1111 Den Uijl DW, Gawrysiak M, Tops LF, Trines SA, Zeppenfeld K,
Schalij MJ, et al. Prognostic value of total atrial conduction time estimated
with tissue Doppler imaging to predict the recurrence of atrial fibrillation
after radiofrequency catheter ablation. Europace. 2011;13(11):1533-40,
http://dx.doi.org/10.1093/europace/eur186.
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,1212 de Vos CB, Weijs G, Crijns HJ, Cheriex EC, Palmans A, Habets J,
et al. Atrial tissue Doppler imaging for prediction of new onset atrial
fibrillation. Heart. 2009;95(10):835-40,
http://dx.doi.org/10.1136/hrt.2008.148528.
http://dx.doi.org/10.1136/hrt.2008.14852...
). In this study, we
hypothesized that the relationship between DM and AF may be mediated by the effect
of subclinical atherosclerosis and inflammation on atrial myocardial tissue.
High-sensitivity C-reactive protein (hsCRP) is an inflammatory biomarker that
independently predicts the cardiovascular risk (1313 Libby P, Ridker PM, Maseri A. Inflammation and Atherosclerosis.
Circulation. 2002;105(9):1135-43,
http://dx.doi.org/10.1161/hc0902.104353.
http://dx.doi.org/10.1161/hc0902.104353...
). The neutrophil to lymphocyte ratio (NLR), as an indicator of
systemic inflammation, is an emerging marker for both cardiac and non-cardiac
disorders (1414 Tamhane UU, Aneja S, Montgomery D, Rogers EK, Eagle KA, Gurm HS.
Association between admission neutrophil to lymphocyte ratio and outcomes in
patients with acute coronary syndrome. Am J Cardiol.
2008;102(6):653-7,
http://dx.doi.org/10.1016/j.amjcard.2008.05.006.
http://dx.doi.org/10.1016/j.amjcard.2008...
-1515 Papa A, Emdin M, Passino C, Michelassi C, Battaglia D, Cocci F.
Predictive value of elevated neutrophil-lymphocyte ratio on cardiac mortality in
patients with stable coronary artery disease. Clin Chim Acta.
2008;395(1-2):27-31,
http://dx.doi.org/10.1016/j.cca.2008.04.019.
http://dx.doi.org/10.1016/j.cca.2008.04....
). The CIMT is a widely accepted marker of subclinical atherosclerosis
(33 Taniwaki H, Kawagishi T, Emoto M, Shoji T, Kanda H, Maekawa K, et
al. Correlation between the intima-media thickness of the carotid artery and
aortic pulse-wave velocity in patients with type diabetes. Vessel wall
properties in type 2 diabetes. Diabetes Care.
1999;22(11):1851-57.).
To date, no studies have investigated the effects of subclinical atherosclerosis and inflammation on the TACT, which is an early predictor of AF development, in patients with T2DM. In this study, we aimed to evaluate the effects of T2DM on the TACT and to investigate the possible relationship between the TACT and echocardiographic findings, the CIMT and the NLR and hsCRP levels in patients with T2DM.
METHODS
Study population
A total of 132 consecutive type 2 diabetic patients who were diagnosed at least one year prior and 80 sex- and age-matched healthy controls were enrolled in this observational, cross-sectional study. T2DM was diagnosed according to the American Diabetes Association criteria (1616 American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37(1):14-80.). Of the diabetic cases, 48 (36.3%) patients were receiving insulin and 84 (63.7%) patients were receiving an oral anti-diabetic treatment. The exclusion criteria for the patients were as follows: a history of coronary artery disease, left ventricular (LV) systolic dysfunction, moderate to severe valvular heart disease, arterial hypertension, AF, pre-excitation syndromes, atrioventricular conduction abnormalities, bundle branch block, previously implanted cardiac pacemakers, anti-arrhythmic medicine use, electrolyte imbalance, thyroid diseases, chronic renal or liver diseases, pulmonary disease, chronic inflammatory disorders, known infectious disease and a history of a hypoglycemic episode in the past month. The study protocol was approved by our local ethics committee and all patients provided their written informed consent to participate in the study.
Echocardiographic examination
Echocardiography was performed using a GE Vivid S5 system (GE Vingmed Ultrasound
AS, Norten, Norway) with a 2.5-MHz phased-array transducer. All subjects were
imaged in the left lateral decubitus position and underwent a complete
transthoracic echocardiographic examination. All examinations were made by two
experienced cardiologists blinded to the clinical data of the subjects. During
the echocardiography, a 1-lead electrocardiogram (ECG) was continuously
recorded. The LV size measurements and diastolic LV filling velocities were
conducted in accordance with the American Society of Echocardiography guidelines
(1717 Quinones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi W.
Recommendations for quantification of Doppler echocardiography: a report from
the Doppler Quantification Task Force of the Nomenclature and Standards
Committee of the American Society of Echocardiography. Jam Soc Echocardiogr.
2002;15(2):167-84, http://dx.doi.org/10.1067/mje.2002.120202.
http://dx.doi.org/10.1067/mje.2002.12020...
). The left ventricular ejection
fraction (LVEF) was calculated using Simpson's biplane method. The LV mass
was calculated with the Devereux formula (1818 Devereux RB, Reichek N. Echocardiographic determination of left
ventricular mass in men. Circulation. 1977;55(4):613-8,
http://dx.doi.org/10.1161/01.CIR.55.4.613.
http://dx.doi.org/10.1161/01.CIR.55.4.61...
). The interventricular septal thickness (IVST), posterior wall
thickness (PWT) and left atrial volumes were also measured. Both the LV mass and
the left atrium (LA) volume were indexed according to the body surface area.
Mitral inflow was assessed from the apical four-chamber view with pulsed-wave
Doppler by placing a 1-2-mm sample volume between the tips of the mitral
leaflets in diastole. From the mitral inflow E and A wave velocities, the
E-deceleration time (DT) and E/A velocity ratio were obtained. TDI was performed
in the apical 4-chamber view by placing a 1-2-mm sample volume at the lateral
and septal mitral annulus. The measurements of the systolic (Sm), early
diastolic (Em) and late diastolic (Am) velocities were obtained and averaged
(1919 Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth
OA, et al. Recommendations for the evaluation of left ventricular diastolic
function by echocardiography. J Am Soc Echocardiogr. 2009;22(2):107-33,
http://dx.doi.org/10.1016/j.echo.2008.11.023.
http://dx.doi.org/10.1016/j.echo.2008.11...
). The Em/Am and E/Em ratios were
calculated. The myocardial performance index (MPI) was measured as previously
defined by Tei (2020 Ulucay A, Tatlı E. Myocardial performance index. Anadolu
Kardiyol Derg. 2008;8(2):143-8.).
The PA-TDI duration is a novel echocardiographic parameter that can be used to
estimate the TACT. The PA-TDI interval was defined as the time interval from the
initiation of the P-wave on the surface ECG to the peak of the A wave on the TDI
of the lateral wall of the LA, just above the mitral annulus (Figure 1) (2121 Merckx KL, De Vos CB, Palmans A, Habets J, Cheriex EC, Crijns
HJ, et al. Atrial activation time determined by transthoracic Doppler tissue
imaging can be used as an estimate of the total duration of atrial electrical
activation. J Am Soc Echocardiogr. 2005;18(9):940-4,
http://dx.doi.org/10.1016/j.echo.2005.03.022.
http://dx.doi.org/10.1016/j.echo.2005.03...
).
Measurement of the total atrial conduction time (PA-TDI interval). The PA-TDI interval was defined as the time interval between the onset of the P-wave on the surface ECG and the peak Am wave on the tissue Doppler tracing. ECG: electrocardiogram; Am: tissue Doppler mitral annular late diastolic velocity.
Two-dimensional echocardiography images for the LA were obtained from the apical
two- and four-chamber views. All images were stored in a cine loop format from
three consecutive beats during a breath hold with a stable electrocardiographic
recording. The frame rate was set between 60 and 80 frames per second.
Speckle-tracking analyses were performed offline using commercially available
software (EchoPAC; GE Medical Systems). The endocardial border was manually
defined and tracing was automatically performed by the software for each view.
An image tracking algorithm automatically divided the LA wall into 6 segments
and the peak LA longitudinal strain (PALS) values for each apical view were
measured by averaging the values observed in all LA segments (Figure 2). The global PALS values were
the averages of the values obtained for each apical view (2222 Cameli M, Lisi M, Reccia R, Bennati E, Malandrino A, Solari M,
et al. Pre-operative left atrial strain predicts post-operative atrial
fibrillation in patients undergoing aortic valve replacement for aortic
stenosis. Int J Cardiovasc Imaging. 2014;30(2):279-86,
http://dx.doi.org/10.1007/s10554-013-0323-6.
http://dx.doi.org/10.1007/s10554-013-032...
,2323 Altekin RE, Yanikoglu A, Karakas MS, Ozel D, Yilmaz H, Demir I.
Evaluation of left atrial function using two-dimensional speckle tracking
echocardiography in end-stage renal disease patients with preserved left
ventricular ejection fraction. Kardiol Pol. 2013;71(4):341-51,
http://dx.doi.org/10.5603/KP.2013.0061.
http://dx.doi.org/10.5603/KP.2013.0061...
).
Assessment of the peak atrial longitudinal strain by two-dimensional speckle-tracking echocardiography. The dashed curve represents the average atrial longitudinal strain along the cardiac cycle.
Assessment of the carotid intima-media thickness
The CIMT was measured using the Toshiba Diagnostic Ultrasound System (Aplio MX
SSA-780A) with a 7.5-MHz transducer in patients lying in the supine position.
The technique used was in accordance with the consensus statement from the
American Society of Echocardiography Carotid Intima-Media Thickness Task Force
(2424 Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER,
et al. Use of carotid ultrasound to identify subclinical vascular disease and
evaluate cardiovascular disease risk: a consensus statement from the American
Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed
by the Society for Vascular Medicine. J Am Soc Echocardiogr.
2008;21(2):93-111,
http://dx.doi.org/10.1016/j.echo.2007.11.011.
http://dx.doi.org/10.1016/j.echo.2007.11...
). Briefly, the CIMT was defined
as the distance between the leading edge of the lumen-intima interface and the
media-adventitia interface on the far wall of the common carotid artery (CCA)
(posterior wall). After examination of the transverse and longitudinal planes of
the carotid arteries, the CIMT was measured in both arteries approximately 1 cm
proximal to the carotid artery bifurcation in an area free of plaque. At least
three measurements were performed on both sides and averaged. Then, the average
of the measurements obtained from both CCAs was taken as the CIMT.
Analysis of blood samples
After fasting overnight for 12 h, venous blood samples were obtained for all patients from the antecubital space. Total and differential leukocyte counts were measured as part of the automated complete blood count using a Coulter LH 780 Hematology Analyzer (Beckman Coulter Inc., Miami, FL, USA). HsCRP and other biochemical parameters were measured by standard laboratory procedures. The NLR was obtained by dividing the total neutrophil count by the total lymphocyte count.
Statistical analysis
Continuous variables are presented as the mean + standard deviation or the median (interquartile range) values and categorical variables are presented as a percentage. The one-sample Kolmogorov-Smirnov test was used to evaluate whether the distribution of continuous variables was normal. Continuous variables between 2 groups were compared with Student's t test or the Mann-Whitney U test. Categorical variables were compared appropriately with the chi-square test or Fisher's exact test. The correlations between variables were tested by Pearson's correlation tests for normally distributed variables and with Spearman's correlation tests for non-normally distributed variables. The TACT was categorized into two groups, with the median as the cut-off point. To determine the independent predictors of supramedian TACT, parameters that were found to have significance (p<0.05) in the univariate analysis were evaluated by stepwise forward logistic regression analysis; 95% confidence intervals (CIs) and odds ratios (ORs) were presented together. Receiver-operating characteristic (ROC) analysis was used to compare the performance and prognostic power of the NLR, CIMT and PALS for supramedian TACT. The predictive validities were quantified as the area under the ROC curves (c statistics) and the comparisons of c statistics were performed using the MedCalc statistical software (version 11.3.8.0, Mariakerke, Belgium). To assess the reproducibility of the CIMT, TACT and global PALS measurements, 20 patients were randomly selected. For the interobserver and intraobserver variability, Bland-Altman analysis and intraclass correlation coefficient were used, respectively. A 2-sided p value <0.05 was considered significant in all analyses. Data were analyzed using SPSS version 15.0 (SPSS Inc., Chicago, Illinois).
RESULTS
The study population comprised 132 T2DM patients (mean age 54.5±9.6 years; 57.6% male) and 80 controls (mean age 53.2±9.0 years; 62.5% male). The demographic findings and laboratory values of the study groups are presented in Table 1. The age, sex, body mass index, smoking status, systolic and diastolic blood pressures and heart rate were similar between the 2 groups (p>0.05). In patients with T2DM, the mean HbA1c level was 8.4%±2.7% and the mean disease duration was 83.4±52.5 months. The patients with T2DM had a significantly increased CIMT compared with the controls (0.80±0.25 vs. 0.66±0.13 mm, p<0.001). When the laboratory findings were compared, T2DM patients had significantly higher NLRs and hsCRP levels (3.7±1.4 vs. 2.5±1.2, p<0.001; 1.0±0.4 vs. 0.8±0.4, p = 0.003, respectively).
The LV echocardiographic findings in the subjects are shown in Table 2. The E/A ratio was significantly decreased in the patients with T2DM. The tissue Doppler Am was higher in the diabetic group; consequently, the average Em/Am ratio was significantly decreased in this group. The left atrial volume index (LAVI) was significantly increased in the diabetic patients (32.7±6.4 vs. 23.6±5.6, p<0.001). Global PALS was found to be significantly decreased in the patients with T2DM compared with the control group (24.5±6.6 vs. 33.4±8.2, p<0.001). TACT was significantly longer in the patients with T2DM than in healthy subjects (131.7±23.6 vs. 113.1±21.3, p<0.001). The LVEF, IVST, PWT, LV mass index, Mitral E and A velocities, DT, Sm and Em values, E/Em ratio, and MPI were similar in both groups (p>0.05).
The TACT was positively correlated with hsCRP levels (r = 0.197, p = 0.024), the NLR (r = 0.311, p<0.001), the CIMT (r = 0.364, p<0.001) and the LAVI (r = 0.184, p = 0.035) and negatively correlated with the Em value (r = -0.296, p = 0.001), the Em/Am ratio (r = -0.195, p = 0.025) and global PALS (r = -0.188, p = 0.031) (Table 3). TACT was categorized into two groups, with the median as the cutpoint (<or ≥125.5). Variables showing significance values of p<0.05 in the univariate analysis (Table 4) between the inframedian and supramedian TACT groups were included in the multiple logistic regression model. There was multicollinearity between the Em value and Em/Am ratio; thus, Em was not included in the model. Accordingly, the NLR (OR: 1.78, 95% CI: 1.28-2.46; p<0.001), CIMT (OR: 7.99, 95% CI: 1.46-33.04; p = 0.016), and PALS (OR: 0.93, 95% CI: 0.87-0.99; p = 0.035) were found to be independent predictors of the TACT (Table 5). The cutoff value for supramedian TACT of the NLR was 4.0, with a sensitivity of 74.2% and a specificity of 72.7% (AUC, 0.708; 95% CI, 0.622-0.784; p<0.001), of CIMT was 0.81 mm, with a sensitivity of 75.8% and a specificity of 72.7% (AUC, 0.684; 95% CI, 0.597-0.762; p<0.001) and of PALS was 19.8%, with a sensitivity of 41% and a specificity of 83.3% (AUC, 0.602; 95% CI, 0.514-0.686; p = 0.038) in the ROC curve analysis (Figure 3). However, the AUC comparison of these parameters did not reach statistical significance (p>0.05). The results of the inter- and intraobserver agreement analyses for TACT, PALS and CIMT are shown in Table 6.
Comparison ROC curves for the CIMT, NLR and PALS in the prediction of a longer TACT. ROC: receiver operating characteristic; CIMT: carotid intima-media thickness; NLR: neutrophil to lymphocyte ratio; PALS: peak atrial longitudinal strain; TACT: total atrial conduction time.
DISCUSSION
The present study demonstrated that the TACT, measured with TDI, was increased and that LA myocardial deformation, assessed by two-dimensional strain imaging, was impaired in patients with T2DM. Furthermore, in this study, we also found that the NLR, CIMT and global PALS were independent predictors of the TACT in these patients.
Epidemiological studies have shown that the rate of AF development in diabetic
subjects is higher than in normal subjects (2525 Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic
features of chronic atrial fibrillation: The Framingham Study.
N Engl J Med. 1982;306(17):1018-22.). A possible explanation for why diabetes mellitus causes
predisposition to AF may involve LV hypertrophy, myocardial ischemia or fibrosis,
left atrial remodeling, altered autonomic tone and inflammation (99 Liu T, Li G. Inflammation: Another potential mechanism between
diabetes mellitus and atrial fibrillation. Am J Cardiol.
2008;101(11):1681-2,
http://dx.doi.org/10.1016/j.amjcard.2008.04.006.
http://dx.doi.org/10.1016/j.amjcard.2008...
,2626 Devereux RB, Roman MJ, Paranicas M, O′Grady MJ, Lee ET,
Welty TK, et al. Impact of diabetes on cardiac structure and function: the
strong heart study. Circulation. 2000;101(19):2271-6,
http://dx.doi.org/10.1161/01.CIR.101.19.2271.
http://dx.doi.org/10.1161/01.CIR.101.19....
,2727 Crandall MA, Horne BD, Day JD, Anderson JL, Muhlestein JB,
Crandall BG, et al. Atrial Fibrillation and CHADS2 Risk Factors are Associated
with Highly Sensitive C-Reactive Protein Incrementally and Independently. Pacing
Clin Electrophysiol. 2009;32(5):648-52,
http://dx.doi.org/10.1111/j.1540-8159.2009.02339.x.
http://dx.doi.org/10.1111/j.1540-8159.20...
). Additionally, the
clinical hypoglycemic episodes in diabetic patients cause sympathetic activation, QT
interval prolongation and cardiac repolarization. These changes may increase the
risk of AF (2828 Graveling AJ, Frier BM. Does hypoglycaemia cause cardiovascular
events? Br J Diabetes Vasc Dis. 2010;10(1):5-13,
http://dx.doi.org/10.1177/1474651409355113.
http://dx.doi.org/10.1177/14746514093551...
). However, the underlying
mechanisms are still not clearly elucidated. The previous studies have demonstrated
that the TACT, measured via the PA-TDI interval, could be used to predict the
development of AF (2929 Özlü MF, Erdem K, Kırış G, Parlar
Aİ, Demirhan A, Ayhan SS, et al. Predictive value of total atrial
conduction time measured with tissue Doppler imaging for postoperative atrial
fibrillation after coronary artery bypass surgery. J Interv Card
Electrophysiol. 2013;37(1):27-33,
http://dx.doi.org/10.1007/s10840-012-9756-4.
http://dx.doi.org/10.1007/s10840-012-975...
). Acar G et al. (3030 Acar G, Akcay A, Sokmen A, Ozkaya M, Guler E, Sokmen G, et al.
Assessment of Atrial Electromechanical Delay, Diastolic Functions, and Left
Atrial Mechanical Functions in Patients with Type 1 Diabetes Mellitus. J Am
Soc Echocardiogr. 2009;22(6):732-8,
http://dx.doi.org/10.1016/j.echo.2009.03.028.
http://dx.doi.org/10.1016/j.echo.2009.03...
) reported that intra- and interatrial
electromechanical coupling and atrial electromechanical delay, measured with TDI,
were higher in patients with type 1 DM than in control subjects. In a recent
experimental study, Fu H et al. (3131 Fu H, Liu C, Li J, Zhou C, Cheng L, Liu T, et al. Impaired
atrial electromechanical function and atrial fibrillation promotion in
alloxan-induced diabetic rabbits. Cardiol J.
2013;20(1):59-67.) detected
that the interatrial conduction time was prolonged in diabetic rabbits. In line with
the results of these studies, in our study, we found that the TACT was significantly
longer in patients with T2DM than in control subjects. In previous studies, chronic
hyperglycemia was reported to cause prolongation of the interatrial conduction time
by aggravating atrial fibrosis (3232 Liu C, Fu H, Li J, Yang W, Cheng L, Liu T, et al. Hyperglycemia
aggravates atrial interstitial fibrosis, ionic remodeling and vulnerability to
atrial fibrillation in diabetic rabbits. Anadolu Kardiyol Derg.
2012;12(7):543-50.). However,
the exact mechanism of TACT prolongation in diabetic patients remains unknown.
In a recent retrospective study, Chen LY et al. (3333 Chen LY, Foo DC, Wong RC, Seow SC, Gong L, Benditt DG, et al.
Increased carotid intima-media thickness and arterial stiffness are associated
with lone atrial fibrillation. Int J Cardiol.
2013;168(3):3132-4.) reported that increased CIMT and arterial stiffness are associated
with lone AF. In the population-based Rotterdam Study, Heeringa J et al. (77 Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Rooij FJ, Lip
GY, et al. Subclinical atherosclerosis and risk of atrial fibrillation: the
Rotterdam Study. Arch Intern Med. 2007;167(4):382-7,
http://dx.doi.org/10.1001/archinte.167.4.382.
http://dx.doi.org/10.1001/archinte.167.4...
) reported that subclinical atherosclerosis,
determined based on the CIMT, predicted new-onset AF in patients without overt
coronary artery disease. In another population-based cohort study, Adamsson ES et
al. (3434 Adamsson Eryd S, Ostling G, Rosvall M, Persson M, Smith JG,
Melander O, et al. Carotid intima-media thickness is associated with incidence
of hospitalized atrial fibrillation. Atherosclerosis. 2014;233(2):673-8,
http://dx.doi.org/10.1016/j.atherosclerosis.2014.01.050.
http://dx.doi.org/10.1016/j.atherosclero...
) found that the CIMT is associated
with the incidence of AF hospitalizations among middle-aged subjects. In contrast,
the Cardiovascular Health Study (CHS) found no association between the CIMT and the
AF incidence (3535 Furberg CD, Psaty BM, Manolio TA, Gardin JM, Smith VE,
Rautaharju PM. Prevalence of atrial fibrillation in elderly subjects (the
Cardiovascular Health Study). Am J Cardiol. 1994;74(3):236-41,
http://dx.doi.org/10.1016/0002-9149(94)90363-8.
http://dx.doi.org/10.1016/0002-9149(94)9...
). Although these studies are
population based, there are important differences in both the age distributions and
the case report methods between the studies that might explain the different
results. Subclinical atherosclerosis may lead to the development of fibrosis and
microscopic scarring with consecutive remodeling of atrial tissue over time by
decreasing the blood flow to the sinus node and atrial tissue (3636 Anderson KR, Sutton MG, Lie JT. Histopathological types of
cardiac fibrosis in myocardial disease. J Pathol. 1979;128(2):79-85,
http://dx.doi.org/10.1002/path.1711280205.
http://dx.doi.org/10.1002/path.171128020...
). Atrial remodeling may account for the atrial conduction
disturbances and the dispersion of the atrial refractory period, thereby
facilitating reentry processes and the onset of atrial fibrillation (3737 Tai CT, Chen SA, Tzeng JW, Kuo BI, Ding YA, Chang MS, et al.
Prolonged fractionation of paced right atrial electrograms in patients with
atrial flutter and fibrillation. J Am Coll Cardiol. 2001;37(6):1651-7,
http://dx.doi.org/10.1016/S0735-1097(01)01215-3.
http://dx.doi.org/10.1016/S0735-1097(01)...
). The TACT is a novel echocardiographic
parameter used to assess the extent of atrial remodeling. In our study, we detected
a weak but statistically significant positive correlation (r = 0.364,
p<0.001) between the CIMT and the TACT, and the CIMT
strongly and independently predicted the TACT in diabetic patients (OR: 7.99).
Additionally, our study showed that a CIMT≥0.81 mm predicted the presence of
a longer TACT, with a sensitivity of 75.8% and a specificity of 72.7%.
Generally, the relationship between AF and inflammation has been well established
(3838 Friedrichs K, Klinke A, Baldus S. Inflammatory pathways
underlying atrial fibrillation. Trends Mol Med. 2011;17(10):556-63,
http://dx.doi.org/10.1016/j.molmed.2011.05.007.
http://dx.doi.org/10.1016/j.molmed.2011....
). Histological studies have
demonstrated evidence of inflammatory infiltrates and oxidative damage within the
atrial tissue in patients with AF compared with control subjects (55 Boos CJ, Anderson RA, Lip GY. Is atrial fibrillation an
inflammatory disorder? Eur Heart J.
2006;27(2):136-49.). Liu T et al. (99 Liu T, Li G. Inflammation: Another potential mechanism between
diabetes mellitus and atrial fibrillation. Am J Cardiol.
2008;101(11):1681-2,
http://dx.doi.org/10.1016/j.amjcard.2008.04.006.
http://dx.doi.org/10.1016/j.amjcard.2008...
) suggested that inflammation was one of the mechanisms
responsible for AF in diabetic patients. Inflammatory stimuli provoke fibroblast
proliferation, migration and transformation into myofibroblasts and lead to atrial
remodeling characterized by the shortening of the atrial refractory period (3838 Friedrichs K, Klinke A, Baldus S. Inflammatory pathways
underlying atrial fibrillation. Trends Mol Med. 2011;17(10):556-63,
http://dx.doi.org/10.1016/j.molmed.2011.05.007.
http://dx.doi.org/10.1016/j.molmed.2011....
). In studies investigating the
AF-inflammation relationship, the most frequently studied inflammatory markers were
CRP, hsCRP and interleukin (IL)-6 (55 Boos CJ, Anderson RA, Lip GY. Is atrial fibrillation an
inflammatory disorder? Eur Heart J.
2006;27(2):136-49.). In a
few studies, the development of AF after cardiac surgery and the recurrence of AF
after cryoballoon-based AF ablation were demonstrated to correlate with the NLR
(3939 Canpolat U, Aytemir K, Yorgun H, Şahiner L, Kaya EB,
Kabakçı G, et al. Role of Preablation Neutrophil/Lymphocyte Ratio on
Outcomes of Cryoballoon-Based Atrial Fibrillation Ablation.
Am J Cardiol. 2013;112(4):513-9,
http://dx.doi.org/10.1016/j.amjcard.2013.04.015.
http://dx.doi.org/10.1016/j.amjcard.2013...
). Acar G et al. (4040 Acar G, Akcay A, Sayarlioglu M, Sokmen A, Sokmen G, Koroglu S,
et al. Assessment of Atrial Conduction Time in Patients with Familial
Mediterranean Fever. Pacing Clin Electrophysiol. 2009;32(3):308-13,
http://dx.doi.org/10.1111/j.1540-8159.2008.02237.x.
http://dx.doi.org/10.1111/j.1540-8159.20...
) have shown that atrial electromechanical
delay is closely associated with the plasma level of CRP in patients with familial
Mediterranean fever.
In our study, we detected a weak but statistically significant positive correlation (r = 0.311, p<0.001 and r = 0.197, p = 0.024, respectively) between the TACT, the NLR and hsCRP levels; in addition, the NLR independently predicted a longer TACT in diabetic patients (OR: 1.78). Furthermore, we showed that an NLR≥4.0 mm predicted the presence of a longer TACT, with a sensitivity of 74.2 and a specificity of 72.7.
In our study, the patients with T2DM had an increased LAVI and decreased E/A and
Em/Am ratios compared with the normal volunteers. These results are consistent with
prior studies in asymptomatic, normotensive type 1 and 2 diabetic patients (4141 Poulsen MK, Henriksen JE, Dahl J, Johansen A, Gerke O, Vach W,
et al. Left ventricular diastolic function in type 2 diabetes mellitus:
prevalence and association with myocardial and vascular disease. Circ Cardiovasc
Imaging. 2010;3(1):24-31,
http://dx.doi.org/10.1161/CIRCIMAGING.109.855510.
http://dx.doi.org/10.1161/CIRCIMAGING.10...
). An increase in the LA volume might change
the atrial fibrillar geometry, which in turn may contribute to TACT prolongation. We
detected statistically significant but weak correlations between the TACT and the
LAVI and the Em/Am ratio. However, it was demonstrated in our study that the LAVI
and the Em/Am ratio were not strong parameters for predicting the longer TACT (OR:
1.03 and OR: 0.26, respectively). In previous studies, impaired LA deformation,
assessed by the global PALS, was shown to correlate with atrial fibrosis and
remodeling and was related to paroxysmal AF (2222 Cameli M, Lisi M, Reccia R, Bennati E, Malandrino A, Solari M,
et al. Pre-operative left atrial strain predicts post-operative atrial
fibrillation in patients undergoing aortic valve replacement for aortic
stenosis. Int J Cardiovasc Imaging. 2014;30(2):279-86,
http://dx.doi.org/10.1007/s10554-013-0323-6.
http://dx.doi.org/10.1007/s10554-013-032...
). In this study, we revealed that the global PALS decreased and was
weakly but significantly correlated with the TACT in patients with T2DM. Among the
echocardiographic parameters, only the global PALS independently predicted TACT (OR:
0.93). In addition, our study demonstrated that a PALS<19.8% predicted the
presence of a longer TACT, with a sensitivity of 41% and a specificity of 83.3%.
In our study, the weak correlations detected between the TACT, the CIMT, the NLR, the
hsCRP level and the echocardiographical parameters may have stemmed from the limited
number of patients included in our study and relatively short disease duration. We
only investigated the effects of subclinical atherosclerosis and inflammation on the
TACT. However, other causes, such as cardiac autonomic neuropathy, renin-angiotensin
aldosterone system activation, sympathetic overactivity, neural remodeling, the left
atrial myocardial injury and fibrotic changes due to sustained hyperglycemia, all of
which may cause an increased AF frequency and left atrial functional deterioration,
could contribute to the prolongation of the TACT (4242 Asghar O, Alam U, Hayat SA, Aghamohammadzadeh R, Heagerty AM,
Malik RA. Obesity, Diabetes and Atrial Fibrillation; Epidemiology, Mechanisms
and Interventions. Curr Cardiol Rev. 2012;8(4):253-64,
http://dx.doi.org/10.2174/157340312803760749.
http://dx.doi.org/10.2174/15734031280376...
). The possible stronger relationships between the TACT and these
factors may have led to the weak correlations observed between the TACT and the
CIMT, NLR and hsCRP levels.
Limitations
The most important limitation is the cross-sectional design of the study; the patients were not prospectively followed-up in terms of arrhythmic episodes. Thus, we do not know whether TACT prolongation, subclinical atherosclerosis and inflammation, and impaired LA deformation predict AF in patients with T2DM. For this reason, the current findings need to be validated by long-term follow-up and in larger prospective studies. In our study, the TACT was not investigated by invasive electrophysiological techniques. Although we did not evaluate the patients who described a hypoglycemic episode within the past month, probable unreported hypoglycemic episodes occurring in the diabetic patients might have affected our study results. Another limitation was the use of non-invasive imaging techniques to exclude coronary artery disease in the study population. Coronary angiography was not performed in our study population on ethical grounds.
In the current study, we found that the TACT predicting AF development was prolonged and that LA myocardial deformation was impaired in patients with T2DM. Our study also indicated that subclinical atherosclerosis, inflammation and the global PALS were independently related to TACT. On the basis of these findings, we suggest that subclinical atherosclerosis and inflammation may be a mechanism related to TACT prolongation and prolonged TACT and impaired LA myocardial deformation may represent an early form of subclinical cardiac involvement in patients with T2DM and without clinical evidence of cardiovascular disease.
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-
No potential conflict of interest was reported.
Publication Dates
-
Publication in this collection
Feb 2015
History
-
Received
14 Sept 2014 -
Reviewed
13 Oct 2014 -
Accepted
12 Nov 2014