The normally distributed continuous data are shown as mean±SD; otherwise, they are presented as medians and interquartile boundaries (25th–75th). The Kolmogorov–Smirnov test was used to determine the normal distribution of the data. The one-way analysis of variance was utilized to compare the mean of the normally distributed data; otherwise, the nonparametric Kruskal–Wallis H-test was used. The Bonferroni-adjusted method was used for pairwise comparisons if the omnibus test was statistically significant. The categorical data are shown as absolute frequencies and percentages. The χ2-test or the Fisher exact test, whichever was appropriate, was used to compare this type of data. Multivariable linear regression models were drawn upon to determine the association between glycemic state and the 2DSTE-derived indices of LA function adjusted for sex, hypertension, heart rate, hematocrit, and e′ and E/e′ (markers of LV diastolic function) as the potential confounders. The 2DSTE-derived indices of LA function were entered into the multivariable analysis. If they showed a skewed distribution after having been transformed logarithmically for normalization, they were entered into this analysis. The statistical analyses were carried out using IBM SPSS statistics for Windows (version 23.0; IBM Corp., Armonk, New York, USA). P values of up to 0.05 were considered statistically significant.
Our study population consisted of 137 men and 68 women, with a mean age of 61.3±8.4 and 60.2±8.2 years, respectively. The demographic, clinical, and laboratory characteristics of the study population, divided into three groups according to their glycemic state, are shown in Table 1. These groups were different in the male sex ratio, history of cigarette smoking, functional capacity class, heart rate, hematocrit, and lipid profile. The number of involved vessels was similar between these groups. There were no statistically significant differences in the other mentioned characteristics between these groups. The echocardiographic data are shown in Table 2. A-wave velocity, e′-wave velocity, E/A ratio, E/e′ ratio, and e′/a′ ratio were different between the three groups. There were no statistically significant differences in the LA volumetric parameters of LA function. SRE was statistically significantly different between the euglycemic group and the diabetic group (P=0.011). EDS was statistically significantly different between the diabetic group and the nondiabetic groups (diabetic vs. euglycemic; P<0.001; and diabetic vs. prediabetic; P=0.003). Also, LDS was statistically significantly different between the diabetic group and the nondiabetic groups (diabetic vs. euglycemic; P=0.049; and diabetic vs. prediabetic; P=0.008). The multivariable analysis (Table 3) showed that after adjustment for the aforementioned confounders, diabetes, female sex, hematocrit, and e′ were the independent determinants of the absolute amount of SRE, whereas female sex, diabetes, and e′ and E/e′ were the independent determinants of the absolute value of log EDS and heart rate was the only independent determinant of log LDS.
Thirty-one patients were reanalyzed to determine intraobserver variability after 3 months. The corresponding intraobserver variability as a coefficient variation for SS, EDS, LDS, SRS, SRE, and SRA was 8.4, 5.8, 6.9, 8.4, 6.7, and 10.0%, respectively.
To our knowledge, our study is the first of its kind to compare LA function in patients with CAD according to their glycemic state (i.e. euglycemic, prediabetes, and diabetes). In our study, we assessed LA function in patients with CAD in terms of volumetric indices and 2DSTE-derived parameters. Our findings showed that in the diabetic patients, LA conduit function parameters (i.e. EDS and SRE) were reduced. Moreover, diabetes (not prediabetes) was an independent determinant of EDS and SRE. In addition, LA contraction function parameter (LDS) was decreased in the diabetic patients compared with the nondiabetic patients (prediabetic and euglycemic). However, diabetes was not an independent determinant of LDS in the multivariate analysis.
Two studies compared LA function between CAD and non-CAD patients 12,13. One of these studies 12 considered diabetes an exclusion criterion and diabetic patients constituted about one-third of the small study population of the other one 13. One of these studies showed a reduction in SRE in the nondiabetic CAD patients compared with the nondiabetic non-CAD patients 12, whereas the other study reported reductions in SS and SRS, SRE, and SRA in the patients with CAD 13.
Although several studies have compared LA function between diabetic and nondiabetic patients 9,14–17, the glycemic state (euglycemic or prediabetes) in nondiabetic patients is still obscure 14–17. In the only available study on this topic, Tadic et al.9 evaluated LA function between prediabetic, diabetic, and euglycemic patients. In all the mentioned studies 14–17, CAD patients were excluded by several methods with different sensitivity. At one end of the spectrum, the exclusion criteria for CAD in the study by Tadic et al.9 were the signs and symptoms of myocardial infarction and at the other end of the spectrum, the exclusion criterion in the study by Liu and colleagues was significant coronary artery stenosis in coronary computed tomography angiography. It, therefore, seems that CAD patients were included in most of these studies inadvertently 9,14–16 and that the populations of the studies were mixed with respect to the presence of CAD. In our study, all the patients had documented significant CAD and the absence of other similar data in the existing literature precluded us from comparing and contrasting our results.
Muranaka and colleagues reported that SRS and SRE were reduced in their diabetic patients compared with the nondiabetic patients. In that study, the researchers used color-coded tissue Doppler imaging and evaluated LA myocardial deformation only in some segments (mid part) of the LA walls. Color-coded tissue Doppler imaging is an angle-dependent method compared with 2DSTE. Mondillo and colleagues showed that SS, SRS, EDS, SRE, and LDS were reduced in their diabetic patients with a normal LA size (<28 ml/m2) compared with their nondiabetic individuals. Nonetheless, the new guideline sets the limit for LA enlargement at more than 35 ml/m2. Kadappu and colleagues reported that SS, SRS, SRE, and SRA were decreased in their diabetic patients. The authors evaluated only some segments of the LA (septal and lateral walls), and their study population included patients with an advanced grade of diastolic function. We excluded patients with an advanced grade of diastolic function from our study. Also, the LA size of the diabetic patients was greater than that of the nondiabetic patients. In our study, there were no statistically significant differences in LA size between the three groups. Liu and colleagues showed that EDS and SRE were reduced in their hypertensive diabetic patients compared with their nondiabetic hypertensive patients. In that study, diabetes was not an independent determinant of EDS and SRE, but early diastolic LV strain rate was one of the several determinants of EDS and SRE. Tadic and colleagues reported that SS, SRS, EDS, and SRE were reduced in their diabetic patients compared with their euglycemic patients, whereas LDS and SRA increased in their diabetic cases. In addition, the authors found that although SS, SRS, and EDS were reduced in their prediabetic patients compared with their normal patients, SRA was increased in the prediabetic patients compared with their euglycemic peers. In addition, EDS was reduced in the diabetic patients compared with the prediabetic ones. It seems that according to the results of the study by Tadic and colleagues, with the progression of impairment in glucose metabolism, EDS is reduced, but SS and SRS decrease after reaching the status of critical impairment in glucose metabolism (prediabetes). Moreover, LDS and SRA increase after reaching this critical point (prediabetes). It should, however, be noted that Tadic and colleagues did not report whether or not prediabetes or diabetes was an independent determinant of the reservoir, conduit, and contraction functions of the LA.
In contrast to the findings of Tadic and colleagues, our results vis-à-vis EDS support the hypothesis that EDS (marker of LA conduit function) is reduced after reaching critical impairment in glucose metabolism (diabetes) in patients with CAD. This difference in the results can be explained by this conceivable point that CAD may modulate the effects of diabetes on LA function. Consequently, the pattern of the effects of impaired glucose metabolism on LA function may be different in CAD patients by comparison with non-CAD patients.
LA contraction function increases in the presence of significant LV systolic dysfunction for the compensation of reduced LV stroke work 20,21, but our study population had preserved LV systolic function. Also, it has been shown that whereas LA contraction increases in the presence of acute induced ischemia and significant stenosis in the proximal portion of the left anterior descending artery, LA contraction decreases in the presence of significant stenosis in the proximal portion of the left circumflex artery. This is probably because of the affected LA branch artery 12,22. In our study, the left anterior descending artery had significant stenosis in all the participants and there was no statistically significant difference in the involvement of the left circumflex artery. Nonetheless, research has shown that the occurrence of LV diastolic dysfunction precedes that of LV systolic dysfunction in diabetic patients 23. It can, therefore, be postulated that in diabetic patients with CAD and in the presence of preserved LV systolic function – similar to the LV – LA conduit function impairment may precede the occurrence of LA contraction function. This hypothesis was discussed previously by Liu et al.17 and supported by some previous studies on LA function in diabetic patients 14,17.
The main myocardial fibers in the subendocardial layer of the LA are longitudinal myocardial fibers 24. It can be postulated that diabetes can be detrimental to these myocardial fibers by mechanisms that damage the subendocardial LV myocardial fibers. These include altered calcium regulation 25, oxidative stress 26, and microvasculopathy 27. There is evidence that diabetes is linked to fibrosis and apoptosis in the atrium 28,29. Fibrosis and apoptosis are also associated with LA conduit function 30. This evidence may be explained by our findings.
It has been proposed that although LV diastolic function is one of the determinants of LA conduit function 31, it is not the only determinant of LA function and that LA structural changes (e.g. the aforementioned changes) can also be determinants. It has been shown that there is impairment in LV diastolic function in postmenopausal women and that estrogen is the main agent involved in this process by several mechanisms such as altered rennin–angiotensin activity, brain natriuretic peptide regulation, Ca handling, myocardial matrix turnover, adrenergic receptor system, and nitric oxide system 32. Most of the women in our study population were postmenopausal (60.4±8.2 years); this can explain our findings of the negative effects of the female sex on the 2DSTE-derived markers of LA conduit function.
It has been shown that chronic anemia is linked to LV diastolic dysfunction in patients with CAD or diabetes 33,34. Also, myocardial ultrastructures such as mitochondria and sarcomere fibers can be affected by chronic anemia 35. Early diastolic LV relaxation is an energy-consuming phase and is dependent on oxidative metabolism 36,37. Consequently, in patients with significant CAD, as was the case in our study population, anemia can prove detrimental to LV diastolic function. As was also mentioned previously, early LV relaxation is one of the major determinants of LA conduit function, of which SRE is a marker. Such evidence supports our findings that hematocrit can be independently one of the determinants of SRE as a marker of LA conduit function. There is evidence that with an increased heart rate, atrial contraction function is increased 38. Our finding for LDS (a marker of atrial contraction function) is aligned with this evidence.
First and foremost among the limitations of the present study is its small sample size. Another major weakness of the current study is the evaluation of LA function with software designed for the assessment of LV function. That we could not assess LA function by three-dimensional STE constitutes another drawback that is noteworthy. In addition, our study population comprised CAD patients who were candidates for coronary artery bypass graft surgery; our findings, therefore, are restricted only to this group of patients.
Our findings showed that EDS and SRE, as the indices of LA conduit function, were reduced in the diabetic CAD patients compared with the euglycemic and prediabetic CAD patients. Diabetes was one of the independent determinants of these indices of LA conduit function. LDS, as a marker of LA contraction function, was increased in the diabetic CAD patients compared with the euglycemic and prediabetic CAD patients, but diabetes was not an independent determinant of this index of LA contraction function.
Conflicts of interest
There are no conflicts of interest.
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Keywords:Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
diabetes; left atrium; prediabetes; two-dimensional speckle-tracking echocardiography