Patients and methods: Between September 2020 and September 2021, a total of 414 consecutive type 2 DM patients (209 males, 205 females; mean age: 44.7±6.1 years; range, 33 to 61 years) without established CVD were included in this prospective study. The patients were divided into two groups according to presence or absence of fQRS on electrocardiography (ECG). Clinical and glycemic parameters of patients were compared based on fQRS, fQRS-T angle, and disease duration of DM.

Results: The frequency of fQRS on ECG was 22.9%. The glycated hemoglobin (HbA1c) levels were higher, and DM duration was longer in patients with fQRS compared to those without fQRS and in patients with fQRS-T angle >90° compared to patients with fQRS-T angle ≤90°. The frequency of fQRS and mean fQRS-T angle were significantly higher in patients with DM duration ≥10 years compared to those with DM duration <10 years. Multivariate analysis revealed that HbA1c and DM duration were independent predictors of both presence of fQRS on ECG (p<0.001 for both) and fQRS-T angle >90° (p<0.001 for both).

Conclusion: The fQRS and fQRS-T angle may predict hyperglycemic status and subclinical cardiovascular involvement in type 2 DM patients without known CVDs.

Fragmented QRS (fQRS) and increased frontal plane QRS-T (fQRS-T) angle are ECG signs of myocardial fibrosis and damage and are independent predictors of adverse cardiovascular events in a wide variety of patients with and without CVDs.[9-16] More importantly, the presence of fQRS on ECG and increased fQRS-T angle, particularly an angle >90°, seem to be associated with subclinical myocardial damage and predict adverse cardiovascular events independently in diabetic patients.[17-19] However, the association of glycemic parameters with these ECG abnormalities in patients with DM has not been well established yet.

In the present study, we aimed to investigate the relationship of clinical and glycemic parameters with fQRS and fQRS-T angle in diabetic patients without known CVDs and to identify the predictors of fQRS and increased fQRS-T angle in patients with type 2 DM in the absence of CVD.

ECG, fQRS, and fQRS-T angle
A standard 12-lead surface ECG (Nihon Kohden, Tokyo, Japan) using a 0.16 to 100 Hz filter range, 25 mm/s speed, and 10 mm/mV amplitude was obtained from all patients. The fQRS was defined as presence of various morphologies in the original QRS complex (<120 ms) which included an additional R wave (R') or notching in the nadir of the S wave, or >1 R' (fragmentation) in two contiguous leads, corresponding to a major coronary artery territory.[21] The fQRS was reported according to its localization on ECG as: fQRS in anterior leads (V1 to V5), inferior leads (DII, DIII, and aVF) and lateral leads (V6, DI and aVL). The fQRS-T angle, which describes the angular difference between depolarization and repolarization vectors, was calculated as absolute difference between QRS axis and T wave axis obtained from automated ECG reports. If the angle exceeded 180°, it was calculated by subtracting from 360°.[12,22] All ECGs were analyzed by two experienced independent cardiologists who were totally blinded to the study protocol. In case of disagreement regarding the presence of fQRS, the final decision was achieved by mutual agreement. Figure 1 demonstrates an example of fQRS and measurement of fQRS-T angle from a 12-lead surface ECG.

Figure 1. An example of fQRS and measurement of frontal plane QRS-T angle from a 12-lead surface electrocardiography.

Statistical analysis
Statistical analysis was performed using the IBM SPSS version 22.0 software (IBM Corp., Armonk, NY, USA). Descriptive data were expressed in mean ± standard deviation (SD), median (min-max) or number and frequency. The normality distribution of continuous variables was tested using the Kolmogorov-Smirnov or Shapiro Wilk tests. Continuous variables were compared using the independent samples Student t-test and categorical data were compared using chi-square test or Fisher exact test. The Spearman or Pearson correlation coefficients were used to investigate the relationship of clinical and glycemic parameters with fQRS and fQRS-T angle. Multivariate logistic regression analysis was performed to identify the independent predictors of fQRS and increased fQRS-T angle. All variables with a p value of <0.1 in the univariate analysis were included in the model. A p value of <0.05 was considered statistically significant.

Table 1 demonstrates the clinical characteristics of patients with and without fQRS.

Table 1 Clinical characteristics of patients with and without fragmented QRS

The mean fQRS-T angle was 55.5°±31.8°, and while 62 (15%) patients had fQRS-T angle >90°, 352 (85%) patients had fQRS-T angle ≤90°. The patients with fQRS-T angle >90° were older, had worse renal functions, and had higher frequency of male gender, hypertension and fQRS compared to those with fQRS-T angle ≤90°. The HbA1c levels were significantly higher and DM duration was also significantly longer in patients with fQRS-T angle >90° compared to patients with fQRS-T angle ≤90°. Table 2 shows the clinical characteristics of patients according to fQRS-T angle.

Additionally, DM duration was ≥10 years in 57 (13.8%) patients. The patients with DM duration ≥10 years were older and had significantly higher HbA1c values. The frequency of fQRS and mean fQRS-T angle were also significantly higher in patients with DM duration ≥10 years compared to those with DM duration <10 years. Table 3 shows the clinical characteristics of patients according to DM duration. The correlation analyses revealed that there was a strong positive correlation between fQRS-T angle and DM duration (r=0.783, p<0.001), a moderate positive correlation between fQRS-T angle and HbA1c (r=0.646, p<0.001), a low positive correlation between fQRS and HbA1c (r=0.472, p<0.001), and a moderate positive correlation between fQRS and DM duration (r=0.558, p<0.001).

Table 2 Comparison of clinical characteristics of patients according to frontal plane QRS-T angle

Table 3 Clinical characteristics of patients according to diabetes duration

The multivariate analysis demonstrated that HbA1c (odds ratio [OR]: 1.136, 95% confidence interval [CI]: 1.054-1.918, p<0.001) and DM duration (OR: 1.201, 95% CI: 1.176-2.132, p<0.001) were the independent predictors of fQRS on ECG, and creatinine level (OR: 1.447, 95% CI: 1.157-1.985, p<0.001), age (OR: 1.572, 95% CI: 1.168-2.241, p<0.001), HbA1c (OR: 1.772, 95% CI: 1.314-2.612, p<0.001) and DM duration (OR: 2.463, 95% CI: 1.854-3.217, p<0.001) were the independent predictors of fQRS-T angle >90°. Table 4 shows the independent predictors fQRS and fQRS-T angle >90° in the multivariate analysis.

Table 4 Independent predictors fragmented QRS and frontal plane QRS-T angle >90° in multivariate analysis

Diabetes mellitus causes significant changes in the physiological properties of the myocardium that leads myocardial fibrosis and diabetic cardiomyopathy,[2,3] and CVD is the major cause of mortality in patients with type 2 DM.[1,23] Of note, ECG has a crucial role in the monitoring of diabetic cardiomyopathy and ECG alterations detected in the clinical follow-up of DM patients are associated with both clinical and subclinical myocardial involvement, and significantly predict adverse cardiovascular events.[5-8] However, little is known regarding the relationship of clinical and glycemic parameters with fQRS and fQRS-T angle in asymptomatic patients with type 2 DM. The fQRS is a depolarization abnormality that is an ECG sign of myocardial fibrosis and damage and is an independent predictor of future cardiovascular events in a wide variety of patients with and without CVD.[9-11,24-26] More importantly, fQRS is significantly associated with subclinical myocardial fibrosis, deteriorated cardiac functions, and adverse events in DM patients even in the absence of apparent CVD.[17,18,27,28] Additionally, as a sign of ventricular repolarization heterogeneity, increased fQRS-T angle is a predictor of abnormal cardiac functions and is associated with adverse cardiovascular events independent of underlying cardiovascular status.[12,13] Moreover, increased fQRS-T angle is significantly associated with diabetic cardiomyopathy and adverse cardiovascular events in DM patients.[19] In this context, both ECG parameters seem to be useful in the monitoring of diabetic cardiomyopathy and to demonstrate the early-stage myocardial fibrosis and damage before the emergence of manifest CVD in patients with DM.

The HbA1c level is a sign of mean blood glucose concentrations over the preceding three months, considered as a cardiovascular risk factor and is significantly associated with cardiovascular complications and adverse cardiovascular events in patients with DM.[1,8] More importantly, hyperglycemia and HbA1c is the leading cause of ECG abnormalities in patients with DM.[5,8] However, little is known regarding the relationship of HbA1c with fQRS and fQRS-T angle in DM patients without known CVD. The results of our study demonstrated that HbA1c was an independent predictor of fQRS on ECG and increased fQRS-T angle and we found a significant positive correlation between HbA1c levels and both ECG parameters. Therefore, our results suggest that fQRS and fQRS-T angle may be useful ECG findings to demonstrate the hyperglycemia related subclinical myocardial damage in the early phase of diabetic cardiomyopathy before the occurrence of clinically evident CVD. Additionally, DM duration is usually considered as a cardiovascular risk factor and is significantly associated with diabetic cardiomyopathy and future cardiovascular events in asymptomatic patients with type 2 DM independent of coexisting risk factors.[8,29] Nevertheless, the impact of DM duration on ECG parameters has not been well described yet. In the present study, we demonstrated that prolonged DM duration was the most powerful predictor of presence of fQRS on ECG and increased fQRS-T angle in DM patients without known CVD. In this context, both ECG parameters may be considered as the ECG signs of prolonged DM duration related subclinical diabetic cardiomyopathy. Hence, fQRS and fQRS-T angle may have a significant association with prolonged hyperglycemia and DM duration and may be useful in the monitoring of subclinical diabetic cardiomyopathy.

Nonetheless, there are some limitations in this study. The main limitation was the lack of data regarding the clinical events. However, this study was not a follow-up study and the association of both ECG parameters with cardiovascular events is well described in previous studies. Also, the clinical importance of our findings needs to be investigated in further studies to demonstrate whether effective treatment of DM leads disappearance of fQRS or narrowing in the fQRS-T angle. Finally, the absence of confirmation of subclinical myocardial fibrosis with cardiac magnetic resonance imaging is another limitation.

In conclusion, type 2 DM confers a significant increase in the risk of CVD and CVD is the leading cause of mortality in DM patients. The ECG has an important role in the monitoring of diabetic cardiomyopathy and demonstrating the cardiovascular involvement in patients with type 2 DM. Our study results demonstrated that glycemic parameters HbA1c and DM duration were significantly associated with fQRS and increased fQRS-T angle in type 2 DM patients without manifest CVDs. Therefore, both ECG parameters may be useful in the monitoring glycemic status and cardiovascular involvement in type 2 DM patients without known CVDs.

Ethics Committee Approval: The study protocol was approved by the Tokat Gaziosmanpaşa University Clinical Research Ethics Committee (date: 25.06.2020, no: 20-KAEK-151). The study was conducted in accordance with the principles of the Declaration of Helsinki.

Patient Consent for Publication: A written informed consent was obtained from each patient.

Data Sharing Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contributions: Idea/concept, data collection and/or processing, writing the article: M.E.; Design, control/ supervision, analysis and/or interpretation, literature review, critical review: M.E., A.Ç.

Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding: The authors received no financial support for the research and/or authorship of this article.

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