WHAT IS NEW?
- Glucose fluctuations (GF), an unstable state reflecting changes in blood glucose levels between peaks and troughs, can significantly prolong the QT interval, QTc interval and T wave duration.
- GF could promote cardiac electrical remodeling and cardiac structural remodeling, ultimately lead to ventricular arrhythmia.
WHAT ARE THE CLINICAL IMPLICATIONS?
- With the increasing number of patients with diabetes mellitus (DM) worldwide, more attention should be paid to controlling GF in patients with DM.
- Therapeutic strategy targeting GF could constitute an innovative approach to decrease ventricular arrhythmia in patients with DM.
Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia that causes severe cardiovascular complications, such as ischemic heart disease, heart failure, arrhythmias, and even sudden death. Hyperglycemia in people with DM can be divided into 2 kinds: chronic sustained hyperglycemia and chronic fluctuating hyperglycemia, also referred to as glucose fluctuation (GF). GF is an unstable state reflecting changes in blood glucose levels between peaks and troughs. Recently, studies have demonstrated that, compared with chronic persistent hyperglycemia, GF strongly promotes the occurrence and development of cardiovascular complications in people with DM.[3,4] Therefore, it is of great clinical significance to investigate the GF-related cardiovascular complications in these individuals.
An electrocardiogram (ECG) indicates the electrical activity of the heart and provides valuable information about the heart’s function and structure, and is thus a useful tool in clinical practice. An increasing number of studies have demonstrated that several ECG parameters, including heart rate, P wave, QRS wave duration, T wave, PR segment, RP interval, QT interval, and corrected QT (QTc) interval, credibly reflect the cardiac electrophysiology of the heart.[6–8] Moreover, abnormal ECG parameters in general represent abnormal cardiac electrophysiology. For instance, a prolonged P wave interval represents delayed atrial conduction velocity, indicating an increased risk of atrial fibrillation,[10,11] and a prolonged QTc interval represents an increased dispersion of ventricular repolarization, which may induce malignant arrhythmias including ventricular tachycardia/fibrillation (VT/VF) and sudden death.[12,13] In the present study, we aimed to assess the effect of GF on ECG parameters and induction of VT/VF.
2. Materials and methods
2.1. Instruments and reagents
A blood glucose meter (Roche, Basel, Switzerland), blood glucose test strips (Roche), BL-420I multi-channel biological function experimental system (Chengdu Taimeng company, Chengdu, Sichuan, China), streptozotocin (STZ; Sigma-Aldrich, Milwaukee, Wisconsin, USA), short-acting insulin (Novo Alle, Copenhagen, Denmark), long-acting insulin (Sanofi-Aventis, Paris, France), 2% isoflurane (Reward, Beijing, China), and 0.9% sodium chloride solution (Hengrui Pharmaceutical Company, Lianyungang, Jiangsu, China) were the main instruments and reagents used in this study.
2.2. Experimental animal models
Male Sprague-Dawley rats (200 ± 20 g) were purchased from Changzhou Cavins Laboratory Animal Co., Ltd (Animal Certificate Number: 201822084). Rats were intraperitoneally injected with STZ (Sigma-Aldrich; 60 mg/kg) to induce a diabetic state, and were included in the study if their blood glucose concentration was less than 16.7 mmol/L after 2 weeks. Thirty rats were divided into 3 groups as described previously: uncontrolled diabetic rats (U-STZ) (n = 10), controlled diabetic rats (C-STZ) (n = 10), and diabetic rats with glucose fluctuations (GF-STZ) (n = 10). The C-STZ group rats received a subcutaneous injection of long-acting insulin (20 U/kg, Glargine, Sanofi-Aventis, Paris, France) twice a day (8:00 and 20:00) to control their blood glucose levels. In the GF-STZ group, GFs were induced by a 24-hour starvation period followed by a 24-hour consumption period with an adequate food. After the starvation period, short-acting insulin (0.5 U/kg, Aspart, Novo Nordisk, Copenhagen, Denmark) was used to reduce glucose levels greater than 5.5 mol/L. Plasma glucose concentrations were measured daily at a fixed time. Rats were kept in a pathogen-free environment. The animal model used in our present study has been widely used to study various complications caused by GF, including arrhythmias.[4,15,16] All protocols involving the use of animal subjects were approved by the Institutional Animal Care and Use Committee of Nanjing Medical University (IACUC-1712028).
2.3. ECG recording and VT/VF induction
To avoid activation of the sympathetic nervous system, after 2 days of exposure to adequate food, ECG was measured using a BL-420I multi-channel biological function experimental system. The P wave (duration and height), PR segment, PR interval, QRS wave duration, QT interval, T wave duration, heart rate, and RR interval were measured in Sprague-Dawley rats after anesthetization with 2% isoflurane gas. The QTc interval was calculated based on Bazett’s formula (QTc = QT/(RR/f)1/2, RR = RR interval, where f = 150 ms).[17–19]
To perform the VT/VF vulnerability test after measuring the baseline ECG, rats received an intraperitoneal injection of caffeine (120 mg/kg body weight) followed by an intravenous injection of dobutamine (50 mg/kg body weight), and measurements were continued for 20 min.[20–22] A ventricular arrhythmia score was assigned to each rat that described the severity of arrhythmia, where: 0 = no arrhythmic events; 1 = one premature VT; 2 = bigeminy and/or salvos; 3 = VT; 4 = VF; and 5 = spontaneously induced VF.[20–22]
2.4. Echocardiography examination
Detailed echocardiography examination was performed on 8 rats from each group. Rats were anesthetized by inhalation of 2% isoflurane gas. Echocardiography (ie33; Philip, Eindhoven, Noord-Brabant, the Netherlands) was used to evaluate heart function, including left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-systolic internal diameter (LVIDs), left ventricular end-systolic posterior wall thickness, end-systolic interventricular septum, left ventricular end-diastolic posterior wall thickness, left ventricular posterior wall thickness at end-diastole, and end-diastolic interventricular septum.
2.5. Hematoxylin and eosin staining
Heart tissue samples were sliced into several sections of 0.5 to 0.8 cm thickness. Pieces were then fixed with 4% paraformaldehyde (#P0099-500; Beyotime Biotechnology Co., Shanghai, China), dehydrated with gradient ethanol, waxed, and embedded with paraffin. Finally, they were cut into 5 μm-thick slices and stained with hematoxylin and eosin (HE) solution (#C0105; Beyotime Biotechnology Co.). Sections were examined with optical microscope (CKX53; OLYMPUS, Tokyo, Japan) under a 40× objective lens.
2.6. Masson staining
Sections of heart tissue (of 5 μm thickness) were stained with Masson trichrome staining solution (#D026; Nanjing Jiancheng Bioengineering Institute, Nanjing, China). The slices were examined with optical microscope (CKX53; OLYMPUS) under a 40× objective lens.
2.7. Statistical analysis
Statistical analysis was performed using SPSS v22.0 (IBM, Armonk, New York, USA) and GraphPad Prism 5 (GraphPad Software, San Diego, California, USA). One-way analysis of variance (ANOVA) was used to compare data between multiple groups, and Chi-square tests were used to compare the VT occurrence among the 3 groups. P < 0.05 was considered statistically significant. Data are presented as the mean ± standard error of the mean (SEM).
3.1. Blood glucose level and body weight of rats
Blood glucose levels in the U-STZ group were all above 22.2 mmol/L. The blood glucose levels in C-STZ rats were maintained at approximately 5.5 mmol/L, and in the GF-STZ rats, the level fluctuated between 5.5 and 22.2 mmol/L [Figure 1A]. Moreover, the mean body weight in rats from the GF-STZ group was significantly lower than in the C-STZ group and U-STZ group (P < 0.05, n = 10) [Figure 1B].
3.2. ECG and echocardiogram parameters in diabetic rats
ECG parameters in diabetic rats are presented in Table 1. Representative ECGs are shown in Figure 2A–C. No significant difference in heart rate, RR interval, P wave, PR segment, PR interval, QRS wave duration, or T wave height was found among the 3 groups. However, the U-STZ and GF-STZ groups had a longer mean T wave duration ((62.41 ± 2.38) ms vs. (78.37 ± 4.64) ms and (96.06 ± 4.60) ms, P < 0.05) [Figure 2D], QT interval ((83.66 ± 2.31) ms vs. (101.75 ± 4.56) ms and (119.14 ± 4.88) ms, P < 0.05) [Figure 2E], and QTc interval ((77.45 ± 1.36) ms vs. (91.36 ± 3.49) ms and (104.55 ± 3.01) ms, P < 0.05) [Figure 2F] compared with the C-STZ group, all of which were found to be longest in the GF-STZ group (P < 0.05).
Table 1 -
ECG parameters for the C-STZ, U-STZ, and STZ-GF groups of rats (n
= 10 in each group).
|Heart rate (beats/min)
||361.9 ± 8.24
||350.30 ± 14.55
||318.00 ± 16.24
|P wave duration (ms)
||23.20 ± 1.06
||25.92 ± 0.60
||27.30 ± 1.92
|P wave height (mv)
||0.16 ± 0.01
||0.13 ± 0.01
||0.14 ± 0.01
|PR interval (ms)
||51.41 ± 2.25
||51.36 ± 2.07
||54.79 ± 1.69
|PR segment (ms)
||28.21 ± 2.24
||25.44 ± 2.39
||27.49 ± 1.75
|RR interval (ms)
||174.62 ± 3.89
||187.64 ± 10.40
||195.92 ± 11.37
|QT interval (ms)
||83.66 ± 2.31
||101.75 ± 4.56*
||119.14 ± 4.88*
|QTc interval (ms)
||77.45 ± 1.36
||91.36 ± 3.49*
||104.55 ± 3.01*
|QRS wave duration (ms)
||21.25 ± 0.45
||23.38 ± 0.91
||23.08 ± 0.84
|T wave duration (ms)
||62.41 ± 2.38
||78.37 ± 4.64*
||96.06 ± 4.60*
|T wave height (mv)
||0.18 ± 0.01
||0.22 ± 0.02
||0.23 ± 0.02
Data are presented as mean ± SEM.
*P < 0.05 vs. C-STZ.
†P < 0.05 vs. U-STZ.
C-STZ: Controlled diabetic rats; ECG: Electrocardiogram; GF-STZ: Diabetic rats with glucose fluctuations; HR: Heart rate; SEM: Standard error of the mean; U-STZ: Uncontrolled diabetic rats.
Echocardiography was used to evaluate heart function. As can be seen in Supplementary Figure 1 (https://links.lww.com/CD9/A26) and Supplementary Table 1 (https://links.lww.com/CD9/A26), in comparison with the C-STZ and U-STZ groups, the LVEF and LVFS were both significantly decreased and the LVIDs was significantly increased in the GF-STZ group, and there was also a significant statistical difference in these values between the U-STZ and GF-STZ rats, indicating that GF significantly aggravated cardiac systolic dysfunction in diabetic rats.
HE and Masson staining were used to evaluate pathological cardiac changes after intervention. HE staining revealed that the morphological structure of myocardial tissue in the U-STZ rats was significantly more disorganized than in the C-STZ rats, and in the GF-STZ rats, it was even more pronounced [Supplementary Figure 2, https://links.lww.com/CD9/A26]. However, none of the groups had cardiac function levels that fell below the standard threshold for heart failure. Furthermore, we also observed the deposition of collagen fibers in the myocardial tissue by Masson staining [Supplementary Figure 2, https://links.lww.com/CD9/A26]. Compared with C-STZ rats, rats in the U-STZ and GF-STZ groups showed increased levels of cardiac fibrosis.
3.3. Increased vulnerability of VT/VF induction
No ventricular arrhythmias were observed in the C-STZ group in the VT/VF vulnerability test [Figure 3A]. However, U-STZ and GF-STZ rats showed abnormal electrical activity following challenge with dobutamine and caffeine, including VT accompanied by sinus rhythm in the U-STZ group [Figure 3B] and VT in the GF-STZ group [Figure 3C]. The VT occurrence in GF-STZ group was higher than in the C-STZ and U-STZ groups (80% vs. 0, P < 0.05 and 80% vs. 40%, respectively; P < 0.05) [Figure 3D]. Similarly, the VT duration was longer [Figure 3E] and the ventricular arrhythmia score greater in the GF-STZ group [Figure 3F].
Diabetic cardiovascular complication is a leading cause of death. Clinical trials have demonstrated that diabetic patients have more ECG abnormalities and a higher incidence of ventricular arrhythmias compared with normal individuals.[23–25] Recent studies have demonstrated that GF are more harmful to patients with DM than sustained hyperglycemia. However, the relationship between GF and lethal ventricular arrhythmias, such as VT or VF, remains elusive.
In this study, we aim to assess the effect of GF on ECG parameters and vulnerability to lethal ventricular arrhythmias in STZ-induced diabetic rats. The most important findings of this study were: (1) the QT interval, QTc interval, and T wave durations were prolonged in the U-STZ group, and even more prolonged in the GF-STZ group, compared with the C-STZ group; (2) the vulnerability to ventricular arrhythmias was significantly increased in the GF-STZ group.
The ECG is an established, useful, non-invasive cardiovascular examination, providing multiple cardiac electrophysiology measures. In general, heart rate and RR interval reflect the frequency of sinus node impulses, which are significantly influenced by cardiac autonomic nerves. The PR segment and PR interval reflect the total conduction duration of the atrioventricular node and the His bundle-Purkinje system. The P wave and QRS wave reflect atrial and ventricular depolarization, respectively.[27,28] Of note, multiple studies have revealed a relationship between the P wave and atrial fibrillation.[10,29,30] The QT interval, QTc interval and T wave duration represent ventricular repolarization, and are thus more closely related to the occurrence of ventricular arrhythmias. Until now, the ECG characteristics in healthy and diabetic rats, and diabetic rats with blood GF, have not been reported. STZ is an organic compound that selectively destroys islet beta cells, thus inducing DM. In our study, STZ-induced diabetic rats were used to establish an animal model of GF and explore the underlying mechanism of diabetic cardiovascular complications, as described previously. Twelve weeks later, ECG recordings were taken in these rats. In this study, detailed ECG parameters were measured in the C-STZ, U-STZ, and GF-STZ groups, providing a reference for further research on diabetic cardiovascular complications.
Accumulating studies demonstrate that prolonged QT interval, QTc interval, and T wave duration are all significantly associated with several chronic diseases, especially in people with DM.[31–33] Previous clinical studies revealed the prevalence of prolonged QTc duration reached 21% to 31% in individuals with type 2 DM.[34,35] Consistent with previously reported results, we found significantly prolonged QT intervals, QTc intervals, and T wave durations in STZ-induced diabetic rats with high blood glucose and GF. GF is the most influential factor in increased QT and QTc intervals and T wave duration. Increasing numbers of studies have demonstrated multiple underlying mechanisms for abnormal ventricular repolarization, including abnormalities in ion channels, neuromodulation of cardiac repolarization, and repolarization remodeling. Importantly, abnormalities in multiple ion channels underlying mechanism for cardiac repolarization is demonstrated to be associated with DM-induced QT prolongation and arrythmias. Monnerat et al demonstrated that the NOD-like receptor protein 3 inflammasome and toll-like receptor 2 in macrophages in the mouse heart increase the level of interleukin (IL)-1β. IL-1β contributes to a K+ current reduction and prolongation of the QTc interval and action potential, eventually contributing to arrhythmia. Similarly, Bohne et al showed that atrial K+ currents, including transient outward and ultrarapid delayed rectifier currents, were significantly reduced in db/db mice (a type 2 diabetic animal model), leading to action potential duration prolongation, increased repolarization heterogeneity, and elevated susceptibility to atrial fibrillation. Additionally, Jin et al revealed that the increased susceptibility to DM-induced arrythmia was associated with an increased late sodium current, which could be reversed by inhibiting the late sodium current. Enhanced inward L-type calcium channel currents (ICa-L) and sodium/calcium exchanger currents were also shown to be involved in the prolongation of action potential duration and increased vulnerability to ventricular arrhythmias. Therefore, the underlying mechanisms of GF-induced prolongation of the QT interval, QTc interval, and T wave duration may include abnormalities in ion channels, neuromodulation of cardiac repolarization, and cardiac repolarization remodeling, which all need to be further investigated.
Accumulating studies have demonstrated that prolonged QT and QTc intervals and T wave durations are significantly associated with ventricular tachycardia and sudden death.[42–44] The underlying mechanism for prolonged cardiac repolarization and increased lethal ventricular arrhythmias has been the subject of significant amounts of research for a long time. Many studies have revealed that prolonged cardiac repolarization may induce various abnormalities in cardiac electrophysiology, including increased frequency of afterdepolarization, abnormal triggered activity, and phase 2 reentry, subsequently leading to malignant arrhythmia, including torsades de pointes and ventricular fibrillation.[37,38,45] The VT/VF vulnerability test has been widely used to evaluate vulnerability to and severity of ventricular arrhythmias.[20–22] Our study showed the highest VT occurrence, VT duration, and arrhythmia score in the GF-STZ group in response to challenge with dobutamine and caffeine, further indicating a high risk of prolonged cardiac repolarization. Collectively, the data from our study indicate that prolonged QT interval, QTc interval, and T wave duration play an important role in malignant ventricular arrhythmias caused by GF.
In future work, we will explore the molecular mechanism of GF leading to a prolonged QT interval and the occurrence of ventricular arrhythmias.
GF significantly prolongs the QT interval, QTc interval, and T wave duration, and increases the vulnerability to VT/VF in diabetic rats, and may thus be an important mechanism of GF-related malignant ventricular arrhythmias.
This work was supported by the Natural Science Foundation of China (81770331) and the Wuxi Health Commission for the Youth Research Foundation (Q202034).
Ru-Xing Wang designed the experiments. Li-Da Wu, Feng Li, Ling-Ling Qian, and Chao Wang performed the experiments. Shi-Peng Dang, Feng Xiao, Guo-Qiang Zhong, and Zhen-Ye Zhang analyzed the data. Ru-Xing Wang and Li-Da Wu wrote the manuscript. Yu-Min Zhang, Cun-Yu Lu, Ying Liu, Jie Zhang edited the manuscript. All authors read and approved the final manuscript.
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