**5. Prognostic significance of changes in the ventricular complex in arrhythmogenesis**

Evaluation of the parameters of the ventricular complex (QT interval, QTc interval, QRS complex, R, and T wave amplitudes) is undoubtedly important because it provides information about the course of depolarization and repolarization of the ventricles. The distance from the beginning of the QRS complex to the end of the T

wave is measured, with the total length corresponding to the duration of depolarization and repolarization of the ventricular muscle.

### **5.1 QT interval**

In rats, the determination of the QT interval is more complicated because the T wave is not clearly separated from the QRS complex. Therefore, it is necessary to develop a method for analyzing repolarization time in nonanesthetized rats. However, the importance of QT interval dispersion is a complex matter involving at least two different phenomena—namely, prolongation of the average action potential duration and myocardial heterogeneity [26]. Based on the evaluation of the QT, as well as the QTc interval in rat experimental models, cardioprotection was also assessed after stimulation of vitamin D receptors and the effect of isoprenaline [42], the effect of doxorubicin [134] and L-glutamine in diabetic rats [135], saffron on atrial and ventricular conduction velocity [64], or the effect of preconditioning at different doses of noradrenaline on ischemia-induced ventricular arrhythmias.

The mentioned examples confirm the informative value of changes in the duration of the QT interval in the evaluation of the severity of disorders in the dispersion of ventricular refractory periods and their impact on the onset and development of ventricular arrhythmias. If we consider the values from telemetry studies, in terms of reference value and range [21, 26, 117, 118], QT interval prolongation was measured with virtually every type of barbiturate anesthesia; as such, under pentobarbital [32, 34, 37, 38, 40, 41, 43–45, 47–50, 122, 124–126], thiopental [61–64, 66, 67, 69], and Nembutal anesthesia [114]. Ketamine/xylazine [45, 78, 85, 87, 89–92, 129, 136], ketamine/medetomidine [96], ketamine/diazepam [96, 98], and ketamine/ midazolam [97], anesthesia had the greatest effect on QT interval prolongation. A moderate prolongation was also found under chloralose anesthesia [77] and similar prolongations under ether anesthesia [99–101, 103, 104]. The shorter QT interval duration was under urethane [45, 52, 55, 56, 60, 135, 137, 138] and tribromoethanol [106] anesthesia compared with telemetry studies. Isoflurane [72, 74, 75, 120, 121] and desflurane anesthesia [72] did not affect QT interval duration. There were virtually no significant changes in QT interval duration in working with isolated hearts [105, 115, 139, 140]. All experiments were performed on males without specifying the adaptation of the animals to the LD cycle and there were no studies investigating sex



*Data presented as average (range); (n, number of baseline or control values from which QT interval was evaluated). Not specified—in the methodology does not specify the lighted period when the experiments were performed.*

#### **Table 4.**

*QT interval duration (ms) under individual types of anesthesia with regard to sex and the cycle of light (inactive) and dark (active).*

differences. Similarly, it was not possible to determine the circadian fluctuation in the duration of the QT interval or the dependence on the LD cycle (**Table 4**, **Figure 3**).

## **5.2 QTc interval**

In human cardiology, QTc interval assessment enables the comparison of QT values overtime at different HRs and improves the identification of patients at increased *Rat Electrocardiography and General Anesthesia DOI: http://dx.doi.org/10.5772/intechopen.104928*

#### **Figure 3.**

*Distribution of ranges of QT intervals from telemetry studies and under different types of general anesthesia in male rats without taking into account the light periods of the rat regimen day when the experiments were performed. Only QT interval ranges from at least three studies in which QT interval was evaluated are shown in the figure. Telemetry studies (n = 4), pentobarbital anesthesia (n = 19), thiopental anesthesia (n = 8), ketamine/ xylazine anesthesia (n = 11), isoflurane anesthesia (n = 6), ether anesthesia (n = 5), urethane anesthesia (n = 9), isolated heart (n = 4). n, number of baseline or control values from which duration of the QT interval was evaluated.*

risk for arrhythmias. Prolonged QTc is caused by premature action potentials during the late phases of depolarization. This increases the risk for ventricular arrhythmias, including fatal ventricular fibrillation [141]. These changes make it difficult to compare QT intervals measured at different HRs. To account for this and, thus, improve the reliability of QT measurements, the QT interval can be corrected for HR (QTc) using various mathematical formulae, a process that modern ECG recorders often perform automatically. The duration of the QTc interval is a key and critical factor in assessing changes in repolarization with regard to drug safety and cardiac disorders. There was only one study that reported changes in the duration of the QTc interval depending on commonly used drugs, especially when used in combination with other substances that affect their metabolism [142, 143]. Possible changes in QTc interval depending on sex and age have also been described in humans. Higher rates of prolonged QTc are observed in women, older patients, with high systolic blood pressure or HR, and low body height [144]. It was found that the rate of QT/RR hysteresis decreases with increasing age, while the duration of the individually corrected QTc interval increases with increasing age. In contrast to longer QTc intervals, the rate of QT/RR hysteresis was faster in women [145]. There are many causes of prolonged QT intervals, and acquired causes are more common than genetic causes [146].

Changes in the QTc interval have also been described in rats, where, for example, induction of ischemia shortened the QTc interval and led to ventricular arrhythmias. Administration of low doses of noradrenaline prevented shortening of the QTc interval during ischemia but could not significantly reduce the severity and incidence of arrhythmias [38]. However, in the experimental field, determination of QTc interval is somewhat more complicated because HR values are extremely variable among different species [147]. In rats, there is a lack of a validated approach to QT interval correction [143] and, despite some efforts [148, 149], there is no validated and widely used method for such QTc interval adjustment. Thus, most researchers in experimental cardiology, pharmacology, and toxicology must use formulas designed for other species, without commenting on their accuracy in rats [26, 150, 151], and its

use should be considered carefully in case of very low HR [143] . This fact is reflected in the data reported in **Table 5** and **Figure 4** of the average values of the QTc interval, where relatively large deviations under different types of anesthesia are evident.

When comparing the duration of the QTc interval with the mean value from telemetry studies [26, 30, 31, 117, 118], significant prolongation occurred under pentobarbital [32, 38, 41–43, 47, 51] ketamine/xylazine [87, 90–92, 129, 136, 152, 153], and urethane [52, 57, 60] anesthesia, with moderate prolongation under thiopental [31, 62, 63, 66, 68, 71] anesthesia. The shortened QTc interval duration compared with the mean value from telemetry studies was under isoflurane anesthesia [72, 74, 75, 121].


*Rat Electrocardiography and General Anesthesia DOI: http://dx.doi.org/10.5772/intechopen.104928*


*Data presented as average (range) n, number of experimental studies in which ventricular parameters were evaluated.*

#### **Table 5.**

*QTc interval, QRS complex duration, R and T wave amplitude, regardless of the synchronization of the animals to the light and dark cycle under individual types of anesthesia.*

#### **Figure 4.**

*Distribution of ranges of QTc interval from telemetry studies and under different types of general anesthesia in male rat males without taking into account the light periods of the rat regimen day when the experiments were performed. Only QTc interval ranges from at least three studies where QTc interval has been evaluated are shown in the figure. Telemetry studies (n = 5), pentobarbital anesthesia (n = 7), thiopental anesthesia (n = 7), ketamine/ xylazine anesthesia (n = 8), urethane anesthesia (n = 3), isoflurane anesthesia (n = 4). n, number of baseline or control values from which duration of QTc interval was evaluated.*

The problem is the comparison between the sexes and to evaluate the effect of the LD cycle, for which insufficient experimental data are available. LD differences were found in females under ketamine/xylazine anesthesia (light 174.5 ± 34.8 ms vs. dark 202.1 ms) [19], unlike pentobarbital anesthesia, where there were no significant differences (light 197.7 ± 40.9 ms vs. dark 190.7 ± 26.6 ms) [20]. Unfortunately, this dependence has not been tested with other types of general anesthesia. The age effect of rats was demonstrated under rather unconventional tribromoethanol anesthesia by da Silva et al. [106], where the duration of the QTc interval was two times longer in older rats (117 ± 4 ms vs. 64 ± 6 ms) than in young rats at relatively the same HR (young, 381 ± 1 beats/min. vs. old, 405 ± 11 beats/min).

#### **5.3 QRS complex**

In some cases, it is also important to evaluate other parameters related to the electrophysiology of the ventricles. For example, the QRS complex indicates depolarization of the right and left ventricles and the contraction of the large ventricular muscles. Any conduction abnormality lasts longer and causes "extended" QRS complexes. The duration, amplitude, and morphology of the QRS complex are useful in the diagnosis of cardiac arrhythmias, conduction abnormalities, ventricular hypertrophy, myocardial infarction, electrolyte disturbances, and other disease states. High-frequency analysis of the QRS complex may be useful for detecting coronary artery disease during a stress test. Evaluation of the amplitude of the R wave as well as the P wave in experimental work on rats also proved to be important. They are informative and changes can help to determine the tendency of the myocardium to arrhythmias.

When comparing the average value of QRS complex duration from telemetry studies [21, 31, 117–119] to barbiturate anesthesia—under pentobarbital [32, 34, 37, 40, 42, 44–49, 51, 122, 124–126, 154], thiopental [31, 61, 63, 64, 68, 69, 71], and Nembutal [114] anesthesia—the average value of the QRS complex duration was somewhat shorter and the ranges did not differ significantly.

Ketamine/xylazine [45, 78, 79, 84, 85, 89, 91, 92, 128, 129, 152], ketamine/diazepam [96, 98], and ketamine/midazolam [97] as well as ether [100, 101] and urethane anesthesia [45, 53, 55–58, 60, 135, 137, 138] shortened the duration of the QRS complex compared to the value(s) from telemetry studies. The longer duration was under phenobarbital [95], ketamine/medetomidine [96], desflurane [72], chloralose [77] anesthesia, and in isolated hearts [105, 115] (**Figure 5**). Of course, such comparisons can be misleading because the values were reported in only one study. Similar to previously described ECG parameters, all experiments were performed on males without specifying the adaptation of the animals to the LD cycle, and there was no study addressing sex differences. Similarly, it was not possible to determine the circadian fluctuation in the duration of the QT interval or the dependence on the LD cycle (**Table 5**, **Figure 5**).

#### **Figure 5.**

*Distribution of ranges of QRS complex from telemetry studies and under different types of general anesthesia in male rats without taking into account the light periods of the rat regimen day when the experiments were performed. Only QRS complex ranges from at least three studies where QRS complex has been evaluated are shown in the figure. Telemetry studies (n = 5), pentobarbital anesthesia (n = 19), thiopental anesthesia (n = 8), ketamine/xylazine anesthesia (n = 12), urethane anesthesia (n = 15), isoflurane anesthesia (n = 4). n, number of baseline or control values from which duration of QT interval was evaluated.*
