## 4 Discussion
### Electrocadiogram Monitoring and Histological Changes of the Heart  
The cardiomyopathy described in the pathophysiology of STZ-induced T1 DM is frequently associated with heart rhythm disturbances and contractile dysfunctions, as reduced contraction amplitude and prolonged time course of contraction and relaxation have been reported in cardiomyocytes to STZ-induced T1 DM [28]. [PERSON] et al. reported that the ECG monitoring of diabetic rats after STZ administration revealed a reduction in HR and HR variability and prolonged QRS complex and QT intervals [29]. These results are similar to those obtained in our study (Figure 3, Table 1). Negative chronotropic effects and impairment of the sinatorial node pointed to be responsible in HR reduction seen in STZ-induced diabetic rats are reversed by insulin treatment [30]. Prolongation of QT interval is considered to be associated with an increased risk of ventricular arrhythmias and/or sudden death. The autonomic neuropathy increases the risk of malignant arrhythmias and mortality rates, as it is correlated with a prolongation of the QT interval [31]. The underlying mechanisms involved in prolonging the QRS complex and QT interval in diabetes mellitus may include slowed inactivation and/or reductions in the activity of Ca2+ and K+ channels of the cardiomyocytes membranes [29].  
The reduction of the RR interval and increased HR recorded after ISO administration can be explained by the fact that ISO is a nonspecific \(\beta\) adrenoreceptor agonist and by activation of \(\beta\)-adrenergic receptors increases the force of contraction of the left ventricle and accelerates the HR [32]. Rats with ISO-induced AMI presented a prolongation of the QRS complex, reduced R-wave amplitude, increased QT and QTc intervals, the elevation of the ST-segment, but had no effect on the PR segment (Figure 3, Table 1). As a result of the ISO cardiotoxic effect, slow ventricular conduction could explain the prolongation of the QRS complex and QT, QTc intervals [33]. The marked decrease in R-amplitude associated with elevation of ST-segment is indicative of AMI [34]. The decreased R-amplitude might result from the onset of myocardial edema following ISO administration, while the ST-segment elevation reflects the loss of cardiomyocytes membrane function potential and the difference in action potentials in the boundary between the ischemic and non-ischemic zones of the myocardial tissue [34]. Our previous study reported that curcumin and curcumin nanoparticle doses increased the RR interval and reduced HR [35]. The exact mechanism of how curcumin reduces HR is not known yet and needs further investigations.  
Pretreatment with curcumin was observed to protect the structure of the cardiomyocytes membrane, offering a cardioprotective effect against ECG alterations and acute fatal complications of AMI [36]. Preservation of cardiomyocytes structure and function could explain the reduction in the QRS complex enlargement after curcumin administration. The anti-inflammatory effects of curcumin and enhanced effects offered by curcumin nanoparticles could explain the reduction of edema in the myocardial tissue and prevention of the decreased R wave [35; 37]. [PERSON] et al. observed that curcumin encapsulated in lipopolysaccharide hybrid nanoparticle formulation increases the bioavailability and stability of the active compound offering a better protection against QT prolongation [38]. [PERSON] et al. showed that liposomal curcumin better prevented QTc prolongation [39].  
Curcumin administration, especially curcumin nanoparticles, reduced the area of cardiac necrosis, as curcumin can reduce the intensity of apoptosis and, therefore, decrease cardiomyocyte injury after AMI by modulating the immune cell filtration rate and improving the mitochondrial function of the injured cardiomyocytes [37].