**4. Ischemic cardiomyopathy**

Ischemia is another of the most typical cardiotoxic effects [87]. This term comes from the Greek language (isch means restriction and haema means blood) and refers to a situation where there is an imbalance between the demand for blood and the supply in the tissue [88]. Cardiomyocytes, unlike other tissue cells, do not store energy in the form of glycogen, hence the relationship between myocardial oxygen use and the amount of oxygen given to the myocardial cells is extremely delicate. Cardiovascular problems are further increased by myocardial ischemia [89]. Stress, aging, alcohol consumption, and poor nutrition are all risk factors [90]. 5-fluorouracil (5-FU), cisplatin, and capecitabine are the most common chemotherapeutic agents that cause cardiac ischemia as a cardiotoxic side effect [88, 91, 92]. Isoproterenol (ISP) is another drug that is commonly used to treat bradycardia and heart block, but it can cause myocardial ischemia [92]. 5-FU is a common anticancer drug that can cause cardiotoxicity and is related to myocardial ischemia. In this case, the potential mechanism that occurs in myocardial ischemia is indirectly induced coronary vasospasm. Coronary vasospasm may be caused by the synthesis of vasoactive compounds, intimal hyperplasia which results in hyperactive coronary arteries, or it can be myocardial cell damage that occurs as an autoimmune reaction in individuals who are susceptible to 5-FU. Eskilsson et al. investigated verapamil to see if it could protect against 5-FU-induced cardiac ischemia, but the results were not significant [88]. Capecitabine, another agent that is used in chemotherapy, is the oral prodrug of 5-FU. In other words, it is the inactive form of 5-FU, which is activated by thymidine phosphorylase in tumor cells. It is used for its advantages compared to 5-FU. However, capecitabine cardiotoxicity is also known to be reported in the literature [92]. In a case of cardiac ischemia associated with capecitabine-induced cardiotoxicity, acute onset of severe anterior chest pain is observed. The development of chest pain and ischemic changes on ECG is no more observed after capecitabine is ceased [93].

Isoproterenol (ISP) is a medication used to treat conditions such as bradycardia, Torsades de pointes (TdP), and heart block. However, ISP also generates free radicals, which cause oxidative stress. Underlying molecular mechanisms in ISP-induced cardiotoxicity include oxidative stress, the renin-angiotensin system (RAS), apoptosis, and DNA damage. All of these causes cell death and, as a result, cardiac injury, including ischemia [90].

Cisplatin is an antineoplastic drug based on platinum. It is used to treat tumors of the lung, ovary, sarcoma, and lymphoma. The most common cardiotoxic complications caused by cisplatin are thromboembolic events, including myocardial ischemia and infarction [94]. Depolarization of the mitochondrial membrane due to structural abnormalities is one of the mechanisms involved in cisplatin-induced myocardial dysfunction. Furthermore, the endoplasmic reticulum stress response is activated, and apoptosis and caspase-3 activity are increased in cardiomyocytes [95].

Arsenic trioxide (As2O3) is an anticancer agent used in patients with acute promyelocytic leukemia. Arsenic is a chemical element that can be consumed or absorbed through the environment, such as through water and air. Arsenic-related cardiopathological consequences include heart failure and arrhythmia. Caspase activation, mitochondrial disruption, and the pk53 and MAPK signaling pathways all contribute to apoptosis in arsenic cardiotoxicity [96].

Following are a few examples of *in vivo* models of ischemic cardiomyopathy and protective agents based on the literature;

Paclitaxel, a taxoloid drug, is a cardiotoxicity-inducing drug that causes ischemia, with mechanisms including oxidative stress and apoptosis [97]. Studies on mice have shown that l-glutamine protects against the cardiotoxicity of the anticancer drug cantharidin, which is similar to ischemia in its mechanism of action [98]. ISP is used in protective drug research to create acute or progressive cardiotoxicity in animal models. Curcumin, quercetin, coriander, Momordica, and Withania somnifera are plant-based agents that have been shown to reduce myocardial ischemia in ISP models [90]. The extract of the Spondias mombin plant was used as a treatment in an ISP model on rats. The findings strongly imply that the plant could be used as a cardioprotective treatment. Spondias mombin improves the contractility of the ISP model rat hearts, which are unable to pump blood due to ischemia [99]. Another ISP model investigation was conducted by Jain et al., and ferulic acid was found to be a cardioprotective agent for ISP-induced cardiotoxicity [100]. Pituitrin, like ISP, induces myocardial ischemia. Another rat model for cardiotoxicity is being investigated, and a flavonoid named latifolin derived from Lignum dalbergiae odoriferae was shown to protect against acute myocardial ischemia induced by pituitrin and ISP [101]. Zhang et al. investigated latifolin's cardioprotective effects on doxorubicin-induced cardiotoxicity. They determined that latifolin protects against the cardiotoxic effects of doxorubicin [102].

### **5. Diabetic cardiomyopathy**

Diabetes mellitus (DM) is a heterogeneous metabolic disease characterized by chronic hyperglycemia resulting from defects in insulin action, insulin secretion, or both. Although, some of the patients die from acute metabolic complications such as ketoacidosis, hyperosmolar hyperglycemic state, and hypoglycemia, the main problem is the increased morbidity and mortality resulting from long-term complications of diabetes. Morbidity and mortality are related to decreased life expectancy and decreased quality of life due to diabetes-related complications [103]. The main cause of morbidity and mortality in diabetic patients is cardiovascular complications [104].

40% of DM patients have heart failure and cardiotoxicity. The increase in the incidence of these conditions is because insulin resistance is a risk factor [105]. Insulin desensitization greatly diminishes the important effects of insulin on heart tissue. It is expressed on many cell surfaces, including cardiomyocytes, where insulin receptor, ligand binding, and insulin receptor substrates (IRS) 1 and 2 are taken up. In addition to IRS1 and IRS2, regulation of the PI3K/Akt pathway is also important in the ERK and MAP kinase cascade. They provide control of metabolism and cell survival. One of the Akt isoforms, AKT1 is involved in the survival of cardiomyocytes; AKT2 is required for the modulation of genes involved in cardiac metabolism. AKT2 promotes glucose uptake through mobilization and fusion of GLU4-containing vesicles to the plasma membrane. Short-term activation of AKT shows cardioprotective effects, can increase glycolysis, and decrease oxidative phosphorylation. The long-term activity of AKT1 in the adult heart is associated with a higher risk of cardiac complications and reduced mitochondrial function [106].

#### *Experimental Model of Cardiotoxicity DOI: http://dx.doi.org/10.5772/intechopen.101401*

Following insulin stimulation, AKT1 phosphorylates and blocks FOXO1 nuclear translocation, inhibiting the expression of proapoptotic proteins belonging to the Bcl-2 family. FOXO1 has emerged as one of the key players in chronic metabolic diseases, promoting hyperglycemia and glucose intolerance [107]. In physiological conditions, pro-survival stimuli were induced by insulin-suppressing FOXO1 activity via the PI3K/AKT1 pathway. Following stress stimuli, FOXO1 translocates in the nucleus and causes negative feedback on the insulin pathway via a JNK-dependent mechanism that greatly reduces IRS-1 activity [108].

The heart of healthy people without DM obtains 60–90% of its energy from free fatty acids (FFA) oxidation and the rest from lactate and glucose [109]. In patients with DM, glucose uptake is greatly reduced, FFA uptake is increased, and the metabolic balance shifts to lipid oxidation. Increased FFA oxidation is complicated by lipotoxicity and high levels of triglyceride synthesis causing myocyte apoptosis. Additionally, in the diabetic heart, increased lipid oxidation increases mitochondrial dissociation and oxidative stress, which can lead to decreased myocardial energy production and myocardial contractile dysfunction [110]. Hyperglycemia is an important component in diabetes-associated cardiotoxicity because glucotoxicity leads to cardiac dysfunction by inducing oxidative stress and producing enhanced glycation end products. In addition, hyperglycemia may activate the renin-angiotensin-aldosterone system (RAAS) and cause an increase in cell necrosis and fibrosis [111]. Another important component is the inflammation that occurs in diabetes. Expression of inflammatory cytokines such as tissue necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) is increased in the myocardium associated with myocardial contractile dysfunction [112]. In a study by Stentz et al., it was reported that acute hyperglycemic crises such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome (HHS) are associated with the inflammatory state and independently cause changes in proinflammatory cytokines, oxidative stress, and cardiovascular markers [113].

Increased leukocytes in the myocardium also contribute to the relationship between diabetes and cardiotoxicity. Pathological stresses such as hyperglycemia, hyperlipidemia, high RAAS, and advanced glycation end products (AGEs) stimulate the secretion of proinflammatory molecules, adhesion molecules, and danger-associated molecular patterns (DAMPs) from leukocytes. In addition, these triggers induce ROS-mediated endothelial dysfunction, which also causes cardiac remodeling. Secreted proinflammatory cytokines bind to receptors such as TLR4-MyD88 complex, the receptor for AGEs (RAGE), and IL-1R and initiate intracellular signaling pathways. These pathways activate NF-kB, resulting in transcriptional upregulation of inflammatory cytokines and NLRP3 inflammasome. NF-kB activation and increased oxidative stress mature IL-1B and IL-18 with induction of pyroptosis. At the same time, stressed and damaged cardiomyocytes contribute to inflammatory cascades by releasing pro-inflammatory cytokines and DAMPs. The chronic inflammatory cytokine-induced intracellular response causes pathological cardiac remodeling and cardiac dysfunction [114].

In summary, it involves complex and multifactorial mechanisms such as hyperglycemia, hyperinsulinemia, insulin resistance, increased free fatty acids, microvascular damage and inflammatory cytokines, changes cellular metabolic pathways in cardiomyocytes and contributes to cardiotoxicity by impairing heart function.

Following are a few examples of *in vivo* models of diabetic cardiomyopathy and protective agents based on the literature;

Rodent models of type 1 and type 2 diabetes share many features with human diabetic cardiomyopathy and have greatly advanced our understanding of the underlying pathology of diabetic cardiomyopathy. Each model has certain limitations, and there is no perfect model that fully phenotypes the human condition. Genetic heterogeneity and lifestyle differences among people make it difficult to produce a suitable model. Some studies with these models are given below.

In one study, empagliflozin treatment was applied to investigate the cardiac metabolic profile of Zucker diabetic fatty rats, which is an early-stage DMT2 model. This treatment activated the cardioprotective master regulator of cellular energy homeostasis, AMP-activated protein kinase, and decreased IL-6 and cardiac mRNA levels while increasing autophagy at the cardiac level. In addition, it reduced cardiac levels of the essential glucose mediators 2,3-bisphosphoglycerate and phosphoenolpyruvate, and regulated several amino acids important in the metabolic control of cardiac function, such as glutamic acid. Therefore, it has been proven that empagliflozin has a protective effect on the development of cardiometabolic diseases associated with cardiac bioenergetic dysregulation and cardiac lipidoma dysregulation [115].

In a study at the ERBAS Institute of Experimental Medicine, 12 rats were used to create a diabetic model after receiving an i.p injection of streptozocin. Rats were randomly assigned to one of two groups: the diabetes group, received 1 mL/ kg saline, and the second one received 160 g/kg/day i.p oxytocin for 28 days. They found that oxytocin treatment reduced cardiac myocyte thicknesses significantly over a 4-week period. Besides, as plasma TGF-β levels increased in diabetic rats, oxytocin application significantly decreased plasma TGF-β levels [116].

In another study, rats with and without diabetes were used as models. The hearts of those predisposed to diabetes exhibited depressed contractility and ventricular relaxation at high filling pressures, and abnormalities in the contractile performance of these hearts were observed [117].

Diabetic patients suffer from dual stress on the heart: (1) diabetic cardiomyopathy caused by hyperglycemia and (2) cardiotoxicity caused by anti-diabetic drugs. The following drugs are used as a solution to cardiotoxicity [118].

Metformin (Met) is an oral biguanide antihyperglycemic drug commonly used in the treatment of type 2 diabetes. It activates AMPK and induces cardiac autophagy through the AMPK signaling pathway and improves cardiac functions. In other words, metformin activates AMP-activated protein kinases that play an important role in insulin signaling and fat and glucose metabolism [119]. Kobashigawa and colleagues demonstrated that the cardioprotective effect of metformin against DOX-induced toxicity is mediated through the upregulation of AMPK and its downstream target molecules [120]. However, treatment with high doses of metformin induces the same change in the AMPK pathway, but its protective effect is lost. The authors suggested that this may be due to the downregulation of the platelet-derived growth factor receptor. Moreover, silencing of adiponectin receptors suppressed AMPK activation and cell viability in metformin and DOX-treated cells [121]. In another study, metformin was able to activate AMPK, restore autophagy, and improve heart function [122].

Another drug, Pio, is hyperglycemic drug; it is FDA (Food and Drug Administration) approved and does not show liver toxicity, but cardiotoxicity. It stimulates the peroxisome proliferator-activated receptor (PPAR) γ, which controls the storage of fatty acids and glucose metabolism [123].

One study shows that curcumin has the potential to reverse cardiotoxicity caused by the anti-diabetic drugs Pio and Met. It confirms the generation of ROS in cardiomyoblasts upon treatment with anti-diabetic drugs that Pio is more toxic than Met. Curcumin significantly reduced the oxidative stress caused by anti-diabetic drugs and strengthened the built-in oxidative machinery. It also reduces mitochondrial changes and thus reduces apoptotic cell death of cardiomyoblasts *in vitro* [118].
