Mitigating diabetic cardiomyopathy: Evaluating exercise training and pyridoxamine as cardioprotective approaches

Abstract

Type 2 diabetes mellitus (T2DM) is a substantial public health concern worldwide and its disease prevalence is increasing at an alarming rate. Patients with T2DM have a two-to-fivefold higher risk of developing heart failure. DCM includes all diabetes-induced structural and functional changes in the myocardium in the absence of other cardiac risk factors, such as coronary artery disease and valvular disorders. The current management of diabetic cardiomyopathy (DCM) mainly focuses on one-for-all-type pharmacological strategies. However, preventive or therapeutic approaches targeting both cardiac and metabolic complications in T2DM are missing. Lifestyle changes, such as physical activity, are highly recommended as basic measures to improve and prevent T2DM with comorbid cardiovascular diseases (CVD). Nevertheless, the most optimal exercise intensity for the management of T2DM in terms of cardioprotection remains unclear. Furthermore, there is a high need to uncover new compounds that target underlying pathways of DCM. In addition, advanced glycation end products (AGEs) are known to play an essential role in the development of CVD, including DCM and diabetes-induced vascular complications. Chronic exposure to high molecular weight AGEs (HMW-AGEs) has been previously shown to disturb the vasomotor function of the aorta of healthy rats. However, the acute effects of HMW-AGEs on the vasomotor balance in the aorta remain unknown. Based on these research gaps, the two central aims of this dissertation were 1. to investigate the cardioprotective potential of exercise training, especially its intensity, and pyridoxamine (PM) in a Western diet (WD)-induced rat model for DCM. 2. to examine the acute effects of HMW-AGEs on vascular function in the aorta of healthy rats. Chapter 1 provides a general introduction to the research topics of this dissertation, including T2DM, pathophysiology and underlying mechanisms of DCM, AGEs and their role in CVD, AGEs inhibitors, and cardiometabolic effects of exercise training in T2DM. In addition, this chapter outlines the knowledge gaps and aims of this thesis. Chapters 2 and 3 focus on exercise training, more specifically moderate-intensity training (MIT) and high-intensity interval training (HIIT), as a curative and preventive strategy for DCM in rats. Furthermore, the preventive effects of PM in the development of DCM in rats were described in chapter 4. To align the clinical situation, our research group previously developed a rat model for DCM induced by a high-sucrose or so-called WD. When feeding WD for 18 weeks, rats display metabolic alterations such as impaired glucose tolerance, insulin resistance, and elevated plasma triglyceride levels, indicating the presence of (pre)diabetes. In the heart, WD-fed rats develop adverse cardiac remodeling characterized by hypertrophy and left ventricular (LV) interstitial fibrosis, and, diastolic dysfunction, both indicators of the restrictive phenotype of DCM. When feeding WD for 30 weeks, the metabolic changes remain and rats display the dilated phenotype of DCM, characterized by LV dilation and systolic dysfunction, as mentioned in chapter 2. Chapter 2 describes that both MIT and HIIT are suitable for improving LV adverse cardiac remodeling and cardiac dysfunction in a rat model for DCM. In this study, we first feed rats a WD for 18 weeks to induce T2DM with adverse cardiac remodeling and cardiac dysfunction. To uncover the therapeutic potential of exercise training with different exercise intensities on DCM, we assign DCM rats to a sedentary lifestyle, MIT, or HIIT for 12 additional weeks. Metabolically, we demonstrate that MIT has a higher potential to lower insulin and plasma AGEs levels, while HIIT has superior positive effects on decreasing blood lipids in DCM rats. Regarding the heart, we show that both MIT and HIIT improve diastolic dysfunction, however, only MIT cures systolic dysfunction. Although we cannot pinpoint one single pathway in this chapter, distinct mechanisms are proposed to underly the exercise-mediated curative adaptations of the heart. Both exercise modalities ameliorate pathological cardiac remodeling, by lowering LV wall thickness and interstitial fibrosis, as well as increasing cardiac citrate synthase activity in DCM rats. However, LV protein expression of tumor necrosis factor α is only decreased following MIT. These results emphasize the potential of implementing MIT and HIIT in the treatment of T2DM patients with cardiac comorbidity. Up till now, experimental studies have mainly focused on the therapeutic impact of an exercise intervention, meaning its effect after diagnosis of T2DM, on cardiac morphology and/or function. However, the potential, preventive cardioprotective effect of exercise training at different intensities, thereby benefitting the individual at risk for T2DM, has not been explored yet. Chapter 3 reports that both MIT and HIIT successfully prevent the development of T2DM with adverse cardiac remodeling and cardiac dysfunction. In this study, rats receive a WD to develop T2DM with adverse cardiac remodeling and cardiac dysfunction and, are simultaneously assigned to a sedentary lifestyle, MIT, or HIIT for 18 weeks. Regarding metabolic effects, we show that both exercise modalities prevent insulin resistance and ameliorate glucose tolerance over time. In the heart, both exercise interventions prevent the onset of diastolic dysfunction, LV wall hypertrophy, and hypertension. This chapter also describes novel insights into the potential underlying mechanisms of exercise training-induced cardiac adaptations in rats developing T2DM. We demonstrate that both exercise modalities prevent adverse cardiac remodeling, as they decrease LV wall thickness and interstitial collagen deposition. Whereas only HIIT tends to promote the gene expression of an enzyme involved in reactive oxygen species production, both MIT and HIIT elevate the expression of proinflammatory macrophage markers and cytokines. HIIT upregulates the gene expression of antioxidant and dicarbonyl defense systems while MIT increases anti-inflammatory macrophage markers. Altogether, the findings of this study propose that both MIT and HIIT are effective cardioprotective approaches to potentially include in the management of the individual at risk for T2DM. While the present strategy to address heart failure in T2DM involves various pharmaceuticals, there is no compound available that prevents both metabolic and cardiac alterations in individuals developing T2DM. In chapter 4, we investigate whether the vitamin B6 analog PM limits adverse cardiac remodeling and dysfunction during the development of T2DM in rats. In this study, rats are administered a WD to develop T2DM with adverse cardiac remodeling and cardiac dysfunction and, simultaneously receive PM via drinking water for 18 weeks. We demonstrate that PM protects against the increase in fasting glucose levels and, thus, the development of prediabetes in WD-fed rats. In addition, LV cardiac dilation tends to be prevented by PM, presumably due to lower interstitial fibrosis and oxidative stress in the myocardium. This chapter suggests PM as a potential strategy to prevent worse cardiac outcomes in patients at risk for T2DM. Chapter 5 gives insights into the acute effects of AGEs on the vasomotor function of the largest blood vessel of the body, namely the aorta. For this, we obtain aortae from healthy rats and pre-treat them acutely with HMW-AGEs in organ baths. Following acute HMW-AGEs incubation, we expose the aortic rings to vasorelaxant compounds to uncover the endothelium-dependent and -independent relaxation responses. In this study, we demonstrate that acute exposure to HMW-AGEs impairs endothelium-dependent aortic relaxation. Furthermore, we show that the aortic dysfunction induced by HMW-AGEs is likely due to increased oxidative stress. These results highlight that HMW-AGEs can be considered novel biological targets in the early phase of vascular complications. In chapter 6, we discuss the main findings of this thesis and elaborate on their clinical relevance. Furthermore, this chapter highlights general limitations in the current dissertation and reports important future perspectives. Based on the results of this thesis, we conclude that MIT and HIIT are promising strategies to implement in the therapeutic and preventive management of diabetes-related cardiac dysfunction. To validate our findings, large randomized controlled clinical trials that investigate the cardioprotective properties of both exercise modalities in individuals with T2DM or at risk for T2DM are warranted in the future. Furthermore, it would be interesting to investigate the application of PM as a preventive strategy against cardiac dysfunction in a diabetic human population. Lastly, it is important to identify the exact role of an increased AGEs level in the development of CVD and T2DM, as they acutely affect the vascular function of the aorta.