Nowadays, people have come to realize that better health decides human happiness and well-being.
Thus, it is very crucial to understand the disease pathology for providing better survival. Non-communicable diseases viz., cardiovascular disease (CVD), diabetes, cancer, contribute to more than 75% of global fatalities of which CVD is the biggest killer. Ischemic heart disease (IHD) is the most common manifestation of coronary artery disease. In IHD patients, timely restoration of coronary blood flow is established by procedures like coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty (PTCA) and thrombolysis. Although restoration of blood flow after prolonged ischemia, known as reperfusion, is essential for cardiomyocyte salvation and limiting myocardial damage and cardiac dysfunction, reperfusion itself paradoxically exacerbates the ischemic injury and is commonly termed as “ischemia-reperfusion injury”. In the past decade, the number of high-risk patients undergoing CABG surgery has increased significantly. This is related to the existence of comorbidities such as diabetes, obesity, hypertension and stroke and as such presents a poorer prognosis for CABG patients.
High-risk patients are more susceptible to peri-operative myocardial injury and infarction, arising from inadequate myocardial protection during surgery. Among the listed comorbidities, diabetes is a major metabolic disease with a rising prevalence. The statistics show that 10% of the US population is diabetic (CDC, 2014). Both insulin-dependent and -independent diabetes were reported as potent risk factors in the development of CVD. In 1972, Rubler et al. observed a new pathological phenomenon in diabetic patients now commonly known as “diabetic cardiomyopathy,” which is clinically defined as the ventricular dysfunction despite the absence of any coronary artery disease and hypertension. IHD is significantly more prevalent and more severe in patients with diabetes than in the non-diabetic population.
However, there exists a controversy in which few animal studies suggest that diabetic hearts show resistance to ischemia, although few other studies suggests the contrary. This highlights the significance of the need to standardize the animal models used for the studies.To ameliorate reperfusion injury, interventions like pre-, post- and pharmacological conditioning were practiced in clinical setting. Preconditioning refers to the implementation of three cycles of short episodes of ischemia followed by reperfusion before global ischemia in the heart.
Post-conditioning involves the execution of three consecutive cycles of ischemia and reperfusion after global ischemia at early reperfusion. In the clinical scenario, preconditioning favors the conditions involved in heart transplantation whereas post-conditioning favors cardiac surgery. Although, reperfusion injury can be effectively managed by classical conditioning techniques, it is very difficult to put into clinical practice due to patient incompliance. This leads researchers and clinicians to look for pharmacological agents which can mimic these two modalities.
Despite many documented successes of several therapeutic agents in pre-clinical trials, the same agents have not fared well in the clinical trials. The prime reason is considered to be the inconsistencies between physiological status of the animal models used and the patients. Animals were of similar type with identical inbred properties and were not associated with any comorbidities. But in our population, there exists numerous factors, absent in pre-clinical but present in the clinical scenario, which actually abrogate the benefits of conditioning. One such factor is diabetes mellitus and its associated cardiac complications.
According to the World Health Organization (WHO), the number of deaths due to diabetes will double between 2005 and 2030. Globally, nearly 3.4 million people die annually of a high blood glucose level. These terrifying statistics reveal our inability to accurately diagnose these diseases due to a gap in the understanding of the pathology behind the same, which result in inadequate treatment and unsatisfactory results. Type 2 diabetes mellitus (T2DM), is definitely dominant among the diabetes population and is strongly associated with mainly visceral obesity.
Both of these metabolic abnormalities (diabetes+obesity=diabesity) are well-established independent risk factors for CVD.A frequently misdiagnosed complication of chronic hyperglycemia is diabetic cardiomyopathy (DCM) whose pathophysiology is not fully understood. However, it is suggested that an appropriate metabolic control of diabetes at an early stage of this deleterious disease, could inhibit the development and progression of DCM to heart failure. Recently, it has been postulated that myocardial ischemia plays an important role in the development of the above-said pathology and could be an important therapeutic target in the treatment of the same. Results of the anti-anginal pharmacological treatment and revascularization are unsatisfactory, which reveals a gap in our knowledge and current approaches in treating DCM.Recently, it was reported that a large proportion of patients with T2DM in Europe and Asia are non-obese. The non-obese T2DM phenotype is characterized by disproportionally reduced insulin secretion and less insulin resistance, as compared to obese patients with T2DM.
It is noteworthy that non-obese patients with T2DM have an increased risk of CVD when taken alongside obese T2DM patients. The risk of T2DM in non-obese patients is influenced by genetics as well as factors operating in utero like low birth weight. It is important to achieve an early diagnosis of DCM in asymptomatic diabetic patients in order to prevent the development of irreversible morphological changes, such as fibrosis, leading to impaired contractility. Choosing the accurate time of surgical revascularization, with the inclusion of the metabolic background, can ensure complete revascularization with better prognosis.
As a current practice, myocardial performance index can be used to assess subclinical damage of systolic and diastolic LV function.In our study, we developed and evaluated an animal model of non-obese DCM rats fed a high fat diet and streptozotocin (STZ) and compared it to a model of STZ induced diabetic rats fed a normal diet. Later, we induced global ischemia/reperfusion using Langendorff isolated heart perfusion apparatus and analyzed for cardiac injury, oxidative stress and mitochondrial dysfunction. We then determined the therapeutic efficacy of hydrogen sulfide against I/R injury in non-obese DCM and evaluated its way of action.