Valvular Heart Disease (VHD) is the third common cause of deaths worldwide. It increases the risk of human morbidity and mortality in developing countries including Pakistan. Stenosis and regurgitation are the major cause of valve dysfunctions. Calcification of aortic valve characterized by both pathological conditions was found mostly in elder ages. However, calcification in bicuspid aortic valve (BAV) characterized by stenosis occurred in 1% of the total cases of valve dysfunction. Rheumatic Heart Disease (RHD) was also found as one of the leading cause of valve dysfunction mostly in teenage. The total incident of RHD in females was observed higher than males. In addition, the total number of post Closed Mitral Valvatomy (CMVs) cases and the patients having history of genetic cardiac complications were also high in females when compared with male patients. The poor life style in Pakistan is highly associated with distinct heart complications including RHD. The use of tobacco (snuff and smoking) might also be the risk factors of various cardiac complication including VHD found mostly in males as compared to females. The redox potential is essential for cardiomyocytes cellular processes and their survival. Cellular stress in cardiomyocyte induce uncontrolled cell proliferation or excessive cell loss which leads to the development of various cardiac complications including VHD and IHD. To date, numerous clinical and animal model studies revealed that cellular stress regarding depolarization of mitochondrial membrane regulatory factors are the leading cause of cardiomyocytes loss through the process of apoptosis. microRNAs are also the key regulators of mitochondrial membrane regulatory genes. However, the cellular stress alters expression levels can directly or indirectly change the expression of various genes both at transcription and translation level during disease progression. This study proposed that miR-15a and miR-29a were downregulated while the expression of miR-214 was upregulated in the VHD human tissues during disease. Cardiomyocytes homeostasis is maintained by the balanced expression of mitochondrial apoptotic and anti-apoptotic whereas altered mitochondrial integrity may lead to cardiomyocytes apoptosis. In the present study, low expression of miR-15a and miR-29a might be related to upregulation of PUMA and DRP1. On the other hand, ARC might be repressed as a result of miR-214 overexpression. In addition, expression studies revealed that miR-15a targets mitochondrial apoptotic gene PUMA however, miR-214 targets anti-apoptotic gene ARC. The extensive free radical generation and their accumulation cause oxidative stress which also contributes in prognosis of various cardiovascular diseases including VHD and IHD. The persistence of cardiomyocytes oxidative stress due to decrease antioxidant enzymatic activity may further leads to damage in cardiomyocytes. Our finding also confirmed that increase in ROS with low antioxidant enzymatic activities were also the suggested reasons of VHD. Furthermore, GATA-4 was also downregulated in the disease conditions of both aortic and mitral valves. Based on these notions, low level of GATA-4 expression has been previously documented with high rate of apoptosis in cardiac cells which leads to various cardiac disorders. Our present study highlights miRNAs that can control the expression of mitochondrial apoptotic and anti-apoptotic regulatory genes, these mRNAs may be the potential candidates for molecular medicines for treating VHD in future. Furthermore, significantly high level of NT- proBNP was observed in all pathological conditions of aortic valve that showed the severity of valvular pathology. However, the uric acid level was mildly high in aortic stenosis. Ischemic Heart Disease (IHD) is also the major cause of death globally is characterized by reduced supply of blood. Restoration of blood supply to the ischemic part can also results in cardiomyocytes loss due to ischemic/ Reperfusion injury (IRI). Recently, a newly introduced therapeutic strategy known as remote ischemic preconditioning (RIPC) can be used to protect cardiac cells from IRI by releasing a large number of exosomes. The detail mechanism of cardioprotective activity of exosomes is still not fully clear which needs to be further investigated. In-vitro analysis of neonatal rats cardiomyocyte cells (NRCM) treated with ischemic preconditioning (IPC) procedure showed that miR-133a, miR-133b and miR-24 were highly expressed both at exosomal and cellular levels which may also have the cardioprotective effects. In summary, many cardiac complications including VHD and IHD are accompanied withhigh oxidative stress. The persistent high oxidative stress might be due to excessive ROS and depletion of antioxidant enzymes. This phenomena may alter the expression of mitochondrial membrane regulatory genes which ultimately leads to cells loss (apoptosis). In addition, microRNAs can also be used as a therapeutic intervention for survival of cardiomyocytes during various cardiac complications including VHD and IHD.