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Propionyl L-carnitine (PPLC), a short -chain fatty acid derivative of carnitine, has been reported to produce beneficial effects in various cardiovascular diseases such as maladaptive cardiac hypertrophy, heart failure, ischemic heart disease, different types of cardiomyopathies and peripheral artery disease. Although all these cardiovascular diseases have diverse epidemiology and pathophysiology, both clinical and preclinical studies have indicated the role of oxidative stress, Ca2+-handling defects and metabolic abnormalities in their development and progression. In heart failure due to myocardial infarction, treatment with PPLC attenuated the inhibition of Na+-K+ ATPase and Na+-Ca2+ exchange activities. PPLC therapy of animals with diabetic cardiomyopathy improved Ca2+- handling abnormalities in cardiomyocytes by affecting the entry of Ca2+ through sarcolemma and regulating the sarcoplasmic reticular Ca2+- pump activities. The improvement of cardiac function recovery by PPLC treatment in ischemia- reperfused hearts was associated with its ability to antagonize the deleterious effects of palmitoyl L-carnitine on Ca2+-handling proteins. Treatment of peripheral artery disease with PPLC increased blood flow by affecting the vascular endothelium and smooth muscle functions in lower limbs. These observations support the view that PPLC improves cardiovascular function in diseased conditions by promoting mitochondrial metabolism, reducing oxidative stress and preventing Ca2+- handling abnormalities.