**3.1. Mitochondrial dysfunction in HF**

HF is an end stage of many heart disorders and a complex chronic clinical syndrome. Although the causes of HF are variable, HF is viewed as an energy-mismatched disease [1, 56]. The first link between HF and mitochondrial dysfunction was described in 1962 in a guinea pig model with HF induced by an aortic restriction [57]. Since this observation, there has been growing interest in the investigation of mitochondrial function in failing hearts [58], and emerging evidence supports the concept that dysregulation of myocardial energetics is tightly associated with the development and progression of HF [1, 56, 59, 60].

The heart requires large amounts of energy to facilitate its continuous contraction and relaxation cycles. HF occurs when the energy demand outweighs the energy supply. Any contributor that leads to HF is accompanied with a gradual but progressive decline in the activity of mitochondrial respiration, leading to diminished capacity for ATP production and subsequent progression of the heart to fail. Reciprocally, a failed heart reduces the blood and oxygen supply to the peripheral tissues and to the heart itself, further exacerbating the decline in cardiac energy production. On the other hand, the amount of ATP required from the mitochondria is increased to meet the abnormally enlarged myocardium size and failing function, augmenting the imbalance between the requirement and supplement of oxygen in the cardiac muscle during the contraction and relaxation cycle. Consequently, the bioenergetic requirements of the heart are beyond what the mitochondria can cope with, and the heart begins to progress to HF. Thus, energy deficiency can be a cause and effect of HF. There are considerable evidences of links between HF and impairment of the energetics of myocardial mitochondria, such as declined mitochondrial synthesis/resynthesis of ATP, shifted fuel selection, impaired mitochondrial biogenesis, and abnormal calcium transport.
