Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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mitochondrial damages and preserves its respiratory function and cardiac myocyte

viability [ 32 , 33 ], confirming mitochondrial damage occurs during the ischemic

period. During ischemia, low intracellular pH precludes the opening of mitochon-

drial permeability transition pore (MPTP) [ 34 , 35 ], which would be greatly favored

by the accumulated mitochondrial injuries.

Although restitution of blood flow should halt and rescue cells form progressive

ischemic injury it actually triggers an adverse cascade of events and may precipitate

death of more severely damaged cardiomyocytes. Reperfusion restores oxygen and

nutrient supply, necessary for aerobic ATP synthesis, unfortunately accumulated

mitochondrial ischemic injuries impair electron transport chain activity and cause

accelerated and profuse ROS formation. Reperfusion-induced oxidative stress

aggravates cardiomyocyte injuries since all cellular components are affected by

ROS. The sarcoplasmic membrane has its fluidity and permeability altered, sarco-

plasmic reticulum becomes stressed, enzymes dysfunctional and NO (important

protective signaling molecule) bioavailability is reduced. Reflow washes out

extruded ions and metabolites, and brings with it cells of the immune system.

Because extracellular and intracellular pH are normalized by removal of accumu-

lated H+ and lactate, MPTP is activated and mitochondrial membrane potential dis-

sipated. MPTPs are located in the inner mitochondrial membrane and form

nonselective pores that, when opened, cause mitochondrial membrane depolariza-

tion and can result in water entry into the matrix, swelling and outer mitochondrial

membrane rupture. This culminates with mitochondrial proapoptotic molecules

Fig. 10.1 Pathophysiology of ischemia reperfusion injury. (a) Normal cardiac myocyte cell func-
tion and ion distribution. (b) Ischemia-induced cell damage and ion balance disruption. (c)
Reperfusion-induced aggravated cell damage. ROS (reactive oxygen species); MPTP (mitochon-
drial permeability transition pore); SERCA (sarcoendoplasmic reticulum Ca2+ ATPase); NHE
(sodium/hydrogen exchanger); NCX (sodium/calcium exchanger)

J.P. Borges and K. da Silva Verdoorn