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

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2 Ischemia/Reperfusion Injury Pathophysiology

Ischemia consists of a lack of blood supply to the tissue. It can result due to aug-

mented tissue metabolism (as in exercise) without accompanying blood flow

increase or due flow obstruction resultant from vasoconstriction, thrombosis or

embolism. These blood supply/demand imbalances cause varying degrees of tissue

insult depending on intensity and duration of ischemia and intrinsic tissue metabo-

lism. Under normal circumstances cardiac myocyte metabolism is predominantly

aerobic (~95%) and therefore these cells possess a high oxygen demand. Of the

great amount of produced ATP, about 2/3 is used by the contractile apparatus to

afford contraction and 1/3 by active ion transport proteins (mainly SERCA and

Na++K+-ATPase) to maintain ion balance [ 29 , 30 ]. Upon ischemia, these cell pro-

cesses, and consequently cell function, will be greatly affected.

Inadequate oxygen supply rapidly decreases mitochondrial ATP production and

depletes the cells high energy phosphates (mainly creatine phosphate). The under-

perfused cardiomyocytes switch from oxidative to anaerobic metabolism and imme-

diately downregulate contraction adapting its mechanical work to its energy supply.

Underlying mechanisms that trigger these adaptations involve depletion of creatine

phosphate pool, accumulation of lactate and intracellular acidosis [ 3 , 31 ]. Perfusion-

contraction match decreases energy consumption and oxygen demand. These work

and metabolic changes consist of a short-term (about 15  min of severe ischemia)

defense mechanism to postpone irreversible injury and avoid cell death.

Anaerobic glycolytic metabolism is not only far from sufficient to sustain con-

traction and ionic balance, but it also has a biphasic nature. While at the onset of

ischemia glycolytic activity is stimulated, with prolonged or severe ischemia it

decreases because of impaired glucose delivery, glycogen depletion and accumula-

tion of inhibitory metabolites (its end products pyruvate and reduced nicotinamide

adenine nucleotide – NADH 2 ).

The ATP-depleted cardiomyocytes have compromised ATPase activity causing

ionic imbalance. Reduced Na++K+-ATPase activity increases intracellular Na+ and

is unable to impede net K+ efflux due to the opening of the KAT P channels (gated by

intracellular ATP/ADP). Accumulated hydrogen ions (H+), produced during anaero-

bic glycolysis, are exchanged for Na+ by the Na+/H+ exchanger (NHE). This coun-

teracts further intracellular pH reduction but adds even more Na+ to the intracellular

pool contributing to cell swelling. Calcium efflux via plasmatic membrane Ca2+

ATPase (PMCA) and reuptake by the endoplasmic reticulum Ca2+ ATPase (SERCA)

are impaired and cytosolic Ca2+ overload ensues (see Fig. 10.1 and video 10.1).

As ischemia advances, mitochondria accumulates ischemic damage (cardiolipin

and cytochrome c lose into the cytosol and oxidative phosphorylation becomes

uncoupled). These damages are mediated by mitochondria themselves, that in the

presence of residual oxygen present a reduced flow of electron transport activity and

consequent production of reactive oxygen species (ROS). Studies have demonstrated

that blocking mitochondria electron transport chain activity (with amobarbital or

rotenone, both block complex I reversibly) immediately prior to ischemia prevents

10 Cardiac Ischemia/Reperfusion Injury: The Bene cial Effects of Exercise