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

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1 Introduction

Coronary artery disease (CAD) continues to be one of the major causes of debilitat-

ing disease and death worldwide, making up more than half of all cardiovascular

events in men and women <75 years of age. In United States, on average, every 34 s

an individual has a coronary event, and approximately every 1 min 24 s, someone

will die of one [ 1 ].

Several CAD complications (e.g. heart failure and myocardial infarct) are pri-

marily caused by IRI damages on the myocardium [ 2 ]. Considering that duration

and magnitude of the ischemic insult predict tissue injury level or death, restoring

local blood supply is crucial to reduce infarct size area [ 3 ]. Despite this, reperfusion

through thrombolytic therapies or percutaneous coronary intervention may induce

further damages ranging from functional impairments to cell death [ 4 ].

In light of the severity of IRI clinical outcomes, several researchers around the

world have focused on studying new strategies to protect the heart against

IRI. Although effective strategies protecting the heart have been discovered, trans-

lating these findings to clinical setting has been challenging [ 2 ].

In this scenario, physical exercise plays a key role as it may be the unique cardio-

protective strategy that can be easily applied regularly in clinical practice and actu-

ally improve patient’s outcome. Indeed, several studies have demonstrated that

exercise not only reduces cardiovascular risk factors, such as hypertension and obe-

sity, but also promotes cardioprotection against IRI through a direct effect on the

myocardium [ 5 , 6 ]. Previous data have shown that a 20-week exercise training in

treadmill significantly improved the intraventricular pressure and reduced the infarct

size by 25% of rats submitted to 1 h of ischemia followed by 2 h of reperfusion [ 5 ].

Interestingly, it has been demonstrated that performing as few as three to five aero-

bic exercise sessions prior to an ischemic event are also sufficient to promote incre-

ment in left ventricle function [ 7 , 8 ], reduce ventricular arrhythmias [ 9 ] and infarct

size area [ 10 – 12 ] upon reperfusion.

Although it is clear that aerobic exercise produces a cardioprotective phenotype,

the mechanisms responsible for this phenomenon remain unclear. It is believed that

these mechanisms are multifactorial and include: (1) changes in coronary arteries

(i.e., increased collateral circulation) [ 13 , 14 ], (2) altered NO signaling [ 15 – 18 ], (3)

increased levels of HSPs [ 19 – 21 ], (4) amplified myocardial cyclooxygenase-2

(COX-2) activity [ 22 ], (5) elevated endoplasmic reticulum stress proteins [ 23 , 24 ],

(6) enhanced function of sarcolemmal and/or mitochondrial ATP-sensitive potas-

sium channels (KAT P) [ 25 , 26 ], (7) increased activation of opioids system [ 10 , 11 ],

and/or (8) increased cytosolic/mitochondrial antioxidant capacity [ 12 , 27 , 28 ].

The following sections describe the pathophysiology of cardiac IRI and how

short and long-term exercise could benefit the heart by attenuating damages induced

by IRI.

J.P. Borges and K. da Silva Verdoorn