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

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Rubler et al. [ 3 ] have first described cardiomyopathy in a small cohort of diabetics

with post-mortem adverse myocardial structural changes in the absence of hyper-

tension, valvular complications or coronary arterial disease. Several experimental

and clinical evidence suggested high predisposition of the diabetic subjects to car-

diomyopathy [ 2 ]. Early impairments in diastolic function, and cardiomyocyte

hypertrophy, apoptosis and fibrosis represent the characteristic features of diabetic

cardiomyopathy (DCM) [ 2 ]. DCM manifests as systolic/diastolic dysfunction and

hypertrophy of the left ventricle, therefore, increases the chances of heart failure [ 4 ,

5 ]. In addition, the higher occurrence of biventricular dysfunction in diabetic

patients suggests that DM is an independent factor for cardiomyopathy [ 6 , 7 ].

Exercise represents a useful non-pharmacological strategy for the prevention of

type 2 DM and obesity [ 8 , 9 ], and therefore of cardiovascular diseases. It is well

established that exercise induces cardioprotective effect in the normal heart through

several molecular mechanisms [ 10 ]. Multiple studies have demonstrated the benefi-

cial effects of appropriate volume and intensity of exercise on cardiac dysfunction

through the amelioration of left ventricle (LV) diastolic and systolic volumes, LV

ejection fraction, ventilatory threshold, cardiac output and maximum oxygen con-

sumption (VO 2 max) [ 11 – 17 ]. The beneficial effects of exercise are not only linked

to the reduced risk factors, but also associated with improved mitochondrial viabil-

ity and antioxidant defenses, and activated physiological cardiac growth through

cellular mechanisms other than those of pathological hypertrophy [ 18 , 19 ]. This

chapter highlights the metabolic derangements in the diabetic heart and how exer-

cise training may influence the progression of diabetic cardiomyopathy, focusing on

myocardial metabolism, and hyperglycemia-induced pathways and oxidative stress.

2 Exercise Improves Myocardial Metabolism

Metabolic flexibility and the ability to ensure adequate adenosine triphosphate

(ATP) production rate are important features of the normal heart [ 20 ]. Lack of this

flexibility contributes to the development of DCM, but the exact mechanism remains

unclear [ 20 ]. Oxidation of fatty acids (FA) is the primary energy source for diabetic

heart, despite the presence of hyperglycemia [ 21 , 22 ]. In diabetes and obesity, myo-

cardial FA uptake and oxidation increase while glucose oxidation decreases.

Increased FA oxidation occurs through the activation of peroxisome proliferator

activated receptor-α (PPAR-α) and induction of enzymes involved in transport and

β-oxidation of FA [ 21 – 23 ]. Genetically modified mice mimicking the diabetic met-

abolic phenotype have been demonstrated to develop cardiac dysfunction [ 24 , 25 ].

In addition, experimental and clinical studies have shown that altered cardiac sub-

strate metabolism precedes ventricular dysfunction [ 22 , 23 ]. Moreover, mainte-

nance of FA oxidation has been reported to have beneficial effects in the diabetic

heart [ 26 – 28 ]. Therefore, targeting myocardial metabolism may represent a thera-

peutic intervention for attenuating DCM [ 29 ].

A.M. Mahmoud