7. Exercise-Induced Hypertrophy

Endurance training (aerobic exercise) increases cardiac work and O2 demand and has been shown by many studies to stimulate coronary angiogenesis (see reviews in Refs. 66 to 68). In the absence of cardiac hypertrophy, angiogenesis increases vascular density and may increase maximal myocardial perfusion/unit heart weight above that of controls. Most studies have shown that when exercise training evokes cardiac hypertrophy that sufficient coronary angiogenesis occurs and is fully compensatory.8,44,69−78 Capillary growth, the parameter most often addressed by these studies, paralleled the increase in cardiac mass in the left or right ventricle was documented in rats,69,77,79,80 pigeons81 and pigs.82

That capillary growth, as evidenced by an increase in numerical capillary density, may exceed the magnitude of ventricular hypertrophy induced by exercise training has also been reported in several studies.70,76,80,83 It appears that the magnitude of hypertrophy is not the key determinant of capillary growth since a 65% exercise-induced increase in heart mass had a minimal effect on intercapillary distance; a 27% increase in capillary diameter maintained volume density despite a 22% reduction in numerical density.84 However, two studies have shown that capillary density in the right ventricle and interventricular septum declines after strenuous exercise training.18,77 In contrast, training that was more moderate in intensity and of a shorter duration (seven weeks) enhanced capillary density in the right ventricle.70

The supposition that exercise-induced cardiac hypertrophy provides a stimulus for growth of pre-capillary vessels sufficient to preserve coronary reserve is supported by data from both myocardial perfusion and morphometric studies. Coronary flow capacity was increased in rats78 and pigs with exercise-induced cardiac hypertrophy.43,85 That enhancement of coronary vascular reserve associated with exercise training is independent of cardiac hypertrophy was demonstrated by Buttrick et al.73 An eight week swimming program enhanced vascular reserve in both male and female rats even though only the females developed cardiac hypertrophy. Arteriolar growth was also documented in pigs with cardiac enlargement ranging from <15% to >30%. Taken together, these studies indicate that exercise training of the appropriate

264 R. J. Tomanek & E. I. Dedkov

intensity provides stimuli(us) for coronary angiogenesis and arteriogenesis. The most likely stimulus for angiogenesis/arteriogenesis in this model appears to be increased blood flow and shear stress.

8. Myocardial Infarction-Induced Hypertrophy

Acute myocardial infarction (MI) results in the sudden death of a great number of cardiac myocytes. To preserve cardiac function, non-infarcted myocytes of the surviving myocardium, which experienced a chronic functional overload, undergo a reactive compensatory hypertrophy.57,86−98 Experimental studies have shown that surviving cardiac myocytes grow in length, as well as in diameter; the magnitude of this reactive hypertrophy is mainly determined by the size of infarct.57,88,90,92−101 The progressive increase in myocyte transverse areas affects a reduction in capillary density, and consequently, increases O2 diffusion distance.90−92,95,97,98,102−104 However, the decreased capillary density is not caused by loss of capillaries per se since capillary to myocyte ratio in the surviving, hypertrophied myocardium is unchanged. Moreover the fact that some capillary growth occurs is supported by work documenting absolute increases in the capillary bed, i.e. increased aggregate capillary length and increases in capillary/myocyte ratio (Table 3). Taken together, these findings demonstrate that the reduction in capillary parameters often detected in the surviving myocardium of post-infarcted hearts is not a consequence of the absence of capillary growth, but it is rather a failure of sufficient capillary bed expansion to match cardiomyocyte enlargement.

Although one study reported that maximal myocardial perfusion is normalized three weeks after myocardial infarction,105 data from our laboratory and others document marked reductions in maximal myocardial perfusion as well as in coronary reserve, in the surviving myocardium of rats between three and eight weeks after infarction.93,101,105−109 Since a strong correlation between minimal coronary resistance and myocyte cross-sectional area was documented,93 it was assumed that the depression in myocardial perfusion was primarily related to the ongoing hypertrophic process. This

hypertrophy.

LV myocyte volume/nucleus ↑28%

LV myocyte length/nucleus ↑14%

HW = Heart weight; RVW, LVW = right and left ventricular weight; VW = total ventricular weight (RVW + LVW); BW = body weight; MCVP = maximal coronary vascular perfusion; CSA = cross-sectional area; NA= numerical density; LV = length density; LV aggregate capillary length was compared between surviving myocardium of post-MI rats and myocardium of sham-operated rats, which destined to survive after MI.

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idea was also confirmed experimentally, since pharmacological prevention (with captopril, enalapril, losartan) of myocardial hypertrophy was able to completely restore a maximal myocardial perfusion.105,110 However, a recent finding showing that angiotensin II type 1 receptor blockade (valsartan), which reduced cardiac hypertrophy but did not limit cardiac interstitial fibrosis, is not able to improve coronary vasodilator reserve and minimal coronary vascular resistance.108 suggests that interstitial fibrosis can be an additional determinant regulating myocardial perfusion in post-infarcted hearts. The contribution of fibrosis is also suggested by recent findings from our laboratory which demonstrated that although arteriolar growth in the remaining myocardium of post-MI rats exceeded that detected in sham-operated animals, it was not associated with a proportional improvement in maximal myocardial perfusion and vasodilator reserve.101 Therefore, fibrosis may also contribute to a decline in maximal myocardial perfusion.

One apparent contributor to the limited post-infarction angiogenesis is the failure of growth factor increases to persist in the surviving myocardium. We found that increases in bFGF, VEGF and Tie-2 were transient, i.e. elevated only during the first few days after infarction.100 Similarly, we reported that increased levels of VEGF, flt-1, flk-1 in the surviving myocardium returned to control levels by seven days.111 Others have found increases in VEGF protein or mRNA to be limited to the ischemic border zone.112−114 Thus, the surviving myocardium distal to the border undergoes compensatory hypertrophy, but limited vascular growth, likely due to the failure of elevated growth factors to persist during the growth period. When rats with infarctions underwent heart rate reduction, we found they had higher VEGF, Flt-1 and bFGF levels than rats with infarction and non-reduced heart rates.109 These experiments support the idea that stretch resulting from increased diastolic dimensions could stimulate expression of angiogenic ligands and receptors.

In sum, the limited angiogenesis after infarction does not compensate for the reactive cardiac hypertrophy characteristic of the post-infarction period. Failure of sufficient angiogenesis to occur is largely due to limited and transient increases in growth factors and their receptors.