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have documented a lack of compensatory vascular growth in cardiac hypertrophy associated with pressure overload. Nevertheless, there is some documentation that coronary angiogenesis and arteriogenesis can occur in some of these models as shown by data from several species. Although the reasons for the discrepancy between these studies are not evident, the stabilization of hypertrophy, its duration, and the specificity of the type of pressure overload are likely factors that facilitate angiogenesis and arteriogenesis.

4. Volume Overload-Induced Cardiac Hypertrophy

Volume overload-induced cardiac hypertrophy is characterized by increased diastolic stress and cardiomyocyte hypertrophy that is largely due to longitudinal growth.25,26 Compensated hypertrophy in this model is usually devoid of ventricular dysfunction, especially when the volume overload is due to an aortocaval fistula.27 Most experimental studies have shown that vascular growth in this model is proportional to the myocardial hypertrophy (Table 2). When a decrease in capillary length or numerical density was reported, it was limited to the subepicardium or was not marked. Anemia, which also induces a volume overload, was found to evoke a marked increase in capillary volume density.28 Most importantly, we documented normal arteriolar length density, despite substantial hypertrophy in rats with five months of volume overload, indicating that vascular growth is proportional to the increase in myocardial mass.26

Vascular growth, especially that of resistance vessels, appears to be the anatomical basis for the normal maximal myocardial perfusion in volume overloaded hearts noted in several studies. Myocardial blood flow per gram and endocardial/epicardial flow ratio during exercise was found to be normal in dogs with A-V shunt.29 Other studies reported that minimal coronary vascular resistance (during adenosine infusion) was also similar in dogs with A-V shunts and their controls.30,31 However, redistribution of myocardial blood flow, that is a decrease in endocardial/epicardial flow ratio, has been noted in dogs during maximal vasodilation and during exercise.31,32 The lower flow to the endocardial portion of the myocardium during maximal perfusion may be,

Table 2. Angiogenesis and arteriogenesis in volume overload cardiac hypertrophy.

LV = Length density; NA = numerical density; RVW, LVW = right and left ventricular weights; BW = body weight; A-V = atrioventricular.

in part, due to the decrease in capillarity in this region previously noted. However, Badke et al. reported that the lower endo/epi flow ratio in dogs with aortocaval fistulas was normalized when the fistula was closed.32 This finding suggested that the perfusion abnormality was due to hemodynamic alterations and not to hypertrophy per se. In dogs

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with experimentally-induced chronic tricuspid regurgitation, myocardial blood flow during adenosine infusion was found to be slightly lower than in controls.33

Data from humans are less definitive. Coronary reactive hyperemia was used to assess coronary reserve in patients with right ventricular hypertrophy secondary to atrial septal defects who suffered a 50% decrease in peak-to-resting blood flow ratio.34 In children with ventral septal defect, coronary flow velocity reserve was reduced because resting flow velocity was increased.35 However, average peak flow velocity was not reduced, indicating that vascular growth paralleled the magnitude of hypertrophy. Moreover, Strauer concluded that patients with volume overload due to aortic insufficiency do not necessarily have a reduced coronary reserve.36

Taken together the experimental data on volume overload-induced cardiac hypertrophy supports the conclusion that this model of hypertrophy provides a stimulus for angiogenesis and arteriogenesis. A major difference between volume and pressure overload is that the former experiences a greater stretch during diastole which may serve as the mechanical trigger for vascular growth (see later discussion).

5. Thyroxine-Induced Hypertrophy

Administration of thyroid hormone leads to rapid cardiac hypertrophy and enhanced ventricular systolic function37−46 and substantial angiogenesis.38,39,41−46 Studies in our lab and those by others have documented both capillary and arteriolar growth in this model of cardiac enlargement.38,39,41−44,47,48 The finding that arteriolar length density in pigs with thyroid hormone-induced hypertrophy (LV weight/body weight increased 47%) is normal indicates a substantial arteriogenesis.43 Minimal coronary resistance during adenosine administration was found to be lower in the thyroxine-treated group. Thus, maximal flow was higher than in controls, a finding in concert with data on rats treated with thyroxine that have a higher maximal myocardial perfusion than controls.41 We subsequently showed that age does not preclude the growth of resistance vessels by providing data that maximal flow in thyroxine-induced hypertrophy is similar in senescent

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as RV muscle fiber diameters increased by 46%, a finding that indicates a growth of capillaries proportional to the increase in myocardial mass.57 Even when RV mass increases dramatically, e.g. more than twofold, capillary density does not decline.58 The hypertrophic response in adult rats to hypobaric hypoxia was less, i.e. 96%, but capillary growth was also proportional. One study documented an increase in capillary density despite a 2.6-fold increase in RV weight.59 Therefore, capillary growth may exceed even a massive increase in RV mass stimulated by chronic hypoxia.

A comparison of guinea pigs either born at high altitude or subjected to high altitude after birth also showed normal capillary densities and diffusion distances.60 The hypothesis that hypoxia can stimulate capillary growth in the heart hypertrophied by pressure overload was tested in rats.61 When spontaneously hypertensive or aortic constricted rats were exposed to six weeks of hypobaric hypoxia, both groups demonstrated an increase in capillary density without a further increase in ventricular mass. Thus, the angiogenic response was not dependent on the development of myocardial hypertrophy.

In sum, chronic hypoxia appears to be a stimulus for myocardial angiogenesis which, in turn, reduces diffusion distances for O2. This occurs when hypoxia is the stimulus for cardiac hypertrophy (as seen in the right ventricle) or when hypoxia is evoked after the development of cardiac hypertrophy by pressure overload (as seen in the left ventricle.) The mechanism underlying right ventricular capillary growth associated with hypoxia may be the persistence of elevated VEGF.62 Although VEGF mRNA increases five-fold in the left ventricle during exposure to hypoxia, it returns to baseline levels by the end of the first day. In contrast, VEGF mRNA is elevated 2.5–4.5-fold in the right ventricle throughout the 30-day period of hypoxic exposure. It is well established that HIF-1 mediates the transcriptional response to O2 levels, and that HIF-α is important in VEGF release.63 VEGF mRNA is also stimulated by adenosine, while adenosine A2 receptor antagonists reduce the VEGF mRNA stimulated by hypoxia.64 Thus, the increase in blood flow that occurs during hypoxia is a factor in the angiogenic response. The angiopoietins may also contribute to vascular growth during hypoxia since Tie-2 expression is enhanced in microvascular endothelial cells exposed to low O2.65