Proliferative growth of the ventricular myocyte (cardiomyocyte) is primarily limited to embryonic, fetal and very early neonatal periods of heart development. In contrast, cardiomyocyte maturation, as evidenced by cellular hypertrophy, is a long-term process that can occupy the bulk of the life-span of the mature organism. As the newborn myocyte undergoes a 'transition' from proliferative to hypertrophic growth, ventricular remodeling of the non-myocyte compartment is characterized by increased extracellular matrix (ECM) formation and coronary capillary angiogenesis. A role for ventricular-derived growth factors (GFs) in these inter-related processes are examined in an animal model of altered heart development produced by neonatal aortic banding. The suprarenal abdominal aorta of five day old rat pups were banded (B), sham operated (S), or untreated (C) and ventricular tissue (left ventricular free wall and septum) obtained at 7-, 14-, and 21-days post-intervention. Using Northern blot RNA hybridizations, expression of growth factors (GFs) and/or GF-receptors (GFR's) temporally associated with heart development were evaluated. Transcript levels for TGF-beta 1, IGF-II, and their associated cell surface receptors were increased in B animals. Concomitant changes in extracellular matrix (ECM) genes (as evaluated by Collagens Type I, III, and IV) were also increased in B animals. In addition, transcript levels for the vascular morphogenesis and remodeling-related protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) was also elevated in the B animals. In several instances, S animals demonstrated changes in steady state transcript levels for genes which may influence myocyte maturation during the postnatal period. This suggests that normal autocrine/paracrine growth regulatory stimuli and responses can be modified (by surgical intervention and/or abdominal aortic banding) and these perturbations in gene expression may be related to previously documented changes in myocyte cell number, vascular composition, and ventricular architecture of the banded, neonatal heart. Future studies using this model will provide an opportunity to evaluate and possibly identify the stimuli and signal transduction machinery that regulate the final phases of myocyte proliferation, stimulate capillary formation and ECM deposition, and orchestrate the transition to hypertrophic growth during heart development.

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Coronary artery occlusion extends perfusion territory boundaries through microvascular collaterals.

Simultaneous in vivo infusions of two different colored 10 microns microsphere suspensions into the left anterior descending (LAD; red spheres) and left circumflex (LCx; blue spheres) coronary arteries of nine anesthetized dogs identified a specific region of canine myocardium perfused by both arterial branches. Subsequently, the LAD was ligated and a third (green) set of micropheres was infused into the patent LCx artery. Analysis of 40 microns serial sections of tissue revealed interface zones with capillaries perfused by both arteries. The first zone, defined as the Interface Transistion Zone (ITZ) was formed by an intermingling of microvessels supplied by the parent arteries of the adjacent perfusion territories; it separated tissue containing only one or the other colored microspheres. Another zone, defined as the Boundary Watershed Zone was located within the ITZ and had capillaries containing both red and blue microspheres. The width of ITZ was 53377 +/- 817 microns (mean +/- SD), and the width of the BWZ was 3358 +/- 618 microns. Green microspheres, infused into the LCx following coronary occlusion were also found in the ITZ and BWZ. Furthermore, capillaries perfused exclusively by the LAD before occlusion (tissue with red but not blue microspheres) adjacent to the perfusion interface contained green microspheres as well as red/green aggregates, indicating lateral extension of the LCx perfusion territory. This extension of the LCx territory was quantitated by comparing the location at which densities of green microspheres or green/red aggregates decreased abruptly compared to the location of the original ITZ and BWZ boundaries, respectively. Results showed that LAD occlusion caused a 24% expansion of the ITZ and a 48% expansion of the BWZ. In addition, all expansions were significantly greater in subepicardial compared to subendocardial regions (p < 0.001). These results clearly demonstrate the capability of microvascular anastomoses in providing blood flow to the periphery of an ischemic region. Furthermore, the perfusion interface is labile and might be amenable to manipulation.

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Changes in calcium handling in atrophic heterotopically isotransplanted rat hearts.

Atrophy of the rat heart induced by hemodynamic unloading after heterotopic transplantation is associated with impaired relaxation while systolic function remains normal when compared to the heart of the recipient animal. To identify possible underlying mechanisms for the above, we studied some aspects of membrane calcium handling using postextrasystolic potentiation of contractions in the isolated right ventricular papillary muscle and in the left ventricle of the Langendorff-perfused heart. We also compared the alterations of the unloaded heart with those of overloaded hypertrophic hearts of rats with suprarenal aortic constriction. In the atrophic heart the degree of potentiation after one extrasystole, considered to be proportional to the trans-sarcolemmal influx of Ca2+ during an action potential, was increased by 125% when compared with recipient hearts. The rate of decay of potentiation which reflects the fraction of activator Ca2+ recirculating in the cells via the sarcoplasmic reticulum, negatively correlated with the degree of potentiation, although its mean value was not significantly altered. In hypertrophic hearts the decay of potentiation was faster when compared with the hearts of sham-operated animals, indicating a decreased recirculating fraction of Ca2+ The data suggest that the relative importance of trans-sarcolemmal Ca2+ fluxes is increased both in cardiac atrophy and hypertrophy; but their quantitative role in the control of cardiac contraction might differ.

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PubMedDate not supplied

Colored microspheres reveal interarterial microvascular anastomoses in canine myocardium.

While the presence of microvascular intercommunication within an individual myocardial arterial bed is well documented, there is a paucity of data to support the existence of anastomoses emanating from independent arterial beds. Simultaneous in-vivo infusion of two different colored microsphere suspensions into the left anterior descending (LAD) and left circumflex (LCx) coronary arteries identified a specific interface region of canine myocardium that was perfused by both arterial branches. Subsequent microscopic/morphometric analysis of 40 microns serial sections in eight hearts revealed clustering of microspheres in their respective perfusion territories (red microspheres in the LAD region away from the interface, blue microspheres in the LCx field away from the interface), along with a mutually perfused borderzone. In each tissue section, two regions within this zone were identified and their maximum widths measured. One region was defined as the Interface Transition Zone (ITZ) (mean width = 5251 +/- 770 microns; mean +/- SD). This region was formed by an intermingling of microvessels supplied by the parent arteries of the adjacent perfusion territories; it separated tissue containing only one or the other colored microspheres. The second region was defined as the Boundary Watershed Zone (BWZ) (mean zone width = 3151 +/- 611 microns; mean +/- SD). This region was formed by capillaries containing sphere aggregates of both colors; it was located exclusively within the ITZ. In addition, the ITZ and BWZ were significantly wider in subepicardial than in subendocardial regions (p less than 0.001).

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PubMedDate not supplied

Change in cardiac myocyte size distribution in aortic-constricted neonatal rats.

Regional changes in cardiac myocyte size and population distribution were examined in Sprague Dawley rats receiving an abdominal aortic constriction at five days of age. At specific time intervals post-constriction, hearts were recovered from constricted animals and weight-matched controls and isolated myocytes were obtained from right and left ventricles using retrograde coronary perfusion with collagenase. Cell volume and cardiac myocyte population distribution curves were determined using a Coulter Channelyzer system. Cell length was measured directly using a Bioquant Image Analysis system. Myocyte cross-sectional area was calculated from cell volume/length. By three months of age, heart weight and heart weight-body weight ratio in constricted animals had increased by approximately 115% (p less than 0.001) in females and 85% (p less than 0.001) in males compared to controls. Between 15 and 90 days of age, the growth response, as indicated by increased cell volume, was approximately 4x greater in constricted females and 2.5x greater in constricted males compared to corresponding controls. This increase was manifested by a shift in the mean size of the myocyte population to the right and a substantial widening of the distribution. Most of the enlargement was due to increased cross-sectional area, with only a moderate contribution from increased cell length. Significant increases in size were seen in both left and right ventricles. By three months of age, a significant interaction was apparent between aortic constriction and sex. The capacity for hypertrophy was greater in the smaller myocytes in female rats of similar age compared to males. The final degree of hypertrophy was similar for male and female rats, possibly indicating a critical upper limit in cell size for cardiac myocytes.

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