Elevations in myocardial stress initiate structural remodeling of the heart in an attempt to normalize the imposed stress. This remodeling consists of cardiomyocyte hypertrophy and changes in the amount of collagen, collagen phenotype and collagen cross-linking. Since fibrillar collagen is a relatively stiff material, a decrease in collagen can result in a more compliant ventricle while an increase in collagen or collagen cross-linking results in a stiffer ventricle. If continued elevations in wall stress exceed the ability of the heart to compensate, then the ventricular wall thickness is disproportionately reduced compared to chamber volume and diastolic and systolic dysfunction ensues. This review describes the structural organization of collagen within the myocardium, discusses its effect on ventricular function and considers whether therapy aimed at reducing fibrosis is efficacious in heart failure. The evidence indicates that chamber stiffness can clearly be affected by alterations in both collagen quantity and quality, with the effect of changes in collagen concentration being modified by the extent of collagen cross-linking. The limited evidence available regarding the effects of collagen on systolic function indicates that pharmacological attempts to reduce interstitial collagen have a negative impact. Accordingly, a shift in treatment strategies directed more specifically at affecting collagen cross-linking, rather than reducing the concentration of collagen, may be warranted in the prevention of the adverse impact of collagen alterations on myocardial remodeling.

The chronic elevation in ventricular wall stress secondary to ventricular volume or pressure overload leads to structural remodeling of the muscular, vascular and extracellular matrix components of the myocardium. While initially a compensatory response, the progressive hypertrophy and ventricular dilatation induced by this condition ultimately have a detrimental effect on ventricular function, resulting in heart failure. Fibrillar collagen provides the skeletal framework which interconnects the cardiomyocytes, thereby maintaining ventricular shape and size and contributing to tissue stiffness. Accordingly, these myocardial collagen fibers must be disrupted for ventricular dilatation, sphericalization and wall thinning to occur. The presence of an abundant, latent matrix metalloproteinase (MMP) population which coexists with myocardial fibrillar collagen has been documented. Thus, the potential for collagen degradation to exceed synthesis exists should there be significant activation of this latent MMP system. Mast cells are known to store and release a variety of biologically active mediators including TNF-alpha and proteases such as tryptase and chymase, which can induce MMP activation. Increased cardiac mast cell density has been implicated in the pathophysiology of human end-stage cardiomyopathy and experimental myocardial infarction, hypertension and chronic volume overload secondary to mitral regurgitation and aorto-caval fistula. The potential role of cardiac mast cells in activating MMPs, which then results in fibrillar collagen degradation and adverse myocardial remodeling secondary to chronic volume and pressure overload will be the subject of this review.

Much is known about the effects of high environmental temperature (HT) on egg production, but very little is understood about the mechanisms that underlie them. Two experiments were conducted to examine the effects of acute heat stress on circulating estradiol, on calcium uptake by gut tissue, on bone resorption, and on the dynamic relationship between estradiol and calcium in the hen during one ovulatory cycle. In one study, hens were moved individually and randomly into a hot [HT: temperature (T) = 35 C, relative humidity (RH) = 50%; n = 18] or a control, thermoneutral (TN: T = 23 C, RH = 50%; n = 18) environment immediately after a mid-sequence oviposition and brachial vein cannulation. Blood samples (2 mL) were collected every 3 h for 21 h for ionized calcium (Ca2+) and pH determinations and from which aliquots were frozen for 17 beta-estradiol (E2), total calcium (TCa), and inorganic P analysis. Excreta and urine were assayed for TCa and hydroxyproline (OHPr), respectively. A second study was conducted to determine the effects of HT (T = 35, H = 50%, 12 h) vs TN (T = 23 C, RH = 50%, 12 h) on the ability of duodenal cells to take up calcium (CaT). Blood pH and calcium responded to HT as expected (pH increased, Ca2+ decreased, and TCa decreased) and the cyclic pattern of Ca2+ in blood was abolished. The ratio of Ca2+:TCa decreased sharply at approximately the onset of shell calcification in control hens, but in HT hens there was no clear change in the ratio of any point in the cycle. The pattern of E2 typical of hens under normal conditions was significantly depressed in plasma of HT hens. Calcium uptake by duodenal epithelial cells of HT hens was lower than in TN hens. There was a clear inverse correlation between blood Ca2+ and urine OHPr in TN hens (r2 = -73, P = 0.0021) but not in HT hens (r2 = -27, P = 0.32). In addition to alterations in acid-base balance and the status of Ca2+, diminished ability of duodenal cells to transport calcium may be a critical factor in the detrimental effects of heat stress on egg production (numbers), eggshell characteristics, and skeletal integrity often documented in the laying hen.

The extracellular matrix plays a critical role in the development and maintenance of the vertebrate heart. Changes in the accumulation, composition, or organization of the extracellular matrix are known to deleteriously affect heart function. Mast cells are thought to stimulate collagen expression and fibroblast proliferation accompanying fibrosis in some organs; however, the effects of mast cells on the heart interstitium are largely unexplored. The present studies were carried out to determine the effects of mast cells on isolated heart fibroblasts. Several in vitro assays were used including collagen gel contraction to examine the effects of mast cells on the function of isolated fibroblasts. Neonatal heart fibroblasts were cultured either with mast cells, mast cell-conditioned medium, or mast cell extracts, and their ability to contract collagen gels measured. Results from these experiments indicated that mast cells inhibit heart fibroblast migration and contraction of 3-dimensional collagen gels. Further experiments indicated that incubation of neonatal heart fibroblasts with extracts of mast cells altered the expression of collagen, matrix metalloproteases, and matrix receptors of the integrin family. These studies suggest that mast cells play an important role in the regulation of the cardiac interstitial matrix. Further studies are warranted to determine the mechanisms whereby mast cells modulate fibroblast activity.

We conclude that the acute increase in mast cell density following volume overload is due to a paracrine response in the heart that stimulates the maturation and differentiation of resident immature cardiac mast cells.

Enzymatic dispersion of cardiac mast cells affects their response to secretagogues.

This novel pericardial aspiration technique facilitates the straightforward characterization of isolated epicardial mast cell functionality in a controlled in vitro environment, furthering our understanding of their contribution to myocardial disease.

No abstract