The fibrillar nature and structure of isoproterenol-induced myocardial fibrosis in the rat.

A study of isoproterenol-induced (1 mg/kg) myocardial fibrosis in the rat was undertaken, taking advantage of the differential colorization provided by thick and thin collagen fibers to picrosirius red and polarization microscopy. The objective was to monitor the sequence (day 1, 2, 3, 4, and 8), fibrillar composition, and nature of isoproterenol-induced collagen remodeling, which was found previously to adversely influence myocardial stiffness. The following were found: 1) a distortion and widening of intermuscular spaces on day 1 that was accompanied by the disruption of collagen fibers; 2) by day 2, these spaces were closing and a new fibrillar collagen network had appeared consisting primarily of thinner collagen fibers that crossed over muscle fibers; 3) the new fibrillar network took on a clear crisscrossing pattern on day 3 and 4 as an ever-increasing number of thicker fibers became entwined perpendicular to the thinner fibers; and 4) by day 8, a dense mesh of thick and thin collagen fibers had formed to encircle muscle while a greater number of intermuscular spaces, previously devoid of collagen, were now filled with thicker and thinner collagen fibers. Thus, isoproterenol-induced myocardial fibrosis is initiated by the appearance of interstitial edema and fibrillar collagen disruption and is followed soon thereafter by the formation of thinner collagen fibers that extend across muscle fibers and into which thicker collagen fibers become entwined in a crisscrossing pattern. Once formed, this mesh of collagen fibers encircles cardiac muscle. This pattern of fibrous tissue formation may entrap and isolate myocytes so that the mechanical behavior of muscle and the intact myocardium becomes abnormal.