Changes in the myocardial interstitium and contribution to the progression of heart failure

Abstract

The myocardial interstitium is highly organized and orchestrated, whereby small disruptions in composition, spatial relationships, or content lead to altered myocardial systolic and/or diastolic performance. These changes in extracellular matrix structure and function are important in the progression to heart failure in pressure overload hypertrophy, dilated cardiomyopathy, and ischemic heart disease. The myocardial interstitium is not a passive entity, but rather a complex and dynamic microenvironment that represents an important structural and signaling system within the myocardium.

Figure 1

Transmission and scanning electron microscopy (EM) were performed on papillary muscle samples which had been fixed at a maximum length preload. The images are of normal myocardium and normal myocardium treated with plasmin, a serine protease that activates matrix metalloproteinases to cleave interstitial proteins including fibrillar collagen. In Panel A, the top left transmission EM depicts intact sarcolemma with individual myofibrils. The bottom left scanning EM of normal myocardium depicts a fine fibrillar collagen weave within the interstitium. The bottom right scanning EM image shows the myocardium after treatment with plasmin, and it demonstrates a significant loss of fibrillar collagen. The top right transmission EM shows that there were no gross changes in sarcolemma architecture or evidence of myocyte injury. B) The normal myocardium treated with plasmin develops less force at a specific muscle length when compared to untreated myocardium. Overall, plasmin treatment moved the developed force versus muscle length relationship downward. C) The graph demonstrates that there was no change in cardiomyocyte shortening extent with plasmin treatment of normal cardiomyocytes, which lays further evidence to support the concept that extracellular matrix degradation does not affect the function of the isolated cardiomyocyte. The figure was reproduced and modified from reference .

Figure 2

A) Histopathologic images of normal myocardium compared to myocardium that has undergone extracellular matrix remodeling secondary to pressure overload hypertrophy. Note the significant collagen accumulation in the myocardium affected by POH (white and blue areas). The images were reproduced and modified from reference . B) The graph illustrates the relationship between pressure and volume of the LV during diastole in both normal patients and patients with POH. With the same diastolic volume during filling, the graph illustrates that patients with POH have increased diastolic pressures in comparison to control patients. This indicates that there is a decrease in compliance of the myocardium in with long-standing POH. The figure was adapted from reference .

Figure 3

Panel A depicts normal myocardial interstitium organization as seen by scanning EM. The schematic illustration depicts the extracellular matrix surrounding the cardiomyocytes in B) normal myocardium, C) POH, D) DCM, and E) MI. B) In the normal myocardium, the interstitium forms a highly organized continuum between cardiomyocytes to provide a structural support system and a functional depot for a wide array of non-collagen matrix proteins, signaling molecules, and other cell types such as fibroblasts. C) In POH secondary to aortic stenosis or hypertension, the schematic illustrates the diffuse collagen accumulation that occurs along with an increase in fibroblast proliferation that leads to myocardial matrix accumulation and diastolic dysfunction. D) In DCM, the schematic demonstrates the increase in extracellular matrix turnover with the hallmarks of increased fibrillar collagen and decreased collagen cross-linking. E) In ischemic heart disease secondary MI, the myocardial remodeling process is region dependent and not uniform with both collagen accumulation (the infarct region) and degradation occurring (the border zone).

Figure 4

A) The graph demonstrates the relationship between time after a MI versus the LV end diastolic volume. Compared to patients without an MI (Normal Range), there is a significant increase in LV end diastolic volume after a MI. B) After a MI, there is a significant increase in the ratio of MMP-9 levels to TIMP-4 levels compared to patients without an MI (range of ratio illustrated by the two dashed lines). C) When the percent change in MMP-9 levels from day 1 to day 5 is compared to the percent change in LV end diastolic volume 1 month after a MI, it is noted that there is a significant increase in the percent change in LV end diastolic volume with an increase in MMP-9 from day 1 to day 5. The graphs were reproduced and modified from reference .