Interstitial Collagen is Increased in the Non-infarcted Human Myocardium After Myocardial Infarction

doi:10.1006/jmcc.1993.1144

Journal of Molecular and Cellular Cardiology

Volume 25, Issue 11, November 1993, Pages 1317-1323

https://doi.org/10.1006/jmcc.1993.1144 Get rights and content

Abstract

In this study we report the changes of interstitial collagen in the human non-infarcted interventricular septum after a myocardial infarction as well as in hypertrophic human hearts with or without hypertension. The collagen amount was determined with the Sirius Red morphometry technique, which enabled us to perform these studies on routinely processed, paraffin embedded sections. The collagen amount was significantly increased in the septum of infarct patients as compared to non-infarcted controls (P < 0.001). The collagen amount in the septum of the hypertensive hypertrophy group (HH) was significantly increased as compared to the non-hypertensive hypertrophy group (NHH) (P < 0.01). The collagen content in the NHH was not significantly different from the controls in the infarct group, while the collagen amount in the HH showed no significant difference to the collagen content in the infarct group. The results indicate that collagen deposition is increased in the non-infarcted myocardium after a myocardial infarction, as well as in the hypertensive hypertrophied myocardium. The data suggest that the appearance of excessive collagen is not mediated by cardiac hypertrophy per se, but that the underlying cause, infarction or hypertension, is the significant factor.

References (0)

Cited by (137)

Computational model predicts paracrine and intracellular drivers of fibroblast phenotype after myocardial infarction
2020, Matrix Biology
Citation Excerpt :
Excessive degradation can lead to ventricular dilation and wall rupture due to the loss of structural integrity in the heart wall [13]. Conversely, excessive ECM deposition, particularly in myocardium remote from the infarct, can lead to diastolic dysfunction [14,15]. Many patients with heart failure post-MI have both dilation and fibrosis [1].
The fibroblast is a key mediator of wound healing in the heart and other organs, yet how it integrates multiple time-dependent paracrine signals to control extracellular matrix synthesis has been difficult to study in vivo. Here, we extended a computational model to simulate the dynamics of fibroblast signaling and fibrosis after myocardial infarction (MI) in response to time-dependent data for nine paracrine stimuli. This computational model was validated against dynamic collagen expression and collagen area fraction data from post-infarction rat hearts. The model predicted that while many features of the fibroblast phenotype at inflammatory or maturation phases of healing could be recapitulated by single static paracrine stimuli (interleukin-1 and angiotensin-II, respectively), mimicking the reparative phase required paired stimuli (e.g. TGFβ and endothelin-1). Virtual overexpression screens simulated with either static cytokine pairs or post-MI paracrine dynamic predicted phase-specific regulators of collagen expression. Several regulators increased (Smad3) or decreased (Smad7, protein kinase G) collagen expression specifically in the reparative phase. NADPH oxidase (NOX) overexpression sustained collagen expression from reparative to maturation phases, driven by TGFβ and endothelin positive feedback loops. Interleukin-1 overexpression had mixed effects, both enhancing collagen via the TGFβ positive feedback loop and suppressing collagen via NFκB and BAMBI (BMP and activin membrane-bound inhibitor) incoherent feed-forward loops. These model-based predictions reveal network mechanisms by which the dynamics of paracrine stimuli and interacting signaling pathways drive the progression of fibroblast phenotypes and fibrosis after myocardial infarction.
Extracellular Matrix in Ischemic Heart Disease, Part 4/4: JACC Focus Seminar
2020, Journal of the American College of Cardiology
Citation Excerpt :
The composition of the ECM modulates interactions between pericytes and endothelial cells (112,113); however, the role of such actions in the maturation of infarct microvessels has not been investigated. In the presence of a large MI, massive loss of contractile tissue results in increased ventricular filling pressures, and typically also with progressive fibrotic changes in viable myocardial segments (114). The deposition of interstitial collagen in the noninfarct zone is attributed to the pathophysiological effects of pressure and volume loads, and may be dependent on neurohumoral pathway activation (115).
Myocardial ischemia and infarction, both in the acute and chronic phases, are associated with cardiomyocyte loss and dramatic changes in the cardiac extracellular matrix (ECM). It has long been appreciated that these changes in the cardiac ECM result in altered mechanical properties of ischemic or infarcted myocardial segments. However, a growing body of evidence now clearly demonstrates that these alterations of the ECM not only affect the structural properties of the ischemic and post-infarct heart, but they also play a crucial and sometimes direct role in mediating a range of biological pathways, including the orchestration of inflammatory and reparative processes, as well as the pathogenesis of adverse remodeling. This final part of a 4-part JACC Focus Seminar reviews the evidence on the role of the ECM in relation to the ischemic and infarcted heart, as well as its contribution to cardiac dysfunction and adverse clinical outcomes.
Entropy as a Novel Measure of Myocardial Tissue Heterogeneity for Prediction of Ventricular Arrhythmias and Mortality in Post-Infarct Patients
2019, JACC: Clinical Electrophysiology
This study proposed entropy as a new late gadolinium enhanced cardiac magnetic resonance–derived parameter to evaluate tissue inhomogeneity, independent of signal intensity thresholds. This study hypothesized that entropy within the scar is associated with ventricular arrhythmias (VAs), whereas entropy of the entire left ventricular (LV) myocardium is associated with mortality.
In patients after myocardial infarction, the heterogeneity of fibrosis determines the substrate for VA. Fibrosis in remote areas has been associated with heart failure and mortality. Late gadolinium-enhanced cardiac magnetic resonance has been used to delineate fibrosis, but available methods depend on signal intensity thresholds and results have been inconsistent.
Consecutive post–myocardial infarction patients undergoing late gadolinium enhanced cardiac magnetic resonance prior to implantable cardioverter-defibrillator implantation were included. From cardiac magnetic resonance imaging, total scar size, scar gray zone, scar transmurality, and tissue entropy were derived. Patients were followed for appropriate implantable cardioverter-defibrillator therapy and mortality.
A total of 154 patients (age 64 ± 10 years, 84% male, LV ejection fraction 29 ± 10%, 47% acute revascularization) were included. During a median follow-up of 56 (interquartile range: 40 to 73) months, appropriate implantable cardioverter-defibrillator therapy occurred in 46 patients (30%), and 41 patients (27%) died. From multivariable analysis, higher entropy of the scar (hazard ratio [HR]: 1.9; 95% confidence interval [CI]: 1.0 to 3.5; p = 0.042) was independently associated with VA, after adjusting for multivessel disease, acute revascularization, LV ejection fraction, scar gray zone, and transmurality. Entropy of the entire LV was independently associated with mortality (HR: 3.2; 95% CI: 1.1 to 9.9; p = 0.038).
High entropy within the scar was associated with VA and may indicate an arrhythmogenic scar. High entropy of the entire LV was associated with mortality and may reflect a fibrosis pattern associated with adverse remodeling.
Tissue ace-angiotensin-AT1 receptor axis and repair in the heart
2018, Encyclopedia of Endocrine Diseases
The fibrogenic ACE/AngII/AT₁R axis represents a generalized response of multiple tissues evoked by injury and the need for repair. It serves to regulate local concentrations of AngII as a mediator of repair in diverse tissues, including the heart. MyoFb-bound ACE is integral to de novo generation of AngII that modulates expression of TGF–β₁ and whose auto-/paracrine properties regulate collagen turnover at sites of fibrous tissue formation that appear in response to various forms of cardiac injury, including infarction, pericarditis, and foreign-body implant. Persistent myoFb, resistant to apoptosis, and their expression of ACE at sites of injury contribute to a sustained metabolic activity, or secretome, that can account for a progressive fibrosis. Ongoing adverse structural remodeling by fibrous tissue eventuates in the progressive nature of chronic cardiac failure. The counterregulatory fibrolytic ACE2/Ang1–7/Mas axis of the myoFb secretome opposes this fibrogenic axis and may come to prove itself an effective cardioprotective strategy. In this article, we focus on these fibrogenic and fibrolytic axes as they relate to the diseased heart.
Late graft dysfunction after pediatric heart transplantation is associated with fibrosis and microvasculopathy by automated, digital whole-slide analysis
2017, Journal of Heart and Lung Transplantation
Histopathologic features of late graft dysfunction (LGD) in endomyocardial biopsies (EMBs) after pediatric heart transplantation (HT) have been incompletely described and rarely quantified. We employed automated, morphometric analysis of whole-slide EMB images to objectively quantify fibrosis and microvasculopathy after pediatric HT.
Nine recipients with clinical LGD were matched with controls on age, listing diagnosis, crossmatch and time since HT. Fibrosis was quantified as percent tissue area with fibrosis and capillary density as capillaries per unit area, number of capillary “neighbors” within 30 μm of each myocyte and myocyte-to-nearest-capillary diffusion distance. Clinical data, including all EMB reports, were also reviewed.
The groups were well matched for age at HT (median 4.0 vs 3.1 years), listing diagnosis (50% congenital heart disease for each), positive crossmatch (11% each) and days post-HT (2,628 vs 2,894, p = 0.69). Despite a similar number of previous EMBs (median 23 each, p = 0.43), areas occupied by fibrosis were greater in LGD cases (44.5% vs 23.2%, p = 0.012). Capillary number/area data were not statistically different between LGD cases and controls (378/mm² vs 559/mm², p = 0.57), but LGD cases more commonly had zero capillary neighbors (35% vs 20%, p = 0.02) and greater myocyte-to-nearest-capillary distances (27.1 μm vs 18.7 μm, p = 0.005). Cumulative rejection history correlated with fibrosis (r = 0.49, p = 0.039) and myocyte-to-nearest-capillary distance (r = 0.5, p = 0.036).
LGD after pediatric HT is associated with previous rejection and characterized histologically by fibrosis and microvasculopathy, which are not readily appreciated by traditional semi-quantitative EMB analysis. Software-assisted EMB analysis may enable greater pathophysiologic understanding of LGD and identification of targets for future study and intervention.
A non-contrast CMR index for assessing myocardial fibrosis
2017, Magnetic Resonance Imaging
Citation Excerpt :
Regions-of-interest (ROIs) were drawn in this region that matched the location of the specimens in histopathology. Despite being comprised of both normal and infarcted myocardium, this region has been shown to develop fibrosis several days after MI with impairment of energy metabolism and myocardial function [28,29]. Non-contrast T1ρ, native T1, mFI, and MBF in these ROIs were then measured on the corresponding maps.
Safe, sensitive, and non-invasive imaging methods to assess the presence, extent, and turnover of myocardial fibrosis are needed for early stratification of risk in patients who might develop heart failure after myocardial infarction. We describe a non-contrast cardiac magnetic resonance (CMR) approach for sensitive detection of myocardial fibrosis using a canine model of myocardial infarction and reperfusion.
Seven dogs had coronary thrombotic occlusion of the left anterior descending coronary arteries followed by fibrinolytic reperfusion. CMR studies were performed at 7 days after reperfusion. A CMR spin-locking T₁ρ mapping sequence was used to acquire T₁ρ dispersion data with spin-lock frequencies of 0 and 511 Hz. A fibrosis index map was derived on a pixel-by-pixel basis. CMR native T₁ mapping, first-pass myocardial perfusion imaging, and post-contrast late gadolinium enhancement imaging were also performed for assessing myocardial ischemia and fibrosis. Hearts were dissected after CMR for histopathological staining and two myocardial tissue segments from the septal regions of adjacent left ventricular slices were qualitatively assessed to grade the extent of myocardial fibrosis.
Histopathology of 14 myocardial tissue segments from septal regions was graded as grade 1 (fibrosis area, < 20% of a low power field, n = 9), grade 2 (fibrosis area, 20–50% of field, n = 4), or grade 3 (fibrosis area, > 50% of field, n = 1). A dramatic difference in fibrosis index (183%, P < 0.001) was observed by CMR from grade 1 to 2, whereas differences were much smaller for T₁ρ (9%, P = 0.14), native T₁ (5.5%, P = 0.12), and perfusion (− 21%, P = 0.05).
A non-contrast CMR index based on T₁ρ dispersion contrast was shown in preliminary studies to detect and correlate with the extent of myocardial fibrosis identified histopathologically. A non-contrast approach may have important implications for managing cardiac patients with heart failure, particularly in the presence of impaired renal function.

View all citing articles on Scopus

View full text

Letter to the EditorInterstitial Collagen is Increased in the Non-infarcted Human Myocardium After Myocardial Infarction

Abstract

Letter to the Editor
Interstitial Collagen is Increased in the Non-infarcted Human Myocardium After Myocardial Infarction