|Year : 2017 | Volume
| Issue : 4 | Page : 481-486
|Histological and morphometric analysis of dilated cardiomyopathy with special reference to collagen IV expression
Parul Jain1, Sudheer Arava1, Sandeep Seth2, Sanjeev Lalwani3, Ruma Ray1
1 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
3 Department of Forensic Medicine, All India Institute of Medical Sciences, New Delhi, India
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|Date of Web Publication||12-Jan-2018|
| Abstract|| |
Introduction: Collagen distribution alterations are well known in dilated cardiomyopathy. There are also changes in microvasculature along with other histomorphorphological features. Aims and Objectives: To study the histomorphological features of DCM along with their quantitative correlation with LVEF. Alterations in collagen IV distribution pattern and microvasculature in DCM were also evaluated. Materials and Methods: The present study includes 34 right ventricular endomyocardial biopsies, 7 explanted native hearts and 41 autopsy control hearts. Sections were taken from lower half of right interventricular septum and stained for H and E, Masson trichrome and immunohistochemistry for CD34, SMA and Collagen IV to study the histological features, pattern of fibrosis, capillary and arteriolar distribution and collagen IV expression respectively. Morphometric analysis was carried out in all cases and controls using Image analysis software Image pro plus 7 and correlated with left ventricular ejection fraction. Results: The histomorphological changes of DCM include myocyte hypertrophy, nucleomegaly, and interstitial fibrosis. Interfiber fibrosis was the commonest. There was evidence of myocarditis, ischemic change and vessel wall alterations. Considerable alteration in Collagen IV distribution was observed with reduction in intensity and proportion of staining around myocytes quantified using Allred scoring against uniform pericellular staining in controls. Morphometric analysis revealed significant increase in nuclear area, myocyte width, percentage of fibrosis and reduction in capillary myocyte ratio in cases as compared to controls. There was no significant difference in arteriolar density. No significant association was observed between morphometric parameters and LVEF. Conclusion: Histomorphological changes in DCM are non-specific. Quantitation of histological parameters cannot be used to predict the disease progression as there was no significant correlation with LVEF. There is appreciable alteration in Collagen IV distribution in DCM owing to extracellular matrix alterations.
Keywords: Collagen IV distribution, dilated cardiomyopathy, microvascular alterations, morphometry
|How to cite this article:|
Jain P, Arava S, Seth S, Lalwani S, Ray R. Histological and morphometric analysis of dilated cardiomyopathy with special reference to collagen IV expression. Indian J Pathol Microbiol 2017;60:481-6
|How to cite this URL:|
Jain P, Arava S, Seth S, Lalwani S, Ray R. Histological and morphometric analysis of dilated cardiomyopathy with special reference to collagen IV expression. Indian J Pathol Microbiol [serial online] 2017 [cited 2019 Jun 26];60:481-6. Available from: http://www.ijpmonline.org/text.asp?2017/60/4/481/222961
| Introduction|| |
Dilated cardiomyopathy (DCM) is the most common cardiomyopathy that has been defined as dilatation and impaired contraction of the left ventricle or both the ventricles following exclusion of ischemic, hypertensive, congenital, valvular, and pericardial heart diseases. It may be idiopathic, familial/genetic, viral, immune mediated, alcohol related/toxic or associated with recognized cardiovascular diseases in which the degree of myocardial dysfunction is not explained by the abnormal loading conditions or the extent of ischemic damage. Microscopically, there is no diagnostic hallmark of DCM and the disease is diagnosed by a constellation of histological findings with an appropriate clinical context of reduced ejection fraction. There is an increase in interstitial fibrosis along with alteration in collagen distribution. Collagen IV is normally distributed around the myocytes in the endomysium and its distribution has been found to be deranged in DCM. The microvasculature is also affected though there is a paucity of literature regarding microvasculature changes in DCM. Other nonspecific microscopic features include myocyte hypertrophy, anisonucleosis and sarcoplasmic degenerative changes. The present study highlights the light microscopic features including morphometric analysis along with alterations in Collagen IV expression, microvasculature in DCM and their prognostic significance by correlating the severity of these changes with the corresponding left ventricular ejection fraction (LVEF).
| Materials and Methods|| |
The present study includes 41 cases and 41 controls. Thirty-four right ventricular endomyocardial biopsies of clinically proven cases of DCM with an ejection fraction between 10% and 45% were collected over a period of 3 years (January 2010–December 2013). Seven specimens of explanted native hearts from end stage DCM were retrieved from the archives of Department of Pathology, All India Institute of Medical Sciences, New Delhi. Clinical data of all the cases were collected including demographic profile, clinical summary and echocardiography findings with special reference to LVEF. This study was approved by the Institutional Ethical Committee.
Forty-one control hearts were procured from the forensic postmortems of individuals who succumbed to death due to noncardiac causes. Appropriate consent was made available before removal of heart.
Endomyocardial biopsies (34) and representative sections from explanted native hearts (7) and autopsied hearts (41) were taken from lower half of the right interventricular septum. Tissue samples were preserved in 10% buffered formalin and processed in automated histokinetic tissue processer. All the paraffin blocks were cut into 4 μ thick sections and stained for routine hematoxylin and eosin stain to study the histomorphology. Masson's trichrome stain (MT) was done to study the fibrosis. Immunohistochemistry was performed for smooth muscle actin (SMA) (dilution 1:100, Clone 1A4, Dako, Denmark), CD34 (dilution 1:50, Clone QBEnd, Dako, Denmark), and collagen IV (dilution 1:50, Clone CIV22, Dako, Denmark) using polymer-based peroxidase method to evaluate arterioles, capillaries and collagen IV distribution, respectively, in the tissue sections.
Microscopic parameters including endocardial thickening, subendocardial fibrosis, myocyte hypertrophy, nuclear enlargement, sarcoplasmic degenerative changes and pattern of interstitial fibrosis, collagen IV distribution, arteriolar and capillary density were considered for evaluation. Semi-quantitative assessment of collagen IV distribution was done by giving an Allred score  for better objectivity and optimization of the observations. In tissues from explanted native hearts and control hearts along with the aforementioned parameters morphology of arterioles and any other morphological change like the presence of myocarditis, etc., were looked for.
For morphometric assessment all the slides were photographed at required magnification using Nikon Digital Sight DS-SM camera and then morphometry was done using image analysis software Image Pro Plus 7 (Media Cybernetics, MD, USA) to study the nuclear area, myocyte width, amount of fibrosis, myocyte:capillary ratio and arteriolar density. Mean values were taken in each case.
For nuclear area - fields were chosen containing at least 30 transversely cut well oriented myocytes at a magnification of ×400 and nuclear outline was defined manually, then area was calculated by software [Figure 1]a.
|Figure 1: Image analysis: (a) Measurement of nuclear area. (b) Measurement of myocyte width in longitudinally oriented myocytes. (c) Selection of field for measuring percentage area of fibrosis (Masson's trichrome stain). (d) Application of different color to the fibrosis with software (red). (e) Measurement of capillary/myocyte ratio (immunohistochemistry CD34) and (f) measurement of arteriolar density (immunohistochemistry smooth muscle actin)|
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For myocyte width, longitudinally oriented myocytes in which nucleus was visible at a magnification of ×400 were considered for evaluation. A single transverse measurement was made through the middle of the nucleus [Figure 1]b. Minimum 30 myocytes were evaluated in each case and the mean value was taken in μm.
Total area occupied by fibrosis was evaluated on MT stained slides at ×100 magnification. Appropriate area with maximum fibrosis was chosen out of the whole section area. Different colors were applied to area occupied by fibrosis (red) and that by myocytes (yellow) with the help of software. Then relative percentage area occupied by fibrosis and myocytes was calculated [Figure 1]c and [Figure 1]d.
Capillary density was calculated by manually counting total number of capillaries in CD34 stained slides at ×400 magnification. Fields were chosen containing transversely cut well oriented myocytes and capillaries with a visible lumen [Figure 1]e. Minimum 30 myocytes were counted for each case to calculate capillary:myocyte ratio (CMR).
Arteriolar density was calculated on SMA stained slides at ×40 magnification by manually counting number of arterioles (SMA+) in all the biopsy fragments along with measuring the total field area using software [Figure 1]f. For explanted native hearts and control sections the maximum area in a single field was measured using the software and number of arterioles was counted in that field.
All the above parameters were finally correlated with the LVEF and compared with the control values. These parameters were individually correlated with each other.
Appropriate statistical formulae were applied including Chi-square test, Man–Whitney test, Krusker–Wallis test, and Spearman correlation tests to analyze the significance of these correlations using SPSS software STATA 11.1 (USA). P ≤ 0.05 was considered statistically significant.
| Results|| |
The median age of cases was 41 year (range 5–65 years) with a male:female ratio of 3:1. Median age of controls was 25 year (range 18–55 years) with a male:female ratio of 3:1.
The mean LVEF of cases was 25.06% ±8.27%. For comparison among various morphometric parameters the cases were divided into two groups: Group 1 – cases with LVEF ≤20% (n = 15) and Group 2 – cases with LVEF >20% (n = 26). For control normal hearts mean LVEF was considered to be 55%.
Endocardial thickening and subendocardial fibrosis
Endocardium was thickened in 20 out of 41 cases of DCM (48.8%). Nineteen cases revealed subendocardial fibrosis (48%) [Figure 2]c. None of the controls had endocardial thickening.
|Figure 2: Histomorphological features: (a) Normal Myocardium-Control heart (H and E, ×200). (b) Dilated cardiomyopathy: myocyte hypertrophy, anisonucleosis, and sarcoplasmic vacuolation (H and E, ×200) (c) Prominent subendocardial, interfiber fibrosis and subendocardial smooth muscle proliferation (Masson's trichrome, ×100) (d) Masson's trichrome stain highlighting the perivascular fibrosis (arrow), ×100 (e) Replacement fibrosis in end stage dilated cardiomyopathy (Masson's trichrome, ×100) (f) Eccentric thickening of medial smooth muscle of vessels walls (H and E, ×100) (g) Large area of myocyte dropout in a case of end stage dilated cardiomyopathy (H and E, ×40) (h) Disruption of sarcolemmal outline by lymphocytes encircling the myocyte (arrow) resulting in myocyte degeneration indicating myocarditis (H and E, ×200)|
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Myocyte hypertrophy and sarcoplasmic degenerative changes [Figure 2]b were evident in 40 out of 41 cases. One case without any myocyte damage was in early course of disease evolution with near normal LVEF. None of the controls showed these myocyte changes [Figure 2]a.
In 38 out of 41 cases (92.7%), there were nucleomegaly and anisonucleosis. The nuclei developed varying shapes such as cookie cutter, crescentic, and star shape. [Figure 2]b. These changes were not evident in control sections [Figure 2]a.
All the 41 cases had interstitial fibrosis, with collagen bundles encircling the myocytes [Figure 2]c. Perivascular and replacement fibrosis were seen in 14 and 6 cases respectively [Figure 2]d and [Figure 2]e. None of the cases had plexiform fibrosis.
One of our cases showed myocarditis that had raised titers for anti-cytomegalovirus IgG, anti-herpes simplex virus, antitoxoplasma antibodies [Figure 2]f. One case with end stage DCM (LVEF <20%) showed large areas of myocyte dropout indicative of ischemic damage to the myocytes along with evidence of old hemorrhage [Figure 2]g. The epicardial coronary arteries were normal.
Blood vessel changes
Two of our cases with end stage DCM (LVEF < 20%) had eccentric thickening of medial smooth muscle wall of intramyocardial vessels [Figure 2]h.
Semi quantitative assessment of collagen IV
All controls had similar collagen IV expression with an Allred score of 8 (which is the maximum value). Collagen IV was decorating the endomysium with uniform complete strong intensity giving a mosaic appearance [Figure 3]a. In sharp contrast, the cases showed variability in distribution of collagen IV around myocytes along with variation in intensity of staining [Figure 3]b,[Figure 3]c,[Figure 3]d. The median Allred score for cases was 4 (0–7). Collagen IV expression among cases showed no significant correlation with LVEF (Group 1 ≥20%, Group 2 <20%) (P = 0.275), though there was a weak trend of increasing Allred score with reducing LVEF. There was no significant correlation between the two groups of LVEF (P = 0.270), though within each group we observed a trend of increasing Allred score with reducing ejection fraction that was statistically insignificant.
|Figure 3: Collagen IV: (a) Normal myocardium (control heart) highlighting the normal endomysial distribution of collagen IV encircling the myocytes. (b) Variation in expression of collagen IV in a case of dilated cardiomyopathy, with reduced intensity and proportion of staining. Allred score 5 (c) photomicrograph depicting reduced intensity and patchy staining. Allred score (d) case of dilated cardiomyopathy with Allred score 4|
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The morphological parameters are tabulated in [Table 1] and [Table 2]
|Table 1: Comparison of mean values of morphometric parameters in cases and controls|
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|Table 2: Correlation of morphometric parameters with left ventricular ejection fraction (r=correlation coefficient)|
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Nuclear area (m m2)
The mean nuclear area of cases was significantly higher than that of controls (P< 0.001). There was an increase in nuclear area as the LVEF increased, but the correlation was not statistically significant (r = 0.258, P = 0.103). No correlation was observed between LVEF subgroups.
Myocyte width (m m)
Median myocyte width of cases was significantly higher than controls (P< 0.001) though there was no significant correlation between myocyte width and LVEF (P = 0.328), myocyte width was less in the group with LVEF ≤20% (16.67 [13.91–105.43]) than that of >20% (17.04 [10.91–60.41]) but the difference was not statistically significant (P = 0.675).
All DCM cases had significant increase in fibrosis as compared to that of controls (P = 0.0005), but significant correlation was not found between the percentage of fibrosis and LVEF (P = 0.713).
CMR of cases was significantly less than that of controls (P = 0.032), though this parameter showed no significant correlation with LVEF (P = 0.226).
Arteriolar density (per mm2)
Median arteriolar density of cases was higher than that of controls but this was not found to be statistically significant (P = 0.942). Arteriolar density showed no significant correlation with LVEF (P = 0.872).
Morphometric parameters when compared individually did not show any significant correlation.
| Discussion|| |
The myocardial structure is mainly composed of cardiomyocytes (76%) and the extracellular matrix (ECM). The latter contains vessels and nerves (14%), water space (7%), collagen network (1%), fibroblasts and macrophages (2%). The fibrous component of interstitial matrix consists of collagen and elastic fibers. The collagen fibrils in myocardial matrix are arranged as small struts interconnecting the myocytes, connecting the myocytes with capillaries and series of sheaths encircling small groups of myocytes and collagen fibrils in perivascular location. Among the various types of collagen, Type IV is present in the endomysium, basement membranes of vascular wall and in replacement fibrotic scar lesion. Among fibrillar, collagen Type I is found in late stages of fibrotic scar while Type III collagen is seen in early stages of scar formation.
The present study revealed that in DCM endomysial weaving of collagen IV was disrupted with discontinuous staining and disproportionate loss around myocytes. The staining intensity was also variable. For quantifying these alterations an Allred score was applied in each case on the basis of percentage of pericellular staining and intensity of staining. There was an appreciable reduction in Allred score in cases as compared to controls which had a uniform maximum score of 8. This could be explained by the fact that there is derangement and loss of normal endomysial collagen IV expression in DCM.
When collagen IV expression was correlated with LVEF, there was an overall trend of increase in Allred score with reducing LVEF (r = –0.17) though the difference was statistically insignificant. In DCM, there is perimyocytic fibrosis which is probably the cause of discontinuous expression of collagen IV. In this regard, other authors have documented variable results, though they did not score the collagen IV expression., Nogami et al. observed that in DCM Type IV collagen contributed not only to basement membrane related fibrosis but also to replacement and wide endomysial fibrotic lesions not related to the basement membrane. In contrast, Yoshikane et al. found that the immunoreactivity for collagen Type IV in DCM did not differ from that of normal hearts, but they also postulated that as Type IV collagen is the earliest type of collagen in wound healing its localization may differ depending on the stage and severity of DCM.
The present study showed an increase in fibrosis as all the cases had interfiber/perimyocytic fibrosis. Alterations in sarcoplasmic and sarcolemmal structural proteins in DCM may lead to abnormal cell–cell, cell-matrix including cell-collagen interactions. These arrangements may lead to abnormal collagen deposition in between the cells. Perivascular and replacement fibrosis was found in 14 and 6 cases, respectively. Replacement fibrosis results from destruction of myocardium, which appears as fibrotic strand formed in the areas of myocyte dropout. Anderson et al. also described that the major types of fibrosis seen in DCM are interfiber and perivascular types, followed by plexiform, and in their study, the least common was replacement fibrosis. In the present study, morphometric analysis of cases revealed significantly more fibrosis than control (P = 0.0005). This finding is in concordance with the available literature., Some authors have documented a correlation between interstitial myocardial collagen and LVEF., Contrary to these observations the present study failed to demonstrate a significant correlation between fibrosis and LVEF (P = 0.713). Grimm et al. (2003) also did not find any significant correlation between the amount of interstitial tissue and patient survival. We did not observe any significant correlation of LVEF with fibrosis in any of our subgroups. This is in contrast to an observation where fibrosis was predictive of survival in the subgroup of patients with LVEF <20%.
Normal coronary microvasculature of myocardium consists of large epicardial coronary arteries (500 μm–2.5 mm), prearterioles (100–500 μm), and intramural arterioles (<100 μm diameter). The capillaries have size of <40 μm and are of 3 types-continuous, fenestrated/perforated and the larger sinusoids. The study highlighted changes in microvasculature of myocardium in DCM both in light microscopy and on morphometric analysis. In two of the explanted native hearts suffering from end stage DCM, there was eccentric thickening in tunica media of both large and small arterioles which might imply an ongoing microvascular abnormality, which has been reported in the literature. However, there was no significant alteration in arteriolar density on morphometry. Laguens et al. did not find any significant change in length density of vessels above 20 μm in diameter. Our observation did not reveal any significant correlation between arteriolar density and LVEF. This observation might be explained by the fact that most of our cases were having less severe disease with LVEF >20%. The available literature documented that coronary microvascular dysfunction can be considered one of the pathogenetic mechanisms involved in the evolution of ventricular dysfunction toward heart failure and has an independent and relevant prognostic value even in the absence of coronary artery disease., There was a significant reduction in CMR in cases as compared to normal hearts. Karch et al. also observed a decrease in capillary density (number of capillaries/mm2) in DCM along with increase in intercapillary distance. Contrary to these findings, Mosseri et al. observed that there was no significant difference in CMR in DCM and normal control hearts. Laguens et al. also studied capillary density in end stage DCM hearts and did not find any significant difference with normal hearts. In the present study, there was no statistically significant correlation between CMR of cases and their LVEF, though it was significantly higher in group with LVEF ≤20% than with >20%. This finding could be explained by ongoing microvascular abnormality leading to hypoxia-induced neovascularization occurring with disease progression. However, definitive comment cannot be made due to limitation of sample size and further works are needed to prove or disprove the hypothesis.
Other histomorphological changes in the present study included endocardial thickening and subendocardial fibrosis. The thickening of endocardium along with increased subendocardial fibroconnective tissue is an adaptive response to the increase in cavitary dimension due to the abnormal volume of ventricle. Characteristic myocyte changes in DCM are hypertrophy of cardiomyocytes and myofibril loss along with sarcoplasmic degeneration in the form of vacuolization. Along with hypertrophy of myofiber, there is nuclear hypertrophy and anisonucleosis. The nuclei develop varying shapes such as cookie cutter, crescentic, and star shape. Morphometrically, nuclear area was significantly increased in DCM. Other authors also observed increase in nuclear size in cardiomyopathic hearts., The present study failed to reveal any significant correlation between nuclear area and LVEF among cases. This finding is contradictory to that of Gallo and Amati (2001) who observed that cases with nuclear area ≥70 μ2 had a significant inverse correlation with EF. The present study showed significant increase in myocyte width indicating myocyte hypertrophy though there was an insignificant correlation with LVEF. Probably myofiber attenuation as a result of stretching might have altered the myocyte width affecting its relation with LVEF. Rowan et al. have documented a similar increase in myocyte width in cases of DCM.
| Conclusions|| |
Collagen IV distribution in the ECM was deranged with loss of uniformity and intensity of staining around myocytes indicative of disruption of basement membrane collagen in DCM. There was increase in interstitial fibrosis. Among microvasculature changes there was a significant reduction in CMR. The light microscopic findings of DCM include myocyte hypertrophy along with sarcoplasmic vacuolation, nucleomegaly, and anisonucleosis. Morphometric analysis revealed a significant increase in nuclear area, myocyte width. There was no significant change in arteriolar density. None of the morphometric parameters showed a significant correlation with LVEF, thus concluding that quantification of light microscopic features of DCM cannot be used to predict the disease progression and prognosis of the patient.
Special thanks to Dr. Kalaivani, Mr. Kamal, Mr. Inderpal for statistical evaluation and technical assistance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Dr. Sudheer Arava
Department of Pathology, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]
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