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European Journal of Heart Failure 2006 8(4):373-380; doi:10.1016/j.ejheart.2005.10.016
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© 2006 European Society of Cardiology

Chronic infarct-related artery occlusion is associated with a reduction in capillary density. Effects on infarct healing

Marek Precha,*, Stefan Grajeka, Andrzej Marszalekb, Maciej Lesiaka, Marek Jemielityc, Aleksander Araszkiewicza, Tatiana Mularek-Kubzdelaa and Andrzej Cieslinskia

a Department of Cardiology, Poznan University of Medical Sciences Dluga 1/2, 61-848 Poznan, Poland
b Department of Clinical Pathomorphology, Poznan University of Medical Sciences Poznan, Poland
c Department of Cardiosurgery, Poznan University of Medical Sciences Poznan, Poland

* Corresponding author. Tel.: +48 61 8549146; fax: +48 61 8549094. E-mail address: marek.prech{at}sk1.am.poznan.pl


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Statistics
 4. Results
 5. Discussion
 6. Limitations of the...
 Acknowledgment
 References
 
Aim: To assess the relationship between infarct-related artery (IRA) stenosis and capillary density and to assess its effect on scar formation in the human heart.

Materials and methods: Morphometric evaluation was performed in 51 human hearts, as follows. Group I non-cardiac death (control), Group II post-Q-wave myocardial infarction (QMI) death and Group III patients who survived QMI and who underwent aneurysmectomy. Using morphometric parameters, the relationship between left ventricle (LV) mass, infarct size, IRA stenosis, cellular hypertrophy and changes in microcirculation were analyzed within the infarcted area and free LV wall.

Results: A significant reduction in capillary density within the infarcted area was noted in group II when compared to the control group (1525.6±378.5/mm2 vs. 2968.7±457.3/mm2; p<0.001). Reduction in capillary density was inversely related to infarct size (r=–0.616; p=0.006) and degree of IRA stenosis (rS=–0.512; p=0.03). The most significant reduction in capillary density was observed in patients with total IRA occlusion (1204.6±156.9/mm2 vs. 1676.6±245.8/mm2; p<0.001). Similarly, a reduction in capillary density of over 60% (1030.7±241.8/mm2) was observed within aneurysms resected surgically.

Conclusions: The study demonstrated precise quantification of the capillary network in patients following QMI. The most significant reduction in capillary density was observed in patients with chronic total IRA occlusion.

Key Words: Myocardial infarction: • Microcirculation • Aneurysm • Total occlusion • Coronary capillaries

Received January 28, 2005; Revised August 3, 2005; Accepted October 13, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Statistics
 4. Results
 5. Discussion
 6. Limitations of the...
 Acknowledgment
 References
 
The process of infarct scar formation and its effect on the architecture of the left ventricle (LV) has been investigated both in human and animal models. Morphologic studies in humans have shown that healing of the necrotic myocardium is completed within 6-8 weeks after myocardial infarction (MI) and results in formation of a fibrous scar. It has also been reported that in 5-10% of patients the process of infarct healing is complicated by the development of an LV aneurysm [1-4]. It has been suggested that total occlusion of the infarct-related artery (IRA), poor collateral blood supply and large transmural infarcts are the main factors predisposing to aneurysm formation [2,3].

Recent studies have questioned the long-term paradigm that the infarct scar is inert fibrous tissue. To describe the ongoing process of collagen turnover and fibrous tissue formation within the infarcted area, Weber recently introduced the term rebuilding of the infarct scar [5]. Moreover, Beltrami et al. have shown that human cardiac myocytes may divide after MI and that the mitotic index is especially high in samples from the border of the infarct [6]. Several clinical studies have shown that the preservation of flow in the IRA prevents the process of LV dilatation and subsequent remodelling and leads to an improvement in regional and global systolic function [7-11]. Penco et al. reported a relationship between coronary patency and LV function in patients with IRA residual stenosis <75% [11]. Others have suggested that the further reduction in the infarct size after hospital discharge may be related to the presence of residual perfusion in the dysfunctional segments [12].

Data on the potentially favourable effects of the restoration of IRA patency are derived mainly from clinical and experimental studies. The aim of this morphometric study was to determine the relationship between the degree of IRA stenosis and the capillary network and to assess its effect on the process of scar formation in the human heart.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Statistics
 4. Results
 5. Discussion
 6. Limitations of the...
 Acknowledgment
 References
 
The investigation conforms with the principles outlined in the Declaration of Helsinki.

Myocardial samples from 51 human hearts were studied in three groups. Samples were obtained during post-mortem examination for the 31 hearts in Groups I and II, and during aneurysmectomy for the 20 patients in Group III. Group I (n=10) consisted of patients who had died due to non-cardiac causes (cerebral injuries or neoplastic tumours) who served as the control (mean age 52.4±11.2 years). Group II (n=21) comprised patients aged between 38 and 78 (mean 58.8) years, who, at least 3 months before death, had been diagnosed as QMI. None of these patients were reperfused during the acute phase of MI and the most common cause of death was progression of heart failure or electrical instability associated with the aggravation of angina pectoris (Table 1). Autopsies were performed between 12 and 36 h after death. Briefly, after the excision, transecting the large body arteries and veins, the hearts were weighed. Coronary arteries were isolated beginning from Valsalva's sinus up to the technically accessible distal parts. Then the origins of the great vessels were removed at their valve rings, and the atria were dissected along the atrial-ventricular groove. After the excision of the right ventricles along the anterior and posterior interventricular groove, the left ventricles (including the interventricular septum) were weighed and cut transversely to the long axis of the heart into 5-6 slices of approximately equal thickness (1.0-1.2 cm). In 13 QMI hearts, autopsy revealed an infarct scar, a firm connective tissue scar with interspersed muscle fibers, these hearts were classified as Group IIA. A true LV aneurysm, defined as a convex protrusion of the full thickness of the ventricular wall, composed of a mature scar, was found in the remaining 8 QMI hearts, which were classified as Group IIB. The identification of an infarct scar or an aneurysm corresponded to the ECG pattern (Table 1). To provide accurate light microscopic and morphometric examination, myocardial samples were collected as follows. In the control group, samples were collected from the free LV wall. In Group II samples were collected from the infarcted area (including the central part of the scar or the aneurysm) and the non-infarcted area (free LV wall).


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  		Table 1 Morphological findings in 21 deceased post-QMI patients; (Group II) Group IIA=infarct scar, Group IIB=LV aneurysm

 
Group III comprised 20 patients (mean age 56.7±9.5 years) diagnosed with a true left ventricular aneurysm, defined as a segment of the ventricular wall showing dyskinetic systolic expansion on ventriculography and/or echocardiography several months after QMI. The presence of coronary stenoses was established by coronary angiography, which preceded aneurysmectomy. Islets of myocytes suitable for morphometry were found in 13 out of 20 resected aneurysms.

2.1. Morphometry
Myocardial samples collected during autopsy and aneurysmectomy were fixed in 5% buffered formalin (pH 7.4; 24 h), processed and embedded in paraffin blocks. All blocks were sectioned at a thickness of 5 µm using a microtome (Jung SM2000, Leica, Germany) and between 20 and 50 sections were selected for morphometric evaluation. Slides for the morphologic and morphometric studies were coded and evaluated by two independent observers. The following parameters were evaluated: myocyte diameter, myocyte nucleus diameter, myocyte nuclear density and capillary density. A morphometric evaluation was performed using a computer based image analyser (Leica Q500MC, Leica, Germany) connected to the microscope (Leica DM RB, Leica, Germany). The computer image frame size was 512x512 pixels and the objective PL Fluotar 40x/0.70 PH2 (Leica, Germany) was used. Measurements were performed using a computer program (Leica Q500MC QWin, Leica, Germany) and results were automatically recalculated for the area of a square millimetre.

2.1.1. Myocyte and myocyte nucleus diameters
To evaluate the degree of cellular hypertrophy myocyte and myocyte nucleus diameters were assessed in the HE stained sections with transversely sectioned muscle fibers. An average myocyte diameter was obtained by measuring 50 myocytes, which were almost round in shape (two perpendicular length axes difference less than 15%) randomly selected from: the free LV wall (Group I), the infarcted area and the free LV wall (group II) and the islet of myocytes in the aneurysms resected surgically (Group III). The same procedure was used to assess myocyte nucleus diameter.

Myocytolysis, defined as a loss of muscular striation and displacement of muscle content by cytoplasmatic vacuoles, was assessed in a semi-quantitatively: from "0"—none, through "+"—mild (myocytolysis visible in up to 30% of myocytes), "++"—moderate (myocytolysis in 30-60% of myocytes), to "+++"—severe (over 60% of myocytes showing variable degree of myocytolysis—Fig. 4A).

2.1.2. Myocyte nuclear density
To assess the change in the number of myocytes in the sampled area, myocyte nuclear density was measured as there is a constant proportion between both parameters [13]. Myocyte nuclear density (ND) was determined using the equation:


Formula

Average nuclear density was determined by calculating the number of nuclei in 10 randomly selected areas in each investigated myocardial sample. The number of selected areas was established according to Weibel's formula.

2.1.3. Evaluation of the microcirculation
Immunostaining using monoclonal anti-CD34 antibodies specific to the endothelial cells (Novocastra, UK) and EnVision+TM complex (DAKO, Denmark) was performed to identify the capillaries. Alterations in the microcirculation were determined by measuring capillary density (CD) according to the equation:


Formula

The number of capillaries (positively stained thin walled microvessels of diameter <30 µm) was calculated in 10 randomly selected areas in each investigated myocardial sample.

2.2. Examination of the coronary arteries
The major coronary arteries (left main coronary artery, left anterior descending artery, left circumflex artery and right coronary artery) were examined in all 31 autopsied hearts. The coronary arteries were transected at 5 mm intervals as far as the periphery. The sectioning yielded 1489 cross sections—from 1 (left main coronary artery) to 29 (right coronary artery) cross sections per artery. Sections were stained according to Weigert's method and the evaluation of the degree of morphologic stenosis was determined using the quantitative planimetric option of a computer program. To assess the degree of coronary obstruction the following parameters were measured: the cross-sectional area of the lumen, intima and media. The main interest was focused on the degree of morphologic stenosis of the IRA. A 75% reduction in cross-sectional area of the lumen was considered significant.

The examination of the coronary arteries in patients who underwent aneurysmectomy was based on coronary angiography and a 50% reduction in lumen diameter was considered significant.

2.3. Determination of infarct size
Slices of LV obtained during the post-mortem examination were divided into 4 equal segments corresponding to: the anterior wall, the posterior wall, the lateral wall and the septum. The number of segments including the scar was grossly assessed. Using a mathematical model, the percentage of the whole LV volume for each segment was calculated. The actual infarct size was estimated as the fractional volume of the LV including the fibrous tissue (segments including the scar) corrected according to the results of a planimetric measurement of the transmurality of the scar. The planimetry of photographed sections of each myocardial sample including the scar was performed using a 600 point grid.


   3. Statistics
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistics
4. Results
 5. Discussion
 6. Limitations of the...
 Acknowledgment
 References
 
Data are presented as means (S.D.) computed from the average measurements obtained from each tissue sample. The statistical significance was determined using an analysis of variance (ANOVA) with the Shapiro-Wilk test for normal distribution and Bartlett's test for homogeneity of variances. To compare means between the two groups Student t-test for unequal variances was used. The correlation between variables was evaluated with Pearson's correlation coefficient r for normal distribution or Spearman's rank correlation coefficient rS for non-normal distribution. Values of p<0.05 were considered significant.


   4. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistics
 4. Results
5. Discussion
 6. Limitations of the...
 Acknowledgment
 References
 
The post-mortem examination showed a significantly increased LV mass in patients after QMI (Group II) when compared to the control group (296.0±81.3 g vs. 150.2±18.6 g; p<0.00001). Detailed results of morphologic measurements obtained in Group II are presented in Table 1.

An increased LV mass was associated with a significant degree of myocyte hypertrophy observed both in the infarcted area and the free LV wall (Fig. 1A) and corresponding but non-significant increase in the myocyte nucleus diameter (Fig. 1B). Myocyte hypertrophy resulted in a significant reduction in nuclear density (Fig. 1C).


Figure 1
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  		Fig. 1 Results of the morphometric measurements in the control group (Group I), and in the free LV wall and infarcted area in Group II. (A) Myocyte diameter, (B) myocyte nucleus diameter, (C) myocyte nuclear density, (D) capillary density.

 
Cellular adaptations were associated with alterations in the microcirculation. Compared to the control group a significant reduction in capillary density was observed within the infarcted area in QMI patients (Fig. 1D). Over 48% reduction in the capillary density was inversely related to the infarct size (Fig. 2). Moreover, a significant negative correlation between the degree of IRA stenosis and the reduction in the capillary density was noted (Fig. 3). A non-significant (4%) decrease in the capillary density observed in the free LV wall was inversely related to the increased myocyte diameter (r=–0.569; p=0.009).


Figure 2
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  		Fig. 2 Correlation between the infarct size and the reduction in capillary density within the infarcted area.

 


Figure 3
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  		Fig. 3 Correlation between the degree of IRA stenosis and the reduction in capillary density within the infarcted area. Data was analysed both including (rS=–0.532; p=0.019) and excluding the one outlier (rS=–0.512; p=0.030). This Figure shows data excluding the outlier.

 
The analysis of the 5 mm long coronary arterial segments showed no significant stenosis in the control group. Among the 21 patients in Group II, 5 had single-vessel disease, 7 had double-vessel disease and 9 had triple-vessel disease. A total IRA occlusion was found in each patient with an LV aneurysm (Group IIB) while in the remaining patients (Group IIA) the degree of IRA stenosis varied between 53.9% and 97%—Table 1. The observed difference (98.9±0.6% vs. 90.3±10.9%) was statistically significant (p<0.001). The degree of IRA stenosis correlated to the infarct size (r=0.608; p=0.004).

Coronary angiography preceding aneurysmectomy showed total IRA occlusion and poor collateral circulation in all 20 patients, while light microscopy evaluation revealed moderate to severe myocytolysis in 13 resected aneurysms. In the remaining 7 cases the wall of the aneurysm was composed of only fibrous tissue. Table 2 shows the results of the morphometric examination of the myocardial samples obtained during aneurysmectomy (Group III) and the comparable parameters in the other patient groups. The morphometric measurements revealed a similar degree of myocyte hypertrophy and microvascular obstruction in patients with LV aneurysms diagnosed in both patients who had died (Group IIB) and patients who were alive (Group III) (Fig. 4B,C). Moreover, when the capillary density: myocyte nucleus ratio was calculated, a shift towards a greater reduction in capillary density was noted (Table 2). Such a reduction in the density of the capillary network observed in patients with a chronic total IRA occlusion was associated with more advanced myocytolysis and larger infarct size (Table 1).


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  		Table 2 Morphometric parameters in: control group, infarcted area of subgroups IIA and IIB and patients referred for aneurysmectomy (group III)

 


Figure 4
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  		Fig. 4 A—Severe myocytolysis (vacuoles in myocytes' cytoplasm) observed in the LV aneurysm (HE, magnification 1000x); B—coronary capillaries in the normal heart (control group); C—coronary capillaries in the LV aneurysm (group IIB); (CD34 immunostaining; magnification 1000x).

 

   5. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistics
 4. Results
 5. Discussion
6. Limitations of the...
 Acknowledgment
 References
 
Evaluation of the microcirculation is of major interest due to its effect on the process of infarct healing [12,14-16]. Early reperfusion of the occluded IRA with the use of thrombolytic therapy and/or coronary angioplasty results in myocardial salvage and a subsequent improvement in left ventricular function and patient survival [17]. It is widely accepted that the time to reperfusion is a major determinant of myocardial salvage [18]. Results of clinical trials and studies on animal models have also suggested a clinical benefit in patients with a late reperfusion, which occurs when myocardial salvage is no longer possible [7,9]. One of the proposed mechanisms of this potential benefit is the preservation of the vascular bed, which may act as a scaffold to reduce progressive ventricular dilatation and remodelling [19-21]. There are, however, few reports in the literature concerning the precise quantification of the capillary network in the ischaemic heart [22]. Moreover, there are some discrepancies regarding the number of capillaries per square millimetre in the human heart, which, according to different authors, varies from 2000 to 4000. The reported differences are thought to be related to the method of tissue sampling (surgical biopsy or autopsy), the precise anatomical site of the tissue sampling, staining and fixation [23-26].

This morphometric study is the first precise quantification of alterations in the microcirculation after MI in humans. A significant negative correlation between the size of scar and the reduction in capillary density was demonstrated. Moreover, a significant negative correlation between IRA stenosis and the density of the capillary network within the infarcted area was shown. The loss of balance between the number of capillaries and the muscle cells observed in patients with a total IRA occlusion may reflect the disproportion between the blood supply and oxygen demand. This reduction in capillary density was associated with more extensive myocytolysis of hypertrophied myocytes (supplied solely through coronary collaterals), subsequent fibrosis which resulted in larger infarct size and might eventually lead to the formation of an aneurysm.

The profound (60%) reduction in the capillary network demonstrated in patients with total IRA occlusion is consistent with experimental and clinical data published previously. A similar reduction in maximal flow has been shown in animal models of chronic coronary occlusion [27]. Olivetti et al., in a series of experiments on rats to assess left ventricular remodelling following myocardial infarction, reported a reduction in capillary density, which was dependant on the infarct size and varied from 21% to 30% in the region bordering the infarct (measurements within the infarcted area were not performed) [22]. Results obtained during quantification of recruitable coronary collateral blood flow in patients undergoing coronary angioplasty have confirmed experimental reports. Fractional collateral blood flow did not exceed 30% of normal values [28].

The present study was focused on the relationship between IRA stenosis and the degree of microvascular obstruction in patients after QMI. This might reflect the natural history of infarct healing, facilitated by spontaneous reperfusion in some patients after MI as none of the deceased QMI patients (Group II) was treated with thrombolysis and/or PCI during the acute phase of MI. Most of the patients (90%) referred to aneurysmectomy were treated with thrombolysis during the acute phase of MI. Angiographic features of the IRA status observed in these patients and the development of an aneurysm were likely associated with the lack of reperfusion or reocclusion.

Results of this morphometric evaluation support conclusions of earlier pathologic, experimental and clinical investigations demonstrating a beneficial effect of late coronary reperfusion and sustained IRA patency in terms of left ventricular structure [29-32]. Alhaddad et al. showed that the beneficial effect of late IRA reperfusion on the infarct expansion was related to the preservation and hypertrophy of small islets of viable myocytes located in the sub-epicardial layer of the scar [29]. Nidorf et al., using an echocardiographic mapping technique, examined the relationship between the timing and adequacy of perfusion of the infarct bed, changes in ventricular size and the extent of abnormal wall motion. They concluded that the change in abnormal wall motion was related to the presence of anterograde flow to the infarct bed independent of the reperfusion time [30]. Moreover, Abbate et al. showed from autopsy data that chronic IRA occlusion is associated with an increased myocardial apoptosis late after MI [31].


   6. Limitations of the study
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistics
 4. Results
 5. Discussion
 6. Limitations of the...
Acknowledgment
 References
 
The study is limited to the chronic phase of infarct healing in non-reperfused patients (Group II) and in patients with unsuccessful thrombolytic therapy (Group III). The morphometric methodology makes it impossible to demonstrate time dependent relationships between the infarct-related artery stenosis and the change in the density of the capillary network. Thus, it is difficult to explain whether the less prominent reduction in the capillary density observed in patients with patent though severely stenosed IRA was associated with preservation of the original vascular bed or proliferation of newly formed capillaries following coronary reperfusion. The effect of IRA reopening is still debated, the benefits demonstrated in previous studies have not been proved unequivocally in clinical practice [9-12,21]. While some authors reported a significant improvement in the LV function following coronary angioplasty performed several days or even weeks after MI others demonstrated no beneficial effects or an even worse outcome, related to a high rate of peri-procedural complications that might offset potential benefits [33-37].

Another important point is the selection of capillaries during quantification—almost round in shape with clearly visible lumen inside. This assumption enabled us to quantify the density of the capillary network and to eliminate positively stained CD34 lymphocytes and monocytes. The exact number of capillaries may, however, be slightly higher, as we did not quantify any immature, newly formed CD34 positive capillaries.

In conclusion, we have demonstrated that the deleterious effect of chronic IRA occlusion is associated with an almost 60% reduction in capillary density. This reduction in capillary density was associated with more extensive myocytolysis of hypertrophied myocytes, subsequent fibrosis and resulted in larger infarct size. These observations suggest that IRA patency as a significant determinant of the density of the capillary network is one of the major factors influencing infarct size, cardiac remodelling and formation of an aneurysm.


   Acknowledgment
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistics
 4. Results
 5. Discussion
 6. Limitations of the...
 Acknowledgment
References
 
We thank Stanislaw Paradowski, MSc, for statistical work.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistics
 4. Results
 5. Discussion
 6. Limitations of the...
 Acknowledgment
 References
 

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K. M. Marques, P. Knaapen, R. Boellaard, N. Westerhof, A. A. Lammertsma, C. A. Visser, and F. C. Visser
Hyperaemic microvascular resistance is not increased in viable myocardium after chronic myocardial infarction
Eur. Heart J., October 1, 2007; 28(19): 2320 - 2325.
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