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J Thorac Cardiovasc Surg 2003;126:1026-1032
© 2003 The American Association for Thoracic Surgery

Surgery for congenital heart disease

Left ventricular remodeling in hearts with tricuspid atresia: morphologic observations and possible basis for ventricular dysfunction after surgery

Maria Angelica Binotto, MDa,*, Maria de Lourdes Higuchi, MDb, Vera Demarchi Aiello, MDb

a Department of Pediatric Cardiology and Adult Congenital Heart Disease, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil
b Laboratory of Pathology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil

Received for publication September 23, 2002; revisions received November 13, 2002; accepted for publication December 2, 2002.

* Address for reprints: Maria Angelica Binotto, MD, Heart Institute (InCor), University of São Paulo Medical School, Pediatric Cardiology, Av. Higienopolis, 1048/86, São Paulo 01238-000, Brazil
conangelica{at}incor.usp.br


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: This study was undertaken to assess the pattern of left ventricular hypertrophy, the myocardial capillary network, and the extracellular matrix in hearts with tricuspid atresia.

METHODS: We examined 32 hearts with tricuspid atresia and 27 normal hearts from control subjects with similar age and sex distribution. Wall thickness, inlet length, and outlet length were obtained from the left ventricle. Immunohistochemical staining for von Willebrand factor was used to label myocardial capillaries. By means of computer-assisted morphometry, the following data were obtained from the inlet, apex, and outlet of the left ventricle: transverse myocyte diameter, myocyte nuclear volume fraction, capillary volume fraction, interstitial fibrous volume fraction, and endocardial thickness.

RESULTS: The wall thickness in affected hearts was not different from that in control hearts. The left ventricular outlet length was significantly greater in the malformed hearts (P = .005). The myocyte diameter did not differ from that in control hearts. The capillary volume fraction was decreased in the malformed hearts (P < .001). The interstitial fibrous deposition was greater in the malformed hearts at all sites analyzed (P < .001). Fibrosis was greater in the inlet and apex (P = .004) and also in the subendocardial half of the ventricular wall than in the subepicardial half. According to a logistic regression model, age was the only variable associated with the probability of occurrence of fibrosis.

CONCLUSIONS: Our findings in hearts with tricuspid atresia possibly represent chronically induced volume overload in the presence of ischemia, rather than a typical model of volume overload. A decreased capillary volume fraction may indicate a greater susceptibility to ischemia. Fibrous deposition probably occurs early in life.

The application of the Fontan principle has improved survival and functional capacity for patients with univentricular atrioventricular connections. However, most centers have documented ongoing morbidity and mortality after surgery.1,2 Abnormal ventricular function, both systolic and diastolic, is clearly related to the late outcome. Myocardial hypertrophy is certainly recognized as a risk factor for the Fontan procedure.3 The systemic ventricle is chronically volume overloaded and subjected to longstanding hypoxemia and variable degrees of pressure overload, factors implicated in the myocardial remodeling process. In addition, the myocardium may be intrinsically abnormal, as has been suggested by Ho and colleagues4 and, more recently, by Sanchez-Quintana and coworkers.5 In addition to the pathologic remodeling, expansion of cardiac mass during postnatal physiologic growth also takes place.

Few studies have addressed ventricular remodeling in hearts with univentricular atrioventricular connections.4-6 The purpose of this study was to analyze several aspects of the ventricular remodeling in hearts with tricuspid atresia, including myocardial hypertrophy, extracellular matrix deposition, and capillary network.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
We studied 32 hearts with tricuspid atresia, obtained at autopsy from the pathology laboratory collection of the Heart Institute, University of São Paulo Medical School. The control group comprised 27 structurally normal hearts from children aged 1 day to 6 years who had died of non–cardiovascular-related diseases. Age and sex distributions were similar for the two groups (study group age 9.6 ± 13.9 months, median 2.5 months, 19 male and 13 female infants; control group age 9.6 ± 17.4 months, median 3 months, 15 male and 12 female infants). The specimens were inspected after a sequential segmental analysis. The following measurements were obtained from the left ventricle (LV): thickness of the free wall at the inlet (the level of the superior edge of the papillary muscles) and at the outlet (the same plane relative to the apex-base axis), inlet and outlet lengths (an estimation of cavity size), arterial valve diameters, and the major diameter of the ventricular septal defect (VSD). The VSD was considered restrictive when its major diameter was smaller than that of the arterial valve emerging from the rudimentary right ventricle. Transmural blocks of tissue were taken from the LV wall at the sites used for the measurements of wall thickness in the inlet and outlet and also from the apex of the LV. The tissue was processed routinely for histologic examination, and 5-µm sections were stained with hematoxylin and eosin and Masson trichrome stain. Histologic sections and staining considered to be technically inadequate were excluded from the analysis.

Morphometric analysis
Myocyte transverse diameter
The morphometric measurements were carried out with an interactive computer-assisted image analyzer (Leica Quantimet; Leica Cambridge Ltd, United Kingdom).7 To avoid interobserver variation, a single investigator operated the analyzer.

The myocyte transverse diameter was measured at the level of the nucleus in the mesocardial layer of the ventricular wall, irrespective of the orientation of the section. Final magnification was x400.

In a pilot study, the evolution of the mean values and variance was analyzed to determine the number of measurements required. The mean values of myocyte diameter in 20, 40, 60, 80, 100, 120, 140, 180, and 200 observations were obtained. We opted to measure 60 myocytes per section.

Capillary volume fraction
Immunohistochemical staining for von Willebrand factor was used to label myocardial capillary endothelial cells. The stained inlet LV sections containing circumferentially oriented capillaries were imaged at a final magnification of x1000. For each section 30 random fields 11,456 µm2 in area were analyzed. With computer-assisted morphometry and an interposed grid of 598 points, incident points on myocardial capillaries were counted. The proportion of the points lying over the structure of interest over the number of points in the grid was used as a measure of the volume fraction, or volume density, of myocardium occupied by that structure.8

Nuclear volume fraction
With the same system described previously and an interposed grid of 598 points, incident points on myocyte nuclei were counted in sections of the LV inlet stained with hematoxylin and eosin. For each section 25 random fields were analyzed at the mesocardial layer of the ventricular wall.

Quantification of fibrous tissue
Fibrous content in the interstitial space was estimated by analyzing at least 10 microscopic fields in the subendocardial and subepicardial halves of the ventricular wall at a magnification of x400 (final resolution of 0.48 µm/pixel). Star-shaped scars and concentric perivascular fibrous tissue were excluded from the analysis. The interstitial fibrous volume fraction (IFVF) was expressed as a percentage of the myocardial area. Microscars were described qualitatively.

Endocardial thickness
Linear measurements of the endocardial thickness were obtained in histologic sections stained with hematoxylin-eosin from the inlet, apex, and outlet of the LV. A mean value was obtained from 10 measurements at each site.

Statistical analysis
Values are given as means, SDs, and medians. Unpaired Student t tests or Mann-Whitney tests as appropriate were used to compare values between control and study groups. Comparisons between subendocardial and subepicardial regions were done with the Wilcoxon test. The Friedman test was carried out for multiple comparisons, followed by the Tukey procedure as modified by Nemenyi. Correlation coefficients were obtained by the Spearman method. Logistic regression was used to identify independent predictors of the occurrence of fibrosis. Data were analyzed with SigmaStat 2.0 software (SPSS Inc, Chicago, Ill).


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Heart specimens
The atrial arrangement was usual in all specimens. The ventriculoarterial connection was concordant in 20 hearts and discordant in 10. One of the remaining specimens showed a common arterial trunk emerging from the dominant LV, and another showed a double outlet from the LV. Twenty specimens showed signs of previous surgical intervention. Of these, 9 had a modified Blalock-Taussig shunt; 5 of them showed pulmonary artery banding, 3 with aortic coarctation repair. Of the remaining specimens, 5 had a Fontan-Kreutzer procedure (1 preceded by a modified Blalock-Taussig shunt and another by pulmonary artery banding) and 1 had undergone a Damus-Kaye-Stansel procedure associated with a bidirectional Glenn anastomosis. Death had occurred between 1 day and 2 years after surgery (median 15 days); 14 of the patients had died within the first postoperative month. Additional data are shown in Table 1.


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  		TABLE 1. Characteristics of patients

 
LV hypertrophy
The inlet and outlet wall thicknesses were not different from those in control hearts (Table 2). The LV outlet length was significantly greater in the malformed hearts (95% confidence interval for difference of means 0.19-1.01; P = .005 by t test). On microscopy, the myocyte transverse diameter did not differ from the controls in any of the sites analyzed (95% confidence intervals for difference of means -2.1 to 1.18 for inlet, -2.29 to 0.95 for apex, and -1.37 to 1.53 for outlet, respectively; Table 3). There was no difference when comparing inlet, apex, and outlet of the LV (P = .38 by Friedman test). In addition, the myocyte nuclear volume fraction was significantly smaller in the malformed hearts (median value 2.4% vs 4.4%, P < .001 by Mann-Whitney test).


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  		TABLE 2. Gross measurements from the inlet and outlet of the LV, comparing hearts with tricuspid atresia and control hearts

 

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  		TABLE 3. Myocyte diameter, interstitial fibrosis and endocardial thickness in the inlet, apex, and outlet of the LV in control hearts and those with tricuspid atresia

 
Capillary volume fraction
The myocardial capillary volume fraction was significantly smaller in hearts with tricuspid atresia than in normal control hearts (median value 6.8% vs 8.1%, P = .01 by Mann-Whitney test).

Interstitial fibrosis
The IFVF was significantly greater in the malformed hearts at all three sites examined (Table 3 and Figure 1, A). The LV inlet and apex were more fibrotic than the outlet in the malformed hearts but not in the control group (P = .004 by Friedman test). In addition, the IFVF was greater in the subendocardial halves of the ventricular wall in the inlet and apex of hearts with tricuspid atresia but not the control hearts (P = .002 and P = .01, respectively, by Wilcoxon test Figure 2).



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  		Figure 1. Photomicrographs of LV myocardium from child with tricuspid atresia (original magnification x20, Masson trichrome stain). A, Diffuse interstitial fibrosis stained in blue. B, Star-shaped scar stained in blue.

 


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  		Figure 2. Box and whisker plots comparing IFVF in subendocardial and subepicardial halves of LV wall of hearts with tricuspid atresia in three sites analyzed. Boxes represent median, upper, and lower quartiles. P values are .002, .01, and .09, respectively, for comparisons in inlet, apex, and outlet of LV.

 
There was a weak but significant positive correlation between IFVF and the age of the patients in the study group (rs = 0.50, P = .006) but not the control group (rs = .16, P = . 45).

The multivariate logistic regression model suggested that age was the only variable associated with an increased probability of occurrence of fibrosis, defined as IFVF greater than 3%. The other variables included in the model (type of ventriculoarterial connection, the presence of a restrictive VSD, presence of aortic coarctation or interruption, decreased pulmonary blood flow physiology, and previous surgery) were not independent predictors of occurrence of fibrosis in the multivariate model. In fact, children older than 3 months had an 8.3 times greater probability of occurrence of fibrosis than had a younger population (odds ratio 95% confidence interval 1.47-47.22, sensitivity 71.4%, specificity 76.9%; Figure 3).



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  		Figure 3. Estimated probability of occurrence of fibrosis in relation to age of patients.

 
Myocardial microscars
Myocardial microscars (Figure 1, B) were present in 7 specimens from patients aged 27 days through 50 months (median 4 months). Five were apical and 4 were restricted to the subendocardial half of the ventricular wall.

Endocardial thickness
LV endocardial thickness was greater at the inlet and apex of the malformed hearts than in the control hearts (Table 3).

Type of ventriculoarterial connection
The age at death was similar between the two groups (concordant 3 days to 34 months, median 3.0 months; discordant 6 days to 50 months, median 2.3 months). There was no difference when comparisons were made between hearts with concordant and discordant ventriculoarterial connections to address the following variables: inlet wall thickness (P = .09 by t test), inlet length (P = .5 by t test), transverse myocyte diameter (P = .24 by t test); IFVF (P = .19 by Mann-Whitney test), and endocardial thickness (P = .76 by t test).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The LV of the heart with tricuspid atresia plays a crucial role because it functions as the only pumping chamber. Few studies have addressed the myocardial structure of malformed hearts, particularly in univentricular atrioventricular connections.

LV hypertrophy
In our study the LVs of the malformed hearts were dilated, without a relative increase in the wall thickness corresponding to eccentric hypertrophy, as would be expected in situations where there is predominantly volume overload. These findings are in accordance with those described by others6 in hearts with pulmonary atresia with intact ventricular septum, suggesting that the ratio of LV mass to end-diastolic volume may be inadequate in univentricular hearts. We did not find specimens in our material with excessive wall thickness, as demonstrated in an autopsy series of patients who died after the Fontan procedure9 and also in a clinical setting.10 This diversity in results is likely to be related to the young age of death of the patients included in our study, most younger than 1 year, and the relative paucity of cases with discordant ventriculoarterial connection in association with a restrictive VSD and subaortic stenosis, in which setting conspicuous ventricular hypertrophy is more frequent.

During the adaptive phase of elevated diastolic wall stress in volume overloads, the ratio of wall thickness to chamber radius remains constant as a result of proportional growth in the transverse and longitudinal dimensions of the myocyte. After the progression toward decompensation, there is a disproportionate lengthening of the myocytes and a dilated, thin-walled ventricular chamber.11 In this study the myocyte transverse diameter in the affected hearts did not differ from that in the control hearts. Although the longitudinal dimension could not be obtained, it is likely that these patients were in the maladaptive phase of eccentric hypertrophy before death.

Experimental data have indicated that the myocyte nuclear volume increases with cellular hypertrophy.12 In addition, previous studies have demonstrated that human myocytes are prevalently mononucleated.13 The myocyte nuclear volume fraction could therefore be viewed as an index of hypertrophy and of cell number in a given area of the histologic section. The decreased nuclear volume fraction found in hearts with tricuspid atresia relative to normal control hearts is in agreement with a predominantly longitudinal growth of the myocytes (eccentric hypertrophy). However, we could not establish a parallel to the hypertrophic process, either because one does not exist or because of the relatively small number of cases analyzed.

Coronary capillaries
The myocardial capillary network expands proportionally during physiologic growth14 but may be inadequate under conditions of hemodynamic overload, increasing the potential for ischemic damage in cardiac hypertrophy. Evidence from animal and human studies indicates that capillary growth in pressure overload hypertrophy does not fully compensate for the increase in ventricular mass,15 although limited capillary growth may occur in young patients16 and during adaptation to a prolonged pressure overload.17 In contrast, several experimental studies in volume overload models suggest that the adaptation of the myocardial capillary network is proportional to the degree of hypertrophy.18 Experimental data on the myocardial capillary supply adaptation in response to hypoxia are controversial.15 Yet hypoxia is considered to be an effective stimulus for growth of endothelial cells.15 The finding of a decreased capillary volume fraction in our cases might indicate a greater vulnerability of these hearts to ischemia.

Extracellular matrix
Hearts with tricuspid atresia showed a higher proportion of fibrous tissue than normal since the first weeks of life, showing a positive correlation with increasing age. The multivariate logistic regression model indicated that infants older than 3 months had an 8.3 times greater probability of occurrence of fibrosis than had younger infants, supporting the view that the myocardium may be inherently abnormal.4,5

It has been well documented that pressure overload cardiac hypertrophy is accompanied by an increased accumulation of collagen in the myocardium.19,20 Fibrosis of the heart accompanies chronic elevations in circulating effector hormones of the renin-angiotensin-aldosterone system, when heart failure or unilateral renal artery stenosis impairs renal perfusion.20 In contrast, most of the published experimental data have indicated that interstitial collagen accumulation does not change in response to induced volume overload.21,22

Much attention is currently focused on the role of apoptosis in the pathogenesis of cardiac disease. Apoptosis has been implicated in a wide range of models, such as ischemia and myocardial infarction, pressure overload hypertrophy, cardiac rejection, and dilated cardiomyopathy.23 It may be a contributing phenomenon in the pathologic remodeling in hearts with tricuspid atresia.

The morphometric method permitted the discrimination of the fibrous deposition across the ventricular wall. Hoyt and colleagues7 compared the quantification of collagen in histologic sections stained with Masson trichrome, performed with a computer-assisted method similar to ours, with those obtained from a hydroxyproline assay. The percentage of collagen from analysis of histologic sections strongly correlated with the hydroxyproline level, with excellent intraobserver and interobserver concordance. Results were unaffected by variations in histochemical staining.

Our study showed a greater deposition of fibrous tissue in the subendocardial half of the LV wall, following the pattern found in concentric hypertrophy,24 dilated cardiomyopathy,25 and ventricular remodeling after myocardial infarction.26 This finding is not in agreement with observations by Ho and colleagues4 in hearts with tricuspid atresia. Experimental studies of physiologic growth have demonstrated a relatively lower capillary luminal volume in the subendocardial layer, indicating a greater vulnerability of this region to ischemic injury.27 In addition, the myocardial tissue pressure and oxygen demands are greater in the subendocardial portion of the wall. Thus the disturbance of oxygen supply and demand may result in chronic tissue injury and subendocardial fibrosis.

This analysis demonstrated regional variations in the fibrous deposition, with the LV inlet and apex being more fibrotic than the outlet in malformed hearts. This finding could explain, at least in part, regional ventricular wall motion abnormalities found in patients with univentricular hearts before and after stages of Fontan reconstruction.28,29

The comparison according to the type of ventriculoarterial connections did not show any significant difference in the content of fibrous tissue. This finding is in conformity with data published by Ho and colleagues,4 possibly reflecting the dominant role of the LV.

The functional consequences of collagen remodeling have been extensively demonstrated.30 It seems clear that both systolic and diastolic properties may be affected. Clinical trials with pharmacologic interventions directed toward collagen remodeling in such malformed hearts should be addressed in future studies.

Conclusion
On the whole, our findings in hearts with tricuspid atresia are more likely to represent a chronically induced volume overload in the presence of ischemia than to represent a typical model of volume overload. Moreover, the pathologic insult occurs in parallel with the expansion of cardiac mass in a growing child. What remains to be clarified is why the capillary network seems not to develop properly in the presence of a strong potential stimulus for angiogenesis (hypoxia).


   Acknowledgments
 
We thank Ms Creusa Maria Roveri dal Bó for assistance with statistical analysis and Professor Antonio Augusto Barbosa Lopes for his valuable suggestions.


   Footnotes
 
Supported by the Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP), grant 98/07636-6.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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