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Cardiothoracic Sciences Centre, All India Institute of Medical Sciences, New Delhi, India
Accepted for publication October 14, 2008.
* Address correspondence to Dr Chowdhury, All India Institute of Medical Sciences, Department of Cardiothoracic Surgery, New Delhi, 110029, India (Email: ujjwalchow{at}rediffmail.com).
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentFootnotesAcknowledgmentsReferences |
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Methods: Operatively excised full-thickness PA tissue from 150 consecutive patients (mean age, 90.8 ± 62.8 months; range, 6 months to 47 years) undergoing primary or second-stage procedures for different cyanotic CHDs were studied by light microscopy. The controls were 43 patients (23.8%) with normally developed central PAs and normal wall histology.
Results: The incidence of elastic fragmentation, increased ground substance, smooth muscle disarray, intimal thickening, and fibrosis was 61.3%, 36.6%, 34.6%, 39.3%, and 42% respectively. The risk of inadequate PA growth was 174.8, 64.7, and 45.5 times higher in patients with muscle disarray of the PA, abnormal lamellar count, and absence of palliative shunting procedures.
Conclusions: Almost all PA walls in shunted patients undergoing primary/second-stage procedures for cyanotic CHD indicate significant lamellar loss and intrinsic pulmonary arteriopathy. These changes are present in infancy, are more pronounced in patients with deep cyanosis, and may account for or may coexist with a higher incidence of PA hypoplasia and inadequate PA growth encountered in these patients.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentFootnotesAcknowledgmentsReferences |
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The normal PA media consists of layers of longitudinally arranged elastic lamellae interspersed with smooth muscle cells and collagen fibrils in a mucopolysaccharide ground substance. Each lamella and the adjacent zone containing the smooth muscle cells synthesize the connective tissue matrix and form a lamellar unit. Once the elastic lamellae reduplicate, there is a corresponding decrease and degeneration of elastic lamellae and partial replacement with collagen, resulting eventually in histologic changes such as elastic fragmentation, increased ground substance accumulation, smooth muscle disarray, medionecrosis, and fibrosis.
With this background, we conducted this study to:
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentFootnotesAcknowledgmentsReferences |
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Between January 2000 and December 2007, histopathologic analysis was done of PA wall specimens excised from 198 consecutive patients, of whom 109 underwent primary intracardiac repair for TOF and 89 had second-stage palliation after different types of systemic-to-PA shunts at our institution. The mean age was 90.8 ± 62.8 months (range, 6 months to 47 years) at the primary operation and 39.9 ± 21.95 months (range, 18 months to 8.3 years) at the second-stage operation. A total of 101 patients (67.3%) were aged younger than 3 years, and 30 (20%) were older than 12 years. The demographic and clinical characteristics of the study group are summarized in Table 1. Of these, 181 samples from 181 patients (111 boys) were found suitable for analysis, and 17 were excluded because of insufficient tissue material or because of morphologic artifacts resulting from inadequate fixation or poor orientation, or both.
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The criteria for candidate selection, the technical details of this novel modification, and the midterm results was addressed in our earlier publication (Fig 1A–F) [12].
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Of 181 patients with cyanotic congenital heart diseases undergoing definitive/staged surgical procedures, 43 (23.8%) had normally developed PAs and normal PA histology and qualified for the definition of control; 92 (50.8%) had hypoplastic PA trunk/central PAs and abnormal histopathology, and 15 (8.3%) had hypoplastic PAs and normal PA histology. In 31 (17.1%) patients, the PAs were normally developed but were histopathologically abnormal.
The size of the PA was normal in 43 patients (28.6%) and hypoplastic in 107 (71.4%). Despite "inadequate PA growth," 29 of these patients had to undergo a second-stage operation for reappearance of cyanosis with a progressive decrease in PaO 2 of 5 mm Hg or more, 24 had a progressive increase in hemoglobin concentration of 2 g/100 mL or more, and 5 had a rise in PA pressure.
Standard cardiopulmonary bypass and myocardial protection strategies were used in all patients. For patients with TOF, intracardiac repair was performed with a transright atrial, transpulmonary approach in 83 (72.8%) and a transright atrial approach in 31 (27.2%). In patients with TOF undergoing purely transatrial repair, a transverse pulmonary arteriotomy was done in the middle portion of the pulmonary trunk for purposes of a PA vent and for obtaining tissue for investigation.
The 43 patients with normally sized PAs did not require a transannular patch or pulmonary arterioplasty. Patients with hypoplastic PAs with or without PA distortion underwent a biventricular repair or a superior cavopulmonary connection with pericardial patch pulmonary arterioplasty.
Distortion in the PA requiring correction at the time of second-stage surgery was present in 16 patients (19.5%). Shunt sizes were 4 mm in 10 patients and 5 mm in 6 patients. In these patients, narrowing and kinking occurred at the site of graft–PA anastomosis. In all, we disconnected the distal anastomosis and reconstructed the distorted PA using autologous pericardium. Five patients had a superior cavopulmonary connection to the reconstructed right PA.
A segment of full-thickness PA tissue (about 2 to 3 mm in width) was excised from the pulmonary arteriotomy site during second- or final-stage palliation as atraumatically as possible. The tissue samples were obtained from the portion of the central PA away from the site of insertion of the PA end of the prosthetic graft and underwent histopathologic evaluation by light microscopy.
Light Microscopy Evaluation
Each biopsy specimen was fixed in 10% buffered formalin solution at room temperature, embedded in paraffin block, and thin sections of 4 to 5 µm were taken. The slides were then stained with hematoxylin and eosin. Special stains like elastic Verhoeff van Gieson and Alcian blue periodic acid Schiff were used as and when indicated. The sections were examined with research light microscope (Nikon Optiphot, Japan, original magnification x100 or x200).
The histopathology slides were simultaneously evaluated by 2 independent observers and included six variables: (1) lamellar count, (2) loss or fragmentation of elastic lamellae, (3) increased ground substance accumulation, (4) smooth muscle disarray, (5) intimal thickening, and (6) fibrosis. The lesions were graded 1 to 3 according to the criteria modified from Schlatmann and Becker [13] and de Sa and colleagues [14].
A more detailed explanation of the terms used in this study can be found in the Appendix Definitions * [2, 7, 11–15].
Statistical Analysis
Statistical analysis was done using STATA 9.0 software (StataCorp, College Station, TX). Continuous and interval-related data are presented as means ± standard deviation. Categoric variables are expressed as frequency distribution and percentages. The difference in proportions was tested with the 
2 test.
The receiver operating characteristic curve (ROC) analysis was used to determine the cutoff value of the lamellar count, which will predictably separate normal from the abnormal considering PA hypoplasia/inadequate PA growth as the outcome. To quantify the predictive accuracy of the lamellar count, we used the area under the ROC (AUROC) curve with the 95% confidence interval (CI), sensitivity, specificity, and the likelihood ratio. The simple logistic regression, followed by backward stepwise multiple logistic regression analysis, was used to identify the independent risk factors associated with the pathologic features and PA hypoplasia. Statistical significance was set at p < 0.05.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsCommentFootnotesAcknowledgmentsReferences |
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The 142 survivors underwent clinical examination, electrocardiogram, and echocardiogram every 3 months. Follow-up was 100% complete (range, 1 to 96 months) and yielded 678.05 patient-years of data with a mean follow-up of 57.30 months ± 21.8 (range, 1 to 96 months). The actuarial survival at 96 months was 94.20% ± 0.01%. At their last follow-up, 137 patients (96.5%) were in New York Heart Association (NYHA) functional class I and II. Only 5 patients (3.5%) were taking diuretics and vasodilators late postoperatively and were in NYHA class III.
Histopathology and Risk Factor Analysis
Elastic fragmentation, increased ground substance, smooth muscle disarray, intimal thickening, and fibrosis were present in 92 (61.3%), 55 (36.6%), 52 (34.6%), 59 (39.3%), and 63 patients (42%), respectively (Appendix Table 1
*). Each of five histologic abnormalities was present in 31 of 150 patients (20.7%).
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Analysis of the ROC Curve
The mean lamellar count in this cohort with and without histologic abnormalities (control group) were 22.4 ± 7.6 (range, 12 to 50) and 37.7 ± 13.8 (range, 16 to 62), respectively, and the difference in lamellar count of both groups of patients was statistically significant (p < 0.001). A mean lamellar count of 22.4 ± 7.6 (range, 12 to 50) was always associated with PA hypoplasia and inadequate PA growth after systemic-to-PA shunting procedures (Table 3). Using a lamellar count of 30 as the optimal cutoff point for inadequate PA growth, the sensitivity was 83.2% and the specificity was 74.4%.
The AUROC analysis indicated that 82.2% (SE, 4.1%; 95% CI, 73% to 90%) of the time, the lamellar count values were lower for patients with PA hypoplasia and inadequate PA growth in patients undergoing primary or second-stage procedures after systemic-to-PA shunts, which is highly significant (p < .001; Fig 6).
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentFootnotesAcknowledgmentsReferences |
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The principal findings of this investigation include:
In our study, elastic fragmentation with disruption of elastic lamellae and fibrosis seemed to occur in greater proportion across all age groups compared with changes like smooth muscle disarray and intimal thickening. Another important finding of this investigation is the close interrelationship between lamellar loss and the appearance of histopathologic changes. A mean lamellar count of 22.4 ± 7.6 was always associated with a histologically abnormal PA and hypoplastic or atretic PA. The nonshunted PAs were at 9.9 times higher risk of elastic fragmentation compared with the shunted PAs. Thus, this study revealed earlier and more frequent occurrence of histopathologic changes in a subset of cyanotic patients undergoing corrective procedures (Table 2).
Despite a functioning systemic-to-PA shunt and normal origin of the PAs without bifurcation stenosis, 35.3% of shunted patients did not achieve adequate PA growth commensurable to body weight at the time of the second-stage operation, and many patients with a previous shunt had abnormal histology. These patients underwent second-stage operations because of unsatisfactory palliation or rising PA pressure.
Elastic fragmentation, increased ground substance accumulation, muscle disarray, intimal thickening, and fibrosis was present in 43.9%, 39.3%, 31.8%, 30.3%, and 27.3% of patients with previous palliative shunts, respectively (Appendix Table 1 *). In addition, this subset of patients exhibited an abnormally low lamellar count of 22.4 ± 7.6 (range, 12 to 48) and required pulmonary arterioplasty using pericardial patch at the time of the second-stage intracardiac repair.
Because late presentation of congenital heart disease is not unusual in developing countries, it is not uncommon to be faced with the grown-up patients with cyanotic congenital heart disease with or without previous palliation. They are more cyanotic and polycythemic and are indeed a different subset from those encountered in industrialized countries. Only 48 patients (58.5%) in this series undergoing second-stage operations were between 18 months and 3 years of age. Although our setting is a tertiary care center, the socioeconomic profile of the patients and the lack of a health care insurance benefit led to delayed referral and operations, accounting for the higher age of the patients.
The reported incidence of PA distortion varies considerably, ranging from 0% to 33% in patients with a modified Blalock-Taussig shunt [1–3]. When observed in our patients, the distortion was centrally located and was easily repaired at the second-stage operation. We divided the shunt in all patients undergoing a second-stage operation to facilitate the subsequent PA mobilization and avoid late PA distortion and vascular ring formation.
It is noteworthy that despite normal PA histology, 15 patients (10%) had hypoplastic PAs. All these patients were aged younger than 3 years and were not shunted. One can speculate that the structural maldevelopment of these 15 patients may simply be secondary to flow restriction because of intracardiac anatomy and not abnormal histopathology. Logistic regression analysis demonstrated a relationship between PA hypoplasia/inadequate PA growth and patients aged younger than 36 months, patients with SaO2 less than 80%, MAPCAs, absence of systemic-to-PA shunts, muscle disarray, and abnormal lamellar count (Table 3).
The predictive accuracy of logistic regression model on PA hypoplasia, as assessed by AUROC curve, was 98.8% (Fig 5). Furthermore, the presence of abnormal lamellar count, muscle disarray, systemic arterial desaturation, and MAPCAs were associated with 64.7, 174.8, 20.2, and 10.3 times higher risk of PA hypoplasia/inadequate PA growth compared with normal PAs (Table 3).
Thus, our study showed a statistically significant interrelationship between lamellar loss and the appearance of histopathologic changes in the PA wall in patients with cyanotic congenital heart diseases. These histopathologic abnormalities possibly reduce the cohesive and tensile strength of the media and suggest an important causative mechanism for pulmonary trunk/branch hypoplasia.
Study Limitations
The principal limitation of this study is that we examined histologically only a small segment of PA wall from the pulmonary trunk, PA confluence, or central intrapericardial PAs. With the current techniques to assess degenerative changes, a prohibitively high number of samples are required to determine the extent of this problem and its correlation with various clinical entities. Second, the population considered in this study is highly heterogeneous and the number of patients in each subgroup is small. Third, it remains uncertain whether these medial abnormalities in the central PAs, even in infants and young children, are inherent or acquired. Finally, whether the loss of elastin is an expression of a hitherto unrecognized genetic defect involving the cellular function or apoptosis remains uncertain.
Larger scale clinical studies of the PA commencing in infancy are required and may shed further light on the risk stratification for PA size abnormalities and the rate of its progression.
Clinical Implications
The present study indicates significant loss of lamellar units and preponderance of degenerative changes in the PA tissue of a subset of patients with cyanotic congenital heart diseases. These changes are present in infancy and may be the causative factors for PA hypoplasia and atresia. These changes may also explain the reasons for inadequate PA growth despite a functioning systemic-to-PA shunt.
Conclusions
In light of these observations, our study suggests the existence of an abnormally low lamellar count and intrinsic pulmonary arteriopathy in a subset of patients with cyanotic congenital cardiac malformations who are less able to respond to the pulsatile flow.
Similar histopathologic changes, ranging from elastic lamellar fragmentation, increased ground substance accumulation, and muscle disarray to fibrosis, have been observed in a subset of shunted cyanotic patients. These changes may impose limitations on their ability to grow despite a functioning shunt or an antegrade PA blood flow, or both. There could be a critical deficiency of the elastic lamellae beyond which even an ideal shunt or antegrade blood flow may not promote adequate growth.
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Appendix |
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Modified Blalock-Taussig Shunt
The shunt was considered a modified Blalock-Taussig shunt if an expanded polytetrafluoroethylene graft was interposed between the subclavian and pulmonary arteries (PAs). All patients in whom shunts were placed between the brachiocephalic artery and the PAs are included within this definition [12].
The Modification of the Modified Blalock-Taussig Shunt (Ujjwal Kumar Chowdhury Shunt)
The systemic-to-PA shunt was considered to have been further modified when the proximal end of the polytetrafluoroethylene conduit was anastomosed to the aortic arch or its branches other than the subclavian or brachiocephalic artery or proximal right descending thoracic aorta, and the distal end was anastomosed intrapericardially to the pulmonary trunk or pulmonary bifurcation as opposed to the right or left PA [12].
The group studied included all patients in whom we modified still further the placement of the prosthetic graft as stated above. We also included 3 patients in whom the transected nondominant end of a double aortic arch was used for the systemic-to-PA connection. Patients undergoing "conventional central aortopulmonary shunting procedures" including those proposed by Waterston, Cooley, Potts, Gazanigga, Amato, and Mee are not included in this definition [12].
Disproportionately Small Right and Left Subclavian Arteries
How small is too small? It is usually the length of the PA to which the shunt is being anastomosed, which limits the size of graft that can be implanted when constructing a modified Blalock-Taussig shunt. This is particularly true on the side of the aortic arch, where one can extend the anastomosis onto the origin of the subclavian artery from the arch, and distally for considerable distance [12].
Hypoplastic Pulmonary Artery
The PA diameters were estimated by echocardiography, angiocardiography, and also at operation. The PAs were considered as hypoplastic and inadequate for complete biventricular or functionally univentricular repair in the presence of one or more of the following:
The Z-value was taken into consideration for assessment of the main pulmonary trunk and the McGoon ratio and the Nakata index were used for measurement of central branch PAs. Because the patients in this study are a heterogenous group from the standpoint of anatomic diagnosis, the above criteria were used on an individualized basis.
Inadequate Pulmonary Artery Growth
Despite an adequate antegrade PA flow or an adequately sized, functioning shunt with normal PA bifurcation without stenosis, or both, if the PAs continue to remain hypoplastic, according to the above-mentioned criteria at the time of the second-stage operation, they were assigned as inadequately grown.
Pulmonary Artery Distortion
Distortion of the PA after systemic-to-PA shunts was considered as mild if there was deformity or luminal narrowing of approximately 25%. Severe PA distortion was defined as stenosis greater than 50% or shunt-related isolation of the right or left PA.
Shunt Patency and Adequacy of Palliation
We used strict criteria suggested by Bove and coworkers [2]. Criterions for unsatisfactory palliation were complete occlusion, reappearance of cyanosis with progressive decrease in arterial oxygen tension of 5 mm Hg or more, progressive increase in hemoglobin concentration of 2 g% or more, need for a second shunt, or complete nonelective repair. For purposes of statistical analysis, the length of satisfactory palliation for any given shunt was determined as that point of time when (1) the shunt "failed" as defined above, (2) the shunt was electively taken down due to rising PA pressure, or at second-stage repair despite adequate palliation.
Aortic Root Dilatation
Age, height, body weight, and sex are known to be the determinants of aortic root dimensions in the normal heart. Therefore, we used the standard normogram for aortic root size at the sinotubular junction adopted from Roman and associates [16], indexed to body surface area and age. Aortic root dilatation was defined as the ratio of observed to expected aortic root diameter exceeding 1.5 [11].
Apoptosis
Apoptosis was defined as a form of programmed cell death and has been recognized as a central feature of fundamental biologic processes, including embryonic morphogenesis, remodelling of mature tissues, and cell replacement in certain adult tissues such as the thymus. In contrast to necrosis, apoptosis occurs in isolated cells without any accompanying cellular reaction.
Elastic Fragmentation
Elastic fragmentation was defined as focal fragmentation of elastic lamellae in the PA media. At any age, in an otherwise normal PA, the elastic tissue is not a continuous plate as it is in the aorta, even though it is easy to recognize the units composed of parallel elastic fibers, with smooth muscle cells, collagen and ground substance in between. In grade 1, there was a small area with fragmented elastic tissue and the smooth muscle cells did not show significant change in the orientation. In grade 2, between one-third and one-half of the medial thickness of the pulmonary artery were unusually fragmented, with the black point aspect of the elastic tissue or loss of parallelism of the lamellar components, or both. It was also associated with focal changes in orientation of the smooth muscle cells. In grade 3, the elastin lamellae were severely fragmented, with the black point aspect spread in the media thickness, and the identification of the lamellar unit was not possible because of the severe disorganization of the media [13, 14].
Accumulation of Ground Substance
The ground substance is a hydrated gel composed of glycosaminoglycans, proteoglycans, and adhesive glycoproteins in which elastic fibers and collagen are embedded. Accumulation of ground substance was characterized by a noninflammatory loss of smooth muscle cells in the presence of intact elastic lamellae and fragmented elastic fibers. There was mucoid degeneration with no identifiable cystic wall.
In grade 1, there was mild fragmentation of elastic fibers with mild increase in ground substance and little or no change in smooth muscle. In grade 2, there was widespread fragmentation of elastic fibers, further increase in ground substance, and widespread loss of smooth muscle. In grade 3, there were large areas of complete loss of elastic fibers and smooth muscle, and large areas of ground substance accumulation [13, 14].
Smooth Muscle Disarray (Changes in Smooth Muscle Orientation)
Three grades were recognized: grade 1—smooth muscle disarray involving less than one-third of the thickness of the media; grade 2—smooth muscle disarray involving one-third to one-half of the thickness of the media; grade 3—large area of smooth muscle disarray involving more than one-half of media thickness, associated with elastic fragmentation [13, 14].
Intimal Thickening
Intimal thickening was characterized by hyperplasia of elastic tissue and smooth muscle cells. Elastic tissue hyperplasia, smooth muscle disorientation, and fibrous replacement are evolutionary phases of this lesion. The severity of intimal thickening was graded as mild (1 to 2 mm), moderate (2 to 5 mm), and severe (>5 mm).
Fibrosis
Fibrosis was defined as an increase in interstitial collagen. Three grades were recognized.
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Acknowledgments |
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TopAbstractIntroductionPatients and MethodsResultsCommentFootnotesAcknowledgmentsReferences |
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Footnotes |
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TopAbstractIntroductionPatients and MethodsResultsCommentFootnotesAcknowledgmentsReferences |
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References |
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TopAbstractIntroductionPatients and MethodsResultsCommentFootnotesAcknowledgmentsReferences |
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