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J Thorac Cardiovasc Surg 2008;135:69-77
© 2008 The American Association for Thoracic Surgery
Surgery for Congenital Heart Disease |
a Department of Cardiothoracic Surgery, All India Institute of Medical Sciences, New Delhi, India
b Department of Cardiac Pathology, All India Institute of Medical Sciences, New Delhi, India
c Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India.
Received for publication February 6, 2007; revisions received May 19, 2007; accepted for publication June 1, 2007. * Address for reprints: Dr. Ujjwal K. Chowdhury, Additional Professor, Department of Cardiothoracic and Vascular Surgery, All India Institute of Medical Sciences, New Delhi–110029, India. (Email: ujjwalchow{at}rediffmail.com; ujjwalchowdhury{at}gmail.com).
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Abstract |
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Methods: Operatively excised full-thickness aortic wall tissue from 98 consecutive patients undergoing intracardiac repair of tetralogy of Fallot aged 6 months to 47 years (mean 104.5 ± 102.8 months; median 72 months) were studied by light microscopy. The receiver operating characteristic curve analysis was done to quantify the diagnostic accuracy of loss of lamellar counts and multiple logistic regression models.
Results: Twenty-five (25.5%) aortic tissue specimens were indicated as histologically normal and were used as normal controls. The incidence of elastic fragmentation, increased ground substance, medionecrosis, smooth muscle disarray, and fibrosis was 74.5%, 54%, 39.8%, 26.5%, and 57.1%, respectively. A lamellar count of less than 60 was associated with a sensitivity of 80% and a specificity of 87.67%. Area under the receiver operating characteristic curve indicated that 93.37% (standard error ± 0.039) of the time the value of lamellar count was lower for the abnormal histopathology group than for the normal group (P < .001). The risk of aortic dilatation was 15.97 times higher in patients with histopathologically abnormal aorta.
Conclusions: The majority of aortic media of the ascending aorta in cyanotic tetralogy of Fallot indicates significant loss of lamellar units and pre-existing intrinsic aortopathy. The changes are present since infancy and are more pronounced in older patients subjected to long-standing cyanosis and volume overload and may account for or may coexist with the higher incidence of aortic dilatation encountered in these patients.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionsReferences |
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Dilatation of the aortic root with or without aortic regurgitation is a well-described feature in patients with tetralogy of Fallot (TOF) and pulmonary stenosis or pulmonary atresia.1-3
A subset of adult patients with TOF exhibit ongoing dilatation of the aortic root even after repair, necessitating aortic valve and aortic root surgery.1-7 It is hypothesized that a medial abnormality coupled with increased aortic blood flow might be the cause for aortic root dilatation in untreated patients.2-4,6,8-13 However, histopathologic or ultrastructural studies to lend credence to this hypothesis have been limited because of limited number of patients and restricted observations.1,7-13
This prospective study aims to (1) elucidate the histopathologic characteristics of the aortic wall in patients with TOF and to identify the relationship, if any, between the lamellar counts and appearance of histopathologic changes; (2) correlate any identifiable pathologic changes with known risk factors such as age at operation, previous systemic–pulmonary arterial shunting procedures, systemic arterial oxygen saturation, hematocrit, right ventricular end-diastolic pressure (RVEDP), degree of aortic override, and aortic regurgitation; (3) identify the histopathologic characteristics that may predispose patients to the higher risk of aortic dilatation seen in these patients; and finally (4) to evaluate the sensitivity, specificity, and predictive accuracy of a low lamellar count as a possible predictor of histopathologically abnormal aorta.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionsReferences |
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Age at correction was 6 months to 47 years (mean 104.5 ± 102.8 months; median 72 months), with 30.6% of patients (n = 30) being younger than 4 years of age and 20.4% (n = 20) being older than 12 years of age. Cardiac catheterization and angiocardiography were performed on all patients to confirm the diagnosis, to define coronary artery anatomy, and to identify major aortopulmonary collateral arteries (MAPCAs). The details of the patients are summarized in Table E1. In 65 (66.3%) patients, the aortic root was dilated. Dilatation was defined as the ratio of observed/expected aortic root diameter indexed to body surface area and age greater than 1.5.14 Thirteen (20%) of 65 patients had evidence of trivial to mild aortic regurgitation.
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Collection and Preparation of Tissues
Excised full-thickness aortic wall tissue during intracardiac repair was subjected to histopathologic evaluation by light microscopy.
Light Microscopic 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 Masson trichrome, 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; Nikon Corporation, Tokyo, Japan, magnification 40x, 100x, or 200x).
The histopathology slides were simultaneously evaluated by two independent observers and there was no interobserver disagreement on interpretation of the presence or absence of disease. The histologic evaluation of the aortic media included 6 variables: (1) lamellar count, (2) loss or fragmentation of elastic lamellae, (3) increased amount of ground substance, (4) medionecrosis, (5) smooth muscle disarray (changes in smooth muscle orientation), and (6) fibrosis. The lesions were graded 1 to 3 according to the criteria adapted from Schlatmann and Becker15 and from de Sa and associates16 (Table E2).
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Definitions
Aortic root dilatation
Age, height, body weight, and sex are known to be the determinants of aortic root dimensions in the normal heart.14,17 Therefore, we used the standard nomogram for aortic root size at the sinotubular junction adopted from Roman and associates,14 indexed to body surface area and age.5,16,17 Aortic root dilatation was defined as the ratio of observed/expected aortic root diameter greater than 1.5.
Apoptosis
Apoptosis is defined as a form of programmed cell death and has been recognized as a central feature of fundamental biological processes including embryonic morphogenesis, remodeling of mature tissues, and cell replacement in certain adult tissues, for example, the thymus. In contrast to necrosis, apoptosis occurs in isolated cells without any accompanying cellular reaction.18-20
Elastic fragmentation
Elastic fragmentation is defined as focal fragmentation of elastic lamellae in the aortic media. Three grades were recognized: grade 1, fewer than 5 foci of elastic lamellae, loss or fragmentation in one microscopic field, each focus comprising 2 to 4 neighboring elastic lamellae; grade 2, 5 to 9 foci of elastic lamellae fragmentation in one microscopic field; and grade 3, presence of 10 or more foci of elastic fragmentation in one microscopic field (Table E2).15,16
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.15,21 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.10,15,21
In grade 1, there were mild fragmentation of elastic fibers with mild increase in ground substance and little or no change in smooth muscle; in grade 2, there were widespread fragmentation of elastic fibers, further increase in ground substance, and widespread loss of smooth muscle; and in grade 3, there were large areas of complete loss of elastic fibers and smooth muscle and large areas of ground substance accumulation (Table E2).15,16
Medionecrosis
Medionecrosis is defined as a focal loss of smooth muscle nuclei in the media. Three grades were recognized (Table E2).
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; and grade 3, large area of smooth muscle disarray involving more than one half of media thickness, associated with elastic fragmentation (Table E2).
Fibrosis
Fibrosis is defined as an increase in interstitial collagen. Three grades were recognized (Table E2).
Statistical Methods and Analysis
Statistical analysis was carried out with Intercooled STATA 9.0 software (Stata, College Station, Tex). Interval-related data were expressed as mean ± standard deviation (SD) and categorical variables were expressed as percentages. The difference in proportions was tested with the 
2 test.
The receiver operating characteristic (ROC) curve analysis was done to determine the cutoff value of the lamellar count, which will predictably separate normal from the abnormal considering aortic dilatation as the outcome and taking histopathology as the gold standard. To quantify the predictive accuracy of the lamellar count, we analyzed the area under the ROC curve.
Aortic tissue specimens without histologic abnormalities were defined as normal and were used as normal controls. The simple logistic regression followed by forward stepwise multiple logistic regression analysis was used to identify the independent risk factors associated with the pathologic features and aortic dilatation. The predictive accuracy of the multiple logistic regression model was assessed using area under the ROC curve. The results were expressed as odds ratio (OR) and 95% confidence interval (CI) for each independent variable.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionsReferences |
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Follow-up
Survivors (n = 95) underwent clinical examination, electrocardiogram, and echocardiogram every 3 months. Follow-up was 100% complete (range 1-36 months) and yielded 191.03 patient-years of data with a mean follow-up time of 24.13 months (±SD 9.99; range 1-36 months). The actuarial survival at 36 months was 96.94% ± 0.01% (95% CI 0.90-0.99). At their last follow-up, 93 (97.9%) patients were in New York Heart Association functional classes I and II. Only 2 (2.1%) patients were receiving diuretics and vasodilators late postoperatively and were in New York Heart Association class III. Reoperation or reintervention was not required for any patient.
Echocardiographic Evaluation
The left ventricular function was normal (ejection fraction > 0.5) in 88 patients and depressed in 7 patients. Fifty-three (55.7%) patients had mild and 12 (12.6%) patients had moderate pulmonary regurgitation. Postoperatively, the mean indexed aortic diameter was 25.90 ± 10.21 mm/m2 (range 0–68 mm/m2; median 24.0 mm/m2). All patients (n = 65) with a preoperatively dilated aorta continued to have indexed aortic dimensions measuring between 24.80 and 32 mm. There was no progression of aortic dilatation or aortic regurgitation in these patients.
Histopathologic and Risk Factor Analysis
Twenty-five (25.5%) aortic tissue specimens were found to be histologically normal and were used as controls. These specimens exhibited layers of longitudinally arranged elastic lamellae interspersed with smooth muscle cells and collagen fibrils in a mucopolysaccharide ground substance (Figure E1, A and B).
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Relationship Between Aortic Root Dilatation and Histologic Abnormalities, Including Other Candidate Variables
Aortic diameter measured echocardiographically in our study showed significant dilatation in 66.3% (n = 65) of patients with TOF. To assess the risk factors related to aortic root dilatation in TOF, we took into consideration aorta with and without histologic abnormalities and other candidate variables. Aortic tissue specimens without histologic abnormalities (n = 25) were defined as normal and were used as the control group. It is noteworthy that of 65 patients with aortic root dilatation, 62 (95.4%) patients exhibited histologic abnormalities and 3 (4.6%) patients were histologically normal (Tables 1 and E3).
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Logistic regression analysis identified histopathologically abnormal aorta, elastic fragmentation, increased ground substance, male sex, degree of aortic override greater than 50%, and double-outlet right ventricle as the predictors for aortic dilatation in this study. The risk of aortic dilatation was 15.97 times higher (95% CI 3.07-83.15) in patients with histopathologically abnormal aorta. The predictive accuracy of the logistic regression model for aortic root dilatation was assessed by the area under the ROC curve, and the value in this cohort was 92.4% (Table 1, Figure 1).
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With a lamellar count of 60 as the optimal cutoff point for abnormal aortic histopathology in patients undergoing intracardiac repair of TOF, the sensitivity was 80% and the specificity was 87.67%. The predictive accuracy of a positive or negative result was 68.7% and 92.3%, respectively (Table 2).
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Figures E2, A, B
and E3, A to F).
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Muscle Disarray
Smooth muscle disarray of grade 3 severity was seen in 26.5% (n = 26) of aortic tissue specimens. All these patients showed grade 2 (n = 3) to grade 3 (n = 23) elastic fragmentation. Age older than 96 months and aortic override greater than 50% were independent risk factors for its development (Tables 3 and E4 and Figure E5, A to D).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionsReferences |
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However, these publications have not assessed the interrelationship of specific histopathologic findings with the potential influencing factors. The major findings of this study include the existence of histologically normal aorta in only 25.5% of aortic tissue specimens and the presence of several intrinsic degenerative pathologic characteristics of varying grades of severity. Other important findings are significant loss of lamellar counts and the prevalence of intrinsic histologic abnormalities of the aortic wall in patients as early as 6 months of age (Tables 1 to 3 and E3).
What Are the Potential Risk Factors Relating to Aortic Dilatation in TOF?
The literature documents up to 15% incidence of aortic root dilatation in patients undergoing intracardiac repair for TOF.1-7 The aortic root dilatation is often progressive, with development of aortic regurgitation necessitating aortic valve replacement or repair,1-7,12,13 and has been reported to occur in patients not treated surgically2,4,6 as well as late after repair in patients treated surgically.1-7,10,12,13
Four variables have been incriminated as the potentially influencing factors for aortic dilatation: (1) abnormal morphogenesis resulting in unequal division of the fetal truncus, favoring aorta, (2) volume overload implicit in the biventricular aorta, (3) aortic regurgitation that augments volume overload and introduces pulsatile flow facilitating dilatation, and (4) intrinsic medial degenerative changes.1-6,10-12 In patients with TOF treated surgically, the cause of aortic root dilatation is thought to be predominantly secondary to chronic hemodynamic stress from volume overload of the aorta.3,7,11-13
Aortic diameter measured echocardiographically in our study showed significant dilatation in 66.3% of patients with TOF. It is noteworthy that of these 65 patients with dilated aorta, 62 (95.4%) exhibited histologic abnormalities and 3 (4.6%) were histologically normal. Logistic regression analysis accounting for the effects of other variables demonstrated a relationship between aortic root dilatation and male sex, aortic override greater than 50%, presence of double-outlet right ventricle, elastic fragmentation, and increased ground substance. The predictive accuracy of logistic regression model on aortic root dilatation, as assessed by area under the ROC curve, was 92.4%. Furthermore, the presence of a histologically abnormal aorta was associated with 15.97 times (95% CI 3.07-83.15) higher risk of aortic dilatation as compared with normal aorta (Tables 1 and 2 and Figure 1).
In this study, there was a clear male predominance among patients with dilated aorta, even after indexing for body surface area and adapting for age from Roman and associates.14 Literature documents significantly greater aortic root size in healthy male compared with female patients.14,17 This was also the case in our patients with TOF undergoing repair. Aortic elasticity and distensibility are known to decline with age, especially among male patients.15,17 This may explain in part the male predominance among patients with aortic dilatation.
Histologic changes in the aortic media of patients with TOF resemble those observed in both bicuspid aortic valve disease and Marfan syndrome.15,16,21 Whether these changes result from a primary or intrinsic medial abnormality inherent in TOF itself or are secondary to the antecedent volume-overloaded aorta before repair remains unknown. Warnes and Child13 have postulated that a combination of intrinsic capacity for premature cellular injury or cell death and programmed stress-induced activation of tissue enzymes might be the causative factors for such apoptotic medial changes in TOF.18-20
Alternatively, there may be one or more cellular abnormalities of the aorta in patients with conotruncal abnormalities. During embryogenesis, occipital neural crest cells derived from cranial neural fold migrate into the cardiac outflow tract and participate in outflow tract septation.22,23 These neuroectodermal immigrants into the ascending aorta in patients with conotruncal abnormalities may influence medial degeneration and aortic dilatation.22,23 On the basis of these observations, Niwa and associates8-10 postulated that patients with TOF may harbor an aortic wall abnormality that reflects a common developmental fault that weakens and attenuates the aortic wall.
In this study, the presence of aortic root dilatation in early infancy and the occurrence of intrinsic aortopathy in patients as early as 6 months of age strongly suggest that intrinsic aortic wall abnormalities also play a causative role in aortic root dilatation, in addition to the effects of volume overloading and physiologic changes associated with ageing.
When Should Aortic Root Replacement Be Considered in Patients With Dilated Aortic Root? Should the Same Criteria Be Used as Are Used for Marfan Syndrome?
Published literature including our observations in this study do not provide any conclusive answer.1,3,6-8,10,12,13 However, if patients are reoperated on for aortic or pulmonary valve replacement, it would appear prudent to consider concomitant aortic root repair or replacement if the aortic root is more than 50 mm in diameter.8,10,24 There is no current consensus on which patients and at what stage of aortic root dilatation isolated aortic root surgery should be considered in the absence of other indications for operation. Nor there is any consensus on β-blocker administration for limiting aortic root dilatation in patients who underwent intracardiac repair.24
In this series, of 65 patients with dilated aorta, 13 (20%) patients had trivial to mild aortic regurgitation. None of them required aortic root repair/replacement at the time of intracardiac repair. These patients are being followed up with 2-dimensional and Doppler echocardiogram and magnetic resonance imaging for serial assessment of aortic root size and quantification of aortic regurgitation. To this point, none of them has aortic regurgitation or aortic root dilatation severe enough to necessitate aortic valve or aortic root surgery. In a Mayo Clinic series, the largest aortic root measured was 85 mm in diameter without dissection.7 On the other hand, literature documents 2 isolated reports of aortic dissection with aortic root diameter measuring 6.45 cm and 6.1 cm, respectively.25,26
Evaluation and Analyses of Risk Factors for Development of Histologic Abnormalities (Elastic Fragmentation, Accumulation of Ground Substance, Medionecrosis, Smooth Muscle Disarray, and Fibrosis) in the Aortic Wall of TOF
The normal aortic 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 (Figure E1, A and B). The parallel elastic lamellae are more numerous in the ascending aorta, usually 55 units, and decrease in number across the descending thoracic aorta.27 The media is not a static structure. The number of elastic lamellae is only 35 at birth; by adult life, it is 55.27 With increasing age, the elastic lamellae reduplicate and there is a corresponding decrease and degeneration of elastic lamellae and partial replacement with collagen, resulting eventually in the aforementioned histologic changes.
In our study, elastic fragmentation and fibrosis seemed to occur in greater proportion among patients with TOF across all age groups in comparison with changes like medionecrosis, which was more prevalent in patients undergoing previous palliative systemic–pulmonary arterial shunts, higher RVEDP, increased indexed aortic diameter, and the presence of MAPCAs (Table 3).
Another important finding of this investigation is the close interrelationship between lamellar loss and appearance of histopathologic changes. A mean lamellar count of 40.85 was always associated with a histologically abnormal aorta and aortic dilatation (OR = 7.46 [95% CI = 2.84-19.58]; P < .0001). A lamellar count of less than 60 was associated with a sensitivity of 80% and a specificity of 87.6%. The predictive value of a positive or negative result was 68.7% and 92.3%, respectively. Area analysis under the ROC curve indicated that 93.37% (SE ±0.039) of the time, the value of lamellar count was lower for the abnormal histopathology group compared with normal (Table 2, Figure 2).
Patients aged more than 96 months, systemic arterial desaturation less than 80%, having aortic override of more than 50%, indexed aortic diameter of more than 24.80 mm, and presence of MAPCAs were the significant risk factors for the development of elastic fragmentation by logistic regression analysis (Table 3). Thus, this study revealed earlier and frequent occurrence of lamellar loss, elastic fragmentation, and disruption in patients with TOF. Elastin has a long half-life of 40 to 70 years, and the loss of elastin in adults is most likely a manifestation of elastolysis rather than insufficient synthesis.21 In children with TOF and pulmonary stenosis/pulmonary atresia, whether the loss of elastin is due to increased elastolysis stimulated by the shear and increased flow volume through the aorta or due to intrinsic problems of elastin synthesis remains uncertain.12 It is hypothesized that this intrinsic abnormality may be an expression of a hitherto unrecognized genetic defect involving the cellular function in the aortic media of patients with TOF, or may be programmed cell death.8-13,18-20
Apoptosis is programmed cell death, not increased or premature destruction of extracellular matrix proteins, that is, elastic fibers. If apoptosis of smooth muscle cells is the underlying mechanism for bicuspid aortopathy, could the elastic fragmentation and disruption seen in our patients with TOF be the final expression of elastolysis of the fibers? The obvious triggering factor here would be the shearing force from volume-overloaded aorta early in life, with the greatest stress being generated at the aortic root and ascending aorta.
Comparison of Patients Younger Than 2 Years of Age With Those Over 14 Years
As late presentation of congenital heart disease is not unusual in the developing world, it is not uncommon to be faced with the grown-up patient with TOF physiology without previous palliation. They are more cyanotic and polycythemic and are indeed a different subset from those encountered in the Western world. Only 11 (11.2%) patients in this series undergoing intracardiac repair were between 6 and 24 months of age. Despite the median age of just under 6 years in this study group, only about a third of the patients (28.5%) were shunted. Although our setting is a tertiary care center, the socioeconomic profile of the patients and the lack of health care insurance benefit led to delayed referral and surgery, accounting for higher age of the patients.
The 2 groups of patients in this study population represent the extremes of age (<2 years and >14 years) and of morphologic alterations. Although severe degenerative changes ranging from grade 3 elastic fragmentation to medionecrosis and fibrosis were present in patients aged more than 14 years, similar changes were observed in a subset of patients under 2 years of age. The additional adverse effects of systemic arterial desaturation (<80%), higher hematocrit (>45%), aortic override (>50%), increased indexed aortic diameter (>24.80 mm/m2), higher RVEDP (>12 mm Hg), presence of right aortic arch, double-outlet right ventricle, and pulmonary atresia might be expected to influence the development of early degenerative process.
Thus, our study shows a statistically significant interrelationship between lamellar loss and the appearance of histopathologic changes in the aortic wall of patients with TOF. These histologic abnormalities possibly reduce the cohesive and tensile strength of the media and suggest an important causative mechanism for aortic root dilatation.
Study Limitations
The principal limitation of this study is its sample size. Degenerative changes in the aortic wall are a complex and variable process. 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. The second limitation is that we examined histologically only a small segment of the ascending aorta.
Thirdly, the aorta is volume overloaded in TOF, with the greatest stress being generated at the aortic root and ascending aorta. The tissue samples in this study were obtained from the aortic cannulation site and not from the aortic sinuses because this could cause further destruction of the aortic sinuses.
Fourth, it remains uncertain whether these medial abnormalities in the ascending aorta, 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 aorta commencing in infancy are required and may shed further light on the risk stratification for aortic dilatation and the rate of its progression.
Clinical Implications and Recommendations
The present study indicates preponderance of degenerative changes in the aortic tissue of adult TOF, in patients with long-standing cyanosis and pressure overload, increased aortic dimensions, right aortic arch, and in patients with raised RVEDP, and it supports the concept of early operative correction if technically appropriate. These observations serve to emphasize that patients undergoing intracardiac repair require meticulous life-long follow-up. Comprehensive assessment should include a clinical and echocardiographic evaluation not only of the right ventricular outflow tract but also of the aorta.
The present impetus to operate on these patients early in life might mean that aortic root dilatation might be a pathologic condition of the past and not of future generations of patients with TOF.
Early surgical repair of these patients may prevent right ventricular dilatation and fibrosis by decreasing the volume and pressure overload. Thus, even if there is an intrinsic developmental tendency to medial disease, limiting the exposure to hemodynamic stress may obviate future aortic dilatation as well as progression of aortic regurgitation. Nevertheless, the range, prevalence, degree, and potential cardiac surgical risk posed by these abnormalities are matters that warrant emphasis.
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Conclusions |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionsReferences |
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Progressive aortic dilatation with aortic regurgitation can occur despite early repair of TOF. The deterioration may take a long time to develop, which emphasizes the need for continued and life-long follow-up of all patients after intracardiac repair.
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Acknowledgments |
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  M. Seki, C. Kurishima, H. Kawasaki, S. Masutani, and H. Senzaki Aortic stiffness and aortic dilation in infants and children with tetralogy of Fallot before corrective surgery: evidence for intrinsically abnormal aortic mechanical property Eur J Cardiothorac Surg, February 1, 2012; 41(2): 277 - 282. [Abstract] [Full Text] [PDF]
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K. Till, H. H. Dave, M. Comber, U. Bauersfeld, and R. Pretre Realignment of the ventricular septum using partial direct closure of the ventricular septal defect in Tetralogy of Fallot Eur J Cardiothorac Surg, October 1, 2011; 40(4): 1016 - 1019. [Abstract] [Full Text] [PDF]
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