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Ventriculo coronary arterial communications (VCAC) and myocardial sinusoids in hearts with pulmonary atresia with intact ventricular septum: two different diseases
Progress in Pediatric Cardiology 13 Ž2001. 157᎐164
Ventriculo coronary arterial communications ž VCAC / and myocardial sinusoids in hearts with pulmonary atresia with intact ventricular septum: two different diseases Adriana C. Gittenberger-de Groot a,U , Cornelia Tennstedt b, Rabih Chaoui c , Heleen Lie-Venemaa , Ursula Sauer d, Robert E. Poelmann a a
Department of Anatomy and Embryology, Leiden Uni¨ ersity Medical Center, The Netherlands b Department of Pathology, Charite´ Hospital, Berlin, Germany c Department of Obstetrics, Uni¨ ersity Hospital of Zurich, Switzerland ¨ d Deutsches Herzzentrum, Munchen, Germany ¨
Abstract Pulmonary atresia with intact septum is a cardiac malformation with a variable phenotype. Those cases that present with abnormal perfusion of the myocardium of the hypoplastic right ventricle can be distinguished in cases with myocardial sinusoids and cases with ventriculo coronary arterial communications. The first group most probably develops on the basis of atresia of the pulmonary orifice, a high pressure in the right ventricle with subsequent dilatation of the intertrabecular myocardial spaces and development of endocardial fibroelastosis. There is evidence that in cases with ventriculo coronary arterial communications the primary problem is formed by the coronary vasculature that connects abnormally to the ventricular lumen and in some cases also to the aortic orifice. This is exemplified in single and sometimes even completely absent coronary orifices. The altered haemodynamic circumstances with preferential flow through the communications lead to serious coronary vascular wall pathology with severe intimal thickening and partial obliteration of the subepicardial arteries. These anomalies are already present in the second trimester of pregnancy. Prenatal diagnosis supports furthermore, that the actual atresia of the pulmonary orifice may in some cases be secondary to the coronary abnormalities. Overall the anomaly primarily remains a right heart problem with myocardial, valvular and coronary vascular exponents. 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Coronary fistulae; Coronary vascular abnormalities; Hypoplastic right heart; Coronary vascular development; Epicardium
1. Introduction Pulmonary atresia with intact ventricular septum is a severe clinical condition that needs immediate postnatal care because of the ductus-dependent nature of U
Corresponding author. Adriana C. Gittenberger-de Groot, Department of Anatomy and Embryology, Leiden University Medical Center, P.O. Box 9602, 2300 RC Leiden, The Netherlands. Tel.: q31-71-5276691; fax: q31-71-5276680. E-mail address: [email protected] ŽA.C. Gittenberger-de Groot..
the anomaly. Temporary treatment with prostaglandins will ensure ductal patency until surgical treatment can be performed w1x. In this respect a number of cases benefit from a congenital persistent ductus arteriosus w2x. Pulmonary atresia can present with and without a ventricular septal defect. For the present review we will concentrate on those cases without a ventricular septal defect and that show abnormalities of the perfusion of the ventricular wall. This group can be subdivided in cases with epicardial coronary arterial
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anomalies in combination with ventriculo coronary arterial communications ŽVCAC. and those without serious coronary artery lesions. It has been estimated that the incidence of VCAC in hearts with pulmonary atresia without ventricular septal defects varies between 10 and 40% w3x. There have been excellent reviews w3x on the pathology of this malformation and the most comprehensive description is provided in a book by Freedom w4x. In general the development of the coronary anomalies as well as the VCAC have been accounted for as secondary to haemodynamic alterations due to the combination of tricuspid stenosis and pulmonary atresia. On the basis of an increased ventricular pressure the persistence of embryonic ventriculo coronary communications has been postulated as the cause for VCAC in the neonate w5x. There are, however, new data from prenatal diagnosis of cases with VCAC that also point towards a primary coronary-myocardial abnormality that secondarily leads to pulmonary atresia w6,7x. These findings allow for new morphogenetic considerations that fit with recent findings in coronary vascular development w8,9x. In this review we will shortly expand on nomenclature issues. Thereafter the coronary arterial anomalies together with the variations in VCAC distribution will be presented. It will be shown that at least two clinically relevant forms can be distinguished. In the most serious case there is dependency of the myocardium on the presence of the VCAC, as the coronary vascular bed has become too severely damaged with interruption of main subepicardial arteries. We
will also present data on the microvasculature of both the right and left ventricle, as well as on myocardial pathology, which is essential for postoperative functional performance. The next issue to be discussed is the clinical relevance of dependency of the myocardial coronary perfusion on the presence of VCAC. Last of all new developmental and pathomorphogenetic data, that bring the coronary vascular abnormalities and the VCAC into a primary causal position, will be presented.
2. Nomenclature of ventriculo coronary arterial communications There have been a variety of terms used for the communications between the right ventricle and the main coronary arteries. These comprise ‘coronary arterial fistulas’, ‘myocardial sinusoidal-coronary arterial connections’, ‘myocardial sinusoids’ and ‘ventriculo coronary arterial communications ŽVCAC.’. In earlier publications w10,11x we have made a distinction between myocardial sinusoids often present as thickwalled distended intertrabecular myocardial spaces that connect to the intramyocardial coronary capillary bed. This is clinically an important distinction as the main subepicardial coronary arteries do not show major pathology in cases of myocardial sinusoids. There is, however, a marked degree of endocardial fibroelastosis lining the right ventricle. The VCAC group does show connections between the intertrabecular spaces and the main coronary
Fig. 1. Schematic representation of pulmonary atresia with intact septum. Ža. Case with pulmonary atresia and myocardial sinusoids ŽMS. lined by endocardial fibroelastosis ŽEFE.. The MS contact the epicardial coronary arteries ŽCO. through a more or less distended capillary bed ŽCAP.. Žb. Case with pulmonary stenosis and VCAC that connect the lumen of the right ventricle ŽRV. with grossly pathological subepicardial coronary arteries that at some sites are interrupted Žarrows.. Aos aorta, LAs left atrium, LV s left ventricle, and PT s pulmonary trunk.
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arteries by thick walled ‘vascular’ communications ŽVCAC.. In this group there is often severe coronary arterial pathology at the site of the connection, but distal and proximal coronary arterial narrowing to even occlusion can also be present. The degree of endocardial fibroelastosis is less as compared to the first group. On the basis of our new developmental data it seems relevant to maintain the above distinction. There are indications that the VCAC are a primary anomaly of the connection between the coronary vasculature and the myocardial trabeculae. The non-committant term, ventriculo coronary arterial communications, is therefore, the best choice. Myocardial sinusoids then refer to the distensions of already existing intertrabecular spaces ŽFig. 1a,b..
3. Coronary arterial abnormalities and histopathology In pulmonary artresia with intact ventricular septum we have already mentioned that in those cases which solely present with distended intertrabecular spaces Žso-called myocardial sinusoids. the main coronary arterial branches are normal in their patterning and distribution and do not show pathology of the vascular wall w10x. This is clearly different in those cases that present with VCAC. First of all there is a tendency in cases with VCAC to have abnormalities of the main branches and as well as the coronary arterial orifices. These can consist of absence or pinpoint orifices to absence of parts of the coronary arterial branches. We have one fetally diagnosed case that completely lacks coronary arterial orifices to both the aorta as well as the pulmonary trunk. In this case there are subepicardial main coronary arterial branches that connect to VCAC as their sole source of perfusion. In literature similar cases have been described w12,13x. In our fetal case, that has been completely serially sectioned, we also could not find remnants of the coronary arteries between the aorta and the main coronary branches. In earlier published data w10x we found several cases with only a single coronary orifice that supported all main branches. In one case the main coronary arterial stem was interrupted leading to a complete dependence of the circulation on the VCAC. Furthermore, we encountered in several cases severe histopathology of the coronary arterial vessel wall. This was always present at the site of a VCAC, but also frequently either distal or proximal of the communication and in some cases both distal and proximal. The pathology was mainly characterised by marked adventitial thickening, a small media and extensive intimal thickening. The latter could be so extensive that it almost to completely blocked the lumen leading to an interruption of the artery. In
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some cases these interrupted arteries could still be evaluated histologically for their vascular wall structure, while in others the distinction between intima and media on the basis of an internal elastic lamina had been lost. Macroscopically these interrupted arteries were detectable as threadlike structures in some of the neonatal cases w10x. Our fetal case shows the possible reason for these thin vascular segments. At 20 weeks gestation this case showed at least four VCAC between the right ventricle and the left anterior descending branch. This latter artery presented with extensive coronary arterial pathology with intimal thickening ŽFig. 2a. and already a completely blocked artery segment ŽFig. 2b.. Subsequent lack of growth could explain the threadlike coronary vascular segments in the neonates. 4. Ventriculo coronary arterial communications These VCAC are found between the lumen of the right ventricle and the main coronary arterial branches with exception of the left circumflex artery. The VCAC have not been reported in connection to the lumen of the left ventricle. The connections can be single or multiple and vary in size w4,10x. VCAC can connect at several sites to the same main branch of a coronary artery. It is not easy to determine the difference between the grossly altered coronary artery with its thick layer of intimal thickening and a VCAC. The latter shows a wall structure with a thick outer fibrous layer and inner layers that resemble a combined media and intimal thickening. An internal elastic lamina can be present or missing. The inner wall of the VCAC consists of scattered smooth muscle cells and fibrous tissue. The distinction with the intertrabecular spaces is more easily made when the VCAC wall connects to the myocardial and endocardial lined wall of the ventricular trabeculae ŽFig. 3a,b.. Endocardial fibroelastosis of the right ventricle is in general missing or minimal in these cases ŽFig. 2a.. The difference between endocardial fibroelastosis, myocardial sinusoids ŽFig. 4. and VCAC can therefore, be somewhat difficult at first sight. In case of endocardial fibroelastosis, however, there is no vascular wall structure with an adventitia and a media. 5. Presence of endocardial fibroelastosis and myocardial fibrosis It has been claimed in earlier literature that there is an inverse relationship between endocardial fibroelastosis and coronary arterial pathology w14x. This is only partly true. It is clear that in case of myocardial sinusoids the right ventricular lumen is generally
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Fig. 2. Ža. Sections of right ventricular ŽRV. wall of a 20-week human fetus with pulmonary atresia and VCAC. The subepicardial coronary arteries show intimal thickening ŽIT. inside the media ŽM.. At the site of a VCAC the vessel wall structure is lost. There is absence of endocardial fibroelastosis. Žb. More distal section of the same specimen showing three abnormal coronary arteries of which one is completely blocked by intimal thickening Žarrow.. The intra-myocardial branch will open up in a few more distal sections in a VCAC. The myocardium of the RV does not yet show fibrosis at this stage. Staining, Elastica van Gieson and bar s 500 m. Fig. 3. Same specimen as depicted in Fig. 2. Detail of the wall of a VCAC. Ža. The wall of the VCAC does not show a muscular media ŽM. as is visible, in yellow, in an adjacent artery. Žb. Staining with resorcine fuchsine shows the internal elastic lamina ŽIEL. of the VCAC on the borderline of the intima and destructed media with a clear demarcation at the site of the ventricular lumen Žarrows.. Staining A, Elastica van Gieson and bar s 500 m. Fig. 4. Section of the wall of a hypoplastic right ventricle of a 5.5-week infant with pulmonary atresia, and myocardial sinusoids. The epicardial coronary arteries are normal. There is extensive endocardial fibroelastosis ŽEFE. lining the right ventricle ŽRV. extending into fibrous tissue that encircles hypertrophied cardiomyocytes ŽM.. Staining, Elastica van Gieson and bar s 500 m. Fig. 5. Section through the right ventricular apex of a HH35 chick embryo that was manipulated to inhibit epicardial transformation and coronary vascular formation. There is a marked ventriculo coronary arterial communication ŽVCAC. between an abnormal coronary artery ŽCoA. and the lumen of the RV. Staining, haematoxylin-eosin and bar s 500 m.
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lined by a thick layer of endocardial fibroelastosis that extends to where the sinusoids contact the coronary capillary network ŽFig. 1a, Fig. 4.. The hypothesis for the development of endocardial fibroelastosis is based on the high pressure and volume load that develops within the right ventricle based on tricuspid stenosis and atresia of the pulmonary orifice. A similar phenomenon is seen in the hypoplastic left heart syndrome in cases with mitral stenosis and aortic atresia w15x. The postulated inverse relationship is not absolute as also in cases with VCAC endocardial fibroelastosis can be present in the right ventricle although to a less severe extent. Our study of complete serial sections of cases with pulmonary atresia do not exclude that VCAC and myocardial sinusoids cannot be present in one and the same specimen. In the paragraph on patho-morphogenesis a hypothesis on this phenomenon will be presented. Interstitial myocardial fibrosis presenting as collagen strands between clusters of myocardial cells as well as diffuse fibrosis between myocytes is found in cases with VCAC as well as those with sinusoids ŽFig. 4.. In the latter group, however, which presents itself as a better surgical candidate w11x, the fibrosis is in general more extensive. We have performed a study on myocardial fibrosis not only in the right ventricle but also in the ventricular septum and left ventricle. The fibrosis concentrates in the right ventricle and the right ventricular surface of the septum w16x. The left ventricle is not showing marked myocardial pathology. Akiba and Becker w17x show on basis of morphometric studies that in some hearts especially subendocardial fibrosis of the left ventricle can be increased.
6. Myocardial disarray and capillary distribution Next to the serious effects that may be postulated on the right ventricular function because of the already presented pathology of the main coronary arteries, it is essential to know to what extent the microvascularisation of both the right and left ventricle is compromised. The presence of myocardial disarray in cases with pulmonary atresia and aortic atresia has already been established w17x. We have performed an extensive study as to the distribution of the capillary network in cases with pulmonary atresia and intact ventricular septum w16x. An important finding was the relative lack of abnormalities of the left ventricular myocardium and the left side of the ventricular septum supported by other data from literature w17x. With regard to the right ventricular pattern it was essential to distinguish those cases with a near normal sized right ventricle and few myocardial sinusoids as the least affected group. The other groups consisted
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of cases with myocardial sinusoids and extensive endocardial fibro-elastosis and cases with VCAC. In these latter hearts the myocardium of the right ventricle presented with a variable pattern of areas of myocardial disarray, myocardial hypertrophy, fibrosis and undisturbed areas. In areas of myocardial disarray the capillaries followed the myocardial pattern and were disoriented and distorted. In cases of myocardial hypertrophy the capillaries were more widely spaced and in case of fibrosis less capillaries were present. The cases with myocardial sinusoids and extensive endocardial fibroelastosis also showed marked areas of myocardial fibrosis and a diminished capillary network. This fibrosis was more extensive as compared to the cases with VCAC. In the latter group myocardial pathology, as exemplified by disarray, fibrosis and hypertrophy, was more severe in those cases with interruptions of the subepicardial arteries.
7. Clinical relevance of a ventriculo coronary arterial communication-dependent circulation The clinical management of neonates with pulmonary atresia and intact ventricular septum has been the issue of many publications w1,3,18,19x. A number of authors have tried to classify the anomaly according to the size of the right ventricle and the presence of three or two components w5x. The idea is that those cases with a tripartite right ventricle have less severe pathology and a more favourable outcome after surgery. This option can be supported from our own pathology studies only for those cases that also have less myocardial and coronary arterial pathology w16x. It was argued both by our group w10,11x as well as by Freedom w3x that the presence of two or three components is not an absolute indication and that right ventricular size may be more reliable to determine the severity. As indicated above, the coronary arterial pathology presents a serious challenge for the clinician. It is evident that the detrimental situation of coronary blood flow steal from the aorta to the right ventricle should be solved w1,11x. Closure of VCAC and decompression of the right ventricle are, however, only successful if the remaining coronary vascular bed is capable of perfusing the myocardium thereafter. The coronary arterial pathology in cases with VCAC needs therefore to be carefully evaluated. The presence of coronary vascular wall thickening by intimal hyperplasia not only at the site of a VCAC connection, but especially proximal or distal of the connection should be investigated. This also counts for the occurrence of single coronary orifices w10x, complete absence of coronary orifices w12,13x as well as interruptions at various sites w10x. Before contemplating the surgical
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approach of choice the coronary vascular bed therefore needs to be studied by angiocardiography or echo-Doppler to exclude a competition of coronary arteries and VCAC w10x. Previous studies have shown that the coronary arterial pathology is a progressive feature also after birth. Postnatal angiographic studies confirmed still patent coronary arteries in neonatal cases while after some weeks or months an interruption had developed w11x. As the coronary arterial disease, consisting of serious intimal hyperplasia, is progressive, it seems to be a matter of chance whether after surgery vessels will still develop a complete occlusion. Early surgical intervention is advisable as the abnormal haemodynamics in the coronary arterial bed will promote pathological changes.
8. Development of ventriculo coronary arterial communications and myocardial sinusoids The presence of VCAC has in general been contributed to the persistence of normally transient embryonic communications between the coronary vascular bed and the ventricular lumen w4,5,7,20x based on observations by Wearn w21x that such communications exist in the human heart. As it is extremely difficult to establish the presence of these communications by classical histological studies we have performed chicken-quail chimera studies combined with immunohistochemical techniques that have shed a new light on this subject. It was shown that the coronary vascular development derives from the epicardium w8,9x and not from the intertrabecular spaces which in part would obliterate to form a coronary vasculature. It was also shown that during embryonic development of the chicken heart the endothelial-lined vessels penetrate the myocardium and only rarely non-lumenized connections between the coronary vascular bed and the lumen of the ventricle can be observed w8,9x. These connections are detectable because quail positive endothelial cells merge with the endocardium of the chicken host. As the injection of India ink in the primitive coronary vascular bed revealed no leakage to the ventricular lumen w9x we assume that these connections are not functional. We have studied coronary vascular development both before and after the coronary vasculature penetrates the aortic semilunar sinuses w8x to develop two lumenized main coronary arterial branches and orifices in general w22x. Recent data also showed an ingrowth of this vascular system into the anterior wall of the right atrium at this time w9x. This dual connection explains why there is no acute congestion with the filling of the aortic branches as a ventricular run-off is not available. Only after the
connection of the coronary vascular system to the aorta, smooth muscle cells differentiate and form a media around the developing arteries w23x. The mechanism that dictates the differentiation of the endothelial-lined vascular bed into a system of arteries, veins and interconnecting capillaries is still under investigation. It has been shown, however, that the smooth muscle cells derive from the overlying epicardium w23,24x and spread from the base of the heart towards the apex. Coronary veins in their proximal connection to the atria have a media consisting of cardiac muscle, and are lined by epicardial derived smooth muscle cells more distally. Unpublished data on human coronary development using immunohistochemical markers for endothelial and smooth muscle cell development reveal a similar mechanism as described above for the avian embryo. The above data on: Ž1. normal coronary vascular development; Ž2. the inadequate explanations for developmental differences between the subgroup of pulmonary atresia with myocardial sinusoids and normal coronary arteries and the group with VCAC w10x; and Ž3. recent data from prenatal diagnosis w6,7x allow for a new hypothesis on development. The group with pulmonary atresia with intact septum, myocardial sinusoids and endocardial fibroelastosis presents with atresia of the pulmonary orifice, stenosis of the tricuspid orifice and small right ventricle. On the basis of previous hypotheses these cases did not develop VCAC because myocardial compaction had already closed off the embryonic coronary ventricular communications w5,7,20x. Serial microscopy of the wall of these ventricles did not reveal a direct luminal contact with the subepicardial and the intramyocardial coronary arteries. Both types of artery do not show pathology of their wall. The endocardial fibroelastosis is found deep into the myocardium lining the intertrabecular spaces. The developmental explanation is provided by the occurrence of a right ventricular volume overload because of tricuspid stenosis and pulmonary atresia, leading to development of endocardial fibroelastosis. A similar mechanism has been described for part of the cases in the hypoplastic left heart syndrome w10,15x. In pulmonary atresia with myocardial sinusoids the development of atresia of the pulmonary orifice is most probably the primary anomaly leading to the myocardial sinusoids. The above explanation for the group with VCAC is not very likely. As we have shown that these coronary ventricular communications do not exist as lumenized structures in the early embryonic heart. There are currently more data that support a primary anomaly of coronary ingrowth even before pulmonary atresia has fully developed. Coronary vascular development and ingrowth into the myocardium aorta and last of
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all right atrium is seen after the bare myocardial heart tube is covered by epicardium w23,25x. The ingrowth of the coronary vasculature and the timing of septation of the aortic and pulmonary orifice coincide in the human embryo at approximately 5᎐6 weeks gestation. Coronary vessel ingrowth is not dependent on outflow tract septation as coronary arteries also exist in cases with a persistent truncus arteriosus w26x. The mechanisms that guide the ingrowth are still not known. It is also not clear why there are differences between the aortic and pulmonary orifice as well as the right and left ventricular wall. In our case it seems that the basic disturbed mechanism is the ingrowth into the myocardium of the right ventricle and into the aortic orifice. In the myocardium the nonlumenized connections for some reason or other do become lumenized and develop a smooth muscle cell media and thick fibrous adventitia. Shortly after this ingrowth in the aortic wall takes place, but is sometimes disturbed as in quite a number of cases pin-point orifices, single orifices w10x, and even complete absence of both coronary orifices w12,13x can be observed. So it is feasible that a connection of the developing vascular bed to the aorta has never been made. Haemodynamic disturbances and altered oxygenation of the right ventricular wall because of already developed arterial ventricular connections may be a secondary causal factor for coronary wall pathology. It has been shown that in early pregnancy the right ventricular outflow tract has a higher after-load as compared to the left ventricular outflow. Blood flow would therefore be preferential through the VCAC and not through the pulmonary valve. This could promote development of pulmonary atresia during gestation. There are now at least two clinical reports that support a primary anomaly of the coronary vascular system. One paper by Chaoui w6x described a 13 week-old fetus with a prenatally detected VCAC and at 20 weeks gestation a pulmonary valve atresia. Another prenatally diagnosed case w7x shows the coexistance of VCAC and pulmonary stenosis. Recently we have observed a VCAC in a chicken embryo that was manipulated by partial blocking of epithelialmesenchymal transformation resulting in inhibited epicardial formation. The coronary artery was very thick-walled and abnormal ŽFig. 5.. The embryo showed a large VCAC and as yet no pulmonary stenosis. This experimental case also supports the separate origin of VCAC and pulmonary atresia. In conclusion both clinical and developmental data point towards a primary coronary vascular anomaly for the development of VCAC. The anomaly as such still remains a disease of the epicardium and myocardium of the right ventricle along with tricuspid and pulmonary valve abnormalities. The many genes
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that are now distinguished differentiating between right and left ventricle and their interactions with the epicardium might provide a clue for the development of this heart malformation in future. References w1x Giglia TM, Mandell VS, Connor AR, Mayer JE, Lock JE. Diagnosis and management of right ventricle-dependent coronary circulation in pulmonary atresia with intact ventricular septum. Circulation 1992;86:1516᎐1528. w2x Gittenberger-de Groot AC, Sutherland K, Sauer U, Kellner M, Schoeber JG, Buhlmeijer K. Normal and persistent ductus arteriosus influenced by prostaglandin E1. Herz 1980;5: 361᎐368. w3x Freedom RM, Wilson G, Trusler GA, Williams WG, Rowe RD. Pulmonary atresia and intact ventricular septum. Scand J Thorac Card 1983;17:1᎐28. w4x Wilson GJ, Freedom RM, Koike K, Perrin DG. The coronary arteries: anatomy and histopathology. Pulmonary atresia with intact ventricular septum. Mount Kisko, New York: Futura Publishing Company Inc, 1989:75᎐88. w5x Bull C, de Leval MR, Mercanti C, Macartney FJ, Anderson RH, Path MRC. Pulmonary atresia and intact ventricular septum: a revised classification. Circulation 1982;2:266᎐273. w6x Chaoui R, Tennstedt C, Goldner B, Bollmann R. Prenatal ¨ diagnosis of ventriculo-coronary communications in a second-trimester fetus using transvaginal and transabdominal color Doppler sonography. Ultrasound Obstet Gynecol 1997;9:194᎐197. w7x Bonnet D, Gautier-Lhermitte I, Bonhoeffer P, Sidi D. Right ventricular myocardial sinusoidal᎐coronary artery connections in critical pulmonary valve stenosis. Pediatr Cardiol 1998;19:269᎐271. w8x Poelmann RE, Gittenberger-de Groot AC, Mentink MMT, Bokenkamp R, Hogers B. Development of the cardiac coro¨ nary vascular endothelium, studied with antiendothelial antibodies, in chicken-quail chimeras. Circ Res 1993;73:559᎐568. w9x Vrancken Peeters M-PFM, Gittenberger-de Groot AC, Mentink MMT, Hungerford JE, Little CD, Poelmann RE. The development of the coronary vessels and their differentiation into arteries and veins in the embryonic quail heart. Dev Dyn 1997;208:338᎐348. w10x Gittenberger-de Groot AC, Sauer U, Bindl L, Babic R, Essed CE, Buhlmeyer K. Competition of coronary arteries and ventriculo-coronary arterial communications in pulmonary atresia with intact ventricular septum. Int J Cardiol 1988; 18:243᎐258. w11x Sauer U, Bindl L, Pilossoff V, Hultisch W, Buhlmeijer K, ¨ Gittenberger-de-Groot AC, De Leval MR, Sink SD. Pulmonary atresia with intact ventricular septum and right ventricle coronary artery fistulae: selection of patients for surgery. In: Doyle EF, Engle MA, Gersony WM, Rashkind WJ, Talner NS, Žeds.. Pediatric Cardiology New York: Springer Verlag, 1986:566᎐578. w12x Lenox CC, Briner J. Absent proximal coronary arteries associated with pulmonic atresia. Am J Cardiol 1972;30:666᎐669. w13x Ueda K, Saito A, Nakano H, Hamazaki Y. Absence of proximal coronary arteries associated with pulmonary atresia. Am Heart J 1983;106:596᎐598. w14x Essed CE, Ho SY, Hunter S, Anderson RH. Atrioventricular conduction system in univentricular heart of right ventricular type with right-sided rudimentary chamber. Thorax 1980; 35:123᎐127.
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w15x Bryan CS, Oppenheimer EH. Ventricular endocardial fibroelastosis, Arch Path 1969;87:82᎐86. w16x Oosthoek PW, Moorman AFM, Sauer U, Gittenberger-de Groot AC. Capillary distribution in the ventricles of hearts with pulmonary atresia and intact ventricular septum. Circulation 1995;91Ž6.:1790᎐1797. w17x Akiba T, Becker AE. Disease of the left ventricle in pulmonary atresia with intact ventricular septum. J Thorac Cardiovasc Surg 1994;108:1᎐8. w18x Giglia TM, Jenkins KJ, Matitiau A, Mandell VS, Sanders SP, Mayer JE, Lock JE. Influence of right heart size on outcome in pulmonary atresia with intact ventricular septum. Circulation 1993;88:2248᎐2256. w19x Gentles TL, Colan SD, Giglia TM, Mandell VS, Mayer JE, Sanders SP. Right ventricular decompression and left ventricular function in pulmonary atresia with intact ventricular septum. Circulation 1993;88:183᎐188. w20x Chaoui R, Machlitt A, Tennstedt C. Letter to the editor. Prenatal diagnosis of ventriculo-coronary fistula in a late first-trimester fetus presenting with increased nuchal translucency. Ultrasound Obstet Gynecol 2000;15:160᎐162. w21x Wearn JT, Mettier SR, Klumpp TG, Zschiesche LJ. The nature of the vascular communications between the coronary arteries and the chambers of the heart. Am Heart J 1933; 9:143᎐164.
w22x Bogers AJJC, Gittenberger-de Groot AC, Poelmann RE, Peault BM, Huysmans HA. Development of the origin of the ´ coronary arteries, a matter of ingrowth or outgrowth. Anat Embryol 1989;180:437᎐441. w23x Vrancken Peeters M-PFM, Gittenberger-de Groot AC, Mentink MMT, Poelmann RE. Smooth muscle cells and fibroblasts of the coronary arteries derive from epithelialmesenchymal transformation of the epicardium. Anat Embryol 1999;199:367᎐378. w24x Dettman RW, Denetclaw W, Ordahl CP, Bristow J. Common epicardial origin of coronary vascular smooth muscle, perivascular fibroblasts, and intermyocardial fibroblasts in the avian heart. Dev Biol 1998;193:169᎐181. w25x Gittenberger-de Groot AC, Vrancken Peeters M-PFM, Mentink MMT, Gourdie RG, Poelmann RE. Epicardial derived cells, EPDCs, contribute a novel population to the myocardial wall and the atrioventricular cushions. Circ Res 1998;82:1043᎐1052. w26x Bogers AJJC, Bartelings MM, Bokenkamp R, Stijnen T, van ¨ Suylen RJ, Poelmann RE, Gittenberger-de Groot AC. Common arterial trunk, uncommon coronary arterial anatomy. J Thorac Cardiov Sur 1993;106:1133᎐1137.
Ventriculo coronary arterial communications ž VCAC / and myocardial sinusoids in hearts with pulmonary atresia with intact ventricular septum: two different diseases Adriana C. Gittenberger-de Groot a,U , Cornelia Tennstedt b, Rabih Chaoui c , Heleen Lie-Venemaa , Ursula Sauer d, Robert E. Poelmann a a
Department of Anatomy and Embryology, Leiden Uni¨ ersity Medical Center, The Netherlands b Department of Pathology, Charite´ Hospital, Berlin, Germany c Department of Obstetrics, Uni¨ ersity Hospital of Zurich, Switzerland ¨ d Deutsches Herzzentrum, Munchen, Germany ¨
Abstract Pulmonary atresia with intact septum is a cardiac malformation with a variable phenotype. Those cases that present with abnormal perfusion of the myocardium of the hypoplastic right ventricle can be distinguished in cases with myocardial sinusoids and cases with ventriculo coronary arterial communications. The first group most probably develops on the basis of atresia of the pulmonary orifice, a high pressure in the right ventricle with subsequent dilatation of the intertrabecular myocardial spaces and development of endocardial fibroelastosis. There is evidence that in cases with ventriculo coronary arterial communications the primary problem is formed by the coronary vasculature that connects abnormally to the ventricular lumen and in some cases also to the aortic orifice. This is exemplified in single and sometimes even completely absent coronary orifices. The altered haemodynamic circumstances with preferential flow through the communications lead to serious coronary vascular wall pathology with severe intimal thickening and partial obliteration of the subepicardial arteries. These anomalies are already present in the second trimester of pregnancy. Prenatal diagnosis supports furthermore, that the actual atresia of the pulmonary orifice may in some cases be secondary to the coronary abnormalities. Overall the anomaly primarily remains a right heart problem with myocardial, valvular and coronary vascular exponents. 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Coronary fistulae; Coronary vascular abnormalities; Hypoplastic right heart; Coronary vascular development; Epicardium
1. Introduction Pulmonary atresia with intact ventricular septum is a severe clinical condition that needs immediate postnatal care because of the ductus-dependent nature of U
Corresponding author. Adriana C. Gittenberger-de Groot, Department of Anatomy and Embryology, Leiden University Medical Center, P.O. Box 9602, 2300 RC Leiden, The Netherlands. Tel.: q31-71-5276691; fax: q31-71-5276680. E-mail address: [email protected] ŽA.C. Gittenberger-de Groot..
the anomaly. Temporary treatment with prostaglandins will ensure ductal patency until surgical treatment can be performed w1x. In this respect a number of cases benefit from a congenital persistent ductus arteriosus w2x. Pulmonary atresia can present with and without a ventricular septal defect. For the present review we will concentrate on those cases without a ventricular septal defect and that show abnormalities of the perfusion of the ventricular wall. This group can be subdivided in cases with epicardial coronary arterial
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anomalies in combination with ventriculo coronary arterial communications ŽVCAC. and those without serious coronary artery lesions. It has been estimated that the incidence of VCAC in hearts with pulmonary atresia without ventricular septal defects varies between 10 and 40% w3x. There have been excellent reviews w3x on the pathology of this malformation and the most comprehensive description is provided in a book by Freedom w4x. In general the development of the coronary anomalies as well as the VCAC have been accounted for as secondary to haemodynamic alterations due to the combination of tricuspid stenosis and pulmonary atresia. On the basis of an increased ventricular pressure the persistence of embryonic ventriculo coronary communications has been postulated as the cause for VCAC in the neonate w5x. There are, however, new data from prenatal diagnosis of cases with VCAC that also point towards a primary coronary-myocardial abnormality that secondarily leads to pulmonary atresia w6,7x. These findings allow for new morphogenetic considerations that fit with recent findings in coronary vascular development w8,9x. In this review we will shortly expand on nomenclature issues. Thereafter the coronary arterial anomalies together with the variations in VCAC distribution will be presented. It will be shown that at least two clinically relevant forms can be distinguished. In the most serious case there is dependency of the myocardium on the presence of the VCAC, as the coronary vascular bed has become too severely damaged with interruption of main subepicardial arteries. We
will also present data on the microvasculature of both the right and left ventricle, as well as on myocardial pathology, which is essential for postoperative functional performance. The next issue to be discussed is the clinical relevance of dependency of the myocardial coronary perfusion on the presence of VCAC. Last of all new developmental and pathomorphogenetic data, that bring the coronary vascular abnormalities and the VCAC into a primary causal position, will be presented.
2. Nomenclature of ventriculo coronary arterial communications There have been a variety of terms used for the communications between the right ventricle and the main coronary arteries. These comprise ‘coronary arterial fistulas’, ‘myocardial sinusoidal-coronary arterial connections’, ‘myocardial sinusoids’ and ‘ventriculo coronary arterial communications ŽVCAC.’. In earlier publications w10,11x we have made a distinction between myocardial sinusoids often present as thickwalled distended intertrabecular myocardial spaces that connect to the intramyocardial coronary capillary bed. This is clinically an important distinction as the main subepicardial coronary arteries do not show major pathology in cases of myocardial sinusoids. There is, however, a marked degree of endocardial fibroelastosis lining the right ventricle. The VCAC group does show connections between the intertrabecular spaces and the main coronary
Fig. 1. Schematic representation of pulmonary atresia with intact septum. Ža. Case with pulmonary atresia and myocardial sinusoids ŽMS. lined by endocardial fibroelastosis ŽEFE.. The MS contact the epicardial coronary arteries ŽCO. through a more or less distended capillary bed ŽCAP.. Žb. Case with pulmonary stenosis and VCAC that connect the lumen of the right ventricle ŽRV. with grossly pathological subepicardial coronary arteries that at some sites are interrupted Žarrows.. Aos aorta, LAs left atrium, LV s left ventricle, and PT s pulmonary trunk.
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arteries by thick walled ‘vascular’ communications ŽVCAC.. In this group there is often severe coronary arterial pathology at the site of the connection, but distal and proximal coronary arterial narrowing to even occlusion can also be present. The degree of endocardial fibroelastosis is less as compared to the first group. On the basis of our new developmental data it seems relevant to maintain the above distinction. There are indications that the VCAC are a primary anomaly of the connection between the coronary vasculature and the myocardial trabeculae. The non-committant term, ventriculo coronary arterial communications, is therefore, the best choice. Myocardial sinusoids then refer to the distensions of already existing intertrabecular spaces ŽFig. 1a,b..
3. Coronary arterial abnormalities and histopathology In pulmonary artresia with intact ventricular septum we have already mentioned that in those cases which solely present with distended intertrabecular spaces Žso-called myocardial sinusoids. the main coronary arterial branches are normal in their patterning and distribution and do not show pathology of the vascular wall w10x. This is clearly different in those cases that present with VCAC. First of all there is a tendency in cases with VCAC to have abnormalities of the main branches and as well as the coronary arterial orifices. These can consist of absence or pinpoint orifices to absence of parts of the coronary arterial branches. We have one fetally diagnosed case that completely lacks coronary arterial orifices to both the aorta as well as the pulmonary trunk. In this case there are subepicardial main coronary arterial branches that connect to VCAC as their sole source of perfusion. In literature similar cases have been described w12,13x. In our fetal case, that has been completely serially sectioned, we also could not find remnants of the coronary arteries between the aorta and the main coronary branches. In earlier published data w10x we found several cases with only a single coronary orifice that supported all main branches. In one case the main coronary arterial stem was interrupted leading to a complete dependence of the circulation on the VCAC. Furthermore, we encountered in several cases severe histopathology of the coronary arterial vessel wall. This was always present at the site of a VCAC, but also frequently either distal or proximal of the communication and in some cases both distal and proximal. The pathology was mainly characterised by marked adventitial thickening, a small media and extensive intimal thickening. The latter could be so extensive that it almost to completely blocked the lumen leading to an interruption of the artery. In
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some cases these interrupted arteries could still be evaluated histologically for their vascular wall structure, while in others the distinction between intima and media on the basis of an internal elastic lamina had been lost. Macroscopically these interrupted arteries were detectable as threadlike structures in some of the neonatal cases w10x. Our fetal case shows the possible reason for these thin vascular segments. At 20 weeks gestation this case showed at least four VCAC between the right ventricle and the left anterior descending branch. This latter artery presented with extensive coronary arterial pathology with intimal thickening ŽFig. 2a. and already a completely blocked artery segment ŽFig. 2b.. Subsequent lack of growth could explain the threadlike coronary vascular segments in the neonates. 4. Ventriculo coronary arterial communications These VCAC are found between the lumen of the right ventricle and the main coronary arterial branches with exception of the left circumflex artery. The VCAC have not been reported in connection to the lumen of the left ventricle. The connections can be single or multiple and vary in size w4,10x. VCAC can connect at several sites to the same main branch of a coronary artery. It is not easy to determine the difference between the grossly altered coronary artery with its thick layer of intimal thickening and a VCAC. The latter shows a wall structure with a thick outer fibrous layer and inner layers that resemble a combined media and intimal thickening. An internal elastic lamina can be present or missing. The inner wall of the VCAC consists of scattered smooth muscle cells and fibrous tissue. The distinction with the intertrabecular spaces is more easily made when the VCAC wall connects to the myocardial and endocardial lined wall of the ventricular trabeculae ŽFig. 3a,b.. Endocardial fibroelastosis of the right ventricle is in general missing or minimal in these cases ŽFig. 2a.. The difference between endocardial fibroelastosis, myocardial sinusoids ŽFig. 4. and VCAC can therefore, be somewhat difficult at first sight. In case of endocardial fibroelastosis, however, there is no vascular wall structure with an adventitia and a media. 5. Presence of endocardial fibroelastosis and myocardial fibrosis It has been claimed in earlier literature that there is an inverse relationship between endocardial fibroelastosis and coronary arterial pathology w14x. This is only partly true. It is clear that in case of myocardial sinusoids the right ventricular lumen is generally
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Fig. 2. Ža. Sections of right ventricular ŽRV. wall of a 20-week human fetus with pulmonary atresia and VCAC. The subepicardial coronary arteries show intimal thickening ŽIT. inside the media ŽM.. At the site of a VCAC the vessel wall structure is lost. There is absence of endocardial fibroelastosis. Žb. More distal section of the same specimen showing three abnormal coronary arteries of which one is completely blocked by intimal thickening Žarrow.. The intra-myocardial branch will open up in a few more distal sections in a VCAC. The myocardium of the RV does not yet show fibrosis at this stage. Staining, Elastica van Gieson and bar s 500 m. Fig. 3. Same specimen as depicted in Fig. 2. Detail of the wall of a VCAC. Ža. The wall of the VCAC does not show a muscular media ŽM. as is visible, in yellow, in an adjacent artery. Žb. Staining with resorcine fuchsine shows the internal elastic lamina ŽIEL. of the VCAC on the borderline of the intima and destructed media with a clear demarcation at the site of the ventricular lumen Žarrows.. Staining A, Elastica van Gieson and bar s 500 m. Fig. 4. Section of the wall of a hypoplastic right ventricle of a 5.5-week infant with pulmonary atresia, and myocardial sinusoids. The epicardial coronary arteries are normal. There is extensive endocardial fibroelastosis ŽEFE. lining the right ventricle ŽRV. extending into fibrous tissue that encircles hypertrophied cardiomyocytes ŽM.. Staining, Elastica van Gieson and bar s 500 m. Fig. 5. Section through the right ventricular apex of a HH35 chick embryo that was manipulated to inhibit epicardial transformation and coronary vascular formation. There is a marked ventriculo coronary arterial communication ŽVCAC. between an abnormal coronary artery ŽCoA. and the lumen of the RV. Staining, haematoxylin-eosin and bar s 500 m.
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lined by a thick layer of endocardial fibroelastosis that extends to where the sinusoids contact the coronary capillary network ŽFig. 1a, Fig. 4.. The hypothesis for the development of endocardial fibroelastosis is based on the high pressure and volume load that develops within the right ventricle based on tricuspid stenosis and atresia of the pulmonary orifice. A similar phenomenon is seen in the hypoplastic left heart syndrome in cases with mitral stenosis and aortic atresia w15x. The postulated inverse relationship is not absolute as also in cases with VCAC endocardial fibroelastosis can be present in the right ventricle although to a less severe extent. Our study of complete serial sections of cases with pulmonary atresia do not exclude that VCAC and myocardial sinusoids cannot be present in one and the same specimen. In the paragraph on patho-morphogenesis a hypothesis on this phenomenon will be presented. Interstitial myocardial fibrosis presenting as collagen strands between clusters of myocardial cells as well as diffuse fibrosis between myocytes is found in cases with VCAC as well as those with sinusoids ŽFig. 4.. In the latter group, however, which presents itself as a better surgical candidate w11x, the fibrosis is in general more extensive. We have performed a study on myocardial fibrosis not only in the right ventricle but also in the ventricular septum and left ventricle. The fibrosis concentrates in the right ventricle and the right ventricular surface of the septum w16x. The left ventricle is not showing marked myocardial pathology. Akiba and Becker w17x show on basis of morphometric studies that in some hearts especially subendocardial fibrosis of the left ventricle can be increased.
6. Myocardial disarray and capillary distribution Next to the serious effects that may be postulated on the right ventricular function because of the already presented pathology of the main coronary arteries, it is essential to know to what extent the microvascularisation of both the right and left ventricle is compromised. The presence of myocardial disarray in cases with pulmonary atresia and aortic atresia has already been established w17x. We have performed an extensive study as to the distribution of the capillary network in cases with pulmonary atresia and intact ventricular septum w16x. An important finding was the relative lack of abnormalities of the left ventricular myocardium and the left side of the ventricular septum supported by other data from literature w17x. With regard to the right ventricular pattern it was essential to distinguish those cases with a near normal sized right ventricle and few myocardial sinusoids as the least affected group. The other groups consisted
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of cases with myocardial sinusoids and extensive endocardial fibro-elastosis and cases with VCAC. In these latter hearts the myocardium of the right ventricle presented with a variable pattern of areas of myocardial disarray, myocardial hypertrophy, fibrosis and undisturbed areas. In areas of myocardial disarray the capillaries followed the myocardial pattern and were disoriented and distorted. In cases of myocardial hypertrophy the capillaries were more widely spaced and in case of fibrosis less capillaries were present. The cases with myocardial sinusoids and extensive endocardial fibroelastosis also showed marked areas of myocardial fibrosis and a diminished capillary network. This fibrosis was more extensive as compared to the cases with VCAC. In the latter group myocardial pathology, as exemplified by disarray, fibrosis and hypertrophy, was more severe in those cases with interruptions of the subepicardial arteries.
7. Clinical relevance of a ventriculo coronary arterial communication-dependent circulation The clinical management of neonates with pulmonary atresia and intact ventricular septum has been the issue of many publications w1,3,18,19x. A number of authors have tried to classify the anomaly according to the size of the right ventricle and the presence of three or two components w5x. The idea is that those cases with a tripartite right ventricle have less severe pathology and a more favourable outcome after surgery. This option can be supported from our own pathology studies only for those cases that also have less myocardial and coronary arterial pathology w16x. It was argued both by our group w10,11x as well as by Freedom w3x that the presence of two or three components is not an absolute indication and that right ventricular size may be more reliable to determine the severity. As indicated above, the coronary arterial pathology presents a serious challenge for the clinician. It is evident that the detrimental situation of coronary blood flow steal from the aorta to the right ventricle should be solved w1,11x. Closure of VCAC and decompression of the right ventricle are, however, only successful if the remaining coronary vascular bed is capable of perfusing the myocardium thereafter. The coronary arterial pathology in cases with VCAC needs therefore to be carefully evaluated. The presence of coronary vascular wall thickening by intimal hyperplasia not only at the site of a VCAC connection, but especially proximal or distal of the connection should be investigated. This also counts for the occurrence of single coronary orifices w10x, complete absence of coronary orifices w12,13x as well as interruptions at various sites w10x. Before contemplating the surgical
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approach of choice the coronary vascular bed therefore needs to be studied by angiocardiography or echo-Doppler to exclude a competition of coronary arteries and VCAC w10x. Previous studies have shown that the coronary arterial pathology is a progressive feature also after birth. Postnatal angiographic studies confirmed still patent coronary arteries in neonatal cases while after some weeks or months an interruption had developed w11x. As the coronary arterial disease, consisting of serious intimal hyperplasia, is progressive, it seems to be a matter of chance whether after surgery vessels will still develop a complete occlusion. Early surgical intervention is advisable as the abnormal haemodynamics in the coronary arterial bed will promote pathological changes.
8. Development of ventriculo coronary arterial communications and myocardial sinusoids The presence of VCAC has in general been contributed to the persistence of normally transient embryonic communications between the coronary vascular bed and the ventricular lumen w4,5,7,20x based on observations by Wearn w21x that such communications exist in the human heart. As it is extremely difficult to establish the presence of these communications by classical histological studies we have performed chicken-quail chimera studies combined with immunohistochemical techniques that have shed a new light on this subject. It was shown that the coronary vascular development derives from the epicardium w8,9x and not from the intertrabecular spaces which in part would obliterate to form a coronary vasculature. It was also shown that during embryonic development of the chicken heart the endothelial-lined vessels penetrate the myocardium and only rarely non-lumenized connections between the coronary vascular bed and the lumen of the ventricle can be observed w8,9x. These connections are detectable because quail positive endothelial cells merge with the endocardium of the chicken host. As the injection of India ink in the primitive coronary vascular bed revealed no leakage to the ventricular lumen w9x we assume that these connections are not functional. We have studied coronary vascular development both before and after the coronary vasculature penetrates the aortic semilunar sinuses w8x to develop two lumenized main coronary arterial branches and orifices in general w22x. Recent data also showed an ingrowth of this vascular system into the anterior wall of the right atrium at this time w9x. This dual connection explains why there is no acute congestion with the filling of the aortic branches as a ventricular run-off is not available. Only after the
connection of the coronary vascular system to the aorta, smooth muscle cells differentiate and form a media around the developing arteries w23x. The mechanism that dictates the differentiation of the endothelial-lined vascular bed into a system of arteries, veins and interconnecting capillaries is still under investigation. It has been shown, however, that the smooth muscle cells derive from the overlying epicardium w23,24x and spread from the base of the heart towards the apex. Coronary veins in their proximal connection to the atria have a media consisting of cardiac muscle, and are lined by epicardial derived smooth muscle cells more distally. Unpublished data on human coronary development using immunohistochemical markers for endothelial and smooth muscle cell development reveal a similar mechanism as described above for the avian embryo. The above data on: Ž1. normal coronary vascular development; Ž2. the inadequate explanations for developmental differences between the subgroup of pulmonary atresia with myocardial sinusoids and normal coronary arteries and the group with VCAC w10x; and Ž3. recent data from prenatal diagnosis w6,7x allow for a new hypothesis on development. The group with pulmonary atresia with intact septum, myocardial sinusoids and endocardial fibroelastosis presents with atresia of the pulmonary orifice, stenosis of the tricuspid orifice and small right ventricle. On the basis of previous hypotheses these cases did not develop VCAC because myocardial compaction had already closed off the embryonic coronary ventricular communications w5,7,20x. Serial microscopy of the wall of these ventricles did not reveal a direct luminal contact with the subepicardial and the intramyocardial coronary arteries. Both types of artery do not show pathology of their wall. The endocardial fibroelastosis is found deep into the myocardium lining the intertrabecular spaces. The developmental explanation is provided by the occurrence of a right ventricular volume overload because of tricuspid stenosis and pulmonary atresia, leading to development of endocardial fibroelastosis. A similar mechanism has been described for part of the cases in the hypoplastic left heart syndrome w10,15x. In pulmonary atresia with myocardial sinusoids the development of atresia of the pulmonary orifice is most probably the primary anomaly leading to the myocardial sinusoids. The above explanation for the group with VCAC is not very likely. As we have shown that these coronary ventricular communications do not exist as lumenized structures in the early embryonic heart. There are currently more data that support a primary anomaly of coronary ingrowth even before pulmonary atresia has fully developed. Coronary vascular development and ingrowth into the myocardium aorta and last of
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all right atrium is seen after the bare myocardial heart tube is covered by epicardium w23,25x. The ingrowth of the coronary vasculature and the timing of septation of the aortic and pulmonary orifice coincide in the human embryo at approximately 5᎐6 weeks gestation. Coronary vessel ingrowth is not dependent on outflow tract septation as coronary arteries also exist in cases with a persistent truncus arteriosus w26x. The mechanisms that guide the ingrowth are still not known. It is also not clear why there are differences between the aortic and pulmonary orifice as well as the right and left ventricular wall. In our case it seems that the basic disturbed mechanism is the ingrowth into the myocardium of the right ventricle and into the aortic orifice. In the myocardium the nonlumenized connections for some reason or other do become lumenized and develop a smooth muscle cell media and thick fibrous adventitia. Shortly after this ingrowth in the aortic wall takes place, but is sometimes disturbed as in quite a number of cases pin-point orifices, single orifices w10x, and even complete absence of both coronary orifices w12,13x can be observed. So it is feasible that a connection of the developing vascular bed to the aorta has never been made. Haemodynamic disturbances and altered oxygenation of the right ventricular wall because of already developed arterial ventricular connections may be a secondary causal factor for coronary wall pathology. It has been shown that in early pregnancy the right ventricular outflow tract has a higher after-load as compared to the left ventricular outflow. Blood flow would therefore be preferential through the VCAC and not through the pulmonary valve. This could promote development of pulmonary atresia during gestation. There are now at least two clinical reports that support a primary anomaly of the coronary vascular system. One paper by Chaoui w6x described a 13 week-old fetus with a prenatally detected VCAC and at 20 weeks gestation a pulmonary valve atresia. Another prenatally diagnosed case w7x shows the coexistance of VCAC and pulmonary stenosis. Recently we have observed a VCAC in a chicken embryo that was manipulated by partial blocking of epithelialmesenchymal transformation resulting in inhibited epicardial formation. The coronary artery was very thick-walled and abnormal ŽFig. 5.. The embryo showed a large VCAC and as yet no pulmonary stenosis. This experimental case also supports the separate origin of VCAC and pulmonary atresia. In conclusion both clinical and developmental data point towards a primary coronary vascular anomaly for the development of VCAC. The anomaly as such still remains a disease of the epicardium and myocardium of the right ventricle along with tricuspid and pulmonary valve abnormalities. The many genes
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that are now distinguished differentiating between right and left ventricle and their interactions with the epicardium might provide a clue for the development of this heart malformation in future. References w1x Giglia TM, Mandell VS, Connor AR, Mayer JE, Lock JE. Diagnosis and management of right ventricle-dependent coronary circulation in pulmonary atresia with intact ventricular septum. Circulation 1992;86:1516᎐1528. w2x Gittenberger-de Groot AC, Sutherland K, Sauer U, Kellner M, Schoeber JG, Buhlmeijer K. Normal and persistent ductus arteriosus influenced by prostaglandin E1. Herz 1980;5: 361᎐368. w3x Freedom RM, Wilson G, Trusler GA, Williams WG, Rowe RD. Pulmonary atresia and intact ventricular septum. Scand J Thorac Card 1983;17:1᎐28. w4x Wilson GJ, Freedom RM, Koike K, Perrin DG. The coronary arteries: anatomy and histopathology. Pulmonary atresia with intact ventricular septum. Mount Kisko, New York: Futura Publishing Company Inc, 1989:75᎐88. w5x Bull C, de Leval MR, Mercanti C, Macartney FJ, Anderson RH, Path MRC. Pulmonary atresia and intact ventricular septum: a revised classification. Circulation 1982;2:266᎐273. w6x Chaoui R, Tennstedt C, Goldner B, Bollmann R. Prenatal ¨ diagnosis of ventriculo-coronary communications in a second-trimester fetus using transvaginal and transabdominal color Doppler sonography. Ultrasound Obstet Gynecol 1997;9:194᎐197. w7x Bonnet D, Gautier-Lhermitte I, Bonhoeffer P, Sidi D. Right ventricular myocardial sinusoidal᎐coronary artery connections in critical pulmonary valve stenosis. Pediatr Cardiol 1998;19:269᎐271. w8x Poelmann RE, Gittenberger-de Groot AC, Mentink MMT, Bokenkamp R, Hogers B. Development of the cardiac coro¨ nary vascular endothelium, studied with antiendothelial antibodies, in chicken-quail chimeras. Circ Res 1993;73:559᎐568. w9x Vrancken Peeters M-PFM, Gittenberger-de Groot AC, Mentink MMT, Hungerford JE, Little CD, Poelmann RE. The development of the coronary vessels and their differentiation into arteries and veins in the embryonic quail heart. Dev Dyn 1997;208:338᎐348. w10x Gittenberger-de Groot AC, Sauer U, Bindl L, Babic R, Essed CE, Buhlmeyer K. Competition of coronary arteries and ventriculo-coronary arterial communications in pulmonary atresia with intact ventricular septum. Int J Cardiol 1988; 18:243᎐258. w11x Sauer U, Bindl L, Pilossoff V, Hultisch W, Buhlmeijer K, ¨ Gittenberger-de-Groot AC, De Leval MR, Sink SD. Pulmonary atresia with intact ventricular septum and right ventricle coronary artery fistulae: selection of patients for surgery. In: Doyle EF, Engle MA, Gersony WM, Rashkind WJ, Talner NS, Žeds.. Pediatric Cardiology New York: Springer Verlag, 1986:566᎐578. w12x Lenox CC, Briner J. Absent proximal coronary arteries associated with pulmonic atresia. Am J Cardiol 1972;30:666᎐669. w13x Ueda K, Saito A, Nakano H, Hamazaki Y. Absence of proximal coronary arteries associated with pulmonary atresia. Am Heart J 1983;106:596᎐598. w14x Essed CE, Ho SY, Hunter S, Anderson RH. Atrioventricular conduction system in univentricular heart of right ventricular type with right-sided rudimentary chamber. Thorax 1980; 35:123᎐127.
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w15x Bryan CS, Oppenheimer EH. Ventricular endocardial fibroelastosis, Arch Path 1969;87:82᎐86. w16x Oosthoek PW, Moorman AFM, Sauer U, Gittenberger-de Groot AC. Capillary distribution in the ventricles of hearts with pulmonary atresia and intact ventricular septum. Circulation 1995;91Ž6.:1790᎐1797. w17x Akiba T, Becker AE. Disease of the left ventricle in pulmonary atresia with intact ventricular septum. J Thorac Cardiovasc Surg 1994;108:1᎐8. w18x Giglia TM, Jenkins KJ, Matitiau A, Mandell VS, Sanders SP, Mayer JE, Lock JE. Influence of right heart size on outcome in pulmonary atresia with intact ventricular septum. Circulation 1993;88:2248᎐2256. w19x Gentles TL, Colan SD, Giglia TM, Mandell VS, Mayer JE, Sanders SP. Right ventricular decompression and left ventricular function in pulmonary atresia with intact ventricular septum. Circulation 1993;88:183᎐188. w20x Chaoui R, Machlitt A, Tennstedt C. Letter to the editor. Prenatal diagnosis of ventriculo-coronary fistula in a late first-trimester fetus presenting with increased nuchal translucency. Ultrasound Obstet Gynecol 2000;15:160᎐162. w21x Wearn JT, Mettier SR, Klumpp TG, Zschiesche LJ. The nature of the vascular communications between the coronary arteries and the chambers of the heart. Am Heart J 1933; 9:143᎐164.
w22x Bogers AJJC, Gittenberger-de Groot AC, Poelmann RE, Peault BM, Huysmans HA. Development of the origin of the ´ coronary arteries, a matter of ingrowth or outgrowth. Anat Embryol 1989;180:437᎐441. w23x Vrancken Peeters M-PFM, Gittenberger-de Groot AC, Mentink MMT, Poelmann RE. Smooth muscle cells and fibroblasts of the coronary arteries derive from epithelialmesenchymal transformation of the epicardium. Anat Embryol 1999;199:367᎐378. w24x Dettman RW, Denetclaw W, Ordahl CP, Bristow J. Common epicardial origin of coronary vascular smooth muscle, perivascular fibroblasts, and intermyocardial fibroblasts in the avian heart. Dev Biol 1998;193:169᎐181. w25x Gittenberger-de Groot AC, Vrancken Peeters M-PFM, Mentink MMT, Gourdie RG, Poelmann RE. Epicardial derived cells, EPDCs, contribute a novel population to the myocardial wall and the atrioventricular cushions. Circ Res 1998;82:1043᎐1052. w26x Bogers AJJC, Bartelings MM, Bokenkamp R, Stijnen T, van ¨ Suylen RJ, Poelmann RE, Gittenberger-de Groot AC. Common arterial trunk, uncommon coronary arterial anatomy. J Thorac Cardiov Sur 1993;106:1133᎐1137.