Definition of so-called cystic medial necrosis
In CHD with great artery dilatation (aortic or pulmonary dilatation), six morphologic variations are possibly represented:
Marfan syndrome (intrinsic connective tissue defect)
Bicuspid aortic valve and/or paracoarctation aorta
Cyanotic CHD with progressive aortic dilatation such as tetralogy of Fallot and pulmonary stenosis/atresia, truncus arteriosus, and single ventricle with pulmonary atresia or stenosis
CHD with pulmonary vascular disease
CHD with large left to right shunt (e.g., atrial septal defect) without pulmonary obstructive disease
Tricuspid aortic stenosis or pulmonary stenosis or “idiopathic pulmonary artery dilatation”
Marfan syndrome, which has a causal association with mutations of fibrillin, involves dilatation of the ascending aorta with morphological finding of the so-called cystic medial necrosis (elastic fiber fragmentation, smooth muscle cell loss) [4–6].
Dilatation of the ascending aorta and pulmonary trunk in CHD has been considered secondary to the basic anomaly. However, a dilated paracoarctation aorta and a dilated ascending aorta above a bicuspid aortic valve may harbor “cystic medial necrosis” that is indistinguishable from Marfan syndrome [7–11], and such dilatation can be observed in bicuspid aortic valve patients even without aortic stenosis or regurgitation. Therefore, this dilatation of the aorta possibly develops due to intrinsic rather than hemodynamic abnormalities. These observations have led us to hypothesize that various types of CHD harbor an aortic medial abnormality that reflects a common developmental fault weakening and attenuating the aortic wall.
2.2 Cause of Aortic Dilatation in Congenital Heart Disease and Histology of the Aortic Media
There are several independent variables that alter the structure of ascending aortic media. In pregnancy , gestational changes in ascending aortic and pulmonary truncal media are characterized by elastic fiber fragmentation, a decrease in ground substance, and hypertrophy/hyperplasia of smooth muscle cells. Those induce reduced peripheral arterial resistance and an increased fetal blood flow and also reduced peripheral pulmonary arterial resistance for an increased cardiac output during pregnancy. With aging, layers of parallel aortic elastic fibers fragment, smooth muscle decreases, and collagen and ground substance increase, especially in the thoracic aorta . In patients with systemic hypertension and increased share stress to the aortic wall, abnormalities of aortic medial elastin and collagen are significantly more prevalent than in normotensive subjects of comparable age . Deletion of transposing growth factor-β (TGF-β) receptor has a relation with aortic dilatation . The genetic fault in Marfan syndrome apparently impairs the aortic medial elastic fibers more extensively than impairment in CHD, and the incidence of ascending aortic dilatation, dissection, or rupture is higher, and the degree of aortic root medial lesions is greater in former than the latter .
After Erdheim referred to medionecrosis aortae idiopathica cystica  in 1929, “cystic medial necrosis” became a part of the medical term. However, the term is misnomer, as the so-called cyst is in fact non-cystic medial structure faults, instead, accumulation of basophilic ground substance. McKusick et al. reported that the association of bicuspid aortic valve and cystic medial necrosis is more than coincidence and cystic medial necrosis was defined as [3, 8]:
Non-inflammatory smooth muscle cell loss
Fragmentation of elastic fibers
Accumulation of basophilic ground substance within cell-depleted areas of the medial layer of the vessel wall
2.3 Marfan Syndrome, Annulo-aortic Ectasia, and Cystic Medial Necrosis
Marfan syndrome is an autosomal dominant disorder with partial deletion of chromosome 15 and fault in making fibrillin which is the main component of elastic fibers [4, 5]. In Marfan syndrome, the morphological analysis of the arterial media in the ascending aorta and pulmonary trunk reveals fragmentation of elastic fiber and smooth muscle cell loss [4, 5, 17, 18]. Annulo-aortic ectasia has been defined as an entity comprising dilatation of the ascending aorta, dilatation of the aortic annulus, and progressive insufficiency of the aortic valve with cystic medial necrosis in the ascending aortic wall. Those without classic Marfan syndrome phenotype [19, 20] possibly have some relation with unknown responsible genes. Marfan syndrome and annulo-aortic ectasia are the typical cases revealing cystic medial necrosis in the aortic media.
2.4 Bicuspid Aortic Valve, Paracoarctation of the Aorta, and Cystic Medial Necrosis
As mentioned before, McKusick et al. suggested that manifestations of an abnormal aortic media are too frequently observed in the paracoarctation aorta and bicuspid aortic valve as to allow postulation of a common underlying defect [8, 21]. After this report, close relations in the incidence among bicuspid aortic valve, paracoarctation aorta, aortic dilatation or dissection, and cystic medial necrosis in the ascending aorta were observed [9–11, 18–24] (Fig. 2.2). Aortic aneurysm and dissection are not rare in paracoarctation aorta, and aortic rupture is a frequently described cause of death in adults with coarctation of the aorta . Arterial hypertension, accompanied by turbulent flow produced at the coarcted segment or the bicuspid aortic valve, can provide an explanation for cystic medial necrosis and aortic rupture . However, aortic aneurysm and rupture may also occur years after successful repair of coarctation [26, 27]. Moreover, dissection in the distal compartment of the paracoarctation aorta is difficult to explain on the basis of hypertension alone [27, 28]. In histological study in CHD with aortic dilatation , 11 of 17 specimens from patients with bicuspid aortic valve and eight of nine specimens from the paracoarctation aorta (including above and below the coarctation), specific cystic medial necrosis could be revealed (Fig. 2.3). Isner et al.  reported that 22 of 33 children, including five infants, with the coarctation of the aorta revealed extensive cystic medial necrosis in the paracoarctation aorta and a 3-week-old coarctation patient revealed typical cystic medial necrosis in the ascending aorta. Therefore, in bicuspid aortic valves or in the paracoarctation aorta, an inherent fragility of the aortic wall may provide an explanation for the high incidence of cystic medial necrosis in ascending aorta. The possible occurrence of an abnormal aortic media in the paracoarctation aorta might contribute to the prevalence of aneurysm formation after balloon dilatation for the coarctation of the aorta [29, 30].
A 51-year-old male with bicuspid aortic valve aortic dissection. (a), (c), and (d) CT images and (b) echo image. Ao aorta, BA bicuspid aortic valve, LVOT left ventricular outflow tract
A 20-year-old male with coarctation of the aorta (COA). Left upper panel: Paracoarctation aneurysm is clearly seen (5.2 cm diameter). Left lower panel: Postsurgical repair (end-to-end repair). Right panel: Severely fragmented elastic fibers (E) and smooth muscle cell (SM) are observed. Light microscopy, EVG (Courtesy by Perloff JK MD)
2.5 Histopathological Abnormalities in Various Congenital Heart Diseases
A similar developmental fault in connective tissue possibly exists in other forms of CHD with great artery dilatation . Niwa K et al.1 reported that in 88 CHD patients with dilated aorta, aging 3 weeks to 81 years (32 ± 6 years) (48 males, 40 females), surgical biopsy aortic specimens were obtained, and cystic medial necrosis was observed in the aortic media in all of them (Figs. 2.4 and 2.5).
Aortic medial histological findings: Light (left side panel) and electron microscopy (right side panel). Left panel: Histological severity is shown with the grading from normal to grade 3 (EVG stain). Right panel: Elastic fibers are severely fragmented. SM smooth muscle cell, E elastic fiber
Histological severity of aortic media by aortic biopsy specimens in various CHD with dilated aorta (n=88). AAE annulo-aortic ectasia, BAV AS bicuspid aortic valve with aortic stenosis, BAV AR bicuspid aortic valve with aortic regurgitation, tetralogy of Fallot tetralogy of Fallot, SV PS single ventricle with pulmonary stenosis, TA PS tricuspid atresia with pulmonary stenosis, DORV double outlet right ventricle, DOLV double outlet left ventricle, VSD ventricular septal defect, Do Ao A double aortic arch, PTA persistent truncus arteriosus, d-TGA d-transposition of the great arteries, controls transplant donor heart
2.6 Progressive Ascending Aorta Dilatation and Cystic Medial Necrosis in Cyanotic Congenital Heart Disease
There is an age-related increase in the incidence and degree of aortic regurgitation in tetralogy of Fallot, especially with pulmonary atresia. Regurgitation is related to the mechanical effects of a dilated aortic root above the aortic valve [31, 32]. Patients with a dilated aortic root in tetralogy of Fallot share similar histological changes of the aortic root, suggestive of cystic medial necrosis, indistinguishable from the aortic root in patients with Marfan syndrome . Higher histologic grading scores in tetralogy of Fallot patients are found even in infants, suggesting the intrinsic abnormality has crucial role for this dilatation .
Dilatation of the ascending aorta in truncus arteriosus or single ventricle with pulmonary atresia or stenosis is also thought to be progressive. In the former study , six of seven patients with tetralogy of Fallot with pulmonary atresia or severe pulmonary stenosis (including three younger than 10 years), a 4-year-old patient with truncus arteriosus, and a 16-month-old patient with complete transposition of the great arteries revealed specific cystic medial necrosis in the dilated ascending aorta. Complete transposition of the great arteries with a nonrestrictive ventricular septal defect was associated with grade 2 medial abnormalities in hypertensive pulmonary trunk. A patient with tetralogy of Fallot and an obstructive pulmonary vascular disease, induced by an oversized Blalock-Taussig shunt, suffered from a rupture of a hypertensive aneurysmal pulmonary trunk with grade 3 medial abnormalities that may have been acquired, although vulnerability might have been enhanced by an inherent reduction in elastic fibers. Truncus arteriosus is neither an aorta nor a pulmonary trunk, differing from a large aorta with pulmonary atresia or a large pulmonary trunk with aortic atresia, both of which have an aortopulmonary septum [34, 35]. Medial abnormalities in neonates and infants with truncus arteriosus may be inherent, albeit facilitated by systemic arterial pressure, volume overload, and a wide pulse pressure. In adults with truncus arteriosus and obstructive pulmonary vascular disease, medial abnormalities must be considered in light of abnormalities in neonates and infants.
It is reported that cystic medial necrosis was observed in 3 of 21 patients with transposition of the great arteries with the mean age of 5 months . Therefore, it is suggested that cystic medial necrosis observed in the ascending aorta in tetralogy of Fallot, truncus arteriosus (Fig. 2.6), and complete transposition of the great arteries may be related to intrinsic weakness of the aortic wall, because it is observed even in early childhood. Also, the ascending aorta in univentricular hearts with pulmonary stenosis/atresia may dilate out of proportion (Fig. 2.7). Dissection or rupture of the ascending aorta in these anomalies is very rare, but it can happen in Fontan patients . Also another Fontan case with aortic dissection was experienced (personal communication). Decreased elasticity in the aortic wall in these patients can possibly induce low coronary flow and systemic ventricular dysfunction in the future. As these patients have a prolonged survival due to recent medical and surgical development, a meticulous follow-up seems to be necessary for preventing dilatation and rupture or dissection of the ascending aorta.
Persistent truncus arteriosus, male 41 years old. Upper panel: MRI finding, the truncal artery is severely dilated. Lower panel: Histopathological findings of the truncus. Severely fragmented elastic fiber in the aortic media, aortic root grade 3 (polychromatic stain). TrA truncal artery, RPA right pulmonary artery, Ca calcium deposition
A 50-year-old female, tricuspid atresia (1b), post-Glenn procedure, right aortic arch, moderate aortic regurgitation, ascending aortic diameter: 50 mm. Left panel: Severe aortic regurgitation by echo. Right panel: Dilated ascending aorta by MRI. AAO ascending aorta, LV left ventricle, LA left atrium (Courtesy by Dr. Katayama H.)
2.7 Hypertensive Pulmonary Trunk Dilatation and Cystic Medial Necrosis
Cystic medial necrosis of the pulmonary trunk is recognized in Marfan syndrome as occurring in concert with similar aortic involvement [5, 6]. However, comparing to the ascending aorta, the incidence of pulmonary trunk aneurysm in Marfan syndrome is not high [6, 17, 18]. Pulmonary trunk aneurysm in ventricular septal defect or patent ductus arteriosus and pulmonary hypertension were reported, and the pulmonary truncal wall in these patients revealed cystic medial necrosis as it was observed in Marfan’s ascending aorta [38–43]. Postpartum maternal death is reported secondary to a dissecting aneurysm of the pulmonary trunk in patent ductus arteriosus and obstructive pulmonary vascular disease . When pulmonary hypertension dates from birth, pulmonary trunk histology is initially indistinguishable from that of the ascending aorta [32, 45], but when pulmonary hypertension is acquired after birth, the pulmonary trunk differs significantly from the ascending aorta. Before 1 year of age, medial abnormalities are absent in hypertensive pulmonary trunks associated with nonrestrictive ventricular septal defects, but they are consistently present after the age of 5 years .
In the histological study [1, 46], a patient with ruptured pulmonary trunk and Eisenmenger ventricular septal defect and a patient with ruptured ascending aorta and Eisenmenger ventricular septal defect revealed cystic medial necrosis in both pulmonary trunk and ascending aortic walls. Even in cyanotic adults with decreased pulmonary blood flow and surgical excessive left to right shunt, obstructive pulmonary vascular disease with pulmonary trunk dilatation is not rare. Dissection or rupture of pulmonary trunk aneurysm in tetralogy of Fallot and Blalock-Taussig shunt is reported [47, 48]. Also, one patient with shunted tetralogy of Fallot with ruptured pulmonary trunk aneurysm and the other patient with shunted single left ventricle with pulmonary stenosis and dissected pulmonary trunk aneurysm revealed typical cystic medial necrosis in pulmonary trunk. The former patient also revealed cystic medial necrosis in ascending aortic wall . It is reported that 7 of 18 patients with nonrestrictive ventricular septal defect, aging from newborn to 38 years, revealed cystic medial necrosis in the pulmonary trunk and four of seven patients revealed cystic medial necrosis in the ascending aorta simultaneously . Three of 21 patients with complete transposition of the great arteries revealed cystic medial necrosis in pulmonary trunk . A patient with tetralogy of Fallot with absent pulmonary valve revealed cystic medial necrosis in the pulmonary trunk . It was reported that in the pulmonary trunk of tetralogy of Fallot, elastin content diminished with increase in the collagen content [50, 51]. Therefore, cystic medial necrosis in the pulmonary trunk in CHD has been considered to be partly related to pulmonary hypertension; however, there may be intrinsic abnormality in the pulmonary trunk in CHD, especially in cyanotic. However, even after repair of tetralogy of Fallot, similar medial abnormality was occasionally found .