—  SHORT COURSE #13  —

Selected Arterial and Venous Diseases

Case 1 - Congenital Stenosing Arteriopathy with Medial Dysplasia

Alan G. Rose


Clinical History
This 2.5-year-old female presented with convulsions and was investigated for systemic hypertension (160/100 mm Hg). Physical examination showed retarded milestones, normal height and weight plus a cardiac systolic murmur and bruit over both carotid arteries. Femoral pulses were equal and there was no radiofemoral delay. Chest radiography showed clear lung fields with left ventricular enlargement. Renal function was normal with no elevation of urinary vanillyl mandelic acid. Normal intravenous pyelogram. An aortogram showed bilateral renal arterial stenosis. The patient collapsed and died less than 10 minutes after the aortogram was completed.

Autopsy revealed concentric hypertrophy of the left ventricle with subendocardial replacement fibrosis. Fresh infarction was absent. Both coronary ostia had narrow, pinhole orifices (90% narrowing). Cardiac valves were normal. Luminal narrowing caused by mural thickening of the coronary arteries affected the proximal 2 cm of the left coronary artery and involved only 0.8 cm of the right coronary artery.

The entire aorta throughout its course was greatly thickened (Figures 1–3) with a much-reduced internal diameter. At the level of the diaphragm the aortic internal diameter was only 5.0 mm and the aortic wall was 2.7 mm thick. Diffuse arterial thickening extended from the aorta into both common iliac arteries as far as their bifurcation points. The diffuse aortic thickening caused severe stenosis of the origins of all of its branches, e.g. innominate artery, carotid arteries, subclavian arteries, superior and inferior mesenteric arteries, celiac artery, and both renal arteries. These arteries showed variable lengths of thickening. An aortogram showed that the superior mesenteric artery gave rise to an abnormal, large artery, which passed anteriorly to the left kidney to reach the colonic splenic flexure where it joined a branch of the superior mesenteric artery to form an arterial arcade. Pulmonary artery was also thickened.


Case 1 - Figure 1 - Aortic arch, its branches and the thoracic aorta are greatly thickened (so-called "macaroni arteries")
Case 1 - Figure 2 - Thickened abdominal aorta
Case 1 - Figure 3 - Transverse section of distal abdominal aorta


Histology of the aorta (Figures 4-6) showed a mainly normal intima, apart from a few areas of intimal sclerosis. Arterial mural thickening was mainly due to hyperplasia of the medial lamellar units (composed of elastin, smooth muscle cells and collagen) with a mean overall total of 129 lamellar units compared to a mean of about 60 lamellar units in the normal human aorta. [1] The lamellar units appeared to be thicker than normal. The outer one-third of the media also showed a disordered, mosaic pattern. Pulmonary artery showed similar changes.


Case 1 - Figure 4 - Histology of aorta seen in Figure 3
Case 1 - Figure 5 - Disordered pattern of lamellar units in the outer media as well as an overall excessive number of lamellar units
Case 1 - Figure 6 - Disordered pattern of lamellar units in the outer media as well as an overall excessive number of lamellar units


The unique macroscopic and microscopic features of congenital stenotic arteriopathy (CSA) distinguish it from other forms of arterial dysplasia. Microscopic features of CSA have been seldom documented. [2, 3, 4, 5] The present case has been previously reportedby Rose et al. [5]

Despite the small diameter of the aorta, the number of lamellar units is increased. In the present patient the lamellar units in the disordered outer media appeared thicker than those in the inner media and in normal control aortas. This patient's aortic arch branches were narrowed by a similar hyperplasia of medial lamellar units, but the coronary and renal arteries were narrowed due to changes like those of the intimal fibroplasia form of fibromuscular dysplasia. [6] These muscular arteries showed intimal longitudinal smooth muscle hyperplasia plus elastosis.

Table 1 lists the features of autopsied patients with CSA:

Table 1: Autopsied Patients with Congenital Stenotic Arteriopathy

Authors Age Sex Aorta Arch Brs. Pulm Coronary Renal Other Associated Conditions
McDonald [2] 10 wk F + + + Iliac Supra AS
Cagle [4] 0 F + + + CAVC
Dominguez [3]
(All sisters)		 5 wk F + + + +
7 wk F + + + +
11 wk F + + + +
Rose [5] 2.5 yr F + + + + + Mesenteric

As indicated in Table 1, some cases of CSA had associated congenital heart disease. The condition may produce sudden infant death or stillbirth. A marked female predominance has been noted (all patients thus far have been females). A familial incidence has also been observed. Because of the diffuse nature of the arterial disease, the options for surgical correction are limited and no adult cases have thus far been reported.

Whereas most aortic diseases are characterized by a loss of medial elastic fibers (e.g. cystic medionecrosis) or a destruction of many lamellar units (aortitis), CSA is characterized by the reverse situation i.e. an increase in the number of aortic medial lamellar units.

Morphometry in Cardiovascular Disease
  1. As we have seen, morphometry of lamellar unit hyperplasia is important in recognition of the underlying abnormality in congenital stenosing arteriopathy.

  2. It is also important in the accurate assessment of the degree of atherosclerotic narrowing of a coronary artery since during life the residual arterial lumen will be fully distended in the form of a perfect circle in the transverse plane. The circumference of the internal elastic lamina is measured as representing the original lumen of the artery and the circumference of the residual lumen is also measured. Using a simple formula both circumferences are converted into the corresponding perfect circles and the relative areas are compared. The degree of narrowing obtained is usually less severe than the impression formed by pathologic ocular examination only.

  3. Muscle fiber diameter has also been assessed in a wide variety of conditions and it has been claimed to help in distinguishing various myocardial diseases. [7]

  4. The so-called caliber persistent artery is a condition where size and situation of an artery is important in diagnosis. Here one has an artery which is too large for its location due to lack of a normal branching pattern. The condition, which is under- diagnosed, is most often recognized in the gastric mucosa where erosion may lead to fatal hemorrhage (Dieulafoy's erosion).


Review of the Pathology of Fibromuscular Dysplasia (Fmd)
A synonym is fibromuscular hyperplasia. FMD is defined as a developmental vascular anomaly of medium-sized and small arteries, and rarely veins, [8] in which the vessel wall is altered by dysplasia, hypoplasia, and/or hyperplasia of the fibromuscular components usually in the media, rarely in the intima or adventitia (< 5%), causing stenosis, aneurysm formation, or medial dissection. [9] The condition is commonest in females of child-bearing age, but involves all ages, including children. [6 ]FMD occurs most often in the renal arteries of young women, followed in frequency of occurrence by the internal carotid arteries, visceral arteries, and rarely, the coronary arteries. Three main morphologic types are recognized: medial hyperplasia (about 95%), intimal fibroplasia (2%), and adventitial fibroplasia (about 2%). Medial hyperplasia is sometimes subdivided in turn into 3 variants: medial fibroplasia, medial hyperplasia and perimedial fibroplasia. Examples of each of these forms of FMD will be demonstrated.

Grossly or on angiography the appearance of the commonest form of FMD (medial hyperplasia/ medial fibroplasia) is that of a segmental, irregular, string of beads or corkscrew pattern, which may mimic the appearance of a vasculitis. Contrary to histologic examination of virtually all other blood vessels, the artery or vein should be sectioned longitudinally rather than transversely for microscopy in order to recognize the condition most effectively. This orientation allows for recognition of the characteristic hill and valley type corrugations of the vessel wall. Elastic van Gieson or Movat's pentachrome staining is mandatory in this condition.

There is an association between FMD and the development of cerebral berry aneurysms. FMD is a potentially curable cause of systemic hypertension. Other complications include dissecting aneurysm (sometimes no intimal tear is present), thromboemboli from the saccular aneurysms in FMD, and sudden death due to narrowing of the artery to the atrioventricular node.

The etiology of FMD remains uncertain, although hormonal causes are considered important in view of the sex incidence. Other postulated etiologic factors include arterial mural ischemia, primary developmental disorder of the multifunctional arterial medial cell and even viral infection. FMD has been treated by surgery and transluminal angioplasty.

Williams Syndrome
Williams syndrome, which is characterized by hypercalcemia, supravalvular aortic stenosis, elfin facies, and mental retardation, may also show peripheral vascular disease including renal artery stenosis, diffuse narrowing of the aorta and aortic coarctation. Coronary arterial stenosis may lead to myocardial infarction. The possibility of abnormal elastic fibers has been raised. [10]

Other Conditions Associated with Arterial Dissection or Rupture
Arterial rupture or dissection is usually associated either with systemic hypertension or cystic medionecrosis of the aortic media. In addition to fibromuscular dysplasia, there are a number of other conditions that may also predispose to these serious complications. These include segmental mediolytic arteriopathy, Ehlers-Danlos syndrome and scurvy amongst others.
  1. Cystic medionecrosis.
    Cystic medionecrosis (CMN) is a misnomer since no true cysts and no necrosis is present. The condition is an accompaniment of aging in the aorta and is present in the aorta in young patients with Marfan syndrome and its forme fruste. Deposits of acid mucopolysaccharides replace lost aortic lamellar units. CMN favors the development of dissection or rupture of the aorta. Marfan patients have mutations in FBN1 (fibrillin gene) on chromosome 15q21 and an autosomal dominant transmission occurs. New mutations comprise 25% of patients with Marfan syndrome. Marfan syndrome may produce severe neonatal pulmonary emphysema (see Case 4), as well as floppy mitral valve and aortic root dilatation. The differential diagnosis of Marfan syndrome in the young includes congenital contractual arachnodactyly, homocystinuria, Shprintzen-Goldberg syndrome, and familial aortic aneurysms and dissections.

  2. Segmental mediolytic arteriopathy.
    Segmental mediolytic arteriopathy (SMA), also termed segmental mediolytic arteritis or arterial mediolysis, is defined as a peculiar noninflammatory lesion of arteries, particularly the visceral arteries, and rarely the coronary arteries, that is characterized by focal lytic changes (vacuolation, mucoid degeneration) of the arterial wall that may result in arterial wall hemorrhage or dissection and thrombosis. Gross findings reflect the pattern of arterial involvement and may include ischemic bowel disease, and visceral or myocardial infarction. Microscopy is characterized by focal, segmental, medial lytic changes (vacuolation, mucoid degeneration) of arteries that may lead to mural tearing, rupture or dissection. Although the entity was originally described by Slavin [11] in 1976, the etiology and pathogenesis of SMA remain unknown. Both (i) an inappropriate vasospastic response to shock or severe hypoxemia, and (ii) a variant of arterial fibromuscular dysplasia [12] have been suggested as causes. Immune complex disease and a link to systemic lupus erythematosus has also been postulated. [13] Most reported cases have been in elderly patients, although a histologically similar condition occurs in hypoxic neonates.

  3. Ehlers-Danlos syndrome (EDS)
    The first comprehensive description of a syndrome of laxity and fragility of the skin associated with hypermobile large joints was published by Tschernogobow [14] in Moscow in 1892. However, the names of a Danish and of a French dermatologist have been used in the eponym for this syndrome. EDS is a heritable disorder of connective tissue having at least 11 subgroups with different clinical manifestations, biochemical defects, and inheritance patterns. Vascular disease is a feature of type IV, the so-called "arterial-ecchymotic" variant, which has a dominant inheritance with about half of the patients being new mutations. The molecular basis for the pathogenesis of Ehlers-Danlos syndrome type IV is believed to be that patients who are heterozygous for mutations in COL3A1 that do not cause premature chain termination produce about equal amounts of normal and abnormal type III procollagen polypeptides. [15] These interact to form the homotripolymer type III procollagen protein. However, only 1/8 of the proteins will contain three normal polypeptides, whereas the other 7/8 will contain at least one mutant polypeptide and will function abnormally. Type IV EDS results from an abnormality of type III collagen.

    Pepin et al. [16] state that although most affected patients survive the first and second major complications, EDS type IV results in premature death. The diagnosis should be considered in young people who come to medical attention because of uterine rupture during pregnancy or arterial or visceral rupture. In the 419 subjects they studied there were 272 arterial complications of which about half involved the thoracic or abdominal arteries. The most common non-lethal CNS events were fistulae involving the carotid artery, carotid artery dissection, aneurysm and rupture. Twelve women died during the peripartum period (5 of uterine rupture during labor, 2 of vessel rupture at delivery, and 5 of postpartum vessel rupture).

    Gross findings of EDS include single or multiple arterial aneurysms, with or without rupture or dissection, affecting aorta, peripheral, visceral and pulmonary arteries. Visceral rupture may also occur repeatedly. Microscopy shows variable degrees of medial degeneration, morphologically indistinguishable from that of Marfan syndrome, cystic medionecrosis and aging. Confirmation of the diagnosis depends on analysis of connective tissue for type III collagen (which is deficient in type IV EDS) and on demonstration of decreased production of type III procollagen by cultured fibroblasts.

  4. Scurvy
    Metabolic abnormalities do not always produce morphologically recognizable changes despite greatly decreased structural strength in a blood vessel. We have encountered a scorbutic (vitamin C deficient) ballet dancer whose femoral artery was ruptured by the thumb of her male dancing partner who caught her thighs in his hands. A small sample of the ruptured artery appeared normal histologically.

Vascular Elastosis: A Cause of Intestinal Ischemia in Patients with Ileal Carcinoid Tumors
Carcinoid tumors of the ileum may be associated with gangrene of the small intestine and some such patients show a unique vascular lesion in the large mesenteric vessels lying close to tumor infiltrated lymph nodes. The changes, which affect both arteries and veins, comprise pronounced adventitial and intimal elastification leading to luminal narrowing. [17] There is no sign of thrombosis or tumor infiltration. Local release of an elastogenic substance by the tumor is the likely basis of this lesion.

References

  1. Wolinsky H, Glagov S. A lamellar unit of aortic medial structure and function in mammals. Circ Res 1967; 20: 99-111.

  2. McDonald AH,Gerlis LM, Somerville J. Familial arteriopathy with associated pulmonary and systemic arterial stenoses. Br Heart J 1969;31: 375-385.

  3. Dominguez FE, Tate LG, Robinson MJ. Familial fibromuscular dysplasia presenting as sudden death. Am J Cardiovasc Pathol 1988;2: 269-272.

  4. Cagle PT, Kim H-S, Titus JL. Congenital stenotic arteriopathy with medial dysplasia. Hum Pathol 1985; 16: 528-530.

  5. Rose AG, Sinclair-Smith CC, Knobel GJ. Congenital stenotic arteriopathy with medial dysplasia of aorta, pulmonary artery, and their major branches. Cardiovasc Pathol 1996; 5: 77-80.

  6. Rose AG. Hypertension and diseases of medium-sized arteries. In Silver MD, ed. Cardiovascular Pathology, 2nd ed., New York: Churchill Livingstone, 1991; 1: 410-412.

  7. Gregory MA, Brouchaert CJ. Bivariate myofibre morphometry in detecting early myocardial pathology. Cardiovasc J South Afr 1993: 61-65.

  8. Wessely Z, Guerry RL, Klavins JV. Disseminated fibromuscular hyperplasia of vascular channels. Arch Pathol 1973; 96: 179-182.

  9. Lie JT. In: Diagnostic Criteria for Cardiovascular Pathology. Acquired Diseases, Bloom S (ed), Lie JT, Silver MD (assoc eds). Lippincott-Raven Publishers, Philadelphia, 1997, pp 183-184.

  10. O'Connor WN, Davis JB, Geissler R, et al. Supravalvular aortic stenosis. Clinical and pathological observations in six patients. Arch Pathol Lab Med 1985; 109: 179- 185.

  11. Slavin RE, Gonzalez-Vitale JC. Segmental mediolytic arteritis. A clinical pathologic study. Lab Invest 1976; 35: 23-29.

  12. Lie JT. Segmental mediolytic arteritis. Not an arteritis but a variant of arterial fibromuscular dysplasia. Arch Pathol Lab Med 1992; 116: 238-241.

  13. Juvonen T, Niemela O, Reinila A, Nissinen J, Kairaluoma MI. Spontaneous intraabdominal hemorrhage caused by segmental mediolytic arteritis in a patient with systemic lupus erythematosus – an underestimated entity of autoimmune origin? Europ J Vasc Surg 1994; 8: 96-100.

  14. Tschernogobow A. Cutis laxa. Mhft Prakt Dermatol 1892; 14: 76.

  15. Pyeritz RE. Editorial: Ehlers-Danlos syndrome. New Engl J Med 2000; 342: 730-732.

  16. Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. New Engl J Med 2000; 342: 673-680.

  17. Qizilbash AH. Carcinoid tumors, vascular elastosis, and ischemic disease of the small intestine. Dis Col Rectum 1977; 20: 554.