Genetic Diseases of the Aorta (Including Aneurysms)

The Normal Aorta: Histology and Function

The aorta is the largest artery, by caliber, in the human body. It is the conduit from the heart that extends from the thoracic cavity to the pelvic area where it bifurcates to create the iliac arteries. In adults, this vessel can measure around 490 cm in length. This elastic artery is important in absorbing the systolic bolus of blood emanating from the contracting left vessel and supplying a continuous flow of blood into all of the body’s organs and extremities. There is a slight vascular expansion that occurs in conjunction with the passing systolic wave followed by elastic recoil that occurs after the wave has passed. With recoil, the vessel returns to its normal caliber. The aortic wall is divided into three anatomic divisions relative to the vessel lumen: the tunica intima, tunica media, and tunica adventitia.

The tunica intima (intima) extends from the endothelium to the internal elastic lamina (IEL).The endothelium is a single layer of endothelial cells forming a barrier between the structural aorta and the passing blood. In healthy aortae, beneath these endothelial cells, is a small amount of connective tissue, primarily type III and type IV collagen. Occasional mesenchymal cells, variably described as fibroblasts, myofibroblasts, or smooth muscle cells, are also present in this space. Endothelial cells are important mediators of vascular activity, providing paracrine control over the vascular smooth muscle cells (VSMCs) of the media (See Chapter 11, Chapter 12 ). One key pathway of this regulation is the nitric oxide system. Nitric oxide, produced by endothelial cells, either constitutively by endothelial nitric oxide synthase (eNOS) or by the stimulated inducible NOS (iNOS), induces vasodilation by signaling underlying smooth muscle cells to relax. Other endothelial function, or more accurately, endothelial dysfunction, is thought to initiate pro-inflammatory signaling resulting in atherosclerosis. An important local factor causing endothelial dysfunction is non-laminar flow, found at branch points and bifurcations. This non-laminar flow results in pro-atherogenic shear stress. A force of 16 dynes/cm and a pulsatile pattern wave form have been shown to be the most atherosclerosis-resistant flow across endothelium, while slower or more turbulent forms are pro-atherogenic. Endothelial dysfunction can also be driven by systemic factors. Toxic metabolites of smoking, advanced glycation end products, cholesterol, hyperglycemic effects and dietary deficiencies all can result in increased endothelial signaling to increase inflammation and drive atherosclerosis. Healthy and intact endothelial cells also prevent vascular thrombosis by acting as a barrier between extracellular matrix and circulating clotting factors.

The intima is sharply demarcated from the tunica media by the internal elastic lamina (IEL). The IEL is a continuous fenestrated elastic fiber. It is reasonably thick and is easily visible and distinguishable when elastic staining is performed on a histologic section. The IEL functions as a barrier preventing the movement of large molecules such as albumin and cholesterol from passing from the intima into the underlying media. The IEL is a feature of all large- and medium-caliber arteries. Beneath the IEL is the tunica media.

The aortic media is a circumferential compaction of lamellar units ( Figure 13.1 ). Each lamellar unit consists of a layer of elastic fibers overlying a layer of smooth muscle cells. Within the lamellar unit is a small amount of other extracellular matrix material including collagen and a fine elastic network of ground substance that is composed of mucopolysaccharides and glycosaminoglycans. The dominant collagen type is type III, followed by type I and type IV. Depending on the proximity to the annulus, there are ∼60 lamellar units within the human aorta stacked from the IEL to the outermost media. Interestingly, lamellar units correlate with animal body size with small animals such as a mouse having an average of five lamellar units and large animals such as pigs having an average of 72 lamellar units. Healthy elastic fibers are roughly 1.5 μm in thickness. The smooth muscle cells of the media are uniformly tapered cells oriented parallel to the arterial wall. They have a contractile apparatus, not visible on histologic slides, that controls vasorelaxation and vasoconstriction.

Embryologically, the VSMCs of the ascending and abdominal aortic media are derived from different founding cell populations. The VSMCs of the ascending aorta originate from ectodermal cardiac neural crest tissues. Conversely, the VSMCs of the abdominal aorta are mesodermally derived from somites. This distinction is believed to be important in the role of TGF-β on the localization of syndromic aortic disease described below.

Due to the thickness of the arterial wall, oxygen and other metabolites are unable to diffuse to the outermost lamellar units. Thus the aorta has a specialized vascular supply system to the outer third of the media. This system is known as the vasa vasorum which runs parallel to the aorta within the adventitia. The ascending aortic vasa vasorum arises from branching vessels of the coronary arteries, and the aortic arch has vasa vasorum derived from neck vessels. The vasa vasorum has small penetrating arteries and veins that enter the outer part of the media.

The external elastic lamina separates the media from the adventitia. This elastic lamina is often less distinct from the IEL and is often recognizable on an elastic stain as the location where the normal lamellar unit structure of the media segues into a more indistinct arrangement of elastic fibers. The adventitia functions to anchor the aorta to other adjacent structures and restrain the vessel from excessive extension and recoil. The adventitia is comprised of a variety of extracellular matrix proteins providing loose and dense irregular connective tissues loosely arranged with intermixed adipocytes, lymphatic channels, nerves, thin-walled vessels and rare chronic inflammatory cells. The adventitia can be variably sized from only a small amount of extracellular matrix material containing the vasa vasorum to a thick rind of fibrous tissue appreciated in some aortic diseases.

Gross Pathologic Changes to the Aorta

The three main disease processes impacting on the aorta are atherosclerosis, inflammation, and aneurysm. Atherosclerosis, common to many large-caliber arteries, is described in detail in Chapter 12 and only briefly here. At the gross level, aortic atherosclerosis forms intimal plaques at areas of bifurcation, branch points, or areas of turbulent flow. The infrarenal aorta and aortic arch are the two sites that most commonly contain plaque. These intimal plaques appear as calcified, thickened, yellow-to-white areas in the aorta measuring up to several centimeters. Some severe plaques can have ulcerations with adherent thrombi. When atherosclerosis results in vessel aneurysm (typically located in the infrarenal aorta), mural thrombi can form in the vessel. This thrombus can appear gray and gelatinous-like.

Inflammatory processes, i.e. arteritis, are also a pathologic entity impacting on the aorta. Arteritis is described in Chapter 11 . Grossly, arteritis of the aorta – aortitis – can cause adventitial thickening and/or intimal thickening as inflammatory cells drive fibrotic changes to the wall. Grossly, aortitis can have a ‘tree bark’ appearance in which the wall has wrinkles and ridges defining separate plaques. Aortitis, from any cause, can also damage the media leading to its thinning and potential aneurysm.

Aneurysms have been defined as dilatations of the arterial wall, over 50% larger than the normal size, in which all layers – the intima, media, and adventitia – are involved. False aneurysms do not involve all three layers. The two major types of aneurysms – are saccular – outpouchings of the wall – and fusiform – concentric expansions of the wall. The so-called ‘berry aneurysm’ of the circle of Willis is a typical saccular aneurysm associated with autosomal dominant polycystic kidney disease (ADPKD), hypertension or smoking. Fusiform aneurysms are more frequent in both the ascending and abdominal aorta. In the ascending aorta, they are strongly associated with genetic influences and are frequently seen in syndromes involving mutation in a single gene. Aortic aneurysms can also be the result of atherosclerosis or aortitis mentioned above. Aneurysms can occur at any location within the arterial tree but certain anatomic locations are more frequent. Common event sites include the ascending thoracic aorta and aortic arch, infrarenal abdominal aorta, carotid artery, renal artery, and the circle of Willis.

While aneurysms are worrisome clinical entities, they may cause no direct morbidity. Aneurysms in the ascending aorta can lead to insufficiency or regurgitation of the aortic valve. Large aneurysms may also rupture, leading to catastrophic events, such as hemoperitoneum and stroke. In contrast to ruptured aneurysms, dissections may occur in an artery either with or without a pre-existing aneurysm ( Figure 13.2 ). Dissections cause mortality primarily through reduced arterial flow to critical organs such as the heart, brain, and abdominal viscera. Similar to aneurysm rupture, dissections can progress through the entire arterial wall allowing blood to exit the blood vessel and fill anatomic spaces resulting in hemothorax, hemoperitoneum, or cardiac compromise through hemopericardium. Even in the current era with excellent medical imaging and surgical techniques, dissections are still associated with a 13–30% rate of in-hospital mortality depending on their location.

Two classification schemes exist to describe the directionality of dissection progression in the aorta. These two schemes, the DeBakey and the Stanford conventions, take into account the initial intimal location of the tear and the direction of their dissection. A dissection that begins in the ascending aorta and extends into the descending/abdominal aorta is a DeBakey I. If the dissection is confined to the ascending aorta it is a DeBakey II, and if it involves only the descending aorta it is a DeBakey III. In the Stanford criteria, any involvement of the ascending aorta is type A and any dissection not in the ascending aorta is a type B.

Demographics of Aneurysms and Dissections

As a result of dissections, thoracic aortic aneurysms precede major morbidity and mortality in industrialized nations, including the United States. Because preclinical aortic aneurysms are difficult to detect, the incidence and prevalence of these aortic lesions are incompletely described. However, aortic dissection, which is the life-threatening sequela of aortic aneurysm, is thought to occur at approximately ∼3 cases per 100000 patient years. Dissection is slightly more likely to occur in males than females and among individuals in the sixth decade of life. Despite the overall advanced age of aneurysm patients, ascending aortic dissection has a bimodal pattern with a second population, harboring genetic mutations in a variety of aortopathic syndromes occurring in adolescents and young adults. This early appearance of aneurysm is associated with different etiologic causes and histopathologic appearances.

Classically, abrupt tearing chest pain is the main symptom of acute aortic dissection. Additional signs and symptoms of dissection include pulse differences between upper and lower extremities, acute congestive heart failure, altered consciousness, a widened mediastinum on chest X-ray and a periaortic hematoma by computed tomography (CT) or magnetic resonance imaging (MRI) scan.

Histopathologic Changes to the Aorta

There are three important overlapping histopathologic observations that can be made in the aorta. These are atherosclerotic plaques, inflammation, and medial degeneration. As mentioned above, atherosclerosis is described in greater detail in Chapter 12 . Briefly, atherosclerosis can be an important cause of aortic aneurysm. It can cause medial thinning in part likely due to anoxic injury to the smooth muscle cells below a large area of intimal atherosclerotic plaque. Once smooth muscle cell loss has occurred, leading to medial thinning, repeated systolic pulse pressure waves can dilate the wall locally in the absence of sufficient vascular strength and recoil. Atherosclerosis is a primary cause of abdominal aortic aneurysms. In the ascending aorta, extensive plaque burden is present in only a small subset of individuals and rarely in individuals harboring mutations in genes that predispose toward aneurysm. Atherosclerosis is generally not as frequent as the constellation of histopathologies known as medial degeneration in this second population. Atherosclerosis occurs throughout the full length of the aorta, but the plaque burden is usually more extensive in the perirenal abdominal aorta than ascending aorta. Extensive plaque burden in the abdominal area leads to a marked thinning of the media. Any degree of plaque severity, from pre-atheromas to complex and fissured plaques, may be present along with marked inflammation. When associated with aneurysm, a large segment of the underlying VSMCs is lost with resultant laminar medial collapse. These histopathologies are described below. Atherosclerotic plaques are also associated with inflammation; generally chronic inflammatory cells present in the adventitia.

Aortic injury can also be the result of an inflammatory process. Several varieties of aortitis can occur including granulomatous (giant cell), lymphoplasmacytic, mixed inflammatory pattern and suppurative. Vasculitis is described in greater detail in Chapter 11 . When the inflammatory infiltrate causes medial injury, wall weakness can occur resulting in aneurysm. Sometimes heavy inflammation is seen in the presence of atherosclerotic plaque. A distinction between atherosclerosis and inflammatory disease can be challenging and likely represents a continuum.

Often, aneurysms can occur in the absence of atherosclerosis or inflammation. Generally this is in the setting of a genetic syndrome. The overarching term ‘medial degeneration’ is used to describe the collection of histopathologic changes seen in this situation. It is important to note that historically a variety of terms have been used to describe these histopathologies that have had overlapping meanings. Many of these terms, such as cystic medial necrosis, are understood by pathologists for the histopathologic change they represent, but are inaccurate to the event. For example, the histology described by cystic medial necrosis contains neither cysts nor necrosis. A report on specific parts of medial degeneration that represent histologic features of aneurysmal disease follows below. In general, these changes are non-specific, i.e. not indicative of any single genetic syndrome, but in general their presence in younger individuals does suggest an underlying genetic causality.

The most commonly recognized histopathologic finding is mucoid extracellular matrix deposition. This mucoid material, alternatively called glycosaminoglycans, glycoproteins, proteoglycans, or mucopolysaccharides increases in the arterial wall and causes either translamellar or intralamellar expansion. This mucoid material may be so abundant as to form ‘pools’ in the tissue, causing large translamellar expansions ( Figure 13.3 ). Historically, this was referred to as cystic medial necrosis or cystic medial degeneration. These terms are falling out of favor for reasons described above. The distribution of mucoid material is a feature that may suggest different underlying genetic etiologies. Translamellar pools of mucoid material are classically described in Marfan syndrome (MFS) and other genetic syndromes. Intralamellar collections of mucoid material are more subtle and appear to be more frequent in Loeys-Dietz syndrome (LDS) ( Figure 13.4 ). Mucoid extracellular matrix can be appreciated on hematoxylin and eosin slides and more easily on Movat Pentachrome stains. To date, it is not clear if there is a functional role of this material in aneurysms, or if it is just a marker of aortic disease.

A second histopathologic change, frequently encountered, is elastic fiber fragmentation and/or loss ( Figure 13.5 ). In syndromic aortic disease, elastic fibers are frequently fragmented, reduced in caliber or completely lost. To see these changes, an elastic fiber stain (Movat Pentachrome, Verhoeff-Van Gieson, or similar) must be performed on the tissue. This elastic fiber loss has a negative effect on aortic recoil after systolic ejection of blood from the heart. It is believed that over time, as the vessel (primarily the aortic root) is unable to achieve effective elastic recoil, the aneurysm expands.

The loss of smooth muscle cells from the media is important in aneurysm formation ( Figure 13.6 ). This loss is a common finding in atherosclerosis, aortitis, and some syndromic forms of aneurysm. VSMC loss is noted by the absence of VSMC nuclei in a segment of aortic media. This regional VSMC loss can be seen in a variety of pathologic states and important to note, occurs in normal aging. When the VSMC loss is extensive allowing the elastic fibers to collapse together in that region, the term laminar medial collapse is used. Laminar medial collapse is best appreciated on an elastic strain ( Figure 13.7 ). Injury to the vasa vasorum can specifically cause VSMC loss in the outer third of the aorta.

It is important to recognize that all of these histopathologic findings have been described as processes of aging in addition to being precursors to aneurysm. Thus, it is the early onset of these histopathologies, rather than the pure uniqueness of these microscopic findings, that is important to appreciate in syndromic and non-syndromic aortopathies. In older adults with ascending aneurysms but without genetic mutations, these findings are often present, generally concurrent to the presence of atherosclerotic plaques.

Specific Genetic Syndromes and Causes of Aneurysm