Disorders of Vascular Fragility
Implications for Active Patients
Reed E. Pyeritz, MD, PhD
Exercise and Sports Cardiology Series
THE PHYSICIAN AND SPORTSMEDICINE - VOL 29 - NO. 6 - JUNE 2021
This article was adapted from the recently published book: Thompson PD (ed): Exercise and Sports Cardiology, New York City, McGraw-Hill Medical Publishing, 2021 (to order: 1-800-262-4729 [ISBN:0-07-134773-9]).
In Brief: Circulatory vessels are subject to diverse pathologic processes that depend on the properties of the vessels. Vascular problems such as dilatation, dissection, and rupture can occur as a result of many disorders. Conditions that affect vessels include inherited disorders such as Marfan syndrome and the Ehlers-Danlos syndromes and poorly understood congenital disorders such as arteriovenous malformations and capillary fragility. Depending on which condition patients have, they must be given proper counseling about activity and options for management. For some patients, strenuous exercise, pregnancy, and competitive sports are prohibited, but for others with milder disorders, participation in selected sports is permitted.
The wall of a blood vessel can be as highly complex as that of an elastic artery (multilayered structure), or as simple as that of a capillary (composed of a single endothelial cell layer and a basement membrane). Blood vessels are subject to diverse pathologic processes, such as atherosclerosis, thrombosis, and calcification, that depend on the intrinsic properties of the vascular wall. The clinical presentations and consequences of these particular vascular problems include the common causes of dilatation, dissection, and rupture of any type of blood vessel. The focus here will be on young, active patients who might be at risk from vigorous exertion rather than on older patients in whom degenerative conditions become increasingly common.
Clinical Presentations of Vascular Fragility
Vascular fragility can occur in several forms, each of which has its own characteristics and causes. Specific disorders require management to lessen the potential for adverse consequences in active patients.
The caliber of any portion of a given artery normally varies with age and body size. Standards, however, exist for major arteries, especially the aorta (1,2). But several terms cause confusion, and, unfortunately, are often used interchangeably.
Nomenclature. Aneurysm can be a subjective term. The degree of dilatation that constitutes an aneurysm varies among studies and clinical usage. For the aorta, a criterion of 1.5 times the expected normal diameter for the vessel at the specific location has been suggested (3). However, an aneurysm is anatomically limited to a short region, though an individual might have multiple aneurysms in the same vessel. Ectasia is an extensive dilatation, which may be confined to a single vessel, be more generalized, or even systemic. The symmetry of dilatation is also used for classification: a fusiform aneurysm is symmetric and extends at least 5 to 8 cm; a saccular aneurysm represents a defect of one portion of the arterial wall and is exemplified by the "berry" aneurysm commonly seen in the cerebral circulation. A pseudoaneurysm is not a true aneurysm, but rather a collection of extravascular blood (clotted, free-flowing, or both). A common cause is traumatic or pathologic rupture contained by organized thrombus and structures surrounding the artery. Occasionally the initial rupture is iatrogenic, such as by arterial cannulation.
Natural history. The caliber of an artery can be abnormally large due to trauma, inflammation, infection, focal or generalized developmental defects, or generalized vascular wall defects. The diameter of the ascending aorta increases modestly, but significantly, as one ages. The causes of aneurysms vary with the type of artery and the location (table 1). Since many causes are systemic, the discovery of one aneurysm should prompt a search for others.
Gradual dilatation of an artery is usually painless, but if the cause is a generalized condition, such as polyarteritis nodosum or adult polycystic kidney disease, the patient may have other symptoms. However, the chronic and progressive dilatation of the aortic root that occurs in Marfan syndrome and of the abdominal aorta that occurs in the common forms of aneurysmal disease are usually without symptoms, even if they have a large diameter (6 to 8 cm). The onset of pain usually means rapid expansion or localized tearing, perhaps signaling impending rupture. Physicians ignore this clue at their patient's—and their own—peril.
Complications. Clinical sequelae of an aneurysm relate to its location and to the vascular forces acting on it. Complications include dissection, rupture, or both; local pressure on surrounding structures; and, in the case of the aortic root, aortic regurgitation. Even large aortic aneurysms rarely cause problems related only to their size. An exception is stretching of the recurrent laryngeal and vagus nerves that course around the aortic arch. Aneurysm is always in the differential diagnosis of otherwise unexplained hoarseness because aortic arch aneurysms can affect the recurrent laryngeal nerve. As a general rule, aneurysms of any part of the aorta that reach 55 mm in diameter should be repaired (4-6).
Arterial Dissection or Rupture
Dissection is the entry of the circulation into the wall of a vessel. This usually occurs when the tunica media vasorum is defective and the intima tears. Occasionally, rupture of the vasovasorum produces an intramural hematoma that may stabilize or progress to frank dissection. A dissection is fully contained within the vessel, and it may progress for any length antegrade or retrograde and even reenter the true lumen of the vessel.
Complications of dissection include blockage of branch vessels (leading to myocardial infarction, stroke, limb ischemia, paraplegia, etc), rupture, and aortic regurgitation (in ascending aortic dissection) (7). Aortic dissections can have diverse causes (table 2). LaPlace's law pertains, especially, to capacitance vessels such as the aorta. This law states that the tension on the vascular wall is directly related to the radius and the blood pressure and indirectly related to the thickness of the wall. For example, in Marfan syndrome, as the radius increases, the wall thins and the tension on the wall increases markedly. This accounts for the well-documented increasing risk of dissection as the aortic root caliber increases, even if there is considerable individual variation in risk at equal aortic diameters. In contrast, in syphilitic aortitis the wall becomes thickened and even calcified, and, despite substantial dilatation, dissection is uncommon.
Because of location, the common and internal carotid arteries are susceptible to blunt and torsional trauma during athletic activities. Dissection can result in an acute cerebral ischemic event (8). Intrinsic abnormalities of the aortic wall clearly predispose the vessel to such events.
Rupture is a tear through all layers of the vessel wall, and in the the aorta it is often preceded by dissection. Arterial rupture can have different causes (table 3). Complications depend on the vessel size and tear location. Dissection of the ascending aorta may extend retrograde and rupture into the pericardial sac, producing tamponade. Rupture of any other portion of the aorta carries a high risk of massive hemorrhage and hypovolemic shock. Occasionally, aortic rupture occurs into the pulmonary artery, esophagus, or intestine. Focal rupture due to trauma, even of the aorta, may produce a pseudoaneurysm that remains contained, at least for a time. Rupture of a peripheral artery often produces a focal hematoma that may tamponade the vascular tear. One risk is that the hematoma will itself cause problems, such as compartment syndrome leading to myonecrosis or venous obstruction leading to edema.
The cause and pathogenesis of vein dilatation are poorly understood. Genetic factors clearly play a role, as varicosities of the superficial veins in the leg occur with increased frequency in Marfan syndrome and in some families without an evident connective-tissue disorder (9). The process is clearly a vicious circle: As a vein dilates, a valve becomes incompetent, which leads to pooling of blood and further intravascular pressure on the dependent (inferior) portion of the vein. Developmental defects of veins occur in several conditions, including Klippel-Trenaunay syndrome and Noonan syndrome. Peripheral edema, especially of the legs, has early onset and persistence, despite aggressive treatment with compression stockings.
The complications of chronic venous varicosities include those of venous stasis: edema, skin atrophy, loss of hair, hyperpigmentation, and poor wound healing.
Arteriovenous Malformations and Capillary Fragility
All normal connections between the arterial and venous circulation occur through capillaries. Capillaries not only mediate the transfer of oxygen and nutrients to tissues in end organs and in uptake of carbon dioxide, but they also allow for arterial pressure to diminish gradually to that of the venous system. Whenever the connection occurs at the level of arterioles and venules or resistance arteries and veins, all normal functions of a patient's capillaries are lost.
Arteriovenous malformations (AVMs). AVMs are most commonly developmental or traumatic. When AVMs are developmental, multiple ones are likely. Traumatic AVMs may occur from blunt trauma (usually of an extremity) or penetrating wounds. Iatrogenic AVMs may be unintentional (surgical complications) or intentional, such as shunts and fistulas for access for hemodialysis.
Complications from AVMs include high-output cardiac failure (usually associated with either multiple AVMs or with a communication between a single large artery and vein); consequences of emboli (stroke, end-organ ischemia, abscess); systemic hypoxemia (pulmonary AVMs); and rupture, usually of the vessel at the arterial side of the malformation.
Capillary fragility. Generalized capillary fragility is usually associated with systemic disorders of connective tissue, such as Ehlers-Danlos syndromes, especially the vascular form. The most common cause of acquired capillary fragility is an excess of adrenocortical hormones, either through glandular overproduction (eg, Cushing syndrome) or from exogenous sources (eg, hormone-producing tumor). The major complication is excessive bruising, with subsequent hyperpigmentation and skin atrophy.
Disorders That Predispose to Vascular Fragility
Several conditions predispose patients to vascular fragility, including Marfan syndrome, Ehlers-Danlos syndromes, and polycystic kidney disease. The disorders present differing degrees of risk, and management strategies have been guided by current knowledge of disease etiology and available therapies.
Marfan syndrome is an autosomal dominant disorder stemming from defects in the FBN1 gene that encodes the microfibrillar protein, fibrillin-1 (10-13). Manifestations occur in many systems, especially the eye, skeleton, dura, lung, and cardiovascular system. The major risks to an athlete with Marfan syndrome are cardiovascular problems (14-16) arising from the two primary defects: aortic root dilatation and mitral valve prolapse.
The syndrome is more prevalent than was generally recognized; occurrence is at least 1 per 5,000 in the general population, and all ethnic groups are equally affected. Diagnosis is based largely on clinical criteria (17). The condition was covered in detail in last month's issue (see "Sports and Marfan Syndrome: Awareness and Early Diagnosis Can Prevent Sudden Death," May, page 80).
A new classification scheme for the Ehlers-Danlos syndromes has been advanced (table 4: not shown) (18-20). The unifying theme is joint and skin involvement; the individual types are distinguished by the severity of joint and skin manifestations and by the involvement of other tissues (19,21). Joints tend to be hypermobile, both passively and actively. Dislocations are somewhat more common than in the general population, and the risks of tendon and ligament rupture are clearly increased. Skin fragility leads to frequent lacerations and an inability to hold standard sutures. Healing is delayed, wounds gape, and scars are atrophic. Bruising is increased in all the types, some more than others. No accurate prevalence estimates exist; fortunately, the vascular type occurs in fewer than 1 per 20,000.
Classic type. Formerly called Ehlers-Danlos syndrome 1 and 2, the classic type manifests with an underrecognized tendency to develop dilatation of the ascending aorta (22,23); however, this is typically not as frequent or severe as in Marfan syndrome. Many people with classic Ehlers-Danlos syndrome do have mitral valve prolapse, occasionally associated with important mitral regurgitation, dysrhythmia, or both. Thus, persons with the classic form should have a screening echocardiogram before they participate in competitive athletics.
Vascular type. Vascular and viscus fragility is the main concern in the vascular form of Ehlers-Danlos syndrome. This condition is due to a functional or relative deficiency of type 3 collagen and is inherited most often as an autosomal dominant trait. Rupture of the bowel, uterus, and bladder can occur either spontaneously or with minimal blunt trauma (21). Most affected individuals also have skin fragility, easy bruising, and poor wound healing.
The most feared complication, however, is arterial rupture (22). The vessels at most risk include the descending aorta and all its major branches. Occasionally some dilatation precedes a rupture, but in most cases the artery simply tears, without dissection. For this reason, people with the vascular form of Ehler-Danlos syndrome should avoid all strenuous exertion (including pregnancy, during which the risk of arterial or uterine rupture is quite high (24),) as well activities that carry a risk of collision (eg, downhill skiing, football).
Polycystic Kidney Disease
Adult polycsytic kidney disease is one of the most common causes of end-stage renal disease and hemodialysis in the developed world. The condition is autosomal dominant and genetically heterogeneous, with mutations in at least three different genes causing the disease (25-27). The most common cause is mutation of the PKD1 locus on chromosome 16p13.3-p13.12, with mutation of the PKD2 locus at 4q21-q23 accounting for about 10% of affected families. In adult polycystic kidney disease arising from mutations in PKD2, the course of renal disease and hypertension is generally milder. People with this disease often develop mild dilatation of the aortic root, which rarely results in clinical problems, and mitral valve prolapse (27). The risk for abdominal aortic aneurysm may also be increased (28).
A much more important vascular feature is the occurrence of cerebral aneurysms of the "berry" type. Approximately 5% of people with adult polycystic kidney disease have clinically relevant but often asymptomatic berry aneurysms (29). It remains uncertain to what extent people with this disease should be screened for cerebral aneurysms, and by what method. One group (29) recommended high-resolution computed tomography (CT). The potential for such aneurysms is a strong motivation for controlling blood pressure, especially as renal function deteriorates. A strong argument could be made that any person with adult polycystic kidney disease should avoid activities that markedly increase the heart rate-blood pressure product.
Molecular testing is available to detect family members who have inherited mutations of PKD1 or PKD2. Alternatively, renal ultrasound can be used, but because the kidney cysts are age-dependent, determination of whether or not a person has inherited the mutant allele will not be clear in some patients until middle-age or later.
Familial Intracranial (Berry) Aneurysm
The frequency with which cerebral aneurysms are hereditary is unclear, but in some families, autosomal dominance is the most likely, but unproven, inheritance pattern. Several population surveys suggest a familial prevalence of 10% to 20% (30,31). As a result, a routine question on athletes' preparticipation medical screening should ask about any relatives who have had strokes or cerebral hemorrhages before they were 50 years old. A positive response should prompt more scrutiny of the family history. However, no one is certain about the extent to which screening modalities such as CT or magnetic resonance imaging can detect those at risk, especially adolescents or young adults. Furthermore, it is unclear whether asymptomatic, small aneurysms, once detected, require surgery (32). Individuals with berry aneurysms should avoid vigorous exercise.
Familial Abdominal Aortic Aneurysm
Aneurysms of the abdominal aorta are a disease of aging, with the prevalence among 50-year-olds quite low but among 70-year-olds about 5% to 10%. Men are much more frequently affected than women. Because of this age distribution, abdominal aorta aneurysms pose little risk, statistically, for the young, competitive athlete. However, because the general population rarely distinguishes among "aneurysms," a positive response to a family history screening question about aneurysms will often reveal relatives who had abdominal aorta aneurysms. While the information may have little relevance at that time to the athlete, it is worth noting that this disease clearly has a strong familial predisposition (33).
Although no data exist to support the following recommendations, individuals with abdominal aorta aneurysms greater than 40 mm in diameter should avoid vigorous exercise and contact sports. Mounting evidence suggests that the underlying cause is inflammation, which induces apoptosis of vascular smooth muscle cells (34). No causative gene has been identified.
Giving Specific Advice
Although many disorders require patients to avoid participation in contact sport, they need not be inactive. Patients can be encouraged to be active and participate in other noncontact activities such as swimming and golf. Physicians must offer advice about and provide specific limits on patient activities to mitigate potential problems.
Dr Pyeritz is a professor in the departments of genetics and medicine at the University of Pennsylvania School of Medicine in Philadelphia and director of the Division of Medical Genetics at the Hospital of the University of Pennsylvania. Address correspondence to Reed E. Pyeritz, MD, PhD, University of Pennsylvania School of Medicine, 36th and Spruce St, Philadelphia, PA 19104-4283.