Elsevier

Cardiovascular Pathology

Volume 14, Issue 4, July–August 2005, Pages 185-188
Cardiovascular Pathology

Review Article
Heritable diseases of the blood vessels,☆☆

https://doi.org/10.1016/j.carpath.2005.04.003Get rights and content

Abstract

Four inherited disorders known to effect major arteries will be discussed, including Marfan syndrome (MS), Ehlers-Danlos syndrome (EDS), bicuspid aortic valve (BAV) and nonsyndromic familial aortic dissection. Recent advances in understanding their pathophysiology are presented, and how this knowledge impacts on diagnosis, prevention and treatment is discussed.

Introduction

The heritable diseases of blood vessels include conditions affecting both the large conducting arteries, such as the aorta, and those involving the microvasculature. These peripheral abnormalities are primarily associated with connective tissue problems that result in capillary fragility and, sometimes, impaired coagulation in response to this local injury. While these conditions are important, this will focus primarily on the life-threatening disorders that occur because of abnormalities in the major arteries. While surgical results for these problems continue to improve on an incremental basis, our understanding of the underlying metabolic problems is making steady progress. Of course, the long-term goal of research in this area is the development of a pharmaceutical or gene-based therapy to correct the basic underlying misstep of the cell. Until this goal can be achieved, however, the identification of individuals at risk for catastrophic vascular problems assumes great importance. Fortunately, in most cases, dilatation precedes arterial rupture or dissection. Thus, once identified, patients can be followed longitudinally and undergo elective surgical intervention. This paper will address four inherited disorders known to affect major arteries. These include Marfan syndrome (MS), Ehlers-Danlos syndrome (EDS), bicuspid aortic valve (BAV) and nonsyndromic familial aortic dissection. Important recent observations have changed our thinking about the pathophysiology of the aortic disease associated with these entities. We once believed that the mutant connective tissue protein corrupted the protein from the normal allele (dominant negative effect). When this was combined with the normal wear and tear to which the aorta is subjected, dilatation and dissection were the result. We are now learning that matrix proteins, in addition to their mechanical properties, have important roles in the homeostasis of the smooth muscle cell (SMC) that produces them. The matrix proteins have a key metabolic function through their ability to sequester, store and participate in the precisely controlled activation and release of bioactive molecules. This loss of function (biochemical rather than mechanical) is thought to alter SMC homeostasis and phenotype. The end result is a change in matrix metabolism that causes structural weakness in the aorta (Fig. 1).

Section snippets

Defining arterial pathology

The aorta and its major branches are affected by two entities that may be present simultaneously or occur at different stages of the disease process. An aneurysm is a dilatation of all three layers of the artery [1]. The most common definition is a 50% increase over the normal diameter. Arterial diameter is dependent on age, gender and body habitus. Aneurysms may, in rare cases, produce symptoms because of compression of surrounding structures, but rupture with exsanguination is the most

Marfan syndrome

MS is among the most prevalent hereditary connective tissue disorders. It is inherited in an autosomal dominant manner, with variable penetrance. Approximately one in four cases is not associated with a family history and is assumed to represent spontaneous mutation. MS is perhaps the best prototype for the heritable diseases of the great vessels because its phenotype often allows for premortem diagnosis, longitudinal follow-up and prophylactic intervention to prevent cardiovascular death [4].

Ehlers-Danlos syndrome Type IV

EDS represents a group of connective tissue disorders with associated skin fragility, easy bruising and susceptibility to osteroarthritis. There are a number of forms of the syndrome, but increased risk of premature death occurs only in EDS Type IV. This “vascular” form of EDS is cause by mutations in the Type III procollagen gene. Type III collagen is abundant in the intestine and arterial wall, accounting for the most common initial clinical presentation for patients with EDS IV, arterial

Bicuspid aortic valve

BAV may be the most common congenital anomaly resulting in aortic dilatation because it occurs in 1% of the general population. Among patients with aortic dissection detected at postmortem examination, 8% have BAVs. Histologic study shows elastin degradation in the aorta above the valve. Echocardiography of patients with BAVs shows that aortic root dilatation is common even in younger patients. BAVs cluster in families and are found in 9% of first-degree relatives of affected individuals.

Nonsyndromic familial thoracic aortic dissection and aneurysms

Studies have shown that as many as 19% of patients referred for repair of thoracic aneurysm or dissection have another affected family member. Many of these families do not meet the clinical criteria for MS or have biochemical abnormalities in Type III collagen. In most of these families, the inheritance appears dominant with variable penetrance, especially regarding the age of onset. These familial aneurysms and dissections have mapped to two loci on the long arms of chromosomes 5 and 11. The

Summary

While our experience with EDS, BAV and familial aortic dissection and aneurysms is in the early stages, there is much to be learned about these disorders following the pattern of investigation used for MS. Our concept of MS has evolved from a simple weakness in a matrix component to a change that alters both the SMC phenotype and matrix metabolism. This understanding came about through a series of steps, including the identification of the involved protein, development of animal models that

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Cited by (0)

Grant support NIH 2 RO-1 HL062400-06.

☆☆

This article is based on a presentation at the Society for Cardiovascular Pathology Companion Meeting at the United States and Canadian Academy of Pathology, February 27, 2005, San Antonio, TX.

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