Download Bicuspid Aortic Valve Disease Beyond the Aortic Root

Journal of the American College of Cardiology
© 2010 by the American College of Cardiology Foundation
Published by Elsevier Inc.
EDITORIAL COMMENT
Bicuspid Aortic Valve Disease
Beyond the Aortic Root
Potential Prognostic Implications
for Ascending Aortic Dilation*
S. Morteza Farasat, MD
Farmington, Connecticut
With an estimated incidence of 1% to 2% in the general
population (1), bicuspid aortic valve (BAV) afflicts more
patients than all other congenital heart anomalies combined
(2). One-third of all patients with BAV experience one of
the serious complications of BAV, including aortic stenosis,
aortic regurgitation, infective endocarditis, and aortic dissection, in their lifetime (3).
See page 660
Aortic root dilation is an important, potentially lethal
complication of BAV (4) that substantially increases the risk
of ascending aortic aneurysm, dissection, and rupture (3).
Curiously, aortic valve replacement does not prevent progressive dilation of the ascending aorta (5), suggesting that
mechanisms unrelated to hemodynamic factors, or to the
valve per se, contribute to the aortopathy of BAV. Aortic
root dilation occurs in nearly one-half of all patients with
BAV (6 – 8). However, presently there are no prognostic
factors to help identify the patients who are at an increased
risk of developing ascending aortic dilation.
Given the strong heritability of BAV (9), genetic factors
are thought to play a role in the pathogenesis of ascending
aortic dilation in patients with BAV. Such a view gains
support from a recent prospective study by Biner et al. (7),
who discovered aortic root dilation in one-third of the
first-degree relatives of BAV patients who had normal
tricuspid aortic valves. Those investigators also found that
indexes of aortic stiffness were higher in both BAV patients
and their first-degree relatives compared with normal control subjects, irrespective of the presence of aortic root
dilation or hypertension status (7). Genetic factors, especially those that regulate extracellular matrix turnover, have
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the Division of Cardiology, Department of Medicine, University of Connecticut School of Medicine, Farmington, Connecticut.
Vol. 55, No. 7, 2010
ISSN 0735-1097/10/$36.00
doi:10.1016/j.jacc.2009.08.081
been implicated as putative mechanisms for these observations. Most notable among these are the genes that regulate
the balance between various members of the matrix metalloproteinase (MMP) family and their tissue inhibitors
(TIMPs).
Gene expression studies have documented increased expression of several MMPs, particularly MMP-2 and the
ratio of MMP-2 to its tissue inhibitor, TIMP-1, in aortic
tissues from BAV patients compared with subjects with a
tricuspid aortic valve with or without aortic aneurysms
(10 –12). There is general agreement that this differential
pattern of gene expression contributes to the classic pathological finding of aortic medial degeneration (4), characterized by loss of collagen and elastin fragmentation in the
aortas of patients with BAV (10,11).
Another interesting observation is that deficiency of
endothelium-derived nitric oxide, a key regulator of
endothelium-dependent flow-mediated vasodilation, also
seems to play a role in the defective valvulogenesis of BAV.
In an experimental study, Lee et al. (13) showed that
endothelium-derived nitric oxide synthase (eNOS) knockout mice had a significantly higher likelihood of developing
BAV than control mice. This is corroborated by human
studies documenting lower eNOS gene expression in the
ascending aortas of BAV patients than in ascending aortas
of control subjects with a tricuspid aortic valve (14).
The study by Tzemos et al. (15) in this issue of the
Journal provides an integrating view of the aforementioned
pathophysiological factors in BAV patients. In their observational study, Tzemos et al. (15) cross-sectionally evaluated
32 men with BAV, without significant aortic stenosis, who
were classified as having nondilated or dilated ascending
aortas. Brachial artery flow-mediated vasodilation, carotidfemoral pulse wave velocity (PWV), circulating plasma
levels of MMP-2 and -9, as well as their respective tissue
inhibitors, TIMP-1 and -2, were measured in the 2 BAV
groups and in 16 healthy male control subjects. The
investigators found that plasma levels of MMP-2 were
higher in men with BAV and dilated aortas compared with
both BAV subjects with nondilated aortas and normal
control subjects. However, the plasma levels of MMP-9,
TIMP-1, and TIMP-2 did not differ among the 3 study
groups. Although plasma levels of MMPs do not necessarily
mirror their tissue activity (16), the feasibility and ease of
measuring plasma MMPs compared with in vivo determination of their activity in aortic tissue render plasma levels of
MMPs an attractive candidate as a prognostic marker for
future ascending aortic dilation in BAV patients.
The finding of impaired flow-mediated vasodilation, a
hallmark of systemic endothelial dysfunction, in BAV patients with dilated aortas but not in those without dilated
aortas suggests that endothelial dysfunction may represent a
risk factor for the development of ascending aortic dilation.
This finding provides a preliminary rationale for investigating whether statins, which are known to have salutary effects
670
Farasat
Bicuspid Aortic Valve Disease Beyond Aortic Root
on endothelial function (17), can ameliorate BAV-related
ascending aortic dilation.
Consistent with previous studies (7,18), Tzemos et al.
(15) observed a higher PWV in BAV patients with dilated
aortas compared with those with nondilated aortas and with
normal control subjects. However, the PWV was similar in
BAV patients with nondilated aortas and normal control
subjects. According to the Moens-Korteweg equation:
PWV ⫽ 公Eh/␳D, where Eh is the aortic elastance-wall
thickness product, ␳ is the density of blood, and D is the
vessel diameter, PWV is inversely related to the square root
of the aortic diameter. Thus, for a given Eh, a larger vessel
diameter would be expected to result in a lower PWV.
However, in the study by Tzemos et al. (15), subjects with
dilated aortas had a higher PWV than the other 2 groups,
who had smaller aortic root diameters. This finding indicates that the lowering effect of the larger aortic root
diameter on PWV in BAV patients with dilated aortas was
counteracted by a more pronounced increase in the aortic
elastance–wall thickness product, reflecting the pathological
alterations in the aortic wall of BAV patients with dilated
aortas.
The cross-sectional design and the exclusion of women
from the study sample are the 2 most important limitations
of the study by Tzemos et al. (15). Nonetheless, this study
lays the groundwork for the future development of a risk
stratification paradigm for predicting the development of
ascending aortic dilation in patients with BAV. If the
findings reported by Tzemos et al. (15) are corroborated in
prospective studies, documenting that they pre-date ascending aortic dilation, they may provide useful tools for risk
stratification and thus guide surveillance and clinical management of patients with BAV.
JACC Vol. 55, No. 7, 2010
February 16, 2010:669–70
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Reprint requests and correspondence: Dr. S. Morteza Farasat,
University of Connecticut School of Medicine, Division of Cardiology, 263 Farmington Avenue, Farmington, Connecticut
06030. E-mail: [email protected].
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Key Words: aortic dilation y bicuspid valve y flow-mediated
vasodilation y MMP-2.