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122 Milewicz et al.
DISCUSSION AND COMMENTARY
Questions for the Authors
Are you sometimes unsure, on clinical grounds, whether a given patient actually
has Marfan disease, despite the Ghent criteria? Doesn’t it sometimes seem that
not all the systems are yet manifesting the Marfan disorders, but that they will in
time? How do you classify these patients?
The current diagnostic criteria (Ghent criteria) are complicated by a number of fac-
tors. First, younger children may not fill the diagnostic criteria and may require repeat
evaluations to be certain that the diagnostic features for MFS do not emerge as the
child grows older. Second, some individuals have skeletal features of MFS, aortic
root dilation, and mitral valve prolapse, but may not meet the diagnostic criteria of
the MFS. A separate diagnosis for these individuals has been suggested in the past
(MASS for mitral valve prolapse, aortic root dilatation, skeletal features of MFS, and
striae atrophicae) (1). It was subsequently determined that some of these patients had
FBN1 mutations and represented the phenotypic spectrum of MFS (2). Whether or
not a diagnosis of MASS is made, the clinical management focuses on routine imag-
ing of the ascending aorta and recommendation of prophylactic repair when the aorta
enlarges to 5.0 cm. and as needed management of the skeletal features.
Finally, we now know that individuals who do or do not fill the diagnostic
criteria for MFS may have mutations in TGFBR1 and TGFBR2. Since the aortic
disease in patients with TGFBR1/2 mutations requires aggressive management
and can extend beyond the ascending aorta, it is important to differentiate these
patients from classic MFS. The diagnostic criteria for MFS need to be revised and
criteria established for the spectrum of disease cause by TGFBR1/2 mutations.
In the practical assessment of a patient with suspected Marfan’s syndrome, is
there currently any role for genetic studies on the patient’s DNA—or are genetic
studies just a research tool at this stage?
Sequencing of the FBN1 gene should be considered if the patient narrowly misses
the diagnostic criteria of MFS. Please note that if the patient has features of Loeys-
Dietz syndrome, sequencing of the TGFBR1/2 genes should be considered. Another
clinical scenario where FBN1 mutational analysis should be considered is when
an individual does not want to transmit the defective gene to their offspring.
Identification of the mutation causing the disease will allow for reproductive
options to prevent passing the defective gene to offspring.
In the practical assessment of a patient with non-Marfan’s aneurysm disease, is
there currently any role for genetic studies on the patient’s DNA—or are genetic
studies just a research tool at this stage?
TGFBR2 mutations are found in approximately 5% of patients with a familial his-
tory of thoracic aortic aneurysms and dissections in the absence of features of
MFS and Loeys Dietz syndrome. We have also determined that a rare family will
have TGFBR1 mutations as the cause of disease (unpublished data). Therefore,
we recommend that all patients with a family history of aortic aneurysms and
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Genetic Basis of Thoracic Aortic Aneurysms 123
dissections have TGFBR1/2 mutational analysis to screen for mutations in these
genes as a cause of disease because finding such a mutation has significant impli-
cations for the subsequent management of the patient and their family. We hope
that in the future, more genes will be identified that can be screened for mutations
in families with thoracic aortic aneurysms and dissections.
Do you think that the ARB drugs will prove to be a panacea for aneurysm disease?
Does this possibility seem almost too good to be true?
It will be determined if the success of losartan in blocking the progressive aortic
disease in a mouse model of MFS will also apply to humans with MFS, in a clini-
cal trial comparing beta adrenergic blocking agents to losartan. The clinical trial,
funded by NHLBI and using the Pediatric Heart Network, will recruit patients
under the age of 26 years with MFS and randomize them to either drug. A similar
trial of adults with MFS is in the planning stage.
It is not certain if the success of losartan in the animal model of MFS will
translate to humans with MFS. In addition, we do not know the role of TGF beta sig-
naling in aortic disease in patients who do not have MFS. Further studies are needed
to determine if ARB drugs will prove to be a panacea for aneurysm disease.
References
1. Glesby MJ, Pyeritz RE. Association of mitral valve prolapse and systemic abnormali-
ties of connective tissue. A phenotypic continuum. JAMA 1989; 262:523–528.
2. Dietz HC, McIntosh I, Sakai LY, et al. Four novel FBN1 mutations: significance for
mutant transcript level and EGF-like domain calcium binding in the pathogenesis of
Marfan syndrome. Genomics 1993; 17:468–475.
Editor’s Comments
Dr. Milewicz et al. have made extraordinary contributions to the fundamental
genetic understanding of aortic diseases, which they enumerate clearly in this
chapter. Their work reflects tremendous industry, acumen, and insight. The entire
vascular community respects and is grateful for it.
Our own team is working with molecular geneticists at Celera Diagnostics in
California to explore the automated SNP avenue of investigation that Dr. Milewicz
describes. Our preliminary findings have shown that (1) aneurysm disease has a
unique “RNA signature” in the peripheral blood. (2) This signature, if confirmed
in further investigations, promises to facilitate clinical diagnosis of aneurysm dis-
ease on a molecular genetic basis. Our separate investigations on 30,000 DNA SNPs
is ongoing. We hope to identify specific alterations in the genome of aneurysm
patients. The DNA studies look at the blueprint which programs the body is to be
made. The RNA studies look at which proteins are actually upregulated or
downregulated in terms of active manufacture at the time of sampling.
In terms of clinical genetic patterns, our most recent examination of
520 family pedigrees of patients with thoracic aortic aneurysms indicates that there
are distinct patterns of inheritance among family members. (3) Family members
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124 Milewicz et al.
of patients with ascending aortic aneurysms are very likely to manifest their
aneurysms in the ascending aorta as well. However, family members of patients
with descending aortic aneurysms are more likely to manifest their aneurysms in
the descending aorta (Fig. A).
References
1. Elefteriades JA. Beating a sudden killer. Sci Am 2005; 293(2):64–71.
2. Elefteriades JA, Wang YY, et al. Gene Expression Profiling of Peripheral Blood for
Diagnosis of Aortic Aneurysm. California: Cambridge Healthtech Institute’s Molecular
Medicine Tri-Conference, San Francisco, February 22, 2006.
3. Albornoz G, Coady MA, Roberts M, et al. Familial thoracic aortic aneurysms and
dissection: Incidence, modes of inheritance, and phenotypic patterns. Ann Thorac
Surg (in press).
Figure A Distribution of aneurysm sites among family of probands with thoracic aortic
aneurysms.
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125
7
Mechanical Properties of the
Aorta—6 cm Is “Special”
John A. Elefteriades
Section of Cardiothoracic Surgery, Yale University,
New Haven, Connecticut, U.S.A.
George Koullias
Department of Thoracic and Cardiovascular Surgery,
AHEPA University Hospital, Aristotle University Medical School,
Thessaloniki, Greece
As emphasized throughout this book, the dimension of the aorta can predict the
onset of acute aortic events—rupture or dissection—with reasonable accuracy.
By and large, bad events occur very frequently as the aortic diameter approaches
6 cm. However, we recognize that dimensional predictive criteria fall short of
ideal. For this reason, we have begun to examine the ascending aorta from an
engineering standpoint, with an eye toward using measurement of mechanical
properties of the aorta as another potential criterion for appropriate timing of
surgical intervention. This chapter reviews our very interesting findings. It is
intriguing how closely our engineering findings correlate with the clinical behavior
of the aorta in patients.
Our technique involves examining the aorta by epi-aortic echocardiography
in the operating room during surgery for replacement of the aorta for aneurysm
disease (Fig. 1) (1). Patients being operated for nonaneurysmal disease consti-
tuted our controls.
As it turns out, the major mechanical parameters of the aorta can be
calculated by measuring the following six easily assessed parameters (Fig. 2):
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126 Elefteriades and Koullias
1. The diameter of the aorta, in systole and diastole.
2. The thickness of the aortic wall, in systole and diastole. (The aortic
wall thins in systole, under the increased stretch of the higher pressure.
This measurement of subtle differences in a small dimension has a
significant learning curve attached to it.)
3. The blood pressure, in systole and diastole. (In our experiments, the
blood pressure was determined very accurately using intraoperative
direct arterial line monitoring.)
What we found was that the distensibility of the aorta essentially vanishes
as the dimension of the aorta increased (Fig. 3). The normally distensible aorta
became essentially a rigid tube at about 6 cm in diameter.
Likewise, wall stress shows dramatic and serious aberrations as the aorta
grows, again reaching critical levels by about 6 cm aortic diameter (Fig. 4). The
maximal strength of the aortic wall is known by prior investigations done directly
Figure 2 The parameters that need to be measured for calculation of mechanical proper-
ties of the aorta.
Mechanical Properties of the Aneurysmal
Human Ascending Aorta
d
t
BP
All mechanical characteristics
can be calculated on the basis of
six parameters:
BP
t
d
diastolesystole
Figure 1 (See color insert) The technique of epi-aortic echocardiography. Note the fluid-
filled interface between the probe and the aortic wall.
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Mechanical Properties of the Aorta 127
on aortic aneurysm tissue by Vorp et al. (2). In the figure, wall stress at an ambient
blood pressure of 100 mmHg is shown in dark gray and at 200 mmHg in light
gray. The dotted line represents the known maximum strength of the aortic wall.
Note that at an aortic dimension of 6 cm and an ambient blood pressure of
200 mmHg, the wall stress “flirts” dangerously close to the ultimate strength of
the aortic wall.
It is, thus, no wonder that patients with aortic enlargement approaching
6 cm are vulnerable to aortic rupture and dissection. This is exactly what we
found in clinical investigations from our database (3–5).
This investigation of the mechanical properties of the aneurysmal aorta shows
that clinical events occur exactly at the same dimensions at which mechanical
Figure 3 Distensibility of the aorta at various dimensions. Note that the aorta becomes
essentially a rigid tube by a dimension of 6 cm.
0
1
2
3
4
5
Normals < 4cm 4-5 cm 5-6 cm > 6 cm
Aortic diameter (cm)
Aortic Distensibility (.001 mmHg)
Figure 4 Wall stress of the aorta at various dimensions. The dotted line shows the known
maximal tensile strength of the aortic wall. The dark gray bars reflect an ambient blood
pressure of 100 mmHg. The light gray bars reflect an ambient blood pressure of 200 mmHg.
Note that at a dimension of 6 cm and an ambient blood pressure of 200 mmHg, the wall
stress approaches the maximal strength of the aortic wall.
0
200
400
600
800
1000
Normals 4.1-5cm 5.1-6cm > 6 cm
aortic diameter(cm)
Wall stress (kPa)
< 4cm
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128 Elefteriades and Koullias
properties deteriorate severely. This represents a dramatic convergence of experi-
mental findings with clinical behavior. These findings lend further credence to the
dimensional criteria for pre-emptive surgical intervention discussed in the clinical
chapters of this book.
Of course, epi-aortic echocardiography is not workable as a clinical monitoring
tool, as the patient is already undergoing operation at the time of the test. We are now
transitioning our studies in the direction of transesophageal echocardiography (TEE).
Specifically, at the same time that we perform the epi-aortic echocardiography on
surgical patients, we are also performing the same measurements by TEE. Our initial
experience seems favorable—that is, it appears that the TEE measurements will be
possible, will be accurate, and will correlate with the epi-aortic calculations.
If we can validate TEE as a means of assessing the mechanical properties
of the aorta, then it becomes reasonable to postulate that direct measurement of
distensibility, wall stress, or other biomechanical variables may be applied to
predict rupture or dissection—and, thus, to guide optimal timing of pre-emptive
surgical intervention. The potential exists to measure mechanical properties by
computed tomography scan or by magnetic resonance angiography as well.
We are hopeful that serial measurement of aortic distensibility and aortic
wall stress may become part and parcel of clinical follow-up of aneurysm patients,
augmenting clinical assessment and aortic diameter as tools for predicting aortic
behavior and timing surgical intervention.
REFERENCES
1. Koullias G, Modak R, Tranquilli MA, et al. Mechanical deterioration underlies malig-
nant behavior of aneurysmal human ascending aorta. J Thorac Cardiovasc Surg 2005;
130(3):677–683.
2. Vorp DA, Schiro BJ, Erlich MP, Juvoven TS, Ergin MA, Griffith BP. Effect of aneu-
rysm on the tensile strength and biomechanical behavior of the ascending aorta.
Ann Thorac Surg 2003; 75:1210–1214.
3. Coady MA, Rizzo JA, Hammond GL, et al. What is the appropriate size criterion for
resection of the thoracic aorta. J Thorac Cardiovasc Surg 1997; 113:476–491.
4. Davies RR, Goldstein LJ, Coady MA, et al. Yearly rupture or dissection rates for thoracic
aortic aneurysms: Simple prediction based on size. Ann Thorac Surg 2002; 73:17–27.
5. Davies RR, Gallo A, Coady MA, et al. A novel measurement of relative aortic size
predicts rupture of thoracic aortic aneurysms. Ann Thorac Surg 2006; 81:169–177.
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Mechanical Properties of the Aorta 129
DISCUSSION AND COMMENTARY
Question for the Authors
The six data points for calculation of mechanical properties of the aorta include
aortic diameter in systole and diastole, blood pressure in systole and diastole, and
aortic wall thickness in systole and diastole. I understand how you can measure
aortic diameter in systole and diastole. Blood pressure in systole and diastole is
also easy to retrieve from the arterial line. However, how can you measure the
thickness of the aorta in systole and diastole? Can this be done accurately?
Yes, this can be done. The shadow of the aortic wall is magnified, and multiple
measurements are taken and averaged. Please note, in Figure A, how clearly the
aorta thins at the beginning of systole (under increased pressure) and thins in
diastole (with relief of pressure).
Figure A Magnified view of aortic wall by epiaortic echocardiography. Aorta thins in
systole (thin arrow) and thickens in diastole (thick arrow).
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131
8
Matrix Metalloproteinases in Aortic
Aneurysm and Dissection
Donald M. Botta, Jr. and John A. Elefteriades
Section of Cardiothoracic Surgery, Yale University,
New Haven, Connecticut, U.S.A.
George Koullias
Department of Thoracic and Cardiovascular Surgery,
AHEPA University Hospital, Aristotle University Medical School,
Thessaloniki, Greece
Thoracic aortic aneurysms (TAAs) (Fig. 1) have an annual incidence in population-
based studies of as high as 10.4 per 100,000 persons (1). The population based
annual rate of thoracic aneurysmal rupture or dissection was 7.0 per 100,000 (2)
in one study, and the rate of rupture was 5.0 per 100,000 in another (3). The gravity
of these occurrences is illustrated by the median survival of three days after aneu-
rysmal dissection in the former study (2), and the 97% to 100% mortality after
rupture in the latter (3). The public health impact of this disease can be brought into
focus by comparing these rates to the 5.0 per hundred thousand mortality rate from
Human Immunodeficiency Virus infection in the United States (4). Operative repair
of TAAs is effective in improving survival (5). However, elective surgical repair for
asymptomatic aneurysms remains a clinical decision, which must be based on the
patient’s operative risk, and the risk that a given TAA will progress, dissect, or
rupture. In order to consider the risks of these complications, a thorough under-
standing of both the natural history and the pathophysiology of TAAs are required.
To understand the natural history of TAAs, we at the Yale Center for zTho-
racic Aortic Disease have been compiling an ongoing, cumulative database since
1995, including data and imaging studies on all patients whom we evaluate for
thoracic aortic disease. The database currently contains information on nearly
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