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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3850_Библиотеки_им_академика_М_И_Перельмана
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I. State of the Art
a
cd
b
f
e
Fig. 4.22.
of guide into the aortic lumen.
Stenting procedure. a Guide with graduations. b Stent during deployment. c Guide into the aortic lumen. d Loop (arrow)
e Impaction of guide (arrow) in a mural thrombus. f Aortic wall debris (arrow) after stenting
weight. Indication of surgical repair is based on the rate
of diameter evolution, especially in Marfan syndrome.
From TEE measurements, some equations to calculate
the risk of rupture have been proposed [20, 24]. They
confirm the ability of TEE for monitoring of these patients. Because of the need of frequent controls, MRI
could be a convenient alternative to TEE.
Despite the accuracy of TEE in the diagnosis of aneurysm of the sinus of Valsalva, surgical indication
could be preceded by an aortic and coronary angiogram.
In coarctation of the aorta, complete diagnosis can
be assessed by TEE. An evaluation of collateral circulation by MRI is recommended before surgical treatment.
In aortic atheroma, TEE is sufficient to detect highrisk plaques and to establish and to evaluate medical
treatment. If a mobile component is present and associated with embolism, surgery may be indicated from
TEE data.
4.3.5 Traumatic Aortic Injuries
If performed by a trained physician, TEE is able to assume diagnosis of traumatic aortic injury and to indicate the precise type and emergency of treatment. Classically, subadventitial disruption requires surgical treat-
P. Massabuau Chapter 4 Transesophageal Echocardiography for Diagnosis and Treatment of Aortic Diseases
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c
e
Fig. 4.23.
aorta (two stents).
row), uncovered aneurysm (AN). b Color Doppler image of
aortic flow. c Guidewire (arrow). d After deployment of the
Stenting procedure for aneurysm of the descending
a After deployment of the first stent (ar-
d
f
second stent, aneurysm is excluded.
duces spontaneous contrast echo in the aneurysm and the aortic lumen upstream.
tic lumen
f Spontaneous contrast echo into the aor-
e Baloon inflation (B) in-
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a
cd
Fig. 4.24.
stent (arrow) deployment.
Stenting procedure for aneurysm of the descending aorta. a Aneurysm (AN) with mural thrombus. b A few seconds after
c Increased thrombosis into aneurysm. d Complete thrombosis of aneurysm
ment. Nevertheless, multiple and severe associated lesions increase the risk of surgery and delayed treatment
may be proposed. In such situations, MRI offers great
advantages: noninvasive examination, evaluation of aortic lesions and complications (mediastinal hematoma,
hemothorax), diagnosis of cerebral, visceral or vertebral
injuries.
b
of the aortic isthmus [3, 4, 8, 22]. These classic indications are now extended to type A dissection (ascending
part, arch), penetrating ulcer and complicated intramural hematoma. Stenting procedures are controlled by
fluoroscopy and angiography. These techniques cannot
provide any information concerning endovascular
events. A stent-graft device is introduced by surgical access of femoral or iliac arteries. TEE can be used to
guide the three different phases of the procedure: be-
4.3.6 Stenting and Fenestration
fore, during and after deployment of the device. The
first phase consists in an evaluation of the aortic wall:
For a few years, new therapies have been available: percutaneous stenting and fenestration [7]. They represent
an alternative to surgical treatment; especially in some
high-risk patients, in the case of an involved descending
aorta: aneurysms, dissection and traumatic rupture of
the isthmus, asacute as in chronicle phases.
Fenestration is particularly useful in aortic dissection. During the procedure, TEE can easily identify true
and false lumen. An immediate evaluation of treatment
can be assessed by color Doppler imaging.
Stenting may be indicated in type B aortic dissection
(compression of true lumen, large intimal tear, enlargement of false lumen), aneurysm and traumatic rupture
detection of the complex atheroma plaque, the thrombus and the site and size of aortic lesions. TEE controls
progression of the guidewire, angiographic catheters
and the sheath containing the stent. It can detect and
avoid some complications: iatrogenic dissection; intimal
tear, wrong passage in false lumen; contact with the
thrombus, plaque of atheroma, aortic prosthetic valve;
Fig. 4.22). A TEE probe could play the role of a landmark and help the interventional radiologist to optimize stent position and deployment. During the next
phase, immediately after stent deployment, TEE allows
visualization of both sides of the stent. Indeed, angiography cannot provide any information about the outer
P. Massabuau Chapter 4 Transesophageal Echocardiography for Diagnosis and Treatment of Aortic Diseases
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51
d
c
Fig. 4.25. Stent leak type I: a partial contact between the aortic wall and the stent (arrows); b, c color Doppler and pulsed Doppler
images of the leak. Stent leak type IV: d stent protrusion (arrows) into the aneurysm (AN); e leak (arrow) through the stent
side of stent. The endoluminal side often presents some
debris (Fig. 4.22), small clots or spontaneous echo contrast. These elements might be consequences of decreased aortic flow due to a medically induced fall in
blood pressure before deployment. Failure of or incomplete stent deployment may be observed. Stent compression by persistency of a patent false lumen may occur a
few days after. The degree of contact between the stent
and the aortic wall can be evaluated and completed by
inflation of a balloon guided by TEE (Fig. 4.23). In the
case of aneurysm, the stent presents an out-pushing as-
e
pect at the neck level. After deployment, the extralumen
side of the stent can only be visualized by TEE. A successful procedure is characterized by an important
spontaneous contrast effect that is a marker of blood
stasis and that precedes thrombus formation (Fig. 4.24).
TEE also appears efficient for detection and quantification of leaks [8, 18]. They are classified in four types:
type I, at the junction of the aorta and the stent; type II,
intra-aneurysm bleeding from the collateral artery;
type III, at the junction between two stents; type IV,
leak through the stent-graft cover tissue (Fig. 4.25).
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I. State of the Art
Stenting procedures are often performed in elderly patients with cardiac or multiorgan failures. Moreover,
spontaneous or induced changes in blood pressure,
bleeding or sudden arrhythmia may have important
consequences in such high-risk patients. TEE can control valvular prosthesis, left ventricular function and
volume.
4.4 Conclusion
TEE is a recognized and accurate method for diagnosis
of all thoracic aortic diseases. This technique does not
expose the patient to radiation or injection of toxic
contrast agent. TEE can be performed at the bedside
and in critical circumstances. In addition, it provides
determinant data concerning left ventricular function,
volumes and associated valve abnormalities. It requires
a trained medical team. Nevertheless, aortic diseases
need a regular follow-up. In that case, MRI offers the
advantage of a noninvasive method. Management of
stenting and other interventional procedures represents
promising new perspectives for TEE.
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Biomarkers
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in Acute Aortic Syndrome
Guglielmina Pepe, Betti Giusti,
Maria Cristina Porciani and Magdi Yacoub
Chapter
5
Contents
5.1 Introduction .......................
5.2 Biochemical Markers .................. 57
5.2.1 Smooth Muscle Myosin Heavy Chains ..... 57
5.2.2 Soluble Elastin Fragments ........... 58
5.2.3 C-Reactive Protein ................ 59
5.2.4 D-dimer ...................... 60
5.2.5 Homocysteine ................... 61
5.2.6 Matrix Metalloproteinases ........... 61
5.2.7 Other Biochemical Markers ........... 62
5.3 Genetic Markers ..................... 63
5.3.1 Genes Associated with Syndromic or Nonsyndromic Monogenic Disorders Presenting
Aortic Aneurysms or Dissections .......
5.3.2 Polymorphic Mutations in Genes Predisposing
to Alterations ...................
5.4 Prospective New Tools to Identify New Biochemical
and Genetic Markers ...................
55
63
65
65
5.1 Introduction
The term acute aortic syndrome (AAS), coined 6 years
ago [111], indicates a heterogeneous group of patients
presenting one of the following acute aortic pathologies:
aortic ulcer, intramural haematoma or classic aortic dissection (Fig. 5.1). More recently, aortitis [109] and intraluminal thrombus [106] were included in this syndrome (Fig. 5.1). Aortic ulcers penetrate the intima
through the media; intramural haematoma presents a
haemorrhage into the aortic media with the formation
of a false lumen; the classic aortic dissection is characterized by the presence of an intimomedial entrance
tear. The term aortitis indicates a thickening of the wall
owing to different mechanisms such as infections and
autoimmune disorders causing systemic vasculitis.
Although these alterations appear mostly distinct, the
fact that in some cases they coexist demonstrates a possible link between them (Fig. 5.1).
Aortic aneurysms and dissections can be classified
on the basis of morphology, aetiology, and anatomic lo-
cation. Although aneurysms may arise at any site along
the aorta, they most frequently occur in the infrarenal
abdominal aorta or the descending portion of the thoracic aorta. The ascending thoracic aorta is another
common location for aortic aneurysm, which may develop in association with hypertension and spontaneous
(type A) aortic dissection, congenital valvular abnormalities (e.g., bicuspid aortic valve, BAV) [98], and inherited connective tissue disorders, e.g., fibrillinopathies
type 1 [30, 64] such as Marfan syndrome (MFS) [18,
19], classic, hypermobile and vascular Ehlers-Danlos
syndromes (EDS) [78], osteogenesis imperfecta [40], Xfragile syndrome [41], and polycystic kidney disease
(PKD) [103]. Aneurysms result primarily from degenerative changes in the aortic wall. Severe intimal atherosclerosis, chronic transmural inflammation, and destructive remodelling of the elastic media are associated
with aneurysms dissections that affect primarily the
descending thoracic aorta and abdominal aorta (thoracoabdominal aortic aneurysms, abdominal aortic aneurysms, AAAs, and type III dissections) [46, 105].
In contrast, aneurysms and dissections that affect
the ascending aorta are primarily due to lesions that
cause degeneration of the aortic media, a poorly understood pathological process called cystic medial necrosis
(CMN) [26, 73, 75] (Fig. 5.2). CMN is characterized by
degeneration and fragmentation of elastic fibres, loss of
smooth muscle cells (SMCs), and interstitial collections
of basophilic-staining ground substance. Although the
pathogenesis of medial necrosis is not understood, it is
almost certainly not a single disease entity. Medial necrosis occurs with normal aging of the aorta [88, 89]
but it can be accelerated by conditions such as hypertension and it is also associated with genetic syndromes, such as MFS and aortic bicuspid valve
(Fig. 5.2).
The specific factors causing aneurismal degeneration
in the different locations remain unresolved.
Pathophysiological studies on human and experimental AAAs have focused on increased expression and
tissue localization of elastin- and collagen-degrading
enzymes, particularly matrix metalloproteinases
(MMPs), cysteine proteases, and their respective inhibi-
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Fig. 5.2. Cross sections of ascending thoracic aorta of a control
subject (A), of an aortic aneurysm associated with Marfan syndrome (B), and with bicuspid aortic valve (C) stained with Alcian blue and Verhoeff±van Gieson. Magnification ´ 250. (From
Nataatmadja et al. [73])
tors (TIMPs) [23, 93, 97]. Genes encoding a number of
proinflammatory cytokines, leukotriene lipid mediators,
chemotactic factors, and cell adhesion molecules have
also been implicated in AAA [50, 77, 119), and depletion of vascular SMCs may influence the process of vascular remodelling that occurs during aneurismal degeneration [35, 58] (Fig. 5.3).
Studies focusing on thoracic aortic aneurysms
(TAAs) have indicated that their hallmark, the cystic
medial, is associated with elastin degradation and fragmentation [17, 62], SMC depletion and apoptosis [9],
and increased expression of some MMPs [53, 56, 91].
Fig. 5.1. Acute aortic syndrome. Arrows indicate
the possible progression of each of these aortic lesions. (Adapted from van der Loo and Jenni [106].
Classic dissection and intramural haematoma
adapted from Vilacosta [110]. Aortitis from Nuenninghoff et al. [76]. Aortic ulcer from Eggebrecht
et al. [21]. Intraluminal thrombus from Wegener
et al. [115])
However, the absence of a significant inflammatory response implies alternative mechanisms of aneurysm formation in TAAs with respect to AAAs, related to the
different embryologic origin of cells populating the ascending and infrarenal aorta, to the different structural
properties and propensities toward atherosclerotic degeneration, or to the distinct haemodynamic conditions
in these two areas. Absi et al. [2] in 2003 by using microarray technology showed distinct patterns of gene
expression for ascending aortic aneurysms and AAAs.
Clinical manifestation of AAS is aortic pain that affects neck, throat, and anterior chest when the ascending aorta is involved, while descending aorta alteration
is associated with back pain and abdominal pain. The
aortic pain (chest pain) is probably due to aortic root
dilatation and is similar to that caused by ischemic syndromes (angina pectoris). Acute coronary syndromes
may result from AAS or be associated with them [109].
Overall, AAS can remain asymptomatic until the initial
dissection and also later since the symptoms are common to many pathologies.
The mortality rate of untreated dissection is about
1%/h for the first 48 h increasing up to 80% at 14 days
[101]; the gold standard techniques for the diagnosis of
AAS are represented by imaging analyses such as computerized tomography, transoesophageal echocardiography, and magnetic resonance. Each of these techniques
has some advantages and some limitations; therefore, at
least two are required for a diagnosis but the common
limit is represented by the fact that the equipment and
the personnel with the necessary expertise to perform
the tests and interpret correctly the data are not available
in all medical set-ups. For these reasons the identification
of biochemical and genetic markers able to readily and
rapidly diagnose and/or to recognize a predisposition
to develop an AAS are highly required, also considering
the importance of prophylactic surgery in all patients.
G. Pepe et al. Chapter 5 Biomarkers in Acute Aortic Syndrome
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57
Fig. 5.3. Aortic remodelling and aneurysm formation. Zhao et
al. [119] provide evidence that adventitial macrophages express
5-LO and its cofactor, FLAP, and generate leukotrienes, which
set in motion a number of proinflammatory events. One of the
leukotrienes, LTD
through binding to CysLT
mation also promotes the recruitment of monocytes ± the precursors of tissue macrophages ± and T cells. Specifically, LTD
binds to CysLT2receptors on endothelial cells of the many microvessels present in the adventitia and media (vasa vasorum),
resulting in increased endothelial release of MIP-2 and leukocyte extravasation. Activated macrophages also release MIP-1a,
, causes autocrine activation of macrophages
4
receptors. Increased leukotriene for-
1
5.2 Biochemical Markers
Aortic dissection is an acute catastrophic aortic disease
associated with high mortality and morbidity [4]. Rapid
diagnosis and initiation of appropriate treatment is pivotal for patients with acute aortic dissection. Unfortunately, the disease is still not well recognized on clinical
presentation owing to lack of specific signs and symptoms. Detection of acute aortic dissection is based on
clinical presentation but mainly relies on imaging techniques [25]. However, up to 30±40% of patients remain
undiagnosed until necropsy [112]. The investigation,
characterization, and development of a biochemical diagnostic approach to the AASs are fundamental for improved survival. So far, there is no laboratory test ± as
opposed to acute coronary syndromes ± to aid the diagnosis; nevertheless, several possible biochemical markers are showing promising results. In contrast to the expanding availability of cardiac biochemical markers (serum transaminase, creatine kinase (CK), lactate dehydrogenase, cardiac myosin light chain, and troponin),
biochemical assays for vascular diseases, however, have
not been available due in part to a lack of specific
markers for vascular disease. With the recent progress
made in the field of vascular biology, markers specific
which may further promote T cell recruitment. Independent of
the 5-LO pathway, activated macrophages generate other proinflammatory factors, including metalloproteinases (MMPs),
which weaken the media. Atherosclerosis in the intima may act
synergistically with adventitial inflammation. Intimal macrophages, T
tory factors, including IFNc, IL-1, MMPs, and TNFa. Mast cells
may also contribute to the conversion of angiotensin I to an-
4
giotensin II, a powerful promoter of aneurysms in mice. Hypercholesterolemia is an essential cofactor of both adventitial
and intimal inflammation. (From Palinski [77])
1 cells, and mast cells secrete many proinflamma-
H
to vascular components have become available. In this
chapter, we review the rapidly accumulating knowledge
in the field of biochemical markers in AAS and in particular in thoracic aortic diseases. We discuss the potential application of some of these biochemical markers,
their advantages and disadvantages in the clinical practice, and outline areas for future research.
5.2.1 Smooth Muscle Myosin Heavy Chains
Smooth muscle myosin heavy chain (SMMHC), a structural protein found in SMCs, is released from the aortic
medial SMC s on insult to the aortic wall [3, 55, 63, 69,
70, 118]. In 1995 an immunoassay of serum SMMHC
was developed [44, 45]. Circulating levels of SMMHC
are elevated in acute aortic dissection [99]. The assay
showed a sensitivity of approximately 90% to detect the
disease at a cutoff level of 2.5 ng/ml (the upper limit of
the control population) during the initial 3 h after onset
of symptoms and a specificity of 97% compared with
healthy volunteers and of 83% compared with patients
with acute myocardial infarction. Sensitivity decreased
to 72.4% in the following 3 h and decreased to 30.3%
thereafter (Fig. 5.4) [102]. The temporal course of circu-
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Fig. 5.4. Sensitivity of the smooth muscle myosin heavy chain
(SMMHC) assay. Temporal sensitivity curves according to cutoff levels. Solid line cutoff level of 2.5 lg/l; dotted line cutoff
level of 5.0 lg/l; and dashed line cutoff level of 10.0 lg/l.
(Adapted from Suzuki et al. [102])
Fig. 5.5. Time course of serum SMMHC levels in patients with
aortic dissection (n = 27). The peak levels are at onset. Rapid
reductions in levels are found during the first 24 h. (Adapted
from Suzuki et al. [99])
lating SMMHC levels in patients with acute aortic dissection showed peak levels at onset with rapid normalization of levels within the initial 24 h (Fig. 5.5). The
rapid decrease in SMMHC is likely due to the unique
spatial localization of myosin within the muscle cells
which affects its release into the circulation upon insult.
Myosin in smooth muscle is loosely interspersed in the
cell. Because of this distribution, upon cellular insult it
is likely that smooth muscle myosin is rapidly released
in a manner similar to cytosolic enzymes and proteins
in acute myocardial infarction. Interestingly, patients
with aortic dissection having negative levels were restricted to patients with distal De Bakey type III lesions.
This is likely because the abdominal aorta upon arteriosclerosis change shows reduced content of smooth muscle, and therefore release of the protein is markedly reduced in these lesions [101]. Although the described as-
say of serum SMMHC was an early experimental assay
which required 5 h for measurement, recent advances
have allowed for a sensitive 30-min rapid assay suited
for clinical use [101].
5.2.2 Soluble Elastin Fragments
Elastin is one of the major structural matrix proteins of
the arterial wall [14, 20, 48, 74, 79, 85, 96, 117]
(Fig. 5.6). Mature elastin is composed of soluble elastin
subunits, which are intermolecularly cross-linked into a
fibrous network (desmosine and isodesmosine formation) and thus construct a highly polymerized insoluble
protein. The main pathological feature of the aortic media in acute aortic dissection is a higher grade of elastin degradation [88, 89, 92, 93]. Once an initial tear is
formed, the dissection tends to expand to the degraded
elastin layers, along with an inflammatory infiltrate, a
major source of proteolytic enzymes such as elastases
and metalloproteinases, which thus dramatically promote the fragmentation process of the elastin network
in the media [68, 88, 89]. As a result, soluble elastin
fragments (sELAF) are released into the circulating
blood and are measurable in the serum [94]. Shinohara
et al. [94] developed an enzyme-linked immunosorbent
assay to measure sELAF in serum by using the newly
created double monoclonal antibodies, which recognize
the different epitopes of human aortic elastin. Using
this system, when the cutoff point for positivity was set
at the mean plus 3 times the standard deviation (SD)
(i.e., 3SD above the mean in healthy subjects, at each
age), they demonstrated that 64% of acute aortic dissection patients (88.9% of those with either an open or a
partially open pseudolumen and 0% with a closed pseudolumen) within 48 h after the onset showed an increase in sELAF levels in serum and only 2% of the
acute myocardial infarction patients were positive
(Fig. 5.7). Discriminating acute aortic dissection from
acute myocardial infarction is still a common clinical
dilemma, and the differential diagnosis is critical, because the management and prognoses for each are quite
different. Misdiagnosis of acute aortic dissection as
acute myocardial infarction frequently results in catastrophic haemorrhage or an exacerbation of acute aortic
dissection, especially when thrombolytic drugs are inappropriately administered [8, 12, 116]. A limitation of
this assay is that it still takes at least 3 h to measure the
sELAF level in serum and further efforts are being
made to shorten the measurement time of the immunoassay system.
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