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54 PART | I Overview
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Annual growth rate calculations for the tabulated studies were all performed by dividing the difference in maximal
aortic sizes between the most recent follow-up scan and the initial baseline scan by the time interval between the
two scans, assuming uniform aortic enlargement over time. However, the dynamic of aortic expansion during transition of the dissection from the acute to chronic state is not a linear phenomenon [28,35]. The aorta grows rapidly in
the early phase immediately after dissection and subsequently, after approximately 25 days, this change in diameter
slows down and eventually plateaus after around 3 months [28] (Fig. 3.12). A period of relatively sustained stability
then ensues without significant variation in aortic growth rate [28]. Descending aortic growth rates also vary significantly between the acute, subacute, and chronic stages of dissection, with rates of 9.31 mm/year, 1.30 mm/year,
and 0.32 mm/year observed, respectively [28]. The very rapid growth in the acute and subacute phases is congruous
with and may explain the clinically observed early virulence and instability of this disease; complications such as
rapid aneurysmal expansion, rupture, malperfusion, refractory hypertension, and recurrent pain are expected and
encountered in the first 3 months after dissection [38,39]. This early accelerated aortic expansion is also why an
intense, closely spaced computed tomography imaging protocol in the early postacute type B dissection phase is
recommended [28] (Table 3.3).
FIGURE 3.12 Temporal dynamic of aortic dilation in type B dissection over time. The figure displays how the growth rate changes postdissection.
The dynamics followed an exponential decay function, with rapid growth in the acute state, deceleration in the subacute (after 25 days from onset) state,
and a plateau in the chronic state (after 88 days from onset). Note that the growth rates in this figure are in mm/day. Reproduced with permission from:
Peterss S, Mansour AM, Ross JA, et al. Changing Pathology of the Thoracic Aorta From Acute to Chronic Dissection: Literature Review and Insights.
Journal of the American College of Cardiology 2016; 68:1054–65.
TABLE 3.3 Imaging Protocol for Medically Treated Type B Aortic Dissection Patients
Period Aortic Institute Protocol
Admission Baseline computed tomography (CT) scan
Hospital stay Repeat CT scan on hospital day 5 (if clinically stable)
Early follow-up Follow-up scan 1 month after hospital discharge
Late follow-up Outpatient scans every 2–3 years
Reproduced with permission from: Peterss S, Mansour AM, Ross JA, et al. Changing pathology of the thoracic aorta from acute to chronic dissection:
literature review and insights. J Am Coll Cardiol 2016;68:1054–65.
Repeat as needed in case of clinical instability
Follow-up scans at 6 months and 1 year
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Progression of the Dissection
Longitudinal progression of the dissection during the transition from the acute to chronic state occurs rarely. Our
investigations revealed a conspicuous absence of distal extension of a type B dissection, no new branch vessel occlusion, and only a 1.7% incidence of proximal extension (native, noniatrogenic retrograde type A dissection after type
B dissection) during long-term follow-up [28,30]. These observations dovetail with the increased fibrosis of the aortic
media, with increasing chronicity; the fibrotic process protectively “knits together” the aortic layers [28].
False Lumen Patency
Morphological characteristics of the false lumen have an impact on aortic growth and therefore long-term outcome in
patients with acute type B dissections. The proportion of patients with acute type B dissections with a completely thrombosed (absence of blood flow/contrast in the false lumen [33,36,40]), partially thrombosed (presence of both blood flow/
contrast and thrombus in the false lumen [33,36,40]), or completely patent (absence of thrombosis and presence of uninterrupted blood flow in the false lumen [33,36,40]) false lumen varies. This information along with the influence of other
characteristics of the false lumen on aortic enlargement and long-term outcome during the natural transition from the acute
to chronic state is tabulated in Table 3.2.
Various investigations have demonstrated a beneficial effect of a completely thrombosed false lumen on aortic
enlargement and clinical outcome [32,33,35,37,41,42]. Complete thrombosis of the false lumen effectively converts
the dissected aorta into a single lumen channel by excluding the false lumen from the circulation, encouraging blood
flow through the true lumen, unifying the dissected layers and thus imparting strength to and inducing favorable
remodeling in the vessel wall [32]. This is an important step in the healing of a dissection, and endovascular treatment
for aortic dissection is based on this concept [43–45]. In contrast, a patent false lumen has been shown to be a risk
factor for aortic dilation and adverse clinical outcome in the long term [31–35,42,46,47]. This is a consequence of the
blood flow through the patent false lumen exerting direct hemodynamic stress and diminishing the structural integrity
of the aortic wall, thereby leading to aneurysmal dilation [32,33]. Investigations regarding the impact of partial thrombosis of the false lumen have yielded contrasting results; some have found there to be no significant effect [33,34],
whereas others have shown it to be significantly associated with increased aortic dilation and mortality in the long
term [35,36,40]. A sequela of partial false lumen thrombosis is the formation of a blind sac (saccular type false lumen
thrombosis) if the distal reentry tear and outflow from the false lumen are obstructed by thrombus [40]. This leads to
raised pressure and consequently increased wall tension within the sac, causing aneurysmal dilation and rupture, thus
explaining the increased mortality and aortic expansion seen in patients with a saccular partially thrombosed false
lumen [33,35,40]. Hypoxic degeneration of the aortic wall due to the presence of contiguous thrombus may also be a
mechanism by which partial false lumen thrombosis weakens the aortic wall [40].
Recent data from our institution showed that 60.2%, 38.2%, and 1.5% of patients with acute type B dissections presented with patent, partially thrombosed, and completely thrombosed false lumens, respectively [28]. Over time, during the
transition from the acute to chronic phase, 23.5% of patients were observed to have a change in false lumen patency, with
a gradual trend toward increasing luminal thrombosis, as depicted in the figure [28] (Fig. 3.13).
Intimal Flap Architecture and Its Dynamics
The morphology of the intimal flap changes significantly during the transition from acute to chronic dissection. The absolute flap
thickness increases over time, with a higher rate of thickening during the early postdissection phase that slows down after 83 days
and eventually plateaus after 235 days [28] (Fig. 3.14). The mean rates of intimal flap thickening during the acute, subacute, and
chronic phases of dissection are 1.20 mm/year, 0.41 mm/year, and 0.02 mm/year, respectively [28]. The intimal flap also becomes
less mobile over time, stiffening and straightening out, and losing its pliability and curvature [28] (Fig. 3.15).
These changes in intimal flap architecture have important implications for both endovascular and open surgical repair of
type B dissections. Thoracic endovascular aortic repair (TEVAR) seeks to close the primary entry tear, promote thrombosis
of the false lumen and blood flow through the true lumen, and eventually induce favorable remodeling of the dissected
aorta [43–45,48,49]. As the flap thickens and stiffens with time, the success of the TEVAR procedure may be adversely
affected by the difficulty in achieving satisfactory graft-wall approximation [43–45,48]. On the other hand, as the intimal
flap stabilizes with time, suturing of the dissected aorta becomes safer and more secure for the surgeon attempting open
surgical repair [28].
This changing morphology of an acute type B dissection during the transition from the acute to the subacute and finally
to the chronic state is vividly depicted in a single patient in Fig. 3.16.
FIGURE 3.13 False lumen status in type B dissection. The degrees of the false lumen patency according to the cumulative images (n = 294) are pre-
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sented. Of the patients (n = 68), 60.2%, 38.2%, and 1.5% initially presented with patent false lumen, partial, and complete thrombosis, respectively. Among
those, 23.5% changed their status during follow-up. Reproduced with permission from: Peterss S, Mansour AM, Ross JA, et al. Changing pathology of the
thoracic aorta from acute to chronic dissection: literature review and insights. J Am Coll Cardiol 2016;68:1054–65.
FIGURE 3.14 Absolute flap thickness and temporal changes of architecture over time in type B dissection. (A) Absolute thickness and (B) thickening
rate (mm/day). The flap thickens over time, also following an exponential decay function, with a rapid drop in the rate of thickening. The changes decelerate
after 83 days from onset and plateau after 235 days from onset in the chronic state. Reproduced with permission from: Peterss S, Mansour AM, Ross JA, et al.
Changing pathology of the thoracic aorta from acute to chronic dissection: literature review and insights. J Am Coll Cardiol 2016;68:1054–65.
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FIGURE 3.15 Flap mobility. Flap mobility is cumulative of type A and B dissection. The figure depicts the absolute movement of the flap in milli-
meters at different time points (in different patients). A gradual drop in flap mobility over time was found. Reproduced with permission from: Peterss S,
Mansour AM, Ross JA et al. Changing pathology of the thoracic aorta from acute to chronic dissection: literature review and insights. J Am Coll Cardiol
2016;68:1054–65.
FIGURE 3.16 Changing pathology of aortic dissection. Changing morphology of a type B dissection over time by computed tomography in a single
illustrative patient with multiple good quality images at the same aortic level. Please note the following: (1) marked early increase in aortic diameter
(orange arrow); (2) intimal thickening over time (orange star); (3) decreased flap motion over time (orange triangles); (4) flap straightening over time
(green star); and (5) increased false lumen thrombosis over time (yellow star). Reproduced with permission from: Peterss S, Mansour AM, Ross JA, et al.
Changing pathology of the thoracic aorta from acute to chronic dissection: literature review and insights. J Am Coll Cardiol 2016;68:1054–65.
Stanford Type A Dissection
The treatment of choice for acute Stanford type A dissection is surgical repair in approximately 90% of patients [29,50,51];
hence the natural transition to a chronic state and the accompanying morphological changes are difficult to analyze.
False Lumen Patency
Subsequent to surgical correction of an acute type A dissection, the dissected segment distal to the site of repair transitions
to a chronic state over time. Patency of the false lumen of this segment is observed if distal entry tears persist or if the distal
part of the ascending aortic graft is improperly anastomosed to the true lumen [47,52–54]. This is a common occurrence
and portends eventual aneurysmal dilation of the distal dissected aortic segment and poor clinical outcome for the patient
[31,47,52,53].
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[45] Tang DG, Dake MD. TEVAR for acute uncomplicated aortic dissection: immediate repair versus medical therapy. Semin Vasc Surg 2009;22:145–51.
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[47] Evangelista A, Salas A, Ribera A, et al. Long-term outcome of aortic dissection with patent false lumen. Predictive role of entry tear size and loca-
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Cardiovasc Surg 2010;139:841–7. e1.
Chapter 4
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The Pathogenesis of Aortic Valvular
Disease
Liviu Chiriac, Viorel Goleanu, Razvan Rosulescu, Alice Munteanu
Central Military Hospital, Bucharest, Romania
Chapter Outline
Pathogenesis of Aortic Stenosis 61
The Inflammatory Process 61
The Lipoprotein Anomalies 62
The Activation of Renin–Angiotensin System 62
Calcification in Aortic Stenosis 63
Aortic Regurgitation 64
References 64
The aortic valve disease is a very important cardiac condition in which the valve between the left ventricule and the
main arterial conduct of the human body, the aorta, does not work properly. There are two types of valvular diseases
represented by the aortic valve stenosis and by the aortic valve regurgitation or aortic disease. In the aortic valve stenosis, the valve opening is narrowed and it prevents the valve from being fully opened and is obstructing the outflow of
the blood from the left ventricule into the aorta lowering the blood flow toward the peripheral vessels. The aortic valve
regurgitation is a pathological medical condition the affects the aortic valve hermetic closure causing blood to flow
backward into the left ventricule in diastole. The aortic stenosis is the most frequent and common form of heart valvular
disease. The most important etiology of this pathology is represented by degeneration. It is a chronic disease that is
associated with three major activation biological processes: accumulation of lipid particles, inflammatory process, and
calcification [1].
All these mechanisms involve angiogenesis, intracellular and extracellular remodeling, and chronic inflammation leading to formation of calcium. There are many studies that confirm the fact that the atherogenic processes in which the inflammatory component is very important are similar to those observed in the aortic valve degeneration [1].
We will depict the main mechanisms involved in the aortic stenosis and then we will present the main mechanisms of
aortic regurgitation.
PATHOGENESIS OF AORTIC STENOSIS
The Inflammatory Process
A series of studies that included patients with aortic valve stenosis revealed chronic inflammatory cells such as T lympho-
cytes, polymorphonuclear cells, and antigenic presenting cells. Also, it was mentioned that the presence of inflammation
molecules represented by interleukin 1, interleukin 2, HLA-DR, class II human leukocyte antigen, tumor necrosis factor,
and mast cells [1–4].
In the aortic valvular remodeling are implicated matrix metalloproteinase, which affects the extracellular matrix of the
cell and are contributing actively in the pathogenesis of the valvular aortic stenosis [3,4].
An important role in the pathogenesis and the physiopathology of aortic valvular disease is represented by the natural inhibitors of the matrix metalloproteinase (MMP) and tissue inhibitors of MMP that are unchanged instead of being
increased [5].
These biomolecules are the center of the development of inflammatory and fibrosing processes.
New Approaches to Aortic Diseases from Valve to Abdominal Bifurcation. http://dx.doi.org/10.1016/B978-0-12-809979-7.00004-3
Copyright © 2018 Elsevier Inc. All rights reserved.
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In the atherosclerosis complex, these biomolecules retain a key role in the vascular remodeling and extracellular matrix
alterations, which lead to vascular plaque instability, rupture, and acute cardiovascular events that affect the cardiac morbidity and mortality [6].
It is unknown yet why in some individuals these biomolecules induce atherosclerosis that can lead to the formation of
vascular atheroma plaque associated with complications such as plaque hemorrhage, thrombosis, and cardiovascular events
but is another group of individuals that the matrix and tissue metalloproteinase participate in the fibrosis process that affects
the valvular aortic leaflet and are inducing rigidity resulting in aortic degradation and valvular stenosis or regurgitation.
The Lipoprotein Anomalies
One of the key role of atherogenic process is represented by plasma lipoproteins and the accumulation in the subendothelial
region becoming the trigger for the atherogenic plaque being chemotactic for various inflammatory cells such as macrophages that will be transformed in foam cells and in the ultimate phase of unstable plaque [7].
Mirroring this process there are lipoproteins very similar to low-density lipoprotein and Lp[a] that are infiltrating the
aortic wall and the valvular leaflets inducing valvular lesions contributing to the valvular rigidity or deficit of coaptation
and valvular apposition [8].
Proteoglycans accumulation such as decorin and biglycan represent the most important processes that have been
revealed in the initiation of the aortic valvular lesions [9].
Proteoglycans are a core protein to which is attached a chain of glycosaminoglycans [10].
The lipoproteins are binding to proteoglycans via a transmembrane electrodynamic gradient interaction between positively charged basic amino acids on apolipoproteins and negatively charged glycosaminoglycan side chains of proteoglycans [11].
A series of studies demonstrates that proteoglycans interactions can link the levels of low-density lipoprotein (LDL)
and the severity of the aortic valvular degradation; so the conclusion to be drawn can be that it may represent a therapeutic
target in the aorta pathology [12].
Besides proteoglycans a leading position in the pathogenesis of human aortic wall and leaflet lesions is occupied by
oxidized lipids. Oxidized lipids are present particularly in the regions of maximum fibrosing and calcification [13].
A number of studies in vitro have shown that oxidized cholesterol stimulates calcified nodule formation by valve fibroblasts and that calcified nodule formation by these cells is inhibited by simvastatin [14].
These observational studies can provide a potential correlation between lipoprotein disorder and accumulation of lipids
that can induce calcification lesions and also can suggest a potential therapeutic benefit of statins.
Supporting this theory are the results of a series of retrospectives studies that have demonstrated a statistical semnificative correlation between the pharmacological use of statins and the regression of aortic valve lesions represented by calcifications and subsequent stenosis [15–17]. However, a prospective randomized trial has shown no benefit in using high
dosages of statin in patients with severe aortic fibrosis and calcification over an average of 3 years [18].
It is also possible that effective statin therapy may require longer treatment periods or targeting of earlier disease stages.
The Activation of Renin–Angiotensin System
A very interesting thesis supported by recent studies is the fundamental role the renin angiotensin system, especially debat-
ing the participation of the angiotensin converting enzyme (ACE) and of the angiotensin II type 1 receptor in the pathogenesis of aortic valvular lesions [19,2].
The angiotensin II is generated from the angiotensin I in the presence of ACE and it has various lesion effects.
Among them we present the stimulating effect regarding inflammation process and macrophage cholesterol accumulation, impairing the fibrinolytic process and the increasing metabolism and bioreactions between oxidized radicals that are
increasing the oxidant stress [19].
The stimulation of fibroblast expression of the lipoprotein-retaining proteoglycan, biglycan is one of the many pathways
in generating the aortic valvular lesions [20,21].
The macrophages that are present in the aortic valvular lesions express the ACE and a very large proportion of valvular
degradation is associated with LDL in the extracellular matrix [19].
The angiotensin II is present in all the valvular lesions that are promoted by the LDL cholesterol and macrophages,
suggesting that the ACE is active [19].
Furthermore, the angiotensin 1 receptor is expressed only on the cellular membrane of the fibroblasts present in the
aortic valvular lesions [2].
Another group of cells that are important in the pathogenesis of aortic lesions are represented by mast cells [2].
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A very interesting aspect is that the degranulated mast cells are present in the histological probes drawn from the aortic
valve lesion [2].
The mast cells contain chymase, a non-ACE enzyme that also can generate angiotensin II.
Summarizing, the aortic valvular lesions contain various sources of angiotensin II:
l LDL-associated ACE
l Macrophage-associated ACE
l Mast cells chymase
Unlike the atherogenic process where angiotensin II can affect the smooth muscle cell, the fibroblast is biologically
inactive until it begins to express on the membrane surface the AT 1 receptor that is responsible for the pathogenic effects
of the angiotensin II on the aortic valve [22].
This aspect was depicted by numerous studies that revealed a strong association between the use of ACE inhibitors and
the regression of aortic stenosis [22].
The same studies have shown that the treatment with ACE inhibitors should be conducted a la long and doing so to affect
the aortic sclerosis [22].
Calcification in Aortic Stenosis
In addition to the fibrosis process, the calcification is one of the main pathogenic mechanisms that lead to aortic valvular lesions.
Calcification can determine valvular leaflet rigidity, obstruction to left ventricular outflow, and progression of valvular deficit.
The extensions of calcic lesions can be predictive for the prognosis to worsen clinical outcomes and the disease progression [23,24].
The aortic valvular calcification is a biologically active process. The calcium deposits are made of calcium and phosphate structured as hydroxyapatite, such as the one that we encounter in bone and calcified arterial tissue [25].
The proteins that are implicated in the regulation of tissue calcification are represented by osteopontin, bone morphogenic protein 2 (BMP 2), bone morphogenic protein 4 (BMP 4), and receptor activator of nuclear factor NF-B ligand
(RANK ligand or RANKL) [26–28].
The osteoprotegerin that prevents the mineral bone resorption is the soluble part that interacts with RANK and is acting
as a competitive inhibitor of RANK binding to the RANKL.
The RANK component is present on the normal aortic valvular leaflets but it was assessed that it is missed by downregulation in the aortic lesions [28].
The calcified nodules may appear in regions of lipid deposition, in particular, when they are present in the oxidized
lipids [12].
Tenascin C is present in the extracellular matrix glycoprotein found in the development of the bone tissue [29].
A group of studies have demonstrated that there exists a subset of fibroblasts that expresses osteoblast markers and can
form hydroxyapatite participating actively in forming the calcium nodules [30]. There are a series of biologic components
that can increase the expression of osteoblast markers on the fibroblast surface inducing an increased rate of calcified nodules formation [30].
These biological components are represented by
l oxidized cholesterol;
l transforming growth factor 1 (TGF 1)
It has been shown that the use of statins can produce the inhibition of calcification and can inhibit the calcified nodules
through the inhibition of protein prenylation [14].
Hyperphosphatemia can determine the induction of calcified microvesicle formation in the intracellular matrix of myofibroblasts [30].
This biological aspect can suggest a potential mechanism linking the chronic kidney disease to valvular leaflet calcification [31].
In one very important recent study, it has been so eloquently demonstrated that osteopontin is an important inhibitor of
valvular leaflet calcification [32].
Osteopontin can promote the dissolution of hydroxyapatite by inducing macrophage carbonic anhydrase expression and
so by establishing an acidic extracellular environment [32].
The carbonic anhydrase can play an inhibitory role in the development of calcification in atheroma plaque [33].
In conclusion, the valvular aortic calcification is an active and complex process that implicates oxidized lipids, T lymphocytes, and producing proinflammatory cytokines.
64 PART | I Overview
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There is also a very important signaling mechanism involved in valvular calcification. In the presence of chronic inflammation RANKL and oxidized lipids in lesions suggest that NF-B activation is a crucial step in the vascular calcification
process [34].
AORTIC REGURGITATION
Aortic regurgitation consists of a diastolic reflux of the blood flux from the ascending aorta to the left ventricle. It may be
caused by malfunction of aortic leaflets, affected aortic root, or a combination of the two physiopathological mechanisms.
Aortic root disease now represents above 50% of the aortic regurgitation etiology.
The main related pathologies that are causing aortic regurgitation are represented by rheumatic disease, bacterial endocarditis with large vegetations, and coaptation interference or leaflets perforation, atherosclerotic degeneration, traumatic
chest events associated with chest trauma or deceleration injury affecting the aortic root, congenital diseases, such as bicuspid aortic valve and dilatation of aortic root dilatation, myxomatous degeneration [35].
There are a few rare conditions associated with aortic regurgitation such as Takayasu disease, ankylosing spondylitis
that can cause aortic root disease, ingesting anorectic drugs, and the existence of membranous subaortic stenosis [35].
The aortic valvular regurgitation can be acute or chronic. The acute aortic regurgitation occurs in bacterial endocarditis,
chest trauma associated with deceleration, and aortic dissection. In those pathological conditions, there is a sudden large
regurgitant volume with no accommodation of the left ventricular cardiomyocytes with a rapid volume overload that leads
to an increased left ventricular end diastolic pressure and left atrium pressures.
The resulting consequence is the inability of the left ventricle to develop compensatory dilatation of the cavity resulting
in an acute decrease of systolic performance with acute cardiac insufficiency having a pulmonary edema or a cardiogenic
shock as clinical presentation [35].
The main compensatory mechanism in this situation is represented by sinus tachycardia that tries to maintain cardiac
output but it is often insufficient.
There is also a functional myocardial ischemia represented by the low coronary pressures, left ventricular end-diastolic
pressure equalizing the coronary arteries pressure resulting in a diminished subendocardium perfusion.
A study published in Cardiovascular Imaging in 2016 by Kim SS et al. revealed that functional myocardial ischemia
can lead to arrhythmic complications and cardiac sudden death.
In the chronic aortic valve regurgitation, there is also a volume and a pressure overload of the left ventricle [36].
A study published by Lefevre in 2015 in the American Journal of Cardiology suggests that cardiac arrhythmic events
posttransaortic valvular replacements are directly related with the increased wall stress secondary to an increased regurgitant volume.
Compensatory eccentric hypertrophy is the main compensatory mechanism that occurs trying to maintain the left ventricular output [37].
The aortic root-related causes are represented by idiopathic aortic root dilatation, aortoannular ectasia, Marfan syndrome, Ehlers–Danlos syndrome, osteogenesis imperfecta, aortic acute or chronic dissection, syphilitic aortitis. In stage
three lues, chest trauma, congenital conditions such as bicuspid aortic valve and rheumatic systemic diseases represented
mainly by ankylosing spondylitis.
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