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FOREWORD
I enjoyed reading this monograph on aortic valve diseases.
Giovanni Concistrè and colleagues from Italy put a lot of
thought in producing Perspectives in Aortic Valve Disease,
hundreds of pages of detailed description of practically all aortic
valve themes from basic sciences to the latest modalities of
treatment, all well documented with pertinent and current
references. It is often difficult to compile a multi-author
textbook and maintain the standard in breadth and depth in its
various sections, but our Italian colleagues delivered excellence
in each of the 21 chapters. Medical students, cardiac surgical
trainees and practicing cardiac surgeons and cardiologists will
enrich their knowledge in aortic valve disorders by spending the
hours required to read the entire monograph. By the end, they will feel that the time was well
spent and they know more about this topic than ever before. I read it during the Covid-19
pandemic and I encourage you to read too. It is not a Shakespearean piece but it is a very
good didactic book.
Aortic valve diseases have become an important subject for cardiologists and surgeons.
This is due to a multitude of factors such as an increase in the median age of the population in
Western countries with a consequent increase in the incidence of calcific aortic stenosis, older
people who want to remain physically active, better diagnostic and operative techniques to
treat congenital and acquired disorders sporadic or associated with genetic syndromes, and
the development of transcatheter therapies to treat aortic valve disease. The book describes
how aortic valve disorders are dealt at the present but undoubtedly it will continue to evolve.
Reading Concistrè’s work will bring you up to speed and will prepare you to understand what
is yet to come in managing patients with aortic valve diseases.
Tirone David, MD
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PREFACE
The aortic valve is located at the center of the heart and is the core of the cardiac
anatomy. The disease of this valve is an important cause of morbidity worldwide. Rheumatic
heart disease is the most common cause of both aortic stenosis (AS) and aortic regurgitation
(AR) in developing countries, while fibro-calcific degeneration and conditions causing aortic
root dilation are the leading causes of AS and AR, respectively, in industrialized countries. A
careful search for signs and symptoms may provide the first clues to the presence of aortic
valve disease, which can then be verified and characterized by imaging techniques, starting
from transthoracic echocardiography. In patients with known aortic valve disease,
identification of disease grade and prompt detection of symptom onset are crucial to refer
them to pharmacological therapy or aortic valve surgery or transcatether technology.
Furthermore, a correct interpretation of the signs and symptoms of acute AR can result in a
rapid diagnostic workup and prompt patient referral to surgery. In the history of cardiac
surgery, the aortic valve prosthesis was the first target of the cardiac surgery, which was
performed by Dr. Hufnagel at Georgetown University, Washington DC, in 1952. Since then,
aortic valve surgery has led the field of cardiac surgery. Many prosthetic heart valves have
been developed to replace defective valves, and numerous surgical procedures have been
created to deal with the complexities of aortic valve surgery. Aortic valve surgery has
developed from a single valve replacement to more complex procedures, such as the Ross
procedure or valve sparing surgery. Recently, a transcatheter aortic valve replacement has
evolved as well. All aspects regarding of the aortic valve are addressed in this book, including
anatomy, physiology, preoperative examination by techniques such as echocardiography, as
well as various surgical procedures, operative risk analysis especially in the senile population,
and newly emerging technologies. The authors are italian cardiologists, radiologists,
pathologists and cardiac surgeons who work in Italy and in Europe. This work is aimed at
cardiology fellows in training, while also helpful to surgeons, cardiologists, imagers,
interventionalists, as well as other clinicians and students involved in the diagnosis and
treatment of aortic valve. I believe this book will help clarify daily questions regarding the
clinical and surgical practice in aortic valve disease, as well as induce inspiration and new
insights into this field. I would like to thank all the chapter authors who sent us splendid
manuscripts albeit their tight schedules and current terrible pandemic situation. I thank
Professor Tirone David who honored the work with his Foreword. I could not have
accomplished editing this book without the help and tremendous support of the staff at Nova
Giovanni Concistrè
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Science Publishers. Finally, I thank my family and my friends for encouraging me to proceed
with this project.
Giovanni Concistrè, MD
In: Perspectives in Aortic Valve Disease ISBN: 978-1-53618-769-4
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Editor: Giovanni Concistrè © 2020 Nova Science Publishers, Inc.
Chapter 1
SURGICAL ANATOMY AND PATHOLOGY OF
AORTIC VALVE: MORPHOGENESIS, NORMAL
AND PATHOLOGICAL ANATOMY
Giacomo Bianchi
Adult Cardiac Surgery, Ospedale del Cuore, Massa, Italy
ABSTRACT
The systematic study of the aortic valve in the surgical perspective should include an
integrated approach. The embryology of semilunar valves and cono-truncal division are
the cornerstone of the entire surgical anatomy. Like other cardiac valve structures, the
aortic valve cannot be analyzed separately but must be framed within the aortic root, both
morphologically and functionally. These aspects not only guide the clinician in the
diagnosis but also the surgeon and the interventionalist in the treatment of aortic
structural heart disease.
Keywords: surgical anatomy, morphogenesis, pathology, aortic valve
INTRODUCTION
The study of aortic valve pathology for the clinician, surgeon and researcher cannot
ignore the knowledge of the mechanisms of formation, its normal and pathological anatomy.
Embryology applied to the surgical anatomy is the basis for the exact knowledge of the
pathological pictures and methods of intervention today. In this chapter, importance is given
both to the molecular processes that determine the development of semilunar valves, with
particular reference to the aortic valve, and to the anatomical pictures and their pathological
variants.
, MD, PhD
Corresponding Author’s Email: gbianchi@ftgm.it.
Giacomo Bianchi
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AORTIC VALVE MORPHOGENESIS
Structural Components
In the 4-chambered heart of the vertebrates, the presence of atrioventricular valves
(tricuspid and mitral) that separate the atria from the ventricles and semilunar (aorta and
pulmonic) to the arterial poles, ensure the unidirectional flow of blood [1]. The leaflets of the
semilunar (SL) valves are composed of superimposed layers of extra-cellular matrix (ECM),
each characterized by a prevalent component: pars ventricularis (elastin), spongiosa
(proteoglycans) and fibrosa (collagen).
The SL valves do not require a supporting apparatus. Instead, the aortic valve (AoV)
cusps are self-supporting and attach to crown-shaped arterial roots via the annulus fibrosus.
Supporting connective tissue is present in the aortic and pulmonic roots and hinge regions of
the SL valves [2].
The first evidence of valvulogenesis during embryonic development is the formation of
endocardial cushions in the AV canal (AVC) and outflow tract (OFT) of the primitive looped
heart tube [3].
The SL valves arise from the complex arrangement of proximal and distal cushions that
form in the OFT. The valve progenitor cells of the endocardial cushions are highly
proliferative, whereas little or no cell cycling is apparent later in remodeling and mature
valves [4].
At E10.5, the OFT cushions are populated by mesenchyme originating from two distinct
lineages. The contribution of endocardially derived cells is restricted to the proximal portion
of the conal cushions and distal part of the truncal ridges [5, 6]. The cranial neural crest cells
(CNCCs) are found mostly in the distal portion wherein they form two prongs of
mesenchymal cells [7]. By E11.5, the interface of endocardium and neural crest-derived
mesenchyme at the conotruncal junction delineates a boundary corresponding to the site of
SL valve development in humans [8].
The fate of CNCCs is controversial: initial studies had shown that these cells were
selectively eliminated during embryonic development, while more recent studies have found
their persistence even in the final stage of development and in the adult [4, 7].
In particular, evidence emerges about the concentration of these cells in the leaflets
adjacent to the aortic-pulmonary septum, i.e., the R-L cusp of the aortic valve and the
pulmonary valve, respectively [7]. This discovery is interesting in the light of hypothesis
about the origin of the bicuspid aortic valve from the neural crest, with the fusion of the R-L
cusp [9].
The secondary heart field (SHF) might constitute a third source of OFT mesenchyme.
These cells cells are added to the myocardial wall as the OFT elongates before septation and
contribute to endocardial lineages within the OFT [10].
Postnatally, bone marrow (BM) – derived cells can contribute to the valve leaflets. Those
cells might be important for valve homeostasis, for example, by providing a population of
valve-interstitial cells (VICs) responsive to injury.
From E11.5 onward, the ECs expand by mesenchyme proliferation driven by Bmp/TGF-
b, Egf, Nf1/ras, and Wnt signaling. Septation of the OFT and AV junctions into separate R–L
ventricular inlets is mediated by fusion of the EC structures. In the OFT, the fusion of the
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larger cushions at midline yields separate outlet lumens, connecting the left and right
ventricles to the AoV and PV, respectively. The primary ECs in the AVC form a partition
between atria and ventricles and determine the alignment of the R–L AV valves and proper
relationship of the great arteries to the ventricular chambers.
In humans, R – L fusion is the most common, followed by R-NC [11]. A comparative
study of inbred Syrian hamsters with R–L morphology and Nos3-knockout mice with R-NC
morphology suggests that the etiologies of these phenotypes are different [9]. R – L fusion
may be the result of defective OFT septation, implicating the neural crest, whereas R-NC
fusion may be caused by defec- tive lateral cushion formation, suggesting in- adequate EMT.
The BAV is usually detected in isolation, but can also coexist with other cardio- vascular
malformations, suggesting a multigenic etiology [11].
The later phases of valve development are char- acterized by the gradual transition from
undifferentiated mesenchyme to specialized VICs. This process is strongly influenced by
hemodynamic stimuli.
Cell proliferation, density, and turnover, substantial in early valvulogenesis, become less
pronounced at this stage; in the OFT cushions the apoptosis process predominates. While in
AV valves a differential and spatial expression of the genes in the leaflets and in the chordal
apparatus is noted, in SL valves the genes are expressed at the same time and space, since
they must give rise to a cellular structure with internal support apparatus [12].
The final process is the complex and continuous extracellular matrix (ECM) stratification
and remodeling driven by the hemodynamic forces.
Dysregulation of the ECM appears to be a general feature of valve disease regardless of
etiology; for example, BAVs from pediatric patients have increased collagen and
proteoglycan content, whereas myxomatous MVs have loose collagen, increased
proteoglycan, and reduced elastin content with altered fiber orientation in all layers.
THE AORTIC ROOT
Anatomical Landmarks and Uniform Terminology
The definitive outflow tracts in the postnatal hearts possess three components. These are
the intrapericardial arterial trunks, the arterial roots, and the subvalvar ventricular outflow
tracts. The distal boundary of the aortic root with the intrapericardial component of the
ascending aorta is clearly marked by the sinutubular junction. The proximal boundary, in
contrast, has no direct anatomic substrate.
The aortic root forms the centerpiece of the cardiac base. It is at the junction of the left
ventricular outflow tract and the intrapericardial component of the ascending aorta. In
surgical view, all cardiac structures normally referred to as “right” and “left” are instead
“anterior” and “posterior,” respectively.
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Definition of the Aortic Root
The aortic root is a complex and functional unit situated between the left ventricular
outflow tract (LVOT) and the ascending aorta (Figure 1). It supports the leaflets of the aortic
valve and gives the origin to the coronary arteries. Delineated superiorly by the sinotubular
junction (STJ) and inferiorly by the ventriculoaortic junction (or “aortic annulus”), consists
of:
Sinotubular ridge/junction
The Valsalva sinuses
The leaflets
The commisures
The interleaflets triangles
The ventriculoaortic junction.
Figure 1. CT scan of the thoracic aorta. STJ: sino-tubular junction; VAJ: ventriculo-aortic junction.
Leaflets: thickened aortic valve leaflets.
The Sinotubular Junction
The sino-tubular junction joins upwards the tubular portion of the aorta and downwards
the sinuses of Valsalva and the aortic commissure with which is in direct continuity. On the
aortic lumen the STJ usually presents a slightly raised ridge of thickened aortic wall, while on
the outside it is smooth and. The sino-tubular junction takes on the contour of the three
sinuses, thus it is not perfectly circular and evidences a mildly trefoil or scalloped outline.
STJ play a fundamental role in the structure of the aortic root and in the function of the
aortic valve being a component of the functional aortic annulus [13]. It has specific
geometrical relationship with the other components of the root. In fact, despite the area of the
STJ increased with age and with hypertensive cardiomyopathy [14], in normal healthy hearts
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echocardiographic diameter of the STJ is about 75% of the maximal sinus diameter [15],
while is larger than aortic annulus at the level of the VBR with a ratio of 1.3.
At the level of the aortic commissures forms a circular ring [16]; its diameter is 10-15%
smaller than that of the ventriculo-aortic junction (VAJ). It provides most of the support for
the valve cusps at their commissures and its integrity is essential fo the correct function of the
valve.
The Valsalva Sinuses
The three-dimensional space of the aortic root surrounding the aortic leaflets are known
as the sinuses of Valsalva. The sinuses of Valsalva represent the most proximal portion of the
arterial system above the aortic valve. In a cross-sectional view the three bulges have a clover
shape, and due to its physiological morphology, characterized by a dilatation, the root is much
wider at the midpoint of the sinuses than at either the STJ or at the basal attachment of the
leaflets.
Although the three sinuses af the root and their leaflets play an identical function, they
anatomy differ [16, 17]. Two of them give rise to the coronary arteries and are named the
right and the left coronary sinuses. A crescent of ventricular musculature, relative to the VAJ,
is incorporated all along the base of the right coronary sinus and in the part of the left
coronary sinuses close to the right sinus. The third sinus, called the non-coronary aortic sinus,
consists exclusively of fibrous wall; its base is part of the mitro-aortic continuity, thus at this
level the VAJ and the VBR coincide.
The base od the left coronary leaflet partially attaches to the septal muscle and partly to
the fibrous skeleton of the heart, as well as to the base of the anterior mitral leaflet. The right
coronary cusp is attached to both the septal muscle and the membranous septum. The noncoronary leaflet attaches to the membranous septum and then along the fibrous skeleton in
continuity with the anterior leaflet of the mitral valve. The fibrous tissue constitutes
approximatively 55% of the posterior aspect of the aortic root, ranging from the membranous
septum to the left trigone.
The Aortic Valve Structure (Semilunar Leaflets and Commissures)
The normal aortic valve is composed of three leaflets that represent the moving parts of
the valve. Each leaflet has a base that contributes to the definition of the ventriculoaortic
junction, a “body,” and a free margin. The superior aspect ends at the level of the sinotubular
junction.
Normal aortic leaflets are soft and pliable. Each leaflet is composed of a free margin that
is slightly thicker than the basal portion and is responsible of the closure of the valve during
the diastole.
The apposition zone, the “lunule,” is on the ventricular surface of the free margin and
represents the place where each leaflet meets the adjacent leaflets during valvar closure. At
the mid-portion of the “lunule,” there is a further thickening called the “nodule of Arantius.”
Leaflets fenestrations above the closure line are common. The valve competence depends on
the coaptation of the three leaflets; at the midline level of each cusp, the coaptation depth is 810 mm.
The basal margin of the leaflets is attached in a semilunar fashion to the aortic root. This
basal attachment has the nadir below the VAJ and the zenith at the level of the STJ, where
each leaflet, joining the adjacent leaflet, form the three commissures respectively. Beneath the
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apex of the commissures, a thin layer of fibrous tissue go down, between the respective
leaflets, towards the VAJ and forms the final part.
Histologically, aortic leaflets show dense collagen bundles at the level of their semilunar
hinge on the arterial wall and of their free margin. The insertion of the apices of the semilunar
hinges on the aortic wall corresponds to the apices of the interleaflets triangles. These regions
are strongly reinforced with connective fibers and elastic aortic lamellae, thus holding the
semilunar leaflets and distributing the tension forces that would otherwise break and distort
the leaflets [18].
Each cusp consists of three layers: the fibrosa, on the aortic side, the spongiosa in the
middle, and the ventricularis. The fibrosa is mostly constituted of collagen fibers, which are
primarily arranged in a circumferential direction, from one commissure to the other. The
spongiosa consists of collagen and elastic fibers, proteoglycans, and mucopolysaccharides
that give it a soft consistency. The ventricularis mainly consists of elastic fibers, structured in
thin sheets, randomly oriented as compared with the highly organized structure of the fibrosa;
it provides the tensile recoil to retain the folded and corrugated shape of the fibrosa and also
prevents diastolic overdistension.
The Interleaflet Triangles
The interleaflets triangles are bordered by insertion of the leaflets and of the leaflet
attachments of the aortic sinuses at their base. They are triangular extensions of the LVOT.
The triangle between the left and the right coronary cusps is partly constituted of myocardial
tissue, the triangle between the right and the noncoronary cusps consists of fibrous tissue and
contains the atrio-ventricular (AV) bundle of the conduction axis, and the triangle between
the noncoronary and the left cusps is only composed of fibrous tissue. The border of the
triangles are delimited on the cusps’ side by a dense collagen fibers layer, forming also the
fibrous layer of the VAJ. The area delimited is the “body” of the triangle. A thin layer of
elastic fibers is also present and in continuity with the elastic layer beneath the endocardium.
The Ventriculo-Aortic Junction
Unlike the ‘annulus,’ the anatomic ventriculo-arterial junction is more reminiscent of a
circle. It is where ventricular myocardium terminates and gives way to the wall of the aortic
sleeve. But, on account of the region of aortic-mitral valvar continuity and the central fibrous
body forming the remaining 60% or so of the ventriculo-arterial junction, the slightly larger
portion of the junction is fibrous. Here, precise location of the junction is not possible and we
can only extrapolate by completing the circle around the outflow tract, and making the
assumption that there is a sharp line between myocardium and sleeve. Nevertheless, the
semilunar hingelines of the valvar leaflets create an intricate arrangement at this junction. The
nadirs of the hingelines are locates below the ventriculo-arterial junction. Thus, where the
hingelines cross muscle, myocar- dial segments are included into the aortic sinuses.
In human, myocardium is present in the non-coronary and posterior half of the left-
coronary sinus only when there is persistence of the left ventriculo-infundibular fold (inner
heart curvature) but this seldom happens. The area of valvar continuity is thickened at both
ends to form the right and left fibrous trigones; the right trigone contributing to the central
fibrous body of the heart.
The anatomic ventriculo-arterial junction, however, does not coincide with the functional
junction, again owing to the configuration of the semilunar hingelines. First, the ventricular
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