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The differences between the two types of hypertrophy and the mechanisms responsible for transformation from physiological to pathological hypertrophy are caused
by launch of certain intracellular programs, i.e., activation of signal transduction
systems, epigenetic, posttranscriptional, posttranslational modifications.
Intracellular programs implemented in physiological hypertrophy contribute to
[32]:
– intensified angiogenesis and maintained capillary density adequate to the
increased needs of cardiomyocytes, and other changes that increase energy supply
of cells;
– optimization of energy consumption;
– cell proliferation and survival, which requires appropriate metabolic changes,
control of apoptosis and autophagy;
– maintenance of contractile function of cardiomyocytes (for example, synthesis
2+
of contractile proteins, control of cytoplasmic concentration of Ca
, increased
sensitivity to inotropic factors);
2+
– inhibition of the negative effects of Ca
(for example, increased reuptake of Ca
into the sarcoplasmic reticulum);
– increased antioxidant potential of cells;
– adequate response to mechanical load;
– inhibition of processes observed in pathological hypertrophy (in many ways, the
opposite of those listed above), including fibrosis, inflammation, cell death, β-
adrenergic desensitization.
2+
Sometimes, the main trend of molecular remodeling events is called the «return
to the fetal gene program». This process, on the one hand, provides less energy
consumption and therefore protects the cell from immediate death, but, on the other
hand, makes it more vulnerable to long-term damage, for example, as some experiments show, it does not provide the phenomenon of preconditioning [33]. This duality
is manifested by the hypofunction of the exchangers SERCA2a of the damaged heart,
which helps to save energy, reduce contractility, but leads to an overload of the cyto-
2+
plasm with Ca
. It is assumed that the transition to the fetal phenotype can prepare
the heart for potential regeneration, which is preceded by dedifferentiation. However,
under ongoing damage, the restoration of normal tissue does not occur [8].
The underlying changes in the expression of fetal genes and genes of the
“adult” heart are regulated by transcription factors (GATA4, NFAT, Csx/Nkx2.5,
SRF, MEF-2, Hand1/2, Smad, products of early response genes), prohypertrophic (microRNAs-21, −195, −199b, −208, −23, −499) and antihypertrophic
microRNAs (−1, −133, −9), methyltransferases (G9a, SUV39H1), demethylases
(Jumonji D1A, D2A, D2B), acetyltransferases (p300/CBP), deacetylases (I, IIa, III
(sirtuins of sirtuins) classes, etc.), poly(ADP-ribose)-polymerase, chromatin remodeling complexes (SWI/SNF families), long non-coding RNAs (CHAER, CHAST,
CHRF, H19, HOTAIR, MALAT1, MEG3, MHRT, etc.), etc. [24, 34, 35]Many
2+
of these transcription regulators, as mentioned above, are activated by Ca
and
free radicals, which, in turn, transmit a signal from mechanosensitive structures,
neurohumoral and immune effects (Fig. 1).
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Such reprogramming has an impact on [8, 35, 36]:
– transdifferentiation of cells to myofibroblasts and fibrosis (expression of the
transgelin-1 gene; see «Mechanisms of fibrosis»);
– structure of contractile apparatus (decrease in the α/β ratio of myosin heavy chain,
change in isoform titin isoforms);
– HCN (hyperpolarization-activated cyclic nucleotide gated), normally expressed
on pacemakers (HCN4), expression of T-type calcium channels;
2+
– electromechanical coupling and control of intracellular Ca
concentration (T-
type calcium channels, reduction of SERCA2/phospholamban ratio);
– arrhythmogenesis;
– reduction of contractility;
– humoral response to damage (ANP, BNP production); metabolism, etc.
Metabolic rearrangements of the damaged heart contribute to saving oxygen
by using instead of fatty acids (105 ATP molecules from palmitic acid using 23
molecules, O
(31 ATP molecules from one glucose molecule using 6 O
P/O = 2.3) substrates that are less “expensive” in this sense—glucose
2
molecules, P/O = 2.6),
2
ketone bodies (P/O = 2.5), lactate utilization, branched-chain amino acid, strengthening anaplerotic reactions, etc. In other words, the Randle cycle is interrupted at
the cardiomyocyte level (normally the heart captures fatty acids that inhibit glucose
metabolism). The activity of key beta-oxidation regulators—intracellular receptors
PPARα, ERRα and their coreceptor PGC1α (they are also the main regulators of mito-
chondrial functions)—decreases—the isoform composition of GLUT transporters
changes: more GLUT-1 and 5 (fructose), less GLUT-4, and the activity of monocarboxylate transporters (MCT-1 and MCT-2) for capturing ketone bodies increases
[37, 38].
However, these changes do not fully meet the energy needs. Glucose utilization
under anaerobic conditions produces less ATP and decreases with the progression
of the disease, and ketone bodies start to act relatively late, as some studies show.
The biological activity of these substances and their metabolites also plays a positive
or negative role: branched-chain amino acids aggravate mitochondrial dysfunction,
leucine stimulates the mTOR signaling pathway, protein glycation (including transcription factors). β-Hydroxybutyrate inhibits lipolysis (via PUMA-G and GPR109A
receptors), SNS activity (via GPR41 receptor), inflammasome assembly, inhibits
class I histone deacetylase, oxidative stress, stimulates the synthesis of fibroblast
growth factor-21 (cardioprotective effects) [37, 38]. Failure of ATP synthesis modifies the work of purinergic signaling (the release of ATP by pannexins, “transformation” into adenosine, interaction with receptors P1 (or A, four types), P2X (seven
types), P2Y (eight types)), possibly having a cardioprotective function [37, 38].
It is these links of pathogenesis that remain the least accessible target of therapy
so far, although neurohumoral inhibitors have pleiotropic and main metabolic effects
(ranolazine and trimetazidine). Interestingly, the cardioprotective effect of sodium
glucose co-transporter 2 (SGLT2) inhibitors may be associated not only with natri-
+/H+
uresis, exposure to Na
exchangers, increased erythropoiesis, but also with hyper-
ketonemia (increased glucagon/insulin ratio, stimulation of hepatic β-oxidation).
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However, the protective effect of ketosis, not caused by SNS, remains a partially
accepted hypothesis [38].
Thus, taking into account all the above, the molecular events of pathological hypertrophy and further remodeling can be described in a simplified way
as follows: primary (hemodynamic) and secondary (neurohumoral and immune)
2+
damages contribute to an increase in the intracellular concentration of Ca
and free
radicals, which, being second messengers, trigger the transition to the fetal gene
program and other related maladaptive programs, including fibrosis.
3 Mechanisms of Fibrosis
Myocardial fibrosis is a morphological substrate of most severe heart diseases. It is
found in children with «blue» heart defects, for example, by increasing the myocardial
extracellular volume during MRI with cardiac magnetic resonance. At the same time,
a feature of defects with insufficient filling of the left ventricle is a decrease in the
mass of working cells. In arterial hypertension or aortic stenosis, on the contrary,
there is a positive correlation between an increase in extracellular volume and the
left ventricular mass index [39, 40].
Depending on the etiopathogenesis and localization, fibrosis variants can be
divided into [40, 41]:
– reactive—connective tissue «between» working cells, the volume of which does
not decrease at the initial stages. Develops in response to hemodynamic load, is
critical for cardiomyocyte ischemia, hyperglycemia, in hypertrophic cardiomyopathy, sarcoidosis, chronic kidney disease or in the framework of degenerative
changes during aging;
– replacement—after the death of cardiomyocytes (myocardial infarction,
sarcoidosis, myocarditis, toxic/drug-induced damage, chronic kidney disease);
– infiltrative—amyloidosis, Anderson-Fabry disease and other infiltrative diseases;
– endomyocardial.
The main producers of excess connective tissue in the heart, as well as in other
organs (in the liver with cirrhosis, in the kidneys with chronic diseases, in the
gastrointestinal tract with inflammatory bowel disease) are myofibroblasts. These
cells combine the properties of fibroblasts (for example, synthesis and secretion
of certain markers: collagens of I and III types, periostin, fibronectin, tenascin-C)
and smooth muscle alpha-actin (acta2, sma), transgelin (tagln, sm22). Myofibroblasts have an increased sensitivity to profibrogenic and proinflammatory mediators,
including chemokines. In addition, they can produce many of mediators themselves
(IL-1β, -6, -10, TNFa), mechanically affect the intercellular substance, for example,
by means of fibronexus connecting the cytoskeleton with fibronectin, and developed
focal adhesions [42]. When an organ is damaged, fibroblasts, epitheliocytes, pericytes, Ito cells, representatives of mononuclear phagocytes, bone marrow precursors
and fibrocytes turn into myofibroblasts [41]. This transdifferentiation is the most
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important event of the «fibrosis program», which also includes hyperproduction of
intercellular matrix components, violation of its degradation, changes in the function
of leukocytes, epithelial cells, pericytes, cardiomyocytes and other cells.
The trigger factors that initiate the fibrosis program include:
–TGF-β, secreted by fibroblasts, macrophages, platelets, cardiomyocytes, vascular
cells when exposed to mechanical overload, ATP II, aldosterone, cytokines;
– activation of already synthesized latent TGF-β bound to the extracellular matrix,
which is produced by enzymes and free radicals;
– platelet growth factor-B (PDGFB), secreted by macrophages, platelets;
– hemodynamic overload, AT II and aldosterone. Cytokines also activate a number
of mechanisms that are not directly related to TGF-β, among them increased
synthesis of matricellular proteins (for example, connective tissue growth
factor, CTGF or CCN2, tenascin-C), membrane proteoglycans (syndecans) lysyl
oxidases, which have a profibrogenic effect.
As a result, there is excessive production of connective tissue by myofibroblasts, which replaces normal functional tissue, therefore, impairing the biomechanical properties of the heart, disrupting myocardial relaxation (diastolic dysfunction),
reducing contractility (systolic dysfunction), aggravating circulatory hypoxia and
also contributing to arrhythmogenesis (creating a morphological substrate for reentry
arrhythmias) [43, 44].
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Diagnostics
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Echocardiography
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I. Y. Baryshnikova
Abstract Echocardiography is a first-line diagnostic tool both for preoperative
assessment of DORV anatomy and postoperative complications. The main goal
of preoperative echocardiography in DORV is to evaluate VSD type, the presence of pulmonary artery stenosis and its nature, mitral–aortic continuity as well
as relationship and course of the arterial trunks and associated cardiac anomalies.
Evolving echocardiographic techniques such as speckle tracking method allows to
obtain volumetric heart models and assess local abnormalities of myocardial performance, respectively. The great limitation of echocardiography is its subjectivity and
low effectiveness in evaluation of extracardiac components of the disease. Overall,
echocardiography is able to provide pivotal parameters for accurate surgical planning.
Keywords Double-outlet right ventricle
DORV is a complex conotruncal anomaly with a wide range of anatomical varieties.
The difficulties of diagnosis of DORV on echocardiography (echo) arise already at
the prenatal stage. In most fetuses, a conotruncal anomaly can be suspected as early
as 11–14 weeks of gestation by echo, but it is difficult to distinguish whether a defect
is tetralogy of Fallot or DORV, on the one hand, and TGA or DORV «TGA» type, on
the other hand. This is not only due to the limited visualization of a fetal heart, but
also due to the lack of universal echo criteria for DORV. As a rule, four-chamber view
at the end of the first and second trimesters is visualized without any particularities;
however, in five-chamber view, VSD and origin of the arterial trunks from the anterior
chamber (right ventricle) are clearly visible [1, 2]. In postnatal period, echo can
provide almost complete information for surgical planning [3].
Echo examination of DORV as well as all CHD should be performed in accordance
with segmental approach with evaluation of each segmental levelof a heart. Diagnosis
of DORV by echo in some cases may be very complicated. Often, sonographers and
I. Y. Baryshnikova (B)
Department of Ultrasound Investigations, A. N. Bakulev National Medical Investigation Center
for Cardiovascular Surgery, Moscow, Russia
e-mail: jatropha@mail.ru
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
K. V. Shatalov and K. M. Dzhidzhikhiya (eds.), Double-Outlet Right Ventricle,
https://doi.org/10.1007/978-3-031-49707-0_6
· Diagnostics · Echocardiography
107
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Fig. 1 The aorta more than
50% takes origin from the
right ventricle (left
parasternal long-axis view).
The asterisk indicates
mitral–aortic continuity.
Ao—aorta; RV—right
ventricle; LV—left ventricle;
LA—left atrium
surgeons cannot come to an agreement regarding the degree of origin of the arterial
trunks from the ventricles since this parameter is highly subjective and may be
interpreted ambiguously depending on the plane of the ultrasound beam and cardiac
phase. For example, from subxiphoid long-axis view aortic origin can be projected
mainly from the right ventricle, whereas from the left parasternal long-axis view
aorta predominantly origins from the left ventricle.
Some specialists in order to simplify the diagnostic of DORV consider the absence
of mitral–aortic fibrous continuity as a direct sign of DORV. However, this approach
can lead to an incorrect classification of ventriculoarterial connections, for example,
when the aorta takes origin predominantly from the left ventricle and there is
mitral–aortic muscular continuity (see “Transitional anatomical forms of DORV”
in the Chap. 2). In this regard, many specialists use the “50% rule” for determining
DORV when both aorta and pulmonary artery predominantly originate from the right
ventricle (Fig. 1).
1 Preoperative Investigation
For correct preoperative surgical decision-making, echo protocol should include
assessment of the following anatomical structures:
•
VSD;
•
morphology of mitral–aortic continuity;
•
relationship and course of the arterial trunks;
•
pulmonary artery stenosis;
•
coronary artery anatomy;
•
associated cardiac abnormalities.
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1.1 VSD
Standard echo is a method of two-dimensional visualization. Sonographers virtually
construct in a head a three-dimensional image of a whole heart based on the set
of two-dimensional projections obtained during the investigation. By means of 3D
echo, it is possible to obtain volumetric nonstandard cuts and provide additional
information for careful surgical planning [4].
VSD location in DORV is determined depending on the projection obtained. On
apical or subxiphoid four-chamber view, the inlet part of IVS is visualized (Fig. 2A),
which helps in diagnosing non-committed VSD. In turn, to diagnose conoventricular
VSD, the visualization of the outlet part of IVS is obtained by apical five-chamber or
subxiphoid view, left parasternal long-axis view, or along the long axis of the right
ventricle from the subxiphoid long-axis view (Fig. 2B–C).
Fig. 2 Echo visualization of different parts of the IVS: A—four-chamber apical view. The line
indicates the inlet part of IVS; B—five-chamber apical view. The line indicates the outlet IVS;
C—subxiphoid short-axis view, cross section of the RVOT. The line indicates the outlet IVS; D—
subxiphoid short-axis view, cross section at the level of the papillary muscles. The line indicates
the IVS. Ao—aorta; PA—pulmonary artery; RV —right ventricle; LV —left ventricle; RA—right
atrium; LA—left atrium
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