The mainstay of the pathogenesis of HCM is due to

its mutation in the sarcomere protein structure

causes the change in structural protein sarcomere
which leads to an increase in the muscle cell size
[13]. Due to these mutations, cardiac muscle
muscles undergo very huge disarrangement of large
muscle cells and lead to cause fibrosis in structural
components of cardiac muscle cells causing left
ventricular hypertrophy and an increase in
interventricular septum thickness [14]. On
histopathological examination arrangement of
cardiomyocytes are in irregular arrangement and
there is an accumulation of extracellular connective
tissue leading to fibrosis and their nuclei are lost
their normal structure [15].
These changes manifest obstruction to the outflow
tract during the systolic stage (contraction stage) of
the cardiac cycle which increases the Left ventricular
end-systolic volume [figure 1] , increase in thickness
of the left ventricular wall progress to dysfunction in
diastole(relaxing stage), and increase in thickness
may also cause the increase in need of blood supply
if not accompanied may cause ischemia of the
tissue, and valves are moved anteriorly leading to
mitral regurgitation [16].

FIGURE 2
An increase in thickness of the left ventricular wall
and interventricular septum causes the obstruction
of the Aorta, causes an increase in left ventricular
diastolic volume and pressure, because of
movement of the mitral valve anteriorly cause the
mitral regurgitation.
MOLECULAR GENETIC VARIAIONS
This disease can be characterised as an single gene
disorder with an autosomal dominant inheritance
pattern, meaning one mutation is usually enough to
cause the disease, although its expression and
penetrance can vary greatly [17].
The disease is clearly inherited by about 60% of
patients with HCM, Inheritance modes other than
autosomal dominant and X-linked have been
described, but are rare [18]. Phenocopy conditions,
such as Fabry disease, are typically associated with
an X-linked inheritance [20]. In addition to
phenocopy conditions, syndromic conditions like the
Noonan syndrome and storage diseases like
Anderson-Fabry disease also occur [19]. The
molecular genetic basis of HCM has been partially
uncovered by pioneering studies by Christine and
Jonathan Seidman , Paré et al. discovered an
important variant of the MYH7 gene, coding for a
sarcomere protein called myosin heavy chain
(MYH7), that was responsible for large-scale
discoveries made later [21,22].
Effects of mutations on transcription and translation

There is a small number of autosomal dominant

mutations that lead to premature truncation of
encoded proteins, The p.Gln425X mutation in the
MYBPC3 gene or the c.2864–2865delCT in the
MYBPC3 gene is either a gain of a stop codon or a
frame shift[23,24].
The nonsense-mediated decay (NMD) pathway
identifies the premature termination codon (PTC )
releases the elongation factors (proteins that attach
amino acids to the template during protein
synthesis), and then the decay-inducing
complex(involved in mRNA degradation)[25,26].
As a result, such transcripts are degraded and
protein levels are reduced. Whenever there is no
natural stop codon in a transcript, a mechanism
called "non-stop decay pathway" identifies the
transcripts and releases them from ribosomes to
prevent translation[27,28]. The released transcripts
are then degraded by the exosome
complexAdditionally, the No-Go mRNA decay
pathway, which stalls ribosome progression during
translation, results in the endonucleolytic cleavage
of the mRNA transcript [26]. As a result of these
quality control mechanisms, truncated proteins
cannot be synthesized.
Those transcripts containing PTC that escape the
NMD are expected to be expressed as truncated
proteins[22].

HEMODYNAMICS –LEFT VENTRICULAR

OUTFLOW OBTRUCTION
An HCM left ventricle typically has a normal end-
diastolic volume, a normal or elevated ejection
fraction (65–70%), and a decreased end-systolic
volume.
When hyperdynamic ejection occurs, the anterior
leaflet of the mitral valve moves anteriorly during
systole, passing against the hypertrophied
interventricular system during that time, which
results in obstruction to outflow in approximately one
third of patients with HCM[29]. HCM is characterized
by dynamic obstructions, This obstruction is
determined by the myocardial contractility, the
ventricular preload, and the afterload,If the LVOT is
severely obstructed, the ventricular volume also
determines how severe the obstruction is,Increasing
contractility, reducing preload, and increasing
afterload reduce ventricular volume, causing or
increasing obstruction, while reducing contractility
and increasing preload and afterload do the
opposite[30-33].
Maron MS et al. studied LVOT obstruction in 320
consecutive HCM patient in these LV outflow
obstruction was present at rest and/or with exercise
in 225 patients ,so Most patients with HCM suffer
from a predominantly obstructive disease,
characterized by LV outflow gradients, often
accompanied by heart failure symptoms and
detectable by exercise alone[34].In HCM patients
most common heart failure is diastolic dysfunction.
The thickened ventricular wall slowed relaxation and
caused increased stiffness due to the interstitial
fibrosis. Patients with HCM often have elevated left
atrial volumes, which is associated with left
ventricular diastolic pressure and predicts the
development of atrial fibrillation and heart failure
[35].
MECHANISMS CAUSING FOR ECTOPIC ATRIAL
FIBRILLATION
There are few mechanisms that lead to change in
the normal automaticity of the cardiac muscle cells
and cause Atrial fibrillation.
The incidence of atrial fibrillation is increased in
patients with HOCM , the main reason changes in
left ventricular thickness leading to an increase in
left atrium promotes the abnormalities in electrical
conduction in left atrial contraction [36].
Action potential of atrial muscle cells are maintained
by inward rectifier K+ current and pacemaker current
(If), through these channels atomicity is attained[37].
The resting action potential is stabilized due to high
flow of K+ ions through the respective channel,
although there is high pacemaker current inward
rectifier K+ current is much larger than this and
maintaining the stable automaticity moreover,
unbalance in this main cause of increased
automaticity by a decrease in K+ current and
increase in pacemaker current [37].
Early afterdepolarizations are caused mainly by
prolongation of action potential duration due to
allowing of L-type Ca2+ current to recover from
inactivation causing depolarizing inward movement
of Ca2+ ions. These changes that take place in the
atrial muscle cell are the main reason for the
increase in the prevalence of atrial fibrillation in
congenital long-QT syndrome patients[38].
Delayed afterdepolarizations due to the abnormal
release of calcium Ca2+ from sarcoplasmic
reticulum stores during diastole, Specialized
sarcoplasmic reticulum Ca2+ channels are called
ryanodine receptors [RyRs]. This abnormal release
is due to the response to Ca2+ in the
transmembrane. RyRs are closed during diastole but
opened due to channel abnormality or overlead of
calcium in the sarcoplasmic reticulum. so there is a
Na+-Ca2+ exchanger where one Ca2+ released is
exchanged with 3 extracellular Na+ leading to net
depolarizing inward positive-ion movement, These
changes lead to delayed afterdepolarizations[39].
Molecular and Cellular Mechanisms of Atrial Fibrosis
in Atrial Fibrillation
The extracellular matrix (ECM) is composed
primarily of small, spindle-shaped cells known as
fibroblasts, Up to 75% of cardiac cells are made up
of these cells, but they account for less than 10% of
total cardiac mass [40].
Profibrotic stimuli activate fibroblasts so they
develop into myofibroblasts, which are
nonproliferative, but secretory, As fibroblasts,
myofibroblasts possess contractile properties that
contribute to scar contraction; one of those proteins
expressed in myofibroblasts is smooth muscle actin,
which is associated with differentiation into
myofibroblasts[41].
It is not known from what sources the fibroblasts and
myofibroblasts originate in the remodeled
myocardium, but bone marrow-derived cells,
endothelial cells,pericytes, and endothelial cells are
likely to contribute [41]. Some of these pathways
have been found to be important for fibroblast
function. The Calcium entry pathway contributes to
ERK phosphorylation and activation in fibroblasts
[42]. Activation of the ERK pathway enhances
fibroblast survival and promotes fibrosis[43].
Combined cultures of cardiomyocytes and
fibroblasts can develop low-resistance electric
junctions and modulate one another's electrical
activity [44].

In addition to encouraging ectopic impulse

generation, significant cardiomyocyte-fibroblast
coupling can slow conduction and promote re-
entrant arrhythmias[45].
There is evidence that the physiological effects of
fibrosis on atrial conduction occur as a consequence
of collagen production that physically separates
cardiomyocytes instead of fibroblasts that couple
with cardiomyocytes and electrically load them [46].
Girmatsion Z et.al studied with Atrial tissue was
obtained from 62 patients (31 with AF)
undergoing mitral valve repair or bypass grafting he
concluded as AF levels of miR-1 are dramatically
reduced, possibly contributing to increased Kir2.1
subunits, which then lead to increased levels of
IK1, This study provides potential new insights into
the molecular mechanisms of AF maintenance,
providing a potential therapeutic
benefit ,Maintenance of the AF is dependent on the
up-regulation of inward-rectifier currents [47].
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