Main stay of pathogesis of HCM is due to its

mutation in the sarcomer protein structure causes

the change in structural protein sarcomere which
leads to increase in the muscle cell size [13].Due to
these mutations cadiac muscle muscles undergoes
very huge diarrangment of large muscle cells and
leading to cause fibrosis in structural components of
cardiac muscle cell causing left ventriculat
hypertrophy and increase in interventricular
septum thickness [14].These changes manifests
obstruction to outflow tract during systolic stage
(contraction stage) of 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
accomapained may cause ischemia of the tissue,and
valves are moved anteriorly leading to mitral
regurgitation [15].
FIGURE 2
Increase in thickness of left ventricular wall and
interventricular septum causes the obstruction of
Aorta,causes increase in left ventricular diastolic
volume and pressure,because of movement of mitral
valve anteriorly cause the mitral regurgitation.
The incidence of atrail fibrillation is increases in
patients with HOCM ,the main reason is changes in
left ventricular thickness leading to increase in left
atrium promotes the abnormalities in
electricalcondiction in left atrial contraction [16].
MOLECULAR GENETIC VARIAIONS
HCM is an archetypical single gene disorder with an
autosomal dominant pattern of inheritance 15,
whereby a single mutation is usually sufficient to
cause the disease, albeit with variable penetrance
and expression.
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.
Greaves SC, Roche AH, Neutze JM, Whitlock RM,
Veale AM. Inheritance of hypertrophic
cardiomyopathy: a cross sectional and M mode
echocardiographic study of 50 families. Heart. 1987
Sep 1;58(3):259-66.
Approximately 60% of patients with HCM have a clearly
recognizable familial disease. Autosomal recessive and X-
linked modes of inheritance have been described but are
rare.
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.    
Branzi A, Romeo G, Specchia S, Lolli C, Binetti G,
Devoto M, Bacchi M, Magnani B. Genetic
heterogeneity of hypertrophic cardiomyopathy.
International journal of cardiology. 1985 Feb
1;7(2):129-33.
An X-linked inheritance typically raises the possibility of a
phenocopy condition, such as Fabry disease.
Phenocopy conditions, such as Fabry disease, are
typically associated with an X-linked inheritance

Marian AJ. Challenges in the diagnosis of Anderson-

Fabry disease: a deceptively simple and yet
complicated genetic disease.

A phenocopy condition also occurs in syndromic

conditions, such as the Noonan syndrome and in storage
diseases, such as Anderson-Fabry disease.
In addition to phenocopy conditions, syndromic
conditions like the Noonan syndrome and storage
diseases like Anderson-Fabry disease also occur.
Elliott P, Baker R, Pasquale F, Quarta G, Ebrahim
H, Mehta AB, Hughes DA. Prevalence of Anderson–
Fabry disease in patients with hypertrophic
cardiomyopathy: the European Anderson–Fabry
Disease Survey. Heart. 2011 Dec 1;97(23):1957-60.

Pioneering studies by Christine and Jonathan Seidman have led to partial elucidation of the molecular genetic basis of
HCM. The discovery of the p.Arg403Glu mutation in the MYH7 gene, encoding sarcomere protein β-myosin heavy chain
(MYH7) in the French-Canadian family described by Paré et al, 21 paved the way for important subsequent discoveries.

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.
Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial
hypertrophic cardiomyopathy: a β cardiac myosin heavy chain gene missense mutation. Cell. 1990 Sep 7;62(5):999-1006.

+++++++

Marian AJ, Braunwald E. Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy.
Circ Res. 2017 Sep 15;121(7):749-770. doi: 10.1161/CIRCRESAHA.117.311059. PMID: 28912181; PMCID: PMC5654557.
Effects of mutations on transcription and translation

In autosomal dominant HCM, a small fraction of the HCM

mutations result in premature truncation of the encoded
proteins because of a gain of a stop codon (such as the
p.Gln425X mutation in the MYBPC3 gene ) or because of
a frame shift (such as the c.2864–2865delCT in
the MYBPC3 gene.
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..

Niimura H, Patton KK, McKenna WJ, Soults J,

Maron BJ, Seidman JG, Seidman CE. Sarcomere
protein gene mutations in hypertrophic
cardiomyopathy of the elderly. Circulation. 2002 Jan
29;105(4):446-51.

Van Dijk SJ, Dooijes D, dos Remedios C, Michels M,

Lamers JM, Winegrad S, Schlossarek S, Carrier L,
ten Cate FJ, Stienen GJ, van der Velden J. Cardiac
myosin-binding protein C mutations and
hypertrophic cardiomyopathy: haploinsufficiency,
deranged phosphorylation, and cardiomyocyte
dysfunction. Circulation. 2009 Mar 24;119(11):1473-
83.

Mechanisms such as the nonsense-mediated decay

(NMD) pathway identify the PTC, releases the elongation
factors (a set of proteins involved in adding amino acids
during protein synthesis) from the template, and recruits
the decay-inducing complex (a complex of proteins
involved in mRNA degradation). 

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).
Popp MW, Maquat LE. Leveraging rules of nonsense-mediated mRNA decay for genome engineering and personalized medicine.
Cell. 2016 Jun 2;165(6):1319-22.

Siwaszek A, Ukleja M, Dziembowski A. Proteins involved in the degradation of cytoplasmic mRNA in the major eukaryotic model
systems. RNA biology. 2014 Sep 2;11(9):1122-36.

The net effect is degradation of such transcripts and

reduced protein levels. In the case of transcripts
lacking a naturally occurring stop codon, the mRNA
surveillance mechanism referred to as “non-stop
decay pathway” identifies and releases the
transcripts from ribosomes to prevent their
translation. 

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. 
Vasudevan S, Peltz SW, Wilusz CJ. Non‐stop decay—a new mRNA surveillance pathway. Bioessays. 2002 Sep;24(9):785-8.

Frischmeyer PA, Van Hoof A, O'Donnell K, Guerrerio AL, Parker R, Dietz HC. An mRNA surveillance mechanism that eliminates transcripts lacking termination
codons. Science. 2002 Mar 22;295(5563):2258-61.

This is followed by degradation of the released transcripts by the exosome complex. Another mechanism is activation of
the No-Go mRNA decay pathway, a mechanism that stalls progression of ribosomes during translation and results in
endonucleolytic cleavage of the mRNA transcript near the stalled site.

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.
Transcripts containing PTC that escape the NMD are
expected to be expressed as truncated proteins

Those transcripts containing PTC that escape the

NMD are expected to be expressed as truncated
proteins.

HEMODYNAMICS –LEFT VENTRICULAR OUTFLOW OBTRUCTION

In the presence of hyperdynamic ejection, there is

systolic anterior motion (SAM) of the anterior leaflet of
the mitral valve, which abuts the hypertrophied
interventricular system during systole, causing
obstruction to outflow, reflected in a systolic pressure
gradient between the left ventricular cavity and the aorta
that is present at rest in approximately one third of
patients with HCM .

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.

Braunwald E. Idiopathic hypertrophic subaortic

stenosis. Circulation. 1964;30(4):3-119.

The obstruction is dynamic in nature, a unique feature of

HCM. The severity of the LVOT obstruction is influenced
by the ventricular volume, which in turn is a function of
the interactions between myocardial contractility,
ventricular preload and afterload. Increases in
contractility, reductions in preload and afterload reduce
ventricular volume and cause or intensify obstruction;
the opposite occurs with reductions in contractility and
increases in preload and afterload.
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

Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, Nistri S, Cecchi F, Udelson JE, Maron BJ. Hypertrophic
cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006 Nov 21;114(21):2232-9.

Shah JS, Esteban MT, Thaman R, Sharma R, Mist B, Pantazis A, Ward D, Kohli SK, Page SP, Demetrescu C, Sevdalis E.
Prevalence of exercise-induced left ventricular outflow tract obstruction in symptomatic patients with non-obstructive hypertrophic
cardiomyopathy. Heart. 2008 Oct 1;94(10):1288-94.

Braunwald E, OLDHAM JR HN, ROSS JR JO, LINHART JW, MASON DT, FORT III LY. The circulatory response of patients with idiopathic hypertrophic subaortic
stenosis to nitroglycerin and to the Valsalva maneuver. Circulation. 1964 Mar;29(3):422-31.

Braunwald E, Ebert PA. Hemodynamic alterations in idiopathic hypertrophic subaortic stenosis induced by sympathomimetic drugs∗.
The American journal of cardiology. 1962 Oct 1;10(4):489-95.

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.
Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, Nistri S, Cecchi F, Udelson JE, Maron BJ.
Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction.
Circulation. 2006 Nov 21;114(21):2232-9. doi: 10.1161/CIRCULATIONAHA.106.644682. Epub 2006 Nov 6. PMID:
17088454.

It is caused by the increased interstitial fibrosis as

well as the slowed relaxation and increased stiffness
of the thickened ventricular wall. Left atrial volume,
an indirect indicator of left ventricular diastolic
pressure, is often increased in patients with HCM
and is a predictor of the development of atrial
fibrillation and heart failure.
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.
Guttmann OP, Pavlou M, O'Mahony C, Monserrat L, Anastasakis A, Rapezzi C, Biagini E, Gimeno JR, Limongelli G, Garcia‐Pavia P, McKenna WJ. Prediction of
thrombo‐embolic risk in patients with hypertrophic cardiomyopathy (HCM Risk‐CVA). European journal of heart failure. 2015 Aug;17(8):837-45.
The 2011 ACC/AHA guidelines for diagnosis and treatment of HCM recognize the importance of AF for HCM prognosis,
extrapolating, however, AF diagnostic and therapeutic options recommended for the general population in HCM patients

Guidelines published by the 2011 ACC/AHA for diagnosis and treatment of HCM mention AF's importance for HCM
prognosis, while extending diagnostic and therapeutic options for AF to all HCM patients.
Molecular and Cellular Mechanisms of Atrial Fibrosis in
Atrial Fibrillation

Fibroblasts are small, spindle-shaped cells that con-

trol the composition and structure of the extracel-
lular matrix (ECM). They constitute up to 75%
ofcardiac cells by number but only 10% to 15% by
mass.
Yue L, Xie J, Nattel S. Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial
fibrillation. Cardiovascular research. 2011 Mar 1;89(4):744-53.

When activated by profibrotic

stimuli,fibroblastsproliferate and differentiate
into a secretory(but nonproliferative) phenotype,
the myofibroblast. Myofibroblasts have
contractile properties thatcontribute to scar
contraction, bequeathed by con-tractile proteins of
which the expression of one,a–smooth muscle
actin, is a hallmark of differentiationinto the
myofibroblast phenotype. The source offi-broblasts
and myofibroblasts in remodeled myocar-dium is
unclear, with evidence for contributions
fromresidentfibroblasts, bone marrow–derived
cells,endothelial cells, perivascular cells, and
pericytes.
Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC. Cardiac fibrosis: the fibroblast awakens. Circulation research. 2016 Mar
18;118(6):1021-40.

42 Recent work has demonstrated the

importance of some of these pathways in the
regulation offibroblast function.Ca2þentry regulates
fibroblast extracellular signal-related kinase (ERK)
phosphorylation and activation
Olson ER, Shamhart PE, Naugle JE, Meszaros JG. Angiotensin II-induced extracellular signal-regulated kinase 1/2 activation is
mediated by protein kinase Cδ and intracellular calcium in adult rat cardiac fibroblasts. Hypertension. 2008 Mar 1;51(3):704-11.

43 ERK pathway activation

enhancesfibroblastsurvival and promotesfibrosis
Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, Castoldi M. MicroRNA-21 contributes to myocardial
disease by stimulating MAP kinase signalling in fibroblasts. Nature. 2008 Dec;456(7224):980-4.

In co-cultured systems, cardiomyocytes andfibro-

blasts are able to develop low-resistance
electricjunctions and modulate each other’s electric
activity
44 Miragoli M, Gaudesius G, Rohr S. Electrotonic modulation of cardiac impulse conduction by myofibroblasts. Circulation research.
2006 Mar 31;98(6):801-10.
Significant cardiomyocyte-fibroblast coupling
canenhance phase 4 depolarization and promote
ectopicimpulse generation and can slow
conductionand promote re-entrant arrhythmia
generation.
Zlochiver S, Munoz V, Vikstrom KL, Taffet SM, Berenfeld O, Jalife J. Electrotonic myofibroblast-to-myocyte coupling increases propensity to reentrant arrhythmias
in two-dimensional cardiac monolayers. Biophysical journal. 2008 Nov 1;95(9):4469-80.

The extent to which the effects of fibrosis on atrial

conduction are due to the production of collagen
that separates cardiomyocytes and physically
uncouples them ,as opposed to the proliferation
offibroblasts that couple to cardiomyocytes and
electrically load them
McDowell KS, Vadakkumpadan F, Blake R, Blauer J, Plank G, MacLeod RS, Trayanova NA. Mechanistic inquiry into the role of
tissue remodeling in fibrotic lesions in human atrial fibrillation. Biophysical journal. 2013 Jun 18;104(12):2764-73.

Girmatsion Z et.al studied with Atrial tissue was obtained from

62 patients (31 with AF) undergoing mitral valve repair or bypass
grafting.
miR-1 levels are greatly reduced in human AF, possibly contributing to up-regulation of Kir2.1 subunits, leading to
increased IK1. Because up-regulation of inward-rectifier currents is important for AF maintenance, these results
provide potential new insights into molecular mechanisms of AF with potential therapeutic implications.

Girmatsion Z, Biliczki P, Bonauer A, Wimmer-Greinecker G, Scherer M, Moritz A, Bukowska A, Goette A, Nattel S, Hohnloser SH, Ehrlich JR. Changes in
microRNA-1 expression and IK1 up-regulation in human atrial fibrillation. Heart rhythm. 2009 Dec 1;6(12):1802-9.
Subsequent experimental work has
demonstratedthe potential to prevent fibrosis
through a host ofsignaling targets, including TGF-b
inflammatorymediators , heat-shock proteins JAK-
STATsignaling miRNAs ,TRPchannels and
peroxisome proliferator-activated receptor–
gamma.

Shimano M, Tsuji Y, Inden Y, Kitamura K, Uchikawa T, Harata S, Nattel S, Murohara T. Pioglitazone, a peroxisome proliferator-activated receptor-gamma
activator, attenuates atrial fibrosis and atrial fibrillation promotion in rabbits with congestive heart failure. Heart Rhythm. 2008 Mar 1;5(3):451-9.

Harada M, Luo X, Qi XY, Tadevosyan A, Maguy A, Ordog B, Ledoux J, Kato T, Naud P, Voigt N, Shi Y. Transient receptor potential
canonical-3 channel–dependent fibroblast regulation in atrial fibrillation. Circulation. 2012 Oct 23;126(17):2051-64.

Girmatsion Z, Biliczki P, Bonauer A, Wimmer-Greinecker G, Scherer M, Moritz A, Bukowska A, Goette A, Nattel S, Hohnloser SH, Ehrlich JR. Changes in
microRNA-1 expression and IK1 up-regulation in human atrial fibrillation. Heart rhythm. 2009 Dec 1;6(12):1802-9.
13 Marian AJ, Braunwald E. Hypertrophic
Cardiomyopathy: Genetics, Pathogenesis, Clinical
Manifestations, Diagnosis, and Therapy. Circ Res.
2017 Sep 15;121(7):749-770. doi:
10.1161/CIRCRESAHA.117.311059. PMID:
28912181; PMCID: PMC5654557.

14 Brigden W. Hypertrophic cardiomyopathy. Br

Heart J. 1987 Oct;58(4):299-302. doi:
10.1136/hrt.58.4.299. PMID: 3314948; PMCID:
PMC1277258.

15 Medical Masterclass contributors, Firth J.

Cardiology: hypertrophic cardiomyopathy. Clin Med
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16 Paur H, Wright PT, Sikkel MB, Tranter MH,
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VO, Diakonov I, Pannell L, Gong H. High levels
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