ILMIAH

Hypertrophic Car-
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diomyopathy
 Contents

DEFINITION EPIDEMIOLOGY ETIOLOGY

HISTOPATHOLOGY
PATHOPHYSIOL- CLINICAL DIAGNO-
AND MORPHOL-
OGY SIS
OGY

SUDDEN CARDIAC
THERAPY DEATH PREVEN-
TION
DEFINITION
 ESC 2014
Definition 01 Hypertrophic cardiomyopathy (HCM) is defined by the presence of
increased left ventricular (LV) wall thickness that is not solely
explained by abnormal loading conditions. Can be caused by
genetic or non-genetic.

AHA 2020
02 Disease state in which morphologic expression is confined solely
to the heart.
Characterized by LVH in the absence of another cardiac,
systemic, or metabolic disease capable of producing the
magnitude of hypertrophy and for which a disease-causing
sarcomere (or sarcomere-related) variant is identified, or genetic
etiology remains unresolved.
 HURST’S
Definition 03 Hypertrophic cardiomyopathy (HCM) is defined as left
ventricular hypertrophy in the absence of abnormal
loading conditions, severe hypertension or valve disease, sufficient to
provoke the observed phenotype

GRIFFINS
04 Presence of LVH of a nondilated LV in the absence of
another cardiac or systemic disease which could
explain the degree of LVH
 BRAUNWALD 11th
Definition 05 Thickened but nondilated left ventricle in the absence of
another cardiac or systemic condition (e.g., aortic
valve stenosis, systemic hypertension, and some expressions of
physiologic athlete’s heart) capable of
producing the magnitude of left ventricular (LV)
hypertrophy evident

Neither the asymmetric distribution nor the

presence of obstruction was necessary for a
diagnosis of HCM
EPIDEMIOLOGY
 Prevalence

More recent estimates, which take into ac-

General population at 1 : 500, equivalent
count genetic and imaging diagnostic
to approximately 700,000 affected people
modalities, place the prevalence closer to
in the United States.
1 : 200.

HCM is transmitted as a mendelian trait

with an autosomal dominant pattern of in-
Men = women heritance, every offspring of an affected
relative has a 50% chance of inheriting the
disease.
ETIOLOGY
 60%
Autosomal dominant trait caused by mutations in cardiac sar-
comere protein genes

10-15%
Etiology Other genetic disorders including inherited metabolic and
neuromuscular diseases

Non-genetic disorders that mimic genetic forms of the dis-

ease, for example, senile (TTR) and (AL) amyloidosis.
Dunn KE, Caleshu C, Cirino AL, Ho CY, Ashley EA. A clinical approach to inherited hypertrophy: the use of family history in diagnosis, risk assessment, and management. Circ Cardiovasc Genet. 2013;6(1):118-131
HCM PHENOCOPY
HISTOPATHOLOGY
and MORPHOLOGY
Histopathology
 Gross Pathology

Asymmetric septal hypertrophy with a small left ventricular cavity

Mural endocardium may be thickened by fibrous tissue

If left ventricular outflow tract obstruction is present, there is often a plaque

located on the upper septal area where the mitral valve repeatedly has come
in contact with the septum

The mitral valve itself may be abnormal, with elongation of the mitral
chordae and anterior displacement of hypertrophied papillary muscles

Left (and sometimes the right) atrium is usually dilated in advanced dis-
ease as a result of mitral regurgitation and diastolic dysfunction
PATHOPHYSIOLOGY
Microvascular Dysfunction

Microvascular Myocardial Adverse LV Affecting the

dysfunction ischemia remodeling clinical course

Angina may result from an inability of the narrowed coronary microcir-

culation to supply the hypertrophied myocardium in the context of high
myocardial oxygen demand
LVOTO

70% of patients show the propensity to

1/3 during rest 1/3 during exercise
develop LVOTO (braunwald)

Instantaneous peak Doppler LV outflow

A gradient of ≥50 mm Hg is usually
tract pressure gradient ≥30 mm Hg at
The true nonobstructive form accounts considered to be the threshold at which
rest or during physiological provocation
for approximately 1/3 LVOTO becomes haemodynamically
such as Valsalva manoeuvre, standing
important.
and exercise.

Long-standing outflow obstruction is

the most relevant clinical determinant of
HCM-related progressive heart failure
symptoms
LVOTO

Sub-aortic LVOTO, with systolic

Obstruction may also occur at mid-
anterior movement (SAM) of the
cavity level, or distally in the form
mitral valve, is the commonest form
of apical obliteration.
and the most amenable to treatment.
 Mechanism of SAM
Facilitated by:
(1) Abnormal valve apparatus with sufficient slack in the leaflets to allow movement:

a. Anterior displacement of the papillary muscles b. Elongated mitral leaflets

• Reducing the posterior tension conferred by the papillary muscles
on the mitral valve
• increasing the proximity of the leaflets to the left ventricular out-
flow stream
• pulling the posterior leaflet upwards so that it meets the anterior
leaflet near its mid-portion
• The anterior mitral leaflet (AML) length often exceeds >30 mm
compared to average of 25 mm in controls; AML length
exceeding 40 mm is also described in rare instances. The
posterior mitral leaflet (PML) length is more than 17 mm
Mechanism of SAM (2)
(2) Haemodynamic force with an anterior component during systole
a. Venturi effect
• Increase in velocity and decrease
in pressure that occurs as fluid
flows through a constriction. An
object in the path of the fluid is
subject to a force perpendicular to
the direction of flow that pulls it
into the stream. Thus, as blood is
ejected into the narrow outflow
tract in systole, it accelerates and a
reduction in the static pressure
occurs.
b. Flow drag effect
• Doppler echocardiography suggests
that SAM begins very early in
systole, when the outflow tract
velocity is normal  The relatively
low velocity is unlikely to generate
significant Venturi force
• Modern concept: flow against the
abnormally positioned mitral valve
apparatus in systole causes a drag
force on a portion of the mitral
valve leaflets  pushes the leaflets
into the LV outflow tract
 Dynamic subaortic obstruction in HCM:
usually produced by systolic anterior
motion (SAM) of the mitral valve in
which elongated leaflets bend sharply,
contacting ventricular septum in
midsystole by means of a drag effect

Producing ↑ intraventricular
systolic pressure

Subaortic gradients: variable, reduced, or

abolished by interventions, which decrease
myocardial contractility (e.g., beta-adrenergic
blocking drugs) or increase ventricular
volume or arterial pressure (e.g., squatting,
isometric handgrip, phenylephrine).
Diastolic Dysfunction

Impaired LV relaxation and filling (diastolic dysfunction) contributes to DOE

Limited exercise capacity is common in HCM.

Decreased time for filling at high heart rates, combined with impaired compliance, leads to a
reduction in end-diastolic volume.

This limits the ability of the left ventricle to augment stroke volume via the Frank–Starling
mechanism. Chronotropic incompetence is common in HCM.
Abnormal Vascular Responses

In normal subjects, cardiac output rises during exercise

At high heart rates, filling time is reduced and augmentation of left ventricular end-diastolic volume requires increased venous return

 dependent on constriction in non-exercising venous capacitance beds

The importance of this mechanism may be greater with HCM and diastolic dysfunction

30% HCM patients  fail to increase SBP by ≥ 25 mmHg during exercise, or had paradoxical fall in BP of ≥ 20 mmHg

Caused by: inappropriate vasodilator response (myocyte disarray and fibrosis  abnormal wall stress  excess stimulation of LV mechanoreceptors 
exaggerated sensitivity of arterial baroreceptors and raised levels of natriuretic peptides)
Pathophysiology: Arryhtmias
Triggers for ventricular arrhythmia in HCM include

• Ischaemia
• LVOTO
• vascular instability
• cellular energy depletion

Substrate for Vas:

• Myocyte disarray and fibrosis

Non-sustained ventricular tachycardia (VT) occurs in around 20%

sustained VT is rare and raises suspicion of a left ventricular apical aneurysm, sometimes seen in patients with mid-cavity ob-
struction

LAE+ MR: AF
Pathophysiology: Wall thinning and cavity di-
lation
Over a longer follow-up period,
A decrease in left ventricular wall wall thinning ≥ 5 mm was noted in
thickness was previously docu- 60% of patients with severe LVH,
mented in up to 15% over 3 years accounting for the rarity of marked
LVH in the elderly

Likely that ischaemia, compro- Cavity dilation and systolic im-

mised energetics and injury from pairment are infrequent, occurring
abnormal haemodynamic loading in less than 5% of patients with
lead to myocyte loss and fibrosis HCM
Nonobstructive Hypertrophic Cardiomyopathy; Dias-
tolic Dysfunction

Nonobstructive HCM patients

are almost 5x less likely to A subgroup previously
develop NYHA III-IV disease underrecognized in the natural
than are patients with history of this disease
obstruction
CLINICAL DIAG-
NOSIS
Clinical Diagnosis
AHA: 2D echocardiography or cardiovascular magnetic resonance (CMR) showing a maximal end-diastolic wall thickness of ≥15
mm anywhere in the left ventricle, in the absence of another cause of hypertrophy in adults.

limited hypertrophy (13–14 mm) can be diagnostic when present in family members of a patient with HCM or in conjunction with a
positive genetic test.

Children: adjust for body size and growth: thresh- old of z >2.5 may be appropriate to identify early HCM in asymptomatic children
with no family history, whereas for children with a definitive family history or a positive genetic test, a threshold of z >2 may suffice
for early diagnosis.

systolic anterior motion (SAM) of the mitral valve nor hyperdynamic LV function is common but is not required for a clinical
diagnosis
ESC: defined by a wall thickness ≥15 mm in one
For milder thickening (13-14 mm): require other
or more LV myocardial segments—as measured
features: including family history, non-cardiac
by any imaging technique (echocardiography,
symptoms and signs, electrocardiogram (ECG)
cardiac magnetic resonance imaging (CMR) or
abnormalities, laboratory tests and multi-modality
computed tomography (CT))—that is not
cardiac imaging.
explained solely by loading conditions.
Clinical Presentation and Natural History

Majority of patients with HCM are asymptomatic

Disease being diagnosed based on an abnormal ECG, heart murmur, or screening echocardio-
gram

Some experience:angina, dyspnoea, palpitations and syncope or near syncope

Symptoms of heart failure may develop at any age, resulting from DOE, fatigue, orthopnea or
PND occasionally occurs in advanced stages.
Symptoms
Might exacerbate symptoms:

• Events that accelerate heart rate

• Decrease preload
• Shorten diastolic filling time
• Increase LV outflow obstruction
• or worsen compliance (i.e., ischemia)

During hot humid weather, presumably as a result of fluid loss and vasodilation that cause decreases in both preload and afterload

Symptoms may be more prominent after eating a large meal or after drinking alcohol

Other concomitant problems, such as anemia or fever, may also exacerbate symptoms
History

Construction of a three- to four-

Age is one of the most important
generation family pedigree helps to
factors to take into account when
confirm a genetic origin of disease and
considering the possible causes for
identifies other family members that
HCM
are at risk of disease development.
Dunn KE, Caleshu C, Cirino AL, Ho CY, Ashley EA. A clinical approach to inherited hypertrophy: the use of family history in diagnosis, risk assessment, and management. Circ Cardiovasc Genet. 2013;6(1):118-131
Clinical Presentation and
Natural History
Symptoms: Heart Failure
In contrast with sudden death risk (which is related to particularly marked LV hypertrophy),
greater LV wall thickness is not associated with an increased likelihood of progressive heart
failure symptoms

3% of patients with HCM develop advanced (end- stage) heart failure associated with systolic
dysfunction (ejection fraction <50%)

Between 5% and 10% of patients with HCM progress to severe LV systolic dysfunction, char-
acterized by progressive LV wall thinning and cavity enlargement
Symptoms: Sudden Cardiac Death
HCM is the most common cause of SCD in children and young adults (age <30. 30-35 years)  significantly less
common in patients 60 years of age or older

Although risk extends into mid-life, rates are lower even with significant risk factors

HCM is the most common cardiovascular cause of sudden death in competitive athletes, including high school, col-
lege and also marathon participants

Patients with SCD often have no or minimal symptoms prior.

Approximately 60% of deaths occur during periods of inactivity; the remaining deaths occur after vigorous physical
exertion.
Symptoms: Sudden Cardiac Death
2° prevention
• Cardiac arrest/sustained VT

1° prevention
• Family history HCM-SD Unexplained syncope Multiple-repetitive NSVT (Holter) Abnormal exercise BP response
LGE ≥ 15% of LV mass
• Massive LVH ≥30 mm

SCD events are generally accepted to be due to sustained ventricular tachyarrhythmias

Proposed arrhythmogenic mechanisms:

• myocardial disarray and fibrosis
• silent ischemia associated with microvascular coronary artery disease
• high sympathetic drive
Physical Examination
General physical examination can provide diagnostic clues in patients with
syndromic or metabolic causes of HCM

Cardiovascular examination is often normal but, unless in patients with LV

outflow tract obstruction (LVOTO):
• rapid up-and-down stroke to the arterial pulse
• ejection systolic murmur at the left sternal edge that radiates to the right upper sternal edge and apex.
• it increases with the Valsalva maneuver, during or immediately after exercise, or on standing.
 Physical Exam in HCM
Inspection
• jugular venous system may reveal a prominent a-wave that indicates hypertrophy and lack of compliance of the right
ventricle
• A precordial heave, representing right ventricular (RV) strain, can be found in persons with concomitant pulmonary hy-
pertension

Palpation
• The apical precordial pulse is usually laterally displaced and diffuse. LVH may cause a presystolic apical impulse or
palpable fourth heart sound (S4). A three-component apical impulse may occur, with the third impulse resulting from a
late systolic bulge of the left ventricle.
• The carotid pulse has been classically described as bifid.
• This rapid carotid upstroke followed by a second peak is caused by a hyperdynamic left ventricle.
• Bisferiens pulse with dynamic obstruction
Palpation
Precordial impulse is usually forceful and displaced leftward

Peripheral arterial pulses are brisk

In patients with marked ventricular hypertrophy:

• Atrial contraction is often especially vigorous  prominent atrial contraction (a) wave in
the jugular venous pulse
• A presystolic apical lift
• Prominent fourth heart sound (S4)
Cardiac Auscultation in HCM
Normal or loud S1, can be preceded by S4.

S2 can be normal or paradoxically split as a result of the prolonged ejection time of patients with severe
outflow obstruction
• Can be due to a concomitant left bundle branch block

classic murmur from LV outflow tract obstruction :

• Crescendo-decrescendo murmur located primarily at LLSB

• Can radiate to the base of the heart as well as to the apex, but in contrast to valvular aortic stenosis, there is seldom radiation to
the carotid arteries

Mitral regurgitation may be a separate murmur audible at the apex and is more holosystolic in nature
Resting and Ambulatory
Electrocardiography
Can be normal at presentation (6% in HCM population)

Generally shows a variable combination of LVH, ST- and T-wave

abnormalities, and pathological Q-waves

Asymptomatic NSVT 120-200 bpm (25% in HCM population)


Deep, narrow (“dagger-
like”) Q waves in lateral (I,
aVL, V5-6) +/- inferior (II,
III, aVF) leads
Q waves seen in HCM can mimic prior myocardial infarction, although the Q-
wave morphology is different:
• Infarction Q waves are typically > 40 ms duration
• Septal Q waves in HCM are < 40 ms
Lateral Q waves are more common than inferior Q waves in HCM
Diagnostic Testing: Ambulatory ECG
Frequency of arrhythmias detected during ambulatory electrocardiographic monitoring is age-related

Holter ECG monitoring is recommended annually

Findings include

• paroxysmal AF, which merits antiarrhythmic therapy for suppression and/or anticoagulation
• non-sustained VT, a risk factor for sudden death

Extended monitoring with an event recorder or implantable loop recorder may be warranted in patients with symptoms suggestive of
arrhythmia.

recommended in the initial evaluation and as part of periodic follow-up (every 1 to 2 years)
 KEY FEATURES IN ECHO FOR HCM
Echocardiography • Assessment of left ventricular wall
thickness
• Associated abnormalities of the mitral
Central to the diagnosis and monitoring of HCM
valve
and left ventricular outflow tract
Mostly involves the interventricular septum in the basal • Assessment of latent obstruction
anterior LV segments but often extends into the lateral
wall, the posterior septum and LV apex • Left atrial enlargement
• Assessment of diastolic function
1/3 patients have resting SAM of the mitral valve leaflets
resulting LVOTO • Systolic function
• Value of echocardiography in
1/3 have latent obstruction only during manoeuvres that
differential diagnosis
change loading conditions and LV contractility • Contrast echocardiography
• Transoesophageal echocardiography
 The most common location of LVH:
Basal anterior septum in continuity with anterior free wall

Common features but NOT REQUIRED for diagnosis:

• Systolic anterior motion
• Hyperdynamic LV
• Hypertrophied, apically displaced papillary muscle
• Anomalous insertion papillary muscle to AML
• Elongated mitral valve
• Myocardial bridging
• RVH
 Diagnostic Screening
Diagnostic criteria by echocardiography are ventricular wall Recommended at 12-month intervals during
thickness ≥15 mm in at least one LV myocardial segment adolescence and every 5 years in adults, as well
as at the onset of symptoms suggestive of HCM

or ≥13 mm in patients with a first-degree relative with confirmed

HCM.

LVOT gradient

• nonobstructive : <30 mmHg at rest

• obstructive : ≥30 mmHg at rest
• latent obstructive form when the LVOT gradient is <30 mmHg at rest, and on
exertion when ≥30 mmHg
Familial Familial assessment is the need for sensitive diagnostic criteria. Since
autosomal dominant inheritance implies a 50% probability of any first-degree

HCM relative carrying the gene, minor abnormalities are more likely to represent
disease expression than in the general population

1 Major Echo

OR

2 Minor Echo

OR

1 minor echo
+
2 Minor Echo
CMR
CMR also allows for quantification of late gadolinium enhancement (LGE), a marker for myocardial fibrosis, with
often multifocal, irregular distribution, and not respecting coronary anatomy

CMR is complementary to echocardiography by resolving technically ambiguous LV wall thicknesses or visual zing
relevant areas of hypertrophy blind to echocardiography (e.g., in the anterolateral free wall, posterior (inferior)
septum, or apical left ventricle).
Genetic Testing
IMAGING TECHNIQUE IN DIAGNOSING HCM
Synopsis in Clinical
Diagnosis
THERAPY
 Management of HCM
• alleviate symptoms
Aims • prevent complications (e.g. AF)
• reduce sudden cardiac death

• improve symptoms by using drugs

In symptomatic pa- • Surgery
tients with LVOTO, the • alcohol ablation
aim • Pacing

Symptomatic without • Arrhythmia

LVOTO focuses on • reduction of LV filling pressures
management of • angina
LVOTO (GENERAL MEASURES)

Avoid dehydration and excess alcohol consumption, and

weight loss should be encouraged

Arterial and venous dilators can exacerbate LVOTO

• including dihydropyridine calcium channel blockers and angiotensin-con-

verting enzyme inhibitors, are potentially harmful

AF can >> symptoms by LVOTO: manage properly

Avoid digoxin
 LVOTO (Drug Therapy)
Improves diastolic filling (lusitropic positive agent), reduce systolic outflow tract obstruction (inotropic
negative agent)

Verapamil (starting dose 40 mg three times daily to maximum

Symptomatic LVOTO  initially with non-vasodilating ß- 480 mg daily) can be used when ß-blockers are contraindicated
blockers titrated to maximum tolerated dose or ineffective

If ß-blockers alone are ineffective, disopyramide (when avail-

Diltiazem (starting dose 60 mg three times daily to maximum
able), titrated up to a maximum tolerated dose (usually 400 –
600 mg/day), may be added 360 mg daily)

•  Class IA antiarryhtmic agent

• << LVO gradient
• QTc interval should be monitored during dose up-titration (reduce dose if QTc > Low-dose loop or thiazide diuretics may be used cautiously
480 ms)
to improve dyspnoea associated with LVOTO

Treatment is indicated when the patient becomes symptomatic or LVH is severe.

Refractoriness to medical therapy usually indicates progression of the disease. At this point more aggressive therapies: such as
alcohol ablation of the septum or surgical septal myectomy are indicated.
Amiodarone is not considered a therapeutic option for prevention of sudden death in
HCM any more.
 Invasive treatment in LVOTO
Septal myectomy : treatment of choice for therapy-refractory (NYHA III-IV) patients with
obstructive HCM but ventricular remodelling with dilatation of the left ventricle may occur in 15 –
20% of patients.

Alcohol ablation preferred and surgical resection of the septum in selected cases (CABG or MV repair)

Alcohol ablation
• Indication: Outflow tract gradients of > 30–50 mmHg at rest and 75–100 mmHg after provocation (extrasystole, isoproterenol
infusion or amyl nitrite inhalation)
• Complications: transient or permanent 3rd degree AV block (7-20%)
• Therefore, the procedure should not be done without a temporary pacemaker; 3 –5% of all patients require definitive pacemaker
implantation.
Management of symptoms in patients
without left ventricular outlow tract ob-
struction : HF
Surgery for HCM
The most commonly performed surgical procedure used to treat LVOTO is ventricular septal myectomy (Mor-
row procedure)

First performed by Cleland in 1958

main surgical complications are

• AV nodal block
• ventricular septal defect
• aortic regurgitation (AR)

Concomitant mitral valve surgery is required in 11–20% of patients

Alcohol Septal Ablation
Brugada et al were the first to treat a patient by injecting absolute alcohol into a
septal branch of the left anterior descending artery

Objective: create a localized septal scar

Due to variability of septal blood supply: myocardial contrast is recommended

prior to alcohol injection
Therapy
Management of Patients
With HCM and
Atrial Fibrillation
Sudden Cardiac
Death Prevention
Prevention of SCD
Prevention of SCD in HCM
ICD for secondary prophylaxis
• Patients who survive VF or sustained VT are at very high risk of
subsequent lethal cardiac arrhythmias  should receive an ICD

ICD for primary prophylaxis

• Identification of individuals without a history of VF, who are at high
risk of SCD,
 Prognostic variables, which are
then used to estimate the 5-year risk
of SCD using the HCM Risk-SCD
model

HCM Risk-SCD should not be used

in patients ,16 years of age, elite
athletes or in individuals with
metabolic/infiltrative diseases
Sudden Cardiac
Death
Take home points:
Not all LVH is HCM
History taking: pedigree, systemic relationship
ECG: LVH, WPW
ECHO
GLS
CMR

Risk sudden cardiac death, primary prevention

Thank You