Therapeutic challenge of hypertrophic

cardiomyopathy – third in series

An article from the e-journal of the ESC Council for Cardiology
Practice
Vol.13,N°18 - 31 Mar 2015

Dr. Irena Peovska Mitevksa

Because a timely diagnosis may help to prevent sudden death, it is important for internists and
general practitioners to be aware of the clinical features of hypertrophic cardiomyopathy, its
management options and prognosis. Here is a 17-point review of the therapeutic challenge and
prognosis of HCM in accordance with the latest European guidelines (2014).
Topic(s):
Congenital Heart Disease in Children and Adults (GUCH)

Background

Hypertrophic cardiomyopathy (HCM) is a common genetic cardiovascular disease with overall

prevalence estimated between 0.05-0.2% of the population (1,2). It is a disease state
characterised by unexplained, marked and asymmetric left ventricular (LV) hypertrophy
associated with non dilated ventricular chambers in the absence of any another cardiac or
systemic disease capable of producing the magnitude of hypertrophy evident in a given patient.
Left ventricular outflow obstruction at rest is present in about 20% of patients. Clinically, HCM
is usually recognised by a maximal LV wall thickness >15 mm. However, it should be
underscored that in principle, any degree of wall thickness is compatible with the presence of
the HCM genetic substrate (3).

1 - Clinical course and natural history

Hypertrophic cardiomyopathy is a heterogeneous cardiac disease with a diverse clinical

presentation and course. Most affected individuals achieve a normal life expectancy without
necessity for major therapeutic interventions. On the other hand, in some patients, HCM is
associated with disease complications which can result in disease progression or premature
death. There are three pathways of clinical progression: 1) Sudden cardiac death due to
unpredictable ventricular tachyarrhythmia’s; 2) Heart failure that may be progressive; 3) Atrial
fibrillation, associated with an increased risk of systemic thromboembolism and stroke.
The natural history of HCM can be altered by a number of therapeutic interventions. For HCM,
it is the peak instantaneous LV outflow gradient rather than the mean gradient that influences
treatment decisions.

2 - Genetic testing and family screening

Evaluation of familial inheritance and genetic counseling is recommended as part of the

assessment of patients with HCM. Screening (clinical, with or without genetic testing) is
recommended in first-degree relatives of patients with HCM (4).

3 - Diagnosis

Patients with CMP might be asymptomatic or may complain of chest pain, heart failure
symptoms or syncope. Morphologic diagnosis is based on the presence of a hypertrophied and
non-dilated left ventricle in the absence of another cardiac or systemic disease capable of
producing the magnitude of hypertrophy evident in a patient (usually>15 mm in an adult or the
equivalent relative to body surface area in children) (5).
The following diagnostic tools can be used for evaluation:

 Two-dimensional echocardiography conventionally enables the clinical diagnosis of HCM.

 Twelve-lead ECG is recommended in the initial evaluation of patients with HCM. 12-lead ECG,
exercise test, resting and exercise 2D and Doppler echocardiography, and 48-hour ambulatory
ECG monitoring are recommended in patients with unexplained syncope.
 Twenty-four–hour ambulatory (Holter) electrocardiographic monitoring is also recommended
in the initial evaluation of patients with HCM to detect ventricular tachycardia (VT) and identify
patients who may be candidates for ICD therapy as well as in patients who develop palpitations
or lightheadedness. Treadmill testing with monitoring of an ECG and blood pressure is
reasonable for SCD risk stratification in patients with HCM. Cardiopulmonary exercise testing,
with simultaneous measurement of respiratory gases, is recommended in severely symptomatic
patients for assessment of severity of exercise intolerance, as well as patient’s with systolic
and/or diastolic LV dysfunction being evaluated for heart transplantation or mechanical support
(6).
 Invasive electrophysiological study is recommended in patients with documented persistent or
recurrent supraventricular tachycardia and in patients with ventricular pre-excitation, in order
to identify and treat an ablatable substrate
 Echocardiography is recommended in the initial evaluation of all patients with suspected HCM.
In order to establish diagnosis of HCM systematic echocardiography approach is necessary. The
examination should include confirming LV hypertrophy, assessing LVOT obstruction, systolic
anterior motion- SAM, systolic and diastolic LV function and left atrial size. Additional novel
echocardiographic modalities add for a better understanding of subclinical LV damage. The
following two-dimensional (2D) echocardiographic criteria are used to aid diagnosis : 1)
unexplained maximal wall thickness >15 mm in any myocardial segment, or 2) septal/posterior
 wall thickness ratio >1.3 in normotensive patients, or 3) septal/posterior wall thickness ratio
>1.5 in hypertensive patients (7). It is clinically important to distinguish between the
obstructive and nonobstructive forms of HCM because management strategies are largely
dependent on the presence or absence of symptoms caused by obstruction. Obstruction to LV
outflow is dynamic, varying with loading conditions and contractility of the ventricle (4).
Increased myocardial contractility, decreased ventricular volume, or decreased afterload
increases the degree of subaortic obstruction.
 Transthoracic echocardiogram (TTE) is recommended as a component of the screening
algorithm for family members of patients with HCM.
 Cardiac Magnetic Resonance CMR imaging is indicated in patients with suspected HCM when
echocardiography is inconclusive for diagnosis (8).

4 - Detection of concomitant coronary disease

Coronary arteriography (invasive or computed tomographic imaging) is indicated in patients

with HCM with chest discomfort who have an intermediate to high likelihood of coronary
artery disease (CAD), in survivors of cardiac arrest and sustained ventricular tachyarrhythmia
when the identification of concomitant CAD will change management strategies. In all patients
aged 40 years or more, invasive or CT coronary angiography should also be considered before
septal reduction therapy, irrespective of the presence of typical exertional chest pain.

5 - Symptoms and complications

Overall treatment of patients with HCM requires a thorough understanding of the complex,
diverse pathophysiology and natural history and must be individualised to the patient. A large
proportion of patients are asymptomatic and it is essential to educate these patients and their
families about the disease process, screening of first-degree relatives and avoiding strenuous
activity or competitive athletics. Risk stratification for SCD should also be performed in all
patients, irrespective of whether symptoms are present. The major goal of pharmacologic
therapy in symptomatic patients with HCM is to alleviate symptoms of exertional dyspnea,
palpitations, and chest discomfort (9,10).

6 - Patients with LVOTO

All patients with LVOTO should avoid dehydration, excess alcohol consumption, and weight
loss should be encouraged. Arterial and venous dilators, including nitrates and
phosphodiesterase type 5 inhibitors should be avoided if possible. New-onset or poorly
controlled AF can exacerbate symptoms caused by VOTO and should be managed by prompt
restoration of sinus rhythm or ventricular rate control. Digoxin should be avoided in patients
with LVOTO because of its positive inotropic effects.
7 - Drugs

Beta-blocking drugs are recommended for the treatment of symptoms in patients with
obstructive or nonobstructive HCM, with a target resting heart rate of less than 60 to 65 bpm.
Verapamil therapy to maximal tolerated doses is recommended for the treatment of symptoms
in patients with obstructive or nonobstructive HCM who do not respond to beta -blocking
drugs, have side effects or contraindications to beta-blocking drugs. Amiodarone is the only
agent proven to reduce the incidence and risk of cardiac sudden death, with or without
obstruction to LV outflow. It is very effective at converting atrial fibrillation and flutter to sinus
rhythm and at suppressing the recurrence of these arrhythmias.

8 - Invasive therapies

For severe refractory symptoms that are attributable to LVOT obstruction, invasive therapies
can be used to improve quality of life. Surgical approaches that provide relief of outflow tract
obstruction and symptoms can be achieved with minimal perioperative morbidity or mortality
in experienced centers.

9 - Surgical myectomy and alcohol ablation

The majority of patients with HCM can achieve control of their symptoms with optimal
pharmacologic therapy. It is very important to use a set of clinical, anatomic, and hemodynamic
criteria before patients are considered candidates for invasive therapies. Surgical septal
myectomy is considered the preferred treatment for most severely symptomatic patients with
obstructive HCM, especially in younger, healthy adults, whereas septal ablation is preferred in
patients for whom surgery is contraindicated or considered high risk (particularly the elderly).
Septal reduction therapy to improve symptoms is recommended in patients with a resting or
maximum provoked LVOT gradient of 50 mm Hg, who are in NYHA functional Class III–IV,
despite maximum tolerated medical therapy. Operator and institutional experience, including
procedural volume, is a key determinant of successful outcomes and lower complication rates
for any procedure. When surgery is contraindicated or the risk is considered unacceptable
because of serious comorbidities or advanced age, alcohol septal ablation, when performed in
experienced centers, can be beneficial in eligible adult patients with HCM with LVOT
obstruction and severe drug-refractory symptoms (usually NYHA functional classes III or IV)
(11,12).

10 - Dual chamber pacing

Sequential AV pacing, with optimal AV interval to reduce the LV outflow tract gradient may be
considered in selected patients with resting or provocable LVOTO 50 mm Hg, sinus rhythm and
drug-refractory symptoms, who have contraindications for septal alcohol ablation or septal
myectomy or are at high risk of developing heart block following septal alcohol ablation or
septal myectomy (13,14).

11 - Implantable cardioverter defibrillator

The implantable cardioverter defibrillator (ICD) has been used for the prevention of sudden
arrhythmic death, certainly the most devastating complication of HCM, which is the most
common cause of SCD in young people. ICD placement is recommended for patients with HCM
with prior documented cardiac arrest, ventricular fibrillation, or hemodynamically significant
VT. It is reasonable to recommend an ICD for patients with HCM with sudden death presumably
caused by HCM in 1 or more first-degree relatives, a maximum LV wall thickness greater than
or equal to 30 mm (15).

12 - Atrial fibrillation

Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM. As left atrial size
is a consistent predictor or AFand stroke in patients with HCM. Patients in sinus rhythm with
LA diameter ≥45mm should undergo 6–12 monthly 48-hour ambulatory ECG monitoring to
detect AF. Anticoagulation with vitamin K antagonists is indicated in patients with paroxysmal,
persistent, or permanent AF and atrial flutter. Assessment of the risk of bleeding with the HAS-
BLED score should be considered when prescribing antithrombotic therapy (whether with VKA
or antiplatelet therapy). Restoration of sinus rhythm, by DC or pharmacological cardioversion
with intravenous amiodarone, should be considered in patients presenting with recent-onset
AF. Amiodarone should be considered for achieving rhythm control and to maintain sinus
rhythm after DC cardioversion. ß-Blockers, verapamil and diltiazem are recommended for
controlling ventricular rate in patients with permanent or persistent AF. Catheter ablation for
atrial fibrillation should be considered in patients without severe left atrial enlargement, who
have drug refractory symptoms or are unable to take anti-arrhythmic drugs. When adjusted-
dose vitamin K antagonist (VKA) (INR 2–3) cannot be used due to failure to maintain
therapeutic anticoagulation, side-effects of VKAs, or inability to attend or undertake INR
monitoring—a direct thrombin inhibitor (dabigatran) or an oral factor Xa inhibitor (e.g.
rivaroxaban, apixaban) is recommended . Unless there is a reversible cause of AF, lifelong OAC
therapy with a VKA (INR 2.0–3.0) is recommended, even if sinus rhythm is restored.
Radiofrequency ablation for AF can be beneficial in patients with HCM who have refractory
symptoms or who are unable to take anti-arrhythmic drugs (16).

13 - Symptomatic patients without LVOT

Heart failure In symptomatic patients with a normal EF and no evidence of resting or

provocable LVOTO, the aim of drug therapy is to improve LV filling by slowing the heart rate
with b-blockers, verapamil or diltiazem and cautious use of loop diuretics. Restoration of sinus
rhythm or ventricular rate control is essentialin patients who have permanent or frequent
paroxysms of AF. It is recommended that patients with reduced EF and heart failure symptoms
should be treated with diuretics, ß-blockers, angiotensin-converting enzyme (ACE) inhibitors,
angiotensin receptor blockers (ARB) and mineralocorticoid receptor antagonists (MRA) in line
with the ESC Guidelines for the management of chronic heart failure.

Cardiac resynchronisation therapy Cardiac resynchronisation therapy is aimed to improve

symptoms and may be considered in patients with maximum LVOTG <30 mm Hg, drug
refractory symptoms, NYHA functional Class II–IV, LVEF <50% and LBBB with a QRS duration
>120 ms (IIb C).

Left ventricular asist devices and cardiac transplantation LVAD therapy may be considered in
selected patients with end-stage HF despite optimal pharmacological and device treatment,
who are otherwise suitable for heart transplantation, to improve symptoms, reduce the risk of
HF hospitalisation and premature death while awaiting a transplant. Cardiac transplantation
should be considered in eligible patients who have an LVEF <50% and NYHA functional Class
III–IV symptoms despite optimal medical therapy.

14 - Sudden cardiac death risk stratification

Estimation of SCD risk is an integral part of clinical management . Recent studies of adult
patients with HCM report an annual incidence for cardiovascular death of 0,8–2%, with SCD,
heart failure and thromboembolism being the main causes of death (17). The most commonly
fatal arrhythmic event is spontaneous ventricular fibrillation (VF), asystole, AV block and
pulseless electrical activity. All patients with HCM should undergo comprehensive SCD risk
stratification at initial evaluation to determine the presence of the following:

 Age- the risk of SCD is increased in younger patients

 A personal history for ventricular fibrillation, sustained VT, or SCD events
 A family history for SCD before age <40 years with or without diagnosis of HCM
 Unexplained syncope
 Documented nonsustained ventricular tachycardia (NSVT) at greater than or equal to 120 bpm
on ambulatory (Holter) ECG
 Maximal LV wall thickness greater than or equal to 30 mm
 Left atrial size
 Abnormal blood pressure (BP) response during exercise stress test defined as a failure to
increase BP by at least 20 mm Hg or a drop of at least 20 mm Hg during effort

15 - Sudden cardiac death

Patients with HCM should be advised against participation in competitive sports and
discouraged from intense physical activity, especially when they have risk factors for SCD
and/or LVOTO. ICD implantation is recommended in patients who have survived a cardiac
arrest due to VT or VF, had spontaneous sustained VT causing syncope, estimated 5-year risk of
sudden death of 6% and life expectancy of >1 year. SCD risk stratification is recommended as a
method of estimating risk of SCD at 5 years in patients without a history of resuscitated VT/VF
or spontaneous sustained VT causing syncope or haemodynamic compromise. The 5-year risk
of SCD should be assessed at first evaluation and re-evaluated at 1–2 year intervals or
whenever there is a change in clinical status.

16 - Pregnancy

Counselling on safe and effective contraception and genetic counseling is indicated in all
women of fertile age. In women with HCM who are asymptomatic or whose symptoms are
controlled with beta-blocking drugs, the drugs should be continued during pregnancy, but
increased surveillance for fetal bradycardia or other complications are warranted. In women
with HCM and resting or provocable LVOT obstruction greater than or equal to 50 mm Hg
and/or cardiac symptoms not controlled by medical therapy alone, pregnancy is associated
with increased risk, and these patients should be referred to a high-risk obstetrician. Patients
should be carefully evaluated in regard to the risk of pregnancy. Scheduled (induced) vaginal
delivery is recommended as first choice in most patients. Therapeutic anticoagulation with
LMWH or vitamin K antagonists depending on the stage of pregnancy is recommended for
atrial fibrillation.

17 - Complications and prognosis

HCM is a progressive condition that worsens over time, as does the gradient across the LV
outflow tract if left untreated. Most patients with HCM are asymptomatic. Unfortunately, the
first clinical manifestation of the disease may include congestive heart failure, ventricular and
supraventricular arrhythmias, infective mitral endocarditis, atrial fibrillation and sudden
death, particularly in younger patients who have a much higher mortality rate. Reported
annual mortality rates in patients with hypertrophic cardiomyopathy (HCM) have ranged from
less than 1% to 3-6%, and studies suggest that they have significantly improved over the past
40 years.

Conclusion

Most people with HCM lead normal and productive lives, but a small number experience
significant symptoms and are at risk of disease-related complications. Irrespective of the
severity of their disease, it is important that individuals receive support and accurate advice
from healthcare professionals, and that they are encouraged to understand and manage the
disease themselves. A full medical evaluation at experienced treatment centers can determine
appropriate therapies for improvement of symptoms and identify those patients who may be at
risk for sudden death.
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VolumeNumber:
Vol13 N18