Therapeutic challenge of hypertrophic cardiomyopathy – third in series

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.