Hypertrophic cardiomyopathy - First in a series

I - Background

The description of hypertrophic cardiomyopathy (HCM) has been attributed to Dr. Braunwald et al from the early 1960s, but Liouville, Hallopeau, Schimincke, Davies, Brock and Teare as early as 1869 had contributed to its functional and anatomical characterisation (1,2) defining it as a variable degree of asymmetric left ventricular hypertrophy in the absence of secondary triggers (3).
An autosomal dominant mutation causes this disorder and the first gene mutation for this condition was identified in 1989. With a vast genetic heterogeneity of more than 1400 mutations, the most common genetically mediated form is myofilament (sarcomere) HCM with hundreds of disease associated mutations in 11 genes encoding proteins critical to the cardiac sarcomere (4). This disease affects both genders, various ethnicities and age ranges, however, its clinical recognition may occur earlier in men and later in women and African-Americans (5).

Diagnosis

Clinical presentation may vary from totally asymptomatic to dyspnea, chest pain, palpitations, syncope or sudden death. HCM should be considered if a patient has unexplained symptoms, a family history of premature cardiac disease, or recognition of a heart murmur or electrocardiographic abnormalities during routine, preparticipation sports examinations or test screening may reveal:

• A large or giant a wave may be present in the contour of the jugular venous pulse. 
• A prominent apical presystolic impulse may be present, but is more characteristic triple apical beat, although less frequent. 
• A systolic heart murmur may be heard between the apex and the lower left sternal border and can be provoked by the Valsalva maneuver, a change in position (standing), or holding one's breath. In addition, a fourth heart sound - S4 - may be audible.
• An abnormal electrocardiogram (widened QRS complex or alterations in the ST and T wave) can be present in 75% to 95% of patients, but a normal or near-normal exam may occur in 10% of cases. 

The diagnosis is confirmed by demonstration of increased left-ventricular wall thickness of 15 mm or more (or the equivalent relative to body surface area in children) in one or more myocardial segnents by two-dimensional echocardiography and/or cardiovascular magnetic resonance. Mitral valve systolic anterior motion that occurs in 10% to a third of patients (6) or hyperdynamic left ventricle are not mandatory for a diagnosis of HCM. The hypertrophy is usually predominant at the confluence of the anterior septum and anterior free wall, but patients may have unusual patterns of hypertrophy.

Risk stratification
Complications attributable to HCM are:

• Risk of sudden arrhythmic death in asymptomatic or mildly symptomatic patients
• Progressive heart failure with preserved systolic function with or without outflow obstruction; 
• Advanced heart failure with systolic dysfunction that can lead to heart transplant in 2% to 3% of patients and responsible for >50% of the disease-related mortality;
• Atrial fibrillation associated with risk for heart failure and embolic stroke that occurs in 20% of patients (7).

Sudden cardiac death (SCD) is frequently the first clinical manifestation of HCM and continues to be the most devastating complication in its natural history despite its annual rate of 1% (annual rate of 6% in a retrospective study in children) (8).  
In adult patients, the risk factors are (9) 

1. Prior aborted cardiac arrest and spontaneous sustained ventricular tachycardia
2. Non-sustained ventricular tachycardia
3. Unexplained syncope
4. Extreme left ventricular hypertrophy
5. Abnormal blood pressure response to exercise testing and 
6. Family history of SCD

Prognosis

• Patients with prior personal history of ventricular fibrillation, ventricular tachycardia or SCD have an annual event risk of 10% and a mortality rate of 4.7% per year. 
• Non-sustained ventricular tachycardia (by ambulatory monitoring or exercise testing) is a significant independent risk factor, especially in the young (< 30 years of age), with an average ratio of 2.89. 
• The average ratio of risk related to unexplained syncope and extreme left ventricular hypertrophy are of 2.68 and 3.10, respectively. 
• The magnitude of hypertrophy ≥ 30 mm is an independent association with SCD. 
• Abnormal blood pressure response to exercise testing, defined as a failure to increase by at least 20 mm Hg or a reduction of at least 20 mm Hg in systolic blood pressure, was considered a risk factor in some studies, with an average ratio of 1.30. 
• Family history was a risk factor for SCD in recent studies with an average reported hazard ratio of 1.27. In multivariate analysis, the combination of two or more major risk factors provided a risk ratio of 5.6, with estimated annual SCD risk of 4–5%.

Despite these established risk markers, about 50% of patients with HCM have no markers for high risk status and the risk of SCD for these patients is not negligible, with an event rate of 0.6% per year (10). On the other hand, and paradoxically, patients in the seventh decade of life are at low risk for disease-related morbidity or mortality, even with the risk markers (11).

II - Special cases and family

Pregnancy 

Pregnant women with HCM usually tolerate pregnancy well, but are considered high risk if symptomatic before pregnancy and if there is a high gradient in the outflow tract of the left ventricle. During pregnancy, there is an increased fluid volume, which overloads their hearts and compromises and increases the obstetrical risk (12).

Athletes

In athletes, HCM is the most common cardiovascular cause of SCD, accounting for 36% of all deaths (13). The guidelines recommend that athletes with HCM should not participate in competitive organised activities, should avoid physical activity in extreme environmental conditions of heat, cold, or high humidity, and should prefer aerobic exercise as opposed to isometric exercise.
Besides the major risk factors, there are the possible risk factors considered thus due to controversial results in the literature (14,15). The others risk factors are left ventricular outflow tract (LVOT) obstruction, myocardial fibrosis or scarring, left ventricular aneurysm, atrial fibrillation, physical exertion and genotype (Table 1). Resting LVOT obstruction occurs in 25% to 30% of patients, and up to two thirds of all patients with HCM has this significant obstruction after provocation with Valsalva maneuver and/or exercise. It reported a significant association between the extent of myocardial scar and the occurrence of ventricular tachyarrhythmia and the presence of conventional risk factors (16). Although the role of clinical genetic testing in HCM is undergoing change and refinement, a positive genetic test can provide for an increased probability of disease progression, particularly with regard to the systolic and diastolic dysfunction and propensity to develop symptoms (17). And genotyping can be a powerful tool for family screening and diagnosis. Genetic testing is recommended (class I) to confirm the diagnosis when performed in laboratories with experience in the interpretation of mutations related cardiomyopathy.

Family screening

As HCM is a familial heart disease, prospective family screening is recommended. Clinical evaluation, with history and physical examination, as well as electrocardiogram and echocardiography and 48-hour ambulatory electrocardiogram monitoring, should be taken every 12 to 24 months, or sooner if necessary. Ambulatory electrocardiogram monitoring should be taken every 6 to 12 months in patients with new palpitations or left atrial diameter ≥ 45 mm.  Cardiovascular magnetic resonance may be made every 5 years in stable patients or every 2-3 years, there is disease progression. Screening under the age of 12 is recommend if there be any of the conditions: onset of symptoms, competitive athlete in an intense training program, malignant family history of premature HCM death or other adverse complications or other clinical suspicion of early LV hypertrophy. This clinical evaluation should be made also for the first-degree relatives who have the same definite disease-causing mutation as the proband. 

III - Treatment

As a general rule, treatment is individualised based on symptoms and whether LVOT obstruction, family history and risk for SCD are present. Possible modalities are pharmacologic, surgical myectomy or percutaneous alcohol septal ablation, or a combination of therapies, and implantable cardioverter defibrillator (ICD) (18). Vasodilators, positive inotropic drugs, norephrine, phosphodieterase-5 inhibitors, nitrates or b-adrenergic agonists, due to the increased LVOT obstruction, should be avoided. 

Drugs

• In symptomatic patients, possible drugs are:Beta blockers - they are the first-line agents. Beta blocker reduces heart rate, increasing the time of diastole, improving ventricular filling, and has a negative inotropic effect, preventing an adrenergic-induced tachycardia.
• Calcium channel blockers may be effective in patients who do not tolerate beta blockers or those with symptoms that do not respond to beta blockers. However, verapamil should be avoided in patients with substantial resting obstruction and especially in those with heart failure and should be used with caution in patients with substantial LVOT obstruction. 
• Combination of blockers and calcium channel blockers or the use of disopyramide may be considered. 
• Potential new therapeutic targets that include aldosterone and angiotensin II antagonists (to prevent myocardial fibrosis), perhexiline (a metabolic modulator that improves intracellular metabolic efficacy,) ranolazine (a potent inhibitor of the late sodium current) and other agents.
• Prophylaxis for bacterial endocarditis before dental procedures, particularly in patients with LVOT obstruction. 

Surgical septal myectomy

For patients refractory to medical treatment in NYHA (New York Heart Association) functional Class III-IV, and with LVOT obstruction of 50 mm Hg or more (at rest or with physiologic provocation), surgical septal myectomy is the preferred treatment option, i.e. ≥ 30 mm). It is a surgical procedure described in 1961 in which a small portion (7 mm) of the thickened ventricular septum is removed. It improves quality of life as well as to offer long-term survival rates and presents operative mortality < 1% (19-20).  

Percutaneous alcohol septal ablation

Percutaneous alcohol septal ablation is an alternative option for selected patients who are not optimal surgical candidates (older patients or those with co-morbidities, profound aversion to surgery, or particularly marked septal hypertrophy). It is a non-surgical procedure, first used in 1995, done by injecting a small amount of absolute alcohol in a small branch of the coronary artery that supplies blood to the upper portion of the left ventricular septum. Complication rates are high, including the need for pacemaker implantation (in 10-20%), cardiac tamponade and ventricular arrhythmias.

Dual-chamber permanent pacing

Dual-chamber permanent pacing is only indicated for patients who have conduction disease or who are not candidates for septal reduction therapy (recommendation class IIb) (21). 
Risk stratification markers have demonstrated strong predictive power in identifying many susceptible patients who have benefited from the introduction of prophylactic ICD therapy to HCM. Currently, ICD is the preferred therapy for patients with HCM resuscitated from prior cardiac arrest (22). ICD has reduced the mortality associated with HCM in adult patients about 10 times, from 5% per year (25 years ago) to 0.5% per year at this time. However, problems with ICD leads and generators (sometimes requiring recalls) have a great impact on patients. The possibility of inappropriate shocks or other complications of devices (by about 5% per year) is an important element in decision making for primary prevention in patients with HCM (23). ICD for primary prevention is recommended for high risk patients (≥ 6% risk of SCD in 5 years).

Conclusions

Patients with major risk factors in HCM present a risk for SCD, but about 50% of all patients have no markers. Beta blockers are the first-line agents for symptomatic patients, surgical septal myectomy is the treatment of choice for refractory patients, and ablation alcohol is an alternative therapy. For patients resuscitated from prior cardiac arrest, ICD is the preferred therapy. It is recommended to conduct prospective family screening and for the role of genetic testing to be defined. 

Table 1 - Major and possible risk factors for sudden cardiac death (3,5,9,14,15)