Современное лечение гипертрофической кардиомиопатии

Fig. 1. Therapeutic strategies based on patient profiles

The global survival of the population of patients with HCM is similar to that of the general population with a quite low mortality (1-2% per year) [1-4]. Modalities of death (each occurring at frequencies <1% per year) include sudden cardiac death (SCD) due to ventricular arrhythmias (VA), heart failure (HF), and stroke due to paroxysmal or permanent atrial fibrillation (AF) [1-3]. Bacterial endocarditis occurs essentially in case of murmur/obstruction, but there is no current consensus for a systematic prophylaxis in that setting. While it is observed at all ages, SCD is more frequent in the youngest patients, reaching up to 6% per year before 20-30 years [2]. One out of three SCDs occurs as the first clinical event, in asymptomatic or mildly symptomatic patients, sometimes during exercise (about 15%, justifying the exclusion of patients from any competitive sport) and often at rest [3]. The asymptomatic patient, with or without (carrying of a morbid gene mutation) hypertrophy who is considered at low risk of SCD and does not present paroxysmal or permanent AF may not require any treatment.

1. Management of exercise symptoms with drugs

Presence of a gradient in HOCM increases symptoms through reduced stroke volume (leading to syncope), increased left ventricular pressure and microcirculatory abnormalities (leading to angina), increased systolic anterior motion of the mitral valve and mitral regurgitation and load-dependant diastolic dysfunction (leading to dyspnea) [5, 6].

In symptomatic patients (Fig. 2), when resting and/or provoked (with a Valsalva, a standing manoeuver or an exercise test) left ventricular outflow tract (LVOT) obstruction is present (70% of all patients), the primary aim is to decrease the resting and/or exercise gradient [7]. In that setting, beta-blockers are often the preferred drug as the first-line therapy (decreasing essentially the provoked gradient) while verapamil is often chosen in patients with contraindications to beta-blockers or in the absence of obstruction (aiming to improve diastolic function). A high daily dosage of each drug should be achieved through a progressive dose increase, corresponding to 320-480 (up to 600) mg of propanolol or 480 mg of verapamil. Both drugs are sometimes prescribed concomitantly at lower dosages (with a strict ECG and eventually Holter ECG monitoring), particularly in case of obstruction associated to angina. When the patient remains symptomatic along with the presence of a residual gradient, each of the former drugs can be associated with disopyramide (200-600 mg), which also decreases contractility and heart rate and is efficient on the gradient. Disopyramide appears not to increase mortality [19], but should not be used along with amiodarone, due to the risk of induced VA [8]. Finally, adjunctive treatment with a diuretic (at low-dose to avoid any increase in obstruction) is sometimes necessary when exercise dyspnoea persists, probably due to elevated left ventricular enddiastolic pressure (suspected at Doppler echocardiography when the ratio of E-wave velocity at the mitral inflow on E velocity at the mitral annulus ex- ceeds 15 cm/s) [9, 10].

2. Management of exercise symptoms with invasive therapies

When patients remain severely symptomatic (NYHA III/IV) despite maximal medical therapy with a resting or provoked obstruction >50 mmHg, they should be considered for invasive procedures including permanent DDD pacing with a short atrioventricular (A-V) delay, ASA or cardiac surgery [11]. Of interest is to note that 50% of HCM patients present with resting or provoked gradient >50 mm Hg [14].

DDD pacing

Even if some patients with HOCM undoubtedly benefit from pacing, the indications of DDD pacing dramatically decreased within the last 10 years, due to controversial results of randomized, controlled studies with relatively short follow-up [12-14]. According to recent guidelines, permanent pacing may be considered in medically refractory symptomatic patients with HCM and significant resting or provoked LVOT obstruction (Class IIB, level of evidence: A) [15]. This is even more so in HOCM patients with coexisting advanced conduction system disease with an independent indication for an ICD or for septal ablation with the presence of left bundle branch block [5].

Alcohol septal ablation

Since 1994 (16) ASA has become an important therapeutic option for severely symptomatic (NYHA class III or IV) patients with HOCM despite maximal medical therapy, with an LVOT gradient >50 mmHg (either at rest or during/after exercise) and predominant upper septal hypertrophy (>18 mm without important mitral valve structural abnormalities) without associated significant coronary atherosclerosis [11].

Small quantities of alcohol (1-2 cc) over 30-60 seconds with a slow continuous infusion to avoid A-V block and overspill from the target territory is generally administrated. Procedure complications also decreased since use of contrast echocardiography, which helps to identify the core of alcohol accumulation and checks for the absence of perfusion of erratic territories [17] and to determine the target coronary artery. While the upper hypertrophied septum is usually perfused by the first septal branch, 5-30% of candidates present a non-suitable septal branch, and in 10-30% of cases, successful ASA necessitates selective administration of alcohol into more than one septal branch. A temporary pacemaker needs to be inserted during the procedure, remaining in place for the following 2-3 days as delayed A-V block (10-25% of all procedures) can arise suddenly after 48 hours [18].

Procedural success defined as >50% reduction in the resting gradient or decreased provoked gradient with no residual resting gradient, occurs in more than 80% of cases. Up to 50% of patients are in NYHA class I after the procedure, along with improved exercise capacity and VO2 peak, decreased septal thickness and ventricular remodelling (decreased mass and increased dimensions) [16, 19]. The complication of ASA include right (up to 50% of cases) or left (6%) bundle branch block, and permanent complete AV block requiring implantation of a pacemaker (<10%); mortality rates ranges 0-4% (mean 2%) [6]. Medium-term follow-up data are now available and the benefits appear comparable to those observed after myectomy, with an overall mortality-free survival, including ICD discharge for VA, reaching 94% at 2 years and 88% at 4 years [5]. At long-term high rates (up to 10% per year) of sustained VA and SCD have been reported but were not confirmed by others [20, 21].

Surgery

In some centers, surgical myectomy remains the primary option for severely symptomatic drugrefractory patients with HOCM, particularly in the young, while ASA is an alternative for patients at increased operative risk, for those without access to expert surgical centres or who refuse operation after both options have been discussed fully [15, 34]. Surgical mortality related to isolated myectomy has approached 1% in major expert centres, with low procedure-related morbidity (2-3%), excellent late results (90% improved) and high long-term survival rates [22]. However, surgery remains the procedure of choice in cases of associated structural mitral valve abnormalities (with frequent mitral valve repair or replacement) or coronary artery disease or in cases of unsuccessful ASA.

3. Prevention of SCD

Rates of appropriate ICD interventions for VA in multicentre HCM registries reach up to 10% per year in patients with a history of aborted SCD and 4% per year in high-risk patients without prior cardiac arrest (sometimes up to 10 years after implantation) [23, 24]. According to the 2008 ACC/AHA guidelines [15] an ICD should be implanted in case of prior cardiac arrest (Class I, level of evidence C), and is reasonable for patients with sustained ventricular tachycardia or if one or more risk factors for SCD is present (IIa, C). It may be considered in patients with syncope in whom invasive and noninvasive investiga- tions have failed to define a cause (IIb, C) or in patients with familial HCM associated with SCD (IIb, C). As 25% and 20% of all patients with HCM have only one or two risk factors, respectively [6] and taking into account that most of these patients will not die suddenly, it would not be reasonable to implant ICDs systematically in this population: instead, management should be patient- and family-orientated. A good example is the adolescent or young adult with a single major risk factor (such as multiple SCDs at a young age in first-degree relatives or malignant hypertrophy or NSVT on Holter ECG monitoring) for whom no definite rules can be provided. However, in a recent cohort of 506 patients, im- plantation complications occurred in 27% of cases, with one (0.00,2%) death linked directly to the procedure [24].

Detection of patients at high risk of SCD remains extraordinary challenging. Five major risk factors for SCD have been proposed, essentially relevant before the age of 50 years: family history of premature SCD (<40 years in first degree relatives), marked (or malignant) left ventricular hypertrophy (LVH) (>30 mm), unexplained recent (<6-12 months) syncope or pre-syncope, non-sustained ventricular tachycardia (NSVT) (>120 bpm) on Holter ECG monitoring and abnormal blood pressure response (ABPR) during upright exercise (BP fall or rise <20-30 mmHg at peak exercise). While the negative predictive values for each of these markers are high (>90%), their positive predictive values are remarkably low (<20%), weakening their role in the stratification of risk in individual patients [1, 2]. The combination of three major risk factors (5% of patients) or the combination of a single major risk factor to>2 minor risk factors might help to identify a subgroup with a markedly elevated risk of SCD (Fig. 3) [6]. Among those minor markers, the presence of resting obstruction (>30 mmHg) has been associated with increased mortality (two fold at 10 years), essentially due to a marked increase in the rate of progression towards severe functional limitation and death from heart failure [25]. The 5-year probability of SCD given the presence of a fibrous scar on cardiac magnetic resonance (CMR) has been estimated to reach approximately 11%, versus 0.7% in its absence [26].

As SCD may occur at all ages even in patients with no classical markers of SCD, a SCD risk prediction model that provides individualized risk estimates has been recently proposed [27]. It includes age, maximal left ventricular wall thickness, left atrial diameter, left ventricular outflow tract gradient, presence or absence of a family history of SCD, NSVT and unexplained syncope. It has been derived from a retrospective, longitudinal cohort study including 3675 consecutive patients from six centres with a median follow-up period of 5.7 years. For example, using that model, the risk of SCD at 5 years in a 27-year old patient with a 27 mm wall thickness, a 45 mm left atrium, a 65 mmHg LVOT gradient, no family history of SCD but one run of NSVT on Holter reaches 9.2%, leading to implant an ICD. Conversely, for a 60 year-old patient with a 22 mm thickness, a 45 mm atrium, a 65 mmHg gradient and a family history of SCD but no syncope or NSVT, the 5-year risk is below 4% (3.4%) and an ICD not indicated.

4. Others

Echocardiographic and ECG screening of proband family members is mandatory.

Prophylactic anticoagulation is essential in patients with paroxysmal or chronic AF. Dysopyramide or amiodarone are used to prevent recurrence of AF [5]. Radiofrequency catheter ablation of AF is possible, with better results in cases of paroxysmal versus permanent atrial fibrillation [28], while A-V node ablation with pacemaker implantation may be a safe alternative.

Heart transplantation can be performed in patients with HCM and end-stage evolution with systolic dysfunction, with similar results to those from patients with idiopathic dilated cardiomyopathy [29].

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