ACC/ESC Recommendations for the Clinical Management of Hypertrophic Cardiomyopathy: A Practical Perspective

Hypertrophic Cardiomyopathy: A Practical Perspective

P. D

, M. B

, L. S

, E. M

, N. S

, L. C

’, E. M

In November 2003 the American College of Cardiology (ACC) and the European Society of Cardiology (ESC) published in the Journal of the American College of Cardiology an expert consensus document on hyper- trophic cardiomyopathy (HCM) to inform practitioners about the state of the art in managing this particular disease [1]. HCM is a genetic disease which can cause sudden cardiac death (SCD), particularly in young people (includ- ing athletes). As HCM is uncommon (1:500 in the general population) [2], many cardiologists do not see many patients with this disease, and may therefore have some difficulty in managing the cases of the patients they do see.

This document has been written by specialists with extensive experience of managing HCM. However, the statements and treatment strategies put for- ward by the panel are very cautious owing to the considerable difficulties involved in reaching conclusions: (1) because the disease is uncommon, the available data are relatively limited; (2) HCM has a broad disease spectrum, so individual patients may have very different risk profiles; (3) large-scale controlled and randomised study designs (as in coronary artery disease) are not available. Consequently most information derives from non-randomised and retrospective studies.

Genetics and Phenotypic Expression of the Disease

HCM is inherited as a mendelian autosomal dominant trait and is caused by mutations in any one of 10 genes, each encoding protein components of car- diac sarcomere composed of thick or thin filaments with contractile, struc-

Division of Cardiology, Hospital of Conegliano (Treviso), Italy

tural, or regulatory functions [3]. This genetic diversity is compounded by intragenic heterogeneity, with about 200 mutations now identified, most of which are missense, with a single amino acid residue substituted by another [4]. The molecular defects responsible for HCM are usually different in unre- lated individuals. The phenotypic expression of HCM is the product not only of the mutation itself but also of modifier genes and environmental factors [5]. These factors account for the phenotypic variability of affected individu- als even in the same family, carrying identical disease-causing mutations.

There is increasing recognition of the role of genetics in the genesis of the electrophysiological abnormalities associated with left ventricular hypertrophy (LVH) such as atrial fibrillation (AF) [6], Wolf-Parkinson-White (WPW), or heart block [7]. Furthermore, particular mutant genes seem to be associated with a particularly high risk of sudden death [3].

Not all individuals harbouring a genetic defect will express the clinical features of HCM at all times during life. In fact there is no minimal LV wall thickness required to be consistent with the presence of an HCM-causing mutant gene [2, 8]. It is common for children less than 13 yeas old to be

‘silent’ mutation carriers without evidence of LVH on an echocardiogram.

Most commonly the spontaneous appearance of LVH occurs during the ado- lescent years, with the morphological expression usually complete at the time of physical maturity, about 17-18 years of age [9]. Finally, some studies have demonstrated age-related penetrance and late onset of the phenotype, in which delayed and de novo appearance of LVH occurs in mid-life and even later [10].

Laboratory DNA analysis for mutant genes is the most definitive method for establishing the diagnosis of HCM. At present, however, even in the USA [1], there are several obstacles to the translation of genetic research into practical clinical applications and routine clinical strategy.

Clinical Characteristics and Natural History of HCM

The diagnosis of HCM is easily established echocardiographically by demon- strating LVH, which is typically asymmetrical in distribution. Left ventricular wall thickening is associated with a non-dilated and hyperdynamic chamber in the absence of any other cardiac or systemic disease (e.g. hypertension).

The usual clinical diagnostic criterion for HCM is a maximum LV thickness greater than or equal to 15 mm. However, genotype–phenotype correlations have shown that virtually any wall thickness (including those within normal range) may be compatible with the presence of a HCM mutant gene [10, 11].

Patients with HCM may present with outflow obstruction under resting

conditions or develop dynamic subaortic gradients in response to provoca-

tive manoeuvres (Valsalva manoeuvre, effort) or agents (isoproterenol) [11].

Obstruction may be either subaortic (caused by systolic anterior motion of the mitral valve leaflets) or mid-cavity in location. It is generally recognised that a subaortic gradient of 30 mmHg or more reflects true mechanical impedance to outflow.

The clinical course of HCM is variable; patients may remain stable over long periods of time, with up to 25% of a HCM cohort achieving normal longevity (> 75 years) [11, 12]. However, for many patients the course may be punctuated by adverse clinical events. The main adverse events are the following: (1) sudden cardiac death (SCD); (2) progressive symptoms (angi- na, dyspnoea, syncope) in the presence of preserved systolic function; (3) progressive congestive heart failure; (4) embolic stroke, mainly attributable to atrial fibrillation (AF).

Recent reports from non-tertiary centres, not subject to referral bias, cite annual mortality rates in the region of about 1% per year [10, 11]. For patients aged over 50 years at diagnosis, the probability of survival for 5, 10, and 15 years is 85%, 74%, and 57%, which is not significantly different from that in the general population [12]. However, there are subgroups of patients within the broad HCM spectrum with annual mortality rates exceeding 1%, in some studies as high as 6% per year [13–15].

Risk Stratification for Sudden Cardiac Death

Sudden cardiac death (SCD) may be the initial manifestation of HCM, most frequently in asymptomatic or mildly symptomatic young people [11, 16, 17].

In the USA, HCM is the most common cause of cardiovascular SCD in young athletes [18].

This devastating complication, however, is infrequent and high-risk HCM patients constitute only a minority of the overall disease population [10–15].

SCD is most frequent in adolescent and young adults (less than 35 years old). However, the risk of SCD also extends through mid-life and beyond [18, 19]. The basis of this particular predilection of SCD for the young is unre- solved. The available data suggest that SCD in HCM is related to malignant ventricular arrhythmias.

Many risk markers have been identified. The highest risk for SCD has

been associated with a number of factors [16, 20] (Table 1). Major factors

are: (1) Prior cardiac arrest or (2) spontaneously occurring and sustained

ventricular tachycardia (VT); (3) family history of premature HCM-related

SCD, particularly in a close relative or multiple in occurrence; (4) unex-

plained syncope, particularly in the young or exertional or recurrent; (5)

wall thickness > 30 mm, particularly in adolescent and young adults; (6)

abnormal blood pressure response during upright exercise; (7) non-sus- tained VT on Holter monitoring of at least 120/min. Minor factors (possible in individual patients) are: (1) AF; (2) myocardial ischaemia; (3) LV outflow obstruction; (4) identification of a high-risk mutant gene; (5) intense physi- cal exertion.

Syncope. Syncope can be a premonitory symptom of SCD. However, the sensitivity and specificity of syncope or presyncope as a predictor of SCD is low, possibly because most such events in this disease are probably not in fact secondary to arrhythmias or related to outflow obstruction. There are many potential causes of syncope in HCM, such as vagal, neurally mediated syndromes, etc. [11, 15].

Extreme LVH (>30 mm). This is observed in about 10% of patients [21].

Paradoxically, most patients with extreme LVH do not experience marked symptomatic disability. Although most patients who die suddenly have a wall thickness of less than 30 mm, extreme LVH is associated with a higher risk of SCD. Some authors suggest a substantial long-term risk in patients with a wall thickness greater than 30 mm: 20% over 10 years and 40% over 20 years (annual mortality 2%) [21]. Other investigators, however, have maintained that extreme hypertrophy is a predictor of SCD only when associated with other risk factors such as unexplained syncope, etc. [22]. On the basis of such data the ACC/ESC panel [1] suggests that, ‘although it is not resolved as to whether extreme hypertrophy as a sole risk factor is sufficient to justify a recommendation for prevention of SCD with an ICD, serious consideration for such an intervention should be given to young patients’.

Table 1. Risk factors for sudden cardiac death in HCM (ACC/ESC consensus docu- ment)

Major

Cardiac arrest (ventricular fibrillation) Spontaneous sustained ventricular tachycardia Family history of premature sudden death Unexplained syncope

LV thickness ≥ 30 mm

Abnormal exercise blood pressure Non-sustained ventricular tachycardia

Possible in individual patients

Atrial fibrillation

Myocardial ischaemia

Left ventricular outflow tract obstruction High-risk mutation

Intense physical exertion

NSVT. Ventricular arrhythmias are a frequent feature in patients with HCM. About 90% of adults present with premature ventricular beats, which are often frequent or complex, ventricular couplets in about 40%, and NSVT in 20–30% [23]. Some authors suggest a prognostic value only for NSVT encountered in young patients, but not in adults [24].

Atrial fibrillation. AF is the most common sustained arrhythmia in HCM, occurring in 20–25% of patients [25]. AF is well tolerated in about one-third of patients and is not considered an independent determinant of SCD [26].

However, it is possible that in certain susceptible patients AF may trigger malignant ventricular arrhythmias [27]. Furthermore, paroxysmal AF may also be responsible for acute clinical deterioration with syncope or heart fail- ure resulting from reduced diastolic filling and cardiac output. AF is inde- pendently associated with heart-failure-related death and the occurrence of fatal and non-fatal stroke [26].

Myocardial ischaemia. Chest pain may be reported both by young and adult patients. In the latter coronary artery disease may coexist with HCM. In any case, chest discomfort in HCM is probably due by bursts of myocardial ischaemia. In fact scars are frequently found at autopsy in HCM [28], while in living patients fixed or reversible myocardial perfusion defects can be documented [29]. Myocardial ischaemia is probably a consequence of abnor- mal microvasculature, consisting of intramural coronary arterioles with thickened walls and narrow lumen. One report suggests that short-tunnelled (bridged) intramyocardial segments of the left anterior descending coronary artery independently convey increased risk for cardiac arrest, probably mediated by myocardial ischaemia [30].

LV outflow obstruction (gradient > 30 mmHg). It is generally accepted that LV outflow obstruction can only be regarded as a minor risk factor for SCD. In fact the impact of gradient on SCD risk is not sufficiently strong to merit a role as the predominant deciding clinical parameter and the primary basis for decision to intervene with an implantable cardioverter–defibrillator (ICD) [31].

High risk mutation. It has been proposed, on the basis of genotype–phe-

notype correlations, that the genetic defects responsible for HCM could rep-

resent the primary determinant and stratifying marker for SCD, with specific

mutations conveying either favourable or adverse prognosis [3, 4, 10]. For

example, it has been suggested that some cardiac β-myosin heavy chain

mutations (such as Arg403Gln and Arg719Gln) and some troponin-T muta-

tions are associated with a higher incidence of SCD [1, 3]. However, some

authors suggest that routine clinical testing has low yield [32], and the

ACC/ESC panel of experts [1] state that at present ‘it is premature to draw

definite conclusions regarding gene-specific clinical outcomes based solely

on the presence of a particular mutation’.

Electrophysiological study (EPS). Programmed ventricular stimulation is of limited value in stratifying the risk of SCD in HCM [11, 15, 33]. In contrast with post acute myocardial infarction patients, monomorphic VT is rarely induced. On the contrary, polymorphic VT and ventricular fibrillation (VF) are frequently induced by aggressive stimulation protocols even in low-risk subjects [33]. As in coronary artery disease and in dilated cardiomyopathy, the induction of polymorphic VT and/or VF is considered a non-specific finding. In sum, EPS is generally not indicated in HCM. It may have a value in patients with unexplained syncope or sustained palpitations to detect supraventricular re-entrant tachycardias or monomorphic VT.

In conclusion, several risk factors have been identified in HCM. However, most of the clinical markers of SCD risk are limited by a relatively low posi- tive predictive value, due in part to relatively low event rates. On the other hand, these markers have a high negative predictive value (> 90%).

Therefore the absence of risk factors can be used to identify patients who have a low likelihood of SCD.

Prevention of Sudden Cardiac Death

Historically, treatment strategies to reduce the risk of SCD have been predi- cated on the administration of drugs such as beta-blockers [11, 15, 34], vera- pamil [11, 34], type IA anti-arrhythmic agents (quinidine, disopyramide) [35] and, more recently, amiodarone [36, 37]. However, there is no evidence that this practice is effective in mitigating the risk of SCD. Other therapies targeted to reduce LV outflow tract obstruction have been employed, such as surgical septal myectomy, percutaneous alcohol septal ablation, and pace- maker implantation. Despite their clinical benefit, no single one of these pro- cedures has demonstrated a favourable effect in reducing the risk of sudden death. Finally, ICD implantation has been proposed, which certainly has the ability to interrupt malignant ventricular arrhythmias, but the indications for which, owing to the difficulty of identify accurately the patients at high- est risk, are in part questionable.

Beta-blockers. Beta-blockers are a preferred drug treatment strategy for symptomatic patients with outflow gradients present only during exertion.

In fact there is little evidence that they reduce LV obstruction at rest. These agents lessen LV contractility and possible reduce microvascular myocardial ischaemia. They should be closely monitored in young patients because even moderate doses can affect growth, impair school performance, or trigger depression in children and adolescents [11].

Verapamil. Verapamil has been widely used empirically in the past with a

reported benefit for many patients [11]. However, this drug may also har-

bour a potential for adverse consequences. It has been reported to cause death in a few HCM patients with severe disabling symptoms related to marked outflow obstruction [34]. Adverse haemodynamic effects are pre- sumably the result of the vasodilating properties predominating over nega- tive inotropic effects, causing a worsening of outflow obstruction and pul- monary hypertension up to the point of cardiogenic shock. SCD has been reported in infants as a result of intravenous administration of the drug [34].

Disopyramide. This drug was introduced for its negative inotropic effect, producing a benefit in severely limited patients by decreasing outflow obstruction and mitral regurgitant volume [35]. Disopyramide may prolong the QT interval, possibly increasing the risk of malignant ventricular arrhythmias.

Amiodarone. Some reports suggest a favourable effect of this drug on the risk of SCD [36, 37]. Amiodarone has been suggested for use as a bridging treatment in very young high-risk children intended to receive an ICD later, after sufficient growth and maturation has occurred [1]. However, its efficacy has not been proved in randomised controlled studies.

Surgical septal myectomy. Persistent, long-lasting improvement in dis- abling symptoms and exercise capacity has been demonstrated for this pro- cedure [11, 15, 34, 38, 39]. The effect of surgery per se on longevity is unre- solved due to the lack of controlled randomised studies. However, there is some suggestion in retrospective non-randomised studies that surgical relief of outflow obstruction in severely symptomatic patients may reduce long- term mortality and possibly SCD [40].

Percutaneous alcohol septal ablation. This treatment reduces LV outflow obstruction, although to a lesser degree than surgery [41]. The long-term effect of this procedure is unknown, because to date only relatively short fol- low-ups are available. As alcohol ablation produces a scar, a facilitating effect on re-entrant arrhythmias cannot be excluded. In any case, the impact of this procedure on the incidence of SCD is unresolved.

Dual-chamber pacing. A favourable effect of pacing in HCM with LV out- flow obstruction has been demonstrated in randomised, cross-over, double- blind studies, although this favourable effect was less than suggested by the observational studies [42, 43]. However, there is no evidence that pacing reduces the risk of SCD.

Implantable cardioverter–defibrillator. According to the ACC/ESC expert

panel [1], when the risk of SCD is judged to be unacceptably high, the ICD is

the most effective and reliable treatment. Randomised controlled studies in

HCM (such as in post acute myocardial infarction or heart failure patients)

are not available. Only one multi-centre retrospective study is available, con-

ducted in high-risk patients who underwent ICD implantation for secondary

or primary prevention of SCD [44]. In this study, appropriate device inter-

ventions occurred at a rate of 11% per year in secondary prevention and 5%

per year for primary prevention. In the latter case, it must be emphasised that patients were generally asymptomatic or mildly symptomatic and were implanted on the basis of common non-invasive risk factors (syncope, family history of SCD, LVH > 30 mm, etc.).

The ICD is strongly warranted for secondary prevention of SCD in patients with spontaneous episodes of cardiac arrest and/or VT (class I according to ACC/AHA/NASPE and ESC guidelines) [20, 45].

Because of the low positive predictive value of any single risk factor, ICD implantation for primary prevention is questionable. The ACC/AHA/NASPE 2002 guidelines designated the ICD for primary prevention of SCD as a class IIb indication [45]. In 2001, the ESC Task Force on Sudden Cardiac Death [20] suggested categorising ICD for primary prevention as a class IIa indica- tion in the presence of multiple major risk factors.

The ACC/ESC expert panel [1] suggests managing patients on an individ- ual basis in clinical practice, taking into account the overall clinical profile including age, the strength of the risk factor identified, and the potential complications, largely related to lead systems and to inappropriate device discharges. Among risk factors, a family history of SCD in close relatives and LVH > 3 mm in subjects less than 35 years old are suggested to be strongly considered in deciding about ICD implantation.

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