Hypertrophic cardiomyopathy in childhood and adolescence – strategies to prevent sudden death

At what age is the risk greatest?

It has been a general perception that risk of sudden death in HCM is at its highest just after puberty and in young adults, which has led to suggestions that family screening for HCM should be commenced after 12 years [9]. However, subsequent published work has shown unequivocally that the risk of sudden cardiac death in a population with HCM diagnosed in childhood is significantly higher in the 9- to 14-year age range than it is in the 16- to 19-year-olds [3], see age distribution in 2. This surprising finding was confirmed from Swedish National Death Registry figures, which showed that annual mortality for HCM in 8- to 16-year-olds (0.112 per 100 000) was significantly outside the 95% CI for the death rate in 17- to 30-year-olds, which amounted to 0.055 per 100 000 age-specific population [95% CI 0.011–0.099] [3]. Much confusion has arisen in the literature from the uncritical habit of many authors of simply assuming that sudden death risk is uniform over the whole childhood, and thus calculating annual death rates without any consideration of the age composition of the cohort. That this introduces grave errors is clear from the Swedish–British cohort study, which showed that the risk of sudden death is extremely low below 8 years of age, rapidly increases from 8 years, rises to a maximum in 10- to 10.9-year-olds where it reaches an annual mortality of 9.7% and is averaging 7.2% between 9 to 13.9 years. After 16 years, it drops to an average annual mortality of 1.7% (all these figures include patients on medical therapy) [3]. Wren et al. [10] found an annual sudden death mortality of 0.074 per 100 000 in the age range 1–20 years. Considering that they include in their estimates the 0- to 8- year age range where virtually no sudden deaths occur, there is good agreement between their figures and the estimate of a risk of 0.112 per 100 000 in the 8- to 16-year age range [3]. Cohort outcome data from Australian and American Pediatric Cardiomyopathy Registries have recently been published claiming lower mortality than earlier studies; these studies do not separate modes of death, do not include patients presenting with sudden death and have few patients in the high-risk age range; thus, their blanket annual mortality rates are not representative for sudden death risk [11,12].

In summary, it can be concluded that the risk of sudden death varies greatly with age in childhood HCM and that in the 8- to 17-year age range, it is significantly higher than the risk both in younger children and in young adults with HCM. This has obvious relevance for timing of risk assessment.

Family screening for HCM

The group with the highest risk of having overt HCM is of course children with one parent with HCM and thereby at 50% risk of being a mutation carrier, and a number of working parties have advocated systematic screening of first degree relatives of patients with HCM [17]. It has been suggested that family screening for HCM should be commenced after 12 years of age, [9] but as shown by Östman-Smith et al. [3], those children with familial disease that show disease expression in childhood have a very high annual mortality in the 10- to 13-year age range. In the large Swedish–British cohort study, 8 out of 57 patients with familial HCM (14%) had severe disease expression already in the first year of life, so an initial screening at 6–12 months of age can certainly be justified. A total of 11 out of the 31 sudden deaths occurring in childhood and adolescence were patients with familial HCM, with six sudden deaths occurring at or below 12 years [3]. The risk of sudden death is low but not non-existent below 8 years, and because one clearly wants a window for therapeutic interventions before the child arrives in the high-risk age range, I would advocate that the first screening of a child with a parent with HCM should be carried out no later than 6 years. A child who does not fulfil diagnostic criteria for HCM at 6 years may on subsequent follow-up develop progressive hypertrophy, particularly during the pubertal growth spurt [18]. However, the important thing is that if both ECG and ultrasound are normal, there is no risk of sudden death before significant hypertrophy develops. There are reports of adults with Troponin T mutations suffering cardiac arrest without fulfilling ultrasound criteria of abnormal hypertrophy [19,20], but these patients did not have normal ECGs. In the Swedish–British large cohort study including 150 patients, with 39 sudden arrhythmia deaths, all the patients that died suddenly had cardiac hypertrophy that was of substantial degree for their age [3]. Ultrasound screening alone is not sufficient, as ECG abnormalities may precede clinically pathological hypertrophy by several years in children with HCM-causing mutations [21]. Neither is ECG screening alone sufficient, as the prevalence of a pathological ECG in children with ultrasound-positive familial HCM is only 56% [22], compared with earlier reports of a prevalence of ECG abnormalities in 61–93% of adult HCM patients attending referral centres [23,24]. In childhood, the most helpful ECG features that correlated with overt HCM were the presence of a 12-lead QRS-amplitude sum >24 mV and/or Q-waves >25% of R-wave amplitude in two leads [22].

Non-familial HCM

About one-third of cohorts with childhood HCM consists of patients with Noonan or Leopard syndrome [3,7,11], and these patients have the same risk of sudden death as other childhood HCM patients [3,7] and should be investigated with the same risk-stratification protocols. A further third of childhood HCM consists of patients with HCM caused by sporadic new mutations, and the main way of diagnosing these patients is by some kind of presenting symptom. The most common presenting symptoms are episodes of palpitations, undue breathlessness on exertion and exercise-related syncope. The latter symptom is of particular importance in indicating an increased risk of sudden death.

Hypertrophy as risk factor in childhood HCM

Increased degree of cardiac hypertrophy is certainly an incremental risk factor in childhood HCM [7], but a cut-off of >3 cm is meaningless in childhood as illustrated in 4, which shows that the majority of children who died suddenly had a maximal wall thickness <3 cm [35]. A more useful approach is to relate the degree of cardiac hypertrophy to the upper limit of normal for age. This can be done in two ways. For long-axis M-mode measurements the 95th centile diastolic wall thickness for age can be predicted using a published formula [septum: 0.625 + (age in years × 0.0269) cm; posterior left ventricular wall: 0.565 + (age in years × 0.030) cm] [7]. The observed value in the patient is divided by the predicted 95th centile value and multiplied by 100 to give a per cent figure, defined as SEPPER for septal thickness and LVPER for posterior wall thickness. The 95th percentile corresponds to a Z-score of + 1.96. A SEPPER value >190% (i.e. a septal Z-score >3.72) was shown to be an optimal cut-off to indicate high risk of sudden death in a large cohort study with 16 sudden deaths, with a sensitivity of 91% and a negative predictive value of 95% if the value from the latest outpatient assessment was used [35]. Odds ratio was 11.1 [95% CI 1.3–95.2], and P = 0.013, and SEPPER was found to be an independent predictor of sudden death in childhood HCM (P = 0.001) [35]. Wall thickness Z-scores were used in another smaller referral centre study, which had much fewer deaths, only three sudden deaths, and found that a wall thickness Z-score >6 predicted all-cause cardiac death, not specifically sudden death, with a hazard ratio of 3.8 (34). Because of the lower statistical power, it would be unsafe to assume from the later study that a Z-score <6 defines a low-risk patient, in particular as 86% received therapy with beta-blockers and 17/96 (18%) had an implantable cardiac defibrillator (ICD) for sudden death prevention, which may well have contributed considerably to the low rate of sudden deaths [34].

ECG for risk factor stratification in childhood HCM

Already in 1999, it was found that large electrocardiographic voltages as expressed by a large Sokolow-Lyon index was a risk factor for disease-related death in childhood HCM [7], but as many patients with HCM have dominant S-waves across the precordium, and it cannot be used in children <2 years, the ECG measure of QRS-amplitude voltage sum in all six limb-leads was in addition used in the subsequent larger cohort study, which found that the QRS-voltage sum from all six limb leads already at diagnosis was a significant risk factor for sudden death in childhood HCM (P < 0.0005) and that it was an independent risk factor from that of septal hypertrophy on Cox hazard regression [35]. A cut-off of QRS-limb-lead sum >10 mV gave an odds ratio for sudden death already at the first ECG at diagnosis of 8.4 [95% CI 2.2–33.7], P = 0.001, (see 5). Using the ECG amplitudes from latest outpatient visit, the odds ratio rises to 33.4, with a sensitivity of 94% and a negative predictive value of 97% [35]. QRS-amplitude sum is a significant risk factor for death even in adults with HCM, but with an optimal cut-off for high risk in adults which is lower, ≥7.7 mV [16]. Limb-lead voltage sum has the same normal values in both genders, unlike ECG measures that include chest leads, which makes it a suitable ECG measure for screening [16]. A multifactorial analysis identified that QRS-axis deviation, increased 12 lead QRS-amplitude x duration product, increasing QTc and T-wave inversion, particularly precordial, as well as ST-segment depression were incremental risk factors for sudden death in adults with HCM [16]. On the basis of these findings, a risk score was constructed (see Table I). A risk score ≥6 points signified a high-risk status with a sensitivity of 84% but an area under the curve better than any other ECG measure, and the specificity of 85%, as well as the positive predictive value, was better than that of any other measure [16]. This score has not yet been validated in childhood HCM, but preliminary observations suggest that it has the potential to improve specificity and positive predictive value in risk stratification in childhood HCM too (Östman-Smith, unpublished observation).

Lifestyle modifications

The European Society of Cardiology has issued recommendations about which types of sports should be avoided for patients with HCM [37], and the Italian experience suggests that pre-participation screening of athletes and lifestyle modifications for diagnosed cases of HCM have reduced the sudden deaths attributable to HCM in the Verona region [14]. A majority of children who die suddenly are engaged in some kind of physical activity at the time, and it has been reported that quite a few sudden deaths of children with HCM under follow-up are associated with violations of exercise restrictions [34], so this aspect requires persistent and consistent counselling. It is often more productive to encourage the uptake of a different and more suitable sports activity than to attempt to stop sports activity altogether.

Which beta-blocker should be chosen?

In relation to sudden deaths caused by dilated cardiomyopathy and ischaemic heart disease, it has been argued that not all beta-blockers are equally protective, in particular that hydrophilic beta-blockers (for example atenolol) are not as good as lipophilic ones (propranolol, metoprolol, bisoprolol) [38]. Propranolol has in addition to beta-adrenoceptor blocking effects also membrane-stabilizing action and increases the threshold for ventricular fibrillation [38–40], and it is my first line choice in patients exhibiting risk factors for sudden death, unless there is a history of asthma in which case metoprolol or bisoprolol can be used. Furthermore, it has been reported from adult patients with HCM that propranolol therapy reduces inappropriate vasodilation in about half of HCM patients with abnormal blood pressure response to exercise, [41], and some patients with a tendency to severe sinus bradycardia or hypotension on exertion tolerate propranolol better than beta₁-selective beta-blockers [see 6].

Which beta-blocker dose range is appropriate in children and adolescents?

Modest doses of beta-blockers were introduced for symptomatic treatment early on but did not appear to reduce sudden death mortality in adults [42]. During the 1970s, Frank et al. [43] developed a treatment approach of trying to achieve profound beta-receptor blockade, which in adult HCM patients required on average 6 mg/kg body weight of propranolol. Long-term follow-up of patients maintained in this way showed unusually low mortality rates and a low rate of serious arrhythmias [44], but they had no control groups, and this treatment was not widely taken up within adult HCM therapy. The consensus document on HCM therapy from AAHA/ESC published in 2003 suggests a dose of 2 mg/kg for children (without any references to support benefit) [17]. However, within the paediatric HCM field, it was reported in 1999, on the basis of contemporary retrospective cohorts of patients, that survival was positively correlated with increasing propranolol dose and that a high-dose propranolol regime in a dose of at least 5 mg/kg/day significantly improved survival with a hazard ratio suggesting a five- to ten-fold reduction in the risk of disease-related death [7]. It was subsequently shown that high-dose beta-blocker therapy reduces both sudden deaths and heart failure-related deaths [35]. 7 illustrates the Kaplan–Meier survival curves of patients positive on at least one of the high-risk criteria for sudden death. The high-risk patients treated with high-dose beta-blocker therapy show a significantly improved survival compared with patients on other treatments, P = 0.003, with a 10- year survival of 90.1% and 61.3%, respectively (subgroup analysis of data from [35]).

It is obviously not very likely that the protective effect of beta-blockers is an on–off effect occurring only above a particular dose level, and if you subdivide paediatric HCM patients who, because they have a higher annual mortality rate than adults, provide more statistical power to detect treatment effects on mortality into subgroups with increasing beta-blocker doses, there is an obvious trend to a dose-related gradual decrease in mortality proportions (P = 0.008 for trend) (see 8) [45]. This mortality trend parallels the effect of therapy on rate of disease progression. In untreated childhood HCM, there is on average a 25% increase in ECG and echocardiographic measures of cardiac hypertrophy over 7.5 years of follow-up, whereas with beta-blocker therapy, there is a dose-dependent effect with partial regression of hypertrophy with the largest doses, and a significant negative correlation between propranolol dose and progression/regression of hypertrophy both for ECG and ultrasound measures [45]. On mortality, it therefore appears that at least from 3 mg/kg upwards, there is some protective effect (8), even if high-dose therapy, the median dose in that group being 9.6 mg/kg, provides better protection. There is probably also an age variation in the dose required. For carvedilol, which, like propranolol, has extensive first pass metabolism by cytochrome P450 in the liver [46], drug kinetics in children have been studied in detail, and it has been shown that weight-adjusted drug clearance was 3.9 times faster in 1-year-olds compared with 19-year-olds and that infants required 4.3 times higher dose, 2- to 11-year-olds 2.9 times higher and 12- to 15-year-olds 1.4 times higher dose to maintain same plasma levels as adult patients [47]. Young children also metabolize propranolol faster than adults and furthermore have a higher sympathetic nervous activity level in general, and in young patients with very severe obstructive HCM, you may have to go as high as 23 mg/kg/BW to achieve satisfactory beta-blockade as revealed by 24-h ECG monitoring (see [7]).

How do you titrate the beta-blocker dose in the individual child?

The best tool to ascertain adequate beta-receptor blockade is to use 24 Holter monitoring, or maximal exercise tests; it is insufficient to just look at resting heart rate [7]. On 24-h Holter monitoring, one needs to look at both heart rate variability and maximal heart rates. In an infant with severe HCM, one should strive for maximal heart rate not to exceed 120/min during significant periods, whereas with an adolescent with severe HCM, it may be necessary to achieve a very flat heart rate response with a maximal heart rate below 90 beats/min for full therapeutic effect and % variability in R-R interval to remain below 5–6% (see 9). Children with less severe HCM may have adequate disease control with maximum heart rates not exceeding 110/min [7]. Surprisingly, at least with propranolol, the minimum heart rate does not fall with increasing beta-blocker dose but may instead increase slightly, may be as a result of central anti-vagal effects of propranolol. Increasing sinus bradycardia is usually only seen with very beta-₁ selective beta-blockers, particularly atenolol (Östman-Smith, unpublished observation). Using a maximal exercise test to judge beta-receptor blockade, one should aim for a maximal heart rate response of 120–140 beats/min, depending on the age of the child and the disease severity (see 3, 6).

Patient acceptability of high-dose beta-blocker therapy

Patient acceptability is best, and side effects are minimized, by a gradual build up of dose, allowing beta-receptors to up-regulate and circulating blood volume to adapt by not increasing the dose more often than about every 2–4 weeks, unless there is an urgent clinical need to move faster. With older children, one may start with 1.5 mg/day of propranolol or equivalent doses of other beta-blockers and then aim to move via 3 mg/kg and 4.5 mg/kg to 6 mg/kg, which should be the minimum target dose in a high-risk patient. In infants, you start with 3 mg/kg/day. If plain propranolol is used, it needs to be given three times daily, and it is advantageous to use slow-release capsules, preferably given twice daily, whenever dosing allows, to achieve smooth serum levels, which reduces side effects. Children followed long term on high-dose beta-blocker therapy have shown normal somatic growth and generally a good tolerance of the therapy, and only about one tenth of patients on high-dose beta-blocker therapy need to change type of beta-blocker because of side effects [7]. If you require unusually large doses to achieve clinical beta-blockade, it is helpful to monitor serum levels if assay is available, both to detect drug non-compliance and to detect individuals with unusually fast (or unusually slow) drug elimination. The serum concentrations of propranolol required in childhood HCM are usually 200–900 μg/L [7], but particularly in young children concentrations up to 1 100 μg/L are sometimes required.

Side effects of beta-blockers

Restless sleep with vivid dreams is the most common side effect complained of with propranolol [7]. Hypoglycaemia after prolonged fasting is a rare problem, five proven or suspected episodes from 430 treatment years with propranolol, but it is the only potentially serious side effect [7]. Parents should be warned to avoid fasting for more than 16 h and informed to watch out for warning symptoms of sweating and shakiness after fasting (for instance caused by intercurrent gastroenteritis) and to administer glucose- or sugar-containing drinks when hypoglycaemia is suspected. A regular meal pattern is important, and access to fruits as extra snack at school is advisable. If hypoglycaemia occurs, the patients ought to be changed to the beta₁-selective metoprolol or bisoprolol, because the impairment of glucose mobilization from glycogen is a beta₂-receptor effect. Impotence is an often mentioned side effect of non-selective beta-blockers in adult males but is only rarely encountered as a problem in adolescent and young adult males, only in 2 out of 23 individuals on non-selective beta-blockers, and in both cases, it resolved on changing to atenolol (Östman-Smith, unpublished observation). A large review about neuropsychiatric effects of cardiovascular drugs has not found any evidence of propranolol being significantly associated with depression, but on the contrary, it gave significant benefit in reducing performance anxiety [48]. Surprisingly, physical exercise tolerance is not reduced by high-dose beta-blockade in patients with HCM compared with pre-treatment values, in spite of a 30% reduction in maximal heart rate [49,50], see also 3, probably because of the beneficial effects of high-dose beta-blockers on diastolic function [51]. A total of 86% of the children reported by Decker et al. [34] were treated with beta-blockers, and 9% with calcium-channel blockers, but in spite of the medication, 66% had a normal blood pressure response to exercise. This concurs with our own observations that beta-blocker therapy does not reduce blood pressure response to exercise compared with pre-therapy blood pressure reaction [49,50], so a poor blood pressure response on exercise testing cannot be assumed to be caused by beta-blocker therapy (3).

Exchange of beta-blocker drug

If one wishes to change from a non-selective to a selective beta-blocker, one should not exchange the whole dose at once, because the beta₂-receptors are up-regulated, but do a gradual change-over with 2 weeks between each step. Propranolol, metoprolol and bisoprolol are metabolized differently, so single-dose potency tables cannot be used for guidance, and effect varies between slow- and fast-metabolizing patients. As a rough guide, propranolol and metoprolol are roughly equipotent in mg doses in children, and 80 mg propranolol can be changed to about 50 mg of atenolol, or 5 mg of bisoprolol, but it is wise to perform a new 24-h Holter recording to compare clinical beta-blockade after completed dose change.

Dose range for disopyramide in children

In terms of pharmacokinetics, disopyramide is cleared more rapidly in children than in adults [66]. Many paediatric drug dose compendiums recommend a dose of 2 mg/kg three times daily for disopyramide, but in my experience, such a low dose has never yet achieved therapeutic plasma levels. I always start with around 8 mg/kg/day, monitor QT prolongation and increase dosage every fourth day until some prolongation of QTc is apparent. If there is no QTc prolongation, you have not reached therapeutic blood levels, but QTc prolongation must never exceed a 25% increase over starting values, and unless there is a clinical need to push doses to maximum, it is safer to aim around a 10–15% prolongation. It is not uncommon to need 10–15 mg/kg/day and occasionally as much as 20 mg/kg/day to achieve therapeutic plasma levels. It is very desirable to monitor plasma levels to guide dose adjustments when using disopyramide. It combines very happily with high-dose propranolol in high-risk patients [7], and my preference would be to always add disopyramide to high-risk patients where the dynamic outflow obstruction is not controlled on high-dose propranolol alone, or where there have been non-sustained ventricular tachycardias on 24-h Holter, or exercise-induced ventricular arrhythmias on adequate beta-blocker therapy. I would use disopyramide before amiodarone for ventricular arrhythmias, as it has a short half-life and quite easily could be replaced with amiodarone after 72-h gap if ineffective, whereas once established on amiodarone therapy, it takes a much longer elimination time before you can safely introduce disopyramide.

Side effects of disopyramide

Anti-cholinergic side effects may occur particularly during the first week of therapy but then usually lessen. A dry mouth can often be relieved by intermittent use of chewing gum, and a tendency to constipation by prophylactic use of lactulose. Difficulty in emptying bladder is exceptionally rare in childhood; if it occurs, one should check serum levels because it may be possible to reduce the dose. The therapeutic range quoted for arrhythmia therapy is 6–16 (exceptionally 20) μmol/L; for adequate effect on dynamic outflow obstructions, plasma levels in the 8–13 μmol/L range are often needed (Östman-Smith, unpublished observation).

Side effects of amiodarone

It is a thyroid hormone analogue with unusual pharmacokinetics and a high incidence of side effects, some of which can be serious or even lethal [68]. In children, it is difficult to avoid toxicity even with serum level monitoring [69], and among patients with HCM in childhood, the majority had to discontinue therapy after a while because of side effects [7]. Apart from pulmonary, hepatic, skin and eye toxicity, long-term amiodarone therapy also reduces exercise tolerance and increases pulmonary artery pressure and pulmonary artery wedge pressure in patients with HCM [70].

Thus, although amiodarone may be effective short-term therapy for ventricular arrhythmias and to control paroxysmal atrial fibrillation, it is not really suitable for long-term therapy in paediatric HCM patients. Furthermore, it does not protect against sudden arrhythmia death [7,71,72], and in a recent uncontrolled comparison, the amiodarone-treated patients showed considerably higher annual mortality than patients with HCM treated with other anti-arrhythmic drugs [42].

Drug therapy for patients with ICD

Treatment with sizeable doses of beta-blockers may reduce inappropriate shocks caused by sinus tachycardia and is to be recommended, not least of course because the prevention of sudden arrhythmia death with an ICD does not cure the myocardial disease, which may also cause heart failure related death [34], unless appropriately treated medically. Effective control of supra-ventricular arrhythmias is also important in reducing risk of inappropriate shocks. Sotalol has been found to significantly reduce the number of delivered shocks in patients with ICD, [83], but its QT-prolonging effect usually precludes doses high enough to give a profound beta-receptor blockade. However, it can of course be combined with another beta-blocker for more effective beta-blockade. An additional consideration for patients on amiodarone therapy is that amiodarone increases defibrillation threshold for monophasic ICD devices [83].

Indications for primary prevention ICD in childhood

There is really no consensus yet about indications in children, but my own view would be that a child who has at least two risk factors remaining while established on therapy with high-dose beta-blockers, and disopyramide in effective doses, should be at least discussed for an ICD implantation, in particular if there is a malignant family history of sudden deaths at a very young age.