Ingegerd Östman-Smith

Age- and gender-specific mortality rates in childhood hypertrophic cardiomyopathy

AIMS Hypertrophic cardiomyopathy (HCM) is the commonest inherited cause of sudden cardiac death in children; current guidelines suggest HCM screening after 12-15 years of age. The study aims to establish the age range at highest risk. METHODS AND RESULTS Cohort study from six regional centres of paediatric cardiology, including children presenting with sudden death; n = 150 (59% = male; 39% familial HCM). Age- and gender-specific mortality was calculated, and compared with rates calculated from the Swedish National Cause of Death Registry. There were 56 deaths within the cohort, 39 were sudden arrhythmia deaths, with 31 at <19 years of age. Between 9-13.9 years of age annual sudden death mortality averages 7.2%, vs. 1.7% after 16 years of age; P = 0.025, odds ratio for proportions 3.75 [95% confidence intervals (CI) 1.18-11.91], similar in both familial and idiopathic HCM. The risk for sudden death peaks earlier in girls (10-11 years), with male preponderance after the age of 15. National cause of death statistics confirm that the mortality rate from HCM is significantly higher in the 8-16 year olds (0.112 per 100,000 age-specific population) than in the 17-30 year olds (0.055 per 100,000; 95% CI 0.011-0.099). CONCLUSION In families with HCM, children should be screened at an early age.

Echocardiographic and electrocardiographic identification of those children with hypertrophic cardiomyopathy who should be considered at high-risk of dying suddenly

BACKGROUND Hypertrophic cardiomyopathy is a common cause of sudden death in children. In this study, we aimed to identify clinical measures for stratification of this risk in childhood. PATIENTS AND METHODS By means of a retrospective cohort study from six regional centres of paediatric cardiology, we identified 128 patients with hypertrophic cardiomyopathy presenting below 19 years of age, with a mean follow-up of 10.8 years. Of the patients, 31 had died, 16 suddenly, with a median age at sudden death of 13.3 years. RESULTS Cox regression shows that electrocardiographic voltages, analysed as the sum of the R and S waves in all six limb leads (p equal to 0.001), and septal thickness expressed as proportion of the 95th centile for age (p equal to 0.036), were independent predictors of sudden death. When the sum of the R and S waves is over 10 millivolts, the odds ratio for sudden death was 8.4, with 95% confidence intervals from 2.2 to 33.7 (p equal to 0.0012), and finding a septal thickness over 190% of 95th centile for age gives an odds ratio of 6.2, with confidence intervals from 1.5 to 25.1 (p equal to 0.011). Noonans syndrome, with a p value equal to 0.043, and the ratio of the left ventricular wall to its cavity in diastole, with a p value equal to 0.005, were independent predictors of death in cardiac failure, with a ratio of the mural thickness to the dimension of the cavity over 0.30 giving an odds ratio of 36.0, with confidence limits from 4.2 to 311, and a p value equal to 0.00009. At follow-up, patients deemed to be at a high risk of dying suddenly were identified by the combination of the sum of the R and S waves greater than 10 millivolts and septal thickness over 190%, with a sensitivity of 91%, specificity of 78%, positive predictive value of 50%, and a negative predictive value of 97%. CONCLUSIONS Children at high risk of dying suddenly with hypertrophic cardiomyopathy, with a subsequent annual mortality of 6.6%, can be distinguished at the time of diagnosis from those patients having a low risk of sudden death, the latter with an annual mortality of 0.27%.

Pathophysiology of hypertrophic cardiomyopathy

Sir—A J Marian (Jan 1, p 58) postulates that cardiac contractility is decreased in hypertrophic cardiomyopathy (HCM) and that the preserved or increased ejection fraction observed in patients with HCM is a result of the concentric nature of the hypertrophy. Marian predicts that study of young patients with familial HCM will reveal decreased myocyte contractility and postulates that insulin-like growth factor-1 (IGF-1) is upregulated and a major contributor to the pathological manifestations of HCM. To test these predictions we looked at echo-cardiographic measurements on our data bases of normal children and children with concentric left ventricular hypertrophy of different aetiologies. In the table we compare normal infants (InfCon; mean [SD] age 0·30 [0·30] years), with infants of diabetic mothers with secondary hypertrophic cardiomyopathy (InfDM; age 0·02 [0·04] years) and with infant presentation of primary HCM (InfHCM; age 0·34 [0·30] years). The infants with primary HCM do not show any reduction in contractility and, indeed, their ejection fraction is significantly higher than that of normal infants. This result is not simply secondary to concentric hypertrophy since the infants of diabetic mothers, which display non-dilated hearts with hypertrophy of the same magnitude, show ejection fractions that are lower than those of normal infants and of infants with true primary HCM. Secondly, we compare prepubertal children with familial non-obstructive HCM (FamHCM; mean age 3·7 [3·6] years) with normal children (ChildCon; age 4·3 [3·4] years) and with children with compensatory concentric cardiac hypertrophy occurring in response to valvar aortic stenosis (AoSten; age 3·3 [0·9] years. This comparison shows that young patients with mild HCM, with a wall thickness still well within normal limits for adults, already have increased systolic contractility compared with normal children and the same contractility as hearts working against a fixed obstruction (table). There seems to be no evidence to support the contention that myocardial contractility is decreased in HCM. Furthermore, concentric hypertrophy caused by excess of insulin and IGF-1 is associated with reduced rather than increased ejection fraction. An alternative hypothesis to that of Marian’s for explaining the pathophysiology in HCM is that the abnormal contractile proteins associated with HCM trigger a reflex increase in sympathetic nervous activity to the heart, possibly because of alterations in characteristics of diastolic filling. Increased cardiac sympathetic nervous activity is probably the final common pathway in the induction of most forms of adaptive cardiac hypertrophy, including pressureoverload of the left ventricle. In keeping with our hypothesis, it has been shown that increased activity of cardiac sympathetic nerves occurs in patients with HCM. The attraction of our hypothesis is that it offers a clinical approach to modify disease progression with pharmacological intervention: administration of highdose -adrenoceptor antagonist therapy. Such treatment does seem to reduce disease progression, and is associated with significantly better survival in patients with childhood presentation of hypertrophic cardiomyopathy. In view of the striking survival advantage seen in children, high-dose -blockade deserves wider evaluation in adult HCM too.