Beta-Blockers in Pediatric Hypertrophic Cardiomyopathies

Abstract

Congestive cardiac failure accounts for 36% of childhood deaths in hypertrophic cardiomyopathy, and in infants with heart failure symptoms before two years of age, the mortality is extremely high unless treatment with beta-receptor antagonists is instituted. The mechanism of heart failure is not systolic dysfunction, but rather extreme diastolic dysfunction leading to high filling pressures.Risk factors for development of heart failure are a generalized pattern of hypertrophy with a left ventricular posterior wall-to-cavity ratio >0.30, the presence of left ventricular outflow tract obstruction at rest, and the co-existence of syndromes in the Noonan/Leopard/Costello spectrum. The 5-year survival of high-risk patients is improved from 54% to 93% by high-dose beta-blocker therapy (>4.5 mg/kg/day propranolol). The mechanism of the beneficial effect of beta-blockers is to improve diastolic function by lengthening of diastole, reducing outflow-obstruction, and inducing a beneficial remodelling resulting in a larger left ventricular cavity, and improved stroke volume. Hypertrophic cardiomyopathy is associated with increased activity of cardiac sympathetic nerves, and infants in heart failure with hypertrophic cardiomyopathy show signs of extreme sympathetic over-activity, and require exceptionally high doses of beta-blockers to achieve effective beta-blockade as judged by 24 h Holter recordings, often 8-24 mg/kg/day of propranolol or equivalent. Conclusion: Beta-blocker therapy is without doubt the treatment of choice for patients with heart failure caused by hypertrophic cardiomyopathy, but the dose needs to carefully titrated on an individual basis for maximum benefit, and the dose required is surprisingly large in infants with heart failure due to hypertrophic cardiomyopathy.

Trends in the off‐label use of β‐blockers in pediatric patients

“…Heart failure accounts for approximately 30% to 40% of childhood deaths in patients with hypertrophic cardiomyopathy (HCM) . There are no FDA‐approved drugs for this condition, which is conventionally treated by β‐blockers in combination with other medications.…”

“…Atenolol can also be used in HCM, but its use is debatable in patients at risk for arrhythmias and heart failure. Carvedilol is avoided due to the risk of hypotension associated with α‐blockade . A second study reported three deaths in patients not treated with β‐blockers compared to 10 survivors that had received β‐blocker for persistent idiopathic HCM .…”

“…It has been observed that children with HCM and heart failure respond to higher doses of β‐blockers. The dose range reported to be effective in studies and case reports is variable, ranging from 4.5 to 24 mg/kg/day (Table ) . The evidence suggests that not all β‐blockers are equally effective in preventing the progression of myocardial hypertrophy in HCM.…”

“…The evidence suggests that not all β‐blockers are equally effective in preventing the progression of myocardial hypertrophy in HCM. For example, atenolol was found to be ineffective in clinical trials …”

“…Heart failure accounts for approximately 30% to 40% of childhood deaths in patients with hypertrophic cardiomyopathy (HCM). 29 There are no FDA-approved drugs for this condition, which is conventionally treated by b-blockers in combination with other medications. The rationale for the use of b-blockers is the increased sympathetic nervous system activity in HCM, which can be inhibited by b-blockers leading to symptomatic improvement.…”