Tailored optimal dosing of angiotensin‐converting enzyme inhibitors and β‐blockers in infantile dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a cardiac disorder characterized by ventricular dilatation and systolic dysfunction and is the leading indication for heart transplantation. Recently, the efficacy of angiotensin-converting enzyme (ACE) inhibitors and β-blockers for pediatric DCM has been reported1, 2; however, the optimal dosage in children, particularly in infants, has not been fully elucidated. Here, we report two cases of infantile DCM in which the administration of tailored optimal dosing of ACE inhibitors and β-blockers led to effective clinical outcomes. A 10-month-old female infant presenting with cardiogenic shock was admitted to our hospital (Figure 1a). Brain natriuretic peptide (BNP) was markedly elevated at 10,848 pg/mL. Chest X-ray revealed cardiomegaly (Figure 1b). Echocardiography showed left ventricular dilatation with a left ventricular end-diastolic dimension (LVEDD) of 47.2 mm (Z-score + 6.26) and systolic dysfunction with an ejection fraction (EF) of 10%. A chest X-ray obtained at a local hospital 19 days earlier similarly demonstrated cardiomegaly. The patient was diagnosed with idiopathic DCM and treated with mechanical respiratory support, sedation, dobutamine, olprinone, and diuretics. She was extubated on the hospital Day 7. Cilazapril was initiated at a dose of 0.003 mg/kg/day after confirming stable blood pressure and urine output following acute-phase management, and was carefully up-titrated by 0.003–0.005 mg/kg/day every 3–7 days. Carvedilol was initiated at a dose of 0.03 mg/kg/day once BNP levels decreased to below 500 pg/mL, and was carefully up-titrated by 0.01 mg/kg/day at weekly intervals while closely monitoring for further deterioration in cardiac function and confirming a reduction in heart rate. The final doses of cilazapril and carvedilol were increased to 0.1 mg/kg/day and 1.0 mg/kg/day, respectively. As a result, olprinone was successfully discontinued, and the patient was subsequently discharged from the hospital. Left ventricular dilatation and systolic dysfunction gradually improved over time (Figure 1c). After cilazapril became commercially unavailable, enalapril was introduced at 0.4 mg/kg/day, achieving similar clinical outcomes. A 6-month-old female infant with labored breathing and ventricular dilatation was admitted to our hospital (Figure 1d). There was no history of preceding infection. BNP was elevated at 653 pg/mL. Chest X-ray showed cardiomegaly (Figure 1e), and echocardiography revealed left ventricular dilatation (LVEDD 48.6 mm, Z-score +7.38) with reduced systolic function (EF 19%). The patient was diagnosed with idiopathic DCM and initially treated with olprinone and diuretics. Enalapril was initiated at a dose of 0.05 mg/kg/day after confirming stable blood pressure and urine output. Carvedilol was initiated at a dose of 0.015 mg/kg/day once BNP levels demonstrated a decreasing trend and had declined to below 500 pg/mL. Enalapril was carefully up-titrated by 0.05 mg/kg/day at weekly intervals, and carvedilol was cautiously increased by 0.015–0.05 mg/kg/day at weekly intervals, while closely monitoring to confirm the absence of any deterioration in cardiac or renal function. Enalapril and carvedilol were ultimately up-titrated to 0.8 mg/kg/day and 0.4 mg/kg/day, respectively, resulting in the discontinuation of olprinone and the patient's subsequent discharge from the hospital. The dose of carvedilol was not increased beyond 0.4 mg/kg/day due to the reduction in heart rate, with the resting heart rate being approximately 90 beats/min. Over time, left ventricular dilatation and systolic dysfunction gradually improved (Figure 1f). The upper limit of the standard dosage of ACE inhibitors and β-blockers in children is primarily determined based on findings from small-scale clinical studies, and is 0.04 mg/kg/day for cilazapril, 0.4 mg/kg/day for enalapril, and 0.4 mg/kg/day for carvedilol.3-5 In our cases, the maximum administered dosages of cilazapril, enalapril, and carvedilol for the treatment of infantile DCM were 0.1 mg/kg/day, 0.8 mg/kg/day, and 1.0 mg/kg/day, respectively, exceeding the commonly recommended doses in current guidelines. Dose escalation was associated with marked improvement in cardiac function and clinical status, highlighting that individualized optimization of drug dosing may be essential when conventional doses prove insufficient. Thus, in infantile DCM treatment, continuous assessment of ACE inhibitors and β-blockers is essential for tailored optimal dosing, with vigilant monitoring for adverse effects and careful attention to the potential risk of hemodynamic instability from over-titration—specifically, heart rate and ventricular function for β-blockers, and renal function and urine output for ACE inhibitors. We hope that sharing these practical considerations will help clinicians manage similar challenging cases more safely and effectively. YM wrote the original manuscript. JA, HY, and AT reviewed and edited the manuscript. YM, JA, HY, and AT treated the patients. AT supervised the study. All authors read and approved the final manuscript. This work was supported, in part, by JST SPRING (YM, grant number JPMJSP2119). The authors declare no conflict of interest. Written informed consent was obtained from the parents of the patients prior to the publication of this paper. The data that support the findings of this study are not publicly available due to the nature of the case report and to protect patient privacy. Further information may be available from the corresponding author upon reasonable request and with appropriate ethical approvals.