mTOR Inhibitors Shrink Dangerous Heart Tumors in Newborns by Over Half

Cardiac rhabdomyoma (CR) is the leading cardiac tumor of childhood, with 75% of cases occurring in infants under one year old and an incidence in newborns estimated at 0.02–0.08%. Between 60–80% of cases are associated with tuberous sclerosis complex (TSC), an autosomal dominant disorder in which mutations in TSC1 or TSC2 genes dysregulate the mTOR pathway, driving abnormal cell proliferation. When CRs obstruct ventricular outflow tracts or trigger uncontrollable arrhythmias, the consequences can be rapidly fatal. Surgery offers resolution but carries substantial procedural risk in neonates. This systematic review, the first of its kind, aimed to synthesize evidence on the safety and efficacy of mTOR inhibitors — specifically everolimus and sirolimus — as a non-surgical intervention for hemodynamically significant CRs in newborns and infants.

The authors searched EBSCO, PubMed, EMBASE, and Lilacs for articles published through July 2023. From an initial 407 identified records, 31 articles met inclusion criteria, encompassing 48 individual patient cases. Studies spanned 2012–2023 and originated predominantly from Asia (54%), followed by North America (21%), Europe (13%), Latin America (10%), and Oceania (2%). Study designs included case reports (58%), case series (31%), and case-control studies (10%). Methodological quality was assessed using the Joanna Briggs Institute critical appraisal checklist for case reports. Because of significant heterogeneity across studies, formal meta-analysis was not feasible, and results were synthesized descriptively.

The patient cohort was 70.4% male, with a median birth weight of 2,927 grams. Approximately 54% were full-term neonates, and 46% were preterm. Multiple CRs were present in 72.9% of cases, most commonly located in the left ventricular outflow tract (36.1%) and right ventricular cavity (27.6%). Hemodynamic instability was the primary reason for initiating mTOR inhibitor therapy in 89.6% of cases, with combined hemodynamic instability and arrhythmia in 6.25%, and isolated arrhythmia in 4.2%. Treatment was initiated at a median age of 6 days of life (Q1=3, Q3=18), reflecting the urgency of the clinical situation.

Everolimus was administered in 83.3% of cases at an average daily dose of 1.03 mg/m²/day, while sirolimus was used in 16.7% at 1.37 mg/m²/day. The median treatment duration was 67 days. The combined result across cases was an average CR size reduction of 57 ± 23%, a clinically substantial effect that translated to hemodynamic stabilization and arrhythmia resolution in most patients. Adverse effects were observed and included hypertriglyceridemia, infections, and hematological abnormalities, but these were generally manageable and did not consistently require treatment discontinuation. No deaths directly attributable to drug toxicity were reported.

The clinical implications are meaningful: this review supports off-label use of mTOR inhibitors as a bridge or alternative to surgery in critically ill neonates with obstructive CRs. Average dosing parameters established here can guide practitioners in the absence of formal guidelines. However, the evidence base is composed entirely of observational reports and case series — no randomized controlled trials exist. Heterogeneity in dosing protocols, monitoring approaches, and outcome reporting limits the strength of conclusions. The authors call explicitly for well-designed RCTs to establish optimal dosing, treatment duration, and long-term safety in this vulnerable population.