Successful Everolimus Therapy for Atrioventricular Block Due to Cardiac Rhabdomyoma Associated With Tuberous Sclerosis Complex

Abstract

Background

Cardiac rhabdomyoma (CR) associated with the tuberous sclerosis complex can cause atrioventricular (AV) block (AVB) by compressing the AV node. Everolimus, an mTOR inhibitor, is known to shrink these tumors and alleviate obstruction and tachycardia; however, improvement in AVB has not been previously described.

Case Summary

A 25-year-old woman was found to have a fetus with subependymal nodules and multiple CRs. After birth, an electrocardiogram demonstrated a persistent 2:1 AVB with a ventricular rate of 60 to 70 beats/min. Echocardiography revealed CRs, including one near the AV node. Everolimus was initiated before considering permanent pacemaker implantation. CRs regressed on echocardiography, and the AVB resolved. After discontinuation of everolimus, no tumor regrowth was observed.

Discussion

In this case, the AVB resolved with rhabdomyoma regression. Although permanent pacemaker implantation was initially considered, everolimus successfully prevented further therapy.

Take-Home Message

Everolimus may be a therapeutic option for AVB due to CR compressing the AV node.

Visual Summary

Visual Summary.

Timeline of the Case

AV = atrioventricular; MRI = magnetic resonance imaging; TSC = tuberous sclerosis complex.

History of Presentation

A 25-year-old pregnant woman with no perinatal complications and no family history of tuberous sclerosis complex (TSC) was found to have a fetus with multiple intracardiac masses as well as subependymal and cortical nodules, raising prenatal suspicion of TSC on fetal echocardiography and maternal magnetic resonance imaging (MRI) at 27 weeks of gestation. Fetal bradycardia was observed at 37 weeks of gestation, prompting emergency cesarean delivery. At birth, the baby's length and weight were 44.5 cm and 2,092 g, respectively. The initial physical examination exhibited no signs of heart failure or respiratory distress.

Differential Diagnosis

Given the tumor's proximity to the atrioventricular (AV) node, mesothelioma and other tumors were considered. However, the presence of multiple intracardiac tumors and intracranial lesions culminated in the diagnosis of cardiac rhabdomyoma (CR) associated with TSC.¹

Investigations

The initial electrocardiogram (ECG) showed a persistent 2:1 AV block (AVB) with a ventricular rate of 60 to 70 beats/min (Figure 1A). Transthoracic echocardiography revealed multiple intracardiac tumors consistent with CR. A prominent 10.5 × 8.0 mm mass was located in the AV septal region adjacent to the expected location of the AV node (Figure 2A, Video 1). Biventricular systolic function was preserved. No right or left ventricular outflow tract obstruction or significant AV valve regurgitation was observed. No additional imaging, such as computed tomography or cardiac MRI, was performed.

Figure 1.

Findings on Serial Electrocardiography

(A) Electrocardiogram on day 0. A 2:1 AV block was observed, with a heart rate of 60 beats/min. (B) Electrocardiogram on day 35. The rhythm transitioned from a 2:1 to a 3:2 AV block, consistent with a Mobitz type 1 AV block. The red arrowheads indicate P waves, and the yellow arrowheads indicate QRS complexes. (C) Electrocardiogram on day 55. An improvement in AV block was observed. (D) Electrocardiogram on day 80. Sinus rhythm was consistently maintained. (E) Electrocardiogram at 18 months. Intermittent AV block was observed. AV = atrioventricular.

Figure 2.

Findings on Serial Echocardiography

(A) Echocardiogram on day 0. Multiple CRs were present within the ventricles, including one located near the AV node. (B) Echocardiogram on day 35. A reduction in the size of all CRs was confirmed. (C) Echocardiogram on day 55. Complete regression of both the CR near the AV node and all other ventricular CRs were confirmed. The yellow circle indicates the CR located near the AV node. AV = atrioventricular; CR = cardiac rhabdomyoma.

Brain MRI revealed subependymal nodules, subcortical nodules, and cortical malformations predominantly in the frontal and parietal lobes (Figure 3).

Figure 3.

Brain Magnetic Resonance Imaging

Subependymal and subcortical nodules, along with cortical dysplasia that mainly affected the frontal and parietal lobes, were identified.

Based on the major clinical criteria of CR, subependymal nodules, and cortical malformation, the patient met the diagnostic criteria for TSC.²

Management

From day 0 of life, a 2:1 AVB persisted, with the ventricular rate fluctuating from 60 to 120 beats/min and dipping to 50 beats/min during sleep on day 2. Despite stable ventricular function on echocardiography and the absence of acidosis or hyperlactatemia on blood gas analysis, further bradycardia was anticipated to precipitate circulatory compromise. Continuous intravenous isoproterenol was initiated at 0.02 μg/kg/min. AV conduction improved modestly but remained unstable, with alternating periods of 1:1 and 2:1 conduction. Temporary isoproterenol cessation led to a recurrent 2:1 AVB, with a heart rate of 60 to 70 beats/min. Oral denopamine at 0.2 mg/kg/d was attempted without benefit, necessitating isoproterenol resumption.

Given the patient's dependence on chronotropic support, permanent pacemaker (PPM) implantation was considered. Nevertheless, the neonatal status and low body weight of the patient, combined with the long-term risks of device therapy in infants (infection, lead failure, pocket complications, and repeated generator replacements), prompted the exploration of a disease-modifying approach. Despite the lack of evidence for bradyarrhythmia, we considered everolimus, an mTOR inhibitor with established efficacy in shrinking CRs and relieving outflow obstruction or tachyarrhythmias, a plausible option for relieving nodal compression and restoring AV conduction.³

To mitigate the risk of supratherapeutic concentrations reported in neonates, we initiated low-dose everolimus at 0.5 mg/m² once daily, lower than the typical starting dose of 3 mg/m².⁴ Everolimus therapy was initiated on day 15 with ongoing isoproterenol infusion, and everolimus dosing thereafter was titrated based on therapeutic drug monitoring.

Outcome and Follow-Up

On day 30, AV conduction started improving gradually, and the rhythm evolved from a fixed 2:1 AVB to a 3:2 pattern (Figure 1B). The 3:2 AVB exhibited a Mobitz type 1 pattern. Echocardiography obtained on day 35 confirmed tumor size reduction (Figure 2B).

By day 45, the patient had achieved sustained 1:1 AV conduction (Figure 4). Serial echocardiography revealed regression of the rhabdomyoma surrounding the AV nodal region (Figure 2C, Video 2).

Figure 4.

Clinical Course

Heart rate (HR) indicates the range from the minimum to the maximum HR recorded in 1 day. Isoproterenol was started on day 2 because the AV block persisted after birth. AV conduction improved slightly with isoproterenol administration; however, the minimum HR remained at approximately 60 beats/min. Therefore, everolimus was administered on day 15. From day 30, AV conduction gradually improved, transitioning from a 2:1 to a 3:2 AV block. From day 45, sinus rhythm was observed. On day 51, everolimus was discontinued, with no signs of AV block recurrence during the follow-up period. AV = atrioventricular.

After the stabilization of the intrinsic rhythm and AV conduction, the concomitant isoproterenol therapy was ceased on day 41. After confirming 1:1 conduction persistence without AVB, everolimus was discontinued on day 50. The ECG on day 55 showed normal AV conduction (Figure 1C).

The total duration of everolimus therapy was 36 days. The trough serum concentration ranged from 7.1 to 10.5 ng/mL, which was within the normal range. No severe adverse events required treatment interruption. Hemoglobin declined from 12.0 to 8.3 g/dL but improved with oral iron and subcutaneous injection of erythropoietin supplement. There were no dermatological or gastrointestinal adverse effects, and feeding tolerance and weight gain were appropriate throughout the treatment.²

The patient was evaluated at our institution until day 70, during which AV conduction was maintained. The family subsequently relocated, and follow-up was continued at a local facility. An ECG was obtained at the discretion of the referring physician on day 80 (30 days after treatment discontinuation), which demonstrated normal sinus rhythm (Figure 1D). However, the ECG recorded on day 99 showed intermittent AVB. Echocardiography revealed no enlargement of the CRs. At 18 months of age, intermittent AVB persisted on ECG (Figure 1E), but the patient remained asymptomatic with no evidence of bradycardia.

Throughout this period, the patient was managed conservatively without reinitiation of everolimus therapy or PPM implantation. Genetic testing revealed a pathogenic TSC2 variant, confirming TSC presence at the molecular level.

Discussion

The present case demonstrates a mechanistically coherent sequence: a rhabdomyoma adjacent to the AV node regressed with everolimus, and AV conduction improved concurrently, progressing from a 2:1 AVB to stable 1:1 conduction. Synchronized structural and electrophysiological changes strongly suggest that relief from mechanical or vascular compression of the AV node is fundamental to recovery. It has been shown that CRs located near the AV node or sinus node can induce bradycardia by compressing these nodes or their supplying arteries.⁵ Although causality cannot be proven in a single case, the temporal association, anatomic plausibility, and absence of alternative explanations support everolimus as a decisive intervention.

Although an electrophysiological study was not performed and a definitive diagnosis could not be established, the AVB in this case was most consistent with a nodal block. The observations of stable QRS duration without the emergence of bundle branch block, improvement in AV conduction with sympathetic stimulation such as isoproterenol infusion, and the Mobitz type 1 AVB collectively argue against an infranodal block and support a nodal level of impairment.⁶

Some studies have noted improvement of outflow tract obstruction and tachyarrhythmias, such as supraventricular tachycardia, after everolimus administration in patients with CR.^7,8 However, none have been conducted on the efficacy of everolimus for bradyarrhythmias associated with CR. To the best of our knowledge, this represents the first report in which AVB was successfully ameliorated by everolimus, thereby circumventing the need for a PPM.

The fundamental treatment for bradyarrhythmias is PPM implantation, which is also considered an effective therapy for bradyarrhythmias associated with CR. However, the indication for PPM in cases of CR should be determined by considering the characteristics of TSC. TSC is a disease that is often diagnosed in childhood, and CR may regress spontaneously over time.² Given the possibility that CR regression could lead to improvement in AV node function, we prioritized everolimus therapy over PPM. In general, PPM implantation in pediatric patients is associated with a higher incidence of complications such as infection and device failure.⁹ Furthermore, as this case involved a neonate, these risks were particularly significant, and thus everolimus was administered as the initial treatment.

For CR-related bradycardia, in which a discrete mass abuts the conduction system, a short, closely monitored trial of everolimus may be reasonable before PPM implantation, provided that the hemodynamics are stable or stabilizable and vigilant monitoring is ensured. This strategy seeks to modify the underlying substrate rather than merely pacing through it and may avert or defer device implantation if conduction recovers. Nevertheless, the duration of therapy with mTOR inhibition remains unknown. Tumor regrowth after cessation has been described, underscoring the need for structured surveillance.¹⁰ In our patient, we opted for a relatively short course (36 days), discontinuing treatment after sustained recovery of 1:1 conduction and the onset of anemia, which responded to oral iron and subcutaneous injection of erythropoietin therapy. Given the emergence of intermittent AVB after discontinuation of therapy, including its reappearance at 50 days, we recommend a follow-up plan that includes more frequent and detailed ECG surveillance in addition to periodic ECGs, ambulatory monitoring, and serial echocardiography to reassess the tumor burden.

This case adds to the therapeutic spectrum of everolimus for TSC-associated cardiac diseases. Beyond its recognized role in relieving outflow obstruction and suppressing tachyarrhythmia, everolimus may, in selected anatomical contexts, permit recovery from AVB by shrinking the mass compressing the AV node. The decision to attempt mTOR inhibition before initiating PPM should consider patient size and comorbidity, the anatomical relationship between the CR and the conduction tissue, the feasibility of close monitoring, and the preferences of the family after an informed discussion of benefits and risks.

Conclusions

In a neonate with TSC, a CR encasing the AV nodal region caused a 2:1 AVB that resolved after a short course of everolimus, thereby obviating permanent pacing. The likely mechanism involved the relief of mechanical and/or vascular compression of the AV node or its arterial supply. A carefully supervised, time-limited everolimus course may be considered before PPM in selected infants with CR-related AVB, particularly when a discrete lesion involves the AV node, and hemodynamics can be safely maintained during therapy.

Data Availability

Data supporting the findings of this case report are available from the corresponding author upon request.

Statement of Consent

On November 11, 2023, patient consent was obtained for publication, as documented in the medical records.

Ethics Approval Statement

As of October 12, 2025, our hospital no longer requires institutional review board approval to submit case reports. No internal approval was obtained for this study.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Take-Home Messages

• •In patients with tuberous sclerosis complex, cardiac rhabdomyomas abutting the AV node can cause a clinically significant AV block. Targeted mTOR inhibition may reverse conduction disturbance by shrinking the compressive mass, potentially avoiding permanent pacemaker implantation.
• •A short, monitored trial of everolimus should be considered before pacemaker implantation when the anatomy suggests nodal compression.

Appendix

Video 1

Echocardiographic Video on Day 0

Echocardiography revealed multiple cardiac rhabdomyomas within the heart, one of which was located at the AV node. The left ventricular contraction was well preserved. AV = atrioventricular.

Video 2

Echocardiographic Video on Day 55

Echocardiography demonstrated complete disappearance of all previously identified intracardiac rhabdomyomas after treatment. Left ventricular contraction was well preserved.