Cardiac rhabdomyoma is the most common neonatal cardiac tumor and is typically associated with tuberous sclerosis complex (TSC). Although these tumors may naturally regress, some patients require surgical resection because of cardiac instability. If not fully resected, patients may also require medical therapy to improve their hemodynamics. Everolimus, a mammalian target of rapamycin inhibitor, has shown promise in reducing rhabdomyoma in patients with TSC, but the drug’s impact in patients without TSC has not been reported. Monitoring of tumor response has typically been limited to echocardiograms, which is not ideal given inherent difficulties in three-dimensional measurements. We report a case of sporadic cardiac rhabdomyoma in a neonate treated with everolimus resulting in tumor regression as documented by cardiac MRI. While on everolimus, our patient had an increased incidence of a preexisting arrhythmia, which resolved with planned cessation of therapy, suggesting that close monitoring is imperative in patients with arrhythmia.

Cardiac rhabdomyoma is the most common neonatal cardiac tumor and is frequently associated with tuberous sclerosis complex (TSC).1 The natural history of cardiac rhabdomyomas is slow spontaneous regression; however, surgery is the standard treatment for tumors that significantly decrease myocardial function, result in ventricular outflow obstruction, or cause arrhythmias.1,4 Unfortunately, some cardiac rhabdomyomas develop in regions that are not amenable to surgical intervention and require medical therapy to improve cardiac hemodynamics.

The recent understanding of TSC pathophysiology has revealed that intracellular signaling via the mammalian target of rapamycin (mTOR) pathway plays an important role in the development of rhabdomyomas; however, the role of mTOR in sporadic rhabdomyoma is not known.5,6 As such, several case reports have revealed that mTOR inhibitors such as everolimus can accelerate the regression of cardiac rhabdomyoma in patients with symptomatic TSC-associated cardiac rhabdomyoma in an inoperable site.1 The effect of mTOR inhibitors on sporadic rhabdomyoma or rhabdomyoma-associated ventricular arrhythmia has not been reported. The echocardiogram is the current standard for characterizing pediatric cardiac tumors; however, cardiac MRI (CMRI) use is becoming more common. Despite this, the use of CMRI in cardiac rhabdomyoma is not reported. There is a paucity of data on the use of everolimus to facilitate the regression of cardiac rhabdomyoma in patients with significant or malignant arrhythmias.

Our patient presented at 3 weeks old with a 1-day history of poor feeding and lethargy. The patient was found to be in cardiogenic shock, with wide complex tachycardia with a right bundle branch block (Fig 1). A two-dimensional echocardiogram revealed a large multilobed echogenic mass arising from the interventricular septum (Fig 2). Although the mass significantly extended into the left ventricle and right ventricular outflow tract with depressed biventricular function, it did not cause significant outflow tract obstruction. Tumor debulking at 4 weeks of age resulted in normalization of biventricular function with no residual outflow tract obstruction. Pathology revealed the mass to be a cardiac rhabdomyoma with large rounded cells with the prominent cytoplasmic vacuolization (typical spider cells) of rhabdomyoma (Fig 3). Testing results for TSC were negative for mutations in TSC 1 and TSC 2, and brain MRI results were normal, without findings suggestive of TSC.

FIGURE 1

Cardiac rhythm revealing wide complex tachycardia with a right bundle branch block. Twelve lead EKG consisting of 3 bipolar limb leads (I, II, III), 3 unipolar limbs leads (augmented vector right [aVR], augmented vector left [aVL], augmented vector foot [aVF], and unipolar chest leads [V1–V7, V3r, and V4r])

FIGURE 1

Cardiac rhythm revealing wide complex tachycardia with a right bundle branch block. Twelve lead EKG consisting of 3 bipolar limb leads (I, II, III), 3 unipolar limbs leads (augmented vector right [aVR], augmented vector left [aVL], augmented vector foot [aVF], and unipolar chest leads [V1–V7, V3r, and V4r])

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FIGURE 2

Echocardiogram revealing large multilobed echogenic mass arising from the interventricular septum. bpm, beats per minute; FR, frame rate; M4, gray scale setting Map 4; P, penetration; R, resolution.

FIGURE 2

Echocardiogram revealing large multilobed echogenic mass arising from the interventricular septum. bpm, beats per minute; FR, frame rate; M4, gray scale setting Map 4; P, penetration; R, resolution.

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FIGURE 3

Pathologic specimen revealing large rounded cells with prominent cytoplasmic vacuolization and spider cells, diagnostic for rhabdomyoma (hematoxylin and eosin stain; original magnification ×200).

FIGURE 3

Pathologic specimen revealing large rounded cells with prominent cytoplasmic vacuolization and spider cells, diagnostic for rhabdomyoma (hematoxylin and eosin stain; original magnification ×200).

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The patient was discharged at 5 weeks of age. Holter monitoring at 3 and 7 months of age revealed a normal sinus rhythm with a right bundle branch block, and the echocardiogram revealed that the cardiac rhabdomyoma was stable in size. At 10 months of age, Holter monitoring revealed frequent runs of nonsustained polymorphic ventricular tachycardia (VT) (5% burden of VT), with the longest run being 5 beats at 169 beats per minute and the fastest run being 3 beats at 207 beats per minute (Fig 4). Although asymptomatic at the time, the patient was admitted to begin amiodarone, and the decision was made to initiate everolimus in an attempt to decrease the tumor burden and potentially alter the frequency of the VT. Amiodarone was started at a loading dose of 10 mg/kg twice per day for 5 days followed by maintenance of 5 mg/kg twice per day. Everolimus (0.25 mg; 0.08 mg/m2 per day) was started once per day, 2 days per week with a target trough range of 8 to 10 ng/mL. This was a 50% dose reduction from previous case reports because of a concern for drug interaction with amiodarone. A baseline echocardiogram and CMRI were obtained to accurately define the tumor burden. With weekly monitoring of everolimus levels, serum chemistry, and blood counts, the everolimus dose was titrated until therapeutic levels were reached after 3 months of therapy.

FIGURE 4

Holter monitor at 10 months of age before initiating everolimus therapy with frequent runs of nonsustained polymorphic VT. Overriding N and V demonstrate the monitor's interpretation of normal sinus rhythm and ventricular rhythm, respectively.

FIGURE 4

Holter monitor at 10 months of age before initiating everolimus therapy with frequent runs of nonsustained polymorphic VT. Overriding N and V demonstrate the monitor's interpretation of normal sinus rhythm and ventricular rhythm, respectively.

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Holter monitoring 3 weeks after initiation of the everolimus showed increased incidence of asymptomatic nonsustained polymorphic VT (9%). The VT persisted and increased in frequency at 2 months (14%) and 3 months (43%) on everolimus. Everolimus was continued because there was a significant decrease in tumor size, and Nadolol (1 mg/kg per day) was added to the amiodarone to aid in control of VT.

The patient experienced an episode of persistent adenovirus pneumonia and gastroenteritis after ∼4 months on therapy, requiring everolimus to be held for 3 weeks. After improvement from the infection, the patient completed 11 additional weeks of everolimus at 0.35 mg twice daily (1.56 mg/m2 per day) with a target trough level of 8 to 10 ng/mL, resulting in 6 months of everolimus therapy.

The patient had a follow-up echocardiogram and CMRI (Figs 5 and 6) at 17 months of age (7 months after initiation of everolimus therapy), which revealed a significant reduction in the size of the cardiac rhabdomyoma. Two weeks after discontinuing everolimus therapy, Holter monitoring revealed sinus tachycardia with a right bundle branch block, but it did not reveal evidence of VT. An additional follow-up 6 weeks after discontinuing everolimus revealed occasional premature ventricular complexes but, again, did not reveal VT.

FIGURE 5

A, CMRI revealing progressively smaller tumor size with short-axis view revealing large mass at diagnosis. B, CMRI revealing 4-chamber view with short-axis view showing large mass at diagnosis. C, CMRI revealing 2-chamber view with short-axis view showing large mass at diagnosis. D, CMRI revealing 3-chamber view with short-axis view showing large mass at diagnosis. E, CMRI revealing progressively smaller tumor size with short-axis view showing large mass after debulking. F, CMRI revealing 4-chamber view with short-axis view showing large mass after debulking. G, CMRI revealing 2-chamber view with short-axis view showing large mass after debulking. H, CMRI revealing 3-chamber view with short-axis view showing large mass after debulking. I, CMRI revealing progressively smaller tumor size with short-axis view showing large mass 7 months after initiating everolimus therapy. J, CMRI revealing 4-chamber view with short-axis view showing large mass 7 months after initiating everolimus therapy. K, CMRI revealing 2-chamber view with short-axis view showing large mass 7 months after initiating everolimus therapy. L, CMRI revealing 3-chamber view with short-axis view showing large mass 7 months after initiating everolimus therapy.

FIGURE 5

A, CMRI revealing progressively smaller tumor size with short-axis view revealing large mass at diagnosis. B, CMRI revealing 4-chamber view with short-axis view showing large mass at diagnosis. C, CMRI revealing 2-chamber view with short-axis view showing large mass at diagnosis. D, CMRI revealing 3-chamber view with short-axis view showing large mass at diagnosis. E, CMRI revealing progressively smaller tumor size with short-axis view showing large mass after debulking. F, CMRI revealing 4-chamber view with short-axis view showing large mass after debulking. G, CMRI revealing 2-chamber view with short-axis view showing large mass after debulking. H, CMRI revealing 3-chamber view with short-axis view showing large mass after debulking. I, CMRI revealing progressively smaller tumor size with short-axis view showing large mass 7 months after initiating everolimus therapy. J, CMRI revealing 4-chamber view with short-axis view showing large mass 7 months after initiating everolimus therapy. K, CMRI revealing 2-chamber view with short-axis view showing large mass 7 months after initiating everolimus therapy. L, CMRI revealing 3-chamber view with short-axis view showing large mass 7 months after initiating everolimus therapy.

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FIGURE 6

A, CMRI reconstruction revealing tumor at diagnosis. B, CMRI reconstruction revealing tumor after debulking. C, CMRI reconstruction revealing tumor 7 months after initiating everolimus therapy. Progressively smaller tumor volume is shown in yellow, and stable left ventricular volume is shown in red.

FIGURE 6

A, CMRI reconstruction revealing tumor at diagnosis. B, CMRI reconstruction revealing tumor after debulking. C, CMRI reconstruction revealing tumor 7 months after initiating everolimus therapy. Progressively smaller tumor volume is shown in yellow, and stable left ventricular volume is shown in red.

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There is emerging evidence that supports the use of everolimus, an mTOR inhibitor, in patients with symptomatic TSC-associated cardiac rhabdomyoma that is not amenable to complete surgical resection.1,7,19 Because our patient did not have TSC, we demonstrate that everolimus treatment in a patient with cardiac rhabdomyoma without TSC can effectively decrease the tumor burden and improve clinical outcomes. We also report on the challenges of managing a patient with cardiac arrhythmia on antiarrhythmic medications while using everolimus, providing guidance for dosing of the drug. Despite significant tumor regression, there was an increase in nonsustained VT, which resolved soon after discontinuing everolimus. As has been reported in cerebral tissue, we suspect that everolimus may alter the conduction of electrical signals in the ventricular myocardium near the rhabdomyoma and may play a role in the increased VT burden.20 This possibility suggests that special consideration is necessary to monitor for arrhythmia progression when initiating everolimus in patients with cardiac rhabdomyoma and arrhythmia.

As imaging techniques evolve, CMRI has become an important tool in following complex cardiac tumors. Although the echocardiogram is the current standard for monitoring, there are inherent limitations to this imaging modality. Because our patient’s tumor involved the intraventricular septum and was causing cardiac arrhythmia, we felt we could best characterize and follow the tumor using CMRI. The use of CMRI provided accurate three-dimensional information about the tumor volume, allowing our team to determine the tumor’s relationship to other cardiovascular structures while also providing information about ventricular function, and the significant improvement while on therapy helped support the discontinuation of everolimus. Given our reliance on serial examinations to determine our patient’s response, we were concerned about potential variability in the echocardiogram assessment and preferred the known improvement in interobserver assessment of CMRI. As in our case, we would suggest that CMRI before tissue debulking may provide necessary preoperative information while avoiding ionizing radiation of computer tomography and may also provide vital diagnostic information for cardiac tumors that are deemed unsafe for surgical biopsy.

The majority of the evidence for everolimus dosing in cardiac rhabdomyoma is based on case reports in infants with TSC. The dosing ranges were variable in these reports, ranging from 0.3 to 5.6 mg/m2 per day; yet, all cases revealed resolution of the cardiac rhabdomyoma.1,8 The key factors in our dosing were drug interactions, possible side effects, and concern for immunosuppression. Our patient was on amiodarone, which is a p-glycoprotein (Pg-P) inhibitor, at the time of initiation. It is known that everolimus is a substrate of Pg-P, and when Pg-P is inhibited by amiodarone, everolimus levels can increase, necessitating a dose decrease.21 Therefore, the lowest effective dose published, 0.25 mg given once per day, 2 days per week (0.08 mg/m2 per day), was selected as our starting dose.

We observed variability in everolimus levels from challenges with product compounding and possible dietary interactions (Fig 7). Everolimus is not available in a premade suspension and has to be made at home into a suspension by parents; therefore, dosing inconsistency is possible at lower doses.6 Additionally, studies have revealed that food plays an important role in the absorption of everolimus; high-fat meals can decrease the maximum concentration of the drug by up to 60%.6,20 In our young patient, it was challenging to give everolimus consistently with or without food, which could lead to level variability. Although levels were variable, the patient achieved near-goal everolimus levels after 3 months on the therapy and responded clinically, suggesting that levels of 8 to 10 ng/mL may not be needed for a clinical response in this population.11 

FIGURE 7

Variability in everolimus levels during the 7-month treatment duration with target trough level of 8 to 10 ng/mL shown in red.

FIGURE 7

Variability in everolimus levels during the 7-month treatment duration with target trough level of 8 to 10 ng/mL shown in red.

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Adverse events potentially attributable to everolimus included the adenoviral infection and a maculopapular rash, which occurred inconsistently around the time of drug administration. Otherwise, we did not encounter significant side effects with this medication. Our patient did have a persistent leukocytosis while on everolimus, which did not have a clear etiology because the leukocytosis predated starting the medication and persisted after it was discontinued. The researchers in the Examining Everolimus in a Study of Tuberous Sclerosis Complex-1 and -2 (EXIST-1 and EXIST-2) trials, larger studies of long-term everolimus use in patients with subependymal giant astrocytoma and renal angiomyolipoma, found that the majority of patients experienced an adverse event with a resultant dose interruption or reduction while on treatment.22,24 This experience supports the need for routine monitoring and a multidisciplinary team managing patients on everolimus. To date, our patient continues to be monitored for new arrhythmia or tumor progression off everolimus therapy and has done well.

CMRI has been shown to improve diagnostic accuracy compared with an echocardiogram; therefore, we support its use to provide important diagnostic information in managing patients with complex cardiac tumors such as cardiac rhabdomyoma.25 Everolimus should be carefully monitored in patients with ventricular arrhythmia given the potential for increasing incidence of VT. Everolimus was generally well tolerated and may be considered for use in pediatric patients who present with inoperable, spontaneous cardiac rhabdomyoma and potentially life-threatening cardiac effects.

Drs Davis and Dodeja cared for the patient, reviewed the patient’s medical chart, reviewed relevant medical literature, drafted the initial manuscript, and reviewed and revised the manuscript; Drs L. Cripe and T. Cripe provided senior leadership for the project and reviewed and revised the manuscript; Dr Clark provided a review of everolimus, reviewed relevant everolimus literature, and reviewed and revised the manuscript; Dr Baker provided the pathologic review and collected the pathology images; Dr Hor provided the review of the cardiac imaging, in particular the cardiac MRI and its impact on the patient’s case; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

CMRI

cardiac MRI

mTOR

mammalian target of rapamycin

Pg-P

p-glycoprotein

TSC

tuberous sclerosis complex

VT

ventricular tachycardia

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.