Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2022;12(3):e2022150 1 Objectives: to evaluate clinical chart of patients with IH who had cardiologic evaluation before pro- pranolol therapy and to compare our findings with literature data. Introduction: Some studies have assessed the incidence of heart defects in children suffering from infantile hemangioma (IH) treated with propranolol, showing a possible higher prevalence of cardiac abnormalities in this group of patients. Methods: We retrospectively reviewed clinical charts of children with infantile hemangiomas referred to our dermatologic division from 2016 to 2021, who underwent our pediatric cardiology protocol screening before starting propranolol therapy. Results: A total of 60 infants were enrolled. Electrocardiograms were available for all the patients and echocardiography for 50/60 (83.3%) children. Electrocardiogram didn’t reveal any alterations in most cases (pathologic in 2/60 ones, 3.3%) while echocardiograms revealed findings in 31/50 (51.7%) pa- tients. Of these, persistent foramenovale, which was found in 14/50 patients (28%), was considered as non-pathologic. Interatrial septal defects were the main pathological finding in 15/50 patients (30%), as single defect or in association with other abnormalities. Conclusions:  Our study confirms the presence of a higher rate of cardiologic findings in patients with infantile hemangioma evaluated before starting oral propranolol, compared to the known rate of those defects in healthy newborns. We also confirm that interatrial septal defects are the most fre- quent pathologic finding with a higher prevalence compared to published studies. Large prospective studies are needed to clarify a possible association of pathological cardiac findings in all patients with infantile hemangiomas and thereafter to evaluate the possible effect of propranolol therapy on these defects during time. Infantile Hemangioma and Cardiac Defects: a Puzzling Association. A Single-center Experience Andrea Bassi1, Andrea Azzarelli2, Angelina Vaccaro3, Carlo Mazzatenta1 1. Dermatology Unit , Azienda Toscana Nord Ovest, Lucca, Italy 2. Pediatric Cardiology, Azienda Toscana Nord Ovest, Lucca, Italy 3. Pediatric and Neonatology Unit, Azienda Toscana Nord Ovest, Lucca, Italy Key words: infantile haemangiomas, hearth, septal defects, propranolol Citation: Bassi A, Azzarelli A, Vaccaro A, Mazzatenta C. Infantile hemangioma and cardiac defects: a puzzling association. A single center experience. Dermatol Pract Concept. 2022;12(3):e2022150. DOI: https://doi.org/10.5826/dpc.1203a150 Accepted: December 28, 2021; Published: July 2022 Copyright: ©2022 Bassi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding author: Andrea Bassi, MD, Dermatology Unit, Azienda Toscana Nord Ovest, Lucca, Italy, Telephone number: +39-3389340371, E-mail address: andrea.bassi@uslnordovest.toscana.it ABSTRACT Dermatology Practical & Conceptual 2 Original Article | Dermatol Pract Concept. 2022;12(3):e2022150 Introduction Infantile hemangiomas (IH) are the most common benign tumor in infancy with an incidence between 5% and 10% in different population [1]. Usually, they undergo a natural regression and do not require any treatment, therefore a “wait and see” approach is considered the best option for most affected newborns. However, in a subset of patients, IH can be worrisome for the risk of functional or aesthetic consequences. In 2008, following a serendipitous clinical observation, oral propranolol has been shown to be highly effective in the treatment of IH since then this drug has been widely used as galenic formulation. In 2014 an oral formu- lation has been licensed in Europe and oral propranolol is now considered the gold standard for the therapy of compli- cated hemangioma. In our hospital patients starts treatment with oral propranolol at 1 mg/kg in 2 divided doses under pediatric observation for 2 hours. The dose is then gradually increased over the subsequent weeks following the standard protocol of stepping the dose up to 2 mg/kg daily the second week of treatment and up to 3 mg/kg daily the third week. Another possibility is to follow an “at home” dose escalation strategy with telemedicine follow-up [2]. We developed and applied this protocol during the lock-down phase related to the SARS-CoV-2 pandemic, but we now offer this possibility to all families aiming to reduce the number of hospital visits. The therapy is usually continued until the 12th month of life with rare exceptions, such as rapid improvement of the le- sion or extensive/recurrent IH in which therapy length could be respectively reduced or prolonged. Potential side effects of propranolol include bradycardia, hypotension, hypoglycemia, bronchospasm and sleep distur- bances. All these are rare and usually not lead to discontinue the treatment [3]. Nevertheless in order to exclude congenital hidden heart disease which would contraindicate proprano- lol administration and to identify children in whom the drug may potentially induce side effects before starting therapy a general evaluation it is usually performed by a pediatrician. However, in our hospital, while not specifically requested in routine practice patients with IH who need propranolol ther- apy are also evaluated by a pediatric cardiologist [4]. Our cardiology unit offers a care package in which next to car- diologic examination also an electrocardiogram (ECG) and echocardiography (ECHO) are performed in all children. Objectives Few published studies have shown a raised incidence of car- diac defects in patients with IH [5,6]. We then decided to ret- rospectively evaluate clinical chart of patients with IH who had cardiologic evaluation before propranolol therapy and to compare our findings with literature data. Methods Study Population We retrospectively evaluated clinical charts of all children with IH requiring propranolol therapy at our countryside hospital between January 2016 and January 2021. Accord- ing to our protocol patients referred to our outpatient service for IH undergo a complete pediatric and cardiology evalua- tion including ECG and ECHOcardiogram before starting therapy. Children with segmental IH are also investigated with magnetic resonance imaging (MRI) to exclude the as- sociation with other congenital vascular malformations. Two-dimensional, M-mode, continuous Doppler and color Doppler echocardiography is performed using iE33 Philips Medical Ultrasound System equipped with a high-frequency phased-array sector scan probe (S8) and second-harmonic technology. All the evaluations are performed by the same senior cardiologist (AA) and comprise a complete sequen- tial segmental analysis for each child. Atrial septal defect is diagnosed when a shunt through the interatrial septum can be documented by color flow mapping in subcostal four-chambers and sagittals views. We do not record as atrial septal defect (ASD) the interatrial communications less than 4 mm in length detected in infants less than 3 months of age. According to the local ethical board, informed consent was not required, since it was retrospective study with anony- mous data. Statistical Analysis Data were analyzed by SPSS Statistics, 24.0 statistics soft- ware. Categorical variables and frequencies were compared by means of the χ2 test or Fisher test, as appropriate. Quan- titative variables were reported as median and interquartile range (IQR) and compared by means of nonparametric tests (Mann–Whitney U). A P value of 0.05 was considered to indicate statistical significance. Results During this study period 950 children with IH presented in our clinic. Of these, 60 (6.3%) patients with IH were treated with oral propranolol in the study frame time and all clinical charts were reviewed to retrieve relevant data. The median corrected age at first evaluation was 3 months (IQR: 2-5). Seventy percent of cases were female (42/60), and the median gestational age at delivery was of 40 weeks (IQR: 36-40). In our population, 18/60 (30%) infants were born preterm. Regarding the localization of IH, in 40/60 (66.7%) children was on the head and among these in 7/40 (17.5%) were “Cyrano” IH. 12/40 (30%) were on the scalp, 5/40 (12.5%) on the cheek (2 of these were diagnosed as Original Article | Dermatol Pract Concept. 2022;12(3):e2022150 3 PHACE syndrome after MRI imaging), 4/40 (10%) on the ears and 12/40 (30%) on the forehead. In 9/60 (15%) IH were localized on the lower and upper arms including shoul- der, 7/60 (11.7%) on the trunk, 1/60 (1.7%) on the diaper area and 3/60 (5%) presented with multiple IH. All data are summarized in Table 1. Data about cardiologic screening in particular for ECG examination were available for all the patients and almost all (58/60, 96.7%) presented a regular ECG for age. Only 2 patients presented a right ventricular overload. Ultrasound examination was available for 83.3% (50/60) of the patients. Among these, 19/50 (38%) didn’t reveal any alterations and 14/50 (28%) had a persistent foramen ovale, a common finding considered to be non-pathological. Pool- ing together these two groups 33/50 patients (66%) had a normal ultrasound, while the remaining 17/50 (34%) showed significant cardiac alterations. The most frequent cardiac defect was an isolated interatrial septal defect observed in 13/17 (26% of all patients). Moreover, one patient had an in- teratrial septal defect associated with persistent left superior vena cava and another one associated with pulmonary steno- sis. Finally, one patient had a patent ductus arteriosus and in another one a flow acceleration in the aortic arch was seen. The median age (corrected for gestational age) at which the interatrial septal defect was observed was 3 months (IQR: 2-4); 9 out of these were observed at ≥ 3 months of age (18% of all patients) and 6 at < 3month (12% of all pa- tients). Of the 9 patients observed at ≥ 3months, 8 presented an interatrial defect > 3mm. The median defects diameter was 4 mm (IQR: 3-6) with an ostium secundum type and left to right shunt in all pa- tients. The 2 patients with abnormal ECG didn’t present any ultrasound alterations. A possible association of abnormal cardiac findings with demographic or clinical variables was evaluated. However, no statistically significant association was found with age (p = 0.354), sex (P = 0.757), gestational age (P = 0.480), prematurity (p = 0.329) or hemangioma localization (P = 0.494). None of the ECG and ECHO findings were considered contraindications for systemic propranolol treatment. Conclusions Since systemic propranolol therapy was introduced for the treatment of IH several protocols of administration and mon- itoring have been proposed in order to reduce the potential risks related to the therapy [1,6]. Pretreatment evaluation is warranted both to exclude congenital hidden heart disease which would contraindicate propranolol administration and Table 1. clinical and cardiological screening results of the study population Characteristics Patients (N = 60) Age starting propranolol and cardiac screening 3 months (IQR: 2-5) Sex (female) 42 Preterm 18 Gestational age 40 weeks (IQR: 36-40) IH localization • face 40 • trunk 7 • arms 9 • diaper 1 • multiple IH 3 Cardiological findings Electrocardiogram (60/60available) 58/60 no pathologic findings Echocardiogram (50/60available) • no findings 19/50 • persistent foramen ovale 14/50 • interatrial septal defect 13/50 • interatrial septal defect+ patent doctus arteriosus 1/50 • interatrial septal defect + pulmunary stenosis 1/50 • flow acceleration in aortic arch 1/50 • persistent left superior vena cava 1/50 IH = infantile hemangiomas; IQR = interquartile range. 4 Original Article | Dermatol Pract Concept. 2022;12(3):e2022150 children older than 3 months (thus excluding children less than 3 months), the prevalence of ASD is anyway clearly greater than data reported in literature for general popula- tion (18% versus 0.8%-1%) [12-13]. The limited number of patients and the intrinsic limita- tions of retrospective studies does not allow us to draw a definitive conclusion however our study along with liter- ature data seems to confirm that patients with IH have a substantially higher prevalence of congenital heart disease in respect to general population. Indeed, these data needs con- firmation in larger prospective, multicenter, studies which should include all patients with IH to be evaluated at spe- cific time points irrespectively of therapy with propranolol. Such a study will also be of interest to reveal a possible effect of propranolol therapy on the closure of ASD and also the significance and the possible value of IH as a clue to sus- pect the presence of a cardiac defect. In particular it would be of great importance to understand whether along with well-known syndromes such as PHACE a particular com- bination of characteristics such as dimension, number and or localization could indicate a raised risk of cardiac dis- ease [19]. References 1. Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangiomas: report of a consen- sus conference. Pediatrics. 2013;131(1):128-140. DOI: 10.1542/ peds.2012-1691. PMID: 23266923. PMCID: PMC3529954. 2. Bassi A, Azzarelli A, Vaccaro A, Mazzatenta C. At-home dose escalation of propranolol for infantile hemangiomas during the COVID-19 pandemic. Dermatol Ther. 2020;33(6):e13977. DOI: 10.1111/dth.13977. PMID: 32633450. PMCID: PMC7361163. 3. Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131(1):128-140. DOI: 10.1542/ peds.2012-1691. PMID: 23266923. PMCID: PMC3529954. 4. Hemangiol summary of product characteristics. Available from: https://www.ema.europa.eu/en/documents/product-information/ hemangiol-epar-product-information_en.pdf 5. Blei F, McElhinney DB, Guarini A, Presti S. Cardiac screening in infants with infantile hemangiomas before propranolol treat- ment. Pediatr Dermatol. 2014;31(4):465-470. DOI: 10.1111/ pde.12344. PMID: 24889812. 6. Frongia G, Byeon JO, Arnold R, Mehrabi A, Günther P. Cardiac diagnostics before oral propranolol therapy in infantile heman- gioma: retrospective evaluation of 234 infants. World J Pediatr. 2018;14(3):254-258. DOI: 10.1007/s12519-018-0137-7. PMID: 29796952.et al. 7. Olsen GM, Hansen LM, Stefanko NS, et al. Evaluating the Safety of Oral Propranolol Therapy in Patients With PHACE Syndrome. JAMA Dermatol. 2020;156(2):186-190. DOI: 10.1001/jamader- matol.2019.3839. PMID: 31825455. PMCID: PMC6990697. 8. Raphael MF, Breugem CC, Vlasveld FA, et al. Is cardiovascular evaluation necessary prior to and during beta-blocker therapy to identify children in whom the drug may potentially in- duce side effects including bradycardia, hypotension, bron- chospasm or hypoglycemia. Whether to perform ultrasound, ECG or simply a clinical examination is however controver- sial. The most recent literature underlines the lack of addi- tional value of performing instrumental evaluations such as ECG as a pretreatment screening tool [7-11]. In our hospital a clinical protocol in which a complete pediatric and cardi- ologic screening, including ECG and ultrasound, is usually performed in all patients as part of a specific care package. In line with previous studies, in our population we didn’t find any cardiac contraindications to start propranolol treat- ment. In particular ECG was performed in all the patients, but no significant findings were found thus confirming the low informative value of this exam. On the contrary some interesting data were derived from ultrasound heart exam- ination. ECHO was available for 83.3% patients and in 38% of patients was normal. A persistent foramen ovale was found in 28% of patients and considered as a normal variant. The most frequent pathological abnormality was an interatrial septal defect that was present in 15/50 of patients (30%) either as an isolated finding (13/50 - 26%) with a pre- sentation as ostium secundum type with left to right shunt or associated with a persistent left superior vena cava or pul- monary stenosis. Few other studies have addressed this topic. In particular, Blei et al analyzed 239 patients and found 16% of interatrial septal defects, while Frongia et al analyzed 234 patients with only 8.1% of prevalence of this defect [5,6]. In any case, these studies clearly showed that in patients with IH there is a higher frequency of cardiac abnormalities compared with the reported incidence of congenital heart disease in the gen- eral population, which has been shown to range from 0.8% to 1.0% and going up to 7.5% only with the inclusion of other alteration such as patent foramen ovale [12-16]. Our study confirms the higher prevalence of cardiac abnormali- ties among patients with IH in particular of interatrial septal defect. The clinical significance of our findings is supported by the median age at observation and the median diameter of the defect which are in line with the criteria of inclusion to define congenital heart disease, ie the observation after 3 months of life and the dimension more or equal 4 mm (our median diameter was 4 mm) [17]. 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