Pediatric restrictive cardiomyopathy with rapid complete atrioventricular block progression

Abstract

Restrictive cardiomyopathy (RCM) is a rare pediatric cardiomyopathy characterized by ventricular diastolic dysfunction, and poor prognosis that often requires heart transplantation. We report the case of a 7-year-old boy with RCM complicated by complete atrioventricular block (CAVB) in whom pathological examination of the explanted heart demonstrated extensive fibrosis involving the cardiac conduction system. At 1 year and 9 months of age, the patient presented with arrhythmia. Echocardiography revealed marked biatrial enlargement and small ventricles. Cardiac catheterization demonstrated elevated filling pressures confirming RCM. One month after diagnosis, the patient developed severe bradycardia and circulatory collapse, requiring extracorporeal membrane oxygenation. Electrocardiography revealed complete atrioventricular (AV) block, and a permanent pacemaker (PM) was implanted. Despite recurrent heart failure episodes, cardiac function was maintained with medical therapy, including carvedilol and enalapril, without mechanical circulatory support until heart transplantation at 5 years of age. Pathology of the explanted heart revealed extensive interstitial fibrosis involving the conduction system, suggesting that conduction tissue fibrosis caused the CAVB. These findings provide pathological insight into the mechanism of advanced atrioventricular block in pediatric RCM. This case demonstrates that RCM may progress from first-degree AV block to CAVB due to conduction fibrosis.

Learning objective

Understanding the clinical and pathological progression of restrictive cardiomyopathy (RCM) complicated by complete atrioventricular block in children is important. This case illustrates that fibrosis of the conduction system can lead to severe bradycardia and circulatory collapse, highlighting the importance of the early detection of conduction abnormalities and timely pacemaker implantation. It has also been demonstrated that appropriate medical therapy combined with pacemaker management can effectively bridge pediatric patients with RCM to heart transplantation.

Introduction

Restrictive cardiomyopathy (RCM) is a rare form of pediatric cardiomyopathy, accounting for approximately 4.5% of all cases [1]. The prognosis is poor, with more than half of patients dying within 2 years of diagnosis, and RCM often requires heart transplantation [2]. Because the ventricular cavity is small, ventricular assist device (VAD) implantation is technically challenging [3], [4]. In Japan, RCM remains a fatal disease, with limited access to heart transplantation compared with the USA [5]. Herein, we report a case of RCM complicated by complete atrioventricular block (CAVB) in which detailed pathological examination of the explanted heart demonstrated extensive fibrosis involving the cardiac conduction system.

Case report

The patient, a 7-year-old boy, was noted to have cardiac arrhythmia and at 1 year and 9 months of age, leading to emergency transport to our hospital. The patient was admitted to the pediatric intensive care unit (PICU) due to frequent premature ventricular contractions (PVC) and impaired cardiac function. His medical history was notable for Kawasaki disease complicated by coronary artery aneurysms treated with aspirin therapy. Family history revealed that his elder sister had died of cardiopulmonary arrest at 5 months of age, but the cause was unknown. On admission, his height was 78.1 cm (−1.7 standard deviations) and his weight was 10.5 kg (−0.4 standard deviations). His heart rate ranged from 100 to 130 beats per minute, systolic blood pressure was approximately 90 mmHg, and oxygen saturation was 98% on room air. Peripheral coldness was observed, and the patient was diagnosed with Ross heart failure class II. There were no signs of developmental delay, muscle weakness, neurological symptoms, or hepatosplenomegaly at the time of admission. Chest radiography revealed a cardiothoracic ratio of 58% consistent with biatrial enlargement (Fig. 1A). Laboratory tests revealed elevated white blood cell count (12.7 × 10³/μL), increased C-reactive protein (CRP) (3.47 mg/dL), and B-type natriuretic peptide levels (BNP, 292 pg/mL: reference range <18.4 pg/mL), along with a mild elevation in troponin T level (0.015 ng/mL: normal value 0.00–0.014 ng/mL). Infectious causes were not identified. Electrocardiography (ECG) revealed an irregular rhythm, and a 12-lead ECG revealed frequent PVC with poorly discernible P waves (Fig. 1B). Transthoracic echocardiography revealed a marked biatrial enlargement with relatively small ventricles. The left atrial-to-aortic root ratio was greater than 1.8, reflecting left atrial enlargement consistent with chronically elevated filling pressures (Fig. 1C) and left atrial apical 4-chamber cross-sectional area was 9.4 cm² (Z-score + 2.7) at the initial presentation (Online Fig. S1A). Cardiac catheterization was performed under general anesthesia with endotracheal intubation at an FiO₂ of 0.21. Hemodynamic evaluation showed a left ventricular end-diastolic pressure of 15 mmHg, a right atrial pressure of 11 mmHg, and a characteristic dip-and-plateau pattern in the left ventricular pressure waveform (Fig. 1D). The mean pulmonary artery pressure was 19 mmHg, pulmonary capillary wedge pressure 14 mmHg, cardiac index 4.00 L/min/m², and pulmonary vascular resistance index 0.70 Wood units·m². Inferior vena cava angiography confirmed biatrial enlargement (Online Fig. S2) and on aortography, no coronary artery dilation was observed. Following stabilization in the PICU, an ECG obtained after the resolution of arrhythmia demonstrated a first-degree atrioventricular (AV) block. No ST changes were observed (Fig. 2A). An electrophysiological study revealed a prolonged AV conduction time of 177 ms. Incremental pacing revealed a Wenckebach-type AV block (AVB) at a pacing rate of 140 bpm and a 2:1 AVB at 180 bpm, consistent with a progressive AV conduction delay under the carvedilol 0.4 mg/kg. From this point of view, this medication was not associated with AV node function (Online Fig. S3). Genetic testing for cardiomyopathy-related genes was performed as a trio analysis, and no pathogenic variants were identified among the 81 genes analyzed by next-generation sequencing examined (Online Table S1). As medical therapy, carvedilol was used cautiously for chronic heart failure (CHF) and PVCs, while enalapril and diuretics were used for CHF due to cardiomyopathy. Constrictive pericarditis was ruled out because no pericardial calcification was observed on chest radiography and no pericardial thickening was detected on echocardiography. Myocarditis or infectious disease was not suggested by any clinical, laboratory, or imaging findings, aside from a mild elevation in CRP. Furthermore, secondary cardiomyopathies were not suspected based on the findings summarized in Online Table S2.

Fig. 1.

(A) Chest radiograph showing a cardiothoracic ratio of 58% with prominence of the right second and left third cardiac borders. (B) Admission 12-lead electrocardiogram, showing indistinct P waves and frequent premature ventricular contractions. (C) Echocardiogram (long-axis view) showing left atrial enlargement relative to the aortic annulus with the left atrial-to-aortic root ratio >1.8. (D) Left ventricular pressure tracing obtained by cardiac catheterization showing an elevated left ventricular end-diastolic mean pressure (15 mmHg) and a characteristic dip-and-plateau pattern consistent with impaired diastolic compliance.

Fig. 2.

(A) Initial admission 12-lead electrocardiogram (ECG) obtained after stabilization. P waves were small and indistinct; signal amplitude was increased to 40 mm/mV. The enlarged V1 lead revealed a first-degree atrioventricular block (PR interval, 170 ms) with a narrow QRS complex (72 ms). The black arrow indicates the position of the P wave. (B) Readmission 12-lead ECG showing marked bradycardia (heart rate: 42 bpm) and complete atrioventricular block on the enlarged V1 lead at 40 mm/mV. The black arrow indicates the position of the P wave. No ST changes suggestive of myocardial ischemia were observed. (BASEL-RS = 0.45) [Grimm K, et al. Eur Heart J Acute Cardiovasc Care 2020;9:857–68.]

At the age of 1 year and 10 months, the patient was brought to the emergency department with severe bradycardia and worsening cardiac function. Despite the administration of inotropic agents, hemodynamic instability persisted and venoarterial extracorporeal membrane oxygenation (ECMO) was initiated after admission to the PICU. The ECG on readmission showed marked bradycardia, demonstrating a CAVB (Fig. 2B). After intensive management and discontinuation of carvedilol, atrioventricular conduction transiently improved, but remained unstable, and a permanent pacemaker was implanted. During follow-up, ventricular pacing became predominant, indicating progression to CAVB. Because conduction worsened despite carvedilol withdrawal and prior electrophysiological study with carvedilol had shown preserved AV nodal function, the deterioration was considered to reflect progression of the underlying disease. Heart failure therapy including carvedilol was therefore resumed (Online Fig. S3). The patient was transferred to a transplant center for further management and successfully underwent orthotopic heart transplantation at 5 years of age. Detailed conduction parameters including PR interval and QRS duration are shown in Online Fig. S3.

Pathological findings

Gross examination of the explanted heart revealed marked biatrial enlargement. The ventricular cavities were small, with prominent trabeculations (Fig. 3A). Histologically, left atrial endocardial thickening and fibrosis were observed, suggesting chronic volume and pressure overload associated with atrial enlargement (Fig. 3B). No inflammatory cell infiltration was observed in the anterior wall of the left ventricle. The endocardium of the left ventricle showed dense fibrous thickening, predominantly composed of proliferating collagen fibers (Fig. 3C, D). Furthermore, fibrofatty degeneration, indicating an extensive loss of AV nodal cells, was observed (Fig. 3E, F). These pathological findings suggest that RCM was the underlying disease and that progressive fibrosis involving the conduction tissue likely led to the development of CAVB.

Fig. 3.

(A) Gross appearance of the heart. Marked enlargement of the left atrium is observed, along with fibrous thickening of the left ventricular endocardium, accompanied by proliferation of elastic fibers. LA, left atrium; LV, left ventricle; AML, anterior mitral leaflet; PML, posterior mitral leaflet. (B) Left atrium (Masson trichrome staining). Endocardial thickening, extensive interstitial fibrosis between the myocardial cells, and stromal fibrosis were also observed. (C, D) Left ventricular anterior wall (Elastica–Van Gieson stain). The endocardium shows dense fibrotic thickening composed of proliferating collagen fibers. (C) Low magnification. (D) High magnification. (E, F) Atrioventricular (AV) node. (E) Masson's trichrome staining. (F) Elastica Van Gieson staining. AV node showing fibrosis and fatty infiltration. The upper left corresponds to the cranial/atrial side, and the lower right corresponds to the His bundle/ventricular side. PS, pyramidal space; CFB, central fibrous body; IVS, interventricular septum.

Discussion

Herein, we report a case of RCM complicated by progressive conduction disease leading to CAVB. PM implantation preserved cardiac function and allowed successful heart transplantation approximately 3 years after onset. This patient had RCM that progressed from first-degree AVB to CAVB. Previous studies reported that RCM is associated with a higher incidence of AVB and atrial arrhythmias than other cardiomyopathies [6]. In a cohort of 16 pediatric patients with RCM, 5 experienced acute cardiac events, including death, and 3 of these developed CAVB. The event group showed significantly longer median PR (166 ms) and QRS durations (92 ms) at initial presentation, with further prolongation observed during follow-up [7]. In the present case, although no QRS prolongation (72 ms, corrected QT interval: 440 ms) was observed at the first visit, the PR interval was prolonged to 170 ms, indicating first-degree AVB. Within approximately 1 month, the conduction abnormality progressed to CAVB. These findings highlight that RCM requires careful monitoring for AV abnormalities. Importantly, detailed pathological examination of the explanted heart in this case demonstrated extensive fibrosis involving the cardiac conduction system, providing structural insight into the mechanism underlying progressive AVB in pediatric RCM. Siegel et al. examined four adult patients with RCM and reported that several required PM implantations, including CAVB. Autopsy findings revealed extensive fibrosis in the His-Purkinje system of all patients requiring PM [8]. Additionally, atrial and ventricular enlargement can contribute to the development of conduction disturbances. The extensive fibrosis of the conduction system observed in this case indicates that the mechanism of CAVB in pediatric RCM, as in adult cases, is primarily due to abnormalities of the conduction system.

In the present case, a PM was implanted for CAVB, and carvedilol therapy for CHF was administered. This approach allowed long-term management with preserved native cardiac function without the use of a VAD, allowing successful heart transplantation 3 years later. Because the ventricular cavity in RCM is typically small, VAD implantation is often technically challenging [3]. Moreover, the waiting period for heart transplantation is considerably longer in Japan than in other countries, making the management of RCM particularly difficult. The reported 5-year survival rate for RCM in Japan is 68% compared with 79% in the USA, and this difference may be partly attributed to the lower number of transplants in Japan [5]. In this context, it is important that the patient undergo heart transplantation without VAD.

According to the pediatric RCM prediction model [9], this patient had a high 1-year risk of major adverse cardiac events at 16.5% (ROSS class II, BNP 292 pg/mL, troponin 0.015 ng/mL, and ECG BASEL-RS = 0.45), indicating severe disease at the time of diagnosis. ECMO support was required because of circulatory failure caused by CAVB. After heart rate stabilization with a PM, carvedilol could be safely initiated. In adults with CHF and low resting heart rates, previous reports have suggested that prophylactic PM implantation to facilitate carvedilol therapy can improve clinical outcomes [10]. However, the therapeutic efficacy of carvedilol in RCM remains controversial, with no definitive consensus.

Consent for publication

Written informed consent for the publication of medical information and images was obtained from the patient's parents reported in this publication.

Funding

This study did not receive any specific grants from funding agencies in the public, commercial, or non-profit sectors.

Declaration of competing interest

The authors have no financial relationships and no conflicts of interest to disclose for this case report.

Appendix A. Supplementary data

Online Table 1 List of the 81 genes analyzed by NGS. NGS: Next Generation Sequencer.

Online Table 2 Evaluation of secondary causes of restrictive cardiomyopathy and atrioventricular block.

Online Fig. 1 Echocardiographic apical 4-chamber (AP4) view. Z-scores were calculated using the Boston Children's Hospital Heart Center Z-score (2D, LA/AP4/Cross-sectional Area vs. BSA).

A: Age 1 year 10 months; LA area in the apical four-chamber view was 9.4 cm² (Z-score 2.7).

B: Age 3 years; LA area in the apical four-chamber view was 16.1 cm² (Z-score 5.2).

Online Fig. 2 (A, B) Inferior vena cava angiography. Frontal (A) and lateral (B) video views demonstrate biatrial enlargement.

Online Fig. 3 Treatment course from the diagnosis of restrictive cardiomyopathy to heart transplantation, along with changes in PR interval and QRS duration. Serial electrocardiographic parameters demonstrate progressive atrioventricular conduction delay leading to complete atrioventricular block, requiring permanent pacemaker implantation. Despite transient improvement after discontinuation of carvedilol^, conduction instability persisted, consistent with progression of the underlying disease. Key clinical events, including pediatric intensive care unit admission, initiation of extracorporeal membrane oxygenation, and heart transplantation, are indicated. PMI, pacemaker implantation; RCM, restrictive cardiomyopathy; CAVB, complete atrioventricular block.