Challenging of ECMO application in pediatric restrictive cardiomyopathy: case report of a novel TNNI3 variant

Abstract

Background: Restrictive cardiomyopathy (RCM) represents a rare cardiovascular disorder stemming from filament-associated genes. Nonetheless, treating RCM presents considerable challenges, particularly concerning device implantation and mechanical support. Furthermore, elucidating the molecular function of specific variants holds promise in benefiting patients and enhancing prognosis, given the significant heterogeneity among RCM variants.

Case presentation: The proband, an eight-year-old female, was admitted to our hospital post cardiopulmonary resuscitation due to sudden cardiac arrest. Echocardiography revealed bilateral atrial enlargement. Whole-exome sequencing uncovered a novel heterozygous mutation (c.509G>A, p.R170Q) in TNNI3. Evaluation using the MutationTaster application deemed c.509G>A pathogenic (probability = 0.99). Following clinical manifestations, imaging assessments, and genetic screening, the proband received an RCM diagnosis. ECMO was recommended along with continuous renal replacement therapy. However, persistent atrial flutter ensued post-ECMO withdrawal. Attempts to restore cardiac rhythm with cardioversion, metoprolol, and amiodarone proved futile. Subsequent heart failure led to the patient's demise due to cardiac shock. Based on crystal protein structural analysis, we observed that cTnI-R170Q and R170W exerted similar impacts on protein structural stability and formation. However, both differed significantly from cTnI-R170G, primarily influencing amino acid regions 32-79 and 129-149, involved in TnC and actin binding. Therefore, cTnI-R170Q was revealed to induce RCM via the same molecular mechanism as cTnI-R170W.

Conclusion: Managing RCM remains a critical challenge. This study underscores the discouragement of device implantations for cardiac pump functional support in RCM, particularly for non-short-term scheduled HTx. Additionally, considering catheter ablation for atrial fibrosis-induced AFs is recommended. Mechanistically, cTnI-R170Q primarily diminishes troponin-actin interactions and destabilizes thin filaments.

Keywords: ECMO; TNNI3; heart failure; heart transplantation; restrictive cardiomyopathy.

Figure 1

Clinical imagines of the proband. (A) Echocardiography demonstrated extremely enlarged bilateral atrium (left atrium dimeter 3.94 × 6.84 cm, right atrium dimeter 4.86 × 6.14 cm), interventricular septum segmentally thickened, partial ventricular wall pulse amplitude segmentally diffusely reduced and uncoordinated, mild mitral regurgitation, reduced left ventricular systolic and diastolic function. (B) Electrocardiogram revealed abnormal bilateral atrial signals, premature atrial beat, junctional ectopic beat, first degree atrioventricular block, complete right bundle branch block, prolonged QT interval, and abnormal Q wave. (C) Electrocardiogram presented persistent AF had been identified after ECMO withdraw.

Figure 2

The TNNI3 molecular analysis. (A) The proband exhibited a de novo heterozygous variant of TNNI3 (c.509G>A, p.R170Q). (B) The variant of TNNI3 c.509G>A had never reported in 1000G and ExAC, it has predicted protein damaging by PolyPhen-2 and SFIT. (C) The protein structure of cTnI has been built and named AF-P19429-F1. (D) Localized structural views had been established by SWISS-MODEL for cTnI-R170Q, R170W and R170G based on Q8MKD5.1.A template, respectively. (E) Comparisons had been made on the structural impaired among cTnI-R170Q, R170W and R170G. Based on the ensemble variance analysis, we found that the cTnI-R170Q and R170W shared the similar impacts on protein structural stability and formation. However, both of them presented significant differences with cTnI-R170G, mainly influencing the regions of 32-79 and 129-149 amino acids, which were involved in TnC and actin binding.