Genetic loci responsible for atrioventricular block in children

Figures

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  FIGURE 1. Overview diagram of Atrioventricular block mechanism. Abnormalities in ion channels (SCN5A, KCNH2), intercalated disc and structural development (GJA1, TJP1, NKX2-5), myocardial energy metabolism (PRKAG2, PPARα), and immune-inflammatory (TRIM21, TROVE2, HLA-II) responses collectively trigger electrophysiological disorders, impaired intercellular electrical coupling, reduced ionic currents, myocardial fibrosis and structural remodeling, as well as oxidative stress and energy metabolism dysfunction. These diverse pathways converge to prolong PR interval, progressing from second-degree AVB (Mobitz/2:1 block) to complete third-degree AVB, with associated risks of slow escape rhythm and sudden cardiac death.

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  FIGURE 2. The mechanisms of ion channels dysfunction inducing AVB. (A). Schematic diagram illustrating key ion channel genes involved in different phases of the cardiomyocyte action potential. SCN5A encodes the cardiac sodium channel responsible for Phase 0 depolarization. HCN4,and GNB contribute to Phase four diastolic depolarization and pacemaker activity. HERG and TRPM4 regulate Phase three repolarization. Pathogenic variants in these genes disrupt action potential kinetics, impair impulse generation and propagation, and collectively lead to AVB. (B). The genes associated with AVB participating in different phases during action potential in cardiomyocyte.

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  FIGURE 3. Schematic diagram of structure, cellular coupling and developmental mechanisms (A) The genes participate in cardiac development and morphology. Genes converge on two core pathogenic pathways: Impaired intercellular electrical coupling and myocardial fibrosis/structural remodeling, ultimately leading to AVB (B) The intracellular changes under MYH and TTN mutations. B1: Normal sarcomere structure with balanced titin isoforms (N2B/N2BA). B2: MYH mutations disrupt myosin autoinhibition, increasing the number of myosin heads available for actin binding, causing hypercontractility and myocardial hypertrophy. B3: TTN mutations shift the titin isoform ratio toward the compliant N2BA isoform, impairing sarcomere mechanical stability and promoting structural remodeling (C) ZO-1 binds to both GJ channels and CAR. In normal conditions, this complex stabilizes the membrane targeting, spatial organization, and retention of connexins and CAR, ensuring efficient electromechanical coupling between adjacent cardiomyocytes (Lower enlarged view). Disruption of ZO-1 diminishes CAR stability at the intercalated disc and promotes the disassembly of functional GJ complexes (Upper enlarged view).

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  FIGURE 4. Schematic diagram of metabolic-organelle-electrophysiological imbalance mechanisms. Pathogenic variants in metabolism-related genes contribute to the development of AVB via distinct pathways. (1) PPGC1 impair mitochondrial respiratory chain function. (2) PPARα impair fatty acid oxidation. (2) PRKAG2 variant cause pathological glycogen deposition and vacuolization in cardiomyocytes. (3) LAMP2 and GLA variants induce lysosomal storage disorders and cytotoxicity. All these pathological changes disrupt myocardial energy metabolism homeostasis and redox equilibrium, ultimately disturbing electrophysiological signal transmission and aggravating cardiac conduction dysfunction.

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  FIGURE 5. Schematic diagram of Immune-mediated mechanisms of Atrioventricular block. (1) Fetal/neonatal autoimmune AVB. Maternal anti-Ro/SSA and anti-La/SSB antibodies cross the placenta, targeting fetal conduction system antigens Ro52/TRIM21 and Ro60/TROVE2. They trigger complement activation and inflammation, while directly inhibiting L-type calcium currents. This dual insult causes fibrosis, structural remodeling, and AVB. (2) Childhood/adolescent acquired AVB. HLA-II variants promote aberrant antigen presentation, inducing pro-inflammatory cytokines, granuloma formation, and progressive fibrosis that disrupts the AV conduction axis, leading to acquired AVB.