Current Topics of Progressive Cardiac Conduction Disease

Figures

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  FIGURE 1. Age‐related differences in the number of pacemaker implantations for AV block. The number of PMIs for cAVB, paroxysmal AVB, Mobitz type II block, and tri‐fascicular block at Saitama Medical University International Medical Center are indicated in this figure. PMIs for AV block increased after 50 years old.

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  FIGURE 2. Structure of voltage‐gated cardiac sodium channels and the time course of the electrocardiogram in a patient with Brugada syndrome. (A) Structure of the voltage‐gated cardiac sodium channel (NaV1.5): The α subunit was encoded by the SCN5A gene and the ß‐subunit was encoded from the SCN1B gene. (B) Serial change in the electrocardiogram. The time course of the ECG changes in a boy with Brugada syndrome (BrS) revealed a gradual prolongation of the QRS duration and QT interval. Genetic analysis revealed an SCN5A gene variant (Q55X). This case was not defined as a classical form of PCCD, but the development of a conduction disturbance may complicate some patients with BrS.

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  FIGURE 3. Structure of Gap junctions and serial electrocardiograms in a PCCD patient with a GJA5 gene variant (Q58L). (A) Structure of Gap junctions between adjacent cells. (B) A 6‐year‐old boy was referred to our clinic for left axis deviation and left bundle branch block detected during heart screening, and was followed up for mild cardiomegaly (CTR 0.5). He suddenly died at 11 years‐old, and his mother died suddenly after delivery of his sister when she was 30 years old. Serial ECGs showed progressive prolongation of the PR interval, QRS duration, and QT interval. Genetic testing of the proband and his sister revealed a GJA5 gene variant (Q58L), which causes a connexin 40 variant in the gap junctions of the myocardium [32].

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  FIGURE 4. Structure of myocardium. (A) Structure of the myofibrils. (B) Structure of myocardial fascicles. (C) Interactions among nuclear envelope proteins, the nuclear lamina, and chromatin. Z = Z‐band; H = H‐band; I = I‐band; A = A‐band; NPC = nuclear pore complex; INM = inner nuclear membrane; ONM = outer nuclear membrane; PNS = perinuclear space; MAN1 = mannosyl‐oligosaccharide 1; LAP2 = lamina‐associated polypeptide 2; SUN1/2 = Sad1p, UNC‐84 domain protein 1 and 2; LBR = Lamin B Receptor.

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  FIGURE 5. ECG of a patient with Emery‐Dreifuss muscular dystrophy. When she was 3‐years‐old, it was noticed she became slower when running and started to climb stairs one step at a time while holding her knee. Grower's sign was positive from 5‐years‐old and genetic testing revealed an de novo heterozygous LMNA mutation (c.810+1G〉T). She was diagnosed with Emery‐Dreifuss muscular dystrophy when she was 9‐years‐old. She underwent catheter ablation of atrial tachycardia and atrial flutter when she was 12‐years‐old. During the electrophysiological study, her AH interval was 154 ms and HV 56 ms. (A) Serial ECG change: Serial electrogram showing progressive prolongation of the PR interval and a decrease in the P wave and R wave amplitudes. (B) Atrial flutter: Frequent episodes of atrial flutter were documented by Holter electrocardiogram when she was 12‐years‐old. (C) Nonsustained ventricular tachycardia: Ventricular arrhythmias were recorded from 17‐years‐old.

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  FIGURE 6. Electrocardiogram in a patient with desminopathy [35]. She was followed up for left axis deviation and an interventricular conduction disturbance from 6‐years‐old. She complained of a headache and dizziness due to paroxysmal heart block, and a pacemaker was implanted. Genetic testing revealed a variant of the DES gene (R454W), suggesting desminopathy as the cause of her disease [37]. (A) Serial electrocardiograms before pacemaker implantation Serial ECGs showed progressive prolongation of the PR interval and QRS duration. (B) Intracardiac electrocardiogram Electrophysiological study showed HV prolongation (AH 82 ms, HV 90 ms) and HV block.

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  FIGURE 7. Congenital heart disease and conduction disturbances. (A) Electrocardiogram of the proband. A 6‐year‐old boy was referred to outpatient clinic for 1st degree AV block and incomplete right bundle branch block detected during heart screening. He was previously diagnosed with a secundum atrial septal defect (ASD) that naturally closed during follow up. His AH interval was 332 ms and HV 54 ms. (B) Family tree of the index patient. His family history was remarkable in that his sister had a repaired ASD and AV block, his father a repaired ASD when he was 11 years old, and the brothers of his father died during infancy with unknown origin heart disease.

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  FIGURE 8. Mitochondria disease. (A) Electron transport chain in mitochondria. I = complex I (NADH–ubiquinone oxidoreductase); II = complex II (succinate–ubiquinone reductase); III = complex III (coenzyme Q‐cytochrome c oxidoreductase); IV = complex IV (cytochrome C oxidase); ADP, adenosine diphosphate; ATP Syn, ATP synthase (complex V); ATP, adenosine triphosphate; CoQ, coenzyme Q (ubiquinone); Cyt C, cytochrome C; FAD, flavin adenine dinucleotide; FADH2: Reduced form of flavin adenine dinucleotide; NAD+, nicotinamide adenine dinucleotide (oxidized form); NADH, reduced form of nicotinamide adenine dinucleotide; Pi, inorganic phosphate; TCA cycle, tricarboxylic acid cycle. (B) Serial ECG changes in Kearns–Sayre syndrome [12]. Serial ECGs show a gradual increase in the PR interval and QRS duration, and a markedly prolonged QT interval. CAVB, complete AV block; PTA, prior to admission. (C) Development of torsade de pointes.

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  FIGURE 9. Possible mechanisms to cause PCCD. The main mechanisms to cause PCCD were shown in this figure. Variants in the ion channels (NaV1.5, TRPM4, HCN4), gap junctions (Cx40 and Cx45), sarcomeres (Desmin, TNNI3K, and DMPK), nuclear lamina (lamin A/C), nuclear membrane protein (Emerin), transcription factors (NKX2‐5 and Tbx5), mitochondria electron transport, and cell storage disease (GL‐3 and glycogen) and autophagic vacuolar myopathies were reported as causes of PCCD. DMPK, dystrophia myotonica‐protein kinase; CS, conduction system; GL‐3, globotriaosylceramide; HPS, His Purkinje system.