Progressive cardiac conduction disease (PCCD)

Progressive cardiac conduction disease is a clinically heterogeneous disorder of the cardiac conduction system. It progressively impairs impulse propagation through the His-Purkinje system in the absence of an identifiable acquired or structural cause. Affected individuals show progressive PR-interval prolongation, QRS widening, bundle branch block, and atrioventricular block of increasing severity on serial 12-lead electrocardiography and ambulatory Holter monitoring. Onset is variable: conduction abnormalities are typically progressive with advancing age and may manifest from childhood through later adulthood. As conduction disease advances, individuals are at risk of syncope, bradycardia-related symptoms, and sudden cardiac death; permanent pacemaker implantation is frequently required as the disease progresses to high-grade or complete atrioventricular block. Inter- and intra-familial variability in severity and rate of progression is well recognised, and overlap phenotypes with and type 3 occur in some affected individuals carrying particular pathogenic variants.

Due to insufficient data, no reliable statement on prevalence can currently be made.

Progressive cardiac conduction disease is inherited in an autosomal dominant manner. First-degree relatives of an affected individual therefore have a 50% a priori  risk of carrying the familial  pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Progressive cardiac conduction disease is caused by germline pathogenic variants in several genes. The most commonly implicated gene is  SCN5A, which encodes the α-subunit of the cardiac voltage-gated sodium channel Nav1.5; pathogenic variants in  TRPM4,  SCN1B, and  LMNA  are also reported. Loss-of-function variants reduce cardiac sodium current or otherwise impair impulse propagation through the His-Purkinje system, producing progressive conduction slowing and block.

Diagnosis rests on electrocardiographic demonstration of progressive conduction-system disease combined with molecular genetic confirmation. Serial 12-lead ECG and ambulatory Holter monitoring document PR-interval prolongation, QRS widening, bundle branch block, and/or atrioventricular block of increasing severity in the absence of an identifiable acquired or structural cause.

Main differential diagnoses include:

• : type 1 coved ST-segment elevation in right precordial leads (V1-V3) and predisposition to polymorphic ventricular tachyarrhythmias rather than progressive infranodal conduction slowing as the dominant phenotype; SCN5A 
• Sick sinus syndrome: predominant sinus node dysfunction with sinus bradycardia, sinus pauses or sinoatrial exit block rather than progressive His-Purkinje conduction delay; SCN5A, HCN4 
• LMNA-related dilated cardiomyopathy: atrioventricular and intraventricular conduction disease accompanied by progressive left ventricular dilatation and systolic dysfunction rather than isolated conduction-system involvement; LMNA 

• Establishing the diagnosis confirms the clinical suspicion at a molecular level and ends the diagnostic odyssey.
• Identification of the underlying pathogenic variant supports specific and  individualised  surveillance and clinical management and provides the prerequisite for any targeted medical care; these decisions are taken by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant has been identified, predictive molecular testing can be offered to at-risk relatives to clarify their personal risk and inform their clinical follow-up.

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