Inherited Arrhythmic Syndromes and Cardiomyopathies in Atrial Fibrillation

Atrial fibrillation (AF) develops in structurally and electrically altered atria.

These alterations also occur in inherited arrhythmic syndromes and cardiomyopathies.
The main mechanisms include:

Overview of inherited arrhythmic syndromes and cardiomyopathies associated with atrial fibrillation, including long QT syndrome, short QT syndrome, and Brugada syndrome with characteristic ECG features and genetic mutations.

Main Mechanisms of Atrial Fibrillation in Inherited Arrhythmic Syndromes and Cardiomyopathies
Diagnoses	Atrial Changes	Mechanism of AF Development
HCM DCM ARVC	Structural atrial changes (dilatation, fibrosis, increased wall stress)	Structural remodelling creates an arrhythmogenic substrate for atrial arrhythmias and atrial fibrillation.
Long QT syndrome Short QT syndrome Brugada syndrome CPVT WPW syndrome	Electrical and ionic alterations in the atria	Ion channel dysfunction and impaired electrical stability increase atrial vulnerability to arrhythmias and AF.
Gene mutations (SCN5A, KCNQ1, KCNH2, RYR2, etc.)	Genetic alterations affecting the atrial myocardium	Mutations involve not only the ventricles but also the atria, thereby creating an arrhythmogenic substrate for AF.
HCM DCM	Chronic overload and diastolic dysfunction	Elevated filling pressures lead to left atrial dilatation and formation of a stable substrate for AF.
CPVT Long QT syndrome	Autonomic dysregulation	Adrenergic stress and impaired autonomic regulation promote atrial arrhythmias and AF.

Arrhythmic syndromes and cardiomyopathies may also arise due to gene mutations.

Gene mutations cause structural and electrical alterations of the atria,
thereby creating a substrate for AF.

Genetic Mutations and Their Association with Atrial Fibrillation
Gene Mutation	AF Prevalence	Associated Cardiac Diagnoses	Mechanism of AF
SCN5A	20–40 %	Brugada syndrome DCM (electrical phenotype) Genetic AF	Electrical atrial instability.
KCNQ1	10–30 %	Long QT syndrome type 1 Familial AF	Atrial repolarization abnormality.
KCNH2 (HERG)	10–25 %	Long QT syndrome type 2	Increased atrial vulnerability.
RYR2	5–15 %	CPVT	Adrenergic Ca²⁺ discharges → ectopy.
CACNA1C	30–50 %	Brugada phenotype Timothy syndrome Atrial arrhythmias	Ca²⁺ channel dysfunction → atrial excitability.
MYH7	20–35 %	HCM DCM LVNC	Atrial fibrosis and dilatation.
MYBPC3	20–35 %	HCM	Atrial fibrosis in HCM.
LMNA	45–70 %	Laminopathy (DCM + AV block)	Atrial remodelling.
TNNI3	15–30 %	HCM	Atrial remodelling in hypertrophy.
TNNT2	20–35 %	HCM DCM	Atrial fibrosis.
PLN	15–25 %	DCM ARVC-like phenotype	Electrical atrial instability.
DSP	10–25 %	ARVC	Atrial fibrotic remodelling.
PKP2	10–20 %	ARVC	Atrial arrhythmias during disease progression.
PRKAG2	20–40 %	Glycogen storage cardiomyopathy Hypertrophy + WPW phenotype	Atrial hypertrophy and pre-excitation.
GLA	30–60 %	Fabry disease	Atrial fibrosis.

ARVC – Arrhythmogenic right ventricular cardiomyopathy, CPVT – Catecholaminergic polymorphic ventricular tachycardia, DCM – Dilated cardiomyopathy, AF – Atrial fibrillation, HCM – Hypertrophic cardiomyopathy, LVNC – Left ventricular non-compaction cardiomyopathy, WPW – Wolff–Parkinson–White syndrome

In the following table, you can review the prevalence of AF in arrhythmic syndromes and cardiomyopathies.

Genetic and Inherited Arrhythmological Syndromes – Prevalence, AF Risk, Contraindications, and Anticoagulation
Diagnosis	Prevalence	AF Prevalence	Contraindications	Anticoagulation
Long QT syndrome	1 : 2 000	2–29 %	QT-prolonging drugs (1)	According to CHA₂DS₂-VA
Short QT syndrome	1 : 100 000	18–70 %	–	According to CHA₂DS₂-VA
Brugada syndrome	1 : 5 000	6–53 %	Class IC anti-arrhythmic drugs	According to CHA₂DS₂-VA
CPVT	1 : 50 000	11–37 %	–	According to CHA₂DS₂-VA
HCM	1 : 500	17–30 %	Class IC anti-arrhythmic drugs	Always (NOAC or warfarin)
ARVC	1 : 2 000	9–30 %	–	According to CHA₂DS₂-VA
DCM (LMNA mutation)	1 : 400	25–49 %	–	According to CHA₂DS₂-VA
WPW syndrome	1 : 500	7–50 %	AV node–blocking drugs (2)	According to CHA₂DS₂-VA

CPVT – Catecholaminergic polymorphic ventricular tachycardia, HCM – Hypertrophic cardiomyopathy, ARVC – Arrhythmogenic right ventricular cardiomyopathy, DCM – Dilated cardiomyopathy.
1 In Long QT syndrome, QT-prolonging drugs are contraindicated:
- IA: Quinidine, Procainamide, Disopyramide
- III: Amiodarone, Sotalol, Dofetilide, Ibutilide, Dronedarone
- IC: Propafenone, Flecainide (relative contraindication)
2 AV node–blocking drugs: Beta-blockers, Digoxin, Verapamil, Diltiazem, Amiodarone, Adenosine