Introduction: The major pore-forming Nav1.5 (α) subunit of the voltage-gated Na+ channel in cardiomyocytes is encoded by the Scn5a gene. Nav1.5 plays a key role in action potential initiation and propagation in both atria and ventricles and hence organisms lacking Scn5a or carrying Scn5a mutations are predisposed to cardiac arrhythmogenesis. Of such pathologies, Brugada Syndrome (BrS) predisposes affected subjects to ventricular tachycardia, ventricular fibrillation, and sudden cardiac death. BrS most commonly arises due to loss-of-function mutations in the Scn5a gene causing Nav1.5 haploinsufficiency. Interestingly, while patients are born with the primary ion channel dysfunction, cardiac arrhythmias tend to occur later in age suggesting later disruption to other components of the heart’s electrophysiological system. The molecular mechanisms underlying this disruption remains poorly understood. A murine model with a heterozygous Scn5a deletion recapitulates the electrophysiological phenotypes of BrS. Aims: Thus, this study aims to investigate the underlying transcriptional molecular alterations which potentially contribute to atrial and ventricular arrhythmogenicity in this Scn5a+/- murine model of BrS. Methods: Atrial and ventricular tissue samples were obtained from aged (11 ± 3 months) homozygous Scn5a+/- (N = 8) and wild-type (WT). Quantitative PCR was used to examine the transcription of 60 genes underlying cardiac tissue excitability. Results: Of selected protein-coding genes related to cardiomyocyte electrophysiological or homeostatic function, concentrations of mRNA transcribed from 15 genes differed significantly from WT (P < 0.05). Of these, Scn5a expression was expectedly halved in ventricular tissue, but was contrastingly not significantly downregulated in atrial tissue suggestive of atria-specific feedback mechanisms increasing expression of the WT allele. Of the 14 remaining genes showing an altered expression, none were shared by both atria and ventricles. Notably, of the statistically significant changes in gene expression, all those in the atria were upregulations, and all those in the ventricles were downregulations. Ventricles showed downregulation of genes related to ion channels permitting surface Ca2+ entry (Cacna1d) and ion channels controlling resting membrane potential (Abcc9). Atria showed upregulation of genes related to ion channels permitting surface Ca2+ entry (Cacna2d1, Cacna2d2, Cacna1h, and Cacna1c), intracellular ion channels, transporters, and enzymes controlling Ca2+ homeostasis (Ryr2, Atp2a2, and Camk2d), Na+/K+-ATPase activity (Atp1b1), ion channels initiating excitation (HCN1), ion channels controlling resting membrane potential (Kcnj5), and cardiac morphological properties (Tbx3 and Col1a1). Conclusions: The present investigation highlights a number of important molecular alterations that may contribute to arrhythmogenesis in BrS. This demonstrates the value of future experiments exploring for and clarifying links between transcriptional control of Scn5a and of genes whose protein products coordinate cardiac electrophysiological activity and may potentially offer novel therapeutic pharmacological targets in the management of BrS.