Background— Valvular heart disease (VHD), which often leads to atrial fibrillation (AF), and AF both cause ion-channel remodeling. We evaluated the ion-channel gene expression profile of VHD patients, in permanent AF (AF-VHD) or in sinus rhythm (SR-VHD), in comparison with patients without AF or VHD, respectively. Methods and Results— We used microarrays containing probes for human ion-channel and Ca ²⁺ -regulator genes to quantify mRNA expression in atrial tissues from 7 SR-VHD patients and 11 AF-VHD patients relative to 11 control patients in SR without structural heart disease (SR-CAD). From the data set, we selected for detailed analysis 59 transcripts expressed in the human heart. SR-VHD patients differentially expressed 24/59 ion-channel and Ca ²⁺ -regulator transcripts. There was significant overlap between VHD groups, with 66% of genes altered in SR-VHD patients being similarly modified in AF-VHD. Statistical differences between the AF- and SR-VHD groups identified the specific molecular portrait of AF, which involved 12 genes that were further confirmed by real-time reverse transcription–polymerase chain reaction. For example, phospholamban, the β-subunit MinK ( KCNE1 ) and MIRP2 ( KCNE3 ), and the 2-pore potassium channel TWIK-1 were upregulated in AF-VHD compared with SR-VHD, whereas the T-type calcium-channel Cav3.1 and the transient-outward potassium channel Kv4.3 were downregulated. Two-way hierarchical clustering separated SR-VHD from AF-VHD patients. AF-related changes in L-type Ca ²⁺ -current and inward-rectifier current were confirmed at protein and functional levels. Finally, for 13 selected genes, SR restoration reversed ion-channel remodeling. Conclusions— VHD extensively remodels cardiac ion-channel and transporter expression, and AF alters ion-channel expression in VHD patients.

Background— We have previously linked hereditary progressive cardiac conduction defect (hereditary Lenègre’s disease) to a loss-of-function mutation in the gene encoding the main cardiac Na ⁺ channel, SCN5A . In the present study, we investigated heterozygous Scn5a -knockout mice ( Scn5a ^+/− mice) as a model for hereditary Lenègre’s disease. Methods and Results— In Scn5a ^+/− mice, surface ECG recordings showed age-related lengthening of the P-wave and PR- and QRS-interval duration, coinciding with previous observations in patients with Lenègre’s disease. Old but not young Scn5a ^+/− mice showed extensive fibrosis of their ventricular myocardium, a feature not seen in wild-type animals. In old Scn5a ^+/− mice, fibrosis was accompanied by heterogeneous expression of connexin 43 and upregulation of hypertrophic markers, including β-MHC and skeletal α-actin. Global connexin 43 expression as assessed with Western blots was similar to wild-type mice. Decreased connexin 40 expression was seen in the atria. Using pangenomic microarrays and real-time PCR, we identified in Scn5a ^+/− mice an age-related upregulation of genes encoding Atf3 and Egr1 transcription factors. Echocardiography and hemodynamic investigations demonstrated conserved cardiac function with aging and lack of ventricular hypertrophy. Conclusions— We conclude that Scn5a ^+/− mice convincingly recapitulate the Lenègre’s disease phenotype, including progressive impairment with aging of atrial and ventricular conduction associated with myocardial rearrangements and fibrosis. Our work provides the first demonstration that a monogenic ion channel defect can progressively lead to myocardial structural anomalies.

Calcification is independently associated with cardiovascular events and morbidity. The calcification burden in atherosclerotic lesions quantitatively and qualitatively differs between arterial beds. Cardiovascular risk factors (CVRF) differentially affect plaque development between arterial beds. The aim of this study was to evaluate the impact of CVRF on atherosclerotic plaque calcification and to further study the molecular arterial heterogeneity that could account for these differences. Histological analysis was performed on atherosclerotic plaques from 153 carotid, 97 femoral and 28 infrapopliteal arteries. CVRF showed minor associations with plaque calcification: age and hypertension affected only the overall presence of calcification but not the type of the calcification, which significantly differed between arterial beds. Transcriptome analysis revealed distinct gene expression profiles associated with each territory in atherosclerotic and healthy arteries. Canonical pathway analysis showed the preferential involvement of immune system-related processes in both atherosclerotic and healthy carotid arteries. Bone development-related genes were among those mostly enriched in atherosclerotic and healthy femoral arteries, which are more prone to developing endochondral calcification. This study highlights the heterogeneous nature of arteries from different peripheral vascular beds and contributes to a better understanding of atherosclerosis formation and evolution.