Bastiaan J. Boukens

Background: Sympathetic modulation via the stellate ganglia is increasingly recognized as a contributor to ventricular arrhythmogenesis after myocardial infarction. However, the mechanisms by which autonomic remodeling interacts with chronic infarct substrates to shape arrhythmic vulnerability remain incompletely understood. Objectives: To test the hypothesis that left- and right-sided stellate ganglion-mediated SNS modulation differentially reshapes ventricular arrhythmic vulnerability in chronic postinfarcted substrates, and that the RVI detects changes in vulnerability beyond conventional stimulation-based inducibility. Methods: Fourteen patient-specific ventricular models with chronic post-infarcted remodeling were reconstructed from imaging data. A total of 336 simulations were performed under different combinations of stellate ganglion modulation, border zone remodeling, and fibroblast density. Arrhythmic vulnerability was quantified using 3D RVI mapping during paced rhythms and compared with conventional stimulation-based inducibility outcomes. Results: Stellate ganglion modulation induced marked, regionally heterogeneous changes in repolarization timing, resulting in lower and more negative RVI values in vulnerable regions. More negative RVI values reflect increased propensity for wavefront-waveback interaction and reentry initiation. Across the cohort, stellate modulation consistently decreased RVImin, even when inducibility outcomes remained unchanged. These findings indicate that SNS modulation can create a substrate more permissive to reentry independently of whether ventricular arrhythmia is triggered during programmed stimulation. Conclusions: Stellate ganglion-mediated sympathetic modulation dynamically reshapes ventricular arrhythmic vulnerability in chronic post-infarcted substrates. RVI provides a spatially resolved, vulnerability-based metric that complements inducibility testing by revealing autonomic-substrate interactions underlying arrhythmogenesis

Aims: Acute myocardial ischaemia causes fatal arrhythmias as result of a flow of ‘injury current’. Left stellate ganglion stimulation (LSGS) modulates the injury current and is arrhythmogenic during left anterior ventricular wall ischaemia. The role of right stellate ganglion stimulation (RSGS) in arrhythmogenesis is unclear. We hypothesized that RSGS is proarrhythmic during left lateral ventricular wall ischaemia. Methods and results: In 11 anaesthetized female pigs, ventricular repolarization was measured in unipolar epicardial electrograms from the left lateral ventricular wall. Seven subsequent episodes of acute ischaemia (5 min) were produced by occlusion of the circumflex coronary artery (CX), separated by 20 min of reperfusion. The second occlusion served as a control. After 3 min of ischaemia during the third occlusion, LSGS was initiated for 30 s. In the 4th occlusion, RSGS was performed. After decentralization of both left and right stellate ganglia and vagal nerves, LSGS and RSGS were initiated (6th and 7th occlusions). RSGS during ischaemia was more arrhythmogenic than LSGS or control with more spontaneous ventricular premature beats (3–5 min of ischaemia) and two instances of ventricular fibrillation. The LSGS-induced effect on repolarization was absent in myocardium that had been ischaemic for 3 min by CX occlusion. Conclusions: LSGS-induced repolarization shortening is absent in ischaemic myocardium. RSGS was more arrhythmogenic following CX occlusion than LSGS or control. These data demonstrate that the arrhythmogenic influence of RSGS or LSGS is contingent on the location of ischaemic zone supporting the clinical findings that bilateral sympathectomy is superior to left sympathectomy alone.

Ablation of sites displaying Purkinje activity is highly effective against idiopathic ventricular fibrillation which often originates in the right ventricular outflow tract. However, during endocardial mapping Purkinje potentials are rarely, if never, detected in the right ventricular outflow tract. In the present study, we aimed to determine whether the Purkinje system extends into the right ventricular outflow tract. Hearts of five female sheep were blood-perfused in a Langendorff setup in which we performed epicardial and endocardial voltage mapping. During atrial pacing, the right ventricular outflow tract epicardium activated later than the epicardium of the left and right ventricular free walls. Endocardial mapping revealed Purkinje spikes at several sites in the free wall of the right ventricular outflow tract. In one heart, Purkinje spikes preceded ventricular premature beats during mapping, but were not visible during sinus rhythm. Subsequent immuno-histological examination showed a network of Connexin 40-positive Purkinje fibers across and within the wall of the right ventricular outflow tract. Quantitative analysis revealed that the transmural Purkinje fiber network was more abundant near the endocardium than epicardium. In conclusion, the Purkinje system extends into the right ventricular outflow tract of the sheep heart. These findings demonstrate that the sheep could be a valuable model for studying Purkinje-related arrhythmias in the right ventricular outflow tract.

Background and Aims: Life-threatening arrhythmias are a well-established consequence of reduced cardiac sodium current (INa). Gene therapy approaches to increase INa have demonstrated potential benefits to prevent arrhythmias. However, the development of such therapies is hampered by the large size of sodium channels. In this study, SCN10A-short (S10s), a short transcript encoding the carboxy-terminal domain of the human neuronal sodium channel, was evaluated as a gene therapy target to increase INa and prevent arrhythmias. Methods: Adeno-associated viral vector overexpressing S10s was injected into wild type and Scn5a-haploinsufficient mice on which patch-clamp studies, optical mapping, electrocardiogram analyses, and ischaemia reperfusion were performed. In vitro and in silico studies were conducted to further explore the effect of S10s gene therapy in the context of human hearts. Results: Cardiac S10s overexpression increased cellular INa, maximal action potential upstroke velocity, and action potential amplitude in Scn5a-haploinsufficient cardiomyocytes. S10s gene therapy rescues conduction slowing in Scn5a-haploinsufficient mice and prevented ventricular tachycardia induced by ischaemia-reperfusion in wild type mice. S10s overexpression increased maximal action potential upstroke velocity in human inducible pluripotent stem cell-derived cardiomyocytes and prevented inducible arrhythmias in simulated human heart models. Conclusions: S10s gene therapy may be effective to treat cardiac conduction abnormalities and associated arrhythmias.

BACKGROUND: Transcriptional dysregulation, possibly affected by genetic variation, contributes to disease etiology. Due to dissimilarities in development, function, and remodeling during disease progression, transcriptional differences between the left atrium (LA) and right atrium (RA) may provide insight into diseases such as atrial fibrillation. METHODS: Lateral differences in atrial transcription were evaluated in CATCH ME (Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly) using a 2-stage discovery and replication design. The design took advantage of the availability of 32 paired samples, for which both LA and RA tissue were obtained, as a discovery cohort, and 98 LA and 69 RA unpaired samples utilized as a replication cohort. RESULTS: A total of 714 transcripts were identified and replicated as differentially expressed (DE) between LA and RA, as well as 98 exons in 55 genes. Approximately 50% of DE transcripts were colocated with another frequently correlated DE transcript ( P _FDR ≤0.05 for 579 regions). These “transcription disequilibrium” blocks contained examples including side-specific differential exon usage, such as the PITX2 locus, where ENPEP showed evidence of differential exon usage. Analysis of this region in conjunction with BMP10 identified rs9790621 as associated with ENPEP transcription in LA, while rs7687878 was associated with BMP10 expression in RA. In RA, BMP10 and ENPEP were strongly correlated in noncarriers, which was attenuated in risk-allele carriers, where BMP10 and PITX2 expression were strongly correlated. CONCLUSIONS: These results significantly expand knowledge of the intricate, tissue-specific transcriptional landscape in human atria, including DE transcripts and side-specific isoform expression. Furthermore, they suggest the existence of blocks of transcription disequilibrium influenced by genetics.

The right ventricular outflow tract (RVOT) is the outlet from the right ventricle of the heart and has received much attention since it was discovered in the early 2000s to be the origin of life-threatening arrhythmias in patients with Brugada syndrome.¹ The reason why these lethal arrhythmias originate in the myocardial wall of the RVOT has been the subject of research ever since. The luminal side of the left and right ventricular free walls is trabeculated, whereas the luminal side of the outflow tract wall of both ventricles is considered to be a-trabecular and smooth.² Our aim was to investigate whether trabeculation could occur in the RVOT and whether this would affect electrical propagation. Figure 1A shows a MRI-based three-dimensional reconstruction of a normal human heart. The right ventricular wall was trabeculated on the luminal side, whereas the anterior superior part was smooth, revealing the RVOT. The right anterior aspect of the luminal side of the RVOT was marked by septo-marginal trabeculations.³ Next, we visualized a subendocardial longitudinal layer of myocardium and subepicardial oblique myocardial bundles using photographs of automatically serially sectioned cryopreserved human RVOT myocardium (Figure 1B). Towards the ventricular apex, the oblique layer became continuous with the compact layer of the right ventricular free wall, whereas the longitudinal layer mostly gave way to trabeculations. Macroscopic examination of one of six post-mortem hearts revealed almost complete trabeculation of the RVOT myocardial wall (Figure 1C). The trabeculations reached the base of the right-facing and non-facing leaflets of the pulmonary valve, and the anterior smooth-walled portion of the RVOT was only ±2 mm. In other five hearts, the anterior smooth-walled portion was ±2 cm in length. To further characterize the variation in the smooth-walled surface of the RVOT myocardium, we analysed the anterior aspect of luminal casts of 11 hearts from the Atlas of Human Cardiac Anatomy⁴ (Figure 1D). In these hearts, the RVOT accounted for ±14% of the right ventricular area from the anterior view, with considerable variation between individual hearts (9–23%) (Figure 1E).

We present a physiological basis for the interpretation of multielectrode array-derived, extracellular, electrical signals.