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Nav channels are essential for metazoan membrane depolarization, and Nav channel dysfunction is directly linked with epilepsy, ataxia, pain, arrhythmia, myotonia, and irritable bowel syndrome. Human Nav channelopathies are primarily caused by variants that directly affect Nav channel permeability or gating. However, a new class of human Nav channelopathies has emerged based on channel variants that alter regulation by intracellular signaling or cytoskeletal proteins. Fibroblast growth factor homologous factors (FHFs) are a family of intracellular signaling proteins linked with Nav channel regulation in neurons and myocytes. However, to date, there is surprisingly little evidence linking Nav channel gene variants with FHFs and human disease. Here, we provide, to our knowledge, the first evidence that mutations in SCN5A (encodes primary cardiac Nav channel Nav1.5) that alter FHF binding result in human cardiovascular disease. We describe a five*generation kindred with a history of atrial and ventricular arrhythmias, cardiac arrest, and sudden cardiac death. Affected family members harbor a novel SCN5A variant resulting in p.H1849R. p.H1849R is localized in the central binding core on Nav1.5 for FHFs. Consistent with these data, Nav1.5 p.H1849R affected interaction with FHFs. Further, electrophysiological analysis identified Nav1.5 p.H1849R as a gain-of-function for INa by altering steady-state inactivation and slowing the rate of Nav1.5 inactivation. In line with these data and consistent with human cardiac phenotypes, myocytes expressing Nav1.5 p.H1849R displayed prolonged action potential duration and arrhythmogenic afterdepolarizations. Together, these findings identify a previously unexplored mechanism for human Nav channelopathy based on altered Nav1.5 association with FHF proteins.

The article discusses a study that hypothesized that intranodal pacemakers and sinoatrial conduction pathways with redundant functions have diverse sensitivities to physiologic and pathophysiologic perturbations. Study highlights include the impact of sequential drug applications on sinus rhythm in individual human hearts, intranodal leading pacemaker and conduction in the human sinoatrial node (SAN), and robustness of SAN automaticity and conduction challenged by adenosine.

Background: Adenosine provokes atrial fibrillation (AF) with a higher activation frequency in right atria (RA) versus left atria (LA) in patients, but the underlying molecular and functional substrates are unclear. We tested the hypothesis that adenosine-induced AF is driven by localized reentry in RA areas with highest expression of adenosine A1 receptor and its downstream GIRK (G protein-coupled inwardly rectifying potassium channels) channels (IK,Ado).Methods: We applied biatrial optical mapping and immunoblot mapping of various atrial regions to reveal the mechanism of adenosine-induced AF in explanted failing and nonfailing human hearts (n=37).Results: Optical mapping of coronary-perfused atria (n=24) revealed that adenosine perfusion (10-100 µmol/L) produced more significant shortening of action potential durations in RA (from 290±45 to 239±41 ms, 17.3±10.4%; P<0.01) than LA (from 307±24 to 286±23 ms, 6.7±6.6%; P<0.01). In 10 hearts, adenosine induced AF (317±116 s) that, when sustained (≥2 minutes), was primarily maintained by 1 to 2 localized reentrant drivers in lateral RA. Tertiapin (10-100 nmol/L), a selective GIRK channel blocker, counteracted adenosine-induced action potential duration shortening and prevented AF induction. Immunoblotting showed that the superior/middle lateral RA had significantly higher adenosine A1 receptor (2.7±1.7-fold; P<0.01) and GIRK4 (1.7±0.8-fold; P<0.05) protein expression than lateral/posterior LA.Conclusions: This study revealed a 3-fold RA-to-LA adenosine A1 receptor protein expression gradient in the human heart, leading to significantly greater RA versus LA repolarization sensitivity in response to adenosine. Sustained adenosine-induced AF is maintained by reentrant drivers localized in lateral RA regions with the highest adenosine A1 receptor/GIRK4 expression. Selective atrial GIRK channel blockade may effectively treat AF during conditions with increased endogenous adenosine. [ABSTRACT FROM AUTHOR]

Background: The hyperpolarization-activated current, If, plays an important role in sinoatrial node (SAN) pacemaking. Surprisingly, the distribution of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in human SAN has only been investigated at the mRNA level. Our aim was to define the expression pattern of HCN proteins in human SAN and different atrial regions. Methods and Results: Entire SAN complexes were isolated from failing (n=5) and nonfailing (n=9) human hearts cardioplegically arrested in the operating room. Three-dimensional intramural SAN structure was identified as the fibrotic compact region around the SAN artery with Connexin 43-negative pacemaker cardiomyocytes visualized in Masson's trichrome and immunostained cryosections. SAN protein was precisely isolated from the adjacent frozen SAN tissue blocks using a 16G biopsy needle. The purity of the SAN protein was confirmed by Connexin 43 immunoblot. All 3 HCN isoform proteins were detected in SAN. HCN1 was predominantly distributed in the human SAN with a 125.1±40.2 (n=12) expression ratio of SAN to right atrium. HCN2 and HCN4 expression levels were higher in SAN than in atria, with SAN to right atrium ratios of 6.1±0.9 and 4.6±0.6 (n=12), respectively. Conclusions: This is the first study to conduct precise 3D molecular mapping of the human SAN by isolating pure pacemaker SAN tissue. All 3 cardiac HCN isoforms had higher expression in the SAN than in the atria. HCN1 was almost exclusively expressed in SAN, emphasizing its utility as a new specific molecular marker of the human SAN and as a potential target of specific treatments intended to modify sinus rhythm. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common heart rhythm disturbance, and its treatment is an increasing economic burden on the health care system. Despite recent intense clinical, experimental and basic research activity, the treatment of AF with current antiarrhythmic drugs and catheter/surgical therapies remains limited. Radiofrequency catheter ablation (RFCA) is widely used to treat patients with AF. Current clinical ablation strategies are largely based on atrial anatomy and/or substrate detected using different approaches, and they vary from one clinical center to another. The nature of clinical ablation leads to ambiguity regarding the optimal patient personalization of the therapy partly due to the fact that each empirical configuration of ablation lines made in a patient is irreversible during one ablation procedure. To investigate optimized ablation lesion line sets, in silico experimentation is an ideal solution. 3D computer models give us a unique advantage to plan and assess the effectiveness of different ablation strategies before and during RFCA. Reliability of in silico assessment is ensured by inclusion of accurate 3D atrial geometry, realistic fiber orientation, accurate fibrosis distribution and cellular kinetics; however, most of this detailed information in the current computer models is extrapolated from animal models and not from the human heart. The predictive power of computer models will increase as they are validated with human experimental and clinical data. To make the most from a computer model, one needs to develop 3D computer models based on the same functionally and structurally mapped intact human atria with high spatial resolution. The purpose of this review paper is to summarize recent developments in clinically-derived computer models and the clinical insights they provide for catheter ablation. [ABSTRACT FROM AUTHOR]

Aims: The adult human sinoatrial node (SAN) has a specialized fibrotic intramural structure (35-55% fibrotic tissue) that provides mechanical and electrical protection from the surrounding atria. We hypothesize that late gadolinium-enhanced cardiovascular magnetic resonance (LGE-CMR) can be applied to define the fibrotic human SAN structure in vivo., Methods and Results: LGE-CMR atrial scans of healthy volunteers (n olu, 23-52 y.o.) using a 3 Tesla magnetic resonance imaging system with a spatial resolution of 1.0 mm3 or 0.625 × 0.625 × 1.25 mm3 were obtained and analysed. Percent fibrosis of total connective and cardiomyocyte tissue area in segmented atrial regions were measured based on signal intensity differences of fibrotic vs. non-fibrotic cardiomyocyte tissue. A distinct ellipsoidal fibrotic region (length: 23.6 ± 1.9 mm; width: 7.2 ± 0.9 mm; depth: 2.9 ± 0.4 mm) in all hearts was observed along the posterior junction of the crista terminalis and superior vena cava extending towards the interatrial septum, corresponding to the anatomical location of the human SAN. The SAN fibrotic region consisted of 41.9 ± 5.4% of LGE voxels above an average threshold of 2.7 SD (range 2-3 SD) from the non-fibrotic right atrial free wall tissue. Fibrosis quantification and SAN identification by in vivo LGE-CMR were validated in optically mapped explanted donor hearts ex vivo (n ivo, 19-65 y.o.) by contrast-enhanced CMR (9.4 Tesla; up to 90 µm3 resolution) correlated with serial histological sections of the SAN., Conclusion: This is the first study to visualize the 3D human SAN fibrotic structure in vivo using LGE-CMR. Identification of the 3D SAN location and its high fibrotic content by LGE-CMR may provide a new tool to avoid or target SAN structure during ablation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)