Adenoviral expression of IKs contributes to wavebreak and fibrillatory conduction in neonatal rat ventricular cardiomyocyte monolayers

Previous studies have shown that the gating kinetics of the slow component of the delayed rectifier K(+) current (I(Ks)) contribute to postrepolarization refractoriness in isolated cardiomyocytes. However, the impact of such kinetics on arrhythmogenesis remains unknown. We surmised that expression of I(Ks) in rat cardiomyocyte monolayers contributes to wavebreak formation and facilitates fibrillatory conduction by promoting postrepolarization refractoriness. Optical mapping was performed in 44 rat ventricular myocyte monolayers infected with an adenovirus carrying the genomic sequences of KvLQT1 and minK (molecular correlates of I(Ks)) and 41 littermate controls infected with a GFP adenovirus. Repetitive bipolar stimulation was applied at increasing frequencies, starting at 1 Hz until loss of 1:1 capture or initiation of reentry. Action potential duration (APD) was significantly shorter in I(Ks)-infected monolayers than in controls at 1 to 3 Hz (P<0.05), whereas differences at higher pacing frequencies did not reach statistical significance. Stable rotors occurred in both groups, with significantly higher rotation frequencies, lower conduction velocities, and shorter action potentials in the I(Ks) group. Wavelengths in the latter were significantly shorter than in controls at all rotation frequencies. Wavebreaks leading to fibrillatory conduction occurred in 45% of the I(Ks) reentry episodes but in none of the controls. Moreover, the density of wavebreaks increased with time as long as a stable source sustained the fibrillatory activity. These results provide the first demonstration that I(Ks)-mediated postrepolarization refractoriness can promote wavebreak formation and fibrillatory conduction during pacing and sustained reentry and may have important implications in tachyarrhythmias.

Wide QRS-complex tachycardia with variable VA-conduction: what is the mechanism?

We describe the case of a 16-year-old woman with a surgically corrected tetralogy of Fallot presenting with recurrent wide-QRS-complex tachycardia. The tachycardia could be induced and terminated with ventricular stimulation only. QRS morphology during sinus rhythm and tachycardia was identical and variable VA-conduction was observed. Mapping of the tachycardia showed that variations of HH intervals preceded VV intervals. Therefore, a mechanism involving re-entry within the bundle branches was suggested. However, detailed mapping showed cranial to caudal depolarization of the His bundle, leading to the diagnosis of atrioventricular node re-entrant tachycardia. The tachycardia was abolished by radiofrequency catheter ablation of the slow AV nodal pathway. We conclude that variable VA conduction can occur in patients with atrioventricular node re-entrant tachycardia. The atrial tissue is not always an integral part of the re-entrant circuit.

Ultrasound-guided needle positioning in sensory nerve conduction study of the sural nerve

OBJECTIVES: To evaluate the usefulness of ultrasound imaging to improve the positioning of the recording needle for nerve conduction studies (NCS) of the sural nerve. METHODS: Orthodromic NCS of the sural nerve was performed in 44 consecutive patients evaluated for polyneuropathy. Ultrasound-guided needle positioning (USNP) was compared to conventional "blind" needle positioning (BNP), electrically guided needle positioning (EGNP), and to recordings with surface electrodes (SFN). RESULTS: The mean distance between the needle tip and the nerve was 1.1 mm with USNP compared to 5.1 mm with BNP (p<0.0001). The mean amplitude of the sensory nerve action potential (SNAP) was 21 microV with USNP and 11 microV with BNP (p<0.0001). Compared to BNP, nerve-needle distances and SNAP amplitudes did not improve with EGNP. SNAP amplitudes recorded with SFN were significantly smaller than with BNP, EGNP and USNP. CONCLUSION: Ultrasound increases the precision of needle positioning markedly, compared to conventional methods. The amplitude of the recorded SNAP is usually clearly greater using USNP. In addition, USNP is faster, less painful and less dependent on the patient. SIGNIFICANCE: USNP is superior to BNP, EGNP, and SFN in accurate measurement of SNAP amplitude. It has a potential use in the routine near-nerve needle sensory NCS of pure sensory nerves.

Association of congenital, diffuse electrical disease in children with normal heart: sick sinus syndrome, intraventricular conduction block, and monomorphic ventricular tachycardia.

INTRODUCTION Rhythm disturbances in children with structurally normal hearts are usually associated with abnormalities in cardiac ion channels. The phenotypic expression of these abnormalities ("channelopathies") includes: long and short QT syndromes, Brugada syndrome, congenital sick sinus syndrome, catecholaminergic polymorphic ventricular tachycardia, Lènegre-Lev disease, and/or different degrees of cardiac conduction disease. METHODS The study group consisted of three male patients with sick sinus syndrome, intraventricular conduction disease, and monomorphic sustained ventricular tachycardia. Clinical data and results of electrocardiography, Holter monitoring, electrophysiology, and echocardiography are described. RESULTS In all patients, the ECG during sinus rhythm showed right bundle branch block and long QT intervals. First-degree AV block was documented in two subjects, and J point elevation in one. A pacemaker was implanted in all cases due to symptomatic bradycardia (sick sinus syndrome). Atrial tachyarryhthmias were observed in two patients. The common characteristic ventricular arrhythmia was a monomorphic sustained ventricular tachycardia, inducible with ventricular stimulation and sensitive to lidocaine. In one patient, radiofrequency catheter ablation was successfully performed. No structural abnormalities were found in echocardiography in the study group. CONCLUSION Common clinical and ECG features suggest a common pathophysiology in this group of patients with congenital severe electrical disease.

A novel C-terminal truncation SCN5A mutation from a patient with sick sinus syndrome, conduction disorder and ventricular tachycardia.

OBJECTIVES Individual mutations in the SCN5A-encoding cardiac sodium channel alpha-subunit cause single cardiac arrhythmia disorders, but a few cause multiple distinct disorders. Here we report a family harboring an SCN5A mutation (L1821fs/10) causing a truncation of the C-terminus with a marked and complex biophysical phenotype and a corresponding variable and complex clinical phenotype with variable penetrance. METHODS AND RESULTS A 12-year-old male with congenital sick sinus syndrome (SSS), cardiac conduction disorder (CCD), and recurrent monomorphic ventricular tachycardia (VT) had mutational analysis that identified a 4 base pair deletion (TCTG) at position 5464-5467 in exon 28 of SCN5A. The mutation was also present in six asymptomatic family members only two of which showed mild ECG phenotypes. The deletion caused a frame-shift mutation (L1821fs/10) with truncation of the C-terminus after 10 missense amino acid substitutions. When expressed in HEK-293 cells for patch-clamp study, the current density of L1821fs/10 was reduced by 90% compared with WT. In addition, gating kinetic analysis showed a 5-mV positive shift in activation, a 12-mV negative shift of inactivation and enhanced intermediate inactivation, all of which would tend to reduce peak and early sodium current. Late sodium current, however, was increased in the mutated channels. CONCLUSIONS The L1821fs/10 mutation causes the most severe disruption of SCN5A structure for a naturally occurring mutation that still produces current. It has a marked loss-of-function and unique phenotype of SSS, CCD and VT with incomplete penetrance.

Bone conduction in Thiel-embalmed cadaver heads

INTRODUCTION Sound can reach the inner ear via at least two different pathways: air conduction and bone conduction (BC). BC hearing is used clinically for diagnostic purposes and for BC hearing aids. Research on the motion of the human middle ear in response to BC stimulation is typically conducted using cadaver models. We evaluated middle ear motion of Thiel-embalmed whole-head specimens in terms of linearity, reproducibility, and consistency with the reported middle ear motion of living subjects, fresh cadaveric temporal bones, and whole-heads embalmed with a Non-Thiel solution of salts. METHODS We used laser Doppler vibrometry to measure the displacement of the skull, the umbo, the cochlear promontory, the stapes, and the round window in seven ears from four human whole-head specimens embalmed according to Thiel's method. The ears were stimulated with a Baha(®) implanted behind the auricle. RESULTS The Thiel model shows promontory velocity similar to that reported in the literature for whole-heads embalmed with a Non-Thiel solution of salts (0- to 7-dB difference). The Thiel heads' relative velocity of the stapes with respect to the promontory was similar to that of fresh cadaver temporal bones (0- to 4-dB difference). The velocity of the umbo was comparable in Thiel-embalmed heads and living subjects (0- to 10-dB difference). The skull and all middle ear elements measured responded linearly to different stimulation levels, with an average difference less than 1 dB. The variability of repeated measurements for both short- (2 h; 4 dB) and long-term (4-16 weeks; 6 dB) repetitions in the same ear, and the difference between the two ears of the same donor (approximately 10 dB) were lower than the inter-individual difference (up to 25 dB). CONCLUSION Thiel-embalmed human whole-head specimens can be used as an alternative model for the study of human middle ear mechanics secondary to BC stimulation. At some frequencies, differences from living subjects must be considered.

Nonlinear behaviour of conduction and block in cardiac tissue with heterogeneous expression of connexin 43

Altered gap junctional coupling potentiates slow conduction and arrhythmias. To better understand how heterogeneous connexin expression affects conduction at the cellular scale, we investigated conduction in tissue consisting of two cardiomyocyte populations expressing different connexin levels. Conduction was mapped using microelectrode arrays in cultured strands of foetal murine ventricular myocytes with prede fi ned contents of connexin 43 knockout (Cx43KO) cells. Corresponding computer simulations were run in randomly generated two-dimensional tissues mimicking the cellular architecture of the strands. In the cultures, the relationship between conduction velocity (CV) and Cx43KO cell content was nonlinear. CV fi rst decreased signi fi cantly when Cx43KO content was increased from 0 to 50%. When the Cx43KO content was ≥ 60%, CV became comparabletothatin100%Cx43KOstrands.Co-culturingCx43KOandwild-typecellsalsoresultedinsigni fi cantly more heterogeneous conduction patterns and in frequent conduction blocks. The simulations replicated this behaviour of conduction. For Cx43KO contents of 10 – 50%, conduction was slowed due to wavefront meandering between Cx43KO cells. For Cx43KO contents ≥ 60%, clusters of remaining wild-type cells acted as electrical loads thatimpairedconduction.ForCx43KOcontentsof40 – 60%,conductionexhibitedfractal characteristics,wasprone to block, and was more sensitive to changes in ion currents compared to homogeneous tissue. In conclusion, conduction velocity and stability behave in a nonline ar manner when cardiomyocytes expressing different connexin amounts are combined. This behaviour results from heterogeneous current-to-load relationships at the cellular level. Such behaviour is likely to be arrhythmogenic in various clinical contexts in which gap junctional coupling is heterogeneous.

Is complex signal processing for bone conduction hearing aids useful?

OBJECTIVES To establish whether complex signal processing is beneficial for users of bone anchored hearing aids. METHODS Review and analysis of two studies from our own group, each comparing a speech processor with basic digital signal processing (either Baha Divino or Baha Intenso) and a processor with complex digital signal processing (either Baha BP100 or Baha BP110 power). The main differences between basic and complex signal processing are the number of audiologist accessible frequency channels and the availability and complexity of the directional multi-microphone noise reduction and loudness compression systems. RESULTS Both studies show a small, statistically non-significant improvement of speech understanding in quiet with the complex digital signal processing. The average improvement for speech in noise is +0.9 dB, if speech and noise are emitted both from the front of the listener. If noise is emitted from the rear and speech from the front of the listener, the advantage of the devices with complex digital signal processing as opposed to those with basic signal processing increases, on average, to +3.2 dB (range +2.3 … +5.1 dB, p ≤ 0.0032). DISCUSSION Complex digital signal processing does indeed improve speech understanding, especially in noise coming from the rear. This finding has been supported by another study, which has been published recently by a different research group. CONCLUSIONS When compared to basic digital signal processing, complex digital signal processing can increase speech understanding of users of bone anchored hearing aids. The benefit is most significant for speech understanding in noise.

Optical recording of calcium currents during impulse conduction in cardiac tissue

We explore the feasibility of obtaining a spatially resolved picture of Ca2+Ca2+ inward currents (ICaICa) in multicellular cardiac tissue by differentiating optically recorded Ca2+Ca2+ transients that accompany propagating action potentials. Patterned growth strands of neonatal rat ventricular cardiomyocytes were stained with the Ca2+Ca2+ indicators Fluo-4 or Fluo-4FF. Preparations were stimulated at 1 Hz, and Ca2+Ca2+ transients were recorded with high spatiotemporal resolution (50  μm50  μm, 2 kHz analog bandwidth) with a photodiode array. Signals were differentiated after appropriate digital filtering. Differentiation of Ca2+Ca2+ transients resulted in optically recorded calcium currents (ORCCs) that carried the temporal and pharmacological signatures of L-type Ca2+Ca2+ inward currents: the time to peak amounted to ∼2.1  ms∼2.1  ms (Fluo-4FF) and ∼2.4  ms∼2.4  ms (Fluo-4), full-width at half-maximum was ∼8  ms∼8  ms, and ORCCs were completely suppressed by 50  μmol/L50  μmol/LCdCl2CdCl2. Also, and as reported before from patch-clamp studies, caffeine reversibly depressed the amplitude of ORCCs. The results demonstrate that the differentiation of Ca2+Ca2+ transients can be used to obtain a spatially resolved picture of the initial phase of ICaICa in cardiac tissue and to assess relative changes of activation/fast inactivation of ICaICa following pharmacological interventions.

Slow conduction in mixed cultured strands of primary ventricular cells and stem cell-derived cardiomyocytes

Modern concepts for the treatment of myocardial diseases focus on novel cell therapeutic strategies involving stem cell-derived cardiomyocytes (SCMs). However, functional integration of SCMs requires similar electrophysiological properties as primary cardiomyocytes (PCMs) and the ability to establish intercellular connections with host myocytes in order to contribute to the electrical and mechanical activity of the heart. The aim of this project was to investigate the properties of cardiac conduction in a co-culture approach using SCMs and PCMs in cultured cell strands. Murine embryonic SCMs were pooled with fetal ventricular cells and seeded in predefined proportions on microelectrode arrays to form patterned strands of mixed cells. Conduction velocity (CV) was measured during steady state pacing. SCM excitability was estimated from action potentials measured in single cells using the patch clamp technique. Experiments were complemented with computer simulations of conduction using a detailed model of cellular architecture in mixed cell strands. CV was significantly lower in strands composed purely of SCMs (5.5 ± 1.5 cm/s, n = 11) as compared to PCMs (34.9 ± 2.9 cm/s, n = 21) at similar refractoriness (100% SCMs: 122 ± 25 ms, n = 9; 100% PCMs: 139 ± 67 ms, n = 14). In mixed strands combining both cell types, CV was higher than in pure SCMs strands, but always lower than in 100% PCM strands. Computer simulations demonstrated that both intercellular coupling and electrical excitability limit CV. These data provide evidence that in cultures of murine ventricular cardiomyocytes, SCMs cannot restore CV to control levels resulting in slow conduction, which may lead to reentry circuits and arrhythmias.

Quality standards for bone conduction implants.

CONCLUSION Bone conduction implants are useful in patients with conductive and mixed hearing loss for whom conventional surgery or hearing aids are no longer an option. They may also be used in patients affected by single-sided deafness. OBJECTIVES To establish a consensus on the quality standards required for centers willing to create a bone conduction implant program. METHOD To ensure a consistently high level of service and to provide patients with the best possible solution the members of the HEARRING network have established a set of quality standards for bone conduction implants. These standards constitute a realistic minimum attainable by all implant clinics and should be employed alongside current best practice guidelines. RESULTS Fifteen items are thoroughly analyzed. They include team structure, accommodation and clinical facilities, selection criteria, evaluation process, complete preoperative and surgical information, postoperative fitting and assessment, follow-up, device failure, clinical management, transfer of care and patient complaints.

Inherited progressive cardiac conduction disorders.

PURPOSE OF REVIEW Progressive cardiac conduction disorder (PCCD) is an inherited cardiac disease that may present as a primary electrical disease or be associated with structural heart disease. In this brief review, we present recent clinical, genetic, and molecular findings relating to PCCD. RECENT FINDINGS Inherited PCCD in structurally normal hearts has been found to be linked to genetic variants in the ion channel genes SCN5A, SCN1B, SCN10A, TRPM4, and KCNK17, as well as in genes coding for cardiac connexin proteins. In addition, several SCN5A mutations lead to 'cardiac sodium channelopathy overlap syndrome'. Other genes coding for cardiac transcription factors, such as NKX2.5 and TBX5, are involved in the development of the cardiac conduction system and in the morphogenesis of the heart. Mutations in these two genes have been shown to cause cardiac conduction disorders associated with various congenital heart defects. SUMMARY PCCD is a hereditary syndrome, and genetic variants in multiple genes have been described to date. Genetic screening and identification of the causal mutation are crucial for risk stratification and family counselling.