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Objective: To assess the quality of life (QoL) of patients with multiple sclerosis in France, Germany, and the United Kingdom with a cross sectional study.Methods: Patients were classified into three severity groups according to the expanded disability severity scale (EDSS); stage I, II, and III, corresponding to mild (EDSS 1.0-3.5), moderate (EDSS 4.0-6.0), or severe (EDSS 6.5-8.0) multiple sclerosis respectively. Ninety patients with multiple sclerosis and 30 control patients without multiple sclerosis were recruited in each country. Control patients were matched to the patients with multiple sclerosis according to age and sex. Quality of life was assessed using the functional status questionnaire (FSQ).Results: The aspects of QoL that were mostly affected in the three countries under study were physical function and general wellbeing. Social role function decreased with increased severity of disease in France and in particular in Germany. Multiple sclerosis did not seem to have an impact on psychological function. The QoL of control patients was systematically higher than that of patients with multiple sclerosis.Conclusions: Use of such a generic scale showed that progression of multiple sclerosis is accompanied by a decrease in QoL and suggested that this could be a relevant measurement in assessing the effect of treatment and progression of disease. Variation between countries, however, may be important. [ABSTRACT FROM AUTHOR]

Background: Isolated posterior leaflet mitral valve prolapse (PostMVP), a common form of MVP, often referred as fibroelastic deficiency, is considered a degenerative disease. PostMVP patients are usually asymptomatic and often undiagnosed until chordal rupture. The present study aims to characterize familial PostMVP phenotype and familial recurrence, its genetic background, and the pathophysiological processes involved., Methods: We prospectively enrolled 284 unrelated MVP probands, of whom 178 (63%) had bi-leaflet MVP and 106 had PostMVP (37%). Familial screening within PostMVP patients allowed the identification of 20 families with inherited forms of PostMVP for whom whole genome sequencing was carried out in probands. Functional in vivo and in vitro investigations were performed in zebrafishand in Hek293T cells., Results: In the 20 families with inherited form of PostMVP, 38.8% of relatives had a MVP/prodromal form, mainly of the posterior leaflet, with transmission consistent with an autosomal dominant mode of inheritance. Compared with control relatives, PostMVP family patients have clear posterior leaflet dystrophy on echocardiography. Patients with PostMVP present a burden of rare genetic variants in ARHGAP24. ARHGAP24 encodes the filamin A binding RhoGTPase-activating protein FilGAP and its silencing in zebrafish leads to atrioventricular regurgitation. In vitro functional studies showed that variants of FilGAP, found in PostMVP families, are loss-of-function variants impairing cellular adhesion and mechano-transduction capacities., Conclusions: PostMVP should not only be considered an isolated degenerative pathology but as a specific heritable phenotypic trait with genetic and functional pathophysiological origins. The identification of loss-of-function variants in ARHGAP24 further reinforces the pivotal role of mechano-transduction pathways in the pathogenesis of MVP., Clinical Perspective: Isolated posterior mitral valve prolapse (PostMVP), often called fibro-elastic deficiency MVP, is at least in some patients, a specific inherited phenotypic traitPostMVP has both genetic and functional pathophysiological origins Genetic variants in the ARHGAP24 gene, which encodes for the FilGAP protein, cause progressive Post MVP in familial cases, and impair cell adhesion and mechano-transduction capacities.

Objective: Variants in the FLNA gene have been associated with mitral valve dystrophy (MVD), and even polyvalvular disease has been reported. This study aimed to analyse the aortic valve and root involvement in FLNA -MVD families and its impact on outcomes., Methods: 262 subjects (37 (18-53) years, 140 male, 79 carriers: FLNA +) from 4 FLNA -MVD families were included. Echocardiography was performed in 185 patients and histological analysis in 3 explanted aortic valves. The outcomes were defined as aortic valve surgery or all-cause mortality., Results: Aortic valve alterations were found in 58% of FLNA + compared with 6% of FLNA - (p<0.001). 9 (13.4%) FLNA + had bicuspid aortic valve compared with 4 (3.4%) FLNA - (p=0.03). Overall, the transvalvular mean gradient was slightly increased in FLNA + (4.8 (4.1-6.1) vs 4.0 (2.9-4.9) mm Hg, p=0.02). The sinuses of Valsalva and sinotubular junction diameters were enlarged in FLNA + subjects (all p<0.05). 8 FLNA + patients underwent aortic valve surgery (0 in relatives; p<0.001). Myxomatous remodelling with an infiltration of immune cells was observed. Overall survival was similar between FLNA+ versus FLNA - subjects (86±5% vs 85±6%, p=0.36). There was no statistical evidence for an interaction between genetic status and sex (p=0.15), but the survival tended to be impaired in FLNA + men (p=0.06) whereas not in women (p=0.71)., Conclusion: The patients with FLNA variants present frequent aortic valve disease and worse outcomes. Bicuspid aortic valve is more frequent in patients carrying the FLNA -MVD variants. These unique features should be factored into the management of patients with dystrophic and/or bicuspid aortic valve., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Mitral valve prolapse (MVP) is a common condition affecting 2-3% of the general population, and the most complex form of valve pathology, with a complication rate up to 10-15% per year in advanced stages. Complications include mitral regurgitation which can lead to heart failure and atrial fibrillation, but also life-threatening ventricular arrhythmia and cardiovascular death. Sudden death has been recently brought to the forefront of MVP disease, increasing the complexity of management and suggesting that MVP condition is not properly understood. MVP can occur as part of syndromic conditions such as Marfan syndrome, but the most common form is non-syndromic, isolated or familial. Although a specific X-linked form of MVP was initially identified, autosomal dominant inheritance appears to be the primary mode of transmission. MVP can be stratified into myxomatous degeneration (Barlow), fibroelastic deficiency, and Filamin A-related MVP. While FED is still considered a degenerative disease associated with aging, myxomatous MVP and FlnA-MVP are recognized as familial pathologies. Deciphering genetic defects associated to MVP is still a work in progress; although FLNA , DCHS1 , and DZIP1 have been identified as causative genes in myxomatous forms of MVP thanks to familial approaches, they explain only a small proportion of MVP. In addition, genome-wide association studies have revealed the important role of common variants in the development of MVP, in agreement with the high prevalence of this condition in the population. Furthermore, a potential genetic link between MVP and ventricular arrhythmia or a specific type of cardiomyopathy is considered. Animal models that allow to advance in the genetic and pathophysiological knowledge of MVP, and in particular those that can be easily manipulated to express a genetic defect identified in humans are detailed. Corroborated by genetic data and animal models, the main pathophysiological pathways of MVP are briefly addressed. Finally, genetic counseling is considered in the context of MVP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Delwarde, Capoulade, Mérot, Le Scouarnec, Bouatia-Naji, Yu, Huttin, Selton-Suty, Sellal, Piriou, Schott, Dina and Le Tourneau.)

In the Middle East and North Africa (MENA) region, dogs are the main reservoir for rabies. In this region, rabies affects more domestic carnivores (50% of cases) than farm animals (40% of cases). Rabies in large livestock animals, which are infected mainly by dogs, results in economic losses, undermines food safety and poses a risk for humans. In the MENA region, rabies is largely an urban problem, the virus being transmitted to humans by free-roaming dogs, 30% of which are less than one year old. In cities, the density of the free-roaming dog population varies between 0.6 and 1.5 dogs per km2, and almost double this figure in suburban and rural areas, where 80% of canine rabies cases occur. In the Maghreb, the annual average number of confirmed human deaths from rabies is around 47, showing a strong correlation with the number of animal cases declared (approximately 1,442 cases a year). In the Middle East, only a few rabies cases in humans are officially reported, suggesting that rabies cases in humans are grossly underreported. National strategies to control rabies include vaccination, controlling the freeroaming dog population and raising awareness among the human population at risk. Owing to limited resources and poor coordination between the different stakeholders, these strategies are only partially implemented. The Food and Agriculture Organization of the United Nations, in close collaboration with the World Organisation for Animal Health and the World Health Organization, supports countries in formulating and implementing coordinated strategies between the ministries concerned, local authorities and non-governmental organisations.

Mitral valve prolapse (MVP) is a common condition that affects 2%-3% of the general population. MVP is thought to include syndromic forms such as Marfan syndrome and non-syndromic MVP, which is the most frequent form. Myxomatous degeneration and fibroelastic deficiency (FED) are regarded as two different forms of non-syndromic MVP. While FED is still considered a degenerative disease associated with ageing, frequent familial clustering has been demonstrated for myxomatous MVP. Familial and genetic studies led to the recognition of reduced penetrance and large phenotypic variability, and to the identification of prodromal or atypical forms as a part of the complex spectrum of the disease. Whereas autosomal dominant mode is the common inheritance pattern, an X linked form of non-syndromic MVP was recognised initially, related to Filamin-A gene, encoding for a cytoskeleton protein involved in mechanotransduction. This identification allowed a comprehensive description of a new subtype of MVP with a unique association of leaflet prolapse and paradoxical restricted motion in diastole. In autosomal dominant forms, three loci have been mapped to chromosomes 16p11-p12, 11p15.4 and 13q31-32. Although deciphering the underlying genetic defects is still a work in progress, DCHS1 mutations have been identified (11p15.4) in typical myxomatous disease, highlighting new molecular pathways and pathophysiological mechanisms leading to the development of MVP. Finally, a large international genome-wide association study demonstrated the implication of frequent variants in MVP development and opened new directions for future research. Hence, this review focuses on phenotypic, genetic and pathophysiological aspects of MVP., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Aims: Filamin-A (FLNA) was identified as the first gene of non-syndromic mitral valve dystrophy (FLNA-MVD). We aimed to assess the phenotype of FLNA-MVD and its impact on prognosis., Methods and Results: We investigated the disease in 246 subjects (72 mutated) from four FLNA-MVD families harbouring three different FLNA mutations. Phenotype was characterized by a comprehensive echocardiography focusing on mitral valve apparatus in comparison with control relatives. In this X-linked disease valves lesions were severe in men and moderate in women. Most men had classical features of mitral valve prolapse (MVP), but without chordal rupture. By contrast to regular MVP, mitral leaflet motion was clearly restricted in diastole and papillary muscles position was closer to mitral annulus. Valvular abnormalities were similar in the four families, in adults and young patients from early childhood suggestive of a developmental disease. In addition, mitral valve lesions worsened over time as encountered in degenerative conditions. Polyvalvular involvement was frequent in males and non-diagnostic forms frequent in females. Overall survival was moderately impaired in men (P = 0.011). Cardiac surgery rate (mainly valvular) was increased (33.3 ± 9.8 vs. 5.0 ± 4.9%, P < 0.0001; hazard ratio 10.5 [95% confidence interval: 2.9-37.9]) owing mainly to a lifetime increased risk in men (76.8 ± 14.1 vs. 9.1 ± 8.7%, P < 0.0001)., Conclusion: FLNA-MVD is a developmental and degenerative disease with complex phenotypic expression which can influence patient management. FLNA-MVD has unique features with both MVP and paradoxical restricted motion in diastole, sub-valvular mitral apparatus impairment and polyvalvular lesions in males. FLNA-MVD conveys a substantial lifetime risk of valve surgery in men.

Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but--even in adult life--remains dynamic and accessible for treatment. This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular-ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.

Although the genetic basis of mitral valve prolapse (MVP) has now been clearly established, the molecular and cellular mechanisms involved in the pathological processes associated to a specific mutation often remain to be determined. The FLNA gene (encoding Filamin A; FlnA) was the first gene associated to non-syndromic X-linked myxomatous valvular dystrophy, but the impacts of the mutations on its function remain un-elucidated. Here, using the first repeats (1-8) of FlnA as a bait in a yeast two-hybrid screen, we identified the tyrosine phosphatase PTPN12 (PTP-PEST) as a specific binding partner of this region of FlnA protein. In addition, using yeast two-hybrid trap assay pull down and co-immunoprecipitation experiments, we showed that the MVP-associated FlnA mutations (G288R, P637Q, H743P) abolished FlnA/PTPN12 interactions. PTPN12 is a key regulator of signaling pathways involved in cell-extracellular matrix (ECM) crosstalk, cellular responses to mechanical stress that involve integrins, focal adhesion transduction pathways, and actin cytoskeleton dynamics. Interestingly, we showed that the FlnA mutations impair the activation status of two PTPN12 substrates, the focal adhesion associated kinase Src, and the RhoA specific activating protein p190RhoGAP. Together, these data point to PTPN12/FlnA interaction and its weakening by FlnA mutations as a mechanism potentially involved in the physiopathology of FlnA-associated MVP.

Introduction: Phosphatidylinositol-4,5-bisphosphate (PIP2) is a cofactor necessary for the activity of KCNQ1 channels. Some Long QT mutations of KCNQ1, including R243H, R539W and R555C have been shown to decrease KCNQ1 interaction with PIP2. A previous study suggested that R539W is paradoxically less sensitive to intracellular magnesium inhibition than the WT channel, despite a decreased interaction with PIP2. In the present study, we confirm this peculiar behavior of R539W and suggest a molecular mechanism underlying it., Methods and Results: COS-7 cells were transfected with WT or mutated KCNE1-KCNQ1 channel, and patch-clamp recordings were performed in giant-patch, permeabilized-patch or ruptured-patch configuration. Similar to other channels with a decreased PIP2 affinity, we observed that the R243H and R555C mutations lead to an accelerated current rundown when membrane PIP2 levels are decreasing. As opposed to R243H and R555C mutants, R539W is not more but rather less sensitive to PIP2 decrease than the WT channel. A molecular model of a fragment of the KCNQ1 C-terminus and the membrane bilayer suggested that a potential novel interaction of R539W with cholesterol stabilizes the channel opening and hence prevents rundown upon PIP2 depletion. We then carried out the same rundown experiments under cholesterol depletion and observed an accelerated R539W rundown that is consistent with this model., Conclusions: We show for the first time that a mutation may shift the channel interaction with PIP2 to a preference for cholesterol. This de novo interaction wanes the sensitivity to PIP2 variations, showing that a mutated channel with a decreased affinity to PIP2 could paradoxically present a slowed current rundown compared to the WT channel. This suggests that caution is required when using measurements of current rundown as an indicator to compare WT and mutant channel PIP2 sensitivity.

Cardiac voltage-gated Na+ (Nav) channels are key determinants of action potential waveforms, refractoriness and propagation, and Nav1.5 is the main Nav pore-forming (α) subunit in the mammalian heart. Although direct phosphorylation of the Nav1.5 protein has been suggested to modulate various aspects of Nav channel physiology and pathophysiology, native Nav1.5 phosphorylation sites have not been identified. In the experiments here, a mass spectrometry (MS)-based proteomic approach was developed to identify native Nav1.5 phosphorylation sites directly. Using an anti-NavPAN antibody, Nav channel complexes were immunoprecipitated from adult mouse cardiac ventricles. The MS analyses revealed that this antibody immunoprecipitates several Nav α subunits in addition to Nav1.5, as well as several previously identified Nav channel associated/regulatory proteins. Label-free comparative and data-driven phosphoproteomic analyses of purified cardiac Nav1.5 protein identified 11 phosphorylation sites, 8 of which are novel. All the phosphorylation sites identified except one in the N-terminus are in the first intracellular linker loop, suggesting critical roles for this region in phosphorylation-dependent cardiac Nav channel regulation. Interestingly, commonly used prediction algorithms did not reliably predict these newly identified in situ phosphorylation sites. Taken together, the results presented provide the first in situ map of basal phosphorylation sites on the mouse cardiac Nav1.5 α subunit.

Objectives: The aim of this study was to describe a new familial cardiac phenotype and to elucidate the electrophysiological mechanism responsible for the disease., Background: Mutations in several genes encoding ion channels, especially SCN5A, have emerged as the basis for a variety of inherited cardiac arrhythmias., Methods: Three unrelated families comprising 21 individuals affected by multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by narrow junctional and rare sinus beats competing with numerous premature ventricular contractions with right and/or left bundle branch block patterns were identified., Results: Dilated cardiomyopathy was identified in 6 patients, atrial arrhythmias were detected in 9 patients, and sudden death was reported in 5 individuals. Invasive electrophysiological studies demonstrated that premature ventricular complexes originated from the Purkinje tissue. Hydroquinidine treatment dramatically decreased the number of premature ventricular complexes. It normalized the contractile function in 2 patients. All the affected subjects carried the c.665G>A transition in the SCN5A gene. Patch-clamp studies of resulting p.Arg222Gln (R222Q) Nav1.5 revealed a net gain of function of the sodium channel, leading, in silico, to incomplete repolarization in Purkinje cells responsible for premature ventricular action potentials. In vitro and in silico studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine., Conclusions: A new SCN5A-related cardiac syndrome, MEPPC, was identified. The SCN5A mutation leads to a gain of function of the sodium channel responsible for hyperexcitability of the fascicular-Purkinje system. The MEPPC syndrome is responsive to hydroquinidine., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Voltage-dependent potassium (Kv) channels are tetramers of six transmembrane domain (S1-S6) proteins. Crystallographic data demonstrate that the tetrameric pore (S5-S6) is surrounded by four voltage sensor domains (S1-S4). One key question remains: how do voltage sensors (S4) regulate pore gating? Previous mutagenesis data obtained on the Kv channel KCNQ1 highlighted the critical role of specific residues in both the S4-S5 linker (S4S5(L)) and S6 C terminus (S6(T)). From these data, we hypothesized that S4S5(L) behaves like a ligand specifically interacting with S6(T) and stabilizing the closed state. To test this hypothesis, we designed plasmid-encoded peptides corresponding to portions of S4S5(L) and S6(T) of the voltage-gated potassium channel KCNQ1 and evaluated their effects on the channel activity in the presence and absence of the ancillary subunit KCNE1. We showed that S4S5(L) peptides inhibit KCNQ1, in a reversible and state-dependent manner. S4S5(L) peptides also inhibited a voltage-independent KCNQ1 mutant. This inhibition was competitively prevented by a peptide mimicking S6(T), consistent with S4S5(L) binding to S6(T). Val(254) in S4S5(L) is known to contact Leu(353) in S6(T) when the channel is closed, and mutations of these residues alter the coupling between the two regions. The same mutations introduced in peptides altered their effects, further confirming S4S5(L) binding to S6(T). Our results suggest a mechanistic model in which S4S5(L) acts as a voltage-dependent ligand bound to its receptor on S6 at rest. This interaction locks the channel in a closed state. Upon plasma membrane depolarization, S4 pulls S4S5(L) away from S6(T), allowing channel opening.

KCNQ1 osmosensitivity is of physiological and pathophysiological relevance in epithelial and cardiac cells, but the mechanism involved remains elusive. In COS-7 cells expressing the KCNE1-KCNQ1 fusion protein, extracellular hypoosmolarity and hyperosmolarity modify the channel biophysical parameters. These changes are consistent with hypoosmolarity increasing the level of membrane phosphatidylinositol-4,5-bisphosphate (PIP(2)), which in turn upregulates KCNE1-KCNQ1 channels. We showed that increasing PIP(2) levels with a water-soluble PIP(2) analogue prevented channel upregulation in hypoosmotic condition, suggesting a variation of the channel-PIP(2) interaction during channel osmoregulation. Furthermore, we showed that polyamines and Mg(2+), already known to tonically inhibit KCNQ channels by screening PIP(2) negative charges, are involved in the osmoregulatory process. Indeed, intracellular Mg(2+) removal and polyamines chelation inhibited the channel osmoregulation. Thus, the dilution of those cations during cell swelling might decrease channel inhibition and explain the channel upregulation by hypoosmolarity. To support this idea, we quantified the role of Mg(2+) in the osmodependent channel activity. Direct measurement of intracellular [Mg(2+)] variations during osmotic changes and characterization of the channel Mg(2+) sensitivity showed that Mg(2+) participates significantly to the osmoregulation. Using intracellular solutions that mimic the variation of Mg(2+) and polyamines, we were able to recapitulate the current amplitude variations in response to extracellular osmolarity changes. Altogether, these results support the idea of a modulation of the channel-PIP(2) interactions by Mg(2+) and polyamines during cell volume changes. It is likely that this mechanism applies to other channels that are sensitive to both osmolarity and PIP(2).

Phosphatidylinositol-4,5-bisphosphate (PIP(2)) is a phospholipid that has been shown to modulate several ion channels, including some voltage-gated channels like Kv11.1 (hERG). From a biophysical perspective, the mechanisms underlying this regulation are not well characterized. From a physiological perspective, it is critical to establish whether the PIP(2) effect is within the physiological concentration range. Using the giant-patch configuration of the patch-clamp technique on COS-7 cells expressing hERG, we confirmed the activating effect of PIP(2). PIP(2) increased the hERG maximal current and concomitantly slowed deactivation. Regarding the molecular mechanism, these increased amplitude and slowed deactivation suggest that PIP(2) stabilizes the channel open state, as it does in KCNE1-KCNQ1. We used kinetic models of hERG to simulate the effects of the phosphoinositide. Simulations strengthened the hypothesis that PIP(2) is more likely stabilizing the channel open state than affecting the voltage sensors. From the physiological aspect, we established that the sensitivity of hERG to PIP(2) comes close to that of KCNE1-KCNQ1 channels, which lies in the range of physiological PIP(2) variations., (2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

The two components of the cardiac delayed rectifier current have been the subject of numerous studies since firstly described. This current controls the action potential duration and is highly regulated. After identification of the channel subunits underlying IKs, KCNQ1 associated with KCNE1, and IKr, HERG, their involvement in human cardiac channelopathies have provided various models allowing the description of the molecular mechanisms of the KCNQ1 and HERG channels trafficking, activity and regulation. More recently, studies have been focusing on the unveiling of different partners of the pore-forming proteins that contribute to their maturation, trafficking, activity and/or degradation, on one side, and on their respective expression in the heterogeneous cardiac tissue, on the other side. The aim of this review is to report and discuss the major works on IKs and IKr and the most recent ones that help to understand the precise function of these currents in the heart., (Copyright 2009 Elsevier Inc. All rights reserved.)

Cell-based therapies have great potential for the treatment of cardiovascular diseases. Recently, using a transgenic mouse model Roell et al. reported that cardiac engraftment of connexin43 (Cx43)-overexpressing myoblasts in vivo prevents post-infarct arrhythmia, a common cause of death in patients following heart attack. We carried out a similar study but in a clinically relevant context via transplantation of autologous connexin43-overexpressing myoblasts in infarcted rats. Seven days after coronary ligation, rats were randomized into three groups: a control group injected with myoblasts, a null group injected with myoblasts transduced with an empty lentivirus vector (null) and a Cx43 group injected with myoblasts transduced with a lentivirus vector encoding connexin43. In contrast to Roell's report, arrhythmia occurrence was not statistically different between groups (58%, 64% and 48% for the control (n= 12), null (n= 14) and Cx43 (n= 23) groups, respectively, P= 0.92). Using ex vivo intramural monophasic action potential recordings synchronous electrical activity was observed between connexin43-overexpressing myoblasts and host cardiomyocytes, whereas such synchrony did not occur in the null-transduced group. This suggests that ex vivo connexin43 gene transfer and expression in myoblasts improved intercellular electrical coupling between myoblasts and cardiomyocytes. However, in our model such electrical coupling was not sufficient to decrease arrhythmia induction. Therefore, we would suggest a note of caution on the use of combined Cx43 gene and cell therapy to prevent post-infarct arrhythmias in heart failure patients.