Interventions for reducing wrong-site surgery and invasive procedures.

BACKGROUND: Specific clinical interventions are needed to reduce wrong-site surgery, which is a rare but potentially disastrous clinical error. Risk factors contributing to wrong-site surgery are variable and complex. The introduction of organisational and professional clinical strategies may have a role in minimising wrong-site surgery. OBJECTIVES: To evaluate the effectiveness of organisational and professional interventions for reducing wrong-site surgery (including wrong-site, wrong-side, wrong-procedure and wrong-patient surgery), including non-surgical invasive procedures such as regional blocks, dermatological, obstetric and dental procedures and emergency surgical procedures not undertaken within the operating theatre. SEARCH METHODS: We searched the following electronic databases: the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register (June 2011), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2011, Issue 6), MEDLINE (1948-June 2011), EMBASE (1947-June 2011), CINAHL (1980-June 2011), Dissertations and Theses (1861-June 2011), African Index Medicus, Latin American and Caribbean Health Sciences database, Virtual Health Library, Pan American Health Organization Database and the World Health Organization Library Information System. A grey literature search was conducted. Database searches were conducted June 2011. SELECTION CRITERIA: We included randomised controlled trials (RCTs), non-randomised controlled trials, controlled before-after studies (CBAs) with at least two intervention and control sites, and interrupted-time-series (ITS) studies where the intervention time was clearly defined and there were at least three data points before and three after the intervention. Studies evaluated the effectiveness of organisational and professional interventions for reducing wrong-site surgery, including wrong site, wrong side and wrong procedure. Participants included all healthcare professionals providing care to surgical patients; studies where patients were involved to avoid the incorrect procedures or studies with interventions addressed to healthcare managers, administrators, stakeholders or health insurers. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the quality and abstracted data of all eligible studies using a standardised data extraction form, modified from the Cochrane EPOC checklists. We contacted study authors for additional information. MAIN RESULTS: We included one study in this review. One ITS study evaluated a targeted educational intervention aiming at reducing the incidence of wrong-site tooth extractions. The intervention included examination of previous cases of wrong-site tooth extractions, educational intervention including a presentation of cases of erroneous extractions, explanation of relevant clinical guidelines and feedback by an instructor. Data was re-analysed using the Prais-Winsten time series and the change in level for annual number of mishaps was statistically significant at -4.52 (95% confidence interval (CI) -6.83 to -2.217) (standard error (SE) 0.5380). The change in slope was statistically significant at -1.16 (95% CI -2.22 to -0.10) (SE 0.2472; P < 0.05). AUTHORS' CONCLUSIONS: The findings of this review identified one ITS study for a non-medical procedure conducted in a dental outpatient setting. The study suggested that the use of a specific educational intervention, in the above-mentioned context, which targets junior dental staff using a training session that included cases of wrong-site surgery, presentation of clinical guidelines and feedback by the instructor, was associated with a reduction in the incidence of wrong-site tooth extractions. Given the nature of the intervention in a very specific population, application of these results to a broader population undergoing other forms of surgery or invasive procedures should be undertaken cautiously.

Contact sensing provides a highly accurate means to titrate radiofrequency ablation lesion depth.

BACKGROUND: Transmural lesions are essential for efficacious ablation. There are, however, no accurate means to estimate lesion depth. OBJECTIVE: Explore use of the electrical coupling index (ECI) from the EnSite Contact™ System as a potential variable for lesion depth estimation. METHODS: Radiofrequency (RF) ablation lesions were created in atria and the thighs of swine using an irrigated RF catheter. Power was 30 W for 20 or 30 seconds intracardiac and 30-50 W for 10-60 seconds for the thigh. Intracardiac, the percentage change in ECI during ablation was compared with transmurality and collateral damage occurrence. For the thigh model, an algorithm estimating lesion depth was derived. Factors included: power, duration, and change in the ECI subcomponents (ΔECI+) during ablation. The ΔECI+ algorithm was compared to one using power and duration (PD) alone. RESULTS: Intracardiac, lesions with ≥12% reduction in ECI were more likely to be transmural (92.3% vs. 59.4%, P < 0.001). Twenty-second lesions were less likely to cause collateral damage compared to 30 seconds (33% vs. 70%, P = 0.003), while transmurality was similar. With the thigh model, ΔECI+ had a better correlation than the PD algorithm (P < 0.01). Accuracy of the ΔECI+ algorithm was unimproved with inclusion of tip orientation, while PD improved (R(2) = 0.64). DISCUSSION: Change in ECI provides evidence of transmural versus nontransmural swine intracardiac atrial lesions. A lesion depth estimation algorithm using ECI subcomponents is unaffected by tip orientation and is more accurate than using PD alone. CONCLUSION: Use of ECI as a factor in a lesion depth algorithm may provide clinically valuable information regarding the efficacy of intracardiac RF ablation lesions.

Open-window mapping of accessory pathways utilizing high-density mapping.

PURPOSE: Accessory pathway (AP) mapping is currently based on point-by-point mapping and identifying if a local electrogram's origin is atrial, pathway, or ventricular, which is time-consuming and prone to insufficient mapping. We sought to determine the feasibility of automated and high-density mapping to define AP location using open-window mapping (OWM), which does not rely on defining the electrogram's origin but simply detects the sharpest local signal at each point. METHODS: We enrolled 23 consecutive patients undergoing catheter ablation for atrioventricular reentrant tachycardia. High-density mapping was performed using OWM and ablation was performed. The successful site of ablation was determined by the loss of pathway function. RESULTS: OWM was 100% effective at identifying the successful site of ablation (average mapping time 7.3 ± 4.3 min.) Permanent AP elimination was achieved using a mean radiofrequency energy time of 18.5 ± 24.5 s/patient. Transiently successful ablations were 4.0 ± 1.8 mm from permanently successful sites and had lower contact force (5.1 ± 2.5 g vs. 11.7 ± 9.0 g; P = 0.041). Unsuccessful sites had similar contact force to permanently successful sites (12.2 ± 9.2 g vs. 11.7 ± 9.0 g; P = 0.856) but were 6.4 ± 2.0 mm away from successful sites. CONCLUSION: A novel technique of high-density, automated, and open-window mapping (OWM) effectively localizes APs without the need to differentiate the signal's site of origin. These findings suggest that OWM can be used to rapidly and successfully map and ablate APs. Both distances from the pathway and contact force were shown to be important for pathway ablation.

When is genetic testing useful in patients suspected to have inherited cardiac arrhythmias?

PURPOSE OF REVIEW: In this article, we will review the appropriate use of genetic testing in those patients suspected to have inherited arrhythmogenic diseases, with specific focus on the indications for testing and the expected probability of positive genotyping. RECENT FINDINGS: Important advances have been made in the identification of new genes, associated mutations, and polymorphisms that modulate susceptibility of acquired arrhythmias. We will examine the most recent advances relevant to the rational application of genetic analysis, guided by genotype-phenotype correlations derived from disease and patient-specific evaluation, as well as discussing novel technologies and recently published cost-effectiveness data. SUMMARY: Genetic analysis can be performed to identify the molecular substrate in those patients suspected to be affected by an inherited arrhythmogenic disease; however, the clinical usefulness of this information is often not straightforward. We hope to emphasize the concept that there is a significant difference in the impact of genetic testing within the various arrhythmogenic disorders, and the benefit of accessing genetic testing is not the same in all patients. The resultant integration between the expected yield of genetic screening and cost may allow the formation of criteria to prioritize access for those who could derive the most clinical benefit.

Pseudopolymorphic Wide Complex Tachycardia in a Child With Long QT Syndrome.

Implantable loop recorders (ILRs) can be a valuable tool in monitoring patients with inherited arrhythmia. This paper reports on a family with long QT syndrome (type 2 [LQT2]) in which a pseudopolymorphic wide complex tachycardia detected by ILR was ultimately diagnosed as a supraventricular aberrant rhythm, facilitated by noncompliance with beta-blocker therapy. (Level of Difficulty: Intermediate.).

Electrochemical sensor for catechol and dopamine based on a catalytic molecularly imprinted polymer-conducting polymer hybrid recognition element.

One of the difficulties with using molecularly imprinted polymers (MIPs) and other electrically insulating materials as the recognition element in electrochemical sensors is the lack of a direct path for the conduction of electrons from the active sites to the electrode. We have sought to address this problem through the preparation and characterization of novel hybrid materials combining a catalytic MIP, capable of oxidizing the template, catechol, with an electrically conducting polymer. In this way a network of "molecular wires" assists in the conduction of electrons from the active sites within the MIP to the electrode surface. This was made possible by the design of a new monomer that combines orthogonal polymerizable functionality; comprising an aniline group and a methacrylamide. Conducting films were prepared on the surface of electrodes (Au on glass) by electropolymerization of the aniline moiety. A layer of MIP was photochemically grafted over the polyaniline, via N,N'-diethyldithiocarbamic acid benzyl ester (iniferter) activation of the methacrylamide groups. Detection of catechol by the hybrid-MIP sensor was found to be specific, and catechol oxidation was detected by cyclic voltammetry at the optimized operating conditions: potential range -0.6 V to +0.8 V (vs Ag/AgCl), scan rate 50 mV/s, PBS pH 7.4. The calibration curve for catechol was found to be linear to 144 microM, with a limit of detection of 228 nM. Catechol and dopamine were detected by the sensor, whereas analogues and potentially interfering compounds, including phenol, resorcinol, hydroquinone, serotonin, and ascorbic acid, had minimal effect (< or = 3%) on the detection of either analyte. Non-imprinted hybrid electrodes and bare gold electrodes failed to give any response to catechol at concentrations below 0.5 mM. Finally, the catalytic properties of the sensor were characterized by chronoamperometry and were found to be consistent with Michaelis-Menten kinetics.

Clinical spectrum of patients with a Brugada ECG.

PURPOSE OF REVIEW: The Brugada syndrome continues to spark intensive investigation since its earliest description. New insight has been gained regarding the genetic, histopathologic, and metabolic mechanisms of this heritable channelopathy - a heterogeneity that is reflected in the diverse clinical presentation. In this review, we will focus on clinical spectrum of patients with a Brugada ECG pattern with a special focus on diagnosis and risk stratification. RECENT FINDINGS: In the past year, multiple case reports have demonstrated that the Brugada ECG pattern is not limited to those with the diagnosed syndrome, with increasing evidence that an 'overlap' exists among inherited channelopathies, especially those involving the sodium and calcium channels. SUMMARY: The clinical spectrum of patients with a Brugada ECG remains broad, reflecting the heterogeneity of the underlying pathophysiology. As the true prevalence of the disease unfolds, knowledge regarding the clinical spectrum of patients with a Brugada ECG is important to implement effective risk stratification and management. It may be proposed that the ECG pattern of ST-segment elevation in the right precordial leads should not be seen as a marker of a specific syndrome, but rather as a common electrical expression of structural abnormalities in the right ventricle that may have genetic, infective, or inflammatory origins.

Chimeric polymers formed from a monomer capable of free radical, oxidative and electrochemical polymerisation.

A new monomer, which incorporates both aniline and methacrylamide functional groups, was shown to possess orthogonal polymerisation behaviour to produce conjugated polyaniline suitable for a wide range of applications.

The genetics of cardiomyopathy: genotyping and genetic counseling.

Three decades of ongoing research into the identification of genes responsible for both cardiomyopathies and ion channel diseases has facilitated a progressive understanding of the pathophysiology of inherited arrhythmogenic diseases. Recent discoveries in the area of genetics promise to significantly change the current clinical practice of cardiology, as rapid advances in technology and a coincident reduction of costs associated with sequencing have pushed the "translation" of genomic information from bench to bedside. In turn, clinicians have at their disposal new tools for more accurate diagnosis of diseases, as well as for better calculation of health risks for affected families. It is clear, however, that the integration of genetic analysis into frontline clinical cardiology has not yet occurred, especially for heritable cardiomyopathic processes; no one simplified method exists for diagnosing these complex cardiac disease states. It therefore is important to assess the present and future roles of genetic analysis and counseling in clinical practice and how to assist the transition of genetic screening into current care to ensure the appropriate practical use of genetic tests in the routine clinical setting. The purpose of this discussion is to provide a concise review of recent developments in the field of heritable cardiomyopathies, with specific regard to genetic testing and genetic counseling.

Imaging of patent foramen ovale with 64-section multidetector CT.

PURPOSE: To investigate the feasibility of 64-section multidetector computed tomography (CT) by using CT angiography (a) to demonstrate anatomic detail of the interatrial septum pertinent to the patent foramen ovale (PFO), and (b) to visually detect left-to-right PFO shunts and compare these findings in patients who also underwent transesophageal echocardiography (TEE). MATERIALS AND METHODS: In this institutional review board-approved HIPAA-compliant study, electrocardiographically gated coronary CT angiograms in 264 patients (159 men, 105 women; mean age, 60 years) were reviewed for PFO morphologic features. The length and diameter of the opening of the PFO tunnel, presence of atrial septal aneurysm (ASA), and PFO shunts were evaluated. A left-to-right shunt was assigned a grade according to length of contrast agent jet (grade 1, 1 cm to 2 cm; grade 3, >2 cm). In addition, 23 patients who underwent both modalities were compared (Student t test and linear regression analysis). A difference with P < .05 was significant. RESULTS: A flap valve, seen in 101 (38.3%) patients, was patent at the entry into the right atrium (PFO) in 62 patients (61.4% of patients with flap valve, 23.5% of total patients). A left-to-right shunt was detected in 44 (16.7% of total) patients (grade 1, 61.4%; grade 2, 34.1%; grade 3, 4.5%). No shunt was seen in patients without a flap valve. Mean length of PFO tunnel was 7.1 mm in 44 patients with a shunt and 12.1 mm in 57 patients with a flap valve without a shunt (P < .0001). In patients with a tunnel length of 6 mm or shorter, 92.6% of the shunts were seen. ASA was seen in 11 (4.2%) patients; of these patients, a shunt was seen in seven (63.6%). In 23 patients who underwent CT angiography and TEE, both modalities showed a PFO shunt in seven. CONCLUSION: Multidetector CT provides detailed anatomic information about size, morphologic features, and shunt grade of the PFO. Shorter tunnel length and septal aneurysms are frequently associated with left-to-right shunts in patients with PFO.

Pacing Mediated Heart Rate Acceleration Improves Catheter Stability and Enhances Markers for Lesion Delivery in Human Atria During Atrial Fibrillation Ablation.

OBJECTIVES: This study sought to investigate the effect of pacing mediated heart rate modulation on catheter-tissue contact and impedance reduction during radiofrequency ablation in human atria during atrial fibrillation (AF) ablation. BACKGROUND: In AF ablation, improved catheter-tissue contact enhances lesion quality and acute pulmonary vein isolation rates. Previous studies demonstrate that catheter-tissue contact varies with ventricular contraction. The authors investigated the impact of modulating heart rate on the consistency of catheter-tissue contact and its effect on lesion quality. METHODS: Twenty patients undergoing paroxysmal AF ablation received ablation lesions at 15 pre-specified locations (12 left atria, 3 right atria). Patients were assigned randomly to undergo rapid atrial pacing for either the first half or the second half of each lesion. Contact force and ablation data with and without pacing were compared for each of the 300 ablation lesions. RESULTS: Compared with lesion delivery without pacing, pacing resulted in reduced contact force variability, as measured by contact force SD, range, maximum, minimum, and time within the pre-specified goal contact force range (p < 0.05). There was no difference in the mean contact force or force-time integral. Reduced contact force variability was associated with a 30% greater decrease in tissue impedance during ablation (p < 0.001). CONCLUSIONS: Pacing induced heart rate acceleration reduces catheter-tissue contact variability, increases the probability of achieving pre-specified catheter-tissue contact endpoints, and enhances impedance reduction during ablation. Modulating heart rate to improve catheter-tissue contact offers a new approach to optimize lesion quality in AF ablation. (The Physiological Effects of Pacing on Catheter Ablation Procedures to Treat Atrial Fibrillation [PEP AF]; NCT02766712).

Detection of phrenic nerves and their relation to cardiac anatomy using 64-slice multidetector computed tomography.

The improved temporal and spatial resolution allowed by multidetector computed tomography (MDCT) has facilitated the noninvasive assessment of cardiac anatomy before transcatheter electrophysiologic procedures. Clarification of spatial relations of phrenic nerves and key cardiac structures is important to decrease potential complications. The purpose of this study was to reconstruct the course of the right and left phrenic pericardiophrenic bundles and their relations to cardiac structures using 64-slice MDCT. One hundred six consecutive subjects (age 61 +/- 13 years; 39% women) who underwent self-referred coronary computed tomographic angiography using 64-slice MDCT underwent retrospective assessment of the phrenic nerves contained within the pericardiophrenic bundles. The course of the nerves was outlined in relation to the left atrial appendage, coronary sinus, and cardiac veins. The ability to individually detect the left and right phrenic nerves, as well as the frequency of direct contact between the left phrenic nerve and cardiac veins, was recorded. The left phrenic nerve was identified in 78 of 106 patients (74%). It crossed the left atrial appendage (n = 72, 91%), great cardiac vein (n = 63, 80%), posterior vein of the left ventricle (n = 39, 49%), posterior interventricular vein (n = 8, 10%), and anterior interventricular vein (n = 7, 9%). Mean Hounsfield units (HUs) of the left phrenic nerve was 81 +/- 25. The right phrenic nerve was identified in 50 of 106 patients (47%). Mean HUs of the right phrenic nerve were 94 +/- 26. In conclusion, cardiac imaging using 64-slice MDCT enabled adequate detection of the left and right phrenic nerves in relation to cardiac anatomy. In the setting of electrophysiologic interventions, MDCT before a procedure may elucidate anatomic relationships and help minimize inadvertent complications.

Utility of cardiac MRI in guiding revascularization therapy in unprotected left main stenosis: a case report.

Decision to select unprotected left main (ULM) stenting versus coronary artery bypass grafting surgery (CABG) depends on a multiplicity of factors, one of the most critical of which is myocardial viability. Delayed enhancement cardiac magnetic resonance (CMR) imaging has emerged as a useful means of comprehensively evaluating viable myocardium in postmyocardial infarct patients who require further revascularization. We present a patient with ULM stenosis in whom CMR imaging assisted in the decision to perform percutaneous coronary intervention over CABG.

Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm.

Plakophilin-2 (PKP2) is a component of the desmosome and known for its role in cell-cell adhesion. Mutations in human PKP2 associate with a life-threatening arrhythmogenic cardiomyopathy, often of right ventricular predominance. Here, we use a range of state-of-the-art methods and a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mouse to demonstrate that in addition to its role in cell adhesion, PKP2 is necessary to maintain transcription of genes that control intracellular calcium cycling. Lack of PKP2 reduces expression of Ryr2 (coding for Ryanodine Receptor 2), Ank2 (coding for Ankyrin-B), Cacna1c (coding for CaV1.2) and Trdn (coding for triadin), and protein levels of calsequestrin-2 (Casq2). These factors combined lead to disruption of intracellular calcium homeostasis and isoproterenol-induced arrhythmias that are prevented by flecainide treatment. We propose a previously unrecognized arrhythmogenic mechanism related to PKP2 expression and suggest that mutations in PKP2 in humans may cause life-threatening arrhythmias even in the absence of structural disease.It is believed that mutations in desmosomal adhesion complex protein plakophilin 2 (PKP2) cause arrhythmia due to loss of cell-cell communication. Here the authors show that PKP2 controls the expression of proteins involved in calcium cycling in adult mouse hearts, and that lack of PKP2 can cause arrhythmia in a structurally normal heart.

Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis.

AIMS: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is often associated with desmosomal mutations. Recent studies suggest an interaction between the desmosome and sodium channel protein Nav1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Nav1.5) in ARVD/C. METHODS AND RESULTS: We performed whole-exome sequencing in six ARVD/C patients (33% male, 38.2 ± 12.1 years) without a desmosomal mutation. We found a rare missense variant (p.Arg1898His; R1898H) in SCN5A in one patient. We generated induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CMs) from the patient's peripheral blood mononuclear cells. The variant was then corrected (R1898R) using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 technology, allowing us to study the impact of the R1898H substitution in the same cellular background. Whole-cell patch clamping revealed a 36% reduction in peak sodium current (P = 0.002); super-resolution fluorescence microscopy showed reduced abundance of NaV1.5 (P = 0.005) and N-Cadherin (P = 0.026) clusters at the intercalated disc. Subsequently, we sequenced SCN5A in an additional 281 ARVD/C patients (60% male, 34.8 ± 13.7 years, 52% desmosomal mutation-carriers). Five (1.8%) subjects harboured a putatively pathogenic SCN5A variant (p.Tyr416Cys, p.Leu729del, p.Arg1623Ter, p.Ser1787Asn, and p.Val2016Met). SCN5A variants were associated with prolonged QRS duration (119 ± 15 vs. 94 ± 14 ms, P < 0.01) and all SCN5A variant carriers had major structural abnormalities on cardiac imaging. CONCLUSIONS: Almost 2% of ARVD/C patients harbour rare SCN5A variants. For one of these variants, we demonstrated reduced sodium current, Nav1.5 and N-Cadherin clusters at junctional sites. This suggests that Nav1.5 is in a functional complex with adhesion molecules, and reveals potential non-canonical mechanisms by which Nav1.5 dysfunction causes cardiomyopathy.

hERG Blockade by Iboga Alkaloids.

The iboga alkaloids are a class of naturally occurring and synthetic compounds, some of which modify drug self-administration and withdrawal in humans and preclinical models. Ibogaine, the prototypic iboga alkaloid that is utilized clinically to treat addictions, has been associated with QT prolongation, torsades de pointes and fatalities. hERG blockade as IKr was measured using the whole-cell patch clamp technique in HEK 293 cells. This yielded the following IC50 values: ibogaine manufactured by semisynthesis via voacangine (4.09 ± 0.69 µM) or by extraction from T. iboga (3.53 ± 0.16 µM); ibogaine's principal metabolite noribogaine (2.86 ± 0.68 µM); and voacangine (2.25 ± 0.34 µM). In contrast, the IC50 of 18-methoxycoronaridine, a product of rational synthesis and current focus of drug development was >50 µM. hERG blockade was voltage dependent for all of the compounds, consistent with low-affinity blockade. hERG channel binding affinities (K i) for the entire set of compounds, including 18-MC, ranged from 0.71 to 3.89 µM, suggesting that 18-MC binds to the hERG channel with affinity similar to the other compounds, but the interaction produces substantially less hERG blockade. In view of the extended half-life of noribogaine, these results may relate to observations of persistent QT prolongation and cardiac arrhythmia at delayed intervals of days following ibogaine ingestion. The apparent structure-activity relationships regarding positions of substitutions on the ibogamine skeleton suggest that the iboga alkaloids might provide an informative paradigm for investigation of the structural biology of the hERG channel.

Desmosomal junctions are necessary for adult sinus node function.

AIMS: Current mechanisms driving cardiac pacemaker function have focused on ion channel and gap junction channel function, which are essential for action potential generation and propagation between pacemaker cells. However, pacemaker cells also harbour desmosomes that structurally anchor pacemaker cells to each other in tissue, but their role in pacemaker function remains unknown. METHODS AND RESULTS: To determine the role of desmosomes in pacemaker function, we generated a novel mouse model harbouring cardiac conduction-specific ablation (csKO) of the central desmosomal protein, desmoplakin (DSP) using the Hcn4-Cre-ERT2 mouse line. Hcn4-Cre targets cells of the adult mouse sinoatrial node (SAN) and can ablate DSP expression in the adult DSP csKO SAN resulting in specific loss of desmosomal proteins and structures. Dysregulation of DSP via loss-of-function (adult DSP csKO mice) and mutation (clinical case of a patient harbouring a pathogenic DSP variant) in mice and man, respectively, revealed that desmosomal dysregulation is associated with a primary phenotype of increased sinus pauses/dysfunction in the absence of cardiomyopathy. Underlying defects in beat-to-beat regulation were also observed in DSP csKO mice in vivo and intact atria ex vivo. DSP csKO SAN exhibited migrating lead pacemaker sites associated with connexin 45 loss. In vitro studies exploiting ventricular cardiomyocytes that harbour DSP loss and concurrent early connexin loss phenocopied the loss of beat-to-beat regulation observed in DSP csKO mice and atria, extending the importance of DSP-associated mechanisms in driving beat-to-beat regulation of working cardiomyocytes. CONCLUSION: We provide evidence of a mechanism that implicates an essential role for desmosomes in cardiac pacemaker function, which has broad implications in better understanding mechanisms underlying beat-to-beat regulation as well as sinus node disease and dysfunction.

Effect of Obstructive Sleep Apnea Treatment on Atrial Fibrillation Recurrence: A Meta-Analysis.

OBJECTIVES: This study aimed to evaluate the cumulative effect of treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) on atrial fibrillation (AF) recurrence. BACKGROUND: OSA is a known predictor for onset and recurrence of AF. The effect of treatment with CPAP on AF recurrence has been evaluated in small studies with varied outcomes. METHODS: We searched MEDLINE, EMBASE, CINAHL, Google Scholar, Cochrane Database of Systematic Reviews, and Cochrane Trials Register for relevant studies. Evaluation of AF recurrence in CPAP users and nonusers in patients with OSA was the primary outcome evaluated in this study. The secondary outcome was evaluation of AF recurrence in CPAP users and nonusers after pulmonary vein isolation (PVI). RESULTS: Seven prospective cohort studies with a total of 1,087 patients met the inclusion criteria. Across all patient groups, the use of CPAP was associated with a significant reduction in AF recurrence (relative risk: 0.58, 95% confidence interval: 0.51 to 0.67; heterogeneity chi-square p = 0.91, I2 = 0%). The beneficial effect of CPAP use was statistically significant in both groups of patients: those who underwent catheter ablation with PVI and those who did not undergo ablation and were managed medically. No other study covariates had any significant association with these outcomes of AF reduction. CONCLUSIONS: The use of CPAP is associated with significant reduction in recurrence of AF in patients with OSA. This effect remains consistent and similar across patient populations irrespective of whether they undergo PVI.

Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias.

SCN5A encodes the α subunit of the major cardiac sodium channel Na(V)1.5. Mutations in SCN5A are associated with conduction disease and ventricular fibrillation (VF); however, the mechanisms that link loss of sodium channel function to arrhythmic instability remain unresolved. Here, we generated a large-animal model of a human cardiac sodium channelopathy in pigs, which have cardiac structure and function similar to humans, to better define the arrhythmic substrate. We introduced a nonsense mutation originally identified in a child with Brugada syndrome into the orthologous position (E558X) in the pig SCN5A gene. SCN5A(E558X/+) pigs exhibited conduction abnormalities in the absence of cardiac structural defects. Sudden cardiac death was not observed in young pigs; however, Langendorff-perfused SCN5A(E558X/+) hearts had an increased propensity for pacing-induced or spontaneous VF initiated by short-coupled ventricular premature beats. Optical mapping during VF showed that activity often began as an organized focal source or broad wavefront on the right ventricular (RV) free wall. Together, the results from this study demonstrate that the SCN5A(E558X/+) pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.

Use of whole exome sequencing for the identification of Ito-based arrhythmia mechanism and therapy.

BACKGROUND: Identified genetic variants are insufficient to explain all cases of inherited arrhythmia. We tested whether the integration of whole exome sequencing with well-established clinical, translational, and basic science platforms could provide rapid and novel insight into human arrhythmia pathophysiology and disease treatment. METHODS AND RESULTS: We report a proband with recurrent ventricular fibrillation, resistant to standard therapeutic interventions. Using whole-exome sequencing, we identified a variant in a previously unidentified exon of the dipeptidyl aminopeptidase-like protein-6 (DPP6) gene. This variant is the first identified coding mutation in DPP6 and augments cardiac repolarizing current (Ito) causing pathological changes in Ito and action potential morphology. We designed a therapeutic regimen incorporating dalfampridine to target Ito. Dalfampridine, approved for multiple sclerosis, normalized the ECG and reduced arrhythmia burden in the proband by >90-fold. This was combined with cilostazol to accelerate the heart rate to minimize the reverse-rate dependence of augmented Ito. CONCLUSIONS: We describe a novel arrhythmia mechanism and therapeutic approach to ameliorate the disease. Specifically, we identify the first coding variant of DPP6 in human ventricular fibrillation. These findings illustrate the power of genetic approaches for the elucidation and treatment of disease when carefully integrated with clinical and basic/translational research teams.