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The most common age range for Atrial Fibrillation (AF) prevalence over the coming decades will potentially be in those over 75 years old. However, despite widespread recognition of the strong association between AF burden and age, the elderly are under-represented within trials evaluating invasive rhythm control strategies. We report the outcomes of a gentleman in his late eighties that underwent Convergent hybrid ablation for highly symptomatic and longstanding persistent AF. Now four years later and into his nineties, he remains in sinus rhythm and enjoys good cardiac health without the need for anti-arrhythmic drugs or further intervention. To our knowledge, this case report is the oldest patient to have successfully undergone Convergent ablation with enduring sinus rhythm with long-term follow-up, despite significant risk factors for AF recurrence. As the overall population ages, the emergence of this minimally invasive multidisciplinary ablation technique for AF may offer to similar patients benefits over percutaneous ablation strategies alone.

Rheumatoid Arthritis (RA) is a chronic inflammatory disorder associated with an increased incidence and prevalence of cardiovascular disease (CVD), including myocardial infarction and heart failure. In addition to traditional risk factors, evidence suggests inflammation is critical to the pathophysiology of both conditions. Despite the association being well-recognised, challenges remain in managing cardiovascular risk in RA.This manuscript analyses the association between CVD and RA and explores the limitations in evaluating cardiovascular risk in RA with available risk assessment tools. The authors review the optimal management of traditional risk factors such as hypertension and dyslipidaemia and contemporary risk factors such as inflammation and analyse the cardiovascular impact of RA medications.Analysis points to the critical role of inflammation in the pathogenesis of RA and CVD. It is well established that conventional disease-modifying anti-rheumatic drugs (DMARDs) improve cardiovascular outcomes; however, underlying risk often remains underappreciated. The authors suggest there remains an opportunity to improve mortality and morbidity with the early recognition and of at-risk populations and the timely initiation of appropriate cardiovascular and anti-inflammatory medications. More research is necessary into the role that imaging may play in stratifying risk and in the longer-term cardiovascular impact of biological DMARDs.

The most common age range for atrial fibrillation (AF) prevalence over the coming decades will potentially be in those over 75 years old. However, despite widespread recognition of the strong association between AF burden and age, the elderly are under-represented within trials evaluating invasive rhythm control strategies. We report the outcomes of a gentleman in his late eighties that underwent Convergent hybrid ablation for highly symptomatic and longstanding persistent AF. Now four years later and into his nineties, he remains in sinus rhythm and enjoys good cardiac health without the need for anti-arrhythmic drugs or further intervention. To our knowledge, this case report is the oldest patient to have successfully undergone Convergent ablation with enduring sinus rhythm with long-term follow-up, despite significant risk factors for AF recurrence. As the overall population ages, the emergence of this minimally invasive multidisciplinary ablation technique for AF may offer to similar patients benefits over percutaneous ablation strategies alone.

The absence of strategies to consistently and effectively address nonparoxysmal atrial fibrillation by nonpharmacological interventions has represented a long-standing treatment gap. A combined epicardial/endocardial ablation strategy, the hybrid Convergent procedure, was developed in response to this clinical need. A subxiphoid incision is used to access the pericardial space facilitating an epicardial ablation directed at isolation of the posterior wall of the left atrium. This is followed by an endocardial ablation to complete isolation of the pulmonary veins and for additional ablation as needed. Experience gained with the hybrid Convergent procedure during the last decade has led to the development and adoption of strategies to optimize the technique and mitigate risks. Additionally, a surgical and electrophysiology "team" approach including comprehensive training is believed critical to successfully develop the hybrid Convergent program. A recently completed randomized clinical trial indicated that this ablation strategy is superior to an endocardial-only approach for patients with persistent atrial fibrillation. In this review, we propose and describe best practice guidelines for hybrid Convergent ablation on the basis of a combination of published data, author consensus, and expert opinion. A summary of clinical outcomes, emerging evidence, and future perspectives is also given.

Atrial fibrillation (AF) is a global disease with rapidly rising incidence and prevalence. It is associated with a higher risk of stroke, dementia, cognitive decline, sudden and cardiovascular death, heart failure and impairment in quality of life. The disease is a major burden on the healthcare system. Paroxysmal AF is typically managed with medications or endocardial catheter ablation to good effect. However, a large proportion of patients with AF have persistent or long-standing persistent AF, which are more complex forms of the condition and thus more difficult to treat. This is in part due to the progressive electro-anatomical changes that occur with AF persistence and the spread of arrhythmogenic triggers and substrates outside of the pulmonary veins. The posterior wall of the left atrium is a common site for these changes and has become a target of ablation strategies to treat these more resistant forms of AF. In this review, we discuss the role of the posterior left atrial wall in persistent and long-standing persistent AF, the limitations of current endocardial-focused treatment strategies, and future perspectives on hybrid epicardial–endocardial approaches to posterior wall isolation or ablation.

INTRODUCTION Atrial fibrillation is often asymptomatic and un-diagnosed in the community resulting in an increased risk of heart failure and stroke to those patients. We evaluated the effectiveness, tolerability, and accuracy of a novel six-channel electrocardiogram digital-health screening device, the RhythmPad, for the detection of atrial fibrillation. METHODS Seven hundred and fifty-two participants attending the cardiology department were recruited. Two recordings were taken-a six-lead electrocardiogram using the RhythmPad device and a standard 12-lead electrocardiogram. Recorded traces were analyzed by two blinded cardiologists. The computer-generated automated diagnostic reports from both systems were also compared. Post-participation feedback was obtained from study participants using a three-part questionnaire. RESULTS The sensitivity of the six-lead electrocardiogram compared to the 12-lead electrocardiogram, analyzed by two blinded cardiologists, for the detection of normal sinus rhythm was 95.9%, with a specificity of 97.2%. The sensitivity for the detection of atrial fibrillation using the six-lead ECG was 93.4%, with specificity 96.8%. The six-lead automated diagnostic report had a sensitivity and specificity of 97.5% and 98.6%, respectively, for correctly diagnosing normal sinus rhythm. For the correct diagnosis of atrial fibrillation, the six-lead automated diagnostic report had a sensitivity and specificity of 95.4% and 98.8%, respectively. A total of 95.4% of participants found RhythmPad to be comfortable, with only 0.5% preferring the 12-lead ECG device in comparison to six-lead ECG acquisitions. CONCLUSION The RhythmPad digital health device and its automated diagnostic report were highly accurate in detecting atrial fibrillation when compared to a standard 12-lead electrocardiogram.

Atrial fibrillation is not only the most common clinical arrhythmia, it is also one of the most challenging conditions to treat in day-to-day clinical practice. In particular, the persistent form of this condition is not easily amenable to traditional forms of therapy, whereas, the paroxysmal form is far more responsive to standard modes of treatment. In our relentless quest to find better solutions to overcome persistent atrial fibrillation, arguably the most promising of these currently appears to be electrical isolation of the left atrial appendage. Whilst surgical amputation of the left atrial appendage for stroke prevention has been practiced for more than half a century, only recently has attention gradually been shifting to electrical isolation of the left atrial appendage for the treatment of persistent atrial fibrillation. In this review article, we present compelling pieces of evidence for the use of this strategy, and the various ways in which it can be achieved.

Aims Protamine sulfate is commonly used to reverse the action of heparin after catheter ablation procedures. Serious protamine-related adverse effect is rare, but its recognition and appropriate management by electrophysiologists and intensivists is important. Direct ventricular fibrillation (VF) soon after a slow infusion of protamine has not been clearly described. Methods and results We examined the records of all patients who suffered apparent adverse events after protamine administration in our electrophysiology lab from 2013 to 2018. We describe a series of three patients, all of whom suffered a precipitous fall in arterial pressure followed by VF within minutes after administration of protamine following ablation for atrial fibrillation. The same supplier of protamine was used in all three cases, but they were from different batches. Serum tryptase levels were measured in all cases, immediately post-cardiac arrest and at 2- and 6-h post-event. Immunoglobulin levels were not measured. Two patients recovered after aggressive supportive therapy; the third died despite similar support. Conclusion We have encountered three cases of profound hypotension followed by VF soon after administration of protamine. Although protamine is safe in a large majority of patients, these adverse events have led our centre to exercise greater selectivity and caution in its use.

There is an increasing need for catheter ablation procedures to treat complex atrial tachycardias (AT) and atrial fibrillation (AF), often requiring detailed endocardial mapping. The sequential point-to-point contact mapping of complex arrhythmias is time-consuming and may not always be feasible. We assessed the utility of a novel spiral duo-decapolar high-density (HD) mapping catheter to delineate complex arrhythmia substrates for ablation.The patients underwent HD mapping using a spiral catheter (AFocusII) and the EnSite NavX system, during catheter ablation procedures, to treat atrial arrhythmias.In 26 patients, a total of 32 atrial arrhythmias were mapped and ablated, comprising of five focal AT, eight macroreentrant AT, 11 persistent AF and eight paroxysmal AF. The HD catheter was used to acquire endocardial surface geometries in all cases and to map the pulmonary veins in patients undergoing AF ablation. In persistent AF, HD catheter mapping permitted the creation of highly detailed complex fractionated electrogram maps (left atrium 449 ± 128 points in 7.2 ± 2.6 min; right atrium 411 ± 113 points in 6.7 ± 1.6 min). In AT, activation mapping was performed with the acquisition of 305 ± 158 timing points in 7.3 ± 2.6 min, guiding successful ablation in all cases. During the follow-up of 7.0 ± 2.6 months, all AT patients remained free of significant arrhythmia.High-density contact mapping with a novel spiral multipolar catheter allows rapid assessment of focal and macroreentrant AT, and complex fractionated electrical activity in the atria. It has further multi-functional capabilities as a pulmonary vein mapping catheter and for accurate geometry creation when used with a 3D mapping system.

We have shown that the gene SCN10A encoding the sodium channel Na(v)1.8 is a susceptibility factor for heart block and serious ventricular arrhythmia. Since Na(v)1.8 is known to be present in nerve fibres that mediate pain, it may be related to both cardiac pain and dysrhythmia. The localisation of Na(v)1.8 and other key nociceptive ion channels, including Na(v)1.7, Na(v)1.9, capsaicin receptor TRPV1, and purinergic receptor P2X(3), have not been reported in human heart. The aim of this study was to determine the distribution of Na(v)1.8, related sodium and other sensory channels in human cardiac tissue, and correlate their density with sympathetic nerves, regenerating nerves (GAP-43), and vascularity. Human heart atrial appendage tissues (n = 13) were collected during surgery for valve disease. Tissues were investigated by immunohistology using specific antibodies to Na(v)1.8 and other markers. Na(v)1.8 immunoreactivity was detected in nerve fibres and fascicles in the myocardium, often closely associated with small capillaries. Na(v)1.8 nerve fibres per mm(2) correlated significantly with vascular markers. Na(v)1.8-immunoreactivity was present also in cardiomyocytes with a similar distribution pattern to that seen with connexins, the specialised gap junction proteins of myocardial intercalated discs. Na(v)1.5-immunoreactivity was detected in cardiomyocytes but not in nerve fibres. Na(v)1.7, Na(v)1.9, TRPV1, P2X(3)/P2X(2), and GAP43 positive nerve fibres were relatively sparse, whereas sympathetic innervation and connexin43 were abundant. We conclude that sodium channel Na(v)1.8 is present in sensory nerves and cardiomyocytes of human heart. Na(v)1.8 and other pain channels provide new targets for the understanding and treatment of cardiac pain and dysrhythmia.

To identify genetic factors influencing cardiac conduction, we carried out a genome-wide association study of electrocardiographic time intervals in 6,543 Indian Asians. We identified association of a nonsynonymous SNP, rs6795970, in SCN10A (P = 2.8 x 10(-15)) with PR interval, a marker of cardiac atrioventricular conduction. Replication testing among 6,243 Indian Asians and 5,370 Europeans confirmed that rs6795970 (G>A) is associated with prolonged cardiac conduction (longer P-wave duration, PR interval and QRS duration, P = 10(-5) to 10(-20)). SCN10A encodes Na(V)1.8, a sodium channel. We show that SCN10A is expressed in mouse and human heart tissue and that PR interval is shorter in Scn10a(-/-) mice than in wild-type mice. We also find that rs6795970 is associated with a higher risk of heart block (P < 0.05) and a lower risk of ventricular fibrillation (P = 0.01). Our findings provide new insight into the pathogenesis of cardiac conduction, heart block and ventricular fibrillation.

Lasso catheter (Biosense Webster) is one of the most commonly employed circular mapping catheters during pulmonary vein isolation (PVI) procedure for atrial fibrillation (AF). Although this catheter has greatly facilitated arrhythmia mapping, it can be associated with serious complications. We report a case of a 59-year-old man who underwent PVI procedure for persistent AF. During the procedure, the Lasso catheter inadvertently slipped into the left ventricular cavity and entangled in the mitral valve apparatus. Various percutaneous manoeuvres to release the catheter were unsuccessful and the patient ultimately required emergency open heart surgery to remove the catheter and repair the valve. To the best of our knowledge, such a case has not previously been reported in the UK necessitating an immediate open heart surgery, avoiding replacement of the valve.

In the human heart connexin(Cx)40, Cx43 and Cx45-containing gap junctional channels electrically couple cardiomyocytes, forming a functional syncytium. In the mouse heart, additionally, Cx30.2-containing gap junctions have been detected in the atrioventricular node where they are implicated, together with Cx45, in impulse delay. However, whether the human ortholog of Cx30.2, Cx31.9, is expressed in the human heart has not previously been investigated. We therefore generated Cx31.9 specific antibodies to test for the expression of Cx31.9 in the human heart. These antibodies recognized the Cx31.9 protein in HeLaCx31.9 transfectants by immunofluorescence and immunoblot analyses. However, we did not find punctate Cx31.9 specific immunofluorescence signals in the working myocardium or in the impulse generation and conduction system of adult or fetal human heart. Complementary immunoblot analyses did not reveal Cx31.9 protein in the adult atrial or ventricular myocardium. We conclude that the Cx31.9 protein, unlike its counterpart in the mouse, is not expressed in detectable quantities and is thus unlikely to contribute to the impulse generation and conduction system or the working myocardium of the human heart.

Gap junction redistribution and reduced expression, a phenomenon termed gap junction remodeling (GJR), is often seen in diseased hearts and may predispose toward arrhythmias. We have recently shown that short-term pacing in the mouse is associated with changes in connexin43 (Cx43) expression and localization but not with increased inducibility into sustained arrhythmias. We hypothesized that short-term pacing, if imposed on murine hearts with decreased Cx43 abundance, could serve as a model for evaluating the electrophysiological effects of GJR. We paced wild-type (normal Cx43 abundance) and heterozygous Cx43 knockout (Cx43+/−; 66% mean reduction in Cx43) mice for 6 h at 10–15% above their average sinus rate. We investigated the electrophysiological effects of pacing on the whole animal using programmed electrical stimulation and in isolated ventricular myocytes with patch-clamp studies. Cx43+/− myocytes had significantly shorter action potential durations (APD) and increased steady-state ( Iss) and inward rectifier ( IK1) potassium currents compared with those of wild-type littermate cells. In Cx43+/− hearts, pacing resulted in a significant prolongation of ventricular effective refractory period and APD and significant diminution of Iss compared with unpaced Cx43+/− hearts. However, these changes were not seen in paced wild-type mice. These data suggest that Cx43 abundance plays a critical role in regulating currents involved in myocardial repolarization and their response to pacing. Our study may aid in understanding how dyssynchronous activation of diseased, Cx43-deficient myocardial tissue can lead to electrophysiological changes, which may contribute to the worsened prognosis often associated with pacing in the failing heart.

The purpose of this study was to determine whether sinus rhythm activation maps could be used to detect the origin and characteristics of reentrant ventricular tachycardia in postinfarction patients.In each of 11 post-myocardial infarction patients, unipolar electrograms were acquired at 256 virtual endocardial sites using noncontact mapping. Electrograms were marked for activation time and mapped on a three-dimensional grid. Spatial differences in sinus rhythm activation time were correlated to isthmus characteristics and to activation through the diastolic pathway during tachycardia on the basis of the presence of contiguous lines of slow conduction and block.Twenty tachycardia morphologies were analyzed. Fourteen sustained reentrant circuit morphologies occurred in nine patients, with dual morphologies having a shared isthmus occurring in five of nine patients. Dual morphologies were caused by changes in entrance-exit point location about a common isthmus. One transient circuit morphology of10 beats occurred in three of nine patients also having sustained reentry. The estimated isthmus determined from sinus rhythm activation overlapped the diastolic pathway determined from tachycardia maps with 83.8% sensitivity and 89.2% specificity. The mean difference in sinus rhythm activation time across the isthmus border was larger in transient compared with sustained morphologies (32.8 +/- 9.5 ms vs. 22.8 +/- 1.8 ms), with smaller isthmus size (4.8 +/- 1.1 cm(2) vs. 10.0 +/- 1.1 cm(2); P.05), narrower entrance-exit points (7.0 +/- 1.5 mm vs. 9.3 +/- 0.8 mm; P.05), and greater activation time difference across them (16.3 +/- 3.5 ms vs. 10.1 +/- 1.0 ms; P.05).In post-myocardial infarction patients, the reentry isthmus can be localized in the endocardial border zone from sinus rhythm activation maps. Nonsustained reentry occurs when isthmus size is small and entrance-exit points are narrow and more electrically discontinuous.

Inherited gain-of-function mutations of genes coding for subunits of the heart slow potassium (IKs) channel can cause familial atrial fibrillation (AF). Here we consider a potentially more prevalent mechanism and hypothesize that β-adrenergic receptor (β-AR)-mediated regulation of the IKs channel, a natural gain-of-function pathway, can also lead to AF. Using a transgenic IKs channel mouse model, we studied the role of the channel and its regulation by β-AR stimulation on atrial arrhythmias. In vivo administration of isoprenaline (isoproterenol) predisposes IKs channel transgenic mice but not wild-type (WT) littermates that lack IKs to prolonged atrial arrhythmias. Patch-clamp analysis demonstrated expression and isoprenaline-mediated regulation of IKs in atrial myocytes from transgenic but not WT littermates. Furthermore, computational modelling revealed that β-AR stimulation-dependent accumulation of open IKs channels accounts for the pro-arrhythmic substrate. Our results provide evidence that β-AR-regulated IKs channels can play a role in AF and imply that specific IKs deregulation, perhaps through disruption of the IKs macromolecular complex necessary for β-AR-mediated IKs channel regulation, may be a novel therapeutic strategy for treating this most common arrhythmia.

Radiofrequency ablation (RFA) for the treatment of paroxysmal Atrial Fibrillation (pAF) has a class 1 indication in patients who have not tolerated or responded to antiarrhythmic medications. Antiarrhythmic medications (AAM) are, however, limited not only by modest efficacy, but also by significant side effects. Discontinuation rates for AAM range from 11-40% in trials. The RAAFT-2 trial evaluates the use of RFA as a first line treatment for pAF compared to optimal pharmacological management (1).

Congestive heart failure is associated with a high risk of life-threatening ventricular re-entrant arrhythmias. Down-regulation of the principal gap-junctional protein of the ventricular myocytes, connexin43, has previously been implicated in arrhythmia in ischaemic heart disease, but it is not known whether connexin43 is similarly reduced in heart failure due to idiopathic dilated cardiomyopathy, whether disease-related connexin43 down-regulation occurs at the level of transcription or translation, or whether the expression of other connexin isotypes is altered in congestive heart failure. We therefore investigated the expression of the four connexins expressed in the heart-connexins 43, 40, 45 and 37-at the mRNA and protein levels in explanted hearts from transplant patients with end-stage heart failure (NYHA class 4) by immunoconfocal analysis, and northern and western blotting. Connexin43 mRNA and protein were markedly downregulated in the left ventricle in end-stage heart failure due both to ischaemic cardiomyopathy and idiopathic dilated cardiomyopathy. Connexin43 content was spatially heterogeneous in the diseased ventricle. Connexin40 mRNA was increased in the ischaemic group, more so in the left ventricle than the right. This correlated with an increased depth of connexin40 protein expression in myocytes at the endocardial surface. Connexin45 mRNA and protein, present only in very low quantities, followed a similar trend to connexin43, while connexin37 (exclusively expressed in endothelium) showed no change. Our findings show that congestive heart failure is associated with significantly reduced levels of the principal gap junction protein, connexin43, in the left ventricle, potentially contributing to enhanced arrhythmogenicity and contractile dysfunction. This down-regulation is due predominantly to a reduced transcript steady-state level. Elevated connexin40 may represent a compensatory response that improves the spread of depolarization in the otherwise compromised ischaemic ventricle.

Gap junctions play essential roles in the normal function of the heart and arteries, mediating the spread of the electrical impulse that stimulates synchronized contraction of the cardiac chambers, and contributing to co-ordination of activities between cells of the arterial wall. In common with other multicellular systems, cardiovascular tissues express multiple connexin isotypes that confer distinctive channel properties. This review highlights how state-of-the-art immunocytochemical and cellular imaging techniques, as part of a multidisciplinary approach in gap junction research, have advanced our understanding of connexin diversity in cardiovascular cell function in health and disease. In the heart, spatially defined patterns of expression of three connexin isotypes-connexin43, connexin40, and connexin45-underlie the precisely orchestrated patterns of current flow governing the normal cardiac rhythm. Derangement of gap junction organization and/or reduced expression of connexin43 are associated with arrhythmic tendency in the diseased human ventricle, and high levels of connexin40 in the atrium are associated with increased risk of developing atrial fibrillation after coronary by-pass surgery. In the major arteries, endothelial gap junctions may simultaneously express three connexin isotypes, connexin40, connexin37, and connexin43; underlying medial smooth muscle, by contrast, predominantly expresses connexin43, with connexin45 additionally expressed at restricted sites. In normal arterial smooth muscle, the abundance of connexin43 gap junctions varies according to vascular site, and shows an inverse relationship with desmin expression and positive correlation with the quantity of extracellular matrix. Increased connexin43 expression between smooth muscle cells is closely linked to phenotypic transformation in early human coronary atherosclerosis and in the response of the arterial wall to injury. Current evidence thus suggests that gap junctions in both their guises, as pathways for cell-to-cell signaling in the vessel wall and as pathways for impulse conduction in the heart, contribute to the initial pathogenesis and eventual clinical manifestation of human cardiovascular disease.

The mouse is currently widely used as a model organism in the analysis of gene function but how developmentally regulated patterns of connexin gene expression in the mouse compare with those in the human is unclear. Here we compare the patterns of connexin expression in the heart during the development of the mouse (from embryonic day 12.5 to 6 weeks postpartum) and the human (at 9 weeks gestation and adult stage). The extent of connexin43 expression in the ventricles progressively increased during development of the mouse heart. The developmental pattern of expression for connexins 40 and 45 in the mouse heart was similar, but not identical, and in the ventricles showed a progressive and preferential expression in the conduction system. In general, these dynamic changes of connexins 43, 40 and 45 during mouse cardiac development appear to be mirrored in the human.

Recent trials have presented compelling evidence for the safety and efficacy of the new oral anticoagulants (NOACs) versus warfarin for stroke prevention in patients with atrial fibrillation (AF). The ENGAGE AF-TIMI 48 trial, the biggest of these trials, aims to evaluate the use of the direct factor Xa inhibitor, edoxaban.

Abstract —Upregulation of connexin43-gap junctions is associated with transition of contractile vascular smooth muscle cells (SMCs) to the synthetic state. To determine whether phenotypically distinct subpopulations of medial SMCs differentially express connexin43, we investigated the human distal internal mammary artery, a structurally heterogeneous vessel with features ranging from elastic to elastomuscular to muscular. Immunoconfocal microscopy combined with quantitative analysis and complemented by in situ hybridization showed that SMCs in the elastic medial regions expressed high levels of connexin43 but low levels of desmin, whereas those of muscular medial regions expressed low levels of connexin43 but high levels of desmin. Ultrastructurally, SMCs of both regions were of the contractile phenotype, but the former cells were irregular in shape with relatively prominent synthetic organelles whereas the latter were spindle shaped with fewer synthetic organelles. Vimentin, smooth muscle α-actin, calponin, h-caldesmon, and myosin heavy chains (SM1 and SM2) were equally highly expressed by most cells in both subpopulations. The connexin43/desmin expression pattern of SMCs in regions of intimal thickening resembled those of elastic medial regions. These findings refine the view suggested from previous studies that high levels of connexin43 expression are associated with SMCs of a less contractile/more synthetic phenotype. In the internal mammary artery, the 2 subpopulations of SMCs with markedly different connexin43 expression levels both represent a differentiated contractile phenotype, but the subpopulation showing high levels of connexin43-gap junctions is characterized by low levels of desmin and structural features that reflect a more synthetic tendency.

We present a case of a 76-year-old man with ischemic cardiomyopathy. Cardiac magnetic resonance imaging demonstrated severe left ventricular (LV) impairment with possibility of scar formation. Cardiac resynchronization therapy was employed with the aid of a novel quadripolar LV lead. The quadripolar LV lead can be programmed for 10 different pacing configurations, allowing the electrophysiologist freedom to optimize the vector around scar and also avoid phrenic nerve stimulation without the requirement of LV lead repositioning.

Background Cardiac insults such as ischemia, infarction, hypertrophy and dilatation are often accompanied by altered abundance and/or localization of the connexin43 gap junction protein, which may predispose towards arrhythmic complications. Models of chronic dyssynchronous cardiac activation have also been shown to result in redistribution of connexin43 in cardiomyocytes. We hypothesized that alterations in connexin43 expression and localization in the mouse heart might be induced by ventricular pacing over a short period of time. Results The subdiaphragmatic approach was used to pace a series of wild type mice for six hours before the hearts were removed for analysis. Mice were paced at 10–15% above their average anesthetized sinus rate and monitored to ensure 1:1 capture. Short-term pacing resulted in a significant reduction in connexin43 mRNA abundance, a partial redistribution of connexin43 from the sarcolemma to a non-sarcolemmal fraction, and accumulation of ubiquitinated connexin43 without a significant change in overall connexin43 protein levels. These early pacing-induced changes in connexin43 expression were not accompanied by decreased cardiac function, prolonged refractoriness or increased inducibility into sustained arrhythmias. Conclusion Our data suggest that short-term pacing is associated with incipient changes in the expression of the connexin43 gap junction, possibly including decreased production and a slowed rate of degradation. This murine model may facilitate the study of early molecular changes induced by pacing and may ultimately assist in the development of strategies to prevent gap junction remodeling and the associated arrhythmic complications of cardiac disease.

Infarct border zone (IBZ) geometry likely affects inducibility and characteristics of postinfarction reentrant ventricular tachycardia, but the connection has not been established.The purpose of this study was to determine characteristics of postinfarction ventricular tachycardia in the IBZ.A geometric model describing the relationship between IBZ geometry and wavefront propagation in reentrant circuits was developed. Based on the formulation, slow conduction and block were expected to coincide with areas where IBZ thickness (T) is minimal and the local spatial gradient in thickness (DeltaT) is maximal, so that the degree of wavefront curvature rho proportional, variant DeltaT/T is maximal. Regions of fastest conduction velocity were predicted to coincide with areas of minimum DeltaT. In seven arrhythmogenic postinfarction canine heart experiments, tachycardia was induced by programmed stimulation, and activation maps were constructed from multichannel recordings. IBZ thickness was measured in excised hearts from histologic analysis or magnetic resonance imaging. Reentrant circuit properties were predicted from IBZ geometry and compared with ventricular activation maps after tachycardia induction.Mean IBZ thickness was 231 +/- 140 microm at the reentry isthmus and 1440 +/- 770 microm in the outer pathway (P0.001). Mean curvature rho was 1.63 +/- 0.45 mm(-1) at functional block line locations, 0.71 +/- 0.18 mm(-1) at isthmus entrance-exit points, and 0.33 +/- 0.13 mm(-1) in the outer reentrant circuit pathway. The mean conduction velocity about the circuit during reentrant tachycardia was 0.32 +/- 0.04 mm/ms at entrance-exit points, 0.42 +/- 0.13 mm/ms for the entire outer pathway, and 0.64 +/- 0.16 mm/ms at outer pathway regions with minimum DeltaT. Model sensitivity and specificity to detect isthmus location was 75.0% and 97.2%.Reentrant circuit features as determined by activation mapping can be predicted on the basis of IBZ geometrical relationships.

Gap junctions, assembled from connexins, form the cell-to-cell pathways for propagation of the precisely orchestrated patterns of current flow that govern the synchronized rhythm of the healthy heart. As in most tissues and organs, multiple connexin types are co-expressed in the heart; the connexins Cx43, Cx40 and Cx45 are found in distinctive combinations and relative quantities in different, functionally specialized subsets of cardiomyocytes. Alterations in connexin expression and gap junction organization, now a well-documented feature of human cardiomyopathies, potentially contribute to the pro-arrhythmic substrate. In the diseased ventricle, the most consistently reported quantitative alteration involves heterogeneous reduction in Cx43 expression and disruption of the normal ordered pattern of Cx43 gap junction distribution. Additional studies suggest that upregulation of Cx40 and Cx45 may also feature in the failing ventricle, the former restricted to ischemic cardiomyopathy and localized to the subendocardial region. By correlating data from studies on the human patient with those from animal and cell models, alterations in connexin expression and gap junction organization have emerged as important factors to be considered in understanding the pro-arrhythmic substrate found in human cardiomyopathies.

In the June 2013 issue of this Journal, we described compelling evidence for the use of three novel anticoagulants, including Dabigatran, on the basis of recent large multi-centre trials.1 We acknowledged the approval of NOACs over warfarin in the ESC update and ACCP guidelines, and foresaw the greater usage of these newer, promising, therapies for stroke prevention in non-valvular atrial fibrillation. In our review article, we also advised a degree of caution with NOACs, as ‘experience with these drugs is relatively limited and that there are no currently available agents to reverse their effect in case of major complications, such as bleeding’. At the time, the concern centred around lack of reversal agents, which was discussed in a letter to the Editor, reflecting repercussions felt in the wider medical community.2,3 We had examined and accepted the data from the RE-LY trial to show how NOACs were becoming more acceptable. In light of the emerging concerns regarding the RE-LY trial and Dabigatran, highlighted by a recent BMJ investigation, we review the debate to date, and ask whether or not we, alongside commissioning bodies, now need to retract support for the drug.

Gap junctions, assembled from connexins, form the cell-to-cell pathways for propagation of the precisely orchestrated patterns of current flow that govern the normal rhythm of the healthy heart. As in most tissues and organs, multiple connexin types are co-expressed in the heart; connexin43, connexin40 and connexin45 are found in distinctive combinations and relative quantities in different, functionally-specialized subsets of cardiomyocyte. Alterations of gap junction organization and connexin expression are now well established as a consistent feature of human heart disease in which there is an arrhythmic tendency. These alterations may take the form of structural remodeling, involving disturbances in the distribution of gap junctions, and/or remodeling of connexin expression, involving alteration of the amount or type of connexin(s) expressed. In the diseased ventricle, the most consistent quantitative alteration involves heterogeneous reduction in connexin43 expression. In the atria, features of gap junction organization and connexin expression may contribute to both the initiation and persistence of atrial fibrillation. By correlating data from studies on the human patient with those from animal and cell models, alterations in gap junctions and connexins have emerged as important factors to be considered in understanding the pro-arrhythmic substrate found in a variety of forms of heart disease. Our knowledge of the functional correlates of the specific patterns of connexin co-expression in different subsets of myocyte in the healthy and diseased heart still remains limited, however, and the development of new experimental cell models heralds future advances in this field.

Heart muscle cells are electrically coupled by gap junctions, clusters of low-resistance transmembrane channels composed of connexins (Cx). The expression of the three major connexins (Cx43, Cx40 and Cx45) present in cardiac myocytes is known to be developmentally regulated but it is not clear how the patterns in the human heart compare with those found in the mouse. This issue is of importance given the wide use of transgenic mice to investigate gene function with the aim of extrapolating the results to human. In the present study we applied immunoconfocal microscopy to investigate the spatial distribution of the three connexins in the developing mouse heart and foetal human heart. Although Cx45 labelling was present at low levels throughout the developing mouse heart and human foetal (9-week) heart, it was most prominent in the conduction tissues. In the developing mouse heart, Cx40 was widely expressed at embryonic day 12.5 (E12.5) but at E17.5 expression was restricted to the conduction tissues and atria. In the 9-week human foetal heart, the Cx40 labelling pattern was similar to the E15 mouse heart, being far more abundant in conduction tissues (bundle branches to Purkinje fibres) and atria than in the ventricular muscle. Cx43 labelling became more apparent in the ventricular myocardium as development of the mouse heart progressed but was virtually undetectable in the central conduction system. In the human foetal heart Cx43 was virtually undetectable in the atria but was the predominant connexin in the ventricles. We conclude that, at least in some key aspects, the pattern of connexin expression in the developing mouse heart parallels that found in the human embryonic heart.

Heart muscle cells are electrically coupled by gap junctions, clusters of low-resistance transmembrane channels composed of connexins (Cx). The expression of the three major connexins (Cx43, Cx40 and Cx45) present in cardiac myocytes is known to be developmentally regulated but it is not clear how the patterns in the human heart compare with those found in the mouse. This issue is of importance given the wide use of transgenic mice to investigate gene function with the aim of extrapolating the results to human. In the present study we applied immunoconfocal microscopy to investigate the spatial distribution of the three connexins in the developing mouse heart and foetal human heart. Although Cx45 labelling was present at low levels throughout the developing mouse heart and human foetal (9-week) heart, it was most prominent in the conduction tissues. In the developing mouse heart, Cx40 was widely expressed at embryonic day 12.5 (E12.5) but at E17.5 expression was restricted to the conduction tissues and atria. In the 9-week human foetal heart, the Cx40 labelling pattern was similar to the E 15 mouse heart, being far more abundant in conduction tissues (bundle branches to Purkinje fibres) and atria than in the ventricular muscle. Cx43 labelling became more apparent in the ventricular myocardium as development of the mouse heart progressed but was virtually undetectable in the central conduction system. In the human foetal heart Cx43 was virtually undetectable in the atria but was the predominant connexin in the ventricles. We conclude that, at least in some key aspects, the pattern of connexin expression in the developing mouse heart parallels that found in the human embryonic heart. (Mol Cell Biochem 242: 121–127, 2002)

[first paragraph of article] Dear Editor, The points raised by Al-Kindi are well made and we accept concerns raised about the current lack of reliable reversal agents for the NOACs. This is also relevant to surgeons and interventionists, not least when performing percutaneous ablation therapy for atrial fibrillation, which is now routinely undertaken without discontinuing warfarin in those patients who are on this therapy. There is some early promise with regard to a specific reversal agent for Dabigatran, but large studies involving patients are necessary to adequately assess this and other such products. Once reversal agents for NOACs are proven to be safe and effective, the use of NOACs are likely to be more widely accepted.

Atrial fibrillation is a common, global problem, with great personal, economic and social burdens. As populations age it increases in prevalence and becomes another condition that requires careful chronic management to ensure its effects are minimised. Assessment of the risk of stroke using well established risk prediction models is being aided by modern computerised databases and the choice of drugs to prevent strokes is ever expanding to try and improve the major cause of morbidity in AF. In addition, newer drugs for controlling rhythm are available and guidelines are constantly changing to reflect this. As well as medications, modern techniques of electrophysiology are becoming more widely embraced worldwide to provide more targeted treatment for the underlying pathophysiology. In this review we consider these factors to concisely describe how AF can be successfully managed.