Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device - the SERCA-LVAD TRIAL.

The SERCA-LVAD trial was a phase 2a trial assessing the safety and feasibility of delivering an adeno-associated vector 1 carrying the cardiac isoform of the sarcoplasmic reticulum calcium ATPase (AAV1/SERCA2a) to adult chronic heart failure patients implanted with a left ventricular assist device. The SERCA-LVAD trial was one of a program of AAV1/SERCA2a cardiac gene therapy trials including CUPID1, CUPID 2 and AGENT trials. Enroled subjects were randomised to receive a single intracoronary infusion of 1 × 1013 DNase-resistant AAV1/SERCA2a particles or a placebo solution in a double-blinded design, stratified by presence of neutralising antibodies to AAV. Elective endomyocardial biopsy was performed at 6 months unless the subject had undergone cardiac transplantation, with myocardial samples assessed for the presence of exogenous viral DNA from the treatment vector. Safety assessments including ELISPOT were serially performed. Although designed as a 24 subject trial, recruitment was stopped after five subjects had been randomised and received infusion due to the neutral result from the CUPID 2 trial. Here we describe the results from the 5 patients at 3 years follow up, which confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Absolute levels of detectable transgene DNA were low, and no functional benefit was observed. There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort which may help guide future trial design.

Achieving good-quality consent: review of literature, case law and guidance.

BACKGROUND: Informed consent is an integral part of clinical practice. There is widespread agreement amongst health professionals that obtaining procedural consent needs to move away from a unidirectional transfer of information to a process of supporting patients in making informed, self-determined decisions. This review aimed to identify processes and measures that warrant consideration when engaging in consent-based discussions with competent patients undergoing elective procedures. METHODS: Formal written guidance from the General Medical Council and Royal College of Surgeons of England, in addition to peer-reviewed literature and case law, was considered in the formulation of this review. RESULTS: A framework for obtaining consent is presented that is informed by the key tenets of shared decision-making (SDM), a model that advocates the contribution of both the clinician and patient to the decision-making process through emphasis on patient participation, analysis of empirical evidence, and effective information exchange. Moreover, areas of contention are highlighted in which further guidance and research are necessary for improved enhancement of the consent process. CONCLUSION: This SDM-centric framework provides structure, detail and suggestions for achieving meaningful consent.

ANTECEDENTES: El consentimiento informado es una parte integral de la práctica clínica. Existe un acuerdo generalizado entre los profesionales de la salud en que lograr el consentimiento del procedimiento no debe ser una transferencia unidireccional de información, sino un proceso de apoyo a los pacientes en la toma de decisiones informadas y autodeterminadas. Esta revisión tiene como objetivo identificar procesos y medidas que deban ser considerados al hablar sobre el consentimiento con pacientes autosuficientes sometidos a procedimientos quirúrgicos electivos. MÉTODOS: Al planear esta revisión se tuvo en cuenta la recomendación formal por escrito del Consejo Médico General y del Royal College of Surgeons of England, además de la literatura revisada por pares y de la jurisprudencia. RESULTADOS: Se presenta un marco para lograr el consentimiento que se basa en los principios clave de la toma de decisiones compartida (Shared Decision-Making, SDM); un modelo que aboga por la contribución, tanto del médico como del paciente, al proceso de toma de decisiones a través del énfasis en la participación del paciente, el análisis de la evidencia empírica y el intercambio efectivo de información. Además, se destacan áreas de contención en las que se necesitan más recomendaciones y más investigación para mejorar aún más el proceso del consentimiento. CONCLUSIÓN: Este marco centrado en la SDM proporciona estructura, detalles y sugerencias sobre cómo se puede lograr un consentimiento informado satisfactorio.

Development of an automaton model of rotational activity driving atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is difficult to treat effectively, owing to uncertainty in where to best ablate to eliminate arrhythmogenic substrate. A model providing insight into the electrical activation events would be useful to guide catheter ablation strategy. Method A two-dimensional, 576×576 node automaton was developed to simulate atrial electrical activity. The substrate field was altered by the presence of differing refractory period at varying locations. Fibrosis was added in the form of short, randomly positioned lines of conduction block. Larger areas of block were used to simulate ablation lesions. Anisotropy was imposed in a 2:1 ratio. A premature electrical impulse from one of four grid corners was utilized to initiate activation. RESULTS: Rotational activity was uninducible when refractory patch dimensions were less than 20×20mm. For larger refractory regions, a single premature stimulus was capable of inducing an average of 1.19±1.10 rotors, which often formed near the patch edges. A maximum of 5 rotors formed when refractory patch dimensions approached the size of the entire left atrial virtual field. Rotors formed along a refractory patch edge, after wavefront arrival was delayed at turning points or due to the presence of a fiber cluster of sufficient size. However, rotational activity could also occur around a large fiber cluster without the need of spatially variable refractoriness. When obstacles to conduction were lacking in size, nascent rotors drifted and either extinguished, or stabilized upon anchoring at a sufficiently large fiber cluster elsewhere in the field. Transient rotors terminated when traversing a region with differing refractory periods, if no obstacle to conduction was present to sufficiently delay wavefront arrival beyond the longest refractory period. Other rotors were annihilated when a nearby rotor with faster spin rate gradually interrupted the activation pathway. Elimination of anchors by removal, or by simulated ablation over a sufficient region, prevented rotor onset at a particular location where it would otherwise form. CONCLUSIONS: The presence of obstacles to conduction and spatial differences in refractory period are important parameters for initiating and maintaining rotational activity in this simulation of an atrial substrate.

Relating specific connexin co-expression ratio to connexon composition and gap junction function.

Cardiac connexin 43 (Cx43), Cx40 and Cx45 are co-expressed at distinct ratios in myocytes. This pattern is considered a key factor in regulating the gap junction channels composition, properties and function and remains poorly understood. This work aims to correlate gap junction function with the connexin composition of the channels at accurate ratios Cx43:Cx40 and Cx43:Cx45. Rat liver epithelial cells that endogenously express Cx43 were stably transfected to induce expression of accurate levels of Cx40 or Cx45 that may be present in various areas of the heart (e.g. atria and ventricular conduction system). Induction of Cx40 does not increase the amounts of junctional connexins (Cx43 and Cx40), whereas induction of Cx45 increases the amounts of junctional connexins (Cx43 and Cx45). Interestingly, the non-junctional fraction of Cx43 remains unaffected upon induction of Cx40 and Cx45. Co-immunoprecipitation studies show low level of Cx40/Cx43 heteromerisation and undetectable Cx45/Cx43 heteromerisation. Functional characterisation shows that induction of Cx40 and Cx45 decreases Lucifer Yellow transfer. Electrical coupling is decreased by Cx45 induction, whereas it is decreased at low induction of Cx40 and increased at high induction. These data indicate a fine regulation of the gap junction channel make-up in function of the type and the ratio of co-expressed Cxs that specifically regulates chemical and electrical coupling. This reflects specific gap junction function in regulating impulse propagation in the healthy heart, and a pro-arrhythmic potential of connexin remodelling in the diseased heart.

Techniques for automated local activation time annotation and conduction velocity estimation in cardiac mapping.

Measurements of cardiac conduction velocity provide valuable functional and structural insight into the initiation and perpetuation of cardiac arrhythmias, in both a clinical and laboratory context. The interpretation of activation wavefronts and their propagation can identify mechanistic properties of a broad range of electrophysiological pathologies. However, the sparsity, distribution and uncertainty of recorded data make accurate conduction velocity calculation difficult. A wide range of mathematical approaches have been proposed for addressing this challenge, often targeted towards specific data modalities, species or recording environments. Many of these algorithms require identification of activation times from electrogram recordings which themselves may have complex morphology or low signal-to-noise ratio. This paper surveys algorithms designed for identifying local activation times and computing conduction direction and speed. Their suitability for use in different recording contexts and applications is assessed.

Haemorrhagic cerebral air embolism from an atrio-oesophageal fistula following atrial fibrillation ablation.

We report the case of a man found unconscious three weeks following atrial fibrillation (AF) ablation. Cranial and thoracic imaging demonstrated multiple areas of pneumo-embolic infarction secondary to an atrio-oesophageal fistula (AEF). AEF is a recognised, but rare, complication of AF ablation.(1-8) Early recognition is critical as the mortality is 100% without surgical intervention. We consider the postulated mechanisms of AEF formation, the spectrum of clinical presentation, investigations and treatment.

Automated analysis of atrial late gadolinium enhancement imaging that correlates with endocardial voltage and clinical outcomes: a 2-center study.

BACKGROUND: For late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) assessment of atrial scar to guide management and targeting of ablation in atrial fibrillation (AF), an objective, reproducible method of identifying atrial scar is required. OBJECTIVE: To describe an automated method for operator-independent quantification of LGE that correlates with colocated endocardial voltage and clinical outcomes. METHODS: LGE CMR imaging was performed at 2 centers, before and 3 months after pulmonary vein isolation for paroxysmal AF (n = 50). A left atrial (LA) surface scar map was constructed by using automated software, expressing intensity as multiples of standard deviation (SD) above blood pool mean. Twenty-one patients underwent endocardial voltage mapping at the time of pulmonary vein isolation (11 were redo procedures). Scar maps and voltage maps were spatially registered to the same magnetic resonance angiography (MRA) segmentation. RESULTS: The LGE levels of 3, 4, and 5SDs above blood pool mean were associated with progressively lower bipolar voltages compared to the preceding enhancement level (0.85 ± 0.33, 0.50 ± 0.22, and 0.38 ± 0.28 mV; P = .002, P < .001, and P = .048, respectively). The proportion of atrial surface area classified as scar (ie, >3 SD above blood pool mean) on preablation scans was greater in patients with postablation AF recurrence than those without recurrence (6.6% ± 6.7% vs 3.5% ± 3.0%, P = .032). The LA volume >102 mL was associated with a significantly greater proportion of LA scar (6.4% ± 5.9% vs 3.4% ± 2.2%; P = .007). CONCLUSIONS: LA scar quantified automatically by a simple objective method correlates with colocated endocardial voltage. Greater preablation scar is associated with LA dilatation and AF recurrence.

A non-traumatic, blue-purple auricle: case report.

OBJECTIVE: We report a typical case of earlobe lymphocytoma. METHOD: A case report and literature review are presented. RESULTS: A 10-year-old girl presented with a blue-coloured earlobe. A diagnosis of Lyme disease was confirmed by serological tests. Lyme borreliosis is the most common tick-borne disease in the northern hemisphere. It is caused by the spirochete Borrelia burgdorferi sensu lato. The patient was successfully treated with antibiotics. CONCLUSION: The diagnostic process and ENT symptomatology of Lyme disease and borrelial lymphocytoma are summarised and discussed.

Comparison of temporary bifocal right ventricular pacing and biventricular pacing for heart failure: evaluation by tissue Doppler imaging.

BACKGROUND: The complications and limitations of biventricular pacing largely relate to left ventricular (LV) pacing. An alternative approach was tested of simultaneously pacing the right ventricular (RV) apex and outflow tract (RVOT) or using bifocal right ventricular pacing (BRVP) to provide cardiac resynchronisation. METHODS: 21 consecutive patients with heart failure and severely impaired left ventricular function were studied. Ejection fraction and tissue Doppler data were collected at baseline, during BRVP, and during biventricular pacing, using a temporary pacing protocol. RESULTS: BRVP was achieved in all patients without complication. BRVP significantly reduced mean baseline intra-LV, inter-LV-RV, and global mechanical dyssynchrony from (mean (SD)) 71 (35) to 44 (18) ms, p = 0.003; 86 (42) to 57 (33) ms, p = 0.029; and 157 (67) to 101 (42) ms, p = 0.005, respectively. It increased the ejection fraction from 21 (8)% to 29 (7)%, p = 0.002. Compared with BRVP, reductions in intra-LV, inter-LV-RV, and global mechanical dyssynchrony were superior with biventricular pacing (31 (12) ms, p = 0.014; 36 (27) ms, p = 0.008; and 67 (34) ms, p = 0.01 compared with BRVP, respectively); improvements in ejection fraction were similar (26 (9)%, NS). CONCLUSIONS: In patients with heart failure, superior mechanical resynchronisation is achieved with biventricular pacing compared with BRVP. BRVP may be useful when left ventricular lead placement is not possible.

The interaction of interventricular pacing intervals and left ventricular lead position during temporary biventricular pacing evaluated by tissue Doppler imaging.

OBJECTIVE: To determine the effects of interventricular pacing interval and left ventricular (LV) pacing site on ventricular dyssynchrony and function at baseline and during biventricular pacing, using tissue Doppler imaging. METHODS: Using an angioplasty wire to pace the left ventricle, 20 patients with heart failure and left bundle branch block underwent temporary biventricular pacing from lateral (n = 20) and inferior (n = 10) LV sites at five interventricular pacing intervals: +80, +40, synchronous, -40, and -80 ms. RESULTS: LV ejection fraction (EF) increased (mean (SD) from 18 (8)% to 26 (10)% (p = 0.016) and global mechanical dyssynchrony decreased from 187 (91) ms to 97 (63) ms (p = 0.0004) with synchronous biventricular pacing compared to unpaced baseline. Sequential pacing with LV preactivation produced incremental improvements in EF and global mechanical dyssynchrony (p<0.0001 and p = 0.0026, respectively), primarily as a result of reductions in inter-LV-RV dyssynchrony (p = 0.0001) rather than intra-LV dyssynchrony (NS). Results of biventricular pacing from an inferior or lateral LV site were comparable (for example, synchronous biventricular pacing, global mechanical dyssynchrony: lateral LV site, 97 (63) ms; inferior LV site, 104 (41) ms (NS); EF: lateral LV site, 26 (10)%; inferior LV site, 27 (10)% (NS)). ECG morphology was identical during biventricular pacing through an angioplasty wire and a permanent lead. CONCLUSIONS: Sequential biventricular pacing with LV preactivation most often optimises LV synchrony and EF. An inferior LV site offers a good alternative to a lateral site. Pacing through an angioplasty wire may be useful in assessing the acute effects of pacing.

A compact electric potential sensor array for the acquisition and reconstruction of the 7-lead electrocardiogram without electrical charge contact with the skin.

Conventional electrocardiogram (ECG) systems make use of separate electrical connections to the arms and legs. These use a 'long baseline' for the voltage reference potential which in the case of precordial ECG leads is provided using a Wilson central terminal (WCT) wiring configuration. The aims of this project were (a) to construct compact, non-invasive surface ECG sensor arrays which would operate without the need for a WCT reference, (b) to obtain high quality precordial ECGs showing fine differences in ECG detail between small adjacent areas of the chest and (c) to reconstruct, from a compact array of four sensors, ECGs which closely match to the conventional 7-lead ECG system, but without the need for multiple wires and long baselines. In this paper, we describe two sensor array configurations which have been constructed using electric potential sensors (EPSs). We show high quality precordial ECGs obtained from small areas of the surface of the chest and show the different angular vectors (leads) in the frontal cardiac plane constructed using signals from the array elements. We suggest that these ECG arrays, which are simple to apply, should prove to be a valuable tool in providing useful information about the state of the heart.

Role of electrophysiological study and ablation in the management of recurrent atrial flutter associated with haemodynamic compromise in a critically ill patient.

Atrial flutter is a common arrhythmia. In the critical care setting, the arrhythmia may present in any patient, but it is most commonly seen in patients with impaired ventricular function, valvular disease, atrial dilatation or after cardiac surgery. We present a 68-year-old lady with recurrent poorly tolerated atrial flutter that was resistant to multiple pharmacological interventions and complicated by cardiogenic shock following direct current cardioversion. The flutter was successfully cured with radiofrequency ablation and was followed by an immediate improvement in her haemodynamic status. We review the management of acute atrial flutter and discuss the role of electrophysiologically guided ablation.

Rapid access arrhythmia clinic for the diagnosis and management of new arrhythmias presenting in the community: a prospective, descriptive study.

OBJECTIVE: To investigate whether a rapid access approach is useful for the evaluation of patients with symptoms suggestive of a new cardiac arrhythmia. DESIGN: Prospective, descriptive study. SETTING: Secondary care based rapid access arrhythmia clinic in West London, UK. PARTICIPANTS: Patients referred by their general practitioner or the emergency department with symptoms suggestive of a new cardiac arrhythmia. MAIN OUTCOME MEASURES: Number of patients with a newly diagnosed significant arrhythmia. Number of patients with diagnosed atrial fibrillation. Number of eligible, moderate, and high risk patients treated with warfarin. RESULTS: Over a 25 month period 984 referrals were assessed. The mean age was 55 years (range 20-90 years) and 56% were women. The median time from referral to assessment was one day. A significant cardiac arrhythmia was newly diagnosed in 40% of patients referred to the RAAC. The most common arrhythmia was atrial fibrillation, with 203 new cases (21%). Of these, 74% of eligible patients over 65 were treated with warfarin. Other arrhythmias diagnosed were supraventricular tachycardias (127 (13%)), conduction disorders (43 (4%)), and non-sustained ventricular tachycardia (21 (2%)). Vasovagal syncope was diagnosed for 53 patients (5%). The most frequent diagnosis was symptomatic ventricular and supraventricular extrasystoles (355 (36%)). CONCLUSION: A rapid access arrhythmia clinic is an innovative approach to the diagnosis and management of new cardiac arrhythmias in the community. It provides a rapid diagnosis, stratifies risk, and leads to prompt initiation of effective treatment for this population.

Haemodynamic effect of intermittent pneumatic compression of the leg after infrainguinal arterial bypass grafting.

BACKGROUND: Intermittent pneumatic compression (IPC) may increase blood flow through infrainguinal arterial grafts, and has potential clinical application as blood flow velocity attenuation often precedes graft failure. The present study examined the immediate effects of IPC applied to the foot (IPC(foot)), the calf (IPC(calf)) and to both simultaneously (IPC(foot+calf)) on the haemodynamics of infrainguinal bypass grafts. METHODS: Eighteen femoropopliteal and 18 femorodistal autologous vein grafts were studied; all had a resting ankle : brachial pressure index of 0.9 or more. Clinical examination, graft surveillance and measurement of graft haemodynamics were conducted at rest and within 5 s of IPC in each mode using duplex imaging. Outcome measures included peak systolic (PSV), mean (MV) and end diastolic (EDV) velocities, pulsatility index (PI) and volume flow in the graft. RESULTS: All IPC modes significantly enhanced MV, PSV, EDV and volume flow in both graft types; IPC(foot+calf) was the most effective. IPC(foot+calf) enhanced median volume flow, MV and PSV in femoropopliteal grafts by 182, 236 and 49 per cent, respectively, and attenuated PI by 61 per cent. Enhancement in femorodistal grafts was 273, 179 and 53 per cent respectively, and PI attenuation was 63 per cent. CONCLUSION: IPC was effective in improving infrainguinal graft flow velocity, probably by reducing peripheral resistance. IPC has the potential to reduce the risk of bypass graft thrombosis.

Slow pathway catheter ablation of atrioventricular nodal re-entrant tachycardia guided by electroanatomical mapping: a randomized comparison to the conventional approach.

BACKGROUND: Electroanatomical mapping may be expected to improve safety, efficiency and efficacy of selective slow pathway ablation for atrioventricular nodal re-entrant tachycardia (AVNRT). The goal of this prospective randomized study was to compare the efficiency of conventional fluoroscopic and electroanatomical mapping in guiding catheter ablation of AVNRT. METHODS AND RESULTS: Following induction of typical AVNRT, 20 consecutive patients were randomized to either conventional fluoroscopic or electroanatomical (CARTO) mapping to guide slow pathway ablation using a 4mm electrode. Endpoints for ablation were non-inducibility and no more than a single AV nodal echo on aggressive retesting. Acute procedural success was 100% in both groups, with no complications. Although there were no differences in time taken for pre- and post-ablation electrophysiological evaluations, in the electroanatomical group the ablation portion of the procedure showed a substantial reduction in duration (12.6+/-6.8 vs 35.9+/-18.3 min; P< 0.001) and fluoroscopic exposure (0.7+/-0.5 vs 9.6+/-5.0 min; P< 0.001) compared with the fluoroscopic group, reflected in reduced total procedure time (83.6+/-23.6 vs 114+/-19.3 min; P=0.008) and total fluoroscopic exposure (4.2+/-1.4 vs 15.9+/-6.4 min; P< 0.001). Electroanatomical mapping was associated with a lower number (2.7+/-1.6 vs 5+/-2.8; P=0.018), duration (165.3+/-181.6 vs 341+/-177.7s; P=0.013), and total energy delivery (24.3+/-3.1 vs 28.7+/-4.5 watts; P=0.042) of RF applications. There were no acute or long-term (8.9+/-2.2 month) complications or arrhythmia recurrence in either group. CONCLUSIONS: While both conventional and non-fluoroscopic electroanatomical mapping are associated with excellent results in guiding ablation of typical AVNRT, the latter offers significantly shorter procedure and fluoroscopy times, improving the efficiency of the procedure and reducing X-ray exposure.

Characterization of the anatomy and conduction velocities of the human right atrial flutter circuit determined by noncontact mapping.

OBJECTIVES: This study was done to characterize human right atrial (RA) flutter (AFL) using noncontact mapping. BACKGROUND: Atrial flutter has been mapped using sequential techniques, but complex anatomy makes simultaneous global RA mapping difficult. METHODS: Noncontact mapping was used to map the RA of 13 patients with AFL (5 with previous attempts), 11 with counterclockwise and 2 with clockwise AFL. "Reconstructed" electrograms were validated against contact electrograms using cross-correlation. The Cartesian coordinates of points on a virtual endocardium were used to calculate the length and thus the conduction velocity (CV) of the AFL wave front within the tricuspid annulus-inferior vena cave isthmus (IS) and either side of the crista terminalis (CT). RESULTS: When clearly seen, the AFL wave front split (n = 3) or turned in the region of the coronary sinus os (n = 6). Activation progressed toward the tricuspid annulus (TA) from the surrounding RA in 10 patients, suggesting that the leading edge of the reentry wave front is not always at the TA. The IS length and CV was 47.73 +/- 24.40 mm (mean +/- SD) and 0.74 +/- 0.36 m/s. The CV was similar for the smooth and trabeculated RA (1.16 +/- 0.48 m/s and 1.22 +/- 0.65 m/s, respectively [p = 0.67]) and faster than the IS (p = 0.03 and p = 0.05 for smooth and trabeculated, respectively). CONCLUSIONS: Noncontact mapping of AFL has been validated and has demonstrated that IS CV is significantly slower than either side of the CT.