Ablation versus anti-arrhythmic therapy for reducing all hospital episodes from recurrent atrial fibrillation: a prospective, randomized, multi-centre, open label trial.

AIMS: There is rising healthcare utilization related to the increasing incidence and prevalence of atrial fibrillation (AF) worldwide. Simplifying therapy and reducing hospital episodes would be a valuable development. The efficacy of a streamlined AF ablation approach was compared to drug therapy and a conventional catheter ablation technique for symptom control in paroxysmal AF. METHODS AND RESULTS: We recruited 321 patients with symptomatic paroxysmal AF to a prospective randomized, multi-centre, open label trial at 13 UK hospitals. Patients were randomized 1:1:1 to cryo-balloon ablation without electrical mapping with patients discharged same day [Ablation Versus Anti-arrhythmic Therapy for Reducing All Hospital Episodes from Recurrent (AVATAR) protocol]; optimization of drug therapy; or cryo-balloon ablation with confirmation of pulmonary vein isolation and overnight hospitalization. The primary endpoint was time to any hospital episode related to treatment for atrial arrhythmia. Secondary endpoints included complications of treatment and quality-of-life measures. The hazard ratio (HR) for a primary endpoint event occurring when comparing AVATAR protocol arm to drug therapy was 0.156 (95% CI, 0.097-0.250; P < 0.0001 by Cox regression). Twenty-three patients (21%) recorded an endpoint event in the AVATAR arm compared to 76 patients (74%) within the drug therapy arm. Comparing AVATAR and conventional ablation arms resulted in a non-significant HR of 1.173 (95% CI, 0.639-2.154; P = 0.61 by Cox regression) with 23 patients (21%) and 19 patients (18%), respectively, recording primary endpoint events (P = 0.61 by log-rank test). CONCLUSION: The AVATAR protocol was superior to drug therapy for avoiding hospital episodes related to AF treatment, but conventional cryoablation was not superior to the AVATAR protocol. This could have wide-ranging implications on how demand for AF symptom control is met. TRIAL REGISTRATION: Clinical Trials Registration: NCT02459574.

Exercise-induced ventricular arrhythmia in coronary cameral fistula: A manifestation of reperfusion injury.

Presentation, Investigation and Management of Coronary fistula and its arrhythmic complications.

Atriofascicular pathway detection with novel ablation catheter.

Atriofascicular pathways are a rare cause of antidromic atrioventricular reciprocating tachycardia. The IntellaTip MiFi ablation catheter (Boston Scientific, MA, USA) is a novel ablation catheter that allows enhanced signal clarity with highly localized electrograms. This is the first report of this catheter being successfully used to map and ablate the atriofascicular pathway potentials.

Double jeopardy.

Torsades de pointes ("twisting of points") (TdP) is a broad complex tachyarrhythmia which was first described in 1966 by Francois Dessertenne and usually results from prolongation of the QT interval.(1) A wide variety of drugs have been shown to prolong the QT interval in susceptible individuals.(2) We present the case of a former intravenous heroin user presenting with several episodes of TdP which were caused by QT prolongation due to methadone treatment and exacerbated by hepatitis B/C infection. Despite aggressive medical treatment and withdrawal of methadone, he had recurrent episodes of TdP which required continuous temporary cardiac pacing for six days. He was found to have moderate LV dysfunction on his echocardiogram and unobstructed coronary arteries on coronary angiography. He underwent implantation of a defibrillator due to concerns about further episodes of ventricular arrhythmias which could recur even in the absence of further methadone use.

Genomic and expression analysis of the flax (Linum usitatissimum) family of glycosyl hydrolase 35 genes.

BACKGROUND: Several ß-galactosidases of the Glycosyl Hydrolase 35 (GH35) family have been characterized, and many of these modify cell wall components, including pectins, xyloglucans, and arabinogalactan proteins. The phloem fibres of flax (Linum usitatissimum) have gelatinous-type cell walls that are rich in crystalline cellulose and depend on ß-galactosidase activity for their normal development. In this study, we investigate the transcript expression patterns and inferred evolutionary relationships of the complete set of flax GH35 genes, to better understand the functions of these genes in flax and other species. RESULTS: Using the recently published flax genome assembly, we identified 43 ß-galactosidase-like (BGAL) genes, based on the presence of a GH35 domain. Phylogenetic analyses of their protein sequences clustered them into eight sub-families. Sub-family B, whose members in other species were known to be expressed in developing flowers and pollen, was greatly under represented in flax (p-value < 0.01). Sub-family A5, whose sole member from arabidopsis has been described as its primary xyloglucan BGAL, was greatly expanded in flax (p-value < 0.01). A number of flax BGALs were also observed to contain non-consensus GH35 active sites. Expression patterns of the flax BGALs were investigated using qRT-PCR and publicly available microarray data. All predicted flax BGALs showed evidence of expression in at least one tissue. CONCLUSION: Flax has a large number of BGAL genes, which display a distinct distribution among the BGAL sub-families, in comparison to other closely related species with available whole genome assemblies. Almost every flax BGAL was expressed in fibres, the majority of which expressed predominately in fibres as compared to other tissues, suggesting an important role for the expansion of this gene family in the development of this species as a fibre crop. Variations displayed in the canonical GH35 active site suggest a variety of roles unique to flax, which will require further characterization.

LuFLA1PRO and LuBGAL1PRO promote gene expression in the phloem fibres of flax (Linum usitatissimum).

KEY MESSAGE: Cell type-specific promoters were identified that drive gene expression in an industrially important product. To identify flax (Linum usitatissimum) gene promoters, we analyzed the genomic regions upstream of a fasciclin-like arabinogalactan protein (LuFLA1) and a beta-galactosidase (LuBGAL1). Both of these genes encode transcripts that have been found to be highly enriched in tissues bearing phloem fibres. Using a beta-glucuronidase (GUS) reporter construct, we found that a 908-bp genomic sequence upstream of LuFLA1 (LuFLA1PRO) directed GUS expression with high specificity to phloem fibres undergoing secondary cell wall development. The DNA sequence upstream of LuBGAL1 (LuBGAL1PRO) likewise produced GUS staining in phloem fibres with developing secondary walls, as well as in tissues of developing flowers and seed bolls. These data provide further evidence of a specific role for LuFLA1 in phloem fibre development, and demonstrate the utility of LuFLA1PRO and LuBGAL1PRO as tools for biotechnology and further investigations of phloem fibre development.

The genome of flax (Linum usitatissimum) assembled de novo from short shotgun sequence reads.

Flax (Linum usitatissimum) is an ancient crop that is widely cultivated as a source of fiber, oil and medicinally relevant compounds. To accelerate crop improvement, we performed whole-genome shotgun sequencing of the nuclear genome of flax. Seven paired-end libraries ranging in size from 300 bp to 10 kb were sequenced using an Illumina genome analyzer. A de novo assembly, comprised exclusively of deep-coverage (approximately 94× raw, approximately 69× filtered) short-sequence reads (44-100 bp), produced a set of scaffolds with N(50) =694 kb, including contigs with N(50)=20.1 kb. The contig assembly contained 302 Mb of non-redundant sequence representing an estimated 81% genome coverage. Up to 96% of published flax ESTs aligned to the whole-genome shotgun scaffolds. However, comparisons with independently sequenced BACs and fosmids showed some mis-assembly of regions at the genome scale. A total of 43384 protein-coding genes were predicted in the whole-genome shotgun assembly, and up to 93% of published flax ESTs, and 86% of A. thaliana genes aligned to these predicted genes, indicating excellent coverage and accuracy at the gene level. Analysis of the synonymous substitution rates (K(s) ) observed within duplicate gene pairs was consistent with a recent (5-9 MYA) whole-genome duplication in flax. Within the predicted proteome, we observed enrichment of many conserved domains (Pfam-A) that may contribute to the unique properties of this crop, including agglutinin proteins. Together these results show that de novo assembly, based solely on whole-genome shotgun short-sequence reads, is an efficient means of obtaining nearly complete genome sequence information for some plant species.

Development of cellulosic secondary walls in flax fibers requires beta-galactosidase.

Bast (phloem) fibers, tension wood fibers, and other cells with gelatinous-type secondary walls are rich in crystalline cellulose. In developing bast fibers of flax (Linum usitatissimum), a galactan-enriched matrix (Gn-layer) is gradually modified into a mature cellulosic gelatinous-layer (G-layer), which ultimately comprises most of the secondary cell wall. Previous studies have correlated this maturation process with expression of a putative ß-galactosidase. Here, we demonstrate that ß-galactosidase activity is in fact necessary for the dynamic remodeling of polysaccharides that occurs during normal secondary wall development in flax fibers. We found that developing stems of transgenic (LuBGAL-RNAi) flax with reduced ß-galactosidase activity had lower concentrations of free Gal and had significant reductions in the thickness of mature cellulosic G-layers compared with controls. Conversely, Gn-layers, labeled intensively by the galactan-specific LM5 antibody, were greatly expanded in LuBGAL-RNAi transgenic plants. Gross morphology and stem anatomy, including the thickness of bast fiber walls, were otherwise unaffected by silencing of ß-galactosidase transcripts. These results demonstrate a specific requirement for ß-galactosidase in hydrolysis of galactans during formation of cellulosic G-layers. Transgenic lines with reduced ß-galactosidase activity also had biochemical and spectroscopic properties consistent with a reduction in cellulose crystallinity. We further demonstrated that the tensile strength of normal flax stems is dependent on ß-galactosidase-mediated development of the phloem fiber G-layer. Thus, the mechanical strength that typifies flax stems is dependent on a thick, cellulosic G-layer, which itself depends on ß-galactosidase activity within the precursor Gn-layer. These observations demonstrate a novel role for matrix polysaccharides in cellulose deposition; the relevance of these observations to the development of cell walls in other species is also discussed.

Generation of a restriction minus enteropathogenic Escherichia coli E2348/69 strain that is efficiently transformed with large, low copy plasmids.

BACKGROUND: Many microbes possess restriction-modification systems that protect them from parasitic DNA molecules. Unfortunately, the presence of a restriction-modification system in a given microbe also hampers genetic analysis. Although plasmids can be successfully conjugated into the enteropathogenic Escherichia coli strain E2348/69 and optimized protocols for competent cell preparation have been developed, we found that a large, low copy (approximately 15) bioluminescent reporter plasmid, pJW15, that we modified for use in EPEC, was exceedingly difficult to transform into E2348/69. We reasoned that a restriction-modification system could be responsible for the low transformation efficiency of E2348/69 and sought to identify and inactivate the responsible gene(s), with the goal of creating an easily transformable strain of EPEC that could complement existing protocols for genetic manipulation of this important pathogen. RESULTS: Using bioinformatics, we identified genes in the unfinished enteropathogenic Escherichia coli (EPEC) strain E2348/69 genome whose predicted products bear homology to the HsdM methyltransferases, HsdS specificity subunits, and HsdR restriction endonucleases of type I restriction-modification systems. We constructed a strain carrying a deletion of the conserved enzymatic domain of the EPEC HsdR homologue, NH4, and showed that its transformation efficiency was up to four orders of magnitude higher than that of the parent strain. Further, the modification capacity of NH4 remained intact, since plasmids that were normally recalcitrant to transformation into E2348/69 could be transformed upon passage through NH4. NH4 was unaffected in virulence factor production, since bundle forming pilus (BFP) subunits and type III secreted (T3S) proteins were present at equivalent levels to those seen in E2348/69. Further, NH4 was indistinguishable from E2348/69 in tissue culture infection model assays of localized adherence and T3S. CONCLUSION: We have shown that EPEC strain E2348/69 utilizes a type I restriction-modification system to limit entry of new DNA. This restriction-modification system does not appear to be involved in virulence determinant expression or infection phenotypes. The hsdR mutant strain should prove useful in genetic analysis of the important diarrheal pathogen EPEC.

Should patients who have persistent severe symptoms receive a left ventricular assist device or cardiac resynchronization therapy as the next step?

Currently, cardiac resynchronization therapy (CRT) should be considered before a left ventricular assist device for most patients who have moderate or severe left ventricular systolic dysfunction and have not responded symptomatically to conventional pharmacologic measures. There is little evidence that the severity of cardiac dyssynchrony as measured using current techniques is useful in predicting the benefits of CRT. QRS duration on the surface ECG is a surrogate marker of the severity of the left ventricular ejection fraction as well as of several types of dyssynchrony. More clinical trials are required to determine whether excluding patients who have QRS duration less than 120 msec or those who have no evidence of dyssynchrony from implantation of CRT is appropriate. Perhaps all patients who have moderate or severe left ventricular systolic dysfunction should be considered for CRT, either to improve symptoms if they are persistent or relapsing, or to improve outcome. In the longer-term future, it is possible that the development of less expensive, small, and safe left ventricular assist devices will supplant the role of both CRT and CRT-defibrillator devices.

Clinical trials update from Heart Rhythm 2007 and Heart Failure 2007: CARISMA, PREPARE, DAVID II, SAVE-PACE, PROTECT and AREA-IN-CHF.

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at Heart Rhythm 2007 organised by the Heart Rhythm Society which was held in Denver, USA and Heart Failure 2007 organised by the Heart Failure Association of the European Society of Cardiology which was held in Hamburg, Germany. Unpublished reports should be considered as preliminary data, as analyses may change in the final publication. The CARISMA study suggests that non-invasive screening tests may help to identify post-MI patients who may benefit from ICD therapy. Data from the PREPARE study show that more conservative ICD programming can reduce morbidity at the cost of an increased risk of arrhythmic syncope. DAVID II indicates that atrial pacing may be a safe alternative to ventricular back-up pacing in patients with left ventricular dysfunction and standard indications for an ICD. The incidence of persistent atrial fibrillation in patients with sinus node disease in SAVE-PACE was reduced by dual chamber minimal ventricular pacing compared to conventional dual chamber pacing. The pilot phase of the PROTECT studies confirmed 30 mg as the dose of the selective A1 adenosine receptor antagonist KW-3902 to be used in pivotal studies. AREA-IN-CHF failed to show a beneficial effect of canrenone on LV volumes compared to placebo however some beneficial effects on secondary clinical endpoints were observed.

Clinical trials update from the American Heart Association 2006: OAT, SALT 1 and 2, MAGIC, ABCD, PABA-CHF, IMPROVE-CHF, and percutaneous mitral annuloplasty.

This article provides information and a commentary on trials presented at the American Heart Association meeting held in November 2006, relevant to the pathophysiology, prevention and treatment of heart failure. All reports should be considered as preliminary data, as analyses may change in the final publication. The OAT study failed to show a benefit of PCI over optimal medical therapy in patients with persistent total occlusion of the infarct related artery following a myocardial infarction. In SALT 1 and 2, tolvaptan was found to correct hyponatraemia of various aetiologies; however, whether this has an impact on heart failure prognosis requires further evaluation. A placebo controlled study of myocardial implantation of skeletal myoblasts in patients with moderate to severe LVSD (MAGIC) showed equivocal/uncertain effects, long term follow-up data are awaited. The ABCD study which compared the ability of an invasive and a non-invasive test to identify patients at risk of arrhythmic events prior to ICD implantation, suggested that the two strategies were comparable, although the practical value of either test remains uncertain and the study had many major flaws. The PABA-CHF study hinted that pulmonary vein antrum isolation might be more effective than AV node ablation with bi-ventricular pacing for the treatment of patients with heart failure in atrial fibrillation. In IMPROVE-CHF, an NT-pro BNP guided treatment strategy was found to reduce the cost of managing patients with acute breathlessness.

Hemodynamic assessment of mitral mechanical prostheses under high flow conditions: comparison between dynamic exercise and dobutamine stress.

BACKGROUND AND AIM OF THE STUDY: The study aim was to compare the effects of dobutamine stress and exercise on prosthetic mitral valve hemodynamics. METHODS: Twenty-three patients who had recently (3 +/- 1 months) undergone mechanical mitral valve implantation were studied. Hemodynamic variables, two-dimensional echocardiographic and Doppler mitral/aortic flows were recorded at rest, and then repeated during exercise and dobutamine stress. The investigations were randomized place to determine which stress would be performed first. RESULTS: Heart rates and pressure drops rose significantly from resting values. At maximum stress, exercise produced maximum and mean pressure drops which were statistically greater than with dobutamine (19.4 +/- 6.0 versus 12.8 +/- 4.7 mmHg (p < 0.001) and 10.2 +/- 3.5 versus 6.8 +/- 2.8 (p < 0.01), respectively). Exercise was associated with statistically shorter diastolic filling times and higher transvalvular diastolic flow rates. Dobutamine produced a greater augmentation in mitral effective orifice area (EOA) (p < 0.05). The slopes of pressure drop/cardiac flow were calculated for stress type and shown to be significantly lower during dobutamine administration (p = 0.03). CONCLUSION: Normally functioning mitral prostheses can generate significant increases in valvular pressure drops under high flow conditions. Physiological differences exist between dobutamine stress and exercise when assessing diastolic filling. At a given flow rate, dobutamine produces a greater augmentation in the mitral EOA and a smaller drop in transvalvular pressure.

Hemodynamic performance of the Ultracor and Carpentier-Edwards aortic prostheses using exercise and dobutamine stress echocardiography.

BACKGROUND AND AIM OF THE STUDY: The study aim was to compare the hemodynamic profiles of the aortic standard porcine Carpentier-Edwards (C-E) and Ultracor (tilting-disc) valve using exercise and dobutamine stress. METHODS: A total of 36 patients was examined, 18 for each valve type. When analyzing the data, valve types were matched for valve size, which ranged from 21 to 25 mm. All patients were analyzed within an 18-month period after implantation. Hemodynamic variables, two-dimensional echocardiography and Doppler flows were recorded at rest. These were repeated during bicycle ergometry, performed for a maximum of four, 3-min stages, with each stage increasing in workload by 20 W. After resting, patients were subjected to dobutamine stress, administered up to a maximum 40 microg/kg/min, dependent upon heart rate. RESULTS: Mean (+/- SD) resting pressure drops across the C-E and Ultracor valves were comparable (maximum drop 19.4 +/- 8.6 versus 22.9 +/- 12.2 mmHg; mean drop 9.96 +/- 3.8 versus 11.83 +/- 6.6 mmHg, respectively). During exercise, the maximum cardiac flow rate attained was approximately 400 ml/s for both valve types. At this flow rate, the maximum and mean pressure differences between valve types were 6.2 mmHg and 4.4 mmHg, respectively (p = NS). During dobutamine stress, the maximum cardiac flow attained was approximately 500 ml/s, which resulted in significant differences between valve types of 11.6 and 7.3 mmHg, for maximum and mean pressure drops, respectively. When slopes of the mean pressure drop/cardiac flow were calculated for individual valves, a difference was observed between the two valve types (p = 0.02 and p = 0.039 for dobutamine and exercise, respectively). CONCLUSION: Both prostheses demonstrated significant increases in pressure drop under stress conditions. The standard porcine C-E valve had a statistically better hemodynamic profile than the Ultracor prosthesis at higher flow rates. When a study cohort of patients is small, these differences will only be evident at optimal flow rates. The higher flow rates seem most easily obtained when using pharmacological stress.