Tomos E. Walters

Hepatitis B treatment: rational combination chemotherapy based on viral kinetic and animal model studies.

Hepatitis B virus (HBV) causes a generally non-cytopathic infection in the liver. Even though HBV is a DNA virus, it replicates via reverse transcription which is coordinated within the viral nucleocapsid by the virus-specific polymerase. The major transcriptional template is the viral mimichromosome from which the viral DNA exists as a covalently closed circular (ccc) molcule. The virus infects hepatocytes but can also be found in non-hepatocyte reservoirs such as bile-duct epithelium, mesangial cells of the kidney, pancreatic islet cells and lymphoid cells. When patients infected with HBV are treated with either interferon alpha or lamivudine, responses are variable and unpredictable. Sophisticated mathematical models analysing the dynamics of viral clearance during antiviral therapy have recently been applied to chronic hepatitis B. Typically complex profiles, rather than the usual biphasic responses seen with other diseases have been observed, indicating that antiviral efficacy requires substantila improvement. This may be achieved with combination chemotherapy. However, chronic hepatitis B is a complex and heterogeneous disease entity, and the challenge for the future is to define measurable end-points of treatment and address key virological issues such as the role of cccDNA and extra-hepatocyte replication in treatment failure. Clearly, new therapies and effective combination therapy protocols are urgently required in order to improve the present poor response rates in patients undergoing treatment.

Pulmonary vein isolation: The impact of pulmonary venous anatomy on long-term outcome of catheter ablation for paroxysmal atrial fibrillation

BACKGROUND Circumferential pulmonary vein (PV) isolation is the cornerstone of catheter ablation for atrial fibrillation (AF); however, PV reconnection remains problematic. OBJECTIVE To assess the impact of PV anatomy on outcome after AF ablation. METHODS One hundred two patients with paroxysmal AF underwent cardiac magnetic resonance (60%) or computed tomography (40%) before AF ablation. PV anatomy was classified according to the presence of common PVs, accessory PVs, PV branching pattern, and the dimensions of the PV ostia, intervenous ridges (IVRs), and the left PV-left atrial appendage ridge. RESULTS Four discrete PVs were present in 48(47%) of the patients: a left common PV in 38(37%), a right common PV in 2(2%), an accessory right PV in 20(20%), and left PV in 4(4%). At a mean follow-up of 12 ± 4 months, 75 of 102 (74%) patients were free of recurrent AF. A LCPV was associated with an increase in freedom from AF (87% vs 66% for 4 PV anatomy; P = .03). Greater left IVR length (16.9 ± 3.5 mm vs 14.0 ± 3.0 mm; P ≤ .001) and width (1.4 ± 0.6 mm vs 1.1 ± 0.6 mm; P = .02) were associated with increased AF recurrence. After multivariate analysis, abnormal anatomy (LCPV or accessory PV) and left IVR length were found to be the only independent predictors of freedom from AF. CONCLUSIONS Four discrete PVs are present in the minority of patients with paroxysmal AF undergoing PV isolation. The presence of a LCPV is associated with an increased freedom from AF after catheter ablation. PV anatomy may in part explain the variable outcome to electrical isolation in patients with paroxysmal AF.

Ten-year trends in the use of catheter ablation for treatment of atrial fibrillation vs. the use of coronary intervention for the treatment of ischaemic heart disease in Australia.

AIMS Percutaneous coronary intervention (PCI) and catheter ablation are well-accepted therapeutic interventions for treatment of coronary artery disease and atrial fibrillation (AF), respectively. We sought to examine temporal trends in the provision of these services over the past decade in Australia. METHODS AND RESULTS A retrospective review of the numbers of PCIs and AF ablations from 2000/01 to 2009/10 was performed on data from three sources: the Australian Institute of Health, Welfare and Aging (AIHW), Medicare Australia database (MA), and local records at a high volume tertiary referral centre (RMH) for AF ablation. Linear regression models were fitted comparing trends in population-adjusted procedural numbers over the 10-year period. There was a 5% per year population-adjusted increment in PCIs over 10 years from both the AIHW and MA sources, respectively (P < 0.001). This was similar to the growth rate of all cardiovascular procedures (AIHW: 5.1 vs. 3.8%/year, P = 0.27). Atrial fibrillation ablations showed a 30.9, 23.2, and 39.8% per year population-adjusted increment over 10 years from the AIHW, MA, and RMH sources respectively (P < 0.001 for all). Growth of AF ablations was significantly higher than PCIs (P < 0.001 for AIHW and MA sources) and all cardiovascular procedures (AIHW: 30.9 vs. 3.8%/year, P < 0.001). CONCLUSION The provision of catheter-based AF ablation services in Australia has increased exponentially over the past decade. Its annual growth rate exceeded that of PCIs and all cardiovascular procedures. Given the increasing epidemic of AF, these data have critical implications for public health policy assessing the adequacy of infrastructure, training, and funding for AF ablation services.

Progression of atrial remodeling in patients with high-burden atrial fibrillation: Implications for early ablative intervention.

BACKGROUND Advanced atrial remodeling predicts poor clinical outcomes in human atrial fibrillation (AF). OBJECTIVE The purpose of this study was to define the magnitude and predictors of change in left atrial (LA) structural remodeling over 12 months of AF. METHODS Thirty-eight patients with paroxysmal AF managed medically (group 1), 20 undergoing AF ablation (group 2), and 25 control patients with no AF history (group 3) prospectively underwent echocardiographic assessment of strain variables of LA reservoir function at baseline and at 4, 8, and 12 months. In addition, P-wave duration (Pmax,, Pmean) and dispersion (Pdis) were measured. AF burden was quantified by implanted recorders. Twenty patients undergoing ablation underwent electroanatomic mapping (mean 333 ± 40 points) for correlation with LA strain. RESULT Group 1 demonstrated significant deterioration in total LA strain (26.3% ± 1.2% to 21.7% ± 1.2%, P < .05) and increases in Pmax (132 ± 3 ms to 138 ± 3 ms, P < .05) and Pdis (37 ± 2 ms to 42 ± 2 ms, P < .05). AF burden ≥10% was specifically associated with decline in strain and with P-wave prolongation. Conversely, group 2 manifest improvement in total LA strain (21.3% ± 1.7% to 28.6% ± 1.7%, P <.05) and reductions in Pmax (136 ± 4 ms to 119 ± 4 ms, P < .05) and Pdis (47 ± 3 ms to 32 ± 3 ms, P < .05). Change was not significant in group 3. LA mean voltage (r = 0.71, P = .0005), percent low voltage electrograms (r = -0.59, P = .006), percent complex electrograms (r = -0.68, P = .0009), and LA activation time (r = -0.69, P = .001) correlated with total strain as a measure of LA reservoir function. CONCLUSION High-burden AF is associated with progressive LA structural remodeling. In contrast, AF ablation results in significant reverse remodeling. These data may have implications for timing of ablative intervention.

Comparison of Sequence Analysis and a Novel Discriminatory Real-Time PCR Assay for Detection and Quantification of Lamivudine-Resistant Hepatitis B Virus Strains

ABSTRACT We report a rapid and accurate real-time PCR-based method to quantify wild-type and lamivudine-resistant hepatitis B virus by using a common forward primer paired with different reverse primers. Excellent concordance was demonstrated between sequencing and the discriminatory real-time assay; however, a mixture of quasispecies was more frequently detected by discriminatory real-time PCR.

Acute atrial stretch results in conduction slowing and complex signals at the pulmonary vein to left atrial junction: insights into the mechanism of pulmonary vein arrhythmogenesis

Background—The pulmonary vein–left atrial (PV–LA) junction is key in pathogenesis of AF, and acute stretch is an important stimulus to AF. We aimed to characterize the response of the junction to acute stretch, hypothesizing that stretch would result in electrophysiological changes predisposing to re-entry. Methods and Results—Fifteen participants undergoing cardiac surgery underwent evaluation of the right superior PV–LA junction using an epicardial mapping plaque. In 10, this was performed before and after atrial stretch imposed by rapid volume expansion, and in 5, it was performed with an intervening observation period. Activation was characterized by conduction slowing and electrogram fractionation transversely across the PV–LA junction, with lines of block also demonstrated perpendicular to the junction. Conduction was decremental (plaque activation time 135.8±46.8 ms with programmed extra stimuli at 10 ms above effective refractory period versus 66.1±22.9 ms with pacing at 400 ms; P<0.001) and percentage fractionation was greater with programmed extra stimuli at 10 ms above (33.5%±15.3% versus 20.7%±14.0%, P=0.001). Right atrial pressure increased by 2.5±1.8 mm Hg (P=0.002) with volume expansion. Stretch resulted in conduction slowing across the PV–LA junction (increase in activation time 10.9±14.6 ms in acute stretch group versus −0.1±4.5 ms in control group; P=0.002). Conduction slowing was more marked with programmed extra stimuli at 10 ms above effective refractory period than with stable pacing (13.4±16.5 ms versus 1.7±5.4 ms; P=0.003). Stretch resulted in a significant increase in fractionated electrograms (7.9%±7.0% versus −0.4±3.3; P=0.004). Conclusions—Acute stretch results in conduction slowing across the PV–LA junction, with a greater degree of signal complexity. This substrate may be important in AF initiation and maintenance by promoting re-entry.

A minimal or maximal ablation strategy to achieve pulmonary vein isolation for paroxysmal atrial fibrillation: a prospective multi-centre randomized controlled trial (the Minimax study)

AIMS Pulmonary vein isolation (PVI) is the cornerstone of catheter ablation of atrial fibrillation (AF). The intervenous ridge (IVR) may be incorporated into ablation strategies to achieve PVI; however, randomized trials are lacking. We performed a randomized multi-centre international study to compare the outcomes of (i) circumferential antral PVI (CPVI) alone (minimal) vs. (ii) CPVI with IVR ablation to achieve individual PVI (maximal). METHODS AND RESULTS Two hundred and thirty-four patients with paroxysmal AF underwent CPVI and were randomized to a minimal or maximal ablation strategy. The primary outcome of recurrent atrial arrhythmia was assessed with 7-day Holter monitoring at 6 and 12 months. PVI was achieved in all patients. Radiofrequency ablation time was longer in the maximal group (46.6 ± 14.6 vs. 41.5 ± 13.1 min; P < 0.01), with no significant differences in procedural or fluoroscopy times. At mean follow-up of 17 ± 8 months, there was no difference in freedom from AF after a single procedure between a minimal (70%) and maximal ablation strategy (62%; P = 0.25). In the minimal group, ablation was required on the IVR to achieve electrical isolation in 44%, and was associated with a significant reduction in freedom from AF (57%) compared with the minimal group without IVR ablation (80%; P < 0.01). CONCLUSION There was no statistically significant difference in freedom from AF between a minimal and maximal ablation strategy. Despite attempts to achieve PVI with antral ablation, IVR ablation is commonly required. Patients in whom antral isolation can be achieved without IVR ablation have higher long-term freedom from AF (the Minimax study; ACTRN12610000863033).

Update on the management of atrial fibrillation.

Atrial fibrillation (AF) is a common arrhythmia, with a prevalence that increases markedly with increasing age. Presence of AF has implications for management of future stroke risk. If the patients pulse is irregular, an electrocardiogram should be ordered. Key management decisions are whether to adopt a rhythm control or a rate control strategy and whether to initiate anticoagulation. The primary aim of a rhythm control strategy is improved symptom control. AF ablation may be considered in younger patients (aged < 65 years) with paroxysmal or early persistent AF. AF increases the risk of stroke, and anticoagulation should be considered on the basis of stroke risk — clearly indicated with a CHADS2 score (congestive heart failure, hypertension, age ≥ 75 years, diabetes, 1 point each; previous stroke or transient ischaemic attack, 2 points) of ≥ 2 — independent of the type of AF. In most patients with AF, the benefit of stroke reduction with systemic anticoagulation will outweigh its bleeding risks. All anticoagulants and antiplatelet agents increase the risk of bleeding. However, the new oral anticoagulants tend to have an improved safety profile, particularly in regard to intracranial bleeding, and are at least as effective as warfarin for stroke prevention.

The role of left atrial imaging in the management of atrial fibrillation.

Atrial fibrillation (AF) is the most commonly encountered sustained cardiac rhythm disorder, is an independent risk factor for stroke, heart failure and death, and its development is promoted by a range of common cardiovascular pathologies. The management of AF is directed at these predisposing conditions, at reducing the risk of systemic thromboembolism, and towards rate or rhythm control of the arrhythmia. Guidelines increasingly support the use of catheter ablation (CA) as an early management strategy, with the efficacy of CA crucially dependent on the extent of left atrial (LA) structural remodeling; LA imaging plays a central role in each of identifying comorbidities, risk stratification for stroke, and identification of suitable candidates for CA. An understanding of the strengths and limitations of various echocardiographic modalities, of cardiac computed tomography and of cardiac magnetic resonance imaging is therefore an increasingly important part of the armory of the electrophysiologist. In particular, individualized use of imaging to select patients more likely to benefit from CA of AF is important, and post-procedural imaging to evaluate the extent of reverse LA remodeling after CA is critical to appropriate decisions regarding ongoing anti-arrhythmic therapy and long-term anticoagulation.

Absence of Gender-Based Differences in the Atrial and Pulmonary Vein Substrate: A Detailed Electroanatomic Mapping Study

Gender‐based differences in the clinical nature of cardiac arrhythmias such as atrial fibrillation (AF) are well established.