Determinants of left atrial local impedance: Relationships with contact force, atrial fibrosis, and rhythm.

INTRODUCTION: The relationships between baseline tissue local impedance (LI), contact force (CF), atrial fibrosis, and atrial rhythm are uninvestigated in a clinical setting. We compared the relationship of LI and CF between atrial fibrillation (AF) and sinus rhythm (SR) accounting for the effects of atrial fibrosis as assessed by bipolar voltage and LI. METHODS: Patients undergoing persistent AF ablation were recruited. LI was recorded referenced to patient blood pool (LIr) and concurrent to changes in CF, with data collected at the same locations in AF and SR. RESULTS: Twenty patients were recruited. 109 locations were sampled obtaining 1903 data points (SR: 966, AF: 937). CF correlated strongly with LI (repeated measures correlation = 0.64). The relationship between CF and LIr was logarithmic. Rhythm and CF had a significant main (both p < .0005) and interaction effect (p = .022) on tissue LI: AF demonstrated higher LIr values than SR for similar CF. Bipolar voltage had no effect on the relationship of CF to LIr in either rhythm. Assessing fibrosis using LIr showed an interaction effect with CF for LIr in SR and AF, (SR: p < .0005, AF: p = .01), with increased fibrosis showing lesser change in LIr per gram of CF. CONCLUSIONS: CF and rhythm significantly affect the measured LIr of LA myocardium. Optimal catheter-tissue coupling may be better achieved with higher levels of CF and in AF rather than SR. Atrial fibrosis, as assessed by LIr but not bipolar voltage, affected the CF-LI relationship.

Comparison of voltages between atria: differences in sinus rhythm and atrial fibrillation.

BACKGROUND: Ultra high-density mapping systems allow for comparison of atrial electroanatomical maps in unprecedented detail. Atrial scar determined by voltages and surface area between atria, rhythm and atrial fibrillation (AF) types was assessed. METHODS: Left (LA) and right atrial (RA) maps were created using Rhythmia HDx in patients listed for ablation for paroxysmal (PAF, sinus rhythm (SR) maps only) or persistent AF (PeAF, AF and SR maps). Electrograms on corresponding SR/AF maps were paired for direct comparison. Percentage surface area of scar was assigned low- (LVM, ≤ 0.05 mV), intermediate- (IVM, 0.05-0.5 mV) or normal voltage myocardium, (NVM, > 0.5 mV). RESULTS: Thirty-eight patients were recruited generating 96 maps using 913,480 electrograms. Paired SR-AF bipolar electrograms showed fair correlation in LA (Spearman's ρ = 0.32) and weak correlation in RA (ρ = 0.19) and were significantly higher in SR in both (LA: 0.61 mV (0.20-1.67) vs 0.31 mV (0.10-0.74), RA: 0.68 mV (0.19-1.88) vs 0.47 mV (0.14-1.07), p < 0.0005 both). Voltages were significantly higher in patients with PAF over PeAF, (LA: 1.13 mV (0.39-2.93) vs 0.52 mV (0.16-1.49); RA: 0.93 mV (0.24-2.46) vs 0.57 mV (0.17-1.69)). Minimal differences were seen in electrogram voltages between atria. Significantly more IVM/LVM surface areas were seen in AF over SR (LA only, p < 0005), and PeAF over PAF (LA: p = 0.01, RA: p = 0.04). There was minimal difference between atria within patients. CONCLUSIONS: Ultra high-density mapping shows paired electrograms correlate poorly between SR and AF. SR electrograms are typically (but not always) larger than those in AF. Patients with PeAF have a lower global electrogram voltage than those with PAF. Electrogram voltages are similar between atria within individual patients.

Radiofrequency Ablation of the Diseased Human Left Ventricle: Biophysical and Electrogram-Based Analysis.

BACKGROUND: Predictors of effective ablation lesion delivery in the human left ventricle are not established, particularly in scar. Impedance drop and electrogram (EGM) attenuation are potential surrogates to assess this. OBJECTIVES: This study sought to establish the relationships between ablation index (AI) and force-time integral (FTI) with impedance drop and EGM attenuation in the human left ventricle. METHODS: Patients undergoing ventricular tachycardia ablation were recruited. EGMs were collected preablation and postablation, with impedance, AI, and FTI measured during. Based on preablation bipolar voltage, myocardium was adjudged a low-voltage myocardium (LVM) (<0.50 mV), intermediate-voltage myocardium (IVM) (0.51-1.50 mV), and normal-voltage myocardium (NVM) (>1.50 mV). Relationships between these parameters were explored. RESULTS: A total of 402 ablations were analyzed in 15 patients. The percent impedance drop correlated with AI and FTI (P < 0.0005; repeated-measures correlation coefficient: 0.54 and 0.44, respectively), a relationship that became weaker with increased myocardial fibrosis, (repeated-measures correlation coefficient for NVM, IVM, and LVM, AI: 0.67, 0.60, and 0.52, respectively; FTI: 0.59, 0.51, and 0.42, respectively). The curve between AI/FTI and impedance drop plateaued at 763 AI and 713 gram-seconds, an impedance drop of 7.5%. Shallower curves occurred progressively from NVM to LVM (P < 0.0005). Mixed models demonstrated that AI and FTI had a greater effect on impedance drop than myocardial fibrosis, drift, or orientation, (standardized ß: 0.54 and 0.48, respectively). EGMs were attenuated with ablation (29.3%; IQR: 4.4%-53.3%; P < 0.0005), but attenuation did not correlate with AI or FTI. CONCLUSIONS: On biophysical analysis, ablation beyond an AI of 763 and FTI of 713 gs offers minimal additional efficacy on average. Fibrosis blunts ablation efficacy. AI is a stronger correlate with impedance drop than FTI. EGM attenuation does not correlate with ablation parameters. (Late Potentials and Ablation Index in Ventricular Tachycardia Ablation; NCT03437408).

Results of two Phase 1, Randomized, Double-blind, Placebo-controlled, Studies (Ascending Single-dose and Multiple-dose Studies) to Determine the Safety, Tolerability, and Pharmacokinetics of Orally Administered LX9211 in Healthy Participants.

PURPOSE: For neuropathic pain, current therapies do not provide relief for most patients; less than half achieve a 50% pain reduction. Current analgesics have adverse effects. We present 2 Phase I studies of LX9211, a new small-molecule AP2-associated kinase 1 inhibitor with preclinical effectiveness in pain relief. METHODS: Both randomized, placebo-controlled studies' primary objectives evaluated the tolerability and pharmacokinetic properties of oral LX9211. In the single-ascending dose (SAD) study, single, oral, liquid doses of 5, 10, 15, 20, 30, 40, 80, 120, 160, 200, and 300 mg of LX9211 or placebo were administered in the fasted state and 40 mg in a fed group. In the multiple-ascending dose (MAD) study, a loading dose was administered on day 1 and maintenance doses were administered daily on days 2 to 14. The treatment groups were designated as: 25/2.5, 50/5.0, 100/10, 150/15, and 200/20 mg. The secondary objectives included ECG evaluation. FINDINGS: The SAD study enrolled 96 participants 19 to 61 years of age (86.5% male) in 12 cohorts (2:6 placebo:LX9211), and the MAD study enrolled 50 participants 20 to 63 years of age (78% male) in 5 cohorts (2:8 placebo:LX9211). Both studies had a good LX9211 safety profile. No deaths or serious adverse events occurred. All treatment-emergent adverse events (TEAEs) were mild, except for moderate nausea and vomiting reported in 1 participant in the SAD 300-mg cohort. All TEAEs were considered recovered or resolved, except for blurred vision (n = 1 in the SAD 300-mg group), which was ongoing at the last visit. One participant in the MAD study (50/5 mg group) discontinued participation in the study early because of TEAEs (angioedema, dermatitis allergic, and urticaria). Headache, dizziness, constipation, and nausea were the most common TEAEs. In the SAD study, 4 participants in the 200-mg cohort developed headache approximately 24 hours after dosing, lasting 24 to 48 hours. Only 1 required treatment (acetaminophen). No notable ECG changes from baseline were found in either study. After both single- and multiple-dose administration, plasma exposure of LX9211 was approximately dose proportional. Steady-state LX9211 plasma concentrations were rapidly attained and maintained by a dosing regimen of a loading dose, followed by daily maintenance doses (1/10 the loading dose). No accumulation was as seen after multiple dosing. IMPLICATIONS: These studies found that LX9211 was safe and well tolerated in healthy participants. These findings suggest it is appropriate to take LX9211 forward into Phase II studies of patients with diabetic peripheral neuropathic pain and postherpetic neuralgia. LX9211 has received fast track designation by the US Food and Drug Administration.

Leakage current from transvenous and subcutaneous implantable cardioverter defibrillators (ICDs): A risk to the rescuer?

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are a well-established therapy for patients at risk of life-threatening ventricular arrhythmias. With rising implant rates, the risk of a rescuer performing chest compressions during discharge is increasing, leading to concerns over rescuer safety from the resultant leakage current. More recently, subcutaneous ICDs (S-ICD) have been developed, which utilise a higher energy and more superficial electrodes compared with transvenous ICDs (T-ICD), raising safety concerns further. OBJECTIVE: We measured the current a rescuer would potentially receive from T-ICDs and S-ICDs if they were in contact with the patient at the time of ICD discharge to assess its magnitude in relation to international safety standards. METHODS: Surface voltages adjacent to ICD electrodes were measured on patients undergoing defibrillation threshold checks. Rescuer current was then calculated assuming a total rescuer circuit impedance of 1696 Ω. RESULTS: Twenty-five patients were recruited. Rescuer current from S-ICDs was significantly higher than those from T-ICDs (S-ICD: Median RMS 135 mA range 91 mA-164 mA, T-ICD: Median RMS 31 mA, range 9 mA-75 mA, P < 0.0001). Surface voltages (median RMS) to which the rescuer is likely to be exposed are higher when performing chest compressions from the patient's left side compared with the right (127 V vs 67 V respectively, 95% CI of difference -34 V to -67 V, P < 0.0001). CONCLUSIONS: Rescuers performing chest compressions on ICD patients are at risk from leakage current, particularly from S-ICDs. Chest compressions should be performed from the opposite side to the ICD to reduce rescuer risk.

The use of fixed appliances in the UK: a survey of specialist orthodontists.

OBJECTIVE: To investigate the use of fixed appliances in the UK. DESIGN: Prospective postal questionnaire. SETTING: UK. PARTICIPANTS: All members of the General Dental Council Specialist List in Orthodontics still in active practice and not in training posts. METHOD: A preemptive letter of explanation was sent inviting orthodontists to participate in the survey. The questionnaire was subsequently posted to 935 specialists. Data analysis investigated differences in clinical practice related to varying provider groups, level of operator experience and geographical region. RESULTS: The response rate achieved was 66.3%. A majority of orthodontists routinely used the 0.022 inch pre-adjusted edgewise system, standard size Siamese pattern stainless steel brackets, conventionally ligated and bonded using standard etch and light cured composite. Nickel titanium and stainless steel were the most popular archwire materials. Anchorage was supported routinely by palatal and lingual arches in up to 25% and by headgear in over a third of respondents. Newer innovations showed variable popularity. Self-etching primer was used routinely by one-third of respondents with 11% use of self-ligating brackets. Banding of first molars was preferred by over 60% of clinicians. Bone screw implants were used by only 0.2% of respondents. Clinicians with less than 10 years experience used more headgear, light curing, MBT prescription and molar bonding. Operators with over 20 years experience used more chemically cured bonding, Roth prescription, banded first molars, 0.018 inch slot size and Tip-Edge(TM), with less use of headgear. Fixed appliance use differed from that reported in the US with lower use in the UK of standard edgewise and Roth systems, aesthetic, miniaturised and 0.018 inch slot brackets and rapid maxillary expansion. CONCLUSION: Most UK orthodontic specialists routinely used the 0.022 inch pre-adjusted edgewise system with standard size Siamese steel brackets bonded using standard etch and light cured composite with conventional ligation. Variations were seen between different provider groups, types of treatment funding, levels of operator seniority and geographical regions. Differences were noted particularly in the use of bracket prescription and design, types of molar attachment and anchorage control.

The Potential Value of Near Patient Platelet Function Testing in PCI: Randomised Comparison of 600 mg versus 900 mg Clopidogrel Loading Doses.

Whilst poor response to clopidogrel is associated with adverse outcomes uncertainty exists as to how (a) response should be assessed and (b) poor responders managed. We utilised VerifyNow P2Y12 and short Thrombelastography (TEG) to assess 900 mg doses in (i) initial poor responders to 600 mg and (ii) in a randomised comparison with 600 mg. Blood was taken before and six hours post clopidogrel in (i) 30 volunteers receiving 600 mg (poor responders received 900 mg > two weeks later) and (ii) 60 patients randomized 1 : 1 to 600 mg or 900 mg doses. Poor response was defined as TEG %Clotting Inhibition (%CIn) or VerifyNow Platelet Response Unit (PRU) reduction <30%. (i) Poor responders to 600 mg had greater PRU reduction (45.0 versus 20.1%, P = 0.03) and greater %CIn (22.9 versus -15.1%, P = 0.01) after 900 mg but (ii) there were no significant differences between the patient groups. Near-patient assessment of response to clopidogrel is feasible and clinically useful. Whilst ineffective on a population basis 900 mg doses increase the effect of clopidogrel in initial poor responders.

Gender and responses to aspirin and clopidogrel: insights using short thrombelastography.

There is significant variability in both baseline clotting tendency and response to antiplatelet therapy. Responses are associated with outcome. We have investigated whether differences could explain the increased risk observed in women presenting with coronary artery disease. We have utilized short thrombelastography to assess (i) baseline clotting responses, (ii) response to aspirin and clopidogrel, and (iii) post-treatment platelet reactivity in 48 young volunteers, 22 older patients and 18 patients with previous stent thrombosis. Baseline responses were significantly higher in young women than in men. While there was no difference in response to aspirin, platelet reactivity on aspirin remained higher in women (area under curve at 15 min [AUC15] of arachidonic acid channel 332 +/- 122 vs. 172 +/- 80, P= 0.04). Young women had less response to clopidogrel (% reduction in AUC15 with adenosine diphosphate [ADP] 36.4 +/- 12.4 vs. 64.0 +/- 13.2, P < 0.01) in addition to higher post-treatment reactivity (AUC15 of ADP 714 +/- 161 vs. 311 +/- 146, P < 0.01) compared to men. There were no such differences between male and female patients over 50. However, young women with previous stent thrombosis had among the highest platelet reactivity observed. Compared to men, young women have greater baseline clotting tendency, reduced response to clopidogrel, and greater post-treatment reactivity while on both aspirin and clopidogrel. Differences in clotting tendency and response to antiplatelet therapy may contribute to the excess risk observed in young women but are not observed in older female patients.

Effects of clopidogrel on "aspirin specific" pathways of platelet inhibition.

The most widely accepted methods of assessing response to clopidogrel involve isolated ADP-induced platelet aggregation. Whilst poor response determined by these assays correlates with adverse clinical events, the number of "poor responders" is far higher than the number of events attributed to treatment failure. Clopidogrel may have effects that cannot be assessed using isolated ADP-induced aggregation. We have investigated the effect of clopidogrel on Arachidonic Acid (AA) induced platelet activation-an "aspirin specific" pathway using a novel near patient assay. Thirty four volunteers on no medication and 36 patients, on maintenance therapy with aspirin 75 mg daily, were recruited. Blood tests for Thrombelastogram PlateletMapping were taken immediately prior to and 6 hours after administration of a 600 mg clopidogrel loading dose. Changes in the area under the response curve at 15 minutes (AUC15) with both ADP- and AA-stimulation were calculated as were the corresponding percentage platelet and percentage clotting inhibition (%PIn and %CIn). There were predictable and significant changes in the AUC15 of the ADP channel in response to clopidogrel and the corresponding %PIn and %CIn in both volunteers and patients. There were also significant reductions in the AUC15 of the AA channel (presented as Mean +/- 95%CI), by 27.2 +/- 11.8%, p = 0.005 in volunteers and 35.0 +/- 8.2%, p < 0.001 in patients) and increases in the %PIn and %CIn calculated using the AA channel in volunteers (by 20.0 +/- 11.4%, p + 0.02 and 32.3 +/- 12.8%, p < 0.001 respectively) and patients (by 24.2 +/- 8.6%, p < 0.001 and by 18.0 +/- 8.6, p < 0.001 respectively). Clopidogrel has both independent and aspirin-synergistic effects on AA-induced platelet activation suggesting potentiation of the antiplatelet activity of aspirin. This effect may be clinically important and is not detected by current "gold standard" methods of assessing response to clopidogrel.

Long-term clinical evaluation of bracket failure with a self-etching primer: a randomized controlled trial.

OBJECTIVE: A long-term comparison of the failure rates of orthodontic brackets bonded with either a self-etching primer (SEP) or conventional etch and primer (AE). DESIGN: Prospective randomized controlled clinical trial. SETTING: UK district general hospital with one operator, 2003-6. PARTICIPANTS: Hospital waiting list patients needing fixed appliances (n=60). METHOD: Experimental (SEP) group patients (n=30) received pre-adjusted edgewise brackets (n=438) bonded with Transbond Plus following manufacturer's instructions. Control (AE) group patients (n=30, brackets n=433) were bonded using a 15-second conventional etch and primer (Transbond XT). In both groups brackets were light-cured for 20 seconds. First-time bond failures were recorded with the time of failure. Bracket bonding time was recorded. All patients were followed to the end or discontinuation of treatment. RESULTS: Bracket failure rates: SEP=4.8%, AE=3.5%, P=0.793. Mean placement time per bracket (seconds): SEP=75.5 (+/-6.7; 95% CI=72.9, 78.0), AE=97.7 (+/-9.1; 95% CI=94.3, 101.2) P=0.000. CONCLUSION: There was no difference in the failure rates of brackets bonded with either Transbond Plus SEP or conventional AE using Transbond XT paste. Bonding with SEP was significantly faster than using conventional AE.

Incremental versus maximum bite advancement during twin-block therapy: a randomized controlled clinical trial.

The aim of this study was to evaluate the effectiveness of incremental and maximum bite advancement during treatment of Class II Division 1 malocclusion with the Twin-block appliance in the permanent dentition. It was performed at 3 district general hospitals in the United Kingdom with 4 operators. Two hundred three patients, 10-14 years old, were randomized. Control patients had the initial bite taken edge-to-edge for appliance construction with a standard Twin-block. Experimental patients had 2 mm initial bite advancement and subsequent 2 mm advancements at 6 weekly intervals with a Twin-block appliance incorporating advancement screws. Data were collected at the start and the finish of Twin-block treatment. The use of incremental advancement of the Twin-block did not confer any advantages in terms of process and outcome of the treatment. However, patient compliance was influenced by operator and patient age. The duration of treatment was influenced by operator and initial overjet. Incremental bite advancement produced no advantages over maximum advancement.