Mechanisms of persistent atrial fibrillation and recurrences within 12 months post-ablation: Non-invasive mapping with electrocardiographic imaging

INTRODUCTION: Catheter ablation of persistent AF has not been consistently successful in terminating AF or preventing arrhythmia recurrences. Non-invasive Electrocardiographic Imaging (ECGI) can help to understand recurrences by mapping the mechanisms of pre-ablation AF and comparing them with the patterns of recurrent arrhythmias in the same patient. METHODS: Seventeen persistent AF patients underwent ECGI before their first catheter ablation. Time-domain activation maps and phase progression maps were obtained on the bi-atrial epicardium. Location of arrhythmogenic drivers were annotated on the bi-atrial anatomy. Activation and phase movies were examined to understand the wavefront dynamics during AF. Eight patients recurred within 12 months of ablation and underwent a follow-up ECGI. Driver locations and movies were compared for pre- and post-ablation AF. RESULTS: A total of 243 focal drivers were mapped during pre-ablation AF. 62% of the drivers were mapped in the left atrium (LA). The pulmonary vein region harbored most of the drivers (43%). 35% of the drivers were mapped in the right atrium (RA). 59% (10/17) and 53% (9/17) of patients had repetitive sources in the left pulmonary veins (LPV) and left atrial appendage (LAA), and the lower half of RA, respectively. All patients had focal drivers. 29% (5/17) of patients had macro-reentry waves. 24% (4/17) of patients had rotors. Activation patterns during persistent AF varied from single macro-reentry to complex activity with multiple simultaneous wavefronts in both atria, resulting in frequent wave collisions. A total of 76 focal driver activities were mapped in 7/8 patients during recurrence. 59% of the post-ablation AF drivers were mapped in the LA. The pulmonary vein region harbored 50% of total drivers. 39% of sources were mapped in the RA. AF complexity remained similar post-ablation. 58% (44/76) of pre-ablation sources persisted during recurrence. 38% (3/8) of patients had macro-reentry and one patient had rotors. CONCLUSION: ECGI provides patient-specific information on mechanisms of persistent AF and recurrent arrhythmia. More than half pre-ablation sources repeated during post-ablation recurrence. This study provides direct evidence for drivers that persist days and months after the ablation procedure. Patient-tailored bi-atrial ablation is needed to successfully target persistent AF and prevent recurrence. ECGI can potentially predict recurrence and assist in choice of therapy

Investigations on Hepatoprotective Activity of Leaf Extracts of Aegle marmelos (L.) Corr. (Rutaceae)

The present study was carried out to screen and evaluate the hepatoprotective activity of leaf extracts of Aegle marmelos (L.) Corr. Hepatoprotective activities of ethanolic and aqueous extracts of A. marmelos were examined against carbon tetrachloride induced liver damage in mice using silymarin as control. Enzyme activities of Serum Glutamate Oxaloacetate Transaminase (SGOT), Serum Glutamate Pyruvate Transaminase (SGPT) and Alkaline Phosphatase (ALP) were analyzed. Results indicate that ethanolic and aqueous leaf extracts of A. marmelos had moderate activity over carbon tetrachloride treatment as compared to control. Results of the present investigation confirm the traditional uses of this plant as a potential hepatoprotective agent

Studies on Hepatoprotective Properties of Leaf Extracts of Azadirachta indica A. Juss (Meliaceae)

The present study was carried out to evaluate the hepatoprotective role of leaf extracts of Azadirachta indica A. Juss. Hepatoprotective activities of ethanolic and aqueous extracts of A. indica were examined against carbon tetrachloride induced liver damage in mice using silymarin as control. Enzyme activities of Serum Glutamate Oxaloacetate Transaminase (SGOT), Serum Glutamate Pyruvate Transaminase (SGPT) and Alkaline Phosphatase (ALP) were analyzed. Phytochemical leaf extracts of A. indica exhibited significant hepatoprotective activity. Ethanolic and aqueous leaf extracts of A. indica exhibited moderate activity over carbon tetrachloride treated animals. Results confirm the traditional - ethnomedicinal use of A. indica as a potential source of hepatoprotective agent

Anti-elastase, anti-collagenase and antimicrobial activities of the underutilized red pitaya peel: an in-vitro study for anti-aging applications

Objective: To investigate the in vitro anti-elastase, anti-collagenase, and antimicrobial activities of the red pitaya peel extract for cosmetic application focusing on skin aging. Methods: Extraction was performed by the reflux method for 103 minutes at 56°C with 82% aqueous ethanol solution and the red pitaya peel extract was evaporated using a rotary evaporator. Anti-elastase and anti-collagenase properties were evaluated using the drug discovery kits (neutrophil elastase colorimetric and matrix metalloproteinase-1 colorimetric, respectively). The antimicrobial potential was analyzed using agar well diffusion method against 10 selected microorganisms, and the presence or absence of the inhibition zones was identified. Results: The red pitaya peel extract exhibited remarkable inhibition percentage 87.62±0.05% and 96.92±0.02% for anti-elastase and anti-collagenase activities, respectively. Red pitaya peel extract showed significant inhibition against the Gram-positive Bacillus subtilis B29 with an inhibition zone diameter of 8.0±0.3 mm. Conclusion: The excellent anti-aging properties displayed by the underutilized red pitaya peel extract highlighted its potential as a natural source of anti-aging agent for cosmetic formulations

The unexplored botanical extracts: a new horizon in skin anti-aging formulation

As skin ages, it loses its natural elasticity and become thinner, more fragile, and laxer, taking on a wrinkle appearance. Ultraviolet light, a sequence of changes in the weather and environmental pollution are among the pivotal factors contributing to the acceleration of the natural aging process. The utilization of botanical extracts and herbs has its origins in ancient times. We tried to investigate the anti-aging potentials of senduduk which is among some of the unexplored plant sources found in Malaysia. Our main idea was to emphasize action mechanisms of these botanical extracts based products, in fighting skin aging in term of its ability to scavenge free radicals, to protect the skin matrix through the inhibition of enzymatic degradation, or to promote collagen synthesis in the skin and to provide photoprotection. The experimental data revealed the percentage of DPPH radical scavenging activity, total phenolic content (TPC), and total flavonoid content (TFC) for senduduk extracts were (DPPH: 89.66% ; TPC: 1072.92 mg/g ; TFC: 5.61 mg/g) respectively. The anti-collagenase (AC) and anti-elastase (AE) assay also exhibited good inhibition values of (AC: 94.35% ; AE: 66.67%) respectively. The sun protection factor (SPF) value obtained was 22.44 for senduduk. Next, a nanoemulsion comprising of a mixture senduduk extracts was formulated and subjected physiochemical and in-vivo analysis. Finally, the image analysis offered a quick and consistent approached for quantifying skin aging feature which showcased reduction in skin wrinkle and improvement in skin texture, thus emphasizing the formulation’s efficacy as a promising natural anti-aging source.

Technical development and feasibility of a reusable vest to integrate cardiovascular magnetic resonance with electrocardiographic imaging

BACKGROUND: Electrocardiographic imaging (ECGI) generates electrophysiological (EP) biomarkers while cardiovascular magnetic resonance (CMR) imaging provides data about myocardial structure, function and tissue substrate. Combining this information in one examination is desirable but requires an affordable, reusable, and high-throughput solution. We therefore developed the CMR-ECGI vest and carried out this technical development study to assess its feasibility and repeatability in vivo. METHODS: CMR was prospectively performed at 3T on participants after collecting surface potentials using the locally designed and fabricated 256-lead ECGI vest. Epicardial maps were reconstructed to generate local EP parameters such as activation time (AT), repolarization time (RT) and activation recovery intervals (ARI). 20 intra- and inter-observer and 8 scan re-scan repeatability tests. RESULTS: 77 participants were recruited: 27 young healthy volunteers (HV, 38.9 ± 8.5 years, 35% male) and 50 older persons (77.0 ± 0.1 years, 52% male). CMR-ECGI was achieved in all participants using the same reusable, washable vest without complications. Intra- and inter-observer variability was low (correlation coefficients [rs] across unipolar electrograms = 0.99 and 0.98 respectively) and scan re-scan repeatability was high (rs between 0.81 and 0.93). Compared to young HV, older persons had significantly longer RT (296.8 vs 289.3 ms, p = 0.002), ARI (249.8 vs 235.1 ms, p = 0.002) and local gradients of AT, RT and ARI (0.40 vs 0.34 ms/mm, p = 0,01; 0.92 vs 0.77 ms/mm, p = 0.03; and 1.12 vs 0.92 ms/mm, p = 0.01 respectively). CONCLUSION: Our high-throughput CMR-ECGI solution is feasible and shows good reproducibility in younger and older participants. This new technology is now scalable for high throughput research to provide novel insights into arrhythmogenesis and potentially pave the way for more personalised risk stratification. CLINICAL TRIAL REGISTRATION: Title: Multimorbidity Life-Course Approach to Myocardial Health-A Cardiac Sub-Study of the MRC National Survey of Health and Development (NSHD) (MyoFit46). National Clinical Trials (NCT) number: NCT05455125. URL: https://clinicaltrials.gov/ct2/show/NCT05455125?term=MyoFit&draw=2&rank=1

Electrophysiological Characterization of Subclinical and Overt Hypertrophic Cardiomyopathy by Magnetic Resonance Imaging-Guided Electrocardiography

BACKGROUND: Ventricular arrhythmia in hypertrophic cardiomyopathy (HCM) relates to adverse structural change and genetic status. Cardiovascular magnetic resonance (CMR)-guided electrocardiographic imaging (ECGI) noninvasively maps cardiac structural and electrophysiological (EP) properties. OBJECTIVES: The purpose of this study was to establish whether in subclinical HCM (genotype [G]+ left ventricular hypertrophy [LVH]-), ECGI detects early EP abnormality, and in overt HCM, whether the EP substrate relates to genetic status (G+/G-LVH+) and structural phenotype. METHODS: This was a prospective 211-participant CMR-ECGI multicenter study of 70 G+LVH-, 104 LVH+ (51 G+/53 G-), and 37 healthy volunteers (HVs). Local activation time (AT), corrected repolarization time, corrected activation-recovery interval, spatial gradients (GAT/GRTc), and signal fractionation were derived from 1,000 epicardial sites per participant. Maximal wall thickness and scar burden were derived from CMR. A support vector machine was built to discriminate G+LVH- from HV and low-risk HCM from those with intermediate/high-risk score or nonsustained ventricular tachycardia. RESULTS: Compared with HV, subclinical HCM showed mean AT prolongation (P = 0.008) even with normal 12-lead electrocardiograms (ECGs) (P = 0.009), and repolarization was more spatially heterogenous (GRTc: P = 0.005) (23% had normal ECGs). Corrected activation-recovery interval was prolonged in overt vs subclinical HCM (P < 0.001). Mean AT was associated with maximal wall thickness; spatial conduction heterogeneity (GAT) and fractionation were associated with scar (all P < 0.05), and G+LVH+ had more fractionation than G-LVH+ (P = 0.002). The support vector machine discriminated subclinical HCM from HV (10-fold cross-validation accuracy 80% [95% CI: 73%-85%]) and identified patients at higher risk of sudden cardiac death (accuracy 82% [95% CI: 78%-86%]). CONCLUSIONS: In the absence of LVH or 12-lead ECG abnormalities, HCM sarcomere gene mutation carriers express an aberrant EP phenotype detected by ECGI. In overt HCM, abnormalities occur more severely with adverse structural change and positive genetic status

Electrophysiological characterization of subclinical and overt hypertrophic cardiomyopathy by magnetic resonance imaging-guided electrocardiography

Background: Ventricular arrhythmia in hypertrophic cardiomyopathy (HCM) relates to adverse structural change and genetic status. Cardiovascular magnetic resonance (CMR)–guided electrocardiographic imaging (ECGI) noninvasively maps cardiac structural and electrophysiological (EP) properties. Objectives: The purpose of this study was to establish whether in subclinical HCM (genotype [G]+ left ventricular hypertrophy [LVH]−), ECGI detects early EP abnormality, and in overt HCM, whether the EP substrate relates to genetic status (G+/G−LVH+) and structural phenotype. Methods: This was a prospective 211-participant CMR-ECGI multicenter study of 70 G+LVH−, 104 LVH+ (51 G+/53 G−), and 37 healthy volunteers (HVs). Local activation time (AT), corrected repolarization time, corrected activation-recovery interval, spatial gradients (GAT/GRTc), and signal fractionation were derived from 1,000 epicardial sites per participant. Maximal wall thickness and scar burden were derived from CMR. A support vector machine was built to discriminate G+LVH− from HV and low-risk HCM from those with intermediate/high-risk score or nonsustained ventricular tachycardia. Results: Compared with HV, subclinical HCM showed mean AT prolongation (P = 0.008) even with normal 12-lead electrocardiograms (ECGs) (P = 0.009), and repolarization was more spatially heterogenous (GRTc: P = 0.005) (23% had normal ECGs). Corrected activation-recovery interval was prolonged in overt vs subclinical HCM (P &lt; 0.001). Mean AT was associated with maximal wall thickness; spatial conduction heterogeneity (GAT) and fractionation were associated with scar (all P &lt; 0.05), and G+LVH+ had more fractionation than G−LVH+ (P = 0.002). The support vector machine discriminated subclinical HCM from HV (10-fold cross-validation accuracy 80% [95% CI: 73%-85%]) and identified patients at higher risk of sudden cardiac death (accuracy 82% [95% CI: 78%-86%]). Conclusions: In the absence of LVH or 12-lead ECG abnormalities, HCM sarcomere gene mutation carriers express an aberrant EP phenotype detected by ECGI. In overt HCM, abnormalities occur more severely with adverse structural change and positive genetic status

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society