Analysis of Predictive Information From Biomarkers Added to Clinical Models of Preeclampsia: Consideration of PAPP-A2, Activin A, and sFlt-1:PlGF Ratio.

BACKGROUND: Preeclampsia remains a major cause of maternal and fetal adverse outcomes in pregnancy; however, accurate and universally acceptable predictive tools remain elusive. We investigated whether a panel of biomarkers could improve risk prediction for preeclampsia when measured at various pregnancy time points. METHODS: In this prospective cohort study, 192 women with first-trimester high-risk singleton pregnancies were consecutively recruited from tertiary obstetrics clinics in Montréal, Canada. Clinical information (height, pre-pregnancy weight, personal and family medical history, medication use) was collected at baseline. Blood pressure was measured and blood samples collected at each trimester to quantify soluble Fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), pregnancy-associated plasma protein A2 (PAPP-A2), PAPP-A, activin A, inhibin A, follistatin, and glycosylated fibronectin. A random-effects hierarchic logistic regression model was used to relate change in biomarker levels to incidence of preeclampsia. RESULTS: When added to a clinical model composed of maternal age, pre-pregnancy body mass index, race, and mean arterial pressure, a positive third-trimester result for both PAPP-A2 and activin A had a better positive predictive value than the sFlt-1:PlGF ratio added to the clinical model (91.67% [95% confidence interval (CI) 78.57%-100%] vs 66.67% [57.14%-100%]), while maintaining a comparable high negative predictive value (97.69% [95% CI 95.34%-100%] vs 96.00% [92.19%-99.21%]). CONCLUSIONS: Whereas the third-trimester sFlt-1:PlGF ratio can predict short-term absence of preeclampsia, PAPP-A2 and activin A had both high positive and negative predictive values and therefore could serve as biomarkers to predict the occurrence (and absence) of preeclampsia; these findings will be validated in future studies.

Meta-Analysis of Randomized Trials: Efficacy and Safety of Colchicine for Secondary Prevention of Cardiovascular Disease.

Background: Colchicine has shown potential cardioprotective effects owing to its broad anti-inflammatory properties. We performed a meta-analysis to assess its safety and efficacy in secondary prevention in patients with established coronary artery disease (CAD). Methods: We searched Ovid Healthstar, MEDLINE, and Embase (inception to May 2022) for randomized controlled trials (RCTs) evaluating the cardiovascular effects of colchicine compared with placebo or usual care in patients with CAD. Study-level data on efficacy and safety outcomes were pooled using the Peto method. The primary outcome was the composite of cardiovascular (CV) death, myocardial infarction (MI), or stroke. Results: A total of 8 RCTs were included with a follow-up duration of ≥1 month, comprising a total of 12,151 patients. Compared with placebo or usual care, colchicine was associated with a significant risk reduction in the primary outcome (odds ratio (OR) 0.70, 95% CI 0.60 to 0.83, P < 0.0001; I2 = 52%). Risks of MI (OR 0.75, 95% CI 0.62 to 0.91, P = 0.003; I2 = 33%), stroke (OR 0.47, 95% CI 0.30 to 0.74, P = 0.001; I2 = 0%), and unplanned coronary revascularization (OR 0.67, 95% CI 0.55 to 0.82, P = 0.0001; I2 = 58%) were all reduced in the colchicine group. Rates of CV and all-cause mortality did not differ between the two groups, but there was an increase in noncardiac deaths with colchicine (OR 1.54, 95% CI 1.10 to 2.15, P = 0.01; I2 = 51%). The occurrence of all other adverse events was similar between the two groups, including GI reactions (OR 1.06, 95% CI 0.94 to 1.20, P = 0.35; I2 = 42%) and infections (OR 1.04, 95% CI 0.84 to 1.28, P = 0.74; I2 = 53%). Conclusions: Colchicine therapy may reduce the risk of future cardiovascular events in patients with established CAD; however, there remains a concern about non-CV mortality. Further trials are underway that will shed light on non-CV mortality and colchicine NCT03048825, and NCT02898610.

Diabetes, antidiabetic medications and risk of dementia: A systematic umbrella review and meta-analysis.

AIMS: The objective of this umbrella review and meta-analysis was to evaluate the effect of diabetes on risk of dementia, as well as the mitigating effect of antidiabetic treatments. MATERIALS AND METHODS: We conducted a systematic umbrella review on diabetes and its treatment, and a meta-analysis focusing on treatment. We searched MEDLINE/PubMed, Embase, PsycINFO, CINAHL and the Cochrane Library for systematic reviews and meta-analyses assessing the risk of cognitive decline/dementia in individuals with diabetes until 2 July 2023. We conducted random-effects meta-analyses to obtain risk ratios and 95% confidence intervals estimating the association of metformin, thiazolidinediones, pioglitazone, dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, meglitinides, insulin, sulphonylureas, glucagon-like peptide-1 receptor agonists (GLP1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) with risk of dementia from cohort/case-control studies. The subgroups analysed included country and world region. Risk of bias was assessed with the AMSTAR tool and Newcastle-Ottawa Scale. RESULTS: We included 100 reviews and 27 cohort/case-control studies (N = 3 046 661). Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with significant reduction in risk of dementia. When studies examining metformin were divided by country, the only significant effect was for the United States. Moreover, the effect of metformin was significant in Western but not Eastern populations. No significant effect was observed for dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, or insulin, while meglitinides and sulphonylureas were associated with increased risk. CONCLUSIONS: Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with reduced risk of dementia. More longitudinal studies aimed at determining their relative benefit in different populations should be conducted.

Synchronizing systolic calcium release with azumolene in an experimental model.

Background: Post-defibrillation myocardial contractile dysfunction adversely affects the survival of patients after cardiac arrest. Attenuation of diastolic calcium (Ca2+) overload by stabilization of the cardiac ryanodine receptor (RyR2) is found to reduce refibrillation after long-duration ventricular fibrillation (LDVF). Objective: In the present study, we explored the effects of RyR2 stabilization by azumolene on systolic Ca2+ release synchrony and myocardial contractility. Methods: After completion of baseline optical mapping, Langendorff-perfused rabbit hearts were subjected to global ischemia followed by reperfusion with azumolene or deionized distilled water (vehicle). Following reperfusion, LDVF was induced with burst pacing. In the first series of experiments (n = 16), epicardial Ca2+ transient was analyzed for Ca2+ transient amplitude alternans and dispersion of Ca2+ transient amplitude alternans index (CAAI). In the second series of experiments following the same protocol (n = 12), ventricular contractility was assessed by measuring the left ventricular pressure. Results: Ischemic LDVF led to greater CAAI (0.06 ± 0.02 at baseline vs 0.12 ± 0.02 post-LDVF, P < .01) and magnitude of dispersion of CAAI (0.04 ± 0.01 vs 0.09 ± 0.01, P < .01) in control hearts. In azumolene-treated hearts, no significant changes in CAAI (0.05 ± 0.01 vs 0.05 ± 0.01, P = .84) and dispersion of CAAI (0.04 ± 0.01 vs 0.04 ± 0.01, P = .99) were noted following ischemic LDVF. Ischemic LDVF was associated with reduction in left ventricular developed pressure (100% vs 36.8% ± 6.1%, P = .002) and dP/dtmax (100% vs 45.3% ± 6.5%, P = .003) in control hearts, but these reductions were mitigated (left ventricular developed pressure: 100% vs 74.0% ± 8.1%, P = .052, dP/dtmax: 100% vs 80.8% ± 7.9%, P = .09) in azumolene-treated hearts. Conclusion: Treatment with azumolene is associated with improvement of systolic Ca2+ release synchrony and myocardial contractility following ischemic LDVF.

Arterial stiffness measurements in pregnancy as a predictive tool for hypertensive disorders of pregnancy and preeclampsia: Protocol for a systematic review and meta-analysis.

Hypertensive disorders of pregnancy (HDPs) are a leading cause of maternal morbidity and mortality worldwide. Unfortunately, accurate early clinical screening methods for the development of these disorders are lacking. Arterial stiffness (AS) is an important hemodynamic indicator of vascular health that has shown promising results for the prediction of HDP onset. Past systematic reviews in the field have reported an increase in AS indices in women who develop HDPs and have highlighted the potential of AS measurements as a predictive tool early in pregnancy. The most recent systematic review, including papers up to 2015, assessed the differences in AS parameters between women with and without pregnancy complications. Since then, there has been a substantial influx of published research on the topic and a growing interest in the incorporation of AS measurements into clinical practice. Thus, we propose a systematic review and meta-analysis that is more inclusive to all HDP subsets and various hemodynamic indices of vascular health to provide a comprehensive overview of the current state of evidence. Specifically, we aim to evaluate these measures in women who develop HDPs compared to normotensive pregnancies to determine which measures are most associated with and/or can predict the development of HDPs. Major databases (Medline, Embase, The Cochrane Library, Web of Science, PubMed, and CINAHL), grey literature (Google Scholar) and clinical trials (clinicaltrials.gov) will be searched to identify studies that report AS and hemodynamic measurements in pregnant women with and without HDPs. No restrictions will be made on study type or year. Articles will be independently evaluated by three authors to determine eligibility based on inclusion and exclusion criteria. Methodological quality of included studies will be assessed. Pooled analyses will be conducted using a random-effects model. Publication bias and between-study heterogeneity will also be assessed. Sources of heterogeneity will be explored by sensitivity, subgroup, and/or meta-regression analyses. Results from this study will be shared through scientific conferences and publications in scientific journals. The analysis of potential AS and hemodynamic markers for HDP onset will help inform the development of screening guidelines and clinically relevant cut-off values of AS and hemodynamic markers for HDP risk, guiding future research. There are no applicable ethical considerations to the writing of this protocol.

Multi-Axes Lead With Tetrahedral Electrode Tip for Cardiac-Implantable Devices: Creative Concept for Pacing and Sensing Technology.

BACKGROUND: We developed a multi-axes lead (MaxLead) incorporating 4 electrodes arranged at the lead-tip, organized in an equidistant tetrahedron. Here, we studied MaxLead performance in sensing, pacing, and activation wavefront-direction analysis. METHODS: Sixteen explanted animal hearts (from 7 pigs, 7 sheep, and 2 rabbits) were used. Pacing threshold was tested from all axes of MaxLead from right-ventricular (RV) apex before and after simulated dislodgement. In addition, conduction-system pacing was performed in sheep heart preparations from all axes of MaxLead. Sensing via MaxLead positioned at RV apex was tested during sinus rhythm (SR), pacing from RV and left-ventricular (LV) free-wall, and ventricular fibrillation (VF). MaxLead-enabled voltage (MaxV), defined as the largest span of the sensed electric field loop, was compared with traditional lead-tip voltage detection. RESULTS: Pacing: MaxLead minimized change in pacing threshold owing to lead dislodgement (average voltage change 0.2 mV; 95% confidence interval [CI], -0.5 to 0.9), using multiple bipoles available for pacing. In animals with high conduction system-pacing thresholds (> 2 mV) in 1 or more bipoles (3 of 7), acceptable thresholds (< 1 mV) were demonstrated in an average of 2.5 remaining bipoles. Sensing: MaxV of SR and VF was consistently higher than the highest bipolar voltage (voltage difference averaged -0.18 mV, 95% CI, -0.28 to -0.07), P = 0.001). Electric field-loop geometry consistently differentiated ventricular activation in SR from that during pacing from RV and LV free walls. CONCLUSIONS: The multi-axes MaxLead electrode showed advantages in pacing, sensing, and mapping and has the potential to allow for improvements in lead-electrode technology for cardiac-implanted electronic devices.

Association of HIV Infection and Antiretroviral Therapy With Arterial Stiffness: A Systematic Review and Meta-Analysis.

[Figure: see text].

Unipolar electrogram-based voltage mapping with far-field cancellation to improve detection of abnormal atrial substrate during atrial fibrillation.

INTRODUCTION: An important substrate for atrial fibrillation (AF) is fibrotic atrial myopathy. Identifying low voltage, myopathic regions during AF using traditional bipolar voltage mapping is limited by the directional dependency of wave propagation. Our objective was to evaluate directionally independent unipolar voltage mapping, but with far-field cancellation, to identify low-voltage regions during AF. METHODS: In 12 patients undergoing pulmonary vein isolation for AF, high-resolution voltage mapping was performed in the left atrium during sinus rhythm and AF using a roving 20-pole circular catheter. Bipolar electrograms (EGMs) (Bi) < 0.5 mV in sinus rhythm identified low-voltage regions. During AF, bipolar voltage and unipolar voltage maps were created, the latter with (uni-res) and without (uni-orig) far-field cancellation using a novel, validated least-squares algorithm. RESULTS: Uni-res voltage was ~25% lower than uni-orig for both low voltage and normal atrial regions. Far-field EGM had a dominant frequency (DF) of 4.5-6.0 Hz, and its removal resulted in a lower DF for uni-orig compared with uni-res (5.1 ± 1.5 vs. 4.8 ± 1.5 Hz; p < .001). Compared with Bi, uni-res had a significantly greater area under the receiver operator curve (0.80 vs. 0.77; p < .05), specificity (86% vs. 76%; p < .001), and positive predictive value (43% vs. 30%; p < .001) for detecting low-voltage during AF. Similar improvements in specificity and positive predictive value were evident for uni-res versus uni-orig. CONCLUSION: Far-field EGM can be reliably removed from uni-orig using our novel, least-squares algorithm. Compared with Bi and uni-orig, uni-res is more accurate in detecting low-voltage regions during AF. This approach may improve substrate mapping and ablation during AF, and merits further study.

Outcomes in Young Adults With Tetralogy of Fallot and Pulmonary Annular Preserving or Transannular Patch Repairs.

BACKGROUND: Early surgical tetralogy of Fallot (ToF) repair involved patching across the pulmonic annulus (transannular patch [TAP] repair), which resulted in severe pulmonic regurgitation. Long-term outcome improvements were anticipated with modifications that preserved the pulmonic annulus (annulus-preserving [AP] repair). The objective of the present study was to evaluate the need for late reintervention in adults with AP repair and those with TAP repair. METHODS: We conducted a retrospective review of adults (born 1981-1996) with childhood intracardiac ToF repairs at a tertiary care center. The primary cardiovascular outcome was need for reintervention after primary intracardiac repair of ToF. Secondary outcomes included a composite of death, heart failure, and ventricular arrhythmias. RESULTS: Two hundred thirty adults were included: 104 with AP repair and 126 with TAP repair. The median age at last follow up was 25 years (interquartile range [IQR] 20-28) and the median follow-up duration was 7.9 years (IQR 3.5-12). Reintervention of any type was significantly more common in the TAP group during both childhood and adulthood (72.2% TAP vs 20.2% AP, HR 5.5, 95% CI 3.4-9.0; P < 0.001). Pulmonary valve replacement (PVR) was almost 6 times more likely in adults with TAP repair (65.1% TAP vs 16.3% AP, HR 5.7, 95% CI 3.4-9.7; P < 0.001). CONCLUSIONS: Patients who had AP ToF repair had significantly fewer late reinterventions compared with TAP repair, with the majority of reinterventions due to PVR. More long-term follow-up is required.

Microvolt QRS Alternans Without Microvolt T-Wave Alternans in Human Cardiomyopathy: A Novel Risk Marker of Late Ventricular Arrhythmias.

Background Action potential alternans can induce ventricular tachyarrhythmias and manifest on the surface ECG as T-wave alternans (TWA) and QRS alternans (QRSA). We sought to evaluate microvolt QRSA in cardiomyopathy patients in relation to TWA and ventricular tachyarrhythmia outcomes. Methods and Results Prospectively enrolled cardiomyopathy patients (n=100) with prophylactic defibrillators had 12-lead ECGs recorded during ventricular pacing from 100 to 120 beats/min. QRSA and TWA were quantified in moving 128-beat segments using the spectral method. Segments were categorized as QRSA positive (QRSA+) and/or TWA positive (TWA+) based on ≥2 precordial leads having alternans magnitude >0 and signal:noise >3. Patients were similarly categorized based on having ≥3 consecutive segments with alternans. TWA+ and QRSA+ occurred together in 31% of patients and alone in 18% and 14% of patients, respectively. Although TWA magnitude (1.4±0.4 versus 4.7±1.0 µV, P<0.01) and proportion of TWA+ studies (16% versus 46%, P<0.01) increased with rate, QRSA did not change. QRS duration was longer in QRSA+ than QRSA-negative patients (138±23 versus 113±26 ms, P<0.01). At 3.5 years follow-up, appropriate defibrillator therapy or sustained ventricular tachyarrhythmia was greater in QRSA+ than QRSA-negative patients (30% versus 8%, P=0.02) but similar in TWA+ and TWA-negative patients. Among QRSA+ patients, the event rate was greater in those without TWA (62% versus 21%, P=0.02). Multivariable Cox analysis revealed QRSA+ (hazard ratio [HR], 4.6; 95% CI, 1.5-14; P=0.009) and QRS duration >120 ms (HR, 4.1; 95% CI, 1.3-12; P=0.014) to predict events. Conclusions Microvolt QRSA is novel phenomenon in cardiomyopathy patients that can exist without TWA and is associated with QRS prolongation. QRSA increases the risk of ventricular tachyarrhythmia 4-fold, which merits further study as a risk stratifier.

Sex differences in the efficacy of antihypertensive treatment in preventing cardiovascular outcomes and reducing blood pressure: protocol for a systematic review and meta-analysis.

INTRODUCTION: Hypertension is a leading cause of mortality worldwide and its prevalence is expected to rise over the next decade. Sex differences exist in the epidemiology and pathophysiology of hypertension. It is well established that antihypertensive treatment can significantly reduce the risk for stroke and other cardiovascular disease events. However, it remains unclear whether this effect is dependent on sex. In this protocol, we outlined a systematic review and meta-analysis to evaluate the effects of antihypertensive therapy in (1) reducing blood pressure and (2) preventing cardiovascular morbidity and mortality outcomes for each sex separately. METHODS AND ANALYSIS: The following electronic databases will be searched: Medline, Embase, The Cochrane Library, PubMed, Cumulative Index of Nursing and Allied Health Literature Plus, Web of Science, grey literature (Google Scholar) and several trial registries. Search strategies will be designed to identify human adult (≥18) randomised (and non-randomised) controlled trials, prospective and retrospective cohort studies, and case-control studies concerning 'sex-specific differences associated with the efficacy of antihypertensive treatment'. A preliminary search strategy was developed for Medline (1946-16 September 2019). Two investigators will independently review each article included in the final analysis. Primary outcomes investigated are cardiovascular morbidity and mortality and systolic and diastolic blood pressure. Pooled analyses will be conducted using the random-effects model. Publication bias will be assessed by visual inspection of funnel plots and by Begg's and Egger's statistical tests. Between-studies heterogeneity will be measured using the I2 test (p<0.10). Sources of heterogeneity will be explored by sensitivity, subgroup and metaregression analyses. ETHICS AND DISSEMINATION: This is the first meta-analysis that will comprehensively compare the efficacy of antihypertensive treatment regimens between men and women. Findings will be shared through scientific conferences and societies, social media and consumer advocacy groups. Results will be used to inform the current guidelines for management of hypertension in men and women by demonstrating the importance of implementing sex-specific recommendations. Ethical considerations are not applicable for this protocol.

Mortality Benefit of Alirocumab: A Bayesian Perspective.

Background The ODYSSEY OUTCOMES (Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome) trial demonstrated that alirocumab reduced major cardiovascular events. However, because of the hierarchical testing strategy used for the multiple outcomes examined, the observed reduction in all-cause mortality was labeled "nominally significant" which has clouded its interpretation. Methods and Results We re-analyzed data from ODYSSEY OUTCOMES using Bayesian methods and generated various prior probabilities by incorporating mortality data from previous similar PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor trials. We first used data from the ODYSSEY OUTCOMES trial with a non-informative prior, then sequentially added data from ODYSSEY LONG TERM and the FOURIER trial, giving FOURIER full weight, 50% weight and 10%. The posterior probability of a mortality reduction using only the ODYSSEY OUTCOMES data was hazard ratio 0.85 (95% CI 0.74-0.99) which corresponded to a 98.4% probability of a mortality benefit. When the ODYSSEY LONG TERM data were added to the analysis, the posterior probability was hazard ratio 0.84 (95% CI 0.72-0.97) with a 99.9% probability of mortality reduction, and when the FOURIER data were added to the analysis the posterior probability was hazard ratio 0.94 (95% CI 0.85-1.04) with an 89.1% probability of a mortality reduction. When the FOURIER trial was given only 50% or 10% weight, the probability of a mortality reduction rose 95.4% and 98.7%, respectively. We estimate that the probability of >1% absolute risk reduction ranges from 8% to 24%, while the probability of >0.5% absolute risk reduction ranges from 66% to 89%. Conclusions Our analysis demonstrates a high likelihood that alirocumab confers a reduction in all-cause mortality, despite the equivocal interpretation of the data in the original ODYSSEY OUTCOMES publication.

Systematic review and meta-analysis of cardiac involvement in mitochondrial myopathy.

OBJECTIVE: Our goal was to perform a systematic review of the literature to demonstrate the prevalence of cardiac abnormalities identified using cardiac investigations in patients with mitochondrial myopathy (MM). METHODS: This systematic review surveys the available evidence for cardiac investigations in MM from a total of 21 studies including 825 participants. Data were stratified by genetic mutation and clinical syndrome. RESULTS: We identified echocardiogram and ECG as the principal screening modalities that identify cardiac structural (29%) and conduction abnormalities (39%) in various MM syndromes. ECG abnormalities were more prevalent in patients with m.3243A>G mutations than other gene defects, and patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) had a higher prevalence of ECG abnormalities than patients with other clinical syndromes. Echocardiogram abnormalities were significantly more prevalent in patients with m.3243A>G or m.8344A>G mutations compared with other genetic mutations. Similarly, MELAS and MERRF had a higher prevalence compared with other syndromes. We observed a descriptive finding of an increased prevalence of ECG abnormalities in pediatric patients compared with adults. CONCLUSIONS: This analysis supports the presence of a more severe cardiac phenotype in MELAS and myoclonic epilepsy with ragged red fibres syndromes and with their commonly associated genetic mutations (m.3243A>G and m.8344A>G). This provides the first evidence basis on which to provide more intensive cardiac screening for patients with certain clinical syndromes and genetic mutations. However, the data are based on a small number of studies. We recommend further studies of natural history, therapeutic response, pediatric participants, and cardiac MRI as areas for future investigation.

Omnipolarity applied to equi-spaced electrode array for ventricular tachycardia substrate mapping.

AIMS: Bipolar electrogram (BiEGM)-based substrate maps are heavily influenced by direction of a wavefront to the mapping bipole. In this study, we evaluate high-resolution, orientation-independent peak-to-peak voltage (Vpp) maps obtained with an equi-spaced electrode array and omnipolar EGMs (OTEGMs), measure its beat-to-beat consistency, and assess its ability to delineate diseased areas within the myocardium compared against traditional BiEGMs on two orientations: along (AL) and across (AC) array splines. METHODS AND RESULTS: The endocardium of the left ventricle of 10 pigs (three healthy and seven infarcted) were each mapped using an Advisor™ HD grid with a research EnSite Precision™ system. Cardiac magnetic resonance images with late gadolinium enhancement were registered with electroanatomical maps and were used for gross scar delineation. Over healthy areas, OTEGM Vpp values are larger than AL bipoles by 27% and AC bipoles by 26%, and over infarcted areas OTEGM Vpp values are 23% larger than AL bipoles and 27% larger than AC bipoles (P < 0.05). Omnipolar EGM voltage maps were 37% denser than BiEGM maps. In addition, OTEGM Vpp values are more consistent than bipolar Vpps showing less beat-by-beat variation than BiEGM by 39% and 47% over both infarcted and healthy areas, respectively (P < 0.01). Omnipolar EGM better delineate infarcted areas than traditional BiEGMs from both orientations. CONCLUSION: An equi-spaced electrode grid when combined with omnipolar methodology yielded the largest detectable bipolar-like voltage and is void of directional influences, providing reliable voltage assessment within infarcted and non-infarcted regions of the heart.

Essential role of ryanodine receptor 2 phosphorylation in the effect of azumolene on ventricular arrhythmia vulnerability in a rabbit heart model.

INTRODUCTION: Following long-duration ventricular fibrillation (LDVF), reinitiation of ventricular fibrillation (VF) poses a major challenge during resuscitation. Ryanodine receptor 2 (RyR2) becomes dysfunctional following VF. The relationship between LDVF, RyR2 modulation, and ventricular refibrillation, as well as the role of RyR2 phosphorylation, remains unknown. METHODS: Langendorff-perfused rabbit hearts were subjected to global ischemia and treated with azumolene (or vehicle alone in controls) upon reperfusion. After electrical induction of an initial LDVF episode, each heart was further stimulated electrically to assess reinducibility of VF. Myocardial calcium dynamics were assessed by optical mapping. RyR2 phosphorylation in left ventricular tissue extracts was analyzed by Western blot analysis. RESULTS: Fewer episodes of refibrillation (lasting ≥ 10 seconds) were induced in azumolene-treated hearts than in controls (P = 0.01); however, this reduction in refibrillation was abrogated in the presence of the protein kinase A inhibitor H89. Spontaneous calcium elevation was significantly lower in azumolene-treated hearts than in control hearts ( P = 0.002) and in hearts pretreated with H89 before azumolene ( P = 0.01). RyR2 phosphorylation at Ser2808 was higher in hearts subjected to LDVF than in non-VF hearts ( P = 0.029), while no significant difference was found at Ser2814. Pretreatment with H89 led to significantly less RyR2 phosphorylation at Ser2808 ( P = 0.04) after LDVF, while pretreatment with KN93 or azumolene alone showed no effects on RyR2 phosphorylation. CONCLUSION: Ventricular refibrillation following LDVF was reduced by azumolene, which also improves calcium dynamics. RyR2 phosphorylation at Ser2808 is a prerequisite for the beneficial effects of azumolene.

Multicenter Study of Ischemic Ventricular Tachycardia Ablation With Decrement-Evoked Potential (DEEP) Mapping With Extra Stimulus.

OBJECTIVES: The authors conducted a multicenter study of decrement-evoked potential (DEEP)-based functional ventricular tachycardia (VT) substrate modification to evaluate if such a mechanistic and physiological strategy is feasible and efficient in clinical practice and provides reduction in the VT burden. BACKGROUND: Only a fraction of the myocardium targeted in current VT substrate modification procedures is involved in the initiation and perpetuation of VT. The physiological basis of the DEEP strategy for identification of areas of initiation and maintenance of VT was recently established. METHODS: We included 20 consecutive patients with ischemic cardiomyopathy. During substrate mapping, fractionated and late potentials (LPs) were tagged, and an extra stimulus was performed to determine which LPs displayed decrement (DEEPs). All patients underwent DEEP-focused ablation: elimination of DEEP + further radiofrequency (RF) if VT was still inducible. Patients were followed during 6 months. RESULTS: Patients were predominantly male (95%), and their mean age was 64.6 ± 17.1 years. Mean left ventricular ejection fraction was 33.4 ± 11.4%. Mean ablation time was 30.6 ± 20.4 min. Specificity of DEEPs to detect the isthmus of VT was better than that of LPs (0.97 [95% confidence interval [CI]: 0.95 to 0.98] vs. 0.82 [95% CI: 0.73 to 0.89]), without significant differences in terms of sensitivity (0.61 [95% CI: 0.52 to 0.69] vs. 0.60 [95% CI: 0.44 to 0.74], respectively). Fifteen of 20 (75%) patients were free of any VT after DEEP-RF at 6 months of follow-up and there was a strong reduction in VT burden compared to 6 months pre-ablation. CONCLUSIONS: In a multicenter prospective study, DEEP substrate mapping identified the functional substrate critical to the VT circuit with high specificity. DEEP-guided VT ablation, by its physiological nature, may enable greater access to focused ablation therapy for patients requiring VT treatment.

Long term outcomes among adults post transcatheter atrial septal defect closure: Systematic review and meta-analysis.

BACKGROUND: Transcatheter Closure (TC) has become the main stay therapy for many secundum atrial septal defects (ASD) based on short and intermediate term outcome data. Long-term safety and efficacy of this approach among adult patients however, is not well established. METHODS AND RESULTS: A comprehensive search of major electronic databases for studies reporting the long-term (≥5 year) outcomes post TC among adults yielded 114 studies, 9 of which had met the inclusion criteria. This included 1015 patients with a mean age of 45 years ±â€¯5.5 years, two third were female with a mean follow up duration 6.4 years ±â€¯2.7 years. The weighted proportions of long-term mortality and stroke with 95% confidence intervals (CI) were 2.4% (95%CI 0.9%-6.1%) and 2.1% (95%CI 0.7%-5.7%) respectively. Atrial arrhythmia occurred in 6.5% (95%CI 3.5%-11.7%) and atrial fibrillation in 4.9% (95%CI 1.9%-11.7%). ASD related re-interventions were encountered in 2.3% (95%CI 1.0%-5.4%) and residual shunt in 4.2% (95% CI 1.3%-12.4%), with 1 case of suspected device erosion 0.9% (95%CI 0.4-2.2%). Frame fractures and late migrations were observed at 4.2% (95%CI 1.5%-11.5%) and 1.2% (95%CI 0.3%-4%) respectively. No cases of occluder endocarditis or thrombosis were reported. IN CONCLUSION: This is the first study that systematically analyzes the long-term outcomes after TC providing important estimates for various clinical and occluder related outcomes. The analysis suggests preserved long-term safety post TC; however, this is limited due to the variable quality of available evidence and requires further assessment by larger studies with more comprehensive follow-up data.