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.

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.

Evaluation of the Pleiotropic Effects of Statins: A Reanalysis of the Randomized Trial Evidence Using Egger Regression-Brief Report.

OBJECTIVE: To reanalyze data from recent randomized trials of statins to assess whether the benefits and risks of statins are mediated primarily via their LDL-C (low-density lipoprotein cholesterol) lowering effects or via other mechanisms. APPROACH AND RESULTS: We adapted Egger regression, a technique frequently used in Mendelian randomization studies to detect genetic pleiotropy, to reanalyze the available randomized control trial data of statin therapy. For cardiovascular end points, each 1 mmol/L change in LDL-C with statin therapy was associated with a hazard ratio of 0.77 (95% confidence interval, 0.71-0.84) with an intercept that was indistinguishable from zero (intercept, -0.0032; [95% confidence interval, -0.090 to 0.084]; P=0.94), indicating no pleiotropy. For incident diabetes mellitus, a 1 mmol/L change in LDL-C with statin therapy was associated with a hazard ratio of 1.07 (95% confidence interval, 0.99-1.16) and an intercept nondistinguishable from zero (intercept, -0.015; [95% confidence interval, -0.30 to 0.27]; P=0.91), again indicating no pleiotropy. CONCLUSIONS: Our reanalysis of the randomized control trial data using Egger regression adds to the existing evidence that the cardiovascular benefits of statins and their association with incident diabetes mellitus are mediated primarily, if not entirely, via their LDL-C lowering properties rather than by any pleiotropic effects.

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.

Diagnostic and prognostic significance of transient ischemic dilation (TID) in myocardial perfusion imaging: A systematic review and meta-analysis.

BACKGROUND: Transient ischemic dilatation (TID) of the left ventricle is a potential marker of high risk obstructive coronary artery disease on stress myocardial perfusion imaging (MPI). There is, however, interstudy variation in the diagnostic performance of TID for identification of severe and extensive coronary disease anatomy, and varied prognostic implications in the published literature. METHODS: We searched MEDLINE, EMBASE, and COCHRANE databases for studies where TID was compared with invasive or CT coronary angiography for evaluation of coronary artery stenosis. Two reviewers independently evaluated and abstracted data from each study. A bivariate random effects model was used to derive pooled sensitivities and specificities, in order to account for correlation between TID in MPI and anatomic disease severity. RESULTS: A total of 525 articles were reviewed, of which 51 met inclusion criteria. Thirty-one studies contributed to the analysis, representing a total of 2037 patients in the diagnostic meta-analysis and 9003 patients in the review of prognosis. The ratio above which TID was deemed present ranged from 1.13 to 1.38. Pooled sensitivity was 44% (95% CI 30%-60%) and specificity was 88% (95% CI 83%-92%) for the detection of extensive or severe anatomic coronary artery disease. Analysis of outcome data demonstrated increased cardiac event rates in patients with TID and an abnormal MPI. In otherwise normal perfusion, TID is an indicator of poor prognosis in patients with diabetes and/or a history of coronary disease. CONCLUSIONS: Among patients undergoing MPI, the presence of TID is specific for the detection of extensive or severe coronary artery disease.

Heart rate in patients with reduced ejection fraction: relationship between single time point measurement and mean heart rate on prolonged implantable cardioverter defibrillator monitoring.

BACKGROUND: Heart rate (HR) is a prognostic marker that is increasingly used as a therapeutic target in patients with cardiovascular disease. The association between resting and mean HR remains unclear. We therefore set out to determine the relationship between resting HR on the electrocardiogram (ECG) obtained at a single time point, and mean HR on implantable cardioverter defibrillator (ICD) interrogation amongst patients with a reduced left ventricular ejection fraction (LVEF). METHODS: Prospective ICD data were obtained from 54 patients with LVEF < 40%. Mean HR determined using the ICD HR histograms was compared with resting HR measured on the ECG performed in the clinic. RESULTS: Average resting and ICD mean HRs were 67.9 ± 10.1 and 67.8 ± 9.6 bpm respectively. There was good correlation in the overall cohort (r = 0.79), in those with resting ECG HRs ≤ 70 bpm (r = 0.62), and amongst the 27 patients on intermediate-to-high dose beta-blockers (r = 0.91). However, Bland-Altman analysis demonstrated wide limits of agreement in the overall cohort (- 12.5, 12.7 bpm), at resting HRs ≤ 70 bpm (- 12.7, 9.8 bpm), and on intermediate-to-high dose beta-blockers (- 8.9, 7.4 bpm). Moreover, resting HR did not predict the 10-bpm interval where the most time was spent. CONCLUSIONS: While resting HR correlated with mean HR in patients with reduced LVEF, and in important subgroups, the limits of agreement were unacceptably wide raising concern over the use of single time point resting HR as a therapeutic target.

Genetic Risk Prediction for Primary and Secondary Prevention of Atherosclerotic Cardiovascular Disease: an Update.

PURPOSE OF REVIEW: This review aims to summarize the research on genetic risk scores and their ability to improve risk prediction in both a primary and a secondary prevention population. RECENT FINDINGS: Several groups have examined the role of genetic scores in different patient populations. Recent studies have capitalized on the growing number of identified genetic variants to construct polygenic risk scores that include hundreds and sometimes thousands of SNPs. Also, recent studies have demonstrated that individuals with high genetic risk scores can attenuate their risk with lifestyle modifications and with statins, for which the benefit of treatment may be greater in those at highest genetic risk. Genetic risk scores when added to existing clinical models appear to improve risk prediction, particularly in the setting of incident cardiovascular disease and may provide actionable information to optimize prevention early in life. Future research will need to establish how to best use this genetic risk information either as a means to further individualize treatment decisions or to better identify high-risk populations.

Association Between Family History, a Genetic Risk Score, and Severity of Coronary Artery Disease in Patients With Premature Acute Coronary Syndromes.

OBJECTIVE: A genetic risk score (GRS) for coronary artery disease has recently been shown to be independent of family history (FHx) in predicting future cardiovascular events. We sought to determine whether the presence of these risk factors, either individually or together, was associated with a higher burden of angiographic coronary artery disease. APPROACH AND RESULTS: We included 763 patients with premature acute coronary syndrome (median age, 50 [46-53] years; 30.8% women) with at least 1 major epicardial vessel stenosis enrolled in the Gender and Sex Determinants of Cardiovascular Disease From Bench to Beyond in Premature Acute Coronary Syndrome (GENESIS-PRAXY) study, a multicentre prospective cohort study of premature patients with acute coronary syndrome (aged ≤55 years). The prevalence of multivessel disease (ie, ≥2 vessels with >50% stenosis) in individuals with FHx was 49.7% as compared with 37.9% in those without FHx (P<0.01 for comparison). In adjusted models for age, sex, traditional risk factors, and GRS, FHx was associated with a higher prevalence of 3-vessel disease (odds ratio [OR], 1.42; 95% confidence interval, 0.91-2.21; P=0.12 for 2-vessel disease and OR, 2.26; 95% confidence interval, 1.29-3.95; P=0.005 for 3-vessel disease). Individuals with a high GRS were also more likely to have multivessel disease (OR, 1.41; 95% confidence interval, 1.01-1.99; P=0.047) after adjustment for traditional risk factors, including FHx. Individuals with both a FHx and a high GRS as compared with those with neither had the highest ORs for multivessel disease (adjusted OR, 2.14; 95% confidence interval, 1.24-3.69; P=0.0064). CONCLUSIONS: In patients with premature acute coronary syndrome, the presence of either a high GRS or FHx is associated with greater severity of coronary artery disease at angiography. Whether preventive strategies targeted to genetically predisposed individuals will reduce the burden of early acute coronary syndrome warrants further study.

Coronary revascularization in diabetic patients: a systematic review and Bayesian network meta-analysis.

BACKGROUND: The optimal revascularization technique in diabetic patients is an important unresolved question. PURPOSE: To compare long-term outcomes between the revascularization techniques of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). DATA SOURCES: English-language publications in PubMed, the Cochrane Central Register of Controlled Trials, Ovid, and EMBASE between 1 January 1990 and 1 June 2014. STUDY SELECTION: Two investigators independently reviewed randomized, controlled trials comparing PCI (with drug-eluting or bare-metal stents) with CABG in adults with diabetes with multivessel or left main coronary artery disease. DATA EXTRACTION: Study design, quality, patient characteristics, length of follow-up, and outcomes were extracted. For duplicate publications, outcomes were obtained from the publication with the longest follow-up. DATA SYNTHESIS: 40 studies were combined using a Bayesian network meta-analysis that accounted for the variation in stent choice. The primary outcome, a composite of all-cause mortality, nonfatal myocardial infarction, and stroke, increased with PCI (odds ratio [OR], 1.33 [95% credible interval {CrI}, 1.01 to 1.65]). Percutaneous coronary intervention resulted in increased mortality (OR, 1.44 [CrI, 1.05 to 1.91]), no change in the number of myocardial infarctions (OR, 1.33 [CrI, 0.86 to 1.95]), and fewer strokes (OR, 0.56 [CrI, 0.36 to 0.88]). LIMITATIONS: Study design and length of follow-up were heterogeneous, and results were driven primarily by a single study. Costs and nonvascular complications of the interventions were not examined. CONCLUSION: Coronary artery bypass grafting seems to be the preferred revascularization technique in diabetics, especially if long-term survival is anticipated. However, because of residual uncertainties and increased risk for stroke with CABG, clinical judgment is required when choosing a revascularization technique in patients with diabetes. PRIMARY FUNDING SOURCE: Fonds de recherche du Québec-Santé.

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.

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.

Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction.

BACKGROUND: Patients prescribed antiplatelet treatment to prevent recurrent acute myocardial infarction are often also given a selective serotonin reuptake inhibitor (SSRI) to treat coexisting depression. Use of either treatment may increase the risk of bleeding. We assessed the risk of bleeding among patients taking both medications following acute myocardial infarction. METHODS: We conducted a retrospective cohort study using hospital discharge abstracts, physician billing information, medication reimbursement claims and demographic data from provincial health services administrative databases. We included patients 50 years of age or older who were discharged from hospital with antiplatelet therapy following acute myocardial infarction between January 1998 and March 2007. Patients were followed until admission to hospital due to a bleeding episode, admission to hospital due to recurrent acute myocardial infarction, death or the end of the study period. RESULTS: The 27,058 patients in the cohort received the following medications at discharge: acetylsalicylic acid (ASA) (n = 14,426); clopidogrel (n = 2467), ASA and clopidogrel (n = 9475); ASA and an SSRI (n = 406); ASA, clopidogrel and an SSRI (n = 239); or clopidogrel and an SSRI (n = 45). Compared with ASA use alone, the combined use of an SSRI with antiplatelet therapy was associated with an increased risk of bleeding (ASA and SSRI: hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.08-1.87; ASA, clopidogrel and SSRI: HR 2.35, 95% CI 1.61-3.42). Compared with dual antiplatelet therapy alone (ASA and clopidogrel), combined use of an SSRI and dual antiplatelet therapy was associated with an increased risk of bleeding (HR 1.57, 95% CI 1.07-2.32). INTERPRETATION: Patients taking an SSRI together with ASA or dual antiplatelet therapy following acute myocardial infarction were at increased risk of bleeding.

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

[Figure: see text].

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.

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.

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.