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Aims: The randomized, double-blind, placebo-controlled HOPE-HF trial assessed the benefit of atrio-ventricular (AV) delay optimization delivered using His bundle pacing. It recruited patients with left ventricular ejection fraction ≤40%, PR interval ≥200 ms, and baseline QRS ≤140 ms or right bundle branch block. Overall, there was no significant increase in peak oxygen uptake (VO 2 max) but there was significant improvement in heart failure specific quality of life. In this pre-specified secondary analysis, we evaluated the impact of baseline PR interval, echocardiographic E-A fusion, and the magnitude of acute high-precision haemodynamic response to pacing, on outcomes., Methods and Results: All 167 randomized participants underwent measurement of PR interval, acute haemodynamic response at optimized AV delay, and assessment of presence of E-A fusion. We tested the impact of these baseline parameters using a Bayesian ordinal model on VO 2 max, quality of life and activity measures. There was strong evidence of a beneficial interaction between the baseline acute haemodynamic response and the blinded benefit of pacing for VO 2 (Pr 99.9%), Minnesota Living With Heart Failure (MLWHF) (Pr 99.8%), MLWHF physical limitation score (Pr 98.9%), EQ-5D visual analogue scale (Pr 99.6%), and exercise time (Pr 99.4%). The baseline PR interval and the presence of baseline E-A fusion did not have this reliable ability to predict the clinical benefit of pacing over placebo across multiple endpoints., Conclusions: In the HOPE-HF trial, the acute haemodynamic response to pacing reliably identified patients who obtained clinical benefit. Patients with a long PR interval (≥200 ms) and left ventricular impairment who obtained acute haemodynamic improvement with AV-optimized His bundle pacing were likely to obtain clinical benefit, consistent across multiple endpoints. Importantly, this gradation can be reliably tested for before randomization, but does require high-precision AV-optimized haemodynamic assessment to be performed., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

In ambulatory patients with complete heart block (CHB), dual-chamber (DDD) pacing confers physiological benefits versus single-chamber (VVI) pacing, however, the impact on mortality is disputed. Nonagenarians constitute an expanding proportion of pacemaker recipients, yet data on device selection and outcomes are limited, especially in emergency situations. In nonagenarians with emergent CHB, we compared the clinical characteristics and outcomes of patients receiving VVI versus DDD pacemakers. Cox proportional-hazards analysis examined all-cause mortality and death from congestive cardiac failure (CCF). There were 168 consecutive patients followed-up for 30.6 ± 15.5 months. Of these, 22 patients (13.1%) received VVI pacemakers; when compared with DDD recipients, these patients had similar median age (93 vs. 91 years, p=0.15) and left ventricular (LV) systolic function (LV ejection fraction [EF] 49.2% ± 9.7 vs. 50.7% ± 10.1, p=0.71), but were more frail (Rockwood scale 5.2 ± 1.8 vs. 4.3 ± 1.1, p=0.004) and more likely to have dementia (27.3% vs. 8.9%, p=0.011). Post-implant, device interrogation demonstrated that VVI recipients had higher respiratory rates (21.3 ± 2.4 vs. 17.5 ± 2.6 breaths per minute, p=0.002), lower mean heart rates (65.5 ± 10.1 vs. 71.9 ± 8.6 bpm, p=0.002), and lower daily activity levels (0.57 ± 0.3 vs. 1.5 ± 1.1 hours of activity, p=0.016) than DDD recipients. Adjusting for age, frailty and dementia, VVI pacing was associated with an increased risk of all-cause mortality (adjusted hazard ratio [HR] 2.1, 95% confidence interval [CI] 1.08 to 4.1, p=0.03) and death from CCF (adjusted HR 7.1, 95%CI 2.5 to 20.6, p<0.001). In conclusion, in nonagenarians with emergent CHB, dual-chamber pacing was associated with improved symptomatic and prognostic outcomes versus singlechamber pacing., Competing Interests: Conflicts of interest None declared., (Copyright © 2024 Medinews (Cardiology) Limited.)

Implantable cardiac devices are a vital treatment option in the management of tachy/brady-arrhythmias and heart failure with conduction disease. In the recent years, these devices have become increasingly sophisticated, with high implantation success rates and longevity. However, these devices are not without risks and complications, which need to be carefully considered before implantation. In an era of rapidly evolving cardiac device therapies, this review article will provide an update on the literature and outline some of the emerging technologies that aim to maximise the efficiency of implantable devices and reduce complications. We discuss novel pacing techniques, including alternative pacing sites in anti-bradycardia and biventricular pacing, as well as the latest evidence surrounding leadless device technologies and patient selection for implantable device therapies., Competing Interests: CM has received speaker fees from Abbott, Boston Scientific, Biotronik, Medtronic, and Phillips and has received consulting fees from Medtronic. As of April 2023 CM is supported by a research grant provided by Boston Scientific. None of the other authors had any conflicts of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Cardiac resynchronisation therapy (CRT) improves prognosis in patients with heart failure (HF) however the role of ABO blood groups and Rhesus factor are poorly understood. We hypothesise that blood groups may influence clinical and survival outcomes in HF patients undergoing CRT. A total of 499 patients with HF who fulfilled the criteria for CRT implantation were included. Primary outcome of all-cause mortality and/or heart transplant/left ventricular assist device was assessed over a median follow-up of 4.6 years (IQR 2.3-7.5). Online repositories were searched to provide biological context to the identified associations. Patients were divided into blood (O, A, B, and AB) and Rhesus factor (Rh-positive and Rh-negative) groups. Mean patient age was 66.4 ± 12.8 years with a left ventricular ejection fraction of 29 ± 11%. There were no baseline differences in age, gender, and cardioprotective medication. In a Cox proportional hazard multivariate model, only Rh-negative blood group was associated with a significant survival benefit (HR 0.68 [0.47-0.98], p = 0.040). No association was observed for the ABO blood group (HR 0.97 [0.76-1.23], p = 0.778). No significant interaction was observed with prevention, disease aetiology, and presence of defibrillator. Rhesus-related genes were associated with erythrocyte and platelet function, and cholesterol and glycated haemoglobin levels. Four drugs under development targeting RHD were identified (Rozrolimupab, Roledumab, Atorolimumab, and Morolimumab). Rhesus blood type was associated with better survival in HF patients with CRT. Further research into Rhesus-associated pathways and related drugs, namely whether there is a cardiac signal, is required., (© 2024. The Author(s).)

Background: Remote monitoring (RM) of implantable cardiac devices provides substantial and complex information, presenting new challenges such as detection of a patient's death., Objective: This study aims to describe RM transmissions indicating death and propose a management strategy for services., Methods: The study included consecutive ambulatory outpatients whose deaths were detected via RM. Clinical and device data were collected from electronic records, and ethical approval was obtained from the service's institutional review board., Results: Over a 9-year period (2014-2023), 28 patients were detected. The deceased patients had implantable cardioverter-defibrillators, pacemakers, and implantable loop recorders. In 54% of the cases, the patient's death had already been recognized. Alert transmissions indicating death were commonly related to ventricular arrhythmia events, but also due to lead measurements, and implantable loop recorder battery status. Several diagnostic features may indicate a patient's death. The most reliable was the presenting electrogram, demonstrating base rate pacing with no capture. Device diagnostics, lead parameters, and arrhythmia recordings may indicate death; however, not all cases present with recordings and diagnosis may not be conclusive. A majority (82%) had ventricular arrhythmia at the time of death. In cases where defibrillator shocks were delivered, the arrhythmia reinitiated shortly after successful cardioversion. Delayed therapy was observed, and some patients did not receive defibrillator shocks because of discriminators or because the arrhythmia rate fell below the shock zone., Conclusion: Detecting a patient death via RM presents unique challenges and considerations for services. Standard operational policies and legal consultation should be established to address the implications., Competing Interests: Disclosures Mr Monkhouse has received speaker fees from Abbott, Boston Scientific (St Paul, MN), Biotronik, Medtronic, and Phillips and has received consulting fees from Medtronic. As of April 2023, Mr Monkhouse is supported by a research grant provided by Boston Scientific that was awarded to Dr Ahsan. Prof Hunter has received speaker fees from Medtronic and Biosense Webster (Irvine, CA), educational grant from Biosense Webster, and an institutional research grant from Medtronic. Prof Lambiase has received research grants and speaker fees from Boston Scientific, Abbott, and Medtronic and is supported by University College London Biomedicine National Institute of Health Research and Barts Biomedical Research Centre. Dr Sporton has received speaker fees from Medtronic. The rest of the authors report no conflicts of interest., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Antimicrobial envelopes reduce the incidence of cardiac implantable electronic device infections, but their cost restricts routine use in the United Kingdom. Risk scoring could help to identify which patients would most benefit from this technology., Methods: A novel risk score (BLISTER [Blood results, Long procedure time, Immunosuppressed, Sixty years old (or younger), Type of procedure, Early re-intervention, Repeat procedure]) was derived from multivariate analysis of factors associated with cardiac implantable electronic device infection. Diagnostic utility was assessed against the existing PADIT score (Prior procedure, Age, Depressed renal function, Immunocompromised, Type of procedure) in both standard and high-risk external validation cohorts, and cost-utility models examined different BLISTER and PADIT score thresholds for TYRX (Medtronic; Minneapolis, MN) antimicrobial envelope allocation., Results: In a derivation cohort (n=7383), cardiac implantable electronic device infection occurred in 59 individuals within 12 months of a procedure (event rate, 0.8%). In addition to the PADIT score constituents, lead extraction (hazard ratio, 3.3 [95% CI, 1.9-6.1]; P <0.0001), C-reactive protein >50 mg/L (hazard ratio, 3.0 [95% CI, 1.4-6.4]; P =0.005), reintervention within 2 years (hazard ratio, 10.1 [95% CI, 5.6-17.9]; P <0.0001), and top-quartile procedure duration (hazard ratio, 2.6 [95% CI, 1.6-4.1]; P =0.001) were independent predictors of infection. The BLISTER score demonstrated superior discriminative performance versus PADIT in the standard risk (n=2854, event rate: 0.8%, area under the curve, 0.82 versus 0.71; P =0.001) and high-risk validation cohorts (n=1961, event rate: 2.0%, area under the curve, 0.77 versus 0.69; P =0.001), and in all patients (n=12 198, event rate: 1%, area under the curve, 0.8 versus 0.75, P =0.002). In decision-analytic modeling, the optimum scenario assigned antimicrobial envelopes to patients with BLISTER scores ≥6 (10.8%), delivering a significant reduction in infections (relative risk reduction, 30%; P =0.036) within the National Institute for Health and Care Excellence cost-utility thresholds (incremental cost-effectiveness ratio, £18 446)., Conclusions: The BLISTER score (https://qxmd.com/calculate/calculator&#95;876/the-blister-score-for-cied-infection) was a valid predictor of cardiac implantable electronic device infection, and could facilitate cost-effective antimicrobial envelope allocation to high-risk patients., Competing Interests: Disclosures None.

Background: There is a paucity of data comparing vitamin K antagonists (VKAs) to direct oral anticoagulants (DOACs) at the time of cardiac implantable electronic device (CIED) surgery. Furthermore, the best management of DOACs (interruption vs continuation) is yet to be determined., Objectives: This study aimed to compare the incidence of device-related bleeds and thrombotic events based on anticoagulant type (DOAC vs VKA) and regimen (interrupted vs uninterrupted)., Methods: This was an observational multicenter study. We included patients on chronic oral anticoagulation undergoing CIED surgery. Patients were matched using propensity scoring., Results: We included 1,975 patients (age 73.8 ± 12.4 years). Among 1,326 patients on DOAC, this was interrupted presurgery in 78.2% (n = 1,039) and continued in 21.8% (n = 287). There were 649 patients on continued VKA. The matched population included 861 patients. The rate of any major bleeding was higher with continued DOAC (5.2%) compared to interrupted DOAC (1.7%) and continued VKA (2.1%) (P = 0.03). The rate of perioperative thromboembolism was 1.4% with interrupted DOAC, whereas no thromboembolic events occurred with DOAC or VKA continuation (P = 0.04). The use of dual antiplatelet therapy, DOAC continuation, and male sex were independent predictors of major bleeding on a multivariable analysis., Conclusions: In this large real-world cohort, a continued DOAC strategy was associated with a higher bleeding risk compared to DOAC interruption or VKA continuation in patients undergoing CIED surgery. However, DOAC interruption was associated with increased thromboembolic risk. Concomitant dual antiplatelet therapy should be avoided whenever clinically possible. A bespoke approach is necessary, with a strategy of minimal DOAC interruption likely to represent the best compromise., Competing Interests: Funding Support and Author Disclosures Dr Creta has received speaker fees from Boston Scientific. Dr Finlay has received research support and speaker fees from Abbott Ltd, Medtronic Ltd, and Biosense Webster; is Chief Medical Officer, Founder, and Shareholder of Echopoint Medical Ltd; is Director, Founder, and Shareholder of Rhythm AI; is Founder and Shareholder of Epicardio Ltd; and has received research funding from National Institutes of HealthR Barts BRC funding. Dr Lambiase has received educational grants from Medtronic and Boston Scientific; and is supported by UCLH Biomedicine National Institute for Health and Care Research and Barts BRC funding. Dr Schilling has had research agreements and has received speaker fees from Abbott, Medtronic, Boston Scientific, and Biosense Webster; and is a shareholder of AI Rhythm. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Left bundle branch pacing (LBBP) can deliver physiological left ventricular activation, but typically at the cost of delayed right ventricular (RV) activation. Right ventricular activation can be advanced through anodal capture, but there is uncertainty regarding the mechanism by which this is achieved, and it is not known whether this produces haemodynamic benefit., Methods and Results: We recruited patients with LBBP leads in whom anodal capture eliminated the terminal R-wave in lead V1. Ventricular activation pattern, timing, and high-precision acute haemodynamic response were studied during LBBP with and without anodal capture. We recruited 21 patients with a mean age of 67 years, of whom 14 were males. We measured electrocardiogram timings and haemodynamics in all patients, and in 16, we also performed non-invasive mapping. Ventricular epicardial propagation maps demonstrated that RV septal myocardial capture, rather than right bundle capture, was the mechanism for earlier RV activation. With anodal capture, QRS duration and total ventricular activation times were shorter (116 ± 12 vs. 129 ± 14 ms, P < 0.01 and 83 ± 18 vs. 90 ± 15 ms, P = 0.01). This required higher outputs (3.6 ± 1.9 vs. 0.6 ± 0.2 V, P < 0.01) but without additional haemodynamic benefit (mean difference -0.2 ± 3.8 mmHg compared with pacing without anodal capture, P = 0.2)., Conclusion: Left bundle branch pacing with anodal capture advances RV activation by stimulating the RV septal myocardium. However, this requires higher outputs and does not improve acute haemodynamics. Aiming for anodal capture may therefore not be necessary., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The use of left bundle branch area pacing (LBBAP) for bradycardia pacing and cardiac resynchronization is increasing, but implants are not always successful. We prospectively studied consecutive patients to determine whether septal scar contributes to implant failure., Methods: Patients scheduled for bradycardia pacing or cardiac resynchronization therapy were prospectively enrolled. Recruited patients underwent preprocedural scar assessment by cardiac MRI with late gadolinium enhancement imaging. LBBAP was attempted using a lumenless lead (Medtronic 3830) via a transeptal approach., Results: Thirty-five patients were recruited: 29 male, mean age 68 years, 10 ischemic, and 16 non-ischemic cardiomyopathy. Pacing indication was bradycardia in 26% and cardiac resynchronization in 74%. The lead was successfully deployed to the left ventricular septum in 30/35 (86%) and unsuccessful in the remaining 5/35 (14%). Septal late gadolinium enhancement was significantly less extensive in patients where left septal lead deployment was successful, compared those where it was unsuccessful (median 8%, IQR 2%-18% vs. median 54%, IQR 53%-57%, p < .001)., Conclusions: The presence of septal scar appears to make it more challenging to deploy a lead to the left ventricular septum via the transeptal route. Additional implant tools or alternative approaches may be required in patients with extensive septal scar., (© 2023 The Authors. Pacing and Clinical Electrophysiology published by Wiley Periodicals LLC.)

Aims: Left bundle branch area pacing (LBBAP) is a promising method for delivering cardiac resynchronization therapy (CRT), but its relative physiological effectiveness compared with His bundle pacing (HBP) is unknown. We conducted a within-patient comparison of HBP, LBBAP, and biventricular pacing (BVP)., Methods and Results: Patients referred for CRT were recruited. We assessed electrical response using non-invasive mapping, and acute haemodynamic response using a high-precision haemodynamic protocol. Nineteen patients were recruited: 14 male, mean LVEF of 30%. Twelve had time for BVP measurements. All three modalities reduced total ventricular activation time (TVAT), (ΔTVATHBP -43 ± 14 ms and ΔTVATLBBAP -35 ± 20 ms vs. ΔTVATBVP -19 ± 30 ms, P = 0.03 and P = 0.1, respectively). HBP produced a significantly greater reduction in TVAT compared with LBBAP in all 19 patients (-46 ± 15 ms, -36 ± 17 ms, P = 0.03). His bundle pacing and LBBAP reduced left ventricular activation time (LVAT) more than BVP (ΔLVATHBP -43 ± 16 ms, P < 0.01 vs. BVP, ΔLVATLBBAP -45 ± 17 ms, P < 0.01 vs. BVP, ΔLVATBVP -13 ± 36 ms), with no difference between HBP and LBBAP (P = 0.65). Acute systolic blood pressure was increased by all three modalities. In the 12 with BVP, greater improvement was seen with HBP and LBBAP (6.4 ± 3.8 mmHg BVP, 8.1 ± 3.8 mmHg HBP, P = 0.02 vs. BVP and 8.4 ± 8.2 mmHg for LBBAP, P = 0.3 vs. BVP), with no difference between HBP and LBBAP (P = 0.8)., Conclusion: HBP delivered better ventricular resynchronization than LBBAP because right ventricular activation was slower during LBBAP. But LBBAP was not inferior to HBP with respect to LV electrical resynchronization and acute haemodynamic response., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Cardiac resynchronization therapy programmed to dynamically fuse pacing with intrinsic conduction using atrioventricular (AV) timing algorithms (e.g. SyncAV) has shown promise; however, mechanistic data are lacking. This study assessed the impact of SyncAV on electrical dyssynchrony across various pacing modalities using non-invasive epicardial electrocardiographic imaging (ECGi)., Methods and Results: Twenty-five patients with left bundle-branch block (median QRS duration (QRSd) 162.7 ms) and intact AV conduction (PR interval 174.0 ms) were prospectively enrolled. ECGi was performed acutely during biventricular pacing with fixed nominal AV delays (BiV) and using SyncAV (optimized for the narrowest QRSd) during: BiV + SyncAV, LV-only single-site (LVSS + SyncAV), MultiPoint pacing (MPP + SyncAV), and LV-only MPP (LVMPP + SyncAV). Dyssynchrony was quantified via ECGi (LV activation time, LVAT; RV activation time, RVAT; LV electrical dispersion index, LVEDi; ventricular electrical uncoupling index, VEU; and biventricular total activation time, VVtat). Intrinsic conduction LVAT (124 ms) was significantly reduced by BiV pacing (109 ms) (P = 0.001) and further reduced by LVSS + SyncAV (103 ms), BiV + SyncAV (103 ms), LVMPP + SyncAV (95 ms), and MPP + SyncAV (90 ms). Intrinsic RVAT (93 ms), VVtat (130 ms), LVEDi (36 ms), VEU (50 ms), and QRSd (163 ms) were reduced by SyncAV across all pacing modes. More patients exhibited minimal LVAT, VVtat, LVEDi, and QRSd with MPP + SyncAV than any other modality., Conclusion: Dynamic AV delay programming targeting fusion with intrinsic conduction significantly reduced dyssynchrony, as quantified by ECGi and QRSd for all evaluated pacing modes. MPP + SyncAV achieved the greatest synchrony overall but not for all patients, highlighting the value of pacing mode individualization during fusion optimization., Competing Interests: Conflict of interest: N.B., L.C.M., and J.O.M. are employees of Abbott., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Excessive prolongation of PR interval impairs coupling of atrio-ventricular (AV) contraction, which reduces left ventricular pre-load and stroke volume, and worsens symptoms. His bundle pacing allows AV delay shortening while maintaining normal ventricular activation. HOPE-HF evaluated whether AV optimized His pacing is preferable to no-pacing, in a double-blind cross-over fashion, in patients with heart failure, left ventricular ejection fraction (LVEF) ≤40%, PR interval ≥200 ms and either QRS ≤140 ms or right bundle branch block., Methods and Results: Patients had atrial and His bundle leads implanted (and an implantable cardioverter-defibrillator lead if clinically indicated) and were randomized to 6 months of pacing and 6 months of no-pacing utilizing a cross-over design. The primary outcome was peak oxygen uptake during symptom-limited exercise. Quality of life, LVEF and patients' holistic symptomatic preference between arms were secondary outcomes. Overall, 167 patients were randomized: 90% men, 69 ± 10 years, QRS duration 124 ± 26 ms, PR interval 249 ± 59 ms, LVEF 33 ± 9%. Neither peak oxygen uptake (+0.25 ml/kg/min, 95% confidence interval [CI] -0.23 to +0.73, p = 0.3) nor LVEF (+0.5%, 95% CI -0.7 to 1.6, p = 0.4) changed with pacing but Minnesota Living with Heart Failure quality of life improved significantly (-3.7, 95% CI -7.1 to -0.3, p = 0.03). Seventy-six percent of patients preferred His bundle pacing-on and 24% pacing-off (p < 0.0001)., Conclusion: His bundle pacing did not increase peak oxygen uptake but, under double-blind conditions, significantly improved quality of life and was symptomatically preferred by the clear majority of patients. Ventricular pacing delivered via the His bundle did not adversely impact ventricular function during the 6 months., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: To determine the incidence, clinical features, management, and outcomes of pacemaker (PM) and implantable cardioverter-defibrillator (ICD) lead cardiac perforation. Cardiac perforations due to PM and ICD leads are rare but serious complications. Clinical features vary widely and may cause diagnostic delay. Management strategies are non-guideline based due to paucity of data., Methods and Results: A multicentre retrospective series including 3 UK cardiac tertiary centres from 2016 to 2020. Patient, device, and lead characteristics were obtained including 6-month outcomes. Seventy cases of perforation were identified from 10 631 procedures; perforation rate was 0.50% for local implants. Thirty-nine (56%) patients were female, mean ( ± standard deviation) age 74 ( ± 13.8) years. Left ventricular ejection fraction 51 ( ± 13.2) %. Median time to diagnosis was 9 (range: 0-989) days. Computed tomography (CT) diagnosed perforation with 97% sensitivity. Lead parameter abnormalities were present in 86% (whole cohort) and 98.6% for perforations diagnosed >24 h. Chest pain was the commonest symptom, present in 46%. The management strategy was percutaneous in 98.6% with complete procedural success in 98.6%. Pericardial effusion with tamponade was present in 17% and was associated with significantly increased mortality and major complications. Anticoagulation status was associated with tamponade by multivariate analysis (odds ratio 21.7, 95% confidence interval: 1.7-275.5, P = 0.018)., Conclusions: Perforation was rare (0.50%) and managed successfully by a percutaneous strategy with good outcomes. Tamponade was associated with increased mortality and major complications. Anticoagulation status was an independent predictor of tamponade. Case complexity is highly variable and requires skilled operators with a multi-disciplinary approach to achieve good outcomes., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The risk factors for developing pacing induced left ventricular dysfunction (LVD) in patients with high burden of right ventricular pacing (RVP) is poorly understood. Therefore, in the present study, we aimed to assess the determinants of pacing induced LVD., Methods: Our data were retrospectively collected from 146 patients with RVP > 40% who underwent generator change (GC) or cardiac resynchronization therapy (CRT) upgrade between 2016 and 2019 who had left ventricular ejection fraction (EF) ≥50% at initial implant., Results: A total of 75 patients had CRT upgrade due to pacing induced LVD (EF < 50%) and 71 patients with preserved LV function (EF ≥ 50%) had a GC. Primary indication for pacing in both groups was complete heart block. Male predominance (p = .008), prior myocardial infarction (MI) (p = .001), atrial fibrillation (AF) (p = .009), chronic kidney disease (CKD) (p = .005), and borderline low systolic function (BLSF) (EF 50%-55%) (p = .04) were more prevalent in the CRT upgrade group. Presence of AF (odds ratio [OR] = 3.05, 95% confidence interval [CI] 1.42-6.58; p = .004), BLSF (OR = 3.8, 95% CI 1.22-11.8; p = .02), and male gender (OR = 2.41, 95% CI 1.14-5.08; p = .02) were independent predictors for RVP induced LVD. Age (OR = 1.08, 95% CI 1.02-1.14; p = .005) and BLSF (OR = 5.33, 95% CI 1.26-22.5; p = .023) were independent predictors of earlier development of LVD after implant., Conclusions: Our results suggested that AF, BLSF, and male gender are predictors for development of pacing induced LVD in patients with high RVP burden. LVD can occur at any time after pacemaker implant with BLSF and increasing age associated with earlier development of LVD., (© 2022 Wiley Periodicals LLC.)

Background: Permanent pacemaker (PPM) implantation is a common complication of transcatheter aortic valve implantation (TAVI). The optimum timing of PPM implantation is still unclear as conduction abnormalities evolve and a balance needs to be struck between conservative delays in the hope of conduction recovery and overutilization of pacing. This study aimed to assess the safety and efficacy of early PPM implantation, without an observation period, among TAVI patients., Methods: This is a retrospective, observational study of 1398 TAVI patients. Clinical and pacing data were collected at baseline, 30 days and at a median of 15 (4-21) months post-TAVI. Study endpoints included PPM-related complications, pacing utilization and hospital length of stay., Results: One hundred five patients (8.2%) required a PPM, of which 13 were implanted pre and 92 post-TAVI. Seventy-six percent required pacing for either second- or third-degree heart block. Time to implantation for post-TAVI PPM was 1 (0-3) day. Six patients experienced a pacing-related complication- lead displacement (n = 3), hematoma (n = 2), and device infection (n = 1). Pacing utilization defined as pacing >10% of the time or a pacing requirement at the time of the pacing check was demonstrated in 83% of patients. Multivariate analysis revealed complete heart block (CHB) was the only independent predictor of pacing utilization. Hospital length of stay for the post-TAVI PPM group was longer than the group without PPM (4 [2-8] vs. 3 [2-4] days; p < .001)., Conclusions: Early PPM implantation in TAVI patients is safe and majority of patients require pacing in the short and mid-term., (© 2021 Wiley Periodicals LLC.)

Despite advances in the field of cardiac resynchronisation therapy (CRT), response rates and durability of therapy remain relatively static. Optimising device timing intervals may be the most common modifiable factor influencing CRT efficacy after implantation. This review addresses the concept of fusion pacing as a method for improving patient outcomes with CRT. Fusion pacing describes the delivery of CRT pacing with a programming strategy to preserve intrinsic atrioventricular (AV) conduction and ventricular activation via the right bundle branch. Several methods have been assessed to achieve fusion pacing. QRS complex duration (QRSd) shortening with CRT is associated with improved clinical response. Dynamic algorithm-based optimisation targeting narrowest QRSd in patients with intact AV conduction has shown promise in people with heart failure with left bundle branch block. Individualised dynamic programming achieving fusion may achieve the greatest magnitude of electrical synchrony, measured by QRSd narrowing., Competing Interests: Disclosure: PL is a section editor and ER is on the Arrhythmia & Electrophysiology Review editorial board, which did not affect the peer-review process. All other authors have no conflicts of interest to declare., (Copyright © 2021, Radcliffe Cardiology.)

Background: His bundle pacing (HBP) is an alternative to biventricular pacing (BVP) for delivering cardiac resynchronization therapy (CRT) in patients with heart failure and left bundle branch block (LBBB). It is not known whether ventricular activation times and patterns achieved by HBP are equivalent to intact conduction systems and not all patients with LBBB are resynchronized by HBP., Objective: To compare activation times and patterns of His-CRT with BVP-CRT, LBBB and intact conduction systems., Methods: In patients with LBBB, noninvasive epicardial mapping (ECG imaging) was performed during BVP and temporary HBP. Intrinsic activation was mapped in all subjects. Left ventricular activation times (LVAT) were measured and epicardial propagation mapping (EPM) was performed, to visualize epicardial wavefronts. Normal activation pattern and a normal LVAT range were determined from normal subjects., Results: Forty-five patients were included, 24 with LBBB and LV impairment, and 21 with normal 12-lead ECG and LV function. In 87.5% of patients with LBBB, His-CRT successfully shortened LVAT by ≥10 ms. In 33.3%, His-CRT resulted in complete ventricular resynchronization, with activation times and patterns indistinguishable from normal subjects. EPM identified propagation discontinuity artifacts in 83% of patients with LBBB. This was the best predictor of whether successful resynchronization was achieved by HBP (logarithmic odds ratio, 2.19; 95% confidence interval, 0.07-4.31; p = .04)., Conclusion: Noninvasive electrocardiographic mapping appears to identify patients whose LBBB can be resynchronized by HBP. In contrast to BVP, His-CRT may deliver the maximum potential ventricular resynchronization, returning activation times, and patterns to those seen in normal hearts., (© 2020 The Authors. Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.)

Aims: Optimum timing of pacemaker implantation following cardiac surgery is a clinical challenge. European and American guidelines recommend observation, to assess recovery of atrioventricular block (AVB) (up to 7 days) and sinus node (5 days to weeks) after cardiac surgery. This study aims to determine rates of cardiac implantable electronic devices (CIEDs) implants post-surgery at a high-volume tertiary centre over 3 years. Implant timing, patient characteristics and outcomes at 6 months including pacemaker utilization were assessed., Methods and Results: All cardiac operations (n = 5950) were screened for CIED implantation following surgery, during the same admission, from 2015 to 2018. Data collection included patient, operative, and device characteristics; pacing utilization and complications at 6 months. A total of 250 (4.2%) implants occurred; 232 (3.9%) for bradycardia. Advanced age, infective endocarditis, left ventricle systolic impairment, and valve surgery were independent predictors for CIED implants (P < 0.0001). Relative risk (RR) of CIED implants and proportion of AVB increased with valve numbers operated (single-triple) vs. non-valve surgery: RR 5.4 (95% CI 3.9-7.6)-21.0 (11.4-38.9) CIEDs. Follow-up pacing utilization data were available in 91%. Significant utilization occurred in 82% and underutilization (<1% A and V paced) in 18%. There were no significant differences comparing utilization rates in early (≤day 5 post-operatively) vs. late implants (P = 0.55)., Conclusion: Multi-valve surgery has a particularly high incidence of CIED implants (14.9% double, 25.6% triple valve). Age, left ventricle systolic impairment, endocarditis, and valve surgery were independent predictors of CIED implants. Device underutilization was infrequent and uninfluenced by implant timing. Early implantation (≤5 days) should be considered in AVB post-multi-valve surgery., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

His-Purkinje conduction system pacing (HPCSP) in the form of His bundle pacing (HBP) and left bundle branch pacing (LBBP) allows normal left ventricular activation, thereby preventing the adverse consequences of right ventricular pacing. HBP has been established for several years with centers from China, Europe, and North America reporting their experience. There is international guidance as to how to implant such systems with the differing patterns of His bundle capture clearly described. LBBP is a more recent innovation with potential advantages including improved pacing parameters. HPCSP has been extensively studied in a variety of indications including cardiac resynchronization therapy, atrioventricular node ablation, and bradycardia pacing. This review will focus on the clinical outcomes of HPCSP including mortality and morbidity of heart failure hospitalization and symptoms., (© 2020 Wiley Periodicals LLC.)

Aims: There is an important need for better biomarkers to predict left ventricular (LV) remodelling in dilated cardiomyopathy (DCM). We undertook a comprehensive assessment of cardiac structure and myocardial composition to determine predictors of remodelling., Methods and Results: Prospective study of patients with recent-onset DCM with cardiovascular magnetic resonance (CMR) assessment of ventricular structure and function, extracellular volume (T1 mapping), myocardial strain, myocardial scar (late gadolinium enhancement) and contractile reserve (dobutamine stress). Regression analyses were used to evaluate predictors of change in LV ejection fraction (LVEF) over 12 months. We evaluated 56 participants (34 DCM patients, median LVEF 43%; 22 controls). Absolute LV contractile reserve predicted change in LVEF (1% increase associated with 0.4% increase in LVEF at 12 months, P = 0.02). Baseline myocardial strain (P = 0.39 global longitudinal strain), interstitial myocardial fibrosis (P = 0.41), replacement myocardial fibrosis (P = 0.25), and right ventricular contractile reserve (P = 0.17) were not associated with LV reverse remodelling. There was a poor correlation between contractile reserve and either LV extracellular volume fraction (r = -0.22, P = 0.23) or baseline LVEF (r = 0.07, P = 0.62). Men were more likely to experience adverse LV remodelling (P = 0.01) but age (P = 0.88) and disease-modifying heart failure medication (beta-blocker, P = 0.28; angiotensin-converting enzyme inhibitor, P = 0.92) did not predict follow-up LVEF., Conclusions: Substantial recovery of LV function occurs within 12 months in most patients with recent-onset DCM. Women had the greatest improvement in LVEF. A low LV contractile reserve measured by dobutamine stress CMR appears to identify patients whose LVEF is less likely to recover., (© 2020 European Society of Cardiology.)

His-Purkinje conduction system pacing (HPCSP) in the form of His bundle pacing and left bundle branch pacing allows normal ventricular activation, thereby preventing the adverse consequences of right ventricular pacing. One potential area where HPCSP could be used is in the field of atrioventricular (AV) node ablation in patients with atrial fibrillation refractory to medical therapy and/or catheter ablation. His bundle pacing has been established for several years, with centres from North America, Europe and China publishing their experience. The differing patterns of His bundle capture are clearly described with established guidance as to how to implant such systems. Left bundle branch pacing has only recently been reported, but there are several advantages with better pacing parameters and lower risk of threshold change after AV node ablation. Six studies have been identified in the literature which describe the experience of His bundle pacing in patients requiring AV node ablation. Overall the results are positive and favour this new technique; however, they are limited by low numbers of patients and non-randomised study design. An observational study was recently published demonstrating better outcomes with left bundle branch pacing in a small number of patients with left ventricular dysfunction and atrial fibrillation that underwent AV node ablation. HPCSP has the potential to be the primary pacing modality in patients with atrial fibrillation requiring AV node ablation. However, it is essential that this is confirmed in large randomised clinical trials.

Introduction: Use of non-vitamin K oral anticoagulants (NOACs) has rapidly increased worldwide. We aimed to systematically assess the available evidence regarding the safety and efficacy of NOACs in patients undergoing cardiac implantable electronic device (CIED) surgery., Methods: We performed a systematic literature search. Eligible randomised controlled trials and cohort studies were included. The primary outcome measures were clinically significant device-pocket haematoma and thromboembolic events., Results: A total of 12 studies were included, equating to 2120 patients. The separate pooling of rate of events showed a low incidence of clinically significant device-pocket haematoma, although numerically higher in patients on continued (1.5%; CI 95% 0.8-3.0) versus interrupted NOAC (0.9%; CI 95% 0.5-1.7). The rate of any device-pocket haematoma was numerically higher in the continued versus interrupted NOAC group (5.4%; CI 95% 3.8-7.7 versus 2.4%; CI 95% 1.8-3.3). The incidence of thromboembolic events (0.4%; CI 95% 0.2-0.8) was low and comparable. From a meta-analysis of 3 studies (equating to 773 subjects) allowing for a comparison of continued versus interrupted NOAC, we found no significant difference between the 2 strategies in terms of clinically significant pocket haematoma (RR1.14; CI 95% 0.43-3.06, p = 0.79), thromboembolic complications (RR1.03; CI 95% 0.06-16.37, p = 0.98), and any pocket haematoma (RR1.19; CI 95% 0.65-2.20, p = 0.57)., Conclusion: Use of NOACs at the time of CIEDs surgery appears to be safe, and either strategy of peri-procedure continuation or interruption might be reasonable. However, continuation of NOAC seems to be associated with a numerically higher rate of bleeding complications. Certainty of the evidence is low, and further studies are required to confirm these findings., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Here we present a rare clinical presentation of papillary muscle rupture in a 55-year-old man who presented to accident and emergency department with chest pain and was diagnosed as having had a non-ST elevation myocardial infarction. During the admission, he developed papillary muscle rupture due to the myocardial infarction resulting in acute mitral regurgitation. This caused significant haemodynamic compromise needing emergency admission to the intensive care unit and eventually surgery to replace the valve., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Almost a third of patients fulfilling current guidelines criteria have suboptimal responses following cardiac resynchronization therapy (CRT). Circulating biomarkers may help identify these patients. We aimed to assess the predictive role of full blood count (FBC) parameters in prognosis of heart failure (HF) patients undergoing CRT device implantation. We enrolled 612 consecutive CRT patients and FBC was measured within 24 hours prior to implantation. The follow-up period was a median of 1652 days (IQR: 837-2612). The study endpoints were i) composite of all-cause mortality or transplant, and ii) reverse left ventricular (LV) remodeling. On multivariate analysis [hazard ratio (HR), 95% confidence interval (CI)] only red cell count (RCC) (p = 0.004), red cell distribution width (RDW) (p < 0.001), percentage of lymphocytes (p = 0.03) and platelet count (p < 0.001) predicted all-cause mortality. Interestingly, RDW (p = 0.004) and platelet count (p = 0.008) were independent predictors of reverse LV remodeling. This is the first powered single-centre study to demonstrate that RDW and platelet count are independent predictors of long-term all-cause mortality and/or heart transplant in CRT patients. Further studies, on the role of these parameters in enhancing patient selection for CRT implantation should be conducted to confirm our findings.

Objectives: This study sought to assess immediate and short-term performance of the Medtronic Attain Stability Quadripolar 4798 lead (Medtronic, Dublin, Ireland)., Background: Cardiac resynchronization therapy (CRT) is an established treatment for appropriately selected patients with left ventricular (LV) systolic dysfunction. The most common reason for failure to implant a lead is the lack of a suitable epicardial vein, due either to an absent vessel in the target site, an unacceptably high threshold, lead instability, phrenic nerve stimulation, or a combination of reasons. In August 2017, a novel quadripolar active fixation LV lead (Medtronic) was released. This paper reports the initial clinical experience with lead implantation and specifically immediate and short-term pacing parameters across 3 United Kingdom centers., Methods: Consecutive patients eligible for CRT were deemed suitable for this lead. Immediate and short-term lead performance data regarding LV threshold, impedance, and displacement rates were collected at standard pacing checks (1 day, 5 weeks, 3 months, and 9 months post-implantation)., Results: CRT using this lead was attempted in 82 cases and was successful in 81 cases (98.8%). LV thresholds and impedance levels were 1.22 ± 0.75 V and 737 ± 319 Ω at implantation; 1.16 ± 0.71 V and 597 ± 218 Ω at day 1; 1.02 ± 0.48 V and 579 ± 148 Ω at week 6; 0.98 ± 0.49 V and 569 ± 133 Ω at 3 months; and 1.06 ± 0.48 V and 570 ± 140 Ω at 9 months. As of the publication of this paper, no LV lead has been displaced., Conclusions: CRT using the Medtronic lead was successful in more than 98% of the patients. Short-to-medium-term data regarding lead performance and stability were excellent, with zero displacements as of the publication of this paper., (Copyright © 2019 American College of Cardiology Foundation. All rights reserved.)

Background: Heart failure with preserved ejection fraction (HFpEF) is an emerging global health problem of which there is limited awareness. HFpEF has a prognosis similar to that of heart failure with reduced ejection fraction (HFrEF) and accounts for approximately half of all patients with heart failure., Objective: The aim of this article is to review HFpEF and its consequences and management, including examples of patients with HFpEF., Discussion: Patients with HFpEF may present with dyspnoea, fluid retention, lethargy and dizziness, making it difficult to differentiate clinically from HFrEF. The risk factors include increasing age, obesity, hypertension, diabetes, chronic kidney disease and obstructive sleep apnoea. The diagnosis requires good clinical acumen combined with echocardiography and elevated plasma B-type natriuretic peptide concentration. Management of HFpEF, especially in later stages, is difficult as there is no evidence-based therapy to date. Prevention is the best strategy. Early recognition and diagnosis are also very important to tackle this global epidemic.

An 85-year-old male was admitted to our center with a non-ST elevation myocardial infarction. The patient had a dual-chamber pacemaker in situ with an atrial and His lead. A transient increase in His threshold and loss of nonselective capture occurred at the presentation of right coronary artery infarction, peaking during rotational atherectomy therapy causing loss of capture and complete atrioventricular block. A follow-up interrogation, 2 weeks postrevascularization, showed a return to a normal nonselective capture morphology and threshold measurements. Physicians should be aware of this complication in patients with His leads, particularly those with a history of coronary artery disease., (© 2019 Wiley Periodicals, Inc.)

Background: His bundle pacing is a new method for delivering cardiac resynchronization therapy (CRT)., Objectives: The authors performed a head-to-head, high-precision, acute crossover comparison between His bundle pacing and conventional biventricular CRT, measuring effects on ventricular activation and acute hemodynamic function., Methods: Patients with heart failure and left bundle branch block referred for conventional biventricular CRT were recruited. Using noninvasive epicardial electrocardiographic imaging, the authors identified patients in whom His bundle pacing shortened left ventricular activation time. In these patients, the authors compared the hemodynamic effects of His bundle pacing against biventricular pacing using a high-multiple repeated alternation protocol to minimize the effect of noise, as well as comparing effects on ventricular activation., Results: In 18 of 23 patients, left ventricular activation time was significantly shortened by His bundle pacing. Seventeen patients had a complete electromechanical dataset. In them, His bundle pacing was more effective at delivering ventricular resynchronization than biventricular pacing: greater reduction in QRS duration (-18.6 ms; 95% confidence interval [CI]: -31.6 to -5.7 ms; p = 0.007), left ventricular activation time (-26 ms; 95% CI: -41 to -21 ms; p = 0.002), and left ventricular dyssynchrony index (-11.2 ms; 95% CI: -16.8 to -5.6 ms; p < 0.001). His bundle pacing also produced a greater acute hemodynamic response (4.6 mm Hg; 95% CI: 0.2 to 9.1 mm Hg; p = 0.04). The incremental activation time reduction with His bundle pacing over biventricular pacing correlated with the incremental hemodynamic improvement with His bundle pacing over biventricular pacing (R = 0.70; p = 0.04)., Conclusions: His resynchronization delivers better ventricular resynchronization, and greater improvement in hemodynamic parameters, than biventricular pacing., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: In patients with heart failure and a pathologically prolonged PR interval, left ventricular (LV) filling can be improved by shortening atrioventricular delay using His-bundle pacing. His-bundle pacing delivers physiological ventricular activation and has been shown to improve acute haemodynamic function in this group of patients. In the HOPE-HF (His Optimized Pacing Evaluated for Heart Failure) trial, we are investigating whether these acute haemodynamic improvements translate into improvements in exercise capacity and heart failure symptoms., Methods and Results: This multicentre, double-blind, randomized, crossover study aims to randomize 160 patients with PR prolongation (≥200 ms), LV impairment (EF ≤ 40%), and either narrow QRS (≤140 ms) or right bundle branch block. All patients receive a cardiac device with leads positioned in the right atrium and the His bundle. Eligible patients also receive a defibrillator lead. Those not eligible for implantable cardioverter defibrillator have a backup pacing lead positioned in an LV branch of the coronary sinus. Patients are allocated in random order to 6 months of (i) haemodynamically optimized dual chamber His-bundle pacing and (ii) backup pacing only, using the non-His ventricular lead. The primary endpoint is change in exercise capacity assessed by peak oxygen uptake. Secondary endpoints include change in ejection fraction, quality of life scores, B-type natriuretic peptide, daily patient activity levels, and safety and feasibility assessments of His-bundle pacing., Conclusions: Hope-HF aims to determine whether correcting PR prolongation in patients with heart failure and narrow QRS or right bundle branch block using haemodynamically optimized dual chamber His-bundle pacing improves exercise capacity and symptoms. We aim to complete recruitment by the end of 2018 and report in 2020., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Heart Failure (HF) is a common disorder associated with substantial morbidity and mortality. beta adrenergic receptors (betaAR) are the primary pathway through which cardiac function is influenced. Chronic beta(1)AR activation is implicated in the pathogenesis of HF and betaAR blockade improves survival in left ventricular systolic dysfunction. Common functional polymorphisms in beta adrenergic receptor genes (ADRB) have been associated with HF phenotypes, and with pharmacogenetic interaction with beta adrenergic receptor blockers (beta blockers). However, these associations have not been consistently replicated. The evidence for ADRB variant involvement in pathogenesis, progression and response to beta blockers in HF is reviewed. In addition, a meta-analysis of three studies analysing the effect of ADRB1 Arg389Gly polymorphism on left ventricular remodelling with the use of beta blockers, demonstrating a 5% improvement in left ventricular ejection fraction in Arg389 homozygotes, is presented. There is now accumulating molecular evidence for a different functional response to beta blockers associated with this polymorphism. In the future, confirmed genotypic associations may enable patients to be identified who are either at greater risk of developing HF, whose HF may rapidly progress, or who are unlikely to benefit from beta blockers, and such patients may benefit from targeted aggressive therapy.

There is strong evidence for the presence of a functional renin-angiotensin system in diabetogenic tissues, and ACE (angiotensin-converting enzyme) inhibitors may improve glucose metabolism in those individuals at high risk of developing T2DM (Type 2 diabetes). In the present study, we tested the hypothesis that subjects with genetically lower plasma and tissue ACE activity, because of their ACE [I/D (insertion/deletion)] genotype, would have a lower risk of T2DM in 2642 healthy middle-aged Caucasian men (mean age, 56 years) followed-up for 15 years. Obesity was the strongest predictor of T2DM, with an HR (95% CI) [hazard ratio (95% confidence interval)] of 3.74 (2.66-5.26) (P<0.0001). Overall there was no association between ACE genotype (II homozygotes, n=623; and D allele carriers, n=2019) and risk of T2DM, and although in lean men there was no genotype difference in risk in D allele carriers compared with II homozygotes [adjusted HR=0.75 (95% CI, 0.46-1.22)], in obese (body mass index >30 kg/m(2)) men the risk of T2DM was higher [adjusted HR=4.26 (95% CI, 1.30-13.93)] with a genotype-obesity interaction of P=0.01. A similar pattern of risk was seen by re-analysis of a previously published case-control study, where D allele carriers had a non-significant 1.30 (0.97-1.74)-fold higher risk of developing T2DM than II homozygotes when non-obese, but a 1.79 (1.17-2.72) (P=0.007)-fold higher risk when obese. Further prospective studies are needed to confirm these findings. The ACE D allele may worsen glucose metabolism, which could raise the prospective T2DM risk in obese men, but not in lean men. In obesity, adipose tissue undergoes inflammatory infiltration and the subsequent higher levels of pro-inflammatory angiotensin II may explain this association.

The impact of the ACE I/D polymorphism on coronary heart disease (CHD) risk is modest at most, however it may act as a modifier gene. ACE genotype was determined in 2711 healthy middle-aged men (mean age 56 years) followed for 15 years. No genotype-CHD risk association was found, but when analyzed by quartiles of systolic blood pressure (SBP), compared with II homozygotes, carriage of each additional D allele was protective at lower SBP, but in the highest quartile (SBP >150 mm Hg) conferred almost 1.5 times the risk for CHD (genotype interaction P=0.003). When SBP was analyzed as a continuous variable, again a highly significant association was seen, with the hazard ratio ([95% CI]) for a 1 SD increase in SBP being 0.90 [0.70 to 1.15] for IIs and 1.40 [1.21 to 1.61] for ID/DD (genotype SBP interaction P=0.002). The D allele was protective against CHD at lower SBP but would overtake the II risk at higher SBP. In hypertension, the proinflammatory or prohypertrophic properties of angiotensin II may explain this association. The LPL S447X polymorphism also impacts on CHD risk through interaction with hypertension, and there was an additive action of these 2 polymorphisms and SBP on CHD risk (hazard ratio for 1 SD increase in SBP for combined genotypes 1.78 [1.30 to 2.45]). Thus in the presence of hypertension, common variation in "modifier" genes confers significant CHD risk.