Effects of haemodynamically atrio-ventricular optimized His-pacing on heart failure symptoms and exercise capacity: The His Optimized Pacing Evaluated for Heart Failure (HOPE-HF) randomised, double-blind, cross-over trial

Aims: Excessive prolongation of PR interval impairs coupling of 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 double-blind cross-over fashion, in patients with heart failure, left ventricular ejection fraction (LVEF) ≤40%, PR interval ≥200ms and either QRS ≤140ms or right BBB. Methods and results: Patients had atrial and His-bundle leads implanted (and an ICD 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. 167 patients were randomized: 90% men, 69±10 years, QRS duration 124±26ms, PR interval 249±59ms, LVEF 33±9%. Neither peak VO2 (+0.25 ml/min/kg, 95% 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). 76% of patients preferred His-bundle pacing-on and 24% pacing-off (p 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

Left ventricular scar and the acute hemodynamic effects of multivein and multipolar pacing in cardiac resynchronization

Background We sought to determine whether presence, amount and distribution of scar impacts the degree of acute hemodynamic response (AHR) with multisite pacing. Multi-vein pacing (MVP) or multipolar pacing (MPP) with a multi-electrode left ventricular (LV) lead may offer benefits over conventional biventricular pacing in patients with myocardial scar. Methods In this multi-center study left bundle branch block patients underwent an hemodynamic pacing study measuring LV dP/dtmax. Patients had cardiac magnetic resonance scar imaging to assess the effect of scar presence, amount and distribution on AHR. Results 24 patients (QRS 171 ± 20 ms) completed the study (83% male). An ischemic etiology was present in 58% and the mean scar volume was 6.0 ± 7.0%. Overall discounting scar, MPP and MVP showed no significant AHR increase compared to an optimized “best BiV” (BestBiV) site. In a minority of patients (6/24) receiver-operator characteristic analysis of scar volume (cut off 8.48%) predicted a small AHR improvement with MPP (sensitivity 83%, specificity 94%) but not MVP. Patients with scar volume > 8.48% had a MPP-BestBiV of 3 ± 6.3% vs. −6.4 ± 7.7% for those below the cutoff. There was a significant correlation between the difference in AHR and scar volume for MPP-BestBiV (R = 0.49, p = 0.02) but not MVP-BestBiV(R = 0.111, p = 0.62). The multielectrode lead positioned in scar predicted MPP AHR improvement (p = 0.04). Conclusions Multisite pacing with MPP and MVP shows no AHR benefit in all-comers compared to optimized BestBiV pacing. There was a minority of patients with significant scar volume in relation to the LV site that exhibited a small AHR improvement with MPP

Catheter ablation improves cardiovascular outcomes in patients with atrial fibrillation and heart failure: a meta-analysis of randomized controlled trials.

AIMS: The effect of atrial fibrillation catheter ablation on cardiovascular outcomes in heart failure is an important outstanding research question. We undertook a meta-analysis of randomized controlled trials comparing ablation to medical therapy in patients with AF and heart failure. METHODS AND RESULTS: We systematically identified all trials comparing catheter ablation to medical therapy in patients with heart failure and atrial fibrillation. The pre-specified primary endpoint was all-cause mortality in trials with at least 2 years of follow-up. The secondary endpoint was heart failure hospitalization. Sensitivity analyses were performed for trials with any follow-up and trials deemed at low risk of bias. Eight trials (1390 patients) were included. Seven hundred and seven patients were randomized to catheter ablation and 683 to medical therapy. In the primary analysis (three trials, n = 977), catheter ablation reduced mortality compared with medical therapy [relative risk (RR): 0.61, 95% confidence interval (CI): 0.44 to 0.84, P = 0.003]. Catheter ablation also reduced heart failure hospitalizations compared with medical therapy (RR: 0.60, 95% CI: 0.49-0.74, P < 0.001). The effect on stroke was not statistically significant (RR: 0.62, 95% CI: 0.28-1.37, P = 0.237). There was low heterogeneity between studies. Sensitivity analyses were consistent with the primary analyses. CONCLUSION: In patients with atrial fibrillation and heart failure, catheter ablation reduces mortality and the occurrence of heart failure hospitalizations

British randomised controlled trial of AV and VV optimization ("BRAVO") study:rationale, design, and endpoints

Background Echocardiographic optimization of pacemaker settings is the current standard of care for patients treated with cardiac resynchronization therapy. However, the process requires considerable time of expert staff. The BRAVO study is a non-inferiority trial comparing echocardiographic optimization of atrioventricular (AV) and interventricular (VV) delay with an alternative method using non-invasive blood pressure monitoring that can be automated to consume less staff resources. Methods/Design BRAVO is a multi-centre, randomized, cross-over, non-inferiority trial of 400 patients with a previously implanted cardiac resynchronization device. Patients are randomly allocated to six months in each arm. In the echocardiographic arm, AV delay is optimized using the iterative method and VV delay by maximizing LVOT VTI. In the haemodynamic arm AV and VV delay are optimized using non-invasive blood pressure measured using finger photoplethysmography. At the end of each six month arm, patients undergo the primary outcome measure of objective exercise capacity, quantified as peak oxygen uptake (VO2) on a cardiopulmonary exercise test. Secondary outcome measures are echocardiographic measurement of left ventricular remodelling, quality of life score and N-terminal pro B-type Natriuretic Peptide (NT-pro BNP). The study is scheduled to complete recruitment in December 2013 and to complete follow up in December 2014. Discussion If exercise capacity is non-inferior with haemodynamic optimization compared with echocardiographic optimization, it would be proof of concept that haemodynamic optimization is an acceptable alternative which has the potential to be more easily implemented

A systematic approach to designing reliable VV optimization methodology: Assessment of internal validity of echocardiographic, electrocardiographic and haemodynamic optimization of cardiac resynchronization therapy

AbstractBackgroundIn atrial fibrillation (AF), VV optimization of biventricular pacemakers can be examined in isolation. We used this approach to evaluate internal validity of three VV optimization methods by three criteria.Methods and resultsTwenty patients (16 men, age 75±7) in AF were optimized, at two paced heart rates, by LVOT VTI (flow), non-invasive arterial pressure, and ECG (minimizing QRS duration). Each optimization method was evaluated for: singularity (unique peak of function), reproducibility of optimum, and biological plausibility of the distribution of optima.The reproducibility (standard deviation of the difference, SDD) of the optimal VV delay was 10ms for pressure, versus 8ms (p=ns) for QRS and 34ms (p<0.01) for flow.Singularity of optimum was 85% for pressure, 63% for ECG and 45% for flow (Chi2=10.9, p<0.005).The distribution of pressure optima was biologically plausible, with 80% LV pre-excited (p=0.007). The distributions of ECG (55% LV pre-excitation) and flow (45% LV pre-excitation) optima were no different to random (p=ns).The pressure-derived optimal VV delay is unaffected by the paced rate: SDD between slow and fast heart rate is 9ms, no different from the reproducibility SDD at both heart rates.ConclusionsUsing non-invasive arterial pressure, VV delay optimization by parabolic fitting is achievable with good precision, satisfying all 3 criteria of internal validity. VV optimum is unaffected by heart rate. Neither QRS minimization nor LVOT VTI satisfy all validity criteria, and therefore seem weaker candidate modalities for VV optimization. AF, unlinking interventricular from atrioventricular delay, uniquely exposes resynchronization concepts to experimental scrutiny

Cardiac resynchronization therapy: mechanisms of action and scope for further improvement in cardiac function.

Aims: Cardiac resynchronization therapy (CRT) may exert its beneficial haemodynamic effect by improving ventricular synchrony and improving atrioventricular (AV) timing. The aim of this study was to establish the relative importance of the mechanisms through which CRT improves cardiac function and explore the potential for additional improvements with improved ventricular resynchronization. Methods and Results: We performed simulations using the CircAdapt haemodynamic model and performed haemodynamic measurements while adjusting AV delay, at low and high heart rates, in 87 patients with CRT devices. We assessed QRS duration, presence of fusion, and haemodynamic response. The simulations suggest that intrinsic PR interval and the magnitude of reduction in ventricular activation determine the relative importance of the mechanisms of benefit. For example, if PR interval is 201 ms and LV activation time is reduced by 25 ms (typical for current CRT methods), then AV delay optimization is responsible for 69% of overall improvement. Reducing LV activation time by an additional 25 ms produced an additional 2.6 mmHg increase in blood pressure (30% of effect size observed with current CRT). In the clinical population, ventricular fusion significantly shortened QRS duration (Δ-27 ± 23 ms, P < 0.001) and improved systolic blood pressure (mean 2.5 mmHg increase). Ventricular fusion was present in 69% of patients, yet in 40% of patients with fusion, shortening AV delay (to a delay where fusion was not present) produced the optimal haemodynamic response. Conclusions: Improving LV preloading by shortening AV delay is an important mechanism through which cardiac function is improved with CRT. There is substantial scope for further improvement if methods for delivering more efficient ventricular resynchronization can be developed. Clinical Trial Registration: Our clinical data were obtained from a subpopulation of the British Randomised Controlled Trial of AV and VV Optimisation (BRAVO), which is a registered clinical trial with unique identifier: NCT01258829, https://clinicaltrials.gov

Catheter Ablation for Ventricular Tachycardia After MI: A Reconstructed Individual Patient Data Meta-analysis of Randomised Controlled Trials.

BACKGROUND: The prognostic impact of ventricular tachycardia (VT) catheter ablation is an important outstanding research question. We undertook a reconstructed individual patient data meta-analysis of randomised controlled trials comparing ablation to medical therapy in patients developing VT after MI. METHODS: We systematically identified all trials comparing catheter ablation to medical therapy in patients with VT and prior MI. The prespecified primary endpoint was reconstructed individual patient assessment of all-cause mortality. Prespecified secondary endpoints included trial-level assessment of all-cause mortality, VT recurrence or defibrillator shocks and all-cause hospitalisations. Prespecified subgroup analysis was performed for ablation approaches involving only substrate modification without VT activation mapping. Sensitivity analyses were performed depending on the proportion of patients with prior MI included. RESULTS: Eight trials, recruiting a total of 874 patients, were included. Of these 874 patients, 430 were randomised to catheter ablation and 444 were randomised to medical therapy. Catheter ablation reduced all-cause mortality compared with medical therapy when synthesising individual patient data (HR 0.63; 95% CI [0.41-0.96]; p=0.03), but not in trial-level analysis (RR 0.91; 95% CI [0.67-1.23]; p=0.53; I2=0%). Catheter ablation significantly reduced VT recurrence, defibrillator shocks and hospitalisations compared with medical therapy. Sensitivity analyses were consistent with the primary analyses. CONCLUSION: In patients with postinfarct VT, catheter ablation reduces mortality

Rationale and study design of the MINERVA study: Multicentre Investigation of Novel Electrocardiogram Risk markers in Ventricular Arrhythmia prediction-UK multicentre collaboration

Introduction The purpose of this study is to assess the ability of two new ECG markers (Regional Repolarisation Instability Index (R2I2) and Peak Electrical Restitution Slope) to predict sudden cardiac death (SCD) or ventricular arrhythmia (VA) events in patients with ischaemic cardiomyopathy undergoing implantation of an implantable cardioverter defibrillator for primary prevention indication. Methods and analysis Multicentre Investigation of Novel Electrocardiogram Risk markers in Ventricular Arrhythmia prediction is a prospective, open label, single blinded, multicentre observational study to establish the efficacy of two ECG biomarkers in predicting VA risk. 440 participants with ischaemic cardiomyopathy undergoing routine first time implantable cardioverter-defibrillator (ICD) implantation for primary prevention indication are currently being recruited. An electrophysiological (EP) study is performed using a non-invasive programmed electrical stimulation protocol via the implanted device. All participants will undergo the EP study hence no randomisation is required. Participants will be followed up over a minimum of 18 months and up to 3 years. The first patient was recruited in August 2016 and the study will be completed at the final participant follow-up visit. The primary endpoint is ventricular fibrillation or sustained ventricular tachycardia >200 beats/min as recorded by the ICD. The secondary endpoint is SCD. Analysis of the ECG data obtained during the EP study will be performed by the core lab where blinding of patient health status and endpoints will be maintained. Ethics and dissemination Ethical approval has been granted by Research Ethics Committees Northern Ireland (reference no. 16/NI/0069). The results will inform the design of a definitive Randomised Controlled Trial (RCT). Dissemination will include peer reviewed journal articles reporting the qualitative and quantitative results, as well as presentations at conferences and lay summaries

Rationale and design of the randomized multicentre His Optimized Pacing Evaluated for Heart Failure (HOPE-HF) trial:HOPE HF Trial rationale and design

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