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

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.

Ablation versus anti-arrhythmic therapy for reducing all hospital episodes from recurrent atrial fibrillation: a prospective, randomized, multi-centre, open label trial.

AIMS: There is rising healthcare utilization related to the increasing incidence and prevalence of atrial fibrillation (AF) worldwide. Simplifying therapy and reducing hospital episodes would be a valuable development. The efficacy of a streamlined AF ablation approach was compared to drug therapy and a conventional catheter ablation technique for symptom control in paroxysmal AF. METHODS AND RESULTS: We recruited 321 patients with symptomatic paroxysmal AF to a prospective randomized, multi-centre, open label trial at 13 UK hospitals. Patients were randomized 1:1:1 to cryo-balloon ablation without electrical mapping with patients discharged same day [Ablation Versus Anti-arrhythmic Therapy for Reducing All Hospital Episodes from Recurrent (AVATAR) protocol]; optimization of drug therapy; or cryo-balloon ablation with confirmation of pulmonary vein isolation and overnight hospitalization. The primary endpoint was time to any hospital episode related to treatment for atrial arrhythmia. Secondary endpoints included complications of treatment and quality-of-life measures. The hazard ratio (HR) for a primary endpoint event occurring when comparing AVATAR protocol arm to drug therapy was 0.156 (95% CI, 0.097-0.250; P < 0.0001 by Cox regression). Twenty-three patients (21%) recorded an endpoint event in the AVATAR arm compared to 76 patients (74%) within the drug therapy arm. Comparing AVATAR and conventional ablation arms resulted in a non-significant HR of 1.173 (95% CI, 0.639-2.154; P = 0.61 by Cox regression) with 23 patients (21%) and 19 patients (18%), respectively, recording primary endpoint events (P = 0.61 by log-rank test). CONCLUSION: The AVATAR protocol was superior to drug therapy for avoiding hospital episodes related to AF treatment, but conventional cryoablation was not superior to the AVATAR protocol. This could have wide-ranging implications on how demand for AF symptom control is met. TRIAL REGISTRATION: Clinical Trials Registration: NCT02459574.

Atrial flutter and fibrillation in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension in the ASPIRE registry: Comparison of rate versus rhythm control approaches.

BACKGROUND: The development of atrial flutter and fibrillation (AFL/AF) in patients with pre-capillary pulmonary hypertension has been associated with an increased risk of morbidity and mortality. Rate and rhythm control strategies have not been directly compared. METHODS: Eighty-four patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) with new-onset AFL/AF were identified in the ASPIRE registry. First, baseline characteristics and rates of sinus rhythm (SR) restoration of 3 arrhythmia management strategies (rate control, medical rhythm control and DC cardioversion, DCCV) in an early (2009-13) and later (2014-19) cohort were compared. Longer-term outcomes in patients who achieved SR versus those who did not were then explored. RESULTS: Sixty (71%) patients had AFL and 24 (29%) AF. Eighteen (22%) patients underwent rate control, 22 (26%) medical rhythm control and 44 (52%) DCCV. SR was restored in 33% treated by rate control, 59% medical rhythm control and 95% DCCV (p < 0.001). Restoration of SR was associated with greater improvement in functional class (FC) and Incremental Shuttle Walk Distance (p both <0.05). It also independently predicted superior survival (3-year survival 62% vs 23% in those remaining in AFL/AF, p < 0.0001). In addition, FC III/IV independently predicted higher mortality (HR 2.86, p = 0.007). Right atrial area independently predicted AFL/AF recurrence (OR 1.08, p = 0.01). DCCV was generally well tolerated with no immediate major complications. CONCLUSIONS: Restoration of SR is associated with superior functional improvement and survival in PAH/CTEPH compared with rate control. DCCV is generally safe and is more effective than medical therapy at achieving SR.

Feasibility and validation of trans-valvular flow derived by four-dimensional flow cardiovascular magnetic resonance imaging in patients with atrial fibrillation.

Background: Four-dimensional (4D) flow cardiovascular magnetic resonance imaging (MRI) is an emerging technique used for intra-cardiac blood flow assessment. The role of 4D flow cardiovascular MRI in the assessment of trans-valvular flow in patients with atrial fibrillation (AF) has not previously been assessed. The purpose of this study was to assess the feasibility, image quality, and internal validity of 4D flow cardiovascular MRI in the quantification of trans-valvular flow in patients with AF. Methods: Patients with AF and healthy controls in sinus rhythm underwent cardiovascular MRI, including 4D flow studies. Quality assurance checks were done on the raw data and streamlines. Consistency was investigated by trans-valvular flow assessment between the mitral valve (MV) and the aortic valve (AV). Results: Eight patients with AF (88% male, mean age 62±13 years, mean heart rate (HR) 83±16 beats per minute (bpm)) were included and compared with ten healthy controls (70% male, mean age 41±20 years, mean HR 68.5±9 bpm). All scans were of either good quality with minimal blurring artefacts, or excellent quality with no artefacts. No significant bias was observed between the AV and MV stroke volumes in either healthy controls (-4.8, 95% CI -15.64 to 6.04; P=0.34) or in patients with AF (1.64, 95% CI -4.7 to 7.94; P=0.56). A significant correlation was demonstrated between MV and AV stroke volumes in both healthy controls (r=0.87, 95% CI 0.52 to 0.97; P=0.001) and in AF patients (r=0.82, 95% CI 0.26 to 0.97; P=0.01). Conclusions: In patients with AF, 4D flow cardiovascular MRI is feasible with good image quality, allowing for quantification of trans-valvular flow.

Radiofrequency ablation of ventricular tachycardia in Anderson-Fabry disease: a case series.

BACKGROUND: Cardiac involvement in Anderson-Fabry disease (AFD) can lead to arrhythmia, including ventricular tachycardia (VT). The literature on radiofrequency ablation (RFA) for the treatment of VT in AFD disease is limited. CASE SUMMARY: We discuss RFA of drug-refractory VT electrical storm in three males with AFD. The first patient (53 years old) had extensive involvement of the inferolateral left ventricle (LV) demonstrated with cardiac magnetic resonance imaging (CMRI), with a left ventricular ejection fraction (LVEF) of 35%. Two VT ablation procedures were performed. At the first procedure, the inferobasal endocardial LV was ablated. Furthermore, VT prompted a second ablation, where epicardial and endocardial sites were ablated. The acute arrhythmia burden was controlled but he died 4 months later despite appropriate implantable cardioverter-defibrillator therapies for VT. The second patient (67 years old) had full-thickness inferolateral involvement demonstrated with CMRI and LVEF of 45%. RFA of several endocardial left ventricular sites was performed. Over a 3-year follow-up, only brief non-sustained VT was identified, but he subsequently died of cardiac failure. Our third patient (69 years old), had an LVEF of 35%. He had RFA of endocardial left ventricular apical disease, but died 3 weeks later of cardiac failure. DISCUSSION: RFA of drug-refractory VT in AFD is feasible using standard electrophysiological mapping and ablation techniques, although the added clinical benefit is of questionable value. VT storm in the context of AFD may be a marker of end-stage disease.

Meta-analysis of echocardiographic quantification of left ventricular filling pressure.

AIMS: The clinical reliability of echocardiographic surrogate markers of left ventricular filling pressures (LVFPs) across different cardiovascular pathologies remains unanswered. The main objective was to evaluate the evidence of how effectively different echocardiographic indices estimate true LVFP. METHODS AND RESULTS: Design: this is a systematic review and meta-analysis. DATA SOURCE: Scopus, PubMed and Embase. Eligibility criteria for selecting studies were those that used echocardiography to predict or estimate pulmonary capillary wedge pressure or left ventricular end-diastolic pressures. Twenty-seven studies met criteria. Only eight studies (30%) reported both correlation coefficient and bias between non-invasive and invasively measured LVFPs. The majority of studies (74%) recorded invasive pulmonary capillary wedge pressure as a surrogate for left ventricular end-diastolic pressures. The pooled correlation coefficient overall was r = 0.69 [95% confidence interval (CI) 0.63-0.75, P < 0.01]. Evaluation by cohort demonstrated varying association: heart failure with preserved ejection fraction (11 studies, n = 575, r = 0.59, 95% CI 0.53-0.64) and heart failure with reduced ejection fraction (8 studies, n = 381, r = 0.67, 95% CI 0.61-0.72). CONCLUSIONS: Echocardiographic indices show moderate pooled association to invasively measured LVFP; however, this varies widely with disease state. In heart failure with preserved ejection fraction, no single echocardiography-based metric offers a reliable estimate. In heart failure with reduced ejection fraction, mitral inflow-derived indices (E/e', E/A, E/Vp, and EDcT) have reasonable clinical applicability. While an integrated approach of several echocardiographic metrics provides the most promise for estimating LVFP reliably, such strategies need further validation in larger, patient-specific studies.

Evaluation of subcutaneous implantable cardioverter-defibrillator performance in patients with ion channelopathies from the EFFORTLESS cohort and comparison with a meta-analysis of transvenous ICD outcomes.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is an alternative to conventional transvenous ICD (TV-ICD) therapy to reduce lead complications. OBJECTIVE: To evaluate outcomes in channelopathy vs patients with structural heart disease in the EFFORTLESS-SICD Registry and with a previously reported TV-ICD meta-analysis in channnelopathies. METHODS: The EFFORTLESS registry includes 199 patients with channelopathies (Brugada syndrome 83, long QT syndrome 24, idiopathic ventricular fibrillation 78, others 14) and 786 patients with structural heart disease. RESULTS: Channelopathy patients were younger (39 ± 14 years vs 51 ± 17 years; P < .001) with left ventricular ejection fraction 59% ± 9% vs 41% ± 18% (P < .001). The complication rate (follow-up: 3.2 ± 1.5 years vs 3.0 ± 1.5 years) was similar: 13.6% vs 11.2% (P = .42). Appropriate shocks rates were 9.5% vs 10.8% (P = .70), with shocks for monomorphic ventricular tachycardia being 2.0% vs 6.9% (P < .02) and for polymorphic ventricular tachycardia/ventricular fibrillation (VT/VF) 8.0% vs 5.7% (P = .30). Conversion effectiveness of VT/VF episodes was similar: 36 of 37 (97.3%) vs 151 of 155 (97.4%, P = .59). VT/VF storm event (2% vs 0.9%, P = .33) and lower inappropriate shock (IAS) (8.5% vs 12.5%, P = .12) rates were statistically similar between channelopathy and non-channelopathy patients, with 45.5% channelopathy vs 31.4% non-channelopathy patients managed with a conditional zone > 200 beats per minute (P = .0002). Annualized appropriate shock, IAS, and complication rates appear to be lower for the S-ICD vs meta-analysis TV-ICD patients, particularly lead complications. CONCLUSION: EFFORTLESS demonstrates similar S-ICD efficacy and a nonsignificant, lower rate of IAS in channelopathy patients as compared to structural heart disease. Comparable IAS rates were achieved with the device programmed to higher rates for channelopathy patients.

An exercise-based cardiac rehabilitation programme for AF patients in the NHS: a feasibility study.

There is increasing evidence for the role of exercise-based cardiac rehabilitation in the management of patients with atrial fibrillation (AF). However, this intervention has not yet been widely adopted within the National Health Service (NHS). We performed a feasibility study on the utilisation of an established NHS cardiac rehabilitation programme in the management of AF, and examined the effects of this intervention on exercise capacity, weight, and psychological health. We then identified factors that might prevent patients from enrolling on our programme. Patients with symptomatic AF were invited to participate in an established six-week exercise-based cardiac rehabilitation programme, composed of physical activity and education sessions. At the start of the programme, patients were weighed and measured, performed the six-minute walk test (6MWT), completed the Generalised Anxiety Disorder Questionnaire (GAD-7), and the Patient Health Questionnaire (PHQ-9). Measurements were repeated on completion of the programme. Over two years, 77 patients were invited to join the programme. Twenty-two patients (28.5%) declined participation prior to initial assessment and 22 (28.5%) accepted and attended the initial assessment, but subsequently withdrew from the programme. In total, 33 patients completed the entire programme (63.9 ± 1.7 years, 58% female). On completion, patients covered longer distances during the 6MWT, had lower GAD-7 scores, and lower PHQ-9 scores, compared with their baseline results. Compared with patients that completed the entire programme, those who withdrew from the study had, at baseline, a significantly higher body mass index (BMI), covered a shorter distance during the 6MWT, and had higher PHQ-9 and GAD-7 scores. In conclusion, enrolling patients with AF into an NHS cardiac rehabilitation programme is feasible, with nearly half of those invited completing the programme. In this feasibility study, cardiac rehabilitation resulted in an improved 6MWT, and reduced anxiety and depression levels, in the short term. Severe obesity, higher anxiety and depression levels, and lower initial exercise capacity appear to be barriers to completing exercise-based cardiac rehabilitation. These results warrant further investigation in larger cohorts.

Arrhythmic Burden and Outcomes in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a devastating, life-limiting disease driven by small vessel vascular remodeling leading to a rise in pulmonary vascular resistance (PVR). Patients present with a range of symptoms including shortness of breath, exercise intolerance, palpitations or syncope. Symptoms may be related to vascular disease progression or arrhythmia secondary to the adaptation of the right heart to pressure overload. Arrhythmic burden is high in patients with left heart disease and guideline-based treatment of arrhythmias improves quality of life and prognosis. In PAH the incidence and prevalence of arrhythmias is less well-defined and there are no PAH-specific guidelines for arrhythmia management. We undertook a literature search identifying 13 relevant papers; detection of arrhythmias was acquired from 12-lead electrocardiogram (ECG) or Holter monitors. In all forms of pulmonary hypertension (PH) the prevalence of supraventricular arrhythmias (SVA) was 26-31%, ventricular arrhythmias (VA) 24% and a 5-year incidence of SVA ~13.2-25.1%. Prevalence and incidence of arrhythmias in PAH is less clear due to limited study numbers and the heterogenous nature of the patient population studied. For arrhythmia treatment, only single-arm studies of therapeutic strategies were reported using antiarrhythmic drugs (AAD), direct current cardioversion (DCCV) and ablation. Periods between ECG or Holter have not been investigated, highlighting the possibility that significant arrhythmias may be undetected. Advances in monitoring allow long-term surveillance via implanted/non-invasive monitors. Use of such technologies may provide an accurate estimate of incidence and prevalence of arrhythmias in patients with PAH, further defining relationships to adverse outcomes, and therapeutic options.

Prescribing dronedarone for paroxysmal atrial fibrillation: how is it done across the UK and is it safe?

Dronedarone, a useful treatment for paroxysmal atrial fibrillation, is often only prescribed in secondary care. To support a protocol shared between primary and secondary care, dronedarone use was audited in our centre and prescribing practices across UK secondary care centres were reviewed. From 2010 to 2015, a total of 181 patients were started on dronedarone. There were no deaths or serious adverse events. Median cessation time due to adverse effects was 52 days and 88% stopped dronedarone within 6 months. Of 17 local prescribing protocols across the UK, 12 involved shared care and 5 purely secondary care follow-up. In our review, dronedarone was safe and well tolerated. The use of shared care protocols is well established in other UK centres. The development of a local shared care protocol between primary and secondary care is feasible with existing systems in place to support its introduction.

Improving haemodynamic optimization of cardiac resynchronization therapy for heart failure.

OBJECTIVE: Optimization of cardiac resynchronization therapy using non-invasive haemodynamic parameters produces reliable optima when performed at high atrial paced heart rates. Here we investigate whether this is a result of increased heart rate or atrial pacing itself. APPROACH: Forty-three patients with cardiac resynchronization therapy underwent haemodynamic optimization of atrioventricular (AV) delay using non-invasive beat-to-beat systolic blood pressure in three states: rest (atrial-sensing, 66 ± 11 bpm), slow atrial pacing (73 ± 12 bpm), and fast atrial pacing (94 ± 10 bpm). A 20-patient subset underwent a fourth optimization, during exercise (80 ± 11 bpm). MAIN RESULTS: Intraclass correlation coefficient (ICC, quantifying information content mean ±SE) was 0.20 ± 0.02 for resting sensed optimization, 0.45 ± 0.03 for slow atrial pacing (p  < 0.0001 versus rest-sensed), and 0.52 ± 0.03 for fast atrial pacing (p  = 0.12 versus slow-paced). 78% of the increase in ICC, from sinus rhythm to fast atrial pacing, is achieved by simply atrially pacing just above sinus rate. Atrial pacing increased signal (blood pressure difference between best and worst AV delay) from 6.5 ± 0.6 mmHg at rest to 13.3 ± 1.1 mmHg during slow atrial pacing (p  < 0.0001) and 17.2 ± 1.3 mmHg during fast atrial pacing (p  = 0.003 versus slow atrial pacing). Atrial pacing reduced noise (average SD of systolic blood pressure measurements) from 4.9 ± 0.4 mmHg at rest to 4.1 ± 0.3 mmHg during slow atrial pacing (p  = 0.28). At faster atrial pacing the noise was 4.6 ± 0.3 mmHg (p  = 0.69 versus slow-paced, p  = 0.90 versus rest-sensed). In the exercise subgroup ICC was 0.14 ± 0.02 (p  = 0.97 versus rest-sensed). SIGNIFICANCE: Atrial pacing, rather than the increase in heart rate, contributes to ~80% of the observed information content improvement from sinus rhythm to fast atrial pacing. This is predominantly through increase in measured signal.

Multicenter Randomized Controlled Crossover Trial Comparing Hemodynamic Optimization Against Echocardiographic Optimization of AV and VV Delay of Cardiac Resynchronization Therapy: The BRAVO Trial.

OBJECTIVES: BRAVO (British Randomized Controlled Trial of AV and VV Optimization) is a multicenter, randomized, crossover, noninferiority trial comparing echocardiographic optimization of atrioventricular (AV) and interventricular delay with a noninvasive blood pressure method. BACKGROUND: Cardiac resynchronization therapy including AV delay optimization confers clinical benefit, but the optimization requires time and expertise to perform. METHODS: This study randomized patients to echocardiographic optimization or hemodynamic optimization using multiple-replicate beat-by-beat noninvasive blood pressure at baseline; after 6 months, participants were crossed over to the other optimization arm of the trial. The primary outcome was exercise capacity, quantified as peak exercise oxygen uptake. Secondary outcome measures were echocardiographic left ventricular (LV) remodeling, quality-of-life scores, and N-terminal pro-B-type natriuretic peptide. RESULTS: A total of 401 patients were enrolled, the median age was 69 years, 78% of patients were men, and the New York Heart Association functional class was II in 84% and III in 16%. The primary endpoint, peak oxygen uptake, met the criterion for noninferiority (pnoninferiority = 0.0001), with no significant difference between the hemodynamically optimized arm and echocardiographically optimized arm of the trial (mean difference 0.1 ml/kg/min). Secondary endpoints for noninferiority were also met for symptoms (mean difference in Minnesota score 1; pnoninferiority = 0.002) and hormonal changes (mean change in N-terminal pro-B-type natriuretic peptide -10 pg/ml; pnoninferiority = 0.002). There was no significant difference in LV size (mean change in LV systolic dimension 1 mm; pnoninferiority < 0.001; LV diastolic dimension 0 mm; pnoninferiority <0.001). In 30% of patients the AV delay identified as optimal was more than 20 ms from the nominal setting of 120 ms. CONCLUSIONS: Optimization of cardiac resynchronization therapy devices by using noninvasive blood pressure is noninferior to echocardiographic optimization. Therefore, noninvasive hemodynamic optimization is an acceptable alternative that has the potential to be automated and thus more easily implemented. (British Randomized Controlled Trial of AV and VV Optimization [BRAVO]; NCT01258829).

Distinct impacts of heart rate and right atrial-pacing on left atrial mechanical activation and optimal AV delay in CRT.

BACKGROUND: Controversy exists regarding how atrial activation mode and heart rate affect optimal atrioventricular (AV) delay in cardiac resynchronization therapy. We studied these questions using high-reproducibility hemodynamic and echocardiographic measurements. METHODS: Twenty patients were hemodynamically optimized using noninvasive beat-to-beat blood pressure at rest (62 ± 11 beats/min), during exercise (80 ± 6 beats/min), and at three atrially paced rates: 5, 25, and 45 beats/min above rest, denoted as Apaced,r+5 , Apaced,r+25 , and Apaced,r+45 , respectively. Left atrial myocardial motion and transmitral flow were timed echocardiographically. RESULTS: During atrial sensing, raising heart rate shortened optimal AV delay by 25 ± 6 ms (P < 0.001). During atrial pacing, raising heart rate from Apaced,r+5 to Apaced,r+25 shortened it by 16 ± 6 ms; Apaced,r+45 shortened it 17 ± 6 ms further (P < 0.001). In comparison to atrial-sensed activation, atrial pacing lengthened optimal AV delay by 76 ± 6 ms (P < 0.0001) at rest, and at ∼20 beats/min faster, by 85 ± 7 ms (P < 0.0001), 9 ± 4 ms more (P  =  0.017). Mechanically, atrial pacing delayed left atrial contraction by 63 ± 5 ms at rest and by 73 ± 5 ms (i.e., by 10 ± 5 ms more, P < 0.05) at ∼20 beats/min faster. Raising atrial rate by exercise advanced left atrial contraction by 7 ± 2 ms (P  =  0.001). Raising it by atrial pacing did not (P  =  0.2). CONCLUSIONS: Hemodynamic optimal AV delay shortens with elevation of heart rate. It lengthens on switching from atrial-sensed to atrial-paced at the same rate, and echocardiography shows this sensed-paced difference in optima results from a sensed-paced difference in atrial electromechanical delay. The reason for the widening of the sensed-paced difference in AV optimum may be physiological stimuli (e.g., adrenergic drive) advancing left atrial contraction during exercise but not with fast atrial pacing.

Evidence that conflict regarding size of haemodynamic response to interventricular delay optimization of cardiac resynchronization therapy may arise from differences in how atrioventricular delay is kept constant.

AIMS: Whether adjusting interventricular (VV) delay changes haemodynamic efficacy of cardiac resynchronization therapy (CRT) is controversial, with conflicting results. This study addresses whether the convention for keeping atrioventricular (AV) delay constant during VV optimization might explain these conflicts. METHOD AND RESULTS: Twenty-two patients in sinus rhythm with existing CRT underwent VV optimization using non-invasive systolic blood pressure. Interventricular optimization was performed with four methods for keeping the AV delay constant: (i) atrium and left ventricle delay kept constant, (ii) atrium and right ventricle delay kept constant, (iii) time to the first-activated ventricle kept constant, and (iv) time to the second-activated ventricle kept constant. In 11 patients this was performed with AV delay of 120 ms, and in 11 at AV optimum. At AV 120 ms, time to the first ventricular lead (left or right) was the overwhelming determinant of haemodynamics (13.75 mmHg at ±80 ms, P < 0.001) with no significant effect of time to second lead (0.47 mmHg, P = 0.50), P < 0.001 for difference. At AV optimum, time to first ventricular lead again had a larger effect (5.03 mmHg, P < 0.001) than time to second (2.92 mmHg, P = 0.001), P = 0.02 for difference. CONCLUSION: Time to first ventricular activation is the overwhelming determinant of circulatory function, regardless of whether this is the left or right ventricular lead. If this is kept constant, the effect of changing time to the second ventricle is small or nil, and is not beneficial. In practice, it may be advisable to leave VV delay at zero. Specifying how AV delay is kept fixed might make future VV delay research more enlightening.

Novel cardiac pacemaker-based human model of periodic breathing to develop real-time, pre-emptive technology for carbon dioxide stabilisation.

BACKGROUND: Constant flow and concentration CO2 has previously been efficacious in attenuating ventilatory oscillations in periodic breathing (PB) where oscillations in CO2 drive ventilatory oscillations. However, it has the undesirable effect of increasing end-tidal CO2, and ventilation. We tested, in a model of PB, a dynamic CO2 therapy that aims to attenuate pacemaker-induced ventilatory oscillations while minimising CO2 dose. METHODS: First, pacemakers were manipulated in 12 pacemaker recipients, 6 with heart failure (ejection fraction (EF)=23.7±7.3%) and 6 without heart failure, to experimentally induce PB. Second, we applied a real-time algorithm of pre-emptive dynamic exogenous CO2 administration, and tested different timings. RESULTS: We found that cardiac output alternation using pacemakers successfully induced PB. Dynamic CO2 therapy, when delivered coincident with hyperventilation, attenuated 57% of the experimentally induced oscillations in end-tidal CO2: SD/mean 0.06±0.01 untreated versus 0.04±0.01 with treatment (p<0.0001) and 0.02±0.01 in baseline non-modified breathing. This translated to a 56% reduction in induced ventilatory oscillations: SD/mean 0.19±0.09 untreated versus 0.14±0.06 with treatment (p=0.001) and 0.10±0.03 at baseline. Of note, end-tidal CO2 did not significantly rise when dynamic CO2 was applied to the model (4.84±0.47 vs 4.91± 0.45 kPa, p=0.08). Furthermore, mean ventilation was also not significantly increased by dynamic CO2 compared with untreated (7.8±1.2 vs 8.4±1.2 L/min, p=0.17). CONCLUSIONS: Cardiac pacemaker manipulation can be used to induce PB experimentally. In this induced PB, delivering CO2 coincident with hyperventilation, ventilatory oscillations can be substantially attenuated without a significant increase in end-tidal CO2 or ventilation. Dynamic CO2 administration might be developed into a clinical treatment for PB. TRIAL REGISTRATION NUMBER: ISRCTN29344450.

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. TRIAL REGISTRATION: Clinicaltrials.gov NCT01258829.