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Background Hemodynamically optimal atrioventricular (AV) delay can be derived by echocardiography or beat-by-beat blood pressure (BP) measurements, but analysis is labor intensive. Laser Doppler perfusion monitoring measures blood flow and can be incorporated into future implantable cardiac devices. We assess whether laser Doppler can be used instead of BP to optimize AV delay. Methods Fifty eight patients underwent 94 AV delay optimizations with biventricular or His-bundle pacing using laser Doppler and simultaneous noninvasive beat-by-beat BP. Optimal AV delay was defined using a curve of hemodynamic response to switching from AAI (reference state) to DDD (test state) at several AV delays (40–320 ms), with automatic quality control checking precision of the optimum. Five subsequent patients underwent an extended protocol to test the impact of greater numbers of alternations on optimization quality. Results 55/94 optimizations passed quality control resulting in an optimal AV delay on laser Doppler similar to that derived by BP (median absolute deviation 12 ms). An extended protocol with increasing number of replicates consistently improved quality and reduced disagreement between laser Doppler and BP optima. With only five replicates, no optimization passed quality control, and the median absolute deviation would be 29 ms. These improved progressively until at 50 replicates, all optimizations passed quality control and the median absolute deviation was only 13 ms. Conclusions Laser Doppler perfusion produces hemodynamic optima equivalent to BP. Quality control can be automatic. Adding more replicates, consistently improves quality. Future implantable devices could use such methods to dynamically and reliably optimize AV delays.

Background His bundle pacing (HBP) is an alternative to biventricular pacing (BVP) for delivering cardiac resynchronisation 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 resynchronised 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, non-invasive epicardial mapping (ECGI) 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 visualise epicardial wavefronts. Normal activation pattern and a normal LVAT range were determined from normal subjects. Results 45 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 ≥10ms. In 33.3%, His-CRT resulted in complete ventricular resynchronisation, 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 resynchronisation was achieved by HBP (logarithmic odds ratio (logOR) 2.19, 95% CI 0.07 to 4.31, p=0.04). Conclusion Non-invasive 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. This article is protected by copyright. All rights reserved.

OBJECTIVE We tested whether ablation methodology and study design can explain the varying outcomes in terms of atrial fibrillation (AF)-free survival at 1 year. BACKGROUND There have been numerous paroxysmal AF ablation trials, which are heterogeneous in their use of different ablation techniques and study design. A useful approach to understanding how these factors influence outcome is to dismantle the trials into individual arms and reconstitute them as a large meta-regression. METHODS Data were collected from 66 studies (6941 patients). With freedom from AF as the dependent variable, we performed meta-regression using the individual study arm as the unit. RESULTS Success rates did not change regardless of the technique used to produce pulmonary vein isolation (PVI). Neither was adjunctive lesion sets associated with any improvement in outcome. Studies that included more males and fewer hypertensive patients were found more likely to report better outcomes. The electrocardiography method selected to assess outcome also plays an important role. Outcomes were worse in studies that used regular telemonitoring (by 23%; P

INTRODUCTION: The ganglionated plexuses (GPs) of the intrinsic cardiac autonomic system are implicated in arrhythmogenesis. GP localization by stimulation of the epicardial fat pads to produce atrioventricular dissociating (AVD) effects is well described. We determined the anatomical distribution of the left atrial GPs that influence AV dissociation. METHODS AND RESULTS: High frequency stimulation was delivered through a Smart-Touch™ catheter in the left atrium of patients undergoing atrial fibrillation (AF) ablation. 3D locations of points tested throughout the entire chamber were recorded on the CARTO™ system. Impact on the AV conduction was categorized as ventricular asystole, bradycardia or no effect. CARTO™ maps were exported, registered and transformed onto a reference left atrial geometry using a custom software, enabling data from multiple patients to be overlaid. In 28 patients, 2108 locations were tested and 283 sites (13%) demonstrated atrioventricular dissociation effects (AVD-GP). There were 10 AVD-GPs (IQR 11.5) per patient. 80% (226) produced asystole and 20% (57) showed bradycardia. The distribution of the two groups were very similar. Highest probability of AVD-GPs (>20%) were identified in: infero-septal portion (41%) and right inferior pulmonary vein base (30%) of the posterior wall, right superior pulmonary vein antrum (31%). CONCLUSION: It is feasible to map the entire left atrium for AVD-GPs prior to AF ablation. Aggregated data from multiple patients, producing a distribution probability atlas of AVD-GPs, identified three regions with a higher likelihood for finding AVD-GPs and these matched the histological descriptions. This approach could be used to better characterise the autonomic network. This article is protected by copyright. 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.

Background: Models of cardiac arrhythmogenesis predict that non-uniformity in repolarization and/or depolarization promotes ventricular fibrillation and is modulated by autonomic tone, but this is difficult to evaluate in patients. We hypothesize that such spatial heterogeneities would be detected by non-invasive ECG imaging (ECGi) in sudden cardiac death (SCD) survivors with structurally normal hearts under physiological stress. Methods: ECGi was applied to 11 SCD survivors, 10 low-risk Brugada Syndrome patients (BrS) and 10 controls undergoing exercise treadmill testing. ECGi provides whole heart activation maps and > 1200 unipolar electrograms over the ventricular surface from which global dispersion of activation recovery interval (ARI) and regional delay in conduction were determined. These were used as surrogates for spatial heterogeneities in repolarization and depolarization. Surface ECG markers of dispersion (QT and Tpeak-end intervals) were also calculated for all patients for comparison. Results: Following exertion, the SCD group demonstrated the largest increase in ARI dispersion compared to BrS and control groups (13±8 ms vs 4±7 ms vs 4±5 ms; p = 0.009), with baseline dispersion being similar in all groups. In comparison, surface ECG markers of dispersion of repolarisation were unable to discriminate between the groups at baseline or following exertion. Spatial heterogeneities in conduction were also present following exercise but were not significantly different between SCD survivors and the other groups. Conclusion: Increased dispersion of repolarization is apparent during physiological stress in SCD survivors and is detectable with ECGi but not with standard ECG parameters. The electrophysiological substrate revealed by ECGi could be the basis of alternative risk-stratification techniques. This article is protected by copyright. All rights reserved

Introduction: Vectorcardiographic (VCG) QRS area of left bundle branch block (LBBB) predicts acute hemodynamic response in cardiac resynchronization therapy (CRT) patients. We hypothesized that changes in QRS area occurring with biventricular pacing (BV) might predict acute hemodynamic CRT response (AHR). Methods and Results: VCGs of 624 BV paced electrocardiograms (25 LBBB patients with 35 different pacing configurations) were calculated according to Frank's orthogonal lead system. Maximum QRS vector amplitudes (X-Ampl, Y-Ampl, Z(Ampl), and 3D(Amp)) and QRS areas (X-Area, Y-Area, Z(Area), and 3D(Area)) in the orthogonal leads (X, Y, and Z) and in 3-dimensional projection were measured. Volume of the 3D vector loop and global QRS duration (QRSD) on the surface electrocardiogram were assessed. Differences (Delta) in VCG parameters between BV paced and LBBB QRS complexes were calculated. An increase of 10% in dP/dt max was considered as AHR. LBBB conduction is characterized by a large Z(Area) (109 mu Vs, interquartile range [ IQR]: 75; 135), significantly larger than X-Area (22 mu Vs, IQR: 10; 57) and Y-Area (44 mu Vs, IQR: 32; 62, P< 0.001). Overall, QRS duration, amplitudes, and areas decrease significantly with BV pacing (P

Background\ud Correctly selecting the end‐diastolic and end‐systolic frames on a 2D echocardiogram is important and challenging, for both human experts and automated algorithms. Manual selection is time‐consuming and subject to uncertainty, and may affect the results obtained, especially for advanced measurements such as myocardial strain.\ud \ud Methods and Results\ud We developed and evaluated algorithms which can automatically extract global and regional cardiac velocity, and identify end‐diastolic and end‐systolic frames. We acquired apical four‐chamber 2D echocardiographic video recordings, each at least 10 heartbeats long, acquired twice at frame rates of 52 and 79 frames/s from 19 patients, yielding 38 recordings. Five experienced echocardiographers independently marked end‐systolic and end‐diastolic frames for the first 10 heartbeats of each recording. The automated algorithm also did this. Using the average of time points identified by five human operators as the reference gold standard, the individual operators had a root mean square difference from that gold standard of 46.5 ms. The algorithm had a root mean square difference from the human gold standard of 40.5 ms (P

Organizational Index Maps of AF. Introduction: Localized rotors have been implicated in the mechanism of persistent atrial fibrillation (AF). Although regions of highest dominant frequency (DF) on spectral analysis of the left atrium (LA) have been said to identify rotors, other mechanisms such as wavefront collisionswillsporadically alsogenerate aninconsistent distributionof highDF.Wehypothesized that if drivers of AF were present, their distinctive spectral characteristics would result more from their temporal stability than their high frequency. Methods and Results: Ten patients with persistent AF underwent LA noncontact mapping. Following subtractionoffar-fieldventricularcomponents,noncontactelectrogramsat256sitesunderwentfastFourier transform.MeanabsolutedifferenceinDFbetween5sequential7-secondsegmentsofAFwasdefinedasthe DF variability (DFV) at each site. Mean ratio of the DF and its harmonics to the total power of the spectrum was defined as the organizational index (OI). Mean DFV was significantly lower in organized areas (OI > 1 SD above mean) than at all sites (0.34 ± 0.04 vs 0.46 ± 0.04 Hz; P < 0.001). When organized areas were

Ripple Mapping: A Novel 3D EGM Display. Background: Three-dimensional (3D) mapping is often used to guide ablation in atrial tachycardia (AT), but maps can be susceptible to annotation and interpolation errors. Ripple Mapping (RM) is a technique that displays electrogram time–voltage data simultaneously as dynamic bars on the surface shell to overcome these limitations. Objectives: We hypothesized that RM would be superior to established 3D activation mapping. Methods: CARTO-XP TM maps of ATs were collected without any manual annotation and studied on a CARTO-based offline RM system. Paired unannotated CARTO-XP and Ripple Maps were presented to experienced CARTO users with limited RM training. These assessors were allowed to annotate the CARTO-XP maps, but were blinded to conventional EP data. Results: CARTO-XP maps of AT (10 patients) were studied in RM format and the diagnosis was confirmed by entrainment in all cases and with termination of tachycardia in 9/10 cases. Blinded assessors (n = 11) reached the correct diagnosis using RM in 35/44 (80%) compared to 22/44 (50%) using CARTO-XP (P = 0.029). The time to the correct diagnosis was also shorter with RM (136 seconds vs. 212 seconds; P = 0.022). The causes of diagnostic errors using RM (insufficient point density, particularly in low-voltage areas, and the operator not assessing all available views) were overcome with an improved MatLab version showing both scar and dynamic bars on the same shell. Conclusion: RM does not need any manual annotation of local activation time and enables rapid diagnosis of AT with higher diagnostic accuracy than conventional 3D activation mapping. (J Cardiovasc

Background: Hemodynamic optimization of cardiac resynchronization therapy (CRT) can be achieved reproducibly and—with bulky, nonimplantable equipment—noninvasively. We explored whether a simple photoplethysmogram signal might be used instead. Method: Twenty patients (age 65 ± 12) with CRT underwent automatic atrioventricular (AV) delay optimization, using a multiple-transitions protocol, at two atrially paced heart rates: just above sinus rate (“slow ApVp,” 77 ± 11 beats per minute [bpm]) and 100 bpm (“fast ApVp”). We then retested to assess short-term reproducibility. Results: All 80 optimizations identified an optimum (correctly oriented parabola). At 100 bpm, the simple photoplethysmogram had wider scatter between repeat optimizations than did Finometer: standard deviation of difference (SDD) 22 ms versus 14 ms, respectively, P = 0.028. The simple photoplethysmogram improved in reproducibility when slope (instead of peak) of its signal was used for optimization, becoming as reproducible as Finometer (SDD 14 ms vs 14 ms, P = 0.50). At slow heart rate, reproducibility of simple photoplethysmogram-based optimization worsened from 14 to 22 ms (P = 0.028), and Finometer-based optimization from 14 to 26 ms (P = 0.005). Increasing the number of replicates averaged improved reproducibility. For example, SDD of simple photoplethysmogram optimization (using peak) fell from 62 ms with two replicates to 22 ms with eight replicates (P < 0.0001). At 100 bpm, the eight-replicate protocol takes ∼12 minutes. Conclusions : A 12-minute protocol of simple photoplethysmographic AV optimization can be processed fully automatically. Blinded test-retest reproducibility of the optimum AV is good and improves with more replicates. If benefits to some patients are not to be neutralized by harm to others, endpoint studies should first test check narrowness of “within-patient error bars.” (PACE 2012; 35:948–960)

Background: Patients receiving implantable cardioverter-defibrillators (ICDs) often have severely impaired left ventricular function and a poor prognosis. Having an ICD in situ effectively denies them the possibility of a quick, arrhythmic death. It is still unclear if and when the end of life and device deactivation should be discussed with patients and how much patients want to know prior to ICD implantation. Methods: Patients with an active ICD for chronic heart failure were interviewed regarding their attitude toward the ICD, their recollection of the consent procedure, and how they felt the end of life should be discussed with ICD patients (n = 54). Patients who had received ICD therapies (n = 25) were reviewed as a subgroup with extended questions regarding attitudes toward device deactivation. Results: Fifty-four patients were recruited. Most patients were not aware that the ICD could be deactivated. The vast majority of patients (84%) wanted to be involved in the deactivation decision; 40% felt this discussion should be prior to ICD implantation but others felt the discussion should only occur if the patient was terminally ill (16%) or in the last few days of life (5%). Conclusion: Patients with ICDs are routinely counseled about the benefits of ICDs, but options for device deactivation are not well understood by patients. Most patients would like to be involved in deactivation decisions and we feel this should be discussed well in advance. (PACE 2011; 34:1628–1633)

Autonomic Stimulation Promotes AFCL Gradients in AF. Introduction: The intrinsic cardiac autonomic nervous system (ANS) is implicated in atrial fibrillation (AF) but little is known about its role in maintenance of the electrophysiological substrate during AF in humans. We hypothesized that ANS activation by high-frequency stimulation (HFS) of ganglionated plexi (GP) increases dispersion of atrial AF cycle lengths (AFCLs) via a parasympathetic effect. Methods and Results: During AF in 25 patients, HFS was delivered to presumed GP sites to provoke a bradycardic vagal response and AFCL was continuously monitored from catheters placed in the pulmonary vein (PV), coronary sinus (CS), and high right atrium (HRA). A total of 163 vagal responses were identified from 271 HFS episodes. With a vagal response, the greatest reduction in AFCL was seen in the PV adjacent to the site of HFS (16% reduction, 166 ± 28 to 139 ± 26 ms, P < 0.0001) followed by the PV-atrial junction (9% reduction, 173 ± 21 to 158 ± 20 ms, P < 0.0001), followed by the rest of the atrium (3–7% reduction recorded in HRA and CS). Without a vagal response, AFCL changes were not observed. In 10 patients, atropine was administered in between HFS episodes. Before atropine administration, HFS led to a vagal response and a reduction in PV AFCL (164 ± 28 to 147 ± 26 ms, P < 0.0001). Following atropine, HFS at the same GP sites no longer provoked a vagal response, and the PV AFCL remained unchanged (164 ± 30 to 166 ± 33 ms, P = 0.34). Conclusions:Activation of the parasympathetic component of the cardiac ANS may cause heterogenous changes in atrial AFCL that might promote PV drivers. (J Cardiovasc Electrophysiol, Vol. pp. 1-8)

The European Society of Cardiology heart failure guidelines firmly recommend regular physical activity and structured exercise training (ET), but this recommendation is still poorly implemented in daily clinical practice outside specialized centres and in the real world of heart failure clinics. In reality, exercise intolerance can be successfully tackled by applying ET. We need to encourage the mindset that breathlessness may be evidence of signalling between the periphery and central haemodynamic performance and regular physical activity may ultimately bring about favourable changes in myocardial function, symptoms, functional capacity, and increased hospitalization-free life span and probably survival. In this position paper, we provide practical advice for the application of exercise in heart failure and how to overcome traditional barriers, based on the current scientific and clinical knowledge supporting the beneficial effect of this intervention.

Autonomic Stimulation Induces PV Ectopy and AF. Introduction: The induction of atrial fibrillation (AF) by pulmonary vein (PV) ectopy is well described. The triggers for these PV ectopy are not so well understood. The intrinsic cardiac autonomic nervous system (ANS) has been suggested as a potential upstream regulator that may cause PV ectopy and atrial fibrillation (AF). We hypothesized that activation of the ANS by high frequency stimulation (HFS) of atrial ganglionated plexi (GP) can initiate PV ectopy. Methods and Results: During sinus rhythm in 12 patients undergoing ablation for paroxysmal AF, short bursts of HFS, synchronized to the local atrial refractory period, were delivered at presumed GP sites. Electrograms were recorded from catheters placed in the PV, coronary sinus (CS) and high right atrium (HRA). A total of 112 episodes of HFS were recorded, producing ectopic activity in 91 of 112 (81%) episodes. Of these 91 episodes, there were 46 episodes of isolated single ectopic beats, 5 episodes of double ectopic responses, 24 episodes of ectopy/tachycardia lasting 30 s. In 63 of 91 episodes, the PV catheter was placed adjacent to the stimulated GP, resulting in ectopy recorded earliest in the PV catheter in 48 of 63 (76%) episodes. In one patient, reproducible ectopy was shown to occur following AV nodal conduction delay in response to HFS. Without HFS, neither AV nodal conduction delay nor ectopy occurred. Conclusions: This study has demonstrated a direct link between activation of the intrinsic cardiac autonomic nervous system and pulmonary vein ectopy in humans. (J Cardiovasc Electrophysiol, Vol. 22, pp. 638-646, June 2011)

Background: During optimization of the atrioventricular (AV) delay of cardiac resynchronization therapy (CRT), it is not known exactly which windows of time around the transition are most informative for identification of the optimum. Method and Results: In 22 patients with CRT, we performed AV delay optimization using continuous noninvasive hemodynamics. We used signal-to-noise ratio to determine the most efficient averaging window location and width. We found that it is most efficient to position the averaging windows immediately before and immediately after the transition in AV delay. For example, skipping five beats after the transition decreases signal-to-noise ratio by 17.5% (P < 0.0001). Similarly, skipping five beats immediately before the transition reduces signal-to-noise ratio by 11.7% (P < 0.0001). The best choice of “fixed” averaging window width was found to be six beats, with signal-to-noise ratio falling by, for example, 41% for a one-beat window (P = 0.0002). However, even better was to set the window width for each patient to match one respiratory cycle. We observed that the pre- and posttransition signal-to-noise ratio traces begin to diverge three beats after the transition in AV delay. We believe this represents the time taken for the peripheral response to pacing-induced changes in stroke volume to occur. Conclusions: The most efficient way to use alternating transitions for the hemodynamic optimization of CRT is to use an averaging window of one respiratory cycle, and not to skip any beats between the pretransition and posttransition averaging windows. (PACE 2011; 34:217–225)

AIM: Severe aortic stenosis frequently involves the development of left ventricular hypertrophy (LVH) creating a dichotomous haemodynamic state within the coronary circulation. Whilst the increased force of ventricular contraction enhances its resultant relaxation and thus increases the distal diastolic coronary "suction" force, the presence of LVH has a potentially opposing effect on ventricular-coronary interplay. The aim of this study was to use non-invasive coronary wave intensity analysis (WIA) to separate and measure the sequential effects of outflow tract obstruction relief and then LVH regression following intervention for aortic stenosis. METHODS: Fifteen patients with unobstructed coronary arteries undergoing aortic valve intervention (11 surgical aortic valve replacement [SAVR], 4 TAVI) were successfully assessed before and after intervention, and at 6 and 12 months post-procedure. Coronary WIA was constructed from simultaneously acquired coronary flow from transthoracic echo and pressure from an oscillometric brachial cuff system. RESULTS: Immediately following intervention, a decline in the backward decompression wave (BDW) was noted (9.7 ± 5.7 vs 5.1 ± 3.6 × 103 W/m2 /s, P

Heart failure and ventilatory disease often coexist; both create abnormalities in cardiopulmonary exercise test measurements. The authors evaluated the relative dependency of a well-recognized index of heart failure, peak oxygen consumption (VO(2)), and 2 newer indices, the minute ventilation (VE)/carbon dioxide production (VCO(2)) slope and oxygen uptake efficiency slope (OUES), on standard markers of impaired cardiac and ventilatory function. One hundred twenty-four patients (median age, 65.8; range, 22.6-84.9), with functional limitation from clinical heart failure were exercised. Peak VO(2) was 17.14 ± 7.58 mL/kg/min, VE/VCO(2) slope 50.1 ± 20.1, OUES 1.46 ± 0.68 L/min, and forced expiratory volume in 1 second (FEV(1) ) 1.88 ± 0.75 L. Peak VO(2) is substantially more sensitive to FEV(1) than ejection fraction (4.0 mL/kg/min difference between above- and below-median FEV(1) and 1.5 mL/kg/min between above- and below-median ejection fraction). OUES does not share this peculiar excess sensitivity to FEV(1) (0.12 L/min difference between above- and below-median FEV(1) and 0.01 L/min between above- and below-median ejection fraction). VE/VCO(2) slope has a borderline effect by FEV(1) (7.07 difference between above- and below-median FEV(1) and 2.07 between above- and below-median ejection fraction). Although widely used as a marker of heart failure severity, peak VO(2) is very sensitive to spirometry status and is indeed more affected by FEV(1) than by ejection fraction. OUES in contrast does not show this preferential sensitivity to impaired FEV(1).

Coupled fluid–structure interaction (FSI) analysis of the human right coronary artery (RCA) has been carried out to investigate the effects of wall compliance on coronary hemodynamics. A 3-D model of a stenosed RCA was reconstructed based on multislice computerized tomography images. A velocity waveform in the proximal RCA and a pressure waveform in the distal RCA of a patient with a severe stenosis were acquired with a catheter delivered wire probe and applied as boundary conditions. The arterial wall was modeled as a Mooney–Rivlin hyperelastic material. The predicted maximum wall displacement (3.85 mm) was comparable with the vessel diameter (∼4 mm), but the diameter variation was much smaller, 0.134 mm at the stenosis and 0.486 mm in the distal region. Comparison of the computational results between the FSI and rigid-wall models showed that the instantaneous wall shear stress (WSS) distributions were affected by diameter variation in the arterial wall; increasing systolic blood pressure dilated the vessel and consequently lowered WSS, whereas the opposite occurred when pressure started to decrease. However, the effects of wall compliance on time-averaged WSS (TAWSS) and oscillatory shear index (OSI) were insignificant (4.5 and 2.7% difference in maximum TAWSS and OSI, respectively). Copyright © 2009 John Wiley & Sons, Ltd.

Observational data suggest that periodic breathing is more common in subjects with low FETCO2 , high apnoeic thresholds or high chemoreflex sensitivity. It is, however, difficult to determine the individual effect of each variable because they are intrinsically related. To distinguish the effect of isolated changes in chemoreflex sensitivity, mean FETCO2 and apnoeic threshold, we employed a modelling approach to break their obligatory in vivo interrelationship. We found that a change in mean CO2 fraction from 0.035 to 0.045 increased loop gain by 70 ± 0.083% (P < 0.0001), irrespective of chemoreflex gain or apnoea threshold. A 100% increase in the chemoreflex gain (from 800 l min −1 (fraction CO2) −1 ) resulted in an increase in loop gain of 275 ± 6% (P < 0.0001) across a wide range of values of steady state CO2 and apnoea thresholds. Increasing the apnoea threshold FETCO2 from 0.02 to 0.03 had no effect on system stability. Therefore, of the three variables the only two destabilizing factors were high gain and high mean CO2; the apnoea threshold did not independently influence system stability. Although our results support the idea that high chemoreflex gain destabilizes ventilatory control, there are two additional potentially controversial findings. First, it is high (rather than low) mean CO2 that favours instability. Second, high apnoea threshold itself does not create instability. Clinically the apnoea threshold appears important only because of its associations with the true determinants of stability: chemoreflex gain and mean CO2.

Summary The aim of this study was to determine the prevalence of sleep-related breathing disorders (SDB) in a UK general heart failure (HF) population, and assess its impact on neurohumoral markers and symptoms of sleepiness and quality of life. Eighty-four ambulatory patients (72 male, mean (SD) age 68.6 (10) yrs) attending UK HF clinics underwent an overnight recording of respiratory impedance, SaO2 and heart rate using a portable monitor (Nexan). Brain natriuretic peptide (BNP) and urinary catecholamines were measured. Subjective sleepiness and the impairment in quality of life were assessed (Epworth Sleepiness Scale (ESS), SF-36 Health Performance Score). SDB was classified using the Apnoea/Hypopnoea Index (AHI). The prevalence of SDB (AHI > 15 events h−1) was 24%, increasing from 15% in mild-to-moderate HF to 39% in severe HF. Patients with SDB had significantly higher levels of BNP and noradrenaline than those without SDB (mean (SD) BNP: 187 (119) versus 73 (98) pg mL−1, P = 0.02; noradrenaline: 309 (183) versus 225 (148) nmol/24 h, P = 0.05). There was no significant difference in reported sleepiness or in any domain of SF-36, between groups with and without SDB (ESS: 7.8 (4.7) versus 7.5 (3.6), P = 0.87). In summary, in a general HF clinic population, the prevalence of SDB increased with the severity of HF. Patients with SDB had higher activation of a neurohumoral marker and more severe HF. Unlike obstructive sleep apnoea, SDB in HF had little discernible effect on sleepiness or quality of life as measured by standard subjective scales.

Background: Patients with heart failure have an abnormally high ventilatory response to exercise associated with gas exchange defects and reduced arterial pCO2. Aims: We examined the possibility of lactic acidosis as the stimulus to this increased ventilation that abnormally depresses pCO2 during exercise in heart failure. Method and results: We studied 18 patients with chronic heart failure. We measured VE/VCO2 slope during exercise, arterial blood gases and lactate concentrations during cardiopulmonary exercise testing (rest, peak exercise and one minute after the end of exercise). Neither VE/VCO2 slope nor arterial pCO2 were related to arterial lactate concentrations at peak exercise (r=� 0.16, p=0.65 and r=� 0.15, p=0.6). During early recovery, patients with a high VE/VCO2 slope had a particularly pronounced rise in arterial lactate and hydrogen ion concentrations (r=0.57, pb0.05 and r=0.84, pb0.0001) and yet their arterial pCO2 rose rather than fell (r=0.79, pb0.001). The rise in arterial pCO2 correlated with the increase in arterial hydrogen concentration (r=0.78, pb0.001) and with arterial pCO2 at peak exercise (r=� 0.76, pb0.001). Conclusions: In heart failure VE/VCO2 slope and low arterial pCO2 at peak exercise are not related to the degree of systemic lactic acidosis. Lactic acidosis is therefore not a plausible mechanism of exercise induced hyperventilation. D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

The diagnostic and prognostic power of the fractal complexity measure 'alpha' of detrended fluctuation analysis (DFA) has remained mysterious because there has been no explanation of its meaning, particularly in relation to spectral analysis. First, we present a mathematical analysis of the meaning of alpha, in weighted power-spectral terms. Second, we test this hypothesis and observe correlations between DFA-based and weighted spectral methods of 0.97 (P < 0.0001) for alpha1 and 0.98 (P < 0.0001) for alpha2. Third, we predict mathematically that even in conventional (unweighted) spectral analysis there should be approximate counterparts to DFA, namely that alpha1 and alpha2 behave broadly in proportion to the conventional (unweighted) ratios LF/(HF + LF) and VLF/(LF + VLF), respectively, where HF is high frequency, LF is low frequency and VLF is very low frequency. Fourth, we test this hypothesis by physiologically manipulating spectral ratios in healthy volunteers in two ways. The effect of 0.1 Hz controlled breathing on LF/(HF + LF) correlates markedly with the effect on alpha1 (r = 0.73, P = 0.01); the effect on VLF/(LF + VLF) correlates markedly with that on alpha2 (r = 0.76, P < 0.01). Likewise, with voluntary periodic breathing the reduction in alpha2 correlates strongly with that in VLF/(LF + VLF) (r = 0.88, P < 0.001); effects on alpha1 and LF/(HF + LF) again clearly correlate (r = 0.73, P = 0.01). Finally, we examine published literature to identify previously undiscussed evidence of the relationship between alpha1 and LF/(HF + LF). We conclude that the alpha1 and alpha2 indices are simply frequency-weighted versions of the spectral ratios LF/(HF + LF) and VLF/(LF + VLF), respectively, multiplied by two (giving a range of 0-2). We can now understand fractal manifestations of physiological abnormalities: depressed baroreflex sensitivity low LF/HF low LF/(HF + LF) low alpha1, while periodic breathing high VLF/LF high VLF/(LF + VLF) high alpha2. Prognostic associations of alpha are no longer mysterious.

The role of skeletal muscle ergoreceptors (afferents sensitive to muscle contraction, differentiated into metaboreceptors, sensitive to metabolic changes, and mechanoreceptors, sensitive to mechanical changes) in the genesis of the increased ventilatory drive in chronic heart failure is controversial. We have aimed to clarify the contribution of muscle metaboreceptors in the leg to ventilation and to compare this with the contribution of mechanoreceptors. Eighteen heart failure patients and 12 controls were studied. Metaboreceptor and mechanoreceptor responses were measured in the leg by bicycle exercise with and without regional circulatory occlusion during recovery, and by active and equivalent passive limb movement, respectively.Patients, in comparison with controls, had a lower peak VO2 (Oxygen uptake) (18.1+/-1.6 vs. 24.5+/-2.5 ml min(-1) kg(-1), P< 0.05), and an evident metaboreceptor contribution to the ventilatory response (3.5+/-1.6 vs. -4.0+/-1.3 l min(-1), P

Oscillations in the cardiovascular system have been observed in patients with periodic breathing. It is not clear whether these are driven by primary oscillations in the respiratory system or whether an intrinsic cardiovascular instability is required, as previous studies with subjects performing voluntary periodic breathing have failed to produce the cardiovascular oscillations. We investigated whether cardiovascular oscillations occurred in healthy controls performing voluntary periodic breathing. Six healthy subjects performed voluntary periodic breathing with guidance from a real-time computer display. We measured ventilation, end-tidal partial pressures of O2 (PO2) and CO2 (PCO2), heart rate, blood pressure (BP), arterial oxygen saturation and stroke volume and cardiac output by transthoracic impedance cardiography. Fourier analysis was used to quantify the size and phase of the periodic breathing-induced oscillations in these parameters. Periodic breathing (amplitude 30% of mean ventilation) induced oscillations in end-tidal PO2 (amplitude 0.8 kPa), end-tidal PCO2 (amplitude 0.3 kPa), R-R interval (amplitude 32.6 ms), systolic BP (amplitude 3 mmHg), diastolic BP (amplitude 3 mmHg), stroke volume (amplitude 8.0 ml, mean 79.5 ml) and cardiac output (amplitude 0.6 1, mean 5.9 l x min(-1)). The oscillations in stroke volume and cardiac output were nearly in phase with ventilation, with their peaks occurring 5.6 and 6.1 s, respectively, after the peak in ventilation. An oscillatory ventilatory pattern entrains the cardiovascular system in healthy controls into fluctuations, not only in heart rate and BP, but also in stroke volume and cardiac output.

Background Patients with chronic heart failure complain of breathlessness. This is associated with an increase in the ventilatory response to carbon dioxide production (Ve/Vco2 slope), yet a reduction in the maximal ventilation achieved at peak exercise. We analysed ventilatory capacity in heart failure in relation to exercise capacity. Methods We analysed data from 74 patients with chronic stable heart failure [age (S.D.) 50.6 (8.8) years; left ventricular ejection fraction 30 (15)%] and 36 controls [48.9 (11.5) years]. Subjects undertook maximal incremental exercise testing with metabolic gas exchange measurements to derive peak oxygen consumption (Vo2), the Ve/Vco2 slope and ventilation. Spirometry was used to measure FEV1 and FVC. Maximal voluntary ventilation (MVV) was calculated as FEV1×35. Results Peak Vo2 was lower in patients [20.9 (7.5) ml min−1 kg−1 vs. 34.5 (10.1); P