Andreas Kyriacou

The right ventricular annular velocity reduction caused by coronary artery bypass graft surgery occurs at the moment of pericardial incision

Background Right ventricular (RV) long-axis function is known to be depressed after cardiac surgery, but the mechanism is not known. We hypothesized that intraoperative transesophageal echocardiography could pinpoint the time at which this happens to help narrow the range of plausible mechanisms. Method Transthoracic echocardiography was conducted in 33 patients before and after elective coronary artery bypass graft. In an intensively monitored cohort of 9 patients, we also monitored RV function intraoperatively using serial pulsed wave tissue Doppler (PW TD) transesophageal echocardiography. Results There was no significant difference in myocardial velocities from the onset of the operation up to the beginning of pericardial incision, change in RV PW TD S′ velocities 3% ± 2% (P = not significant). Within the first 3 minutes of opening the pericardium, RV PW TD S′ velocities had reduced by 43% ± 17% (P < .001). At 5 minutes postpericardial incision, 2 minutes later, the velocities had more than halved, by 54% ± 11% (P < .0001). Velocities thereafter remained depressed throughout the operation, with final intraoperative S′ reduction being 61% ± 11% (P < .0001). One month after surgery, in the full 33-patient cohort, transthoracic echocardiogram data showed a 55% ± 12% (P < .0001) reduction in RV S′ velocities compared with preoperative values. Conclusions Minute-by-minute monitoring during cardiac surgery reveals that, virtually, all the losses in RV systolic velocity occurs within the first 3 minutes after pericardial incision. Right ventricular long-axis reduction during coronary bypass surgery results not from cardiopulmonary bypass but rather from pericardial incision.

Improvement in Coronary Blood Flow Velocity with Acute Biventricular Pacing is Predominantly Due to an Increase in a Diastolic Backward-Travelling Decompression (Suction) Wave

Background— Normal coronary blood flow is principally determined by a backward-traveling decompression (suction) wave in diastole. Dyssynchronous chronic heart failure may attenuate suction, because regional relaxation and contraction overlap in timing. We hypothesized that biventricular pacing, by restoring left ventricular (LV) synchronization and improving LV relaxation, might increase this suction wave, improving coronary flow. Method and Results— Ten patients with chronic heart failure (9 males; age 65±12; ejection fraction 26±7%) with left bundle-branch block (LBBB; QRS duration 174±18 ms) were atriobiventricularly paced at 100 bpm. LV pressure was measured and wave intensity calculated from invasive coronary flow velocity and pressure, with native conduction (LBBB) and during biventricular pacing at atrioventricular (AV) delays of 40 ms, 120 ms, and separately preidentified hemodynamically optimal AV delay. In comparison with LBBB, biventricular pacing at separately preidentified hemodynamically optimal AV delay (BiV-Opt) enhanced coronary flow velocity time integral by 15% (7%–25%) (P=0.007), LV dP/dtmax by 15% (10%–21%) (P=0.005), and negdP/dtmax by 17% (9%–22%) (P=0.005). The cumulative intensity of the diastolic backward decompression (suction) wave increased by 26% (18%–54%) (P=0.005). The majority of the increase in coronary flow velocity time integral occurred in diastole (69% [41%–84% ]; P=0.047). The systolic compression waves also increased: forward by 36% (6%–49%) (P=0.022) and backward by 38% (20%–55%) (P=0.022). Biventricular pacing at AV delays of 120 ms generated a smaller LV dP/dtmax (by 12% [5%–23% ], P=0.013) and negdP/dtmax (by 15% [8%–40% ]; P=0.009) increase than BiV-Opt, against LBBB as reference; BiV-Opt and biventricular pacing at AV delays of 120 ms were not significantly different in coronary flow velocity time integral or waves. Biventricular pacing at AV delays of 40 ms was no different from LBBB. Conclusions— When biventricular pacing improves LV contraction and relaxation, it increases coronary blood flow velocity, predominantly by increasing the dominant diastolic backward decompression (suction) wave.

Noninvasive electrocardiographic mapping to guide ablation of outflow tract ventricular arrhythmias

Background Localizing the origin of outflow tract ventricular tachycardias (OTVT) is hindered by lack of accuracy of electrocardiographic (ECG) algorithms and infrequent spontaneous premature ventricular complexes (PVCs) during electrophysiological studies. Objectives To prospectively assess the performance of noninvasive electrocardiographic mapping (ECM) in the pre-/periprocedural localization of OTVT origin to guide ablation and to compare the accuracy of ECM with that of published ECG algorithms. Methods Patients with symptomatic OTVT/PVCs undergoing clinically indicated ablation were recruited. The OTVT/PVC origin was mapped preprocedurally by using ECM, and 3 published ECG algorithms were applied to the 12-lead ECG by 3 blinded electrophysiologists. Ablation was guided by using ECM. The OTVT/PVC origin was defined as the site where ablation caused arrhythmia suppression. Acute success was defined as abolition of ectopy after ablation. Medium-term success was defined as the abolition of symptoms and reduction of PVC to less than 1000 per day documented on Holter monitoring within 6 months. Results In 24 patients (mean age 50 ± 18 years) recruited ECM successfully identified OTVT/PVC origin in 23/24 (96%) (right ventricular outflow tract, 18; left ventricular outflow tract, 6), sublocalizing correctly in 100% of this cohort. Acute ablation success was achieved in 100% of the cases with medium-term success in 22 of 24 patients. PVC burden reduced from 21,837 ± 23,241 to 1143 ± 4039 (P < .0001). ECG algorithms identified the correct chamber of origin in 50%–88% of the patients and sublocalized within the right ventricular outflow tract (septum vs free-wall) in 37%–58%. Conclusions ECM can accurately identify OTVT/PVC origin in the left and the right ventricle pre- and periprocedurally to guide catheter ablation with an accuracy superior to that of published ECG algorithms.

Multinational evaluation of the interpretability of the iterative method of optimisation of AV delay for CRT

BACKGROUND AV delay optimisation of biventricular pacing devices (cardiac resynchronisation therapy, CRT) is performed in trials and recommended by current guidelines. The Doppler echocardiographic iterative method is the most commonly recommended. Yet whether it can be executed reliably has never been tested formally. METHODS 36 multinational specialists, familiar with using the echocardiographic iterative method of CRT optimisation, were shown 20-40 sets of transmitral Doppler traces at 6-8 AV settings and asked to select the optimal AV delay. Unknown to the specialists, some Doppler datasets appeared in duplicate, allowing assessment of both inter and intra-specialist interpretation. RESULTS On the Kappa scale of agreement (1 = perfect agreement, 0 = chance alone), the agreement regarding optimal AV delay between specialists was poor (kappa=0.12 ± 0.08). More importantly, agreement of specialists with themselves (i.e. viewing identical sets of traces, twice) was also poor, with Kappa=0.23 ± 0.07 and mean absolute difference in optimum AV delay of 83 ms between first and second viewing of the same traces. CONCLUSION Iterative AV optimisation is not executed reliably by experts, even in an artificially simplified context where biological variability and variation in image acquisition are eliminated by use of identical traces. This cannot be blamed on insufficient skills of some experts or discordant methods of selecting the optimum, because operators also showed poor agreement with themselves when assessing the same trace. Instead, guidelines should retract any recommendation for this algorithm. Guideline-development processes might usefully begin with a rudimentary check on proposed algorithms, to establish at least minimal credibility.

Cardiac resynchronization therapy and AV optimization increase myocardial oxygen consumption, but increase cardiac function more than proportionally

Background The mechanoenergetic effects of atrioventricular delay optimization during biventricular pacing (“cardiac resynchronization therapy”, CRT) are unknown. Methods Eleven patients with heart failure and left bundle branch block (LBBB) underwent invasive measurements of left ventricular (LV) developed pressure, aortic flow velocity-time-integral (VTI) and myocardial oxygen consumption (MVO2) at 4 pacing states: biventricular pacing (with VV 0 ms) at AVD 40 ms (AV-40), AVD 120 ms (AV-120, a common nominal AV delay), at their pre-identified individualised haemodynamic optimum (AV-Opt); and intrinsic conduction (LBBB). Results AV-120, relative to LBBB, increased LV developed pressure by a mean of 11(SEM 2)%, p = 0.001, and aortic VTI by 11(SEM 3)%, p = 0.002, but also increased MVO2 by 11(SEM 5)%, p = 0.04. AV-Opt further increased LV developed pressure by a mean of 2(SEM 1)%, p = 0.035 and aortic VTI by 4(SEM 1)%, p = 0.017. MVO2 trended further up by 7(SEM 5)%, p = 0.22. Mechanoenergetics at AV-40 were no different from LBBB. The 4 states lay on a straight line for Δexternal work (ΔLV developed pressure × Δaortic VTI) against ΔMVO2, with slope 1.80, significantly > 1 (p = 0.02). Conclusions Biventricular pacing and atrioventricular delay optimization increased external cardiac work done but also myocardial oxygen consumption. Nevertheless, the increase in cardiac work was ~ 80% greater than the increase in oxygen consumption, signifying an improvement in cardiac mechanoenergetics. Finally, the incremental effect of optimization on external work was approximately one-third beyond that of nominal AV pacing, along the same favourable efficiency trajectory, suggesting that AV delay dominates the biventricular pacing effect — which may therefore not be mainly “resynchronization”.

Applicability of the iterative technique for cardiac resynchronization therapy optimization: full-disclosure, 50-sequential-patient dataset of transmitral Doppler traces, with implications for future research design and guidelines

AIMS Full-disclosure study describing Doppler patterns during iterative atrioventricular delay (AVD) optimization of biventricular pacemakers (cardiac resynchronization therapy, CRT). METHOD AND RESULTS Doppler traces of the first 50 eligible patients undergoing iterative Doppler AVD optimization in the BRAVO trial were examined. Three experienced observers classified conformity to guideline-described patterns. Each observer then selected the optimum AVD on two separate occasions: blinded and unblinded to AVD. Four Doppler E-A patterns occurred: A (always merged, 18% of patients), B (incrementally less fusion at short AVDs, 12%), C (full separation at short AVDs, as described by the guidelines, 28%), and D (always separated, 42%). In Groups A and D (60%), the iterative guidelines therefore cannot specify one single AVD. On the kappa scale (0 = chance alone; 1 = perfect agreement), observer agreement for the ideal AVD in Classes B and C was poor (0.32) and appeared worse in Groups A and D (0.22). Blinding caused the scattering of the AVD selected as optimal to widen (standard deviation rising from 37 to 49 ms, P < 0.001). By blinding 28% of the selected optimum AVDs were ≤60 or ≥200 ms. All 50 Doppler datasets are presented, to support future methodological testing. CONCLUSION In most patients, the iterative method does not clearly specify one AVD. In all the patients, agreement on the ideal AVD between skilled observers viewing identical images is poor. The iterative protocol may successfully exclude some extremely unsuitable AVDs, but so might simply accepting factory default. Irreproducibility of the gold standard also prevents alternative physiological optimization methods from being validated honestly.

Fully Automatable, Reproducible, Noninvasive Simple Plethysmographic Optimization: Proof of Concept and Potential for Implantability

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.

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

Background In 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 results Twenty 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 10 ms for pressure, versus 8 ms (p = ns) for QRS and 34 ms (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 9 ms, no different from the reproducibility SDD at both heart rates. Conclusions Using 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.

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.