Punam A. Pabari

The Limit of Plausibility for Predictors of Response: Application to Biventricular Pacing

OBJECTIVES We sought a method for any reader to quantify the limit, imposed by variability, to sustainably observable R(2) between any baseline predictor and response marker. We then apply this to echocardiographic measurements of mechanical dyssynchrony and response. BACKGROUND Can mechanical dyssynchrony markers strongly predict ventricular remodeling by biventricular pacing (cardiac resynchronization therapy)? METHODS First, we established the mathematical depression of observable R(2) arising from: 1) spontaneous variability of response markers; and 2) test-retest variability of dyssynchrony measurements. Second, we contrasted published R(2) values between externally monitored randomized controlled trials and highly skilled single-center studies (HSSCSs). RESULTS Inherent variability of response markers causes a contraction factor in R(2) of 0.48 (change in left ventricular ejection fraction [ΔLVEF]), 0.50 (change in end-systolic volume [ΔESV]), and 0.40 (change in end-diastolic volume [ΔEDV]). Simultaneously, inherent variability of mechanical dyssynchrony markers causes a contraction factor of between 0.16 and 0.92 (average, 0.6). Therefore the combined contraction factor, that is, limit on sustainably observable R(2) between mechanical dyssynchrony markers and response, is ~0.29 (ΔLVEF), ~0.24 (ΔESV), and ~0.30 (ΔEDV). Many R(2) values published in HSSCSs exceeded these mathematical limits; none in externally monitored trials did so. Overall, HSSCSs overestimate R(2) by 5- to 20-fold (p = 0.002). Absence of bias-resistance features in study design (formal enrollment and blinded measurements) was associated with more overstatement of R(2). CONCLUSIONS Reports of R(2) > 0.2 in response prediction arose exclusively from studies without formally documented enrollment and blinding. The HSSCS approach overestimates R(2) values, frequently breaching the mathematical ceiling on sustainably observable R(2), which is far below 1.0, and can easily be calculated by readers using formulas presented here. Community awareness of this low ceiling may help resist future claims. Reliable individualized response prediction, using methods originally designed for group-mean effects, may never be possible because it has 2 currently unavailable and perhaps impossible prerequisites: 1) excellent blinded test-retest reproducibility of dyssynchrony; and 2) response markers reproducible over time within nonintervened individuals. Dispassionate evaluation, and improvement, of test-retest reproducibility is required before any further claims of strong prediction. Prediction studies should be designed to resist bias.

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.

The Acute Effects of Changes to AV Delay on BP and Stroke Volume Potential Implications for Design of Pacemaker Optimization Protocols

Background— The AV delay optimization of biventricular pacemakers (cardiac resynchronization therapy) may maximize hemodynamic benefit but consumes specialist time to conduct echocardiographically. Noninvasive BP monitoring is a potentially automatable alternative, but it is unknown whether it gives the same information and similar precision (signal/noise ratio). Moreover, the immediate BP increment on optimization has been reported to decay away: it is unclear whether this is the result of an (undesirable) decrease in stroke volume or a (desirable) compensatory relief of peripheral vasoconstriction. Methods and Results— To discriminate between these alternative mechanisms, we measured simultaneous beat-to-beat stroke volume (flow) using Doppler echocardiography, and BP using finger photoplethysmography, during and after AV delay changes from 40 to 120 ms in 19 subjects with cardiac pacemakers. BP and stroke volume both increased immediately ( P <0.001, within 1 heartbeat). BP showed a clear decline a few seconds later (average rate, −0.65 mm Hg/beat; r =0.95 [95% CI, 0.86–0.98]); in contrast, stroke volume did not decline ( P =0.87). The immediate BP increment correlated strongly with the stroke volume increment ( r =0.74, P <0.001). The signal/noise ratio was 3-fold better for BP than stroke volume (6.8±3.5 versus 2.3±1.4; P <0.001). Conclusions— Improving AV delay immediately increases BP, but the effect begins to decay within a few seconds. Reassuringly, this is because of compensatory vasodilatation rather than reduction in cardiac function. Pacemaker optimization will never be reliable unless there is an adequate signal/noise ratio. Using BP rather than Doppler minimizes noise. The early phase (before vascular compensation) has the richest signal lode.Background— The AV delay optimization of biventricular pacemakers (cardiac resynchronization therapy) may maximize hemodynamic benefit but consumes specialist time to conduct echocardiographically. Noninvasive BP monitoring is a potentially automatable alternative, but it is unknown whether it gives the same information and similar precision (signal/noise ratio). Moreover, the immediate BP increment on optimization has been reported to decay away: it is unclear whether this is the result of an (undesirable) decrease in stroke volume or a (desirable) compensatory relief of peripheral vasoconstriction. Methods and Results— To discriminate between these alternative mechanisms, we measured simultaneous beat-to-beat stroke volume (flow) using Doppler echocardiography, and BP using finger photoplethysmography, during and after AV delay changes from 40 to 120 ms in 19 subjects with cardiac pacemakers. BP and stroke volume both increased immediately (P<0.001, within 1 heartbeat). BP showed a clear decline a few seconds later (average rate, −0.65 mm Hg/beat; r=0.95 [95% CI, 0.86–0.98]); in contrast, stroke volume did not decline (P=0.87). The immediate BP increment correlated strongly with the stroke volume increment (r=0.74, P<0.001). The signal/noise ratio was 3-fold better for BP than stroke volume (6.8±3.5 versus 2.3±1.4; P<0.001). Conclusions— Improving AV delay immediately increases BP, but the effect begins to decay within a few seconds. Reassuringly, this is because of compensatory vasodilatation rather than reduction in cardiac function. Pacemaker optimization will never be reliable unless there is an adequate signal/noise ratio. Using BP rather than Doppler minimizes noise. The early phase (before vascular compensation) has the richest signal lode.

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”.

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.

A novel fully automated method for mitral regurgitant orifice area quantification

Background Effective regurgitant orifice area (EROA) in mitral regurgitation (MR) is difficult to quantify. Clinically it is measured using the proximal isovelocity surface area (PISA) method, which is intrinsically not automatable, because it requires the operator to manually identify the mitral valve orifice. We introduce a new fully automated algorithm, (“AQURO”), which calculates EROA directly from echocardiographic colour M-mode data, without requiring operator input. Methods Multiple PISA measurements were compared to multiple AQURO measurements in twenty patients with MR. For PISA analysis, three mutually blinded observers measured EROA from the four stored video loops. For AQURO analysis, the software automatically processed the colour M-mode datasets and analysed the velocity field in the flow-convergence zone to extract EROA directly without any requirement for manual radius measurement. Results Reproducibility, measured by intraclass correlation (ICC), for PISA was 0.80, 0.83 and 0.83 (for 3 observers respectively). Reproducibility for AQURO was 0.97. Agreement between replicate measurements calculated using Bland-Altman standard deviation of difference (SDD) was 21,17 and 17mm2for the three respective observers viewing independent video loops using PISA. Agreement between replicate measurements for AQURO was 6, 5 and 7mm2for automated analysis of the three pairs of datasets. Conclusions By eliminating the need to identify the orifice location, AQURO avoids an important source of measurement variability. Compared with PISA, it also reduces the analysis time allowing analysis and averaging of data from significantly more beats, improving the consistency of EROA quantification. AQURO, being fully automated, is a simple, effective enhancement for EROA quantification using standard echocardiographic equipment.

Evidence-based recommendations for PISA measurements in mitral regurgitation: systematic review, clinical and in-vitro study ☆ ☆☆

Background Guidelines for quantifying mitral regurgitation (MR) using “proximal isovelocity surface area” (PISA) instruct operators to measure the PISA radius from valve orifice to Doppler flow convergence “hemisphere”. Using clinical data and a physically-constructed MR model we (A) analyse the actually-observed colour Doppler PISA shape and (B) test whether instructions to measure a “hemisphere” are helpful. Methods and results In part A, the true shape of PISA shells was investigated using three separate approaches. First, a systematic review of published examples consistently showed non-hemispherical, “urchinoid” shapes. Second, our clinical data confirmed that the Doppler-visualized surface is non-hemispherical. Third, in-vitro experiments showed that round orifices never produce a colour Doppler hemisphere. In part B, six observers were instructed to measure hemisphere radius rh and (on a second viewing) urchinoid distance (du) in 11 clinical PISA datasets; 6 established experts also measured PISA distance as the gold standard. rh measurements, generated using the hemisphere instruction significantly underestimated expert values (− 28%, p < 0.0005), meaning rh2 was underestimated by approximately 2-fold. du measurements, generated using the non-hemisphere instruction were less biased (+ 7%, p = 0.03). Finally, frame-to-frame variability in PISA distance was found to have a coefficient of variation (CV) of 25% in patients and 9% in in-vitro data. Beat-to-beat variability had a CV of 15% in patients. Conclusions Doppler-visualized PISA shells are not hemispherical: we should avoid advising observers to measure a hemispherical radius because it encourages underestimation of orifice area by approximately two-fold. If precision is needed (e.g. to detect changes reliably) multi-frame averaging is essential.

The Acute Effects of Changes to AV Delay on Blood Pressure and Stroke Volume: Potential Implications for Design of Pacemaker Optimization Protocols

Background— The AV delay optimization of biventricular pacemakers (cardiac resynchronization therapy) may maximize hemodynamic benefit but consumes specialist time to conduct echocardiographically. Noninvasive BP monitoring is a potentially automatable alternative, but it is unknown whether it gives the same information and similar precision (signal/noise ratio). Moreover, the immediate BP increment on optimization has been reported to decay away: it is unclear whether this is the result of an (undesirable) decrease in stroke volume or a (desirable) compensatory relief of peripheral vasoconstriction. Methods and Results— To discriminate between these alternative mechanisms, we measured simultaneous beat-to-beat stroke volume (flow) using Doppler echocardiography, and BP using finger photoplethysmography, during and after AV delay changes from 40 to 120 ms in 19 subjects with cardiac pacemakers. BP and stroke volume both increased immediately ( P <0.001, within 1 heartbeat). BP showed a clear decline a few seconds later (average rate, −0.65 mm Hg/beat; r =0.95 [95% CI, 0.86–0.98]); in contrast, stroke volume did not decline ( P =0.87). The immediate BP increment correlated strongly with the stroke volume increment ( r =0.74, P <0.001). The signal/noise ratio was 3-fold better for BP than stroke volume (6.8±3.5 versus 2.3±1.4; P <0.001). Conclusions— Improving AV delay immediately increases BP, but the effect begins to decay within a few seconds. Reassuringly, this is because of compensatory vasodilatation rather than reduction in cardiac function. Pacemaker optimization will never be reliable unless there is an adequate signal/noise ratio. Using BP rather than Doppler minimizes noise. The early phase (before vascular compensation) has the richest signal lode.Background— The AV delay optimization of biventricular pacemakers (cardiac resynchronization therapy) may maximize hemodynamic benefit but consumes specialist time to conduct echocardiographically. Noninvasive BP monitoring is a potentially automatable alternative, but it is unknown whether it gives the same information and similar precision (signal/noise ratio). Moreover, the immediate BP increment on optimization has been reported to decay away: it is unclear whether this is the result of an (undesirable) decrease in stroke volume or a (desirable) compensatory relief of peripheral vasoconstriction. Methods and Results— To discriminate between these alternative mechanisms, we measured simultaneous beat-to-beat stroke volume (flow) using Doppler echocardiography, and BP using finger photoplethysmography, during and after AV delay changes from 40 to 120 ms in 19 subjects with cardiac pacemakers. BP and stroke volume both increased immediately (P<0.001, within 1 heartbeat). BP showed a clear decline a few seconds later (average rate, −0.65 mm Hg/beat; r=0.95 [95% CI, 0.86–0.98]); in contrast, stroke volume did not decline (P=0.87). The immediate BP increment correlated strongly with the stroke volume increment (r=0.74, P<0.001). The signal/noise ratio was 3-fold better for BP than stroke volume (6.8±3.5 versus 2.3±1.4; P<0.001). Conclusions— Improving AV delay immediately increases BP, but the effect begins to decay within a few seconds. Reassuringly, this is because of compensatory vasodilatation rather than reduction in cardiac function. Pacemaker optimization will never be reliable unless there is an adequate signal/noise ratio. Using BP rather than Doppler minimizes noise. The early phase (before vascular compensation) has the richest signal lode.