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

Siana Jones, Joost Lumens, S M Afzal Sohaib, Judith A Finegold, Prapa Kanagaratnam, Mark Tanner, Edward Duncan, Philip Moore, Francisco Leyva, Mike Frenneaux, Mark Mason, Alun D Hughes, Darrel P Francis, Zachary I Whinnett, BRAVO Investigators, Nishi Chaturvedi, Wyn Davies, Boon Lim, David Lefroy, Nicholas S Peters, Emma Coady, Katherine March, Suzanne Williams, Karikaran Manoharan, Nadia Do Couto Francisco, Vasco Miranda Carvalho, Andreas Kyriacou, Amelia Rudd, Nadiya Sivaswamy, Satnam Singh, Martin Thomas, Jon Swinburn, Paul Foley, Tim Betts, David Webster, Dominic Rogers, Tom Wong, Rakesh Sharma, Susan Ellery, Zaheer Yousef, Lisa Anderson, Mohamed Al-Obaidi, Nicky Margerison, Stephanie Barrett, Paul Kalra, Raj Khiani, Mark Dayer, Siana Jones, Joost Lumens, S M Afzal Sohaib, Judith A Finegold, Prapa Kanagaratnam, Mark Tanner, Edward Duncan, Philip Moore, Francisco Leyva, Mike Frenneaux, Mark Mason, Alun D Hughes, Darrel P Francis, Zachary I Whinnett, BRAVO Investigators, Nishi Chaturvedi, Wyn Davies, Boon Lim, David Lefroy, Nicholas S Peters, Emma Coady, Katherine March, Suzanne Williams, Karikaran Manoharan, Nadia Do Couto Francisco, Vasco Miranda Carvalho, Andreas Kyriacou, Amelia Rudd, Nadiya Sivaswamy, Satnam Singh, Martin Thomas, Jon Swinburn, Paul Foley, Tim Betts, David Webster, Dominic Rogers, Tom Wong, Rakesh Sharma, Susan Ellery, Zaheer Yousef, Lisa Anderson, Mohamed Al-Obaidi, Nicky Margerison, Stephanie Barrett, Paul Kalra, Raj Khiani, Mark Dayer

Abstract

Aims: Cardiac resynchronization therapy (CRT) may exert its beneficial haemodynamic effect by improving ventricular synchrony and improving atrioventricular (AV) timing. The aim of this study was to establish the relative importance of the mechanisms through which CRT improves cardiac function and explore the potential for additional improvements with improved ventricular resynchronization.

Methods and results: We performed simulations using the CircAdapt haemodynamic model and performed haemodynamic measurements while adjusting AV delay, at low and high heart rates, in 87 patients with CRT devices. We assessed QRS duration, presence of fusion, and haemodynamic response. The simulations suggest that intrinsic PR interval and the magnitude of reduction in ventricular activation determine the relative importance of the mechanisms of benefit. For example, if PR interval is 201 ms and LV activation time is reduced by 25 ms (typical for current CRT methods), then AV delay optimization is responsible for 69% of overall improvement. Reducing LV activation time by an additional 25 ms produced an additional 2.6 mmHg increase in blood pressure (30% of effect size observed with current CRT). In the clinical population, ventricular fusion significantly shortened QRS duration (Δ-27 ± 23 ms, P < 0.001) and improved systolic blood pressure (mean 2.5 mmHg increase). Ventricular fusion was present in 69% of patients, yet in 40% of patients with fusion, shortening AV delay (to a delay where fusion was not present) produced the optimal haemodynamic response.

Conclusions: Improving LV preloading by shortening AV delay is an important mechanism through which cardiac function is improved with CRT. There is substantial scope for further improvement if methods for delivering more efficient ventricular resynchronization can be developed.

Clinical trial registration: Our clinical data were obtained from a subpopulation of the British Randomised Controlled Trial of AV and VV Optimisation (BRAVO), which is a registered clinical trial with unique identifier: NCT01258829, https://clinicaltrials.gov.

Keywords: AV delay; CRT; CRT mechanisms; Cardiac resynchronization therapy; Resynchronization.

© The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Figure 1
Figure 1
Simulated ventricular activation patterns. Four different LV activation states were simulated: (A) typical LBBB; (B) LV activation time of 110 ms (CRT-110), which represents the typical electrical resynchronization obtained with current CRT; and (C and D) additional 25 and 50 ms reduction in ventricular activation time, over and above that obtained with current CRT. This represents LV activation times of 85 ms (CRT-85) and 60 ms (CRT-60), respectively. Red stars indicate RV and LV lead positions.
Figure 2
Figure 2
Simulation-based assessment of the relative importance of AV delay optimization and left ventricular activation time (LVAT) with current CRT methods and predicted impact of additional improvements in LV resynchronization. The left plot shows the relationship between AV delay and SV, and the right plot shows the relationship between AV delay and SBP. Four different ventricular activation states are displayed. Typical LBBB (LV activation time 135 ms). The typical electrical resynchronization obtained with current CRT [LV activation time of 110 ms (CRT-110)]. Additional 25 and 50 ms reductions in ventricular activation time, over and above that obtained with current CRT [LV activation times of 85 ms (CRT-85) and 60 ms (CRT-60)]. The Turquoise vertical arrow shows the improvement gained from optimizing AV timing relative to a baseline AV delay of 200 ms. Improvements gained from each additional reduction in LVAT are indicated by the red vertical arrows.
Figure 3
Figure 3
Categorization of patients. Patients were grouped according to their optimal AV delay determined by haemodynamic optimization at low and high heart rates and by the presence or absence of AV node decrementation. BVP and CHB.
Figure 4
Figure 4
Untapped potential for ventricular resynchronization. QRS duration is shown during intrinsic conduction (no CRT), with CRT, and with CRT pacing allowing fusion of paced and intrinsic conduction, and previously published data for QRS duration from healthy subjects are shown for normal conduction.
Figure 5
Figure 5
Example haemodynamic optimization data from an individual patient in each group. Low (Turquoise) and high (red) heart rates for each tested AV delay are shown. Each point represents the mean of 6–10 measurements, and the vertical bar represents the SD. Periods of complete capture, fusion, and native activation are shown, and AV delays that resulted in fusion are displayed as points filled with colour. QRS duration at each tested AV delay is plotted for low and high heart rates below the optimization curves. Abbreviations: heart rate (HR), change in SBP relative to value at AV delay 120 ms (ΔSBP).

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Source: PubMed

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