title: Cardiac resynchronization therapy: mechanisms of action and scope for further improvement in cardiac function.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  BACKGROUND
  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.
authors.affiliation: Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.
authors.forename: Siana
authors.initials: S
authors.lastname: Jones
authors.affiliation: CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht 6229 ER, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Lumens
authors.affiliation: NHLI-Cardiovascular Science, Imperial College London, National Heart and Lung Institute, The Hammersmith Hospital, B Block South, 2nd Floor, Du Cane Road, London W12 ONN, UK.
authors.forename: S M Afzal
authors.initials: SMA
authors.lastname: Sohaib
authors.affiliation: NHLI-Cardiovascular Science, Imperial College London, National Heart and Lung Institute, The Hammersmith Hospital, B Block South, 2nd Floor, Du Cane Road, London W12 ONN, UK.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Finegold
authors.affiliation: NHLI-Cardiovascular Science, Imperial College London, National Heart and Lung Institute, The Hammersmith Hospital, B Block South, 2nd Floor, Du Cane Road, London W12 ONN, UK.
authors.forename: Prapa
authors.initials: P
authors.lastname: Kanagaratnam
authors.affiliation: St Richards Hospital, Western Sussex Hospitals Foundation Trust, Chichester PO19 6SE, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Tanner
authors.affiliation: Bristol Royal Infirmary, Marlborough Street, Bristol BS2 8HW, UK.
authors.forename: Edward
authors.initials: E
authors.lastname: Duncan
authors.affiliation: Watford General Hospital, Vicarage Road, Watford WD18 0HB, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Moore
authors.affiliation: Queen Elizabeth Hospital, Mindelsohn Way, Edgbaston, Birmingham B15 2WB, UK.
authors.forename: Francisco
authors.initials: F
authors.lastname: Leyva
authors.affiliation: School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Frenneaux
authors.affiliation: Harefield Hospital, Hill End Road, Harefield, Middlesex UB9 6JH, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Mason
authors.affiliation: Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.
authors.forename: Alun D
authors.initials: AD
authors.lastname: Hughes
authors.affiliation: NHLI-Cardiovascular Science, Imperial College London, National Heart and Lung Institute, The Hammersmith Hospital, B Block South, 2nd Floor, Du Cane Road, London W12 ONN, UK.
authors.forename: Darrel P
authors.initials: DP
authors.lastname: Francis
authors.affiliation: NHLI-Cardiovascular Science, Imperial College London, National Heart and Lung Institute, The Hammersmith Hospital, B Block South, 2nd Floor, Du Cane Road, London W12 ONN, UK.
authors.forename: Zachary I
authors.initials: ZI
authors.lastname: Whinnett
mesh_terms: D000200:Action Potentials; D000368:Aged; D001283:Atrioventricular Node / Q000503:physiopathology*; D001794:Blood Pressure; D002037:Bundle-Branch Block / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy*; D058406:Cardiac Resynchronization Therapy / Q000009:adverse effects / Q000379:methods*; D003198:Computer Simulation; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy*; D006339:Heart Rate; D006439:Hemodynamics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular; D020127:Recovery of Function; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom; D016277:Ventricular Function, Left
keywords: AV delay; CRT; CRT mechanisms; Cardiac resynchronization therapy; Resynchronization