Shortening of time-to-peak left ventricular pressure rise (Td) in cardiac resynchronization therapy

Abstract

Aims: We tested the hypothesis that shortening of time-to-peak left ventricular pressure rise (Td) reflect resynchronization in an animal model and that Td measured in patients will be helpful to identify long-term volumetric responders [end-systolic volume (ESV) decrease >15%] in cardiac resynchronization therapy (CRT).

Methods: Td was analysed in an animal study (n = 12) of left bundle-branch block (LBBB) with extensive instrumentation to detect left ventricular myocardial deformation, electrical activation, and pressures during pacing. The sum of electrical delays from the onset of pacing to four intracardiac electrodes formed a synchronicity index (SI). Pacing was performed at baseline, with LBBB, right and left ventricular pacing and finally with biventricular pacing (BIVP). We then studied Td at baseline and with BIVP in a clinical observational study in 45 patients during the implantation of CRT and followed up for up to 88 months.

Results: We found a strong relationship between Td and SI in the animals (R = 0.84, P < 0.01). Td and SI increased from narrow QRS at baseline (Td = 95 ± 2 ms, SI = 141 ± 8 ms) to LBBB (Td = 125 ± 2 ms, SI = 247 ± 9 ms, P < 0.01), and shortened with biventricular pacing (BIVP) (Td = 113 ± 2 ms and SI = 192 ± 7 ms, P < 0.01). Prolongation of Td was associated with more wasted deformation during the preejection period (R = 0.77, P < 0.01). Six patients increased ESV by 2.5 ± 18%, while 37 responders (85%) had a mean ESV decrease of 40 ± 15% after more than 6 months of follow-up. Responders presented with a higher Td at baseline than non-responders (163 ± 26 ms vs. 121 ± 19 ms, P < 0.01). Td decreased to 156 ± 16 ms (P = 0.02) with CRT in responders, while in non-responders, Td increased to 148 ± 21 ms (P < 0.01). A decrease in Td with BIVP to values similar or below what was found at baseline accurately identified responders to therapy (AUC 0.98, P < 0.01). Td at baseline and change in Td from baseline was linear related to the decrease in ESV at follow-up. All-cause mortality was high among six non-responders (n = 4), while no patients died in the responder group during follow-up.

Conclusions: Prolongation of Td is associated with cardiac dyssynchrony and more wasted deformation during the preejection period. Shortening of a prolonged Td with CRT in patients accurately identifies volumetric responders to CRT with incremental value on top of current guidelines and practices. Thus, Td carries the potential to become a biomarker to predict long-term volumetric response in CRT candidates.

Keywords: Cardiac resynchronization therapy; Reverse volumetric remodelling; Time-to-peak dP/dt.

Conflict of interest statement

None declared.

H.H.O. had an honorary from Abbott Medical, Stockholder Pacertool, and patent applications within the field of cardiac resynchronization therapy. R.C. is an employee of Medtronic Inc, Stockholder Medtronic Inc. T.H. and E.K. have no conflict of interest.

© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Figures

Figure 1

Regional myocardial deformation, relationship towards time‐to‐peak LV dP/dt, Td, and synchronicity index (SI). (A) Regional myocardial deformation with right ventricular (RV) free wall pacing. The electrical activation sequence is early in the septal electrode and last in the lateral. Lengthening occurs between anterior–posterior crystals and shortening between the septal and lateral crystals (septal beaking). This deformation represents a transfer of forces from one region to the other and indicates dyssynergy of contraction. Hence, more deformation equals more dyssynergy of contraction. Tension builds up with completion of electrical activation with rebound lengthening in the septal‐lateral crystal pair before peak LV dP/dt and aortic valve opening. Total deformation is calculated as the sum of absolute maximum deformation values measured from the onset of pacing to peak LV dP/dt (A and B) and is limited to the isovolumetric period. (B) BIVP with RV apex and left ventricular (LV) lateral electrodes. The activation sequence is early lateral and late septal. Only minimal deformations occur (less dyssynergy) while tension increases towards the end of electrical activation up to peak LV dP/dt that occur early due to improved synergy from stimulation. (C) We found a linear relationship between Td and the total deformation, as measured between each pair of crystals (panel A and panel B), indicating that more deformation delays Td. (D) Synchronicity index (SI, ms) was constructed based on the sum of the four intervals 1–4 from the onset of pacing to the deflections in the respective equatorial EGMs (absolute dV/dt). BIVP, biventricular pacing; RV, right ventricle; dP/dt, left ventricular pressure derivative.

Figure 2

Demonstration of shortening of time‐to‐peak dP/dt (Td) with biventricular pacing and myocardial synergy with simultaneous pacing of the RV and the LV (resynchronization). (A) Left bundle branch block (LBBB) with electrical activation patterns showing a sequence of septal‐anterior–posterior‐lateral activation with dyssynergistic septal and lateral wall contraction patterns with pressure rise reaching its peak just before aortic valve opening. Red arrow: Septal beaking. Grey arrow: shortening of the lateral segment. Green arrow: onset of ejection. (B) Biventricular pacing from an apical positioned left ventricular epicardial electrode demonstrates a simultaneous sequence of activation with synergistic septal and lateral wall contraction patterns and peak left ventricular pressure rise (that occur before aortic valve opening). Grey arrow: shortening of the lateral segment. Green arrow: onset of ejection. V1, ECG lead; RV, right ventricle; LV, left ventricle; LVP, left ventricular pressure; LV dP/dt, LV pressure derivative; Td, time‐to‐peak LV dP/dt.

Figure 3

Correlations between Td and synchronicity index (SI) with Bland–Altman plot and Td and LV dP/dtmax. (A) A strong positive relationship was found between Td and SI in the animals with all pacing modes and intrinsic conduction with narrow QRS and LBBB pooled. (B) We divided SI by four since it is made up of four numbers to avoid a bias with higher numbers for the creation of the Bland–Altman plot against Td with limits of agreement. The plot indicates that the two methods reflect the same underlying pathology within limits of agreement with a bias of 64.45 ms with consistent variability and no trend. The correlation between Td and SI/4 was good with β = 0.9, R = 0.84, P < 0.01 with no visual bias in the residual plot. (C) LV dP/dtmax was only weakly correlated with SI. (D) A significant relationship between the left ventricular electrical delay (Q‐LV) measured from onset of Q to the lateral electrode, at baseline, with LBBB and with RV pace. Td, time‐to‐peak LV dP/dt; SI, synchronicity index; LBBB, left bundle branch block; LV dP/dtmax, maximum left ventricular first‐order pressure derivative.

Figure 4

Synergy from biventricular resynchronization on the timing of peak dP/dt. The panel shows atrial, RV, LV and biventricular pacing with pacing electrode EGMs, LV pressure, LV pressure derivative, and femoral artery pressure from one patient. Td is longer with RV pace than with LV pace, and without myocardial synergy between RV pace and LV pace, one would expect Td with BIV pace (which includes the two pacing electrodes) to be similar to the shorter of that from RV or LV pace; however, BIV pace shortens by 10 ms compared with LV pace demonstrating the presence of myocardial synergy resulting in an earlier pressure increase with BIV pace. Note that a long Q‐LV, RV pace to LV sensed interval, and LV pace to RV sensed interval, confirming the placement of the LV electrode in a late activated region of the LV electrically distant from the RV electrode. Asterisk denotes a pacing artefact. V1, ECG lead; RV, right ventricle; LV, left ventricle; LVP, left ventricular pressure; LV dP/dt, LV pressure derivative; Td, time‐to‐peak LV dP/dt.

Figure 5

Crude estimates of the relationship between the baseline Td and reverse remodelling and the relationship between the corrected change in Td and reverse remodelling. (A) Scatterplot is showing the relationship between Td and ESV decrease. Stippled lines mark corresponding baseline Td values for a 15% and 53% ESV decrease—the line of equality in blue with the corresponding equation for the linear regression. (B) Scatterplot is showing the relationship between the corrected Td change from baseline and ESV decrease. The corrected change means that 15 ms is added to the baseline Td to compensate for the capture latency with pacing. The stippled lines show the corresponding value of Td change to a 50% decrease in ESV. Line of equality in blue with the corresponding equation for the linear regression. (C) Scatterplot is showing the relationship between the ratio Td/QRSd and Td. The relationship shows that a longer baseline Td is also longer relative to the baseline QRS duration. ESV, end‐systolic volume; Td, time‐to‐peak dP/dt; QRSd, QRS duration.

Figure 6

Receiver operating characteristics. The figure displays QRS duration, Td at baseline, Q‐LV and corrected Td change from baseline as predictors of long‐term volumetric response to cardiac resynchronization therapy. Top panel: Scatterplot and corresponding receiver operating characteristics curve displaying QRS duration as a predictor of response to cardiac resynchronization therapy. Top middle panel: Scatterplot and corresponding receiver operating characteristics curve displaying Q‐LV as a predictor of response to cardiac resynchronization therapy. Lower middle panel: Scatterplot and corresponding receiver operating characteristics curve displaying Td baseline as a predictor of response to cardiac resynchronization therapy. Lower panel: Scatterplot and corresponding receiver operating characteristics curve displaying corrected Td change from baseline as a predictor of response to cardiac resynchronization therapy. ESV, end‐systolic volume; Q‐LV, left ventricular electrical delay; Td, time‐to‐peak dP/dt; AUC, area under the curve.