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ETUDE DE LA DYSSYNCHRONIE CONTRACTILE DANS L'INSUFFISANCE CARDIAQUE CHEZ LE CHIEN ET SA MODULATION PAR DES AGENTS PHARMACOLOGIQUES

Abstract : Cardiac resynchronization therapy (CRT) has become a standard of care for patients with heart failure (HF) associated with left ventricular (LV) dyssynchrony. CRT benefits are heterogeneous between patients and approximately one third of severe patients are either non eligible or non-responders (clinically or echocardiographically). Thus, guidelines restrict CRT to HF patients with both mechanical dyssynchrony and wide QRS. The relationship of mechanical dyssynchrony and QRS widening has been described among populations. However, the longitudinal evolution of this relationship along the impairment of cardiac function has not been characterized. The dog model of dilated cardiomyopathy (DCM) induced by rapid ventricular pacing is recognize as a predictive and translational model to investigate HF mechanism. Using healthy and DCM dogs, this work investigates the interplay of the mechanical dyssynchrony and the different phases of the cardiac electrophysiology (assessed by electrocardiogram, ECG), especially on ventricular depolarization and repolarization, i.e, QRS complex, JTp interval and Tp-Te interval. Mechanical dyssynchrony was assessed by the measurement of septal to posterior wall motion delay (SPWMD) using echocardiography and the QRS complex, JTp interval and Tp-Te interval durations were monitored on ECG. Three series of experiments were conducted: firstly, mechanical dyssynchrony and QRS complex duration were correlated along the degradation of LV on dogs who underwent rapid ventricular pacing for seven weeks at 240 bpm (n=6) through a right ventricular pacemaker. Secondly, dyssynchrony was evoked on healthy dogs by flecainide (Class Ic anti-arrhythmic, fast sodium channels blocker, infused i.v. at 10mg/kg over 45 minutes, n=6). Finally, the HMR1556 (blocker of the slow delayed rectifier potassium current IKs, administered at 30 mg/kg, P.O, n=4) on healthy dogs and dogs with moderate and severe heart failure. In pacing-induced DCM dogs, SPWMD progressively increased and became significant after 14 days of pacing to reach 122 ± 2.7 ms on day 42 of pacing vs 35 ± 8.4 ms before pacing (p=0.0001) while QRS duration progressively increased from 39 ± 2 ms to 48 ± 3 ms after 21 days of pacing (p<0.0001). In healthy dogs, the block of INa and IKs channels modified ECG duration and increased SPWMD. Flecaïnide widened QRS complex (+ 30±7%) and increased SPWMD by 40±10% (p <0.01 vs baseline). HMR1556 elongated the late repolarization evaluated by the ECG index (Tp-Te/QT and Tp-Te/JTp) and increased SPWMD by 46%. Whereas, in pacing-induced DCM dogs, HMR1556 decreased by 13% SPWMD with a pronounced effect on early repolarization (JT/QT increased). In pacing-induced DCM dogs, mechanical dyssynchrony preceded QRS widening and QRS complex duration started to increase after SPWMD had reached a plateau. QRS widening is a marker of dyssynchrony severity. The ventricular depolarization and repolarization modulation on healthy and DCM dogs impacted the mechanical dyssynchrony especially in DCM dogs where HMR1556 decreased the SPWMD. In conclusion, mechanical dyssynchrony in HF patients seems to be curable with new "resynchronizing" drugs whose mechanisms of action would not be electrophysiological correction but rather modulating electrophysiological for reintegrate wasted contraction in dyssynchrony into a fully efficient and coordinated systole.
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Submitted on : Thursday, March 5, 2020 - 4:21:11 PM
Last modification on : Wednesday, September 28, 2022 - 4:20:11 PM
Long-term archiving on: : Saturday, June 6, 2020 - 12:45:15 PM

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L. Ly Nguyen. ETUDE DE LA DYSSYNCHRONIE CONTRACTILE DANS L'INSUFFISANCE CARDIAQUE CHEZ LE CHIEN ET SA MODULATION PAR DES AGENTS PHARMACOLOGIQUES. Cardiologie et système cardiovasculaire. 2019. ⟨hal-02470545⟩

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