The Clinical And Experimental Study Of The Impact Of Physiological Pacing On Left Ventricular Synchrony And Function

Part One:The Impact of Septal Right Ventricular Outflow TractPacing and Right Ventricular Apex Pacing on Left Ventricular Synchrony and Function in Patients with Normal Cardiac FunctionObjective:To compare the impact of septal right ventricular outflow tract (RVOT) pacing and right ventricular apex (RVA) pacing on left ventricular synchrony, cardiac function and remodeling in patients with normal cardiac function.Methods: A total of 96 consecutive patients with high or third degree atrial-ventricular block were enrolled and randomized into two groups:RVOT pacing group (n=48) and RVA pacing group (n=48). Tissue Doppler Imaging (TDI) and two-dimensional echocardiography (2DE) were performed to investigate left ventricular (LV) systolic and diastolic synchrony, LV systolic and diastolic function and LV volumes before pacemaker implantation and after 12 months of ventricular pacing. Using the 2DE apical 4 chamber views, we acquired the left ventricular (LV) end-diastolic volume (LVEDV), end-systolic volume (LVESV) and LV ejection fraction (LVEF) measured by Simpson's rule. From color TDI, the time to peak myocardial systolic velocity during the ejection phase (Ts) and the time to peak myocardial early diastolic velocity (Te) were measured with referenced to QRS complex, the peak myocardial systolic velocities (Sm) and peak myocardial early diastolic velocities (Em) were recorded. The standard deviation of Ts (Ts-12SD) of all the 12 LV segments, and the maximal difference in Ts (Ts-Dif) between any 2 of the 12 LV segments were calculated. The standard deviation of Te (Te-12SD) of all the 12 LV segments and the maximal difference in Te (Te-Dif) were measured.Results:Two patients in group A and 4 patients in group B were lost during the 12 months of follow-up. There were no significant differences in baseline characteristics and all echocardiography parameters between the two groups. After 12 months of ventricular pacing, Ts-12SD (26.43±14.39 ms vs 35.53±15.53 ms, P<0.05) and Te-12SD (23.82±8.90 ms vs 27.98±11.07 ms, P<0.05) increased in group B, and remained unchanged in group A (Ts-12SD:24.98±15.49 ms vs 28.30±15.09 ms; Te-12SD:25.84±14.69 ms vs 28.31±10.12 ms; both NS). Ts-Dif prolonged (P< 0.05) and Te-Dif did not change (both NS) in both groups. Ts-12SD and Ts-Dif in group B were greater than those in group A (both P<0.05), while Te-12SD and Te-Dif were not different between the two groups at 12 months of follow-up (NS). After 12 months of ventricular pacing, Sm (group A:5.03±1.14 vs 4.44±1.08 cm/s; group B:5.10±1.56 vs 4.24±1.15 cm/s; both P<0.05) and Em (group A:5.79±2.62 vs 4.43±1.65 cm/s; group B:5.42±1.95 vs 4.44±1.74 cm/s; both P<0.05) decreased but LVEF did not change (NS) in both groups. LVEDV and LVESV did not change both in group A and group B (all NS). There were no significant differences with respect to Sm, Em, LVEF, LVEDV and LVESV in the two groups at 12 months of follow-up (all NS).Conclusions:Although RVOT septal pacing caused more synchronous LV contraction compared with RVA pacing, it did not benefit over RVA pacing in the aspect of preventing cardiac remodeling and preserving LV systolic function after 12 months of pacing in patients with normal cardiac function.Part Two:The Predictive Value of Clinical and Echocardiographic Parameters on Cardiac Resynchronization TherapyObjective:To compare and assess the value of echocardiographic parameters of M-mode, pulsed-wave Doppler and tissue Doppler imaging which were usually used for selecting cardiac resynchronization therapy (CRT) candidates, N-terminal pro-brain natriuretic peptide (NT-ProBNP), and the duration of QRS wave in predicting the response to CRT and to evaluate the possible best parameter to predict the response to CRT.Methods:Eighty patients accepted CRT because of refractory heart failure were enrolled from 2006.9 to 2009.12. Two-dimensional echocardiography (2DE), M-mode, pulsed-wave Doppler and tissue Doppler imaging (TDI) were performed before and after 6 months of CRT. Using the 2DE, we acquired the left ventricular (LV) diastolic diameter (LVDD), LV systolic diameter (LVDS), left atria diameter (LAD), LV end diastolic volume (LVEDV), LV end systolic volume (LVESV) and LV ejection fraction (LVEF) measured by Simpson's rule. M-mode echocardiography, pulsed-wave Doppler and TDI were used to evaluate inter- and intra- ventricular dyssynchrony. M-mode echocardiography was used to acquire the septal- to- posterior wall motion delay (SPWMD), pulsed-wave Doppler was used to acquire aortic wave pre- ejection interval (APEI) and pulmonary wave pre- ejection interval (PPEI), and inter-ventricular mechanical delay (IVMD) was calculated. TDI were used to get the standard deviation of time to peak myocardial systolic velocity (Ts-12SD). Meanwhile, the concentration of NT-ProBNP was detected before and after 7 days of CRT implantation and transformed to logarithm log (NT-ProBNP). The duration of QRS wave (QRSd) were measured preoperation and after one week of CRT, and the difference of two QRS wave (AQRSd) was computed. At least 15% reduction in LVESV at the 6-month after CRT was defined as responders. We aimed to compare the changes of all parameters between responders and non-responders and to investigate the predictive value of ail the parameters.Results:Seventy patients complete the 6 months of follow up, and there were 43 (61%) responders. There were no significance between responders and non-responders in terms of LVDD, LVDS, LAD, LVEDV, LVESV, LVEF, SPWMD, PPEI, APEI and IVMD before CRT implantation (all NS), but responders had relatively high Ts-12SD than non-responders (42.03±16.33 ms vs 33.04±8.33 ms, P=0.018). After 6 months of CRT, the LVDD, LVDS, LAD, LVEDV and LVESV decreased significantly (P<0.05), LVEF increased significantly (P<0.05) and Ts-12SD decreased significantly (42.03±16.33 ms vs 29.40±8.96 ms, P<0.05) in responders, while there were no significant changes with respect to all the parameters in non-responders (all NS). Ts-12SD is relatively valuable in predicting CRT responders (AUC=0.703, P=0.019), Ts-12SD≥34.65ms has the relatively high sensitivity of 61.8% and specificity of 70.6%。The level of log (NT-ProBNP) preoperation could predict the response to CRT (AUC=0.751, P=0.005), log (NT-ProBNP)≤3.04 (NT-ProBNP<1096pg/ml) has the sensitivity of 48.3%, specificity of 94.1% to predict the response to CRT. The QRSd,△QRSd and other synchrony parameters could not predict the response to CRT (NS).Conclusions:Tissue Doppler imaging is relatively better than M-mode echocardiography and pulsed Doppler parameters, but it is still not satisfactory. It is necessary to look for more reliable echocardiography parameters to predict the response to CRT. The level of NT-ProBNP before CRT implantation is valuable in predicting the response to CRT. The QRSd and AQRSd could not predict the response to CRT. Part Three:The Animal Study of the Impact of Cardiac Resynchronization Therapy on Left Ventricular Synchrony and Cardiac Function3.1:The Value of New Echocardiography Parameters in Evaluating and Predicting the Response to Cardiac Resynchronization Therapy: An Animal studyObjective:To establish the animal model in terms of rapid pacing induced heart failure and possible mechanism of cardiac resynchronization therapy (CRT) in treating heart failure, and to investigate the value of new echocardiography parameters in appraising the therapeutic effect of CRT.Methods:Twenty-one adult Beagle dogs were divided into Group A (CRT group, n= 10), Group B (non-CRT group, n=7) and Group C (control group, n=4). All of them were implanted left ventricle epicardial electrodes, right atrium and right ventricle leads. Group A and'B received rapid right ventricular pacing (VOO mode,260bpm) to induce heart failure. When their LVEF decreased below 35%, dogs in Group A treated with CRT and dogs in Group B were just terminated pacing. Dogs in Group C were not received rapid pacing and used as control group. Echocardiography including Tissue Doppler Imaging (TDI), Real-time three-dimensional echocardiography (RT3DE) and Speckle tracking strain imaging (STSI) and electrocardiography were performed at baseline, heart failure,2 and 4 weeks after CRT or termination of pacing. The dyssynchrony parameters included the standard deviation of time to maximum systolic velocity of the 12 LV segments (Ts-12SD) by TDI, the standard deviation of time to minimum systolic volume of the 16 LV segments (Tmsv-16SD) by RT3DE, standard deviation of time from onset of QRS to peak radial strain (Trs-6SD) and peak circumferential strain (Tcs-6SD) of the 6 middle LV segments by STSI. LV ejection fraction (LVEF), LV end diastolic volume (LVEDV) and LV end systolic volume (LVESV) were measured by RT3DE. At least 15% reduction in LVEDV at the 4-weeks after CRT was defined as responders. We aimed to compare the changes of all parameters in the animal model and to investigate the predictive value of all the parameters.Results:Two dogs in Group A and one dog in Group B died of severe heart failure. The success rate was 82.4%(14/17). In Group A and B,2 weeks of rapid right ventricular pacing decreased LVEF (58.67±3.26% vs 31.97±1.84%, P<0.05), enlarged LVEDV (26.53±3.17ml vs 35.50±6.46 ml, P<0.05) and LVESV (9.61± 2.01 ml vs 24.32±4.60 ml, P< 0.05), increased Ts-12SD (1.98±0.88% vs 5.47±2.28%,P＜0.05),Trs-6SD (1.70±0.78% vs 11.12±7.53%, P<0.05),Tcs-6SD (3.50±0.89% vs 9.13±1.65%, P<0.05) and Tmsv-16SD (0.94±0.24% vs 3.70±0.82%, P<0.05), dyssynchronized LV segments and prolonged QRS duration (57.62±13.00 ms vs 81.18±20.27 ms, P<0.05). After 4 weeks of CRT, the LVEF, LVEDV, LVESV, Ts-12SD, Tmsv-16SD, Trs-6SD and Tcs-6SD of Group A were all improved (P<0.05). After 4 weeks of pacing termination, LVEF, LVESV and the dyssynchronized index of Group B also recovered significantly (P<0.05), but LVEDV remained enlarged (34.6±5.1 ml vs 33.8±3.3 ml, NS). Covariance analysis showed that LVEF (57.0±2.4% vs 47.5±7.5%, P<0.05), LVESV (14.3±2.2 ml vs 17.9±2.2 ml, P<0.05), Ts-12SD (2.26±1.21% vs 3.61±0.80%, P<0.05), Trs-6SD (4.04±1.58% vs 6.83±3.15%, P<0.05), Tcs-6SD (6.10±1.70% vs 7.80±1.22%, P<0.05) and Tmsv-16SD (1.95±0.64% vs 3.29±0.93%, P<0.05) in Group A were better than in Group B. Ts-12SD, Tmsv-16SD, Trs-6SD and Tcs-6SD had good negative correlation with LVEF (r was-0.77,-0.86,-0.75,-0.83 relatively, all P<0.01) and positive correlation with LVEDV (r was 0.44,0.66,0.66,0.73 relatively, all P<0.01). Trs-6SD is relatively valuale in predicting the response to CRT (AUC=0.85, P=0.054), Trs-6SD≥12.16% has the relatively high sensitivity of 83.3% and specificity of 100%。Conclusions:Rapid right ventricular pacing in 260 bpm could induce obvious heart failure, and in the canine model of CRT after rapid right ventricular pacing induced heart failure, RT3DE and STS1 can effectively detect left ventricular dyssynchrony. CRT improved cardiac dyssynchrony. Among the new echocardiography parameters, Trs-6SD might be an optimal parameter to predict the effect of CRT.3.2: The possible molecular mechanism of cardiac resynchronization therapyObjective: To study the possible molecular mechanism of cardiac resynchronization therapy (CRT) through establishing the animal model in terms of quick pacing induced heart failure and how CRT treat heart failure. Methods:Twenty-one adult beagle dogs were divided into Group A (CRT group, n= 10), Group B (non-CRT group, n=7) and Group C (control group, n=4). All of them were implanted left ventricle epicardial electrodes, right atrium and right ventricle leads. Group A and B received rapid right ventricular pacing (VOO mode,260bpm) to induce heart failure. When their LVEF decreased below 35%, dogs in Group A treated with CRT and dogs in Group B were just terminated pacing. Dogs in Group C were not received rapid pacing and used as control group. After 4 weeks of CRT or terminated pacing, LV myocardium was taken out for HE staining and elcectron microscope inspection. The mRNA transcription levels of contractile, calcium regulatory proteins such as phospholamban (PLN) and sarcoplasmic reticulum Ca (2+)-ATPase protein (SERCA), and mitochondria related proteins such as acetaldehyde dehydrogenase-2 (ALDH2) were measured by reverse transcription polymerase chain reaction (RT-PCR) and normalized for glycer-aldehyde 3-phosphate dehydrogenase (GAPDH).Results:Two dogs in Group A and one dog in Group B died because of severe heart failure. By HE staining of the heart failure myocardium, we observed small vessel congestion, myofilament thinningz, and myofilament of group A thickened obviously compared with group B. Electron microscope showed cellular edema, mitochondrial swelling and fine myofibril in heart failure cardiac muscle. After 4 weeks of CRT, there were no mitochondria swelling and on cellular edema in Group A, after terminated pacing for 4 weeks, there were still different extent of mitochondria swelling in Group B. The results of RT-PCR show that the grey level of PLN, SERCA2a and ALDH2 in Group B were all lower than in Group A, and expression of ALDH2 was significantly lower than in Group A (P=0.028), but there were no significant difference in PLN and SERCA2a among three groups (MS).Conclusions:In the canine model of CRT after rapid right ventricular pacing induced heart failure, functional improvement related to CRT is associated with reversal of the HF related gene programming, CRT may produce a marked effect through mitochondria ALDH2 and energy metabolism.