Name: benefits of cardiac resynchronization therapy in an asynchronous heart failure model induced by left bundle branch ablation and rapid pacing
Uploaded: 2017-12-11T13:00:00
Description: Watch this Scientific Journal Video about Benefits of Cardiac Resynchronization Therapy in an Asynchronous Heart Failure Model Induced by Left Bundle Branch Ablation and Rapid Pacing at JoVE.com

This work is funded by National Natural Science Foundation of China (81671685) and Shanghai Commission of Health and Family Planning (No. 201440538)

Fifteen male beagle dogs (12 to 18 months old, weighing around 10.0-12.0 kg) were purchased and subjected to experiments. All procedures were performed in compliance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (Publication No. 85-23, revised 1996) and were approved by the Animal Care Committee in Zhongshan Hospital, Fudan University. Figure 1 shows the schematic workflow for all protocol steps.
1. Pre-s...

<ol>
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Dilated cardiomyopathy constitutes a major cause of CHF, which is characterized by ventricular dilation, systolic dysfunction with reduced LVEF, and abnormalities of diastolic filling11. Since chronic tachycardia-mediated HF is a recognized clinical condition, rapid pacing of either atrium or ventricle for at least 3 to 4 weeks serves as a frequently used animal model to induce CHF11. Hemodynamic changes occur as soon as 24 h after rapid pacing, with continued deterioration...

Advanced chronic HF is a leading cause of mortality for various cardiovascular diseases. A subset of patients with congestive heart failure (CHF) also develop ventricular conduction discoordination that aggravates symptoms and prognosis. CRT, also referred to as biventricular pacing, has been introduced as an alternative therapy for these patients for over 20 years1,2. Unfortunately, about 20-40% of the patients show poor response to CRT. Since then, many studies have been carried out in order to maximize CRT response3. It is now well recognized that patients with LBBB could benefit more from CRT than those with non-LBBB4, since an LBBB pattern causes a larger magnitude of cardiac dyssynchrony due to asymmetry in the freedom of wall movement between septal and lateral walls. Meanwhile recent studies have begun exploring changes in gene expression and molecular remodeling associated with CRT5. Accompanying the structural reverse remodeling induced by CRT, cellular and molecular reversion to a normal level is of great interest6. Hence, it is essential to establish an optimal model of CHF with isolated LBBB for studying CRT benefits.
Chronic, rapid ventricular pacing was once used to produce CHF in a canine model. RV pacing could undoubtedly produce delayed LV contraction as a model of the LBBB-like contraction pattern. However, this type of functional asynchrony with an intact conduction system may not emulate anatomical LBBB and is not considered an appropriate model for studying CRT performance, the essence of which is to coordinate impaired electrical activation and myocardial contraction. Rapid restoration of LV contractility and partial recovery of LV dimensions after cessation of pacing were also reported7.
Experimental studies have induced chronic LBBB by RF ablation to establish asynchronous ventricular contraction8. A combination of reduction in global pump function and regional invalid mechanical work could exacerbate CHF by generating cardiac inefficiency as well as cardiac remodeling at the tissue, cellular, and molecular levels. In LBBB hearts, workload is lowest in the septum and highest in the LV lateral wall. As a consequence, cardiac remodeling is most pronounced in the lateral wall9. The purpose of the present study is: (i) to advance a stable and chronic HF model with interventricular and intraventricular mechanical asynchrony by means of rapid RV pacing in combination with LBB ablation; (ii) to confirm dyssynchronous HF in our model and CRT benefits in coordinating contraction by two-dimensional speckle tracking echocardiography and aVTI; and (iii) to preliminarily explore cellular reverse remodeling elicited by CRT.

<table>
	<tbody>
		<tr>
			<td>Closed iv catheter system (0.9mm&#215;25mm)</td>
			<td>Becton Dickinson Medical</td>
			<td>5264442</td>
			<td>Used as venous retention needle</td>
		</tr>
		<tr>
			<td>Sodium pentobarbital</td>
			<td>Sigma-Aldrich Company</td>
			<td>130205</td>
			<td>For anesthesia</td>
		</tr>
		<tr>
			<td>Pet clipper</td>
			<td>Wuhan Shernbao pet supplies Co., Ltd.</td>
			<td>PGC-660</td>
			<td>For hair shaving</td>
		</tr>
		<tr>
			<td>Electrocardiograph</td>
			<td>Shanghai photoelectric medical electronic instrument Co., Ltd.</td>
			<td>ECG-6511</td>
			<td>For electrocardiogram recording</td>
		</tr>
		<tr>
			<td>Echocardiograph</td>
			<td>GE-Vingmed Ultrasound Company</td>
			<td>VIVID E9</td>
			<td>For echocardiographic assessment</td>
		</tr>
		<tr>
			<td>EchoPAC software</td>
			<td>GE healthcare</td>
			<td>Version201</td>
			<td>Offline analysis</td>
		</tr>
		<tr>
			<td>Laryngoscope</td>
			<td>Shanghai Medical Instrument Co., Ltd</td>
			<td></td>
			<td>Orotracheal intubation</td>
		</tr>
		<tr>
			<td>Endotracheal tube</td>
			<td>SIMS Portex Inc, UK</td>
			<td>274093</td>
			<td>Orotracheal intubation</td>
		</tr>
		<tr>
			<td>Volume cycled respirator</td>
			<td>Newport Corporation</td>
			<td>C100</td>
			<td>Artificial ventilation</td>
		</tr>
		<tr>
			<td>HeartStart XL Defibrillator/Monitor</td>
			<td>Philips Medical Systems</td>
			<td>M4735A</td>
			<td>Electrocardiogram monitor during operation</td>
		</tr>
		<tr>
			<td>Benzalkonium Bromide Tincture</td>
			<td>Shanghai Yunjia Pharmaceutical Co., Ltd.</td>
			<td>H31022694</td>
			<td>Used for skin disinfection</td>
		</tr>
		<tr>
			<td>Rib retractor</td>
			<td>Shanghai Medical Instrument Co., Ltd.</td>
			<td></td>
			<td>For thoracotomy</td>
		</tr>
		<tr>
			<td>4-0 suture</td>
			<td>Shanghai Pudong Jinhuan Medical Products Co., LTD.</td>
			<td>24L1005</td>
			<td>Suture of LV epicardial electrode</td>
		</tr>
		<tr>
			<td>2-0/T suture</td>
			<td>Shanghai Pudong Jinhuan Medical Products Co., LTD.</td>
			<td>11M0505</td>
			<td>Suture of pacing leads, fascia, vessels, etc.</td>
		</tr>
		<tr>
			<td>0-suture</td>
			<td>Shanghai Pudong Jinhuan Medical Products Co., LTD.</td>
			<td>11P0501</td>
			<td>Skin suture</td>
		</tr>
		<tr>
			<td>penicillin powder</td>
			<td>North China Pharmaceutical Co., Ltd.</td>
			<td>F6034105</td>
			<td></td>
		</tr>
		<tr>
			<td>DSA X-ray machine</td>
			<td>Philips</td>
			<td>Allura Xper FD10</td>
			<td>X-ray for fluoroscopy</td>
		</tr>
		<tr>
			<td>LV pacing electrode</td>
			<td>Medtronic, Inc.</td>
			<td>LBT 4965</td>
			<td></td>
		</tr>
		<tr>
			<td>RV pacing electrode</td>
			<td>St. Jude Medical</td>
			<td>Tendril 1888</td>
			<td></td>
		</tr>
		<tr>
			<td>RA pacing electrode</td>
			<td>St. Jude Medical</td>
			<td>IsoFlex 1642T</td>
			<td></td>
		</tr>
		<tr>
			<td>Pacemaker pulse generator</td>
			<td>Medtronic, Inc.</td>
			<td>Enpulse E2DR01</td>
			<td>For rapid RV pacing</td>
		</tr>
		<tr>
			<td>CRT pulse generator</td>
			<td>St. Jude Medical</td>
			<td>Anthem PM 3212</td>
			<td>For CRT performance</td>
		</tr>
		<tr>
			<td>Multi-channel electrophysiologic recorder</td>
			<td>GE Medical Systems</td>
			<td>2003232-004</td>
			<td>For surface and intracardiac electrogram</td>
		</tr>
		<tr>
			<td>Catheter input module</td>
			<td>GE Medical Systems</td>
			<td>301-00202-08</td>
			<td>Multiple pole switches for stimulation or recording</td>
		</tr>
		<tr>
			<td>Radiofrequency generator</td>
			<td>Johnson-Johnson Company</td>
			<td>ST-4460</td>
			<td>For RF current delivery</td>
		</tr>
		<tr>
			<td>Cordless return electrode</td>
			<td>Covidien</td>
			<td>E7509</td>
			<td>For current circuit formation</td>
		</tr>
		<tr>
			<td>Cordis 6-Fr sheath</td>
			<td>Johnson-Johnson Company</td>
			<td>504-606X</td>
			<td>Access for mapping catheter</td>
		</tr>
		<tr>
			<td>Cordis 7-Fr sheath</td>
			<td>Johnson-Johnson Company</td>
			<td>504-607X</td>
			<td>Access for mapping and ablation catheter</td>
		</tr>
		<tr>
			<td>6-Fr quadripolar catheter</td>
			<td>Johnson-Johnson Company</td>
			<td>F6QRA005RT</td>
			<td>Mapping catheter</td>
		</tr>
		<tr>
			<td>7-Fr 4mm-tip steerable ablation catheter</td>
			<td>St. Jude Medical</td>
			<td>402823</td>
			<td>Mapping and ablation catheter</td>
		</tr>
		<tr>
			<td>Prucka Cardio-Lab&#174;2000</td>
			<td>GE Medical Systems</td>
			<td>6.9.00.000</td>
			<td>Software package for electrogram recording</td>
		</tr>
		<tr>
			<td>Heparin</td>
			<td>Haitong Pharmaceutical Co., Ltd</td>
			<td>160505</td>
			<td>Anticoagulant during catheter ablation</td>
		</tr>
		<tr>
			<td>Digital image analysis system</td>
			<td>Leica Microsystems</td>
			<td>Qwin V3</td>
			<td>For histologic analysis</td>
		</tr>
	</tbody>
</table>

benefits of cardiac resynchronization therapy in an asynchronous heart failure model induced by left bundle branch ablation and rapid pacing

It is now well recognized that heart failure (HF) patients with left bundle branch block (LBBB) derive substantial clinical benefits from cardiac resynchronization therapy (CRT), and LBBB has become one of the important predictors for CRT response. The conventional tachypacing-induced HF model has several major limitations, including absence of stable LBBB and rapid reversal of left ventricular (LV) dysfunction after cessation of pacing. Hence, it is essential to establish an optimal model of chronic HF with isolated LBBB for studying CRT benefits. In the present study, a canine model of asynchronous HF induced by left bundle branch (LBB) ablation and 4 weeks of rapid right ventricular (RV) pacing is established. The RV and right atrial (RA) pacing electrodes via the jugular vein approach, together with an epicardial LV pacing electrode, were implanted for CRT performance. Presented here are the detailed protocols of radiofrequency (RF) catheter ablation, pacing leads implantation, and rapid pacing strategy. Intracardiac and surface electrograms during operation were also provided for a better understanding of LBB ablation. Two-dimensional speckle tracking imaging and aortic velocity time integral (aVTI) were acquired to validate the chronic stable HF model with LV asynchrony and CRT benefits. By coordinating ventricular activation and contraction, CRT uniformed the LV mechanical work and restored LV pump function, which was followed by reversal of LV dilation. Moreover, the histopathological study revealed a significant restoration of cardiomyocyte diameter and collagen volume fraction (CVF) after CRT performance, indicating a histologic and cellular reverse remodeling elicited by CRT. In this report, we described a feasible and valid method to develop a chronic asynchronous HF model, which was suitable for studying structural and biologic reverse remodeling following CRT.

Successful LBB Ablation:
Figure 2 represents a typical surface and intracardiac electrogram in the course of catheter ablation. The mean LBP-V measured is 18.8 &#177;2.8 ms, which was about 10 ms shorter than the baseline H-V interval (28.8 &#177;2.6 ms, p &#60;0.01). The QRS duration prolonged from 59.2 &#177;6.8 ms to 94.2 &#177;8.6 ms (p &#60;0.01) after LBB ablation. The loss of t...

Watch this Scientific Journal Video about Benefits of Cardiac Resynchronization Therapy in an Asynchronous Heart Failure Model Induced by Left Bundle Branch Ablation and Rapid Pacing at JoVE.com

Benefits of Cardiac Resynchronization Therapy in an Asynchronous Heart Failure Model Induced by Left Bundle Branch Ablation and Rapid Pacing

The establishment of a chronic asynchronous heart failure (HF) model by rapid pacing combined with left bundle branch ablation is presented. Two-dimensional speckle tracking imaging and aortic velocity time integral are applied to validate this stable HF model with left ventricular asynchrony and the benefits of cardiac resynchronization therapy.

It is now well recognized that heart failure (HF) patients with left bundle branch block (LBBB) derive substantial clinical benefits from cardiac ...

The overall goal of this experiment is to describe a feasible and valid method to establish a chronic asynchronous heart failure model for studying benefits of cardiac resynchronization therapy. Rapid pacing together with left bundle branch ablation helps to establish a stable heart failure model for studying CRT performance, including echocardiographic parameters, molecular and biologic modifications. The key point of this technique is the left bundle branch ablation, where you prevent the cardiac function recovery on this continuation of rapid pacing.We first had the idea for this method when we found a significant recovery from heart failure once the rapid pacing was terminated. The epicardial left ventricle lead implantation is performed by mister Yao Ruiming, technician from our laboratory who is expert at this procedure. After preparing the canine for the LV pacing electrode implantation, begin with a transverse incision from the left parasternal line at the fourth intercostal space in a right lateral decubitus position.After a blunt dissection of the thoracic muscle, open the left pleural cavity at the fourth intercostal space using sharp dissection. Use a rib retractor to hold open the intercostal space. Next, carefully incise the lateral pericardium and open it using stay sutures to fully expose the LV lateral wall.Then, using a 4-0 suture, secure the LV pacing electrode to the myocardium in one stich. Now, measure the electrode lead parameters. Check that the pacing threshold and other parameters are correct, and then proceed by removing the stay sutures and closing the pericardium with two stitches.Now, use two pericostal sutures to approximate the fourth and fifth ribs using size 0 suture and close the intercostal fascia muscularis with five stitches of 2-0/T sutures. Be sure to inflate the lungs adequately before the last suture. Then, put the muscle layers back in place.Next, build a subcutaneous tunnel above the deep fascia from precordial area to the left cervix. Then, pull the terminal pin at the lead through the tunnel and suture the lead around an insulation sleeve to the fascia. Embed the lead locally.To complete the surgery, provide penicillin and close the two incisions. Implant the RA and RV pacing electrodes two weeks after the LV electrode implantation, by which time the animal should have recovered from the thoracotomy. Carry out the operation in a cardiac catheterization surgery room equipped with the fluoroscopy apparatus.After preparing the animal for surgery, begin with a small vertical incision close to the preceding wound on the left side of the cervical area. Then, using blunt dissection, separate the fascia to expose the left external jugular vein. Be sure to carefully separate the vein from the connective tissues.With the aid of stay sutures, cut a small hole on the vein using iris scissors. Then, using a vein pick, insert a passive J-shaped RA lead and active RV lead into the left external jugular vein. Now, under fluoroscopy, advance the RV lead to the lower right atrium or inferior vena cava.Then withdraw the straight stylet from the RV lead and insert a J-shaped stylet. With the help of the J-shaped stylet, introduce the lead across the tricuspid valve and into the outflow tract. Then, slowly withdraw both the lead and the stylet, allowing the lead tip to prolapse toward the RV apex.Now, replace the curved stylet with a straight one and advance the lead towards the apex. Then, slowly withdraw the stylet a little while keeping the RA lead directed toward the high anterior atrium. Slowly withdraw the straight stylet.Then, retract the tip of the J-shaped lead into the appendage. A characteristic to-and-fro motion of the electrode with atrial activity may be observed. After obtaining satisfactory lead parameters and checking the stability of both leads, tighten the suture proximal to the venotomy.Then, tie down both leads to the underlying deep fascia around the suture sleeves. Then, check the positioning of the leads under fluoroscopy before proceeding with the pulse generator implantation. For sham surgeries, skip this procedure.To implant the pulse generator, first dissect bluntly with the aid of a curved clamp to make a pocket for the pulse generator near the venous entry just above the fascia layer and below the subcutaneous fat. Next, clean and dry the lead pins. Cover the terminal pin at the atrial lead with an insulating sleeve, then suture the lead to the floor of the pocket.Then, insert the ventricular lead into a pacemaker pulse generator and tighten it with a distal connector pin past the set screws of the generator. Now, place the generator into the pocket and quell the redundant bleeds beneath the device. Then, secure the generator to the fascia using another suture to the tie-down hole.Now, perform a fluoroscopic examination of the entire system and check for homeostasis. To complete the surgery, sprinkle 200, 000 units of penicillin into the pocket and suture the superficial fascia layer closed using 2-0/T sutures. Then, approximate the skin edges with both sutures.Carry out the catheter ablation under the guidance of fluoroscopy. Have a multi-general electrophysiological recorder prepared for simultaneous surface and intracardiac electrogram recording. Shave the hair off the chest, back and right inguinal region.Keep the animal in a supine position. The first surgical steps are to insert sheets into the femoral vein and femoral artery for catheter placement. This is described in detail in the text protocol.To proceed, advance a six French steerable quadripolar catheter into the femoral vein and connect the end of the catheter to the recorder. Then, pass the catheter into the right atrium and across the tricuspid valve until it is clearly in the right ventricle. Using a right anterior oblique 30-degree view, withdraw the catheter across the tricuspid orifice until the atrial potential appears and it increases in amplitude.When the atrial and ventricular potentials are approximately equal in size, a biphasic or triphasic deflection will appear between them. This represents the right side of His bundle potential. Now, introduce a number seven French formula meter tip steerable ablation catheter into the femoral artery to map the left bundle branch potential.Then, connect the ablation catheter to the RF generator and the multichannel electrophysiological recorder. Using a right anterior oblique 30-degree view, pass the arterial catheter retrogradely across the aortic valve and advance it into the left ventricle. There, deflect the catheter tip toward the intraventricular septum where it should remain in contact with the septum.Now, using a left anterior oblique 45-degree view, slowly withdraw the catheter along the septum until the left side of His bundle potential is recorded between the atrial and ventricular electrogram just below the aortic valve. Then, slightly advance the catheter along the septum and manipulate the tip to identify a discrete left bundle potential, which is recorded beneath the aortic valve. It is usually located one to one and a half centimeters inferior to left side of His bundle recording site.When the potential to ventricular electrogram interval is 10 milliseconds or so shorter than the HV interval and the AV electrogram ratio of less than one to 10, then the left bundle potential has been identified. Next, perform the ablation with the RF generator unless it is a sham surgery. Deliver 500 kilohertz of unmodulated sine wave energy at 30 to 40 watts to achieve a target temperature of 60 degrees Celsius at the electrode-tissue interface.When a typical LBBB QRS morphology appears on the surface electrogram, continue the energy application. Then, observe the surface electrogram for a stabilization period of 30 minutes. To complete the procedure, remove both catheters.Then, remove the sheets and tighten the suture knots rapidly to prevent hemorrhaging. Lastly, provide penicillin and close the incisions. The typical surface and intracardiac electrogram in the course of catheter ablation shows the mean LVPV to be about ten milliseconds shorter than the baseline HV interval, and after the LBB ablation, the QRS duration is prolonged.Baseline echocardiographic parameters showed no difference between the groups. After the experimental intervention, the heart failure group had an obvious deterioration in cardiac function from which no measured parameter improved over eight weeks of observation. However, with eight weeks of CRT, the left ventricle and diastolic volume returned to normal, as did the left ventricle and systolic volume.CRT also returned the lost left ventricle ejection fraction. Longitudinal strain curves of six segments from each plain made by speckle tracking analysis showed a measurable increase in the dispersion of the time to peak longitudinal strain in the heart failure group. By contrast, the therapy corrected the asynchrony.This was observable in the four-chamber view, the two-chamber view and in the long axis view. Furthermore, the heart failure animals presented a significantly lower aortic velocity time integral than the shams. This metric was significantly increased by the CRT.Histology revealed a remarkable decrease in cardiomyocyte diameter and a significant increase in the collagen volume fraction in the heart failure group. However, eight weeks of CRT provided a significant restoration of these metrics, indicating that the therapy invoked remodeling of the tissue. After watching this video, you should have got a good understanding of how to establish a chronic heart failure with isolated LBBB for studying CRT benefits.Following the left bundle branch ablation, apart from rapid pacing, we can still use some other method to induce heart failure such as a coronary ligation to induce an ischemic heart failure. This well established technique was paved the way for researches to study cardiovascular diseases in large animal models of heart failure.

Research

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Biology

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