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

<ol>
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A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pathobiology+of+left+ventricular+dyssynchrony+and+resynchronization.">Pathobiology of left ventricular dyssynchrony and resynchronization.</a> Prog Cardiovasc Dis. 49 (1), 26-41 (2006).</li><li>Wang, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effect+of+Cardiac+Resynchronization+Therapy+on+Myocardial+Fibrosis+and+Relevant+Cytokines+in+a+Canine+Model+With+Experimental+Heart+Failure.">Effect of Cardiac Resynchronization Therapy on Myocardial Fibrosis and Relevant Cytokines in a Canine Model With Experimental Heart Failure.</a> J Cardiovasc Electrophysiol. 28 (4), 438-445 (2017).</li><li>Houser, S. 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The authors declare that they have no competing financial interests.

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 of cardiac function for up to 3 to 5 weeks. However, the recovery from pacing-induced HF is a dramatic and unique feature of this model, accompanied by a reversal of neurohormonal activation, indicating a reversible nature of this myopathy. It is documented that LVEF shows significant recovery within 1 to 2 weeks after termination of pacing and nearly all hemodynamic variables return towards normal levels at 4 weeks after cessation of rapid pacing12. Hence, the prevention of cardiac function recovery on the discontinuation of pacing is of great importance in this attractive model.
LBBB could result in delayed LV activation and a corresponding delayed LV systole. Asynchronous contraction of the septum and the LV free wall performs a disproportionate amount of net myocardial work, and the work is wasted in both regions. Though a mere LBBB produces a low-grade myopathy, the synergy between HF and LBBB may produce substantial functional and clinical decline over time, which could be ameliorated by CRT. The functional LBBB induced by RV pacing is temporary, which is very different from the case where an anatomical LBBB is present. In the present study, a permanent LBBB was created by catheter ablation and its presence was confirmed during the subsequent experiments. Canines have a relatively longer, more left side oriented penetrating bundle of His and common left bundle, which may account for the high success rate of LBB ablation. LBP is located between His bundle and Purkinje potentials. Correct identification of LBP and a guarantee of A:V electrogram ratio &#60;1:10 favors successful LBB ablation and avoidance of complete A-V block13. The common left bundle is divided into anterior and posterior fascicles at the proximal one-thirds along the muscular ventricular septum. If the ablation catheter is positioned on a distal portion of the bundle branch, an anterior or posterior fascicle might be ablated. However, the ablation of these fascicles could not obviously prolong the QRS duration. Based on a previous study, the QRS duration could increase by 40-50 ms following LBB ablation13. In the present study, the QRS prolongation averaged 35 ms, which might be due to different animal species. On intracardiac electrogram, the mean LBP-V interval for successful ablation measured about 16-19 ms, usually 10 ms shorter than the H-V interval, neither too close nor too far from the His bundle. In addition, the LBP usually disappeared after successful ablation14.
A previous study has reported that rapid pacing for at least 3 to 4 weeks produces a reliable and reproducible HF model11. There may exist some difference among different animals as for the necessary period of tachypacing. So, echocardiography was performed every 2 weeks during rapid pacing. None of the animals showed an LVEF &#60;35% after 2 weeks of tachypacing, suggesting that 3 to 4 weeks of rapid pacing is essential. After 4 weeks, once the LVEF was below 35%, rapid pacing was terminated. Such a strategy helped to uniform the baseline HF severity. In addition, since RV apical (RVA) pacing has long been proven to induce LV dyssynchrony and HF15, we selected RVA instead of RA for rapid pacing. Thus, rapid pacing-induced HF with superimposed LBBB-induced dyssynchrony in our study helped to establish a model of stable and chronic dyssynchronous HF. More importantly, the LV systolic dysfunction hardly recovered in up to 8 weeks of observation in the control group. Such an animal model favored investigation of CRT benefits instead of self-recovery.
To establish the HF model, first we implanted the LV epicardial lead via left thoracotomy. After 2 weeks of recovery from thoracotomy, we implanted the RV and RA leads via a jugular vein approach, followed by LBB ablation. Although limited left thoracotomy, muscle sparing, and rib preservation strategies are excellent minimally invasive approaches for exposure of the LV lateral wall, operative trauma and postoperative infection are still associated with high mortality. So, the LV lead implantation was performed before other procedures. Only those surviving 2 weeks after the operation are submitted to LBB ablation and rapid pacing. Overall, this was an economical strategy.
Echocardiographic data demonstrated persistence of significant systolic dysfunction, increased ventricular volumes, and higher asynchrony index in our CHF model. CRT improved cardiac function with reduced asynchrony index. Speckle tracking strain analysis is a novel method which permits the assessment of myocardial deformation. It has proven to be significantly associated with long-term outcome after CRT and has additive prognostic value to routine selection criteria for CRT. Of the three different patterns of myocardial deformation including radial strain, circumferential strain, and longitudinal strain, it is still under debate with conflicting data, which one used for LV dyssynchrony index may best predict CRT response16,17. However, it is reported that global longitudinal strain consistently showed good reproducibility, while reproducibility was moderate for circumferential strain and poor in the radial direction18. Therefore, in the present study, we adopted the apical tri-plane longitudinal strain analysis as the LV asynchrony index by calculating PSD. A higher PSD indicated a severer asynchrony. aVTI has been commonly used for AV and VV delay optimization in CRT patients. Changes in aVTI can serve as a surrogate for changes in stroke volume as it is directly proportional to the LV outflow tract VTI19. Hence, we assessed aVTI to evaluate hemodynamic benefits from CRT. A higher aVTI suggested better LV systolic performance.
Cardiac fibrosis, as characterized by interstitial collagen and extracellular matrix deposit, is a hallmark of end-stage CHF. Recent studies have demonstrated that LV reverse remodeling after CRT is independently associated with diffuse interstitial myocardial fibrosis, which is assessed with myocardial T1 mapping cardiac magnetic resonance (CMR)20. Besides, CRT-induced LV reverse remodeling is also associated with a decreased plasma level of pro-fibrotic cytokines such as transforming growth factor (TGF)-&#946;1 and osteopontin (OPN)21,22. In the present study, histologic analysis revealed decreased cardiomyocyte diameter and increased myocardial fibrosis in the failing heart at 8 weeks after cessation of rapid pacing, suggesting a histologic and cellular remodeling in our HF model. Along with the structural reverse remodeling, however, CRT restored myocyte configuration and alleviated collagen deposits. Such a histologic reverse remodeling yields more beneficial effects beyond CRT itself.
Recent recommendations for CRT implantation include persistent HF symptoms, impaired LV systolic function with LVEF &#8804;35%, LBBB QRS morphology, and a widened QRS duration4. Our experimental model is a practicable, reproducible, and stable HF model, which satisfies almost all these criteria. While it is noteworthy that our work established a canine model of non-ischemic dilated cardiomyopathy, it may not apply to other conditions such as valvular heart disease, congenital heart disease, ischemic HF, etc. Especially, coronary ligation or microembolization is commonly used to produce ischemic HF, which has a higher risk of sudden cardiac death. However, due to the discrepancy of myocardial scar burden in ischemic HF, it is not easy to objectively evaluate CRT benefits. By contrast, our experimental model is relatively homogeneous and is a suitable model for studying CRT performance, including electrical behavior, echocardiographic assessment, and biologic and molecular modifications.

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&amp;times;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&lt;sup&gt;&amp;reg;&lt;/sup&gt;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 the LBP electrogram confirmed successful LBB ablation.
A Chronic Dyssynchronous CHF Model and CRT Benefits Quantified by Echocardiography:
Baseline echocardiographic parameters showed no significant difference among the sham, HF control, and CRT groups. As was published in our previous data10, an obvious deteriorated cardiac function characterized by increased LVEDV and LVESV, and decreased LVEF could be observed in the HF control group at the end of the experiment (Figure 3). CRT improved cardiac function with decreased LVEDV and LVESV, and increased LVEF. For speckle tracking analysis, tri-plane apical longitudinal views including A4C, A2C, and APLAX were acquired simultaneously. After tracing each apical view, the longitudinal strain curves of six segments from each plane were obtained. Then the TTP and PSD were calculated. As a result, an increased asynchrony index (PSD) was induced in the HF control group compared with the sham group (51.6 &#177;5.9 ms vs. 32.6 &#177;2.3 ms, p &#60;0.01); while CRT corrected LV asynchrony, as exhibited by a significantly lower PSD (44.0 &#177;4.6 ms vs. 51.6 &#177;5.9 ms, p &#60;0.05). Furthermore, the HF control animals presented a significantly lower aVTI than the sham group (8.09 &#177;1.19 cm vs. 14.53 &#177;2.38 cm, p &#60;0.01), which was significantly increased in the CRT group (10.92 &#177;1.31 cm vs. 8.09 &#177;1.19 cm, p &#60;0.05) (Figure 3 and Figure 4).
Histologic and Cellular Reverse Remodeling Induced by CRT:
Myocardial tissues excised from the LV lateral wall were subjected to histologic analysis. Compared with the sham group, a remarkably decreased cardiomyocyte diameter was noted in the HF control group (4.77 &#177;0.86 &#181;m vs. 7.68 &#177;1.25 &#181;m, p &#60;0.01), which might be responsible for the LV dilation. Masson trichrome staining revealed a significant increase of CVF in the HF control group in contrast with the sham group (12.56 &#177;2.10% vs. 1.88 &#177;0.23%, p &#60;0.01). However, 8 weeks of CRT performance resulted in a significant restoration of cardiomyocyte diameter (6.26 &#177;0.93 &#181;m vs. 4.77 &#177;0.86 &#181;m, p &#60;0.01) and CVF (6.28 &#177;1.61% vs. 12.56 &#177;2.10%, p &#60;0.01) compared with the HF control group, indicating a biologic reverse remodeling invoked by CRT (Figure 5).
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/56439/56439fig1.jpg" /> 
Figure 1: The schematic workflow of all protocol steps. <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56439/56439fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/56439/56439fig2.jpg" /> 
Figure 2: 12-lead ECG and intracardiac electrogram recorded before (A) and after (B) catheter ablation. (A) Typical surface and intracardiac electrogram at a successful ablation site. Right-sided His bundle potential was mapped by the distal electrode of the quadripolar catheter with an H-V interval of 28 ms. The LBP was mapped by the ablation catheter with an LBP-V interval of 17 ms. The LBP-V interval was 11 ms shorter than the H-V interval. (B) Typical LBBB morphology after successful ablation. The QRS duration prolonged from 63 ms to 95 ms after LBB ablation, which was positive in leads I, aVF, V6, with notched R wave, and negative in lead V1. The LBP disappeared and the right-sided His bundle potential still existed after ablation. <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56439/56439fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/56439/56439fig3.jpg" /> 
Figure 3: Bar graphs expressed as mean &#177; SD for LVEDV, LVESV, LVEF, PSD, and aVTI among the three experimental groups (n = 5 for each) at baseline and the end of experiment, respectively. Values between the experimental groups were compared using one-way ANOVA test. Compared with the sham group, *p &#60;0.05, **p &#60;0.01; Compared with the HF control group, #p &#60;0.05, ##p &#60;0.01. <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56439/56439fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/56439/56439fig4.jpg" /> 
Figure 4: Speckle tracking strain imaging and aortic velocity time integral measurement. (A) Two-dimensional longitudinal strain analysis using speckle tracking imaging from 3 standard apical views. A1 showed tri-plane apical longitudinal views acquired using 4VD transducer of GE VIVID E9. Images were carefully adjusted to ensure that apical four chamber view (A4C), two chamber view (A2C), and long axis view (APLAX) were displayed at the same time. A2 displayed an example of longitudinal strain curves of six segments created by a tracking algorithm from APLAX view. Segments of basal-posterior wall, mid-posterior wall, apical-posterior wall, basal-anterior septum, mid-anterior septum and apical-anterior septum were automatically defined. A3 showed the time to peak longitudinal strain (TTP) of each segment calculated with QRS onset as a reference when all the segmental time-strain curves were constructed from the three apical views. A significantly higher dispersion of TTP could be observed in the HF control group, which was formulated as standard deviation. CRT performance significantly reduced the difference between TTP of each segment. (B) Assessment of aortic velocity time integral averaged from 3 consecutive beats. B1, B2, and B3 represent typical images of the sham group, HF control group, and CRT group, respectively. <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56439/56439fig4large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/56439/56439fig5.jpg" /> 
Figure 5: Typical photograph of the HE staining (400X) and Masson&#39;s trichrome staining (400X). Diameters of myocardial fibers were measured from longitudinally cut sections, and collagen volume fraction (CVF) was assessed from the percentage of fibrotic area divided by total tissue area. Scale bars =&#160;50 &#181;m. <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56439/56439fig5large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

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 ...

benefits-cardiac-resynchronization-therapy-an-asynchronous-heart

Nanyang Technological University

Research

JoVE Journal

Biology

10.4K Views.  Zhongshan Hospital, Fudan University. De oprichting van een model van de chronische asynchrone hartfalen (HF) door snelle pacing gecombineerd met linker bundel tak ablatie wordt gepresenteerd. Tweedimensionale spikkel bijhouden van beeldvorming en aorta snelheid tijd integraal worden toegepast om deze stabiele HF-model met links ventriculaire asynchrony en de voordelen van cardiale synchronisatieprocedure therapie te valideren.

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

Programmed Electrical Stimulation in Mice

Genetically-modified mice have emerged as a preferable animal model to study the molecular mechanisms underlying conduction abnormalities, atrial and ventricular arrhythmias, and sudden cardiac death.1 Intracardiac pacing studies can be performed in mice using a 1.1F octapolar catheter inserted into the jugular vein, and advanced into the right atrium and ventricle. Here, we illustrate the steps involved in performing programmed electrical stimulation in mice. Surface ECG and intracardiac electrograms are recorded simultaneously in the atria, atrioventricular junction, and ventricular myocardium, whereas intracardiac pacing of the atrium is performed using an external stimulator. Thus, programmed electrical stimulation in mice provides unique opportunities to explore molecular mechanisms underlying conduction defects and cardiac arrhythmias.

Programmed electrical stimulation provides the ability to determine conduction properties of the heart, and the possibility to induce and terminate cardiac arrhythmias using various pacing protocols. Using a transvenous catheter, intracardiac electrogram recordings can be obtained in mice following programmed electrical stimulation protocols to identify arrhythmogenic substrates.

Genetically-modified mice have emerged as a preferable animal model to study the molecular mechanisms underlying conduction abnormalities, atrial and ...

Medicine

Simultaneous Electrical and Mechanical Stimulation to Enhance Cells' Cardiomyogenic Potential

Cardiovascular diseases are the leading cause of death in developed countries. Consequently, the demand for effective cardiac cell therapies has motivated researchers in the stem cell and bioengineering fields to develop in vitro high-fidelity human myocardium for both basic research and clinical applications. However, the immature phenotype of cardiac cells is a limitation on obtaining tissues that functionally mimic the adult myocardium, which is mainly characterized by mechanical and electrical signals. Thus, the purpose of this protocol is to prepare and mature the target cell population through electromechanical stimulation, recapitulating physiological parameters. Cardiac tissue engineering is evolving toward more biological approaches, and strategies based on biophysical stimuli, thus, are gaining momentum. The device developed for this purpose is unique and allows individual or simultaneous electrical and mechanical stimulation, carefully characterized and validated. In addition, although the methodology has been optimized for this stimulator and a specific cell population, it can easily be adapted to other devices and cell lines. The results here offer evidence of the increased cardiac commitment of the cell population after electromechanical stimulation. Electromechanically stimulated cells show an increased expression of main cardiac markers, including early, structural, and calcium-regulating genes. This cell conditioning could be useful for further regenerative cell therapy, disease modeling, and high-throughput drug screening.

Here we present a protocol for training a cell population using electrical and mechanical stimuli emulating cardiac physiology. This electromechanical stimulation enhances the cardiomyogenic potential of the treated cells and is a promising strategy for further cell therapy, disease modeling, and drug screening.

Cardiovascular diseases are the leading cause of death in developed countries. Consequently, the demand for effective cardiac cell therapies has motivated ...

Bioengineering

Tachycardia-Induced Cardiomyopathy As a Chronic Heart Failure Model in Swine

A stable and reliable model of chronic heart failure is required for many experiments to understand hemodynamics or to test effects of new treatment methods. Here, we present such a model by tachycardia-induced cardiomyopathy, which can be produced by rapid cardiac pacing in swine.
A single pacing lead is introduced transvenously into fully anaesthetized healthy swine, to the apex of the right ventricle, and fixated. Its other end is then tunneled dorsally to the paravertebral region. There, it is connected to an in-house modified heart pacemaker unit that is then implanted in a subcutaneous pocket. 
After 4 - 8 weeks of rapid ventricular pacing at rates of 200 - 240 beats/min, physical examination revealed signs of severe heart failure - tachypnea, spontaneous sinus tachycardia, and fatigue. Echocardiography and X-ray showed dilation of all heart chambers, effusions, and severe systolic dysfunction. These findings correspond well to decompensated dilated cardiomyopathy and are also preserved after the cessation of pacing.
This model of tachycardia-induced cardiomyopathy can be used for studying the pathophysiology of progressive chronic heart failure, especially hemodynamic changes caused by new treatment modalities like mechanical circulatory supports. This methodology is easy to perform and the results are robust and reproducible.

Here, we present a protocol to produce tachycardia-induced cardiomyopathy in swine. This model represents a potent way to study the hemodynamics of progressive chronic heart failure and the effects of applied treatment.

A stable and reliable model of chronic heart failure is required for many experiments to understand hemodynamics or to test effects of new treatment ...

Ablation of Ischemic Ventricular Tachycardia Using a Multipolar Catheter and 3-dimensional Mapping System for High-density Electro-anatomical Reconstruction

Ventricular tachycardia (VT) in patients with ischemic cardiomyopathy mainly results from endocardial scars after myocardial infarction; those scars represent zones of slow conduction that allow the occurrence and maintenance of reentrant circuits. Catheter ablation enables substrate modification of those low voltage areas and thus can help to alter the scar tissue in such a way that arrhythmias cannot appear anymore. Hospitalizations of concerned patients decrease, quality of life and outcome rise. Consequently, VT ablation represents a growing field in electrophysiology, especially for patients with endocardial scars in ischemic heart disease after myocardial infarction. However, ablation of ventricular tachycardia remains one of the most challenging procedures in the electrophysiology lab. Precise scar definition and localization of abnormal potentials are critical for ablation success. The following manuscript describes the use of a multipolar mapping catheter and 3-dimensional (3D) mapping system to create a high density electro-anatomical map of the left ventricle including a precise scar representation as well as mapping of fractionated and late potentials in order to allow a highly accurate substrate modification.

With the following protocol, we provide an approach to Ventricular Tachycardia (VT) ablation using high density mapping with a multipolar catheter and 3D mapping system enhancing the success of the procedure.

Ventricular tachycardia (VT) in patients with ischemic cardiomyopathy mainly results from endocardial scars after myocardial infarction; those scars ...

Use of a Percutaneous Ventricular Assist Device/Left Atrium to Femoral Artery Bypass System for Cardiogenic Shock

The left atrial to femoral artery bypass (LAFAB) system is a mechanical circulatory support (MCS) device used in cardiogenic shock (CS) that bypasses the left ventricle by draining blood from the left atrium (LA) and returning it to the systemic arterial circulation via the femoral artery. It can provide flows ranging from 2.5-5 L/min depending on the size of the cannula. Here, we discuss the mechanism of action of LAFAB, available clinical data, indications for its use in cardiogenic shock, steps of implantation, post-procedural care, and complications associated with the use of this device and their management.
We also provide a brief video of the procedural component of device therapy, including the pre-placement preparation, percutaneous placement of the device via transseptal puncture under echocardiographic guidance and the post-operative management of device parameters.

The following article describes the stepwise procedure for placement of a device (e.g., Tandemheart) in cardiogenic shock (CS) that is a percutaneous left ventricular assist device (pLVAD) and a left atrial to femoral artery bypass (LAFAB) system that bypasses and supports the left ventricle (LV) in CS.

The left atrial to femoral artery bypass (LAFAB) system is a mechanical circulatory support (MCS) device used in cardiogenic shock (CS) that bypasses the ...

Advanced Cardiac Rhythm Management by Applying Optogenetic Multi-Site Photostimulation in Murine Hearts

Ventricular tachyarrhythmias are a major cause of mortality and morbidity worldwide. Electrical defibrillation using high-energy electric shocks is currently the only treatment for life-threatening ventricular fibrillation. However, defibrillation may have side-effects, including intolerable pain, tissue damage, and worsening of prognosis, indicating a significant medical need for the development of more gentle cardiac rhythm management strategies. Besides energy-reducing electrical approaches, cardiac optogenetics was introduced as a powerful tool to influence cardiac activity using light-sensitive membrane ion channels and light pulses. In the present study, a robust and valid method for successful photostimulation of Langendorff perfused intact murine hearts will be described based on multi-site pacing applying a 3 x 3 array of micro light-emitting diodes (micro-LED). Simultaneous optical mapping of epicardial membrane voltage waves allows the investigation of the effects of region-specific stimulation and evaluates the newly induced cardiac activity directly on-site. The obtained results show that the efficacy of defibrillation is strongly dependent on the parameters chosen for photostimulation during a cardiac arrhythmia. It will be demonstrated that the illuminated area of the heart plays a crucial role for termination success as well as how the targeted control of cardiac activity during illumination for modifying arrhythmia patterns can be achieved. In summary, this technique provides a possibility to optimize the on-site mechanism manipulation on the way to real-time feedback control of cardiac rhythm and, regarding the region specificity, new approaches in reducing the potential harm to the cardiac system compared to the usage of non-specific electrical shock applications.

This work reports a method for controlling the cardiac rhythm of intact murine hearts of transgenic channelrhodopsin-2 (ChR2) mice using local photostimulation with a micro-LED array and simultaneous optical mapping of epicardial membrane potential.

Ventricular tachyarrhythmias are a major cause of mortality and morbidity worldwide. Electrical defibrillation using high-energy electric shocks is ...

Transesophageal Atrial Burst Pacing for Atrial Fibrillation Induction in Rats

Animal studies have brought important insights into our understanding regarding atrial fibrillation (AF) pathophysiology and therapeutic management. Reentry, one of the main mechanisms involved in AF pathogenesis, requires a certain mass of myocardial tissue in order to occur. Due to the small size of the atria, rodents have long been considered 'resistant' to AF. Although spontaneous AF has been shown to occur in rats, long-term follow-up (up to 50 weeks) is required for the arrhythmia to occur in those models. The present work describes an experimental protocol of transesophageal atrial burst pacing for rapid and efficient induction of AF in rats. The protocol can be successfully used in rats with healthy or remodeled hearts, in the presence of a wide variety of risk factors, allowing the study of AF pathophysiology, identification of novel therapeutic targets, and evaluation of novel prophylactic and/or therapeutic strategies.

The present work describes an experimental protocol of transesophageal atrial burst pacing for efficient induction of atrial fibrillation (AF) in rats. The protocol can be used in rats with healthy or remodeled hearts, allowing the study of AF pathophysiology, identification of novel therapeutic targets, and evaluation of new therapeutic strategies.

Animal studies have brought important insights into our understanding regarding atrial fibrillation (AF) pathophysiology and therapeutic management. ...

A Model of Long-Term Ventricular Fibrillation in Isolated Rat Hearts

Ventricular fibrillation (VF) is a fatal arrhythmia with a high incidence in cardiac patients, but VF arrest under perfusion is a neglected method of intraoperative arrest in the field of cardiac surgery. With recent advances in cardiac surgery, the demand for prolonged VF studies under perfusion has increased. However, the field lacks simple, reliable, and reproducible animal models of chronic ventricular fibrillation. This protocol induces long-term VF through alternating current (AC) electrical stimulation of the epicardium. Different conditions were used to induce VF, including continuous stimulation with a low or high voltage to induce long-term VF and stimulation for 5 min with a low or high voltage to induce spontaneous long-term VF. The success rates of the different conditions, as well as the rates of myocardial injury and recovery of cardiac function, were compared. The results showed that continuous low-voltage stimulation induced long-term VF and that 5 min of low-voltage stimulation induced spontaneous long-term VF with mild myocardial injury and a high rate of recovery of cardiac function. However, the low-voltage, continuously stimulated long-term VF model had a higher success rate. High-voltage stimulation provided a higher rate of VF induction but showed a low defibrillation success rate, poor recovery of cardiac function, and severe myocardial injury. On the basis of these results, continuous low-voltage epicardial AC stimulation is recommended for its high success rate, stability, reliability, reproducibility, low impact on cardiac function, and mild myocardial injury.

This protocol presents a model of long-term ventricular fibrillation in rat hearts induced by continuous stimulation with low-voltage alternating current. This model has a high success rate, is stable, reliable, and reproducible, has a low impact on cardiac function, and causes only mild myocardial injury.

Ventricular fibrillation (VF) is a fatal arrhythmia with a high incidence in cardiac patients, but VF arrest under perfusion is a neglected method of ...

Optimizing Pulmonary Artery Banding for Consistent Right Heart Failure Induction

Rat Model of Right-Sided Cardiac Remodeling and Arrhythmia Using Pulmonary Artery Banding

Clinical conditions, including chronic obstructive pulmonary disease or pulmonary arterial hypertension (PAH), can lead to chronic right ventricle pressure overload and progressive right heart failure (RHF). RHF can be identified by right-sided cardiac hypertrophy and dilation associated with abnormal myocardial function affecting the RV and the right atrium (RA). We recently demonstrated that severe RHF is accompanied by an increased risk of atrial inflammation, atrial fibrosis, and atrial fibrillation (AF), the most common type of cardiac arrhythmia (CA). Recent studies have shown that RV and RA inflammation plays an important role in the arrhythmogenesis of CA, including AF. However, the impact of inflammation in the development of CA and AF in RHF is poorly described.
Experimental models of RHF are required to better understand the association between right-sided myocardial inflammation and CA. The rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH) is well-established to provoke RHF. However, MCT triggers severe pneumo-toxicity and pulmonary inflammation. Hence, MCT-induced RHF does not help to distinguish whether the subsequent myocardial inflammation originates from the RHF per se or circulating inflammatory signals secreted by the injured lung.
In this article, a mechanical method involving pulmonary artery trunk banding (PAB) was used to provoke right-sided cardiac arrhythmogenesis. The PAB consists of performing a permanent suture of the pulmonary artery trunk for 3 weeks. Such an approach generates increased right-sided pressure overload. At D21 post-PAB, the suture results in hypertrophied, dilated, and inflamed RV and RA. The PAB-induced RHF is also accompanied by vulnerability to ventricular and atrial arrhythmias, including AF.

Right heart failure (RHF) is characterized by right-sided cardiac dilation and hypertrophy, leading to ventricular and atrial malfunction. Cardiopulmonary conditions associated with RHF are accompanied by an increased risk for cardiac arrhythmias. This article describes a standardized model of pulmonary artery banding-induced RHF associated with enhanced ventricular and atrial arrhythmogenesis.

Clinical conditions, including chronic obstructive pulmonary disease or pulmonary arterial hypertension (PAH), can lead to chronic right ventricle ...

Optimization of Transesophageal Atrial Pacing to Assess Atrial Fibrillation Susceptibility in Mice

Mouse models of genetic and acquired risk factors for atrial fibrillation (AF) have proven valuable in investigating the molecular determinants of AF. Programmed electrical stimulation can be performed using transesophageal atrial pacing as a survival procedure, thus enabling serial testing in the same animal. However, numerous pacing protocols exist, which complicates the reproducibility. The present protocol aims to provide a standardized strategy to develop model-specific experimental parameters to improve reproducibility between studies. Preliminary studies are performed to optimize the experimental methods for the specific model under investigation, including age at the time of the study, sex, and parameters of the pacing protocol (e.g., mode of pacing and definition of AF susceptibility). Importantly, care is taken to avoid high stimulus energies, as this can cause stimulation of the ganglionic plexi with inadvertent parasympathetic activation, manifested by exaggerated atrioventricular (AV) block during pacing and often associated with artifactual AF induction. Animals demonstrating this complication must be excluded from the analysis.

The present protocol describes the optimization of experimental parameters when using transesophageal atrial pacing to assess atrial fibrillation susceptibility in mice.

Mouse models of genetic and acquired risk factors for atrial fibrillation (AF) have proven valuable in investigating the molecular determinants of AF. ...

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

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