Development of a Canine Model for Chronic Heart Failure Treatment Using a Pacemaker-Compatible Vagus Nerve Stimulation Device

doi:10.21203/rs.3.rs-3814528/v1

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Development of a Canine Model for Chronic Heart Failure Treatment Using a Pacemaker-Compatible Vagus Nerve Stimulation Device

https://doi.org/10.21203/rs.3.rs-3814528/v1

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This present study aims to develop a vagus nerve stimulator compatible with a pacemaker to treat chronic heart failure(CHF) in a canine model, with the goal of alleviating side effects induced by Vagus Nerve Stimulation (VNS), such as bradycardia.Five dogs underwent rapid right ventricular pacing at a rate of 180–200 beats per minute for three months, and their clinical manifestations, electrocardiograms, echocardiography, and cardiac function were assessed. Subsequently, a canine model combining VNS with a pacemaker was established, and this combined system was continuously stimulated for one month. Electrocardiograms and program-controlled monitoring were observed after VNS implantation to evaluate its effectiveness.Each dog displayed clinical symptoms, encompassing reduced activity and wheezing. Echocardiography validated changes in both cardiac function and structure. Additionally, the electrocardiogram and programmable monitoring affirmed that treatment with VNS led to a reduction in heart rate. Subsequently, the pacemaker commenced operation post-monitoring, a development detectable by both the pacemaker and programmable monitoring. The establishment of a canine model integrating VNS with pacing confirmed the potential of a vagus nerve stimulator compatible with pacing to enhance the efficacy of standalone VNS.

Health sciences/Cardiology/Cardiac device therapy

Health sciences/Medical research

Health sciences/Signs and symptoms

vagus nerve stimulation

chronic heart failure

pacing

beagle

model

Chronic heart failure (CHF) represents the ultimate manifestation and a primary cause of death in numerous cardiovascular diseases [1]. There is a continual upward trajectory in both the incidence and mortality rates of CHF each year. Despite the availability of various treatment modalities for CHF, including pharmaceutical interventions, myocardial revascularization procedures such as PCI or CABG, cardiac resynchronization therapy, stem cell transplantation, and heart transplantation, persistent challenges arise due to limitations in efficacy, technical complexity, potential hazardous complications, and elevated costs [2–5]. Therefore, there is an urgent demand for innovative therapeutic approaches aimed at addressing the complexities of CHF.

VNS, as an innovative device therapy for CHF, has demonstrated significant therapeutic effects. Supported by a series of validated studies [6, 7], VNS contributes to the enhancement of myocardial function, ventricular remodeling, attenuation of inflammatory infiltration, reduction of myocardial cell apoptosis, and the deceleration of CHF progression. Consequently, this leads to improved prognoses for CHF patients and a reduction in mortality rates. Research conducted by Hamann JJ, Xuan Y, and others [8–10] reveals that animals subjected to VNS exhibit marked improvements in heart failure biomarkers, coupled with significant enhancements in left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). Clinical experiments performed by Schwartz PJ, De Ferrari GM, and others [11, 12] on VNS treatment for CHF have confirmed noteworthy improvements in left ventricular ejection fraction (LVEF), 6-minute walking distance, and NYHA functional class for patients undergoing VNS therapy. Consequently, numerous ongoing studies aim to explore the therapeutic potential of VNS in CHF. Recognizing that animal experiments serve as the foundation for clinical research, the establishment of standardized animal models is both essential and imperative for advancing this field.

Relevant research reports indicate the development of mature methods for establishing models of CHF and VNS. Muhammad S Khan, Ren Y, and others [13–15] created a stable CHF model by ligating the left anterior descending (LAD) coronary artery in dogs and rats, restricting collateral blood flow and inducing chronic myocardial ischemia. Additionally, standard CHF models were established by increasing volume and pressure loads. However, ligating arteries and increasing loads have limitations in simulating all the characteristics of chronic heart failure, and the surgical trauma is substantial. Therefore, some studies have adopted rapid pacing of the right ventricle to induce chronic heart failure in dogs, achieving promising results. This method is considered safer and more effective than previous approaches, allowing the simulation of the CHF formation process and its application in large animals [16–18]. Subsequently, ZHOU L, Shen MJ, and others [19–21], building upon the CHF model, developed methods to explore the use of VNS in animal models. They discussed the establishment methods, effective stimulation intensity, and treatment approaches. However, simple VNS may lead to bradycardia (negative chronotropic effect) and atrioventricular conduction slowing (negative dromotropic effect), potentially causing hemodynamic disturbances such as hypotension. Therefore, this study aims to mitigate the side effects of VNS, such as bradycardia, through the use of a pacemaker. The goal is to simulate a VNS device compatible with pacing, thereby treating chronic heart failure in a canine model. This research aims to provide a foundation for subsequent related studies and to offer a more optimal and effective treatment for VNS in the context of CHF.

Materials

Implantable Vagus Nerve Stimulation Pulse Generator Kit (PINs, Beijing Pinchi Medical Equipment Co., Ltd.), Human Cardiac Pacemaker (BIOTRONIK, Biotronik SE & Co. KG), programmable frequency of 40–200 beats per minute, Select SiteTM Sheath System (SELECTSITE C304 S-59) (Medtronic, Inc.), Implantable Cardiac Pacing Screw-in Electrode (Siello S 60 BIOTRONIK), Implantable Vagus Nerve Stimulation Electrode (PINs, Beijing Pinchi Medical Equipment Co., Ltd.), Multi-Channel Electrophysiological Recorder (Johnson & Johnson), BICOR PICOR/TOP Dual C-Arm DSA X-ray Imaging System (SIEMENS, Siemens AG), Surface 12-Lead Electrocardiogram Machine (Marquette, GE Healthcare), Vivid q Type Color Doppler Echocardiography System (GE, General Electric Company), Programmable Pacing System Console (BIOTRONIK, Biotronik SE & Co. KG).

Experimental animals and preoperative preparation

The use of dogs approved by the Experimental Animal Ethics Committee of Kunming Medical University of Traditional Chinese Medicine in accordance with NIH guidelines. Ethical approval number: kmmu2021303. The authors complied with the ARRIVE guidelines.Five healthy adult beagle dogs, with weights ranging from 12 to 14 kg and aged between 7 and 12 months, irrespective of gender, were carefully selected from the Experimental Animal Center of Kunming Medical University. The dogs underwent a fasting period of 8–12 hours prior to the surgical procedures. Body weight measurements were taken before anesthesia, and thorough skin preparation was conducted in designated areas, including bilateral necks, anterior chest, lower back, and limbs.

Establishment of a Canine Model of Chronic Heart Failure through Right Ventricular Rapid Pacing

Following meticulous preoperative preparations for five healthy Beagle dogs, intravenous induction of anesthesia was accomplished using 30 mg/kg of 3% pentobarbital sodium. Intraoperatively, anesthesia was maintained at 4 mg/kg, supplemented by low-flow oxygen delivered through a nasal cannula. Continuous monitoring of surface limb lead electrocardiography, blood oxygen saturation, heart rate, and other pertinent vital signs was diligently conducted throughout the procedure. The surgery adhered to stringent aseptic techniques.The left side of the neck was selected for intervention, and a cut was made in the skin and subcutaneous tissue to expose the external jugular vein. The vein was sequentially punctured, and a guide wire and vascular sheath were introduced. Under X-ray guidance, the screw-in electrode was advanced along the guide wire into the apex of the right ventricle (Fig. 1A). After confirming satisfactory X-ray localization, pacing parameters such as right ventricular sensing, pulse width, voltage, and resistance were meticulously tested.A horizontal incision of approximately 5 cm, parallel to the outer side of the dog's left neck, was made. A pocket tailored to the size of the pacemaker was created, and the pacemaker was connected to the electrode and embedded in the pre-made pocket (Fig. 1B). Subsequently, the electrode was secured, and the skin was closed layer by layer. After confirming normal vital signs, penicillin was administered for three days postoperatively to prevent infection.

Post-surgery, a CHF canine model was established using an extracorporeal pacemaker system controller from BIOTRONIK, a European joint-stock company. The pacemaker was programmed to the VVI pacing mode, delivering continuous stimulation to the dogs. The pacing frequency commenced at 100 beats per minute and was gradually adjusted with increments of 10–20 beats per minute until reaching the upper limit of the pacemaker frequency. Throughout the adjustment process, the fundamental conditions of the experimental dogs, including respiration, heart rate, and diet, were closely observed, and corresponding adjustments were made as necessary.Following 3 months of rapid pacing stimulation, the dogs exhibited varying degrees of symptoms indicative of chronic heart failure, such as dyspnea, persistent wheezing, and reduced exercise tolerance. The LVEF measured less than 50%, confirming the successful establishment of the chronic heart failure model.

Establishment of a Canine Model Combining Vagus Nerve Stimulation with Pacing

Following the successful establishment of the chronic heart failure model, the pacing frequency in the dogs was gradually reduced in decrements of 20 beats per minute each time until reaching 80% of the chronic heart failure canine's intrinsic heart rate threshold. Subsequently, the dogs underwent preoperative preparations and anesthesia, as outlined previously, with low-flow oxygen administered through a nasal cannula. Continuous monitoring of surface limb lead electrocardiography, blood oxygen saturation, heart rate, and other relevant vital signs was maintained throughout the surgery. The surgical procedure strictly adhered to aseptic techniques.With the dogs positioned on their left side and their heads slightly extended forward to tighten the skin of the neck, the right carotid sheath was identified and marked using ultrasound guidance (Fig. 1C, D). A skin incision was made, and subcutaneous fat was dissected using an electric scalpel. Muscle was horizontally transected, and the carotid sheath was opened to expose the left vagus nerve trunk. Sharp dissection was performed between the carotid artery and internal jugular vein, revealing and separating the main trunk of the left vagus nerve for approximately 3 cm. The vagus nerve electrode was then coiled around the nerve (Fig. 1E, F). Initially, the fixed screw-in electrode at the distal end of the vagus nerve was installed, followed by the installation of the positive and negative electrodes. Subsequently, a suitably sized pocket was created on the back of the dog's right neck, and the lead wires were connected to the vagus nerve pulse generator through a tunnel created by a tunneling device. The wires were then buried in the pre-made pocket, and routine parameter testing (including threshold and impedance) was conducted. After achieving satisfactory parameters, the pocket and skin were sutured, and penicillin was administered for three days postoperatively to prevent infection.

One week postoperatively, continuous low-intensity vagus nerve stimulation was initiated in the dogs. The initial stimulation parameters were configured as follows: a stimulation current of 0.2 mA, pulse width of 0.5 ms, and frequency of 20 Hz. The stimulation intensity underwent gradual adjustments, with increments of 0.2 mA each time, until reaching the predetermined standard stimulation intensity range (0.7-1.0 mA) [22], tailored to the individual condition of each dog. Once the standard stimulation intensity was achieved, continuous stimulation was maintained for one month.Simultaneously, pacing was conducted in conjunction with the pacemaker to emulate the pacemaker-compatible Vagus Nerve Stimulation device. The pacing frequency was set at 80% of the chronic heart failure canine's intrinsic heart rate threshold.

Echocardiography

Before inclusion in the experiment, Beagle dogs underwent a preoperative examination with echocardiography, utilizing the American GE Vivid q cardiac color ultrasound imaging system equipped with a probe emission frequency of 2.5 MHz. Following 3 months of rapid pacing of the right ventricle, the experimental dogs underwent echocardiographic examination. The measured parameters encompassed left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular end-systolic diameter (LVIDs), left ventricular end-diastolic diameter (LVIDd), and left ventricular stroke volume (LVSV).

Electrocardiogram examination

The Beagle dogs selected for the experiment underwent preoperative electrocardiography examinations using limb leads. Postoperative electrocardiography was conducted subsequent to both the pacemaker implantation and VNS procedures. The electrocardiograms were carried out at 9 AM to minimize potential abnormal variations attributed to circadian rhythm differences. The examinations comprised the measurement of heart rate, PR interval, QT interval, and ST segment. These parameters were assessed to evaluate changes in cardiac electrophysiological function.

Pacemaker system programmable controller monitoring

Following the successful establishment of the combined VNS and pacing model in Beagle dogs, the external pacemaker system console was employed to monitor their heart rate variability. After attaining and maintaining the standard Vagus Nerve Stimulation intensity for one month, the pacing frequency was adjusted using the programmable console. The pacing frequency was systematically decreased at intervals of every 3–5 days by 20 beats per minute. Simultaneously, daily monitoring of heart rate variability was conducted using the programmable console.

Statistical analysis

Data were analyzed using SPSS 26 and expressed as x ± s. An unpaired t-test was employed to perform statistical analysis between groups before and after the establishment of the chronic heart failure canine model.

Clinical Manifestations Following 3 Months of Pacing and VNS

After three months of pacing stimulation, all five dogs exhibited varying degrees of clinical manifestations, including reduced food intake, decreased activity levels, and shortness of breath. While their body weight had increased compared to pre-pacing levels, there were no significant changes in urination and defecation. During the VNS treatment phase, all five dogs experienced varying degrees of coughing and muscle contractions in the neck. However, after adjusting the stimulation intensity, these adverse reactions were improved. Moreover, each dog showed a noticeable improvement in symptoms such as shortness of breath and activity levels compared to the period after pacing.

Changes in Cardiac Function Indicators and Echocardiography Before and After Establishing the Canine Chronic Heart Failure Model

Table 1 illustrates the cardiac function indicators before and after establishing the chronic heart failure canine model. Following 3 months of pacing, there were significant reductions observed in the LVEF, LVFS, and LVSV. Concurrently, significant increases were noted in LVIDd, LVIDs, LVEDV, and LVESV (P < 0.05 for all comparisons, Fig. 2A to Fig. 2G). Furthermore, the left atrium and left ventricle of the Beagle dogs exhibited significant enlargement compared to pre-surgery measurements. Additionally, the left ventricular wall motion amplitude was notably weakened, the end-diastolic diameter was significantly increased, and the ventricular wall thickness was significantly reduced.

Table 1

Comparison of Canine Cardiac Function Parameters Before and After Rapid Right Ventricular Pacing
Cardiac Parameters	Before	After
LVIDd	31.60 ± 2.51	36.00 ± 1.00 **
LVIDs	21.20 ± 1.64	28.80 ± 0.84 ****
LVEDV	42.28 ± 9.77	54.80 ± 3.70 *
LVESV	14.94 ± 3.26	32.20 ± 2.49 ****
LVSV	29.22 ± 4.73	22.70 ± 2.01 *
LVFS	34.20 ± 2.95	19.72 ± 1.12 ****
LVEF	64.60 ± 3.78	41.00 ± 2.00 ****
Compared with pre-pacing: P < 0.05;P < 0.01,***P < 0.0001

ECG monitoring

Before and after rapid right ventricular pacing, the QRS wave shape and duration in dogs with CHF underwent significant alterations compared to the pre-pacing period (Fig. 3A, B). Similarly, the PR interval, QT interval, and ST segment duration also exhibited noteworthy changes. Prior to VNS surgery (Fig. 3C), a programmable device was employed to reduce the pacing frequency to 80% of the dog's native heart rate (120 beats/min) in cases of CHF. Notably, even after heart failure, the QRS wave, PR interval, QT interval, and ST segment continued to display significant alterations when compared to the pre-pacing period. However, following the combined treatment of VNS and pacing (Fig. 3D), there was a remarkable improvement in the QRS wave morphology, PR interval, QT interval, and ST segment in dogs with CHF. Although there were slight changes compared to the pre-pacing surgery, the differences were minimal. Additionally, as depicted in Fig. 3D, there was a distinct pacing signal wave in the QRS complex, likely resulting from the pacemaker sensing and stimulating the reduced heart rate during VNS treatment.

Programmed Monitoring During Vagus Nerve Stimulation Combined with Pacemaker Therapy

In Fig. 2H, it is illustrated that after achieving the standard vagus nerve stimulation intensity and completing 1 month of stimulation, the pacing frequency was adjusted and monitored through the programmable controller. We observed that even at a pacing frequency of 120 times/min, the pacemaker was still able to sense and perform pacing. However, upon gradually decreasing the pacing frequency, it ranged from 80–100 times/min (which is lower than the lower limit of a healthy dog's heart rate), with the pacemaker sensing and pacing occurring within 24 hours at a percentage of 20–30%. Importantly, even when the pacing frequency was reduced to 60 beats/min, significantly lower than the lower limit of a healthy dog's heart rate, the pacing percentage still reached 10–15%. Previous research on the application of VNS in chronic heart failure has suggested that it may lead to a decrease in heart rate and limit its effectiveness. Our program-controlled monitoring results confirmed that VNS does indeed have the side effect of lowering heart rate.

VNS, as an innovative therapeutic approach for treating CHF, operates by ameliorating autonomic nervous system imbalance, mitigating CHF symptoms and prognosis, and consequently reducing the associated mortality rate [23–26]. This article offers a comprehensive description of the establishment of a chronic heart failure model through rapid right ventricular pacing and the combination of vagus nerve stimulation with pacing in canine models. We observed significant changes in clinical manifestations, electrocardiograms, echocardiograms, and cardiac functional indicators in dogs before and after modeling. Importantly, through programmable monitoring, our research revealed that VNS could significantly reduce heart rate, while the pacemaker accurately sensed and prevented excessively low heart rates, potentially providing cardiac protection. In contrast, previous studies, such as the one conducted by Tamar et al. [27], failed to demonstrate the effective reduction of bradycardia with the cardiofit device.

The typical heart rate range for healthy adult Beagle dogs is 90 to 130 beats per minute. Numerous studies have employed rapid pacing of the right ventricle as a method to induce canine CHF. Belevych et al. [28] adjusted the pacing frequency, initiating continuous stimulation at a rate of 180 beats per minute for 2 weeks, followed by stimulation at a rate of 200 beats per minute for 6 weeks, and finally maintaining stimulation at a rate of 180 beats per minute for 2 months. To avoid adaptability issues in dogs during the modeling process, reduce mortality, and align with Belevych's study, we adopted a gradual increase in pacing frequency, maintaining treatment at 180–200 beats per minute for 3 months, successfully establishing the CHF model.In contrast, Miller WL et al. [29] utilized a dedicated cardiac pacemaker for animals, programmable at a frequency of 200–600 beats per minute, maintaining stimulation at a rate of 260 beats per minute for 4–5 weeks. This approach offers advantages such as a shorter timeframe and efficient model production. However, its stimulation duration is relatively brief, failing to fully simulate the progression of CHF. The safety and effectiveness of this method warrant further consideration.

Several studies [20, 30, 31] suggest that by adjusting appropriate stimulation parameters, a successful model of VNS for treating CHF can be achieved. Additionally, studies focusing on the placement of vagus nerve stimulators in dogs [22] have now applied standard parameters for the explanation of the spiral electrode placement position in dogs. Therefore, following the successful establishment of the CHF canine model, we proceeded to establish a combined vagus nerve stimulation and pacing canine model. The successful establishment of the model was confirmed through electrocardiogram results and programmable monitoring.

Relevant studies [29, 32] indicate that during the establishment of a CHF model in dogs, there is a varying degree of weight loss. However, in accordance with animal welfare principles and care considerations, we meticulously cared for the dogs to ensure their health and body weight. Moreover, our experiment was the first to combine VNS therapy with a pacemaker, preserving the effectiveness of VNS in treating chronic heart failure and ensuring the safety of VNS therapy. The programmable monitoring data illustrated the critical role of the pacemaker in preventing heart rate reduction during the process of VNS therapy for CHF. Nevertheless, our study has certain limitations: 1. The sample size of modeled dogs is relatively small, which may introduce some randomness and errors. 2. Arterial blood pressure is also an indicator for assessing potential side effects of VNS; however, we did not measure femoral artery blood pressure in our experiment, indicating a lack of evidence regarding the effectiveness of VNS combined with pacing in preventing other adverse reactions apart from heart rate reduction. 3. Our study aimed to improve indicators such as LVEF through VNS therapy for CHF. Still, we solely decreased pacing frequency to simulate the function of a pacemaker compatible with VNS and did not consider the potential changes in LVEF due to the reduction in pacing frequency. 4. The VNS stimulation parameters we controlled only considered low amplitude and high frequency characteristics, lacking a discussion on the duty cycle, and the quantification of heart rate response was not addressed. Therefore, future research should further explore and refine relevant mechanisms to provide more effective treatments.

A current study on the treatment of CHF using a pacemaker-compatible vagus nerve stimulation device is currently underway. This research holds the potential to provide new insights into the treatment of CHF with VNS and may offer more effective clinical treatment approaches for CHF.

The use of VNS alone may lead to a decrease in heart rate, potentially affecting treatment efficacy. This paper, by establishing a combined vagus nerve stimulation and pacing canine model to simulate the functionality of a pacemaker-compatible vagus nerve stimulation device in treating CHF, demonstrates that this approach may improve the efficacy of VNS alone. Additionally, it provides a foundation for establishing a canine model for treating chronic heart failure using a pacemaker-compatible vagus nerve stimulation device.

Competing interests

The authors declare no competing interests.

Funding

This research was funded by National Natural Science Foundation (82160080); Yunnan Province Revitalizing Yunnan Talents Support Plan Project(YNWR-MY-2020-011); Yunnan Province Revitalizing Yunnan Talents Support Plan Project(XDYC-QNRC-2022-0315).

Author Contribution

Y.C.H and L.L.Zhao contributed with the conception, design, plan, acquisition, and analysis of the results, and participated in editing the manuscript. Y.C.H: Statistical analysis, Writing - original manuscript. L.Z and B.T.H contributed with conception, supervision, and writing the manuscript.The remaining authors critically reviewed the manuscript, gave final approval, and agreed to be accountable for all aspects of the work and ensure its completeness and accuracy.

Acknowledgments

The authors thank all the medical and technology team.

Data availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request

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Development of a Canine Model for Chronic Heart Failure Treatment Using a Pacemaker-Compatible Vagus Nerve Stimulation Device

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Abstract

Figures

Introduction

Materials and methods

Materials

Experimental animals and preoperative preparation

Establishment of a Canine Model of Chronic Heart Failure through Right Ventricular Rapid Pacing

Establishment of a Canine Model Combining Vagus Nerve Stimulation with Pacing

Echocardiography

Electrocardiogram examination

Pacemaker system programmable controller monitoring

Statistical analysis

Results

Clinical Manifestations Following 3 Months of Pacing and VNS

ECG monitoring

Programmed Monitoring During Vagus Nerve Stimulation Combined with Pacemaker Therapy

Discussion

Conclusion

Declarations

Competing interests

Funding

Author Contribution

Acknowledgments

Data availability

References

Additional Declarations

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