Research Article, Int J Cardiovasc Res Vol: 7 Issue: 1

Multisite Pacing in Intact Myocardium and after Acute Myocardial Infarction: Experimental Study

Matthaios I^*, Kaladaridou A, Skaltsiotes E, Agrios J, Antoniou A, Georgiopoulos G, Papadopoulou E and Toumanidis S

Department of Clinical Therapeutics, Medical School, National and Kapodistrian University of Athens, “Alexandra” Hospital, 80 Vas. Sophias Ave Lourou, Athens, 11528, Greece

*Corresponding Author : Ioannis Matthaios MD,PhD
Department of Clinical Therapeutics, “Alexandra” Hospital, 80 Vas. Sophias Ave – Lourou, Athens, 11528, Greece
Tel: 0030 210 3381497
Fax: 0030 210 3381497
E-mail: giannismat@gmail.com

Received: November 24, 2017 Accepted: January 12, 2018 Published: January 16, 2018

Citation: Matthaios I, Kaladaridou A, Skaltsiotes E, Agrios J, Antoniou A, et al. (2018) Multisite Pacing in Intact Myocardium and after Acute Myocardial Infarction: Experimental Study. Int J Cardiovasc Res 7:1. doi: 10.4172/2324-8602.1000337

Abstract

Keywords: Pacing; Torsion; Acute myocardial infarction; Cardiac mechanics

Introduction

More than a half a century has passed since Furman and Schwedel published their work on endocardial lead placement for cardiac pacing in humans [1]. Since then, the apex of the right ventricle (RV) remains the standard of choice regarding the site of lead placement due to the accessibility, feasibility, and the safety it provides.

However, in the last decade there is growing evidence which demonstrates that pacing the apex of the RV has unfavourable effects, influencing morbidity and mortality [2-5]. These findings are consistent with Wigger’s observations, who, in 1925, reported about the adverse left ventricular (LV) hemodynamic effects that occurred, secondary to RV apical pacing [6]. These harmful effects are produced, mostly due to the alteration of the normal conduction pathway. The electrical stimulation bypasses the atrioventricular node and the highly specialised His-Purkinje system, and is spread slowly through the common myocardium, causing abnormal ventricular contraction and reducing pump function.

Obviously, it is time to seek alternative pacing sites to minimise the adverse clinical outcomes of RV apex stimulation. Investigation in this area is also extensive due to the introduction of cardiac resynchronisation therapy (CRT) and the fact that almost one-thirds of patients receiving this therapy do not respond to treatment [7,8].

A number of studies have been published about alternative pacing sites, mostly in patients with heart failure [9-11]. However, data about the impact of different pacing sites on LV function in intact myocardium and myocardium under ischemia is scarce. Moreover, the evaluations of cardiac mechanics in this condition, with novel techniques such as two-dimensional speckle tracking echocardiography (STE), are limited. The STE allows detailed evaluation of LV mechanics, including LV mechanical dyssynchrony, LV strain, and LV torsion, and provides important additional information for the selection of the optimal pacing site [12,13]. Data based on STE- comparing the effects of different LV pacing and sites on the LV mechanics, LV strain, and LV torsion-are still limited [14,15].

The purpose of this study was to assess the acute hemodynamic and echocardiographic response to different pacing configurations in intact myocardium after experimental acute myocardial infarction (AMI). The ultimate goal was to determine the optimal combination of pacing sites that preserve LV function under ischemic conditions.

Methods

The protocol complied with the “Principles for the Care of Experimental Animals” and the “Guidelines for the Care and Use of Experimental Animals” issued by the US National Academy of Sciences and National Institute of Health (version 85-23, revision 1996), and was approved by the Scientific Committee of our Hospital.

Surgical preparation

16 healthy pigs, weighing 40 ± 5 kg, were pre-medicated with intramuscular administration of ketamine potassium 5 mg/kg, and midazolam 5 mg/kg. Anaesthesia was induced with thiopental sodium 5 mg/kg intravenously (IV), and the animals were then intubated and ventilated by mechanical ventilation (Sulla 808V, Drager Medizintechnik GmbH Germany). Throughout the experiment anaesthesia was maintained with IV propofol 0.1-0.2 mg/kg, and analgesia was maintained with the administration of opioid-fentanyl. Lead II of the standard electrocardiogram (ECG), haemoglobin oxygen saturation, and the animal’s temperature with a rectal thermometer were monitored constantly by a multichannel device (Dynamap Plus Vital Signs Monitor, Criticon, Tampa, FL, USA).

A 6F sheath was inserted into the right internal jugular vein for the delivery of drugs and fluids. A suprapubic urinary catheter was inserted to measure urine output, and fluid loss was compensated by continuous infusion of saline into the right jugular vein. Moreover, left external carotid artery was cannulated and a 6F pigtail catheter was placed into the LV cavity and used for the measurement of LV pressure and peak rate of LV pressure increase (dP/dtmax). To avoid endovascular thrombus formation, a 5000 IU heparin bolus was administered. Loading conditions were kept constant during the different manoeuvres.

We used the same surgical procedure that we have developed in our previous experiments [15,16]. Briefly, a regular median sternotomy was performed after thyme resection, and a longitudinal pericardiotomy was performed. The left anterior descending (LAD) coronary artery was surgically exposed, and two 3-0 Prolene sutures (Ethicon, Johnson & Johnson Co., European Logistics Centre, Sint- Stevens- Woluwe, Belgium) were placed after the origin of the first diagonal branch of the LAD, to be used for future ligation. Before ligation, left coronary artery entrapment was confirmed by upward traction. The apex of the LV was observed for evidence of myocardial blanching indicating interruption to coronary flow, confirming epicardial ischemia (Figure 1).

Pacing

Temporary myocardial pacing leads (Medtronic, type 6500, Minneapolis, MN, USA) were attached to the surface of the right atrium, to the epicardium of the RV apex, and in different positions of the epicardium of the LV. These different positions of the LV were the basal posterior wall, the basal anterior wall, and the apex lateral wall (Figure 2). All pacing positions were kept outside the infarcted zone.

The pacing leads were connected to an external pacemaker (Medtronic Model 5388 dual chamber temporary pacemaker, Minneapolis, MN, USA). Pacing was unipolar with an indifferent electrode positioned in between the intercostal muscles. The AV delays were short enough to produce an activation wave originating from the ventricular pacing lead, and were not modified between the different pacing configurations. Pacing was performed at about twice the stimulation threshold and the pacing rate was set at 10 beats/min above the intrinsic heart rate in each case.

Standard echocardiography

The echocardiographic study was performed using a Vivid i digital ultrasound system (GE Medical Systems Ultrasound Israel Ltd., Tirat Hacarmel, Israel) and a 3.5 MHz phased array transducer. Echocardiographic measurements were performed intrathoracically, by placement of the probe directly on the epicardium. A soft silicone pad, placed between the probe and the epicardium, acted as a cushion for the moving heart and as an offset to prevent near-field artifacts. Two-dimensional grey-scale echocardiographic images were obtained, using second-harmonic imaging. Instrument settings were held constant for each experiment. Three consecutive cardiac cycles were stored in cineloop format for offline analysis. Averaged values were calculated for each parameter.

Two-dimensional speckle tracking echocardiography

An assessment of the LV rotation and twist was obtained by the acquisition of specific short-axis planes with internal landmarks: the basal plane was acquired at the level of the mitral valve leaflets while excluding the mitral annulus and the apical plane was acquired distal from the papillary muscles. The frame rate range was 65-80/s. In each phase, three consecutive cardiac cycles’ cineloop images were stored for offline analysis with a dedicated platform Echo Pac PC (version 7.0, GE Medical Systems).

Experimental protocol

After completion of the surgical preparations, a steady-state period of 15 minutes was allowed. Epicardial atrioventricular pacing in multiple sites was performed simultaneously. The combinations of pacing sites we studied are demonstrated in Table 1. These pacing combinations were performed in a random order. Baseline measurements were obtained in sinus rhythm, and then repeated during every pacing combination. Measurements were taken after 5 minutes of pacing at each combination, separated by 5-minute intervals in sinus rhythm. Data were obtained 30 minutes after ligation of the LAD. The ligation was placed in the same position in all the animals.

Table 1: Combinations of the different pacing sites we studied.

Statistical analysis

Continuous variables are displayed as medians, and 25^th/75^th percentiles. Statistical analysis was performed on absolute values, and each experiment served as its own control. Differences in variables of interest among various pacing sites were established with the Friedman non-parametric test for k-related samples (where k=number of alternative pacing sites). Pair-wise comparisons were subsequently performed, using the Wilcoxon Signed Rank Analysis, for two related samples. Bonferroni correction was implemented to account for multiple comparisons.

Variation of main hemodynamic, echocardiographic, and torsional parameters among different pacing sites was further assessed by linear mixed models with unstructured variance-covariance matrix. All mixed models incorporated at least one random effect (i.e., random intercept) to address heterogeneity among subjects. Diagnostics for linear mixed models were based on graphical analysis of the corresponding residuals (Q-Q plots). The level of significance was set at p<0.05. The statistical software package SPSS for Windows, version 17, was used for data analysis (SPSS Inc., Chicago, IL, USA).

Results

A total of 16 experiments were performed and completed by protocol. Three animals were excluded from the analysis due to unsuccessful recovery from lethal ventricular fibrillation, immediately after LAD ligation.

Intact myocardium

Data analysis revealed that in intact LV myocardium sinus rhythm is superior of all the different combinations of epicardial pacing sites we studied in most of hemodynamic and conventional echocardiographic parameters (Table 2).

Table 2: Comparison of hemodynamic and conventional echocardiographic variables during sinus rhythm and during pacing with the different configurations in intact myocardium.

In the intact myocardium, pacing with every configuration we tested significantly decreased most of the systolic and diastolic parameters. The stroke volume and the ejection fraction were reduced (in all sites p<0.05) even though the cardiac output seemed to be preserved in all sites, except from site 1 (p=0.04), mostly because the heart rate was higher during pacing (all sites p<0.05). The changes in dP/dt_max and mean arterial pressure were not significantly affected by pacing (all sites p>0.05). Moreover, the e/e�?�? ratio, which is an index of the diastolic performance of the LV, was increased by all pacing configurations although it reached a statistically significant level in three of them (configuration 1 p=0.008, configuration 5 p=0.02 and configuration 7 p=0.04) [17]. For every pacing mode and pacing site, the heart rate was significantly higher and the QRS duration significantly longer in comparison to sinus rhythm (all sites p<0.05).

In addition, data analysis revealed that most of the LV torsional and strain parameters also deteriorated significantly during pacing in the intact myocardium (Table 3 and Figure 3). Torsion and twist were reduced significantly (all sites p<0.05). Pacing with every configuration led to reduction of rotation, circumferential and radial strain of the apex and the base of the LV. However, this reduction was not uniform and in some pacing sites it reached a significance level while in others it remained statistically insignificant. The untwisting rate, which is a novel indicator of the relaxation of the LV, was reduced significantly only in site 4 (p=0.03) and site 6 (p=0.03) [18]. On the contrary, the torsion rate, which provides additional information about the systolic performance of the LV, remained statistically unaffected by pacing (all sites p>0.05) [19].

Table 3: Comparison of left ventricular torsional and strain parameters during sinus rhythm and during pacing with the different configurations in intact myocardium.

In conclusion, by linear mixed model analysis, sinus rhythm was superior than pacing sites for major hemodynamic parameters (ejection fraction and stroke volume) as well as for twist index.

Post AMI

Measurements after AMI revealed a significant deterioration in LV performance compared to the intact myocardium (Figure 4 and Table 4). Moreover after AMI and during pacing, the hemodynamic and conventional echocardiographic variables were altered to a different degree in comparison to sinus rhythm (Table 4). Stroke volume and ejection fraction were reduced significantly in all sites, except site 2 and site 6 (p>0.05). Additionally, the QRS duration was prolonged (all p>0.05). Cardiac output did not present a statistically significant change, mainly due to an increase in heart rate (all p<0.05) during pacing. Furthermore, the e/e�?�?ratio was increased in absolute values in all pacing sites, but a statistically significant increment was found only in site 1 (p=0.03) and site 7 (p=0.04). Hemodynamic parameters, such dP/dtmax, LV systolic pressure, and mean arterial pressure, did not decrease to statistically significant levels (p>0.05).

Table 4: Comparison of the hemodynamic and conventional echocardiographic variables during sinus rhythm and during pacing with the different configurations after AMI.

Torsional and strain parameters of the LV were also affected by the different pacing configurations in comparison with sinus rhythm (Table 5 and Figure 5). Pacing mostly affected the base of the heart, leading to a decrease in the rotation and the circumferential and radial strain of the base. The rotation and the circumferential strain of the apex did not change remarkably in comparison with the sinus rhythm— although the radial strain was reduced significantly-except in site 4, where it increased significantly (22.1% vs. 19.9%, p<0.01). Furthermore, the torsion and the twist were reduced during pacing but this reduction was only significant during pacing with the combination 7 (p=0.01, and p=0.02, respectively). The torsion rate and the untwisting rate also did not change significantly (all p>0.05).

Table 5: Comparison of left ventricular torsional and strain parameters during sinus rhythm and during pacing with the different configurations after AMI.

Data analysis also revealed, that the combination of pacing LV apex lateral wall and LV basal posterior wall (site 6), manages to preserve almost all hemodynamic, echocardiographic, and rotational parameters at levels similar to sinus rhythm.

Discussion

This study is one of the few experimental works in the area of pacing, that combines hemodynamic data, conventional echocardiographic variables, and torsional and deformation parameters, to investigate the effects of different pacing sites in the intact and infarcted myocardium. The usage of only echocardiographic parameters was avoided, as the results of the PROSPECT study revealed that echocardiographic mechanical indices alone were unreliable measures of optimal LV response during biventricular pacing, although the STAR study (Speckle Tracking and Resynchronisation study) showed that speckle tracking echocardiography is a moderately helpful tool to predict CRT response [20,21].

Previous studies have demonstrated that single site LV pacing is superior to RV pacing [22-24]. In addition, these studies have revealed that LV apex pacing has a favourable hemodynamic effect, probably because pacing from the apex creates a relatively physiological propagation of electrical conduction [15,25-27]. Prior studies have demonstrated that the earliest part that is activated is the middle inferior septum. From there, the wave of depolarisation sweeps rapidly to the entire septal and apical myocardium, leaving the basal and posterior aspects of the heart to be the latest areas excited [28- 30]. However, it is the system of the Purkinje fibres that will pass the depolarisation through the myocardium. These fibres extend from the apex, where their concentration is high toward the atrioventricular septum and the base of the heart. Hence, pacing the apex could justify a favourable effect, since this is the site where the impulses exit the Purkinje system [31-33].

Right atrial-single site LV pacing, even though superior to right atrial-RV pacing, was not studied here, as it is not considered sufficiently reliable, especially in pacemaker-dependent patients with transvenously implanted LV leads, because of their higher dislodgement rate [34,35].

In this study, the pacing leads were kept outside the infarct zone. This was considered essential, since in our previous research works we managed to demonstrate that after LAD ligation, pacing inside the infarcted area deteriorated the LV function as compared to pacing in sites away from this area [16,36]. The same conclusion in clinical settings has been announced by Bleeker et al., who found that an LV lead, positioned in an area with a transmural scar, reduces the beneficial effects of CRT on the clinical outcome and cardiac performance [37].

The use of simultaneous biventricular pacing was considered necessary, since this is the usual modality of CRT to date. Moreover, as stated in the current European Society of Cardiology guidelines for CRT, this practice is largely empirically derived from pathophysiological reasoning, and from the evidence provided by earlier clinical trials [38]. Additionally, the RHYTHM II ICD trial has demonstrated that VV delay (interventricular delay) optimisation with sequential biventricular pacing did not improve hemodynamic response during CRT [39].

AV delays, as mentioned at the methodology, were not modified between the different pacing configurations. We decided to not include AV delays as a variable in an already too complex protocol, since there are a number of studies, which investigated pacing sites with different AV delays and the majority of them have concluded that the pacing site is more important than AV delay optimisation in enhancing a favourable pacing result [40,41]. This reflects the current European guidelines for CRT, where it is stated that current evidence does not strongly support the performance of AV and VV optimisation routinely, in all patients receiving CRT [38].

The present study shows that, in the intact myocardium, sinus rhythm is superior of all the different combinations of epicardial pacing sites that were studied. However after AMI, the pacing combination of LV apex lateral and LV basal posterior wall (site 6) preserves LV function, at a level similar to sinus rhythm. This finding probably has to do with the fact that this configuration combines two regions of the LV with discrete characteristics. Firstly, the basal posterior wall is a region of late activation. Studies have shown that pacing at the site of latest mechanical activation resulted in superior echocardiographic response after six months of CRT, and better prognosis during long-term follow-up [42,43]. This is the reason why most electro physiologists are targeting a posterolateral vein to place the LV lead at CRT. On the contrary, the lateral apex provides the nearest region to the apex of the LV outside the infarct zone, where the impulses exit the Purkinje system, leading to faster engagement of the pacing impulse.

Our findings indicated that the best LV performance after AMI did not occur at the shortest QRS length; however, this is further supported by the results of other researchers [44,45]. In addition, this is also one of the reasons that QRS duration after lead implantation is not the best indicator of CRT response.

Although in the present study, only the acute effects of different pacing sites were investigated, there are a number of studies in clinical settings, showing that the immediate response of LV twist after CRT predicts LV reverse remodelling [46,47]. In concordance with this, in the current study, LV twist was mostly preserved during pacing configuration 6, as compared to all other configurations, suggesting this to be an important site to be considered in future investigations.

Clinical implications

The quest for finding the best pacing site and the best pacing combination in the impaired myocardium is in progress. This quest is imperative, considering the numerous patients with an impaired myocardium that have to undergo cardiac surgery. Pacing wires are frequently inserted at the end of cardiac surgical procedures. Their main use is to improve haemodynamic function in the presence of arrhythmias, as well as to suppress atrial and ventricular tachyarrhythmias [48,49]. Moreover, pacing leads are used perioperative as a precaution of dangerous bradyarrhythmias. Our study provides additional information and options for pacing these patients.

Cardiac resynchronisation therapy is a major breakthrough in treatment for advanced congestive heart failure patients. However, there is substantial rate of non-response to this therapy, and this problem might become increasingly important, because it is anticipated that larger groups of heart failure patients are indicated to undergo the therapy [7,8]. Hence, there is extensive research in exploring various ways to increase the response to the technique. Our findings could guide the way to patients with anterior myocardial infarction that requires CRT. For these patients, we provide evidence that pacing the LV apex lateral and LV basal posterior wall is superior to the classic CRT. It is worth mention, that CRT is provided using epicardial pacing electrodes, because conventional access for lead positioning (via coronary sinus or by thoracotomy) results in an epicardial location of the LV pacing electrode. With the currently available leads, the LV apex lateral could be reached using the trans coronary venous approach, if the lead can be advanced far enough. Alternatively, a minimally invasive thoracotomy can be used to place the lead in this position, a technique that is already in use for patients who, anatomically, are not suitable for a transvenous approach [50].

Limitations

This is an experimental study in animals and the results should be used with caution in clinical situations. In addition, the present study assessed only acute effects of the different pacing sites on LV mechanics, even though in swine models, acute coronary occlusion, due to the lack of collaterals, depresses the LV function and prompts neurohormonal activation, thus satisfying several criteria characteristic of the heart failure phenotype [51]. The impact of the pacing site in patients with chronic ischemia, is more clinically relevant, and needs to be further investigated. In addition, to avoid intrinsic ventricular conduction, the pacing rate was set at 10 beats/ min above the intrinsic heart rate in each case, resulting in a high heart rate. These non-physiological conditions may preclude us from drawing conclusions about the long-term effects of chronic pacing with different combinations on LV performance. Moreover, this was an animal study focused on anterior myocardial infarction, and the potential future clinical application should be specifically aimed at patients with this type of infarction. Extrapolation of the data from the present study in other types of failing myocardium should be done with care.

Conclusions

In the present study, hemodynamic data, combined with speckle tracking analysis applied to conventional 2D echocardiography was used, to investigate the acute effects of different combination pacing sites on LV mechanics. In pig hearts with an intact myocardium sinus rhythm is superior from every pacing combination we studied, however after anterior AMI, the pacing combination of LV apex lateral wall and LV posterior wall managed to preserve LV function similar to sinus rhythm.

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