Comparing the Effects of Newer Pacemakers and Their Effects on the Heart and Valve Function in the Short-term.

Overview

Conventional pacemakers involve placing a lead through a valve into the bottom right chamber of the heart. Research has shown that this is associated with an increased risk of valve dysfunction and mortality as well as impairment of heart function.Newer pacemakers such as leadless pacemakers and pacemakers that engage directly with the heart's native conduction system (known as left bundle branch pacemakers), are increasingly being adopted. However, the impact of these newer pacing technologies on the heart and tricuspid valve, as well as how they compare against each other, is unclear. We aim to study the impact of leadless pacemakers and left bundle branch pacemakers on cardiac function and tricuspid valve by conducting an acute study that will be performed in addition to the routine pacemaker implantation that the participant has been referred for. Both procedures will be performed in one sitting under general anaesthesia. Outcomes from this study will improve our understanding of how these pacing technologies affect heart and valve function and how they compare against each other. This will guide decision-making regarding the ideal type of pacemaker to be adopted, especially in patients who stand to suffer the most from developing tricuspid valve or heart dysfunction.

Transvalvular right ventricular pacing (TVP) is a guideline-directed first-line treatment for high degree AV block and sick sinus syndrome. However, TVP is associated with increased risk of pacing-induced cardiomyopathy (PIM), tricuspid regurgitation (TR) and right ventricular dysfunction (RVD). Leadless right ventricular pacing (LP) and left bundle branch area pacing (LBBAP) are emerging as attractive alternatives to conventional TVP. While preliminary studies have investigated the impact of LP and LBBAP on left ventricular function, there is limited information on how they compare against each other and their effects on RV and tricuspid valve function. We aim to perform an acute mechanistic study involving a head-to-head comparison of LBBAP versus LP on their acute effects on biventricular function and tricuspid valve function. EXPERIMENTAL DETAILS AND DESIGN Study design: Twenty patients will be prospectively recruited and undergo an acute mechanistic study in the same sitting prior to undergoing their allocated permanent pacemaker implantation, which will be performed as per standard clinical practice. Study population: Inclusion criteria: All patients aged ≥18 referred for a permanent pacemaker at a single centre (Guys and St. Thomas' NHS Foundation Trust, UK) with high degree AV block, including Mobitz II and complete heart block, or scheduled AV node ablation, and LVEF ≥50%. Exclusion criteria: LVEF \<50%, severe TR, severe RV dysfunction, clinically unstable AV block requiring temporary pacing or isoprenaline infusion, left bundle branch block, previous TV annuloplasty or replacement, aortic valve replacement, life expectancy \<1 year, end-stage renal failure, contraindication to cardiac MRI, CT or TOE, pregnancy, contraindication to anticoagulation, peripheral vascular disease precluding insertion of femoral catheters and insufficient capacity to consent to the study. Cardiac MRI (CMR): All patients will undergo a CMR with late gadolinium enhancement (LGE) to characterise the presence and location of LV and septal scarring. Steady-state free precession sequences will be used to obtain cine images in standard two-, three- and four-chamber long axis views, with subsequent contiguous short-axis cines from the mitral annulus to the LV apex. The location and extent of septal LGE will be defined and quantified. LV and RV volumes, stroke volume and ejection fraction will be measured. Electrophysiological procedure: This procedure will be performed under general anaesthesia to allow concurrent use of TOE intraprocedurally. A quadripolar catheter (5F Josephson, St Jude Medical, St Paul, MN) will be placed in the high right atrium (HRA) via femoral venous access. A decapolar catheter (6F Livewire 115 cm, St Jude Medical) inserted via the femoral vein will be placed at the level of the His bundle on the RV septum. An identical decapolar catheter will be inserted via the femoral artery using a 5F MPA catheter retrogradely into the LV and placed on the septum where a left bundle potential is seen. Intracardiac recordings will be observed to determine the level of AV block (nodal, intraHisian or infraHisian). A dissociation between the HRA and His signals will be interpreted as nodal block. If the level of block is infranodal, a left bundle potential to ventricular (LB-V) interval will be recorded. If the LB-V interval is \<35ms or split His signals are recorded, then intraHisian block is assumed. If the LB-V interval is \>35ms or LB-V block is demonstrated with pacing from the LV catheter, then infraHisian block is assumed57. The RV catheter will be paced at different points, in the order of the RVOT-S, mid-septum and apical-septum to simulate LP at these levels. The LV catheter will be paced at the level of the left bundle followed by the left posterior fascicle. A pressure wire (Pressure Wire X, Abbott, St. Paul, MN) will be inserted via the femoral vein into the RV cavity. An identical pressure wire will be inserted into the LV using existing arterial access. Pacing settings: A device programmer will be used to perform either dual chamber pacing, if the patient is in sinus rhythm, with an AV delay of 100ms, or single chamber ventricular pacing if the patient is in AF. All pacing will be performed at 10bpm above the patient's intrinsic rate. Where no intrinsic rate is present (e.g. no ventricular escape rhythm), pacing will be performed at 60bpm to simulate real-world pacing rates in this cohort. Following the acute mechanistic study, the patient will undergo their allocated permanent pacemaker as per standard clinical practice. ECGi: All patients will be fitted with a 252-electrode vest (Medtronic, Minneapolis, MN). They will undergo a computed tomography (CT) scan to acquire the cardiac-torso geometry as previously described58. Epicardial activation maps will be constructed and LVAT, RVAT, BVAT, VEU and LVDI will be measured at baseline and after each pacing configuration, using a method previously described59. LVDI is the standard deviation of activation times of LV segments. VEU is the absolute difference between LVAT and RVAT. Acute haemodynamics: During the electrophysiology study, LV dP/dt¬max and RV dP/dtmax will be measured at baseline and during each pacing configuration, as a surrogate marker of LV and RV contractility, respectively. An average of 3 measurements will be taken at baseline and after each pacing configuration. A 20-second wait will be adopted before any measurement is taken to allow for haemodynamic stabilisation. Acute haemodynamic response in the RV and LV will be presented as percentage change from baseline. An increase of \>10% in LV dP/dt¬max from baseline will be considered as a positive acute haemodynamic response (AHR), based on our previous study demonstrating positive remodelling in patients with \>10% increase in LV dP/dt¬max with LV endocardial pacing51. Transoesophageal echocardiography (TOE): A TOE probe will be inserted into the oesophagus after induction of general anaesthesia. Quantitative measurements taken will include RV end systolic volume (RVESV), RV end diastolic volume (RVEDV), RV global longitudinal strain (GLS), RV free wall strain, 3D RVEF and if TR is present, vena contracta diameter and PISA. Qualitative measurements will include upper-oesophageal, mid-oesophageal and 'grasping' view of the TV with colour doppler. TR severity will be assessed using the British Society of Echocardiography (BSE) guidelines and will be graded by semiquantitative visual grading (grade 0: none/trace, 1: mild, 2: moderate, 3: moderate-to-severe, 4: severe)60. TR progression will be defined as an increase in 1 grade. LV function will be assessed by measuring the LVEF, LV global longitudinal strain (LV GLS), LV end systolic volume (LVESV) and LV end diastolic volume (LVEDV). A drop of \>10% in LVEF to an LVEF of \<50% will be considered as PIM. Measurements will be taken at baseline and with each pacing configuration. Meta-analysis: Studies comparing PIM rates between TVP and LP to date have yielded mixed outcomes. As part of this fellowship, I will also be performing a systematic review and meta-analysis comparing the rates of PIM between LP and TVP to provide a more definitive picture on whether LP is superior to TVP in reducing the rate of PIM. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Hypothesis 1: There is a significant difference in the risk of acute PIM between LP and LBBAP. We will measure acute PIM using TOE. χ2 test will be used to compare the proportion of acute PIM between the LBBAP and LP pacing configurations. Hypothesis 2: LP is associated with a lower risk of acute TR progression compared to LBBAP. We will measure acute TR progression with TOE by assessing the degree of TR at baseline and with temporary pacing. χ2 test will be used to compare the proportion of TR progression between the LBBAP and LP pacing configurations. Hypothesis 3: There is no significant difference in the risk of acute RVD between LP and LBBAP. We will assess for acute RVD with TOE by measuring TAPSE, RVEF, RV GLS at baseline and with temporary pacing. Analysis of variance (ANOVA) test will be used to compare the mean change in TAPSE, RVEF and RV GLS respectively between the LBBAP and LP pacing configurations. Mechanistic hypotheses: Hypothesis 4: LBBAP is associated with less electrical dyssynchrony compared to LP. We will assess for electrical dyssynchrony with ECGi to measure VEU and LVDI at baseline and with the LBBAP and LP pacing configurations. ANOVA or Kruskal-Wallis test will be used, depending on distribution, to compare VEU and LVDI respectively between the LBBAP and LP pacing configurations. Hypothesis 5: LBBAP is associated with a higher rate of positive acute haemodynamic response than LP. We will assess for acute haemodynamic response using intracardiac pressure wires to measure LV dP/dt and RV dP/dt at baseline and with the LBBAP and LP pacing configurations. ANOVA test will be used to compare LV dP/dt and RV dP/dt respectively between the LBBAP and LP pacing configurations. Hypothesis 6: There is no significant difference in activation times and electrical dyssynchrony measurements produced by in silico modelling and in vivo study using ECGi. We will compare activation times and electrical dyssynchrony between our in-silico modelling and in vivo study. Specifically, we will compare LVAT, BVAT, VEU and LVDI respectively between the two groups using the student t-test or Man-Whitney U test, depending on distribution.