Cardiac pacing is the primary treatment for symptomatic bradycardia or high-grade atrioventricular block [1]. In clinical practice, right ventricular pacing (RVP) has been a well-established technique for decades. Accumulated evidence indicates that chronic RVP can cause dyssynchronous left ventricular electrical activation and consequently results in deleterious impacts on cardiac function [2, 3, 4]. This is particularly true for patients with a high percentage of ventricular pacing (VP%), typically defined as VP% $>$40%. Left bundle branch area pacing (LBBAP), an emerging physiological pacing modality, has been introduced in recent years [5]. By directly stimulating the cardiac conduction system, LBBAP can preserve intraventricular and interventricular electrical and mechanical synchrony [6, 7]. Multiple studies have demonstrated the clinical superiority of LBBAP over conventional RVP, including improvements in all-cause mortality, reductions in heart failure hospitalization, and a decreased risk of atrial fibrillation [8, 9, 10].

Blood pressure (BP) is a useful hemodynamic indicator that is dynamically modulated by both the autonomic nervous system (ANS, sympathetic and vagal reflex) and neurohumoral factors (circulating catecholamines, neuropeptides, rein-angiotensin-aldosterone-system). Several studies have reported that patients with chronic bradycardia may experience elevated systolic blood pressure (SBP) [11, 12, 13], which can be attributed to an increased myocardial contraction force (Frank-Starling mechanism) and excessive sympathetic activation secondary to bradycardia. Vice versa, elevated SBP can also lead to bradycardia via baroreflex. An unexpected phenomenon commonly observed is that RVP receivers can undergo BP variations after the implantation, which is termed ‘pacemaker syndrome’ [14, 15]. It refers to a complex of symptoms, consisting of fatigue, palpitations, and shortness of breath, which are related to the adverse hemodynamic and electrophysiological consequences of ventricular pacing. Several potential causes have been linked to the occurrence of pacemaker syndrome, which include retrograde atrial conduction, disruption of regular atrial synchrony at a normal atrioventricular (AV) interval, and insufficient cardiac rate response [14]. Previous studies proposed that pacing might participate in hemodynamic abnormalities by adversely impacting cardiac autonomic baroreflex function, particularly in non-physiological pacing [16, 17]. However, the exact hemodynamic effect of pacing has received little attention in the literature, and no studies have yet focused on the BP variations associated with novel physiological pacing.

We hypothesized that the magnitude of BP variations in ventricular-paced individuals might differ depending on the pacing modalities. Given that LBBAP produces physiological cardiac contractile outcomes of the left ventricle due to the native conduction system, it is likely to confer more favorable hemodynamic effects over less physiological RVP. To test this hypothesis, we examined the BP values pre- and post-implantation in patients who received either LBBAP or RVP.

In this retrospective cohort study with a large sample size, we provided further insight into acute blood pressure changes post-implantation of LBBAP and RVP. Our PS-matched comparison between the LBBAP and RVP group yielded several significant and clinically meaningful findings: (1) the implantation of permanent pacemakers for patients with conduction system disease could contribute to a significant decrease in systolic blood pressure shortly after the implantation; (2) this immediate effect was more pronounced in LBBAP receivers than in RVP receivers, suggesting that LBBAP might have stronger physiological hemodynamic effects; and (3) baseline SBP and the use of anti-hypertensive drugs were potentially associated with the magnitude of arterial BP reduction post pacemaker implantation.

An earlier study noted a potential correlation between the maximal arterial BP differences observed during ventricular pacing, especially comparing AV synchrony with maximal AV asynchrony, and the subsequent improvement in cardiac index [23]. That study suggested that BP variability could be a more valuable indicator of the hemodynamic impact in ventricular-paced individuals. Channon et al. [17] reported that paced individuals exhibit a reduction in BP, and the beat-to-beat BP variability was greatly increased when changed from DDD to VVI pacing. A cohort of 24 dual-pacemaker patients focused on the effects of pacing sites on blood pressure, showed that right ventricle (RV) septal pacing was associated with less BP variation compared with RV apical pacing in the VVI mode [15]. Our results with a large study cohort demonstrated an immediate and substantial systolic BP reduction after pacemaker implantation.

Several possible pathophysiological mechanisms may have been responsible for the acute hemodynamic changes in response to pacing. First, almost all patients receiving permanent pacemaker implantation suffer from bradycardias. Compensatory elevation of SBP may occur due to an increased contraction force following increased ventricular filling during bradycardia (the Frank-Starling mechanism), leading to a greater stroke volume (SV) and hence the increased systolic BP [24]. Furthermore, increased left ventricle (LV) filling may stimulate the sympathetic afferent fibers distributed in the heart through cardiac wall distension. Pacing corrects the bradycardia and thus prevents overcompensation of BP. A recent case report [13] suggested that pacemaker implantation resulted in increased cardiac output and a marked reduction in peripheral resistance, which might be due to other less well-understood mechanisms contributing to the decrease in BP.

A similar trend of SBP reduction was observed in both LBBAP and RVP receivers in the present study, however, the magnitude of BP reduction was more profound in the LBBAP group. LBBAP involves placing the ventricular electrode in the left bundle branch region, and our results were consistent with previous studies [25, 26, 27] showing that it produced a narrower paced QRS complex and a relatively lower pacing threshold, leading to improved LV synchrony. In general, improved LV synchrony may increase the stroke volume and cardiac output (CO), which could lead to decreased BP variation. An unexpected trend was observed in the present study. Since the ANS plays an important role in modulating cardiovascular functions and maintaining blood pressure homeostasis [28], we speculated that the ANS might participate in this hemodynamic regulation, since improved cardiac work during LBBAP may cause a decrease in elevated sympathetic activation. RVP is essentially a non-physiological modality that mimics left bundle branch block (LBBB), which may disrupt normal electrical activity and activate the sympathetic nerve system. Therefore, increased sympathetic activity may compensate for the magnitude of BP reduction by pacing. Further research that includes a more comprehensive assessment of ANS and more hemodynamic parameters may prove helpful to evaluate this hypothesis.

Patients with AVB tend to have a higher VP% than those with SND. Our study found that BP variations appeared to be more pronounced in the high-VP% group, which could be attributed to loss of AV synchrony and atrial contraction in patients with a high VP%. However, this does not necessarily imply a direct linear correlation between VP% and BP variations. To date, there is no evidence suggesting a dose-dependent correlation between BP reduction and pacing burden. In patients with a low VP% (e.g., VP% $\le$1%), atrial pacing may still cause BP variations, yet its influence may be less than ventricular pacing. Nevertheless, we did not find a significant difference in SBP between patients with AVB and those with SND. In fact, several confounding factors related to conduction system dysfunction (baseline BP, atrioventricular conduction, ANS modulation), might play a more important role in blood pressure fluctuations and could have influenced the combined results. Therefore, these factors should be comprehensively considered when interpreting our findings, and further research is needed to determine the exact association between BP reduction and VP%.

The regulation of blood pressure in humans is a highly intricate process. In the present study, we tried to identify which subgroup would experience more pronounced BP variations. A significant difference in SBP change was found between patients grouped by their baseline SBP and those grouped by the use of AHDs, while changes were not comparable between patients grouped by their combined history of hypertension. Multiple studies have clearly illustrated that abnormal sympathetic activity may be responsible for the appearance and maintenance of high blood pressure [29, 30, 31]. In our study, the mean baseline SBP was around 145 mmHg in the group with a higher baseline SBP, meeting the diagnostic criteria for hypertension [20]. Instantaneous sympathetic tone may be higher in these patients. In contrast, certain anti-hypertensive medications may reduce sympathetic activity and improve vagal cardiac control [32, 33], potentially resulting in a relatively lower basal sympathetic tone in patients treated with these drugs compared to those without AHDs. Conversely, patients with a history of hypertension, who have undergone long-term anti-hypertensive treatments, may no longer differ from those without a HTN history in baseline BP and sympathetic tone. This could explain why higher baseline BP was potentially linked to high BP variation while the use of AHDs produced an opposite trend. Based on these findings, we assumed that higher baseline sympathetic activity may contribute to a greater magnitude of SBP reduction after the initiation of pacing therapy that alleviates sympathetic activity. No relevant studies are currently available, and future experimental and clinical investigations are necessary to validate our assumption.

As a new emerging pacing strategy, LBBAP delivers a huge breakthrough in conduction system pacing, and it is meaningful to illustrate its hemodynamic outcomes. This study produced a preliminary insight into the acute variations in blood pressure during pacemaker implantation and the initiation of pacing therapy by comparing LBBAP with RVP using propensity score matching. Our findings will help clinicians gain a comprehensive understanding of the LBBAP technique and promote its further adoption. It is worth noting that the acute hemodynamic responses may differ between de-novo pacemaker recipients and chronically paced patients, highlighting the requirement for further research on its long-term hemodynamic impact. Moreover, it is necessary for future prospective studies to comprehensively measure and record more hemodynamic parameters such as cardiac output, total peripheral resistance, and respiratory rate, and characterize the timeline of hemodynamic changes during pacing therapy. Since LBBAP produces a more synchronized ventricular motion, future studies could also incorporate echocardiographic assessment to evaluate the relationship between hemodynamic changes and improved cardiac function.

The present study has several limitations. First, it was a single-center retrospective analysis, and the potential bias inherent in a non-randomized design cannot be avoided. Although we performed PSM to minimize the confounding factors between LBBAP and RVP patients, heterogeneity among patients still remained. Second, blood pressure is a dynamic parameter that can be influenced by various factors. Specifically, some of the enrolled patients receiving pacemaker implantation were critically ill. During critical illness, the body undergoes significant stress and physiological changes that can affect blood pressure. Inpatient hospital stays can cause BP fluctuations for other hospitalized patients, stemming from factors such as stress, medications, fluid imbalances, and illness progression. In contrast to home/ambulatory blood pressure, measuring blood pressure during inpatient stays may offer a less comprehensive assessment. This limitation can interfere with our ability to accurately reflect the true BP changes. Third, the use of an arm pressure cuff for BP measurement could have introduced some measurement errors. As this study was conducted retrospectively, it was not feasible to utilize invasive blood pressure transducers to confirm the accuracy of external arm cuff-based pressure readings for each participant. Additionally, the majority of enrolled patients had no indications for invasive blood pressure monitoring. In the future, we can consider applying invasive blood pressure monitoring techniques to observe the effects of pacing on blood pressure in appropriate patients. Fourth, the present study did not investigate the physiological mechanisms underlying the acute BP reduction caused by pacing. We speculate that pacing may have corrected the bradycardia and thereby eliminated the associated compensatory BP elevation. We considered this phenomenon as a physiological response, returning the blood pressure to the patient’s normal level. However, it is essential to note that significant periprocedural BP fluctuations could increase the risk of adverse events. Therefore, close monitoring of blood pressure should be implemented during the periprocedural period of pacing. Future well-designed clinical or mechanical studies could simultaneously measure other hemodynamic parameters to gain deeper insights into the mechanisms underlying this phenomenon.

Permanent pacemaker implantation may contribute to a decrease in systolic blood pressure shortly after implantation, which is more prominent in LBBAP receivers. Baseline SBP and the use of anti-hypertensive drugs are potentially associated with the magnitude of BP variation. Further large-scale prospective studies are needed to confirm the exact relationship between cardiac pacing and blood pressure variation, as well as the long-term hemodynamic effects of LBBAP versus RVP.

ACEi/ARB, angiotensin-converting enzyme inhibitor /angiotensin receptor blocker; AF/AFL, atrial fibrillation/atrial flutter; AHDs, antihypertensive drugs; ANS, autonomic nervous system; AVB, atrioventricular block; BP, blood pressure; CCB, calcium channel blockers; CO, cardiac output; DBP, diastolic blood pressure; ECG, electrocardiogram; HR, heart rate; HTN, hypertension; IVS, interventricular septum; LBBAP, left bundle branch area pacing; LVAT, left ventricular activation time; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; PSM, propensity score-matching; RBBD, right bundle branch conduction delay; RVP, right ventricular pacing; SBP, systolic blood pressure; SD, standard deviation; SND, sinus node dysfunction.

The original data presented in the study are included in the article, further inquiries can be directed to the corresponding authors.

SW, WL, YD, and KC designed of the study. ZC, QH, YL, YG and WW were involved in data collection. SW, YW, RC and SZ were involved in the interpretation of data. SW and WL drafted the first version of the manuscript, and YD, KC, and SZ revised the manuscript for critically intellectual content. All authors read, critically revised and approved the manuscript. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of the study are appropriately investigated and resolved.

This study conformed with the Declaration of Helsinki and was approved by the Ethics Committee of Fuwai hospital (No.2019-1149). All participants provided written informed consent for pacemaker implantation and use of data for clinical investigation.

The authors thank Dr. Xiaohong Zhou (Medtronic, Inc.) for his diligent review of our manuscript.

This study was funded by the National Natural Science Foundation (NSFC) of China (Grant Number: 81870260) and National High Level Hospital Clinical Research Funding (Grant Number: 2022-GSP-GG-31).

The authors declare no conflict of interest.