Rationale and design of the PACE HFpEF trial: Physiologic accelerated pacing as a holistic treatment of heart failure with preserved ejection fraction.

Background: In heart failure with preserved ejection fraction (HFpEF), it has been assumed that pharmacologic heart rate suppression should provide clinical benefits through an increase in diastolic filling time. Contrary to this assumption, heart rate lowering in patients with preserved left ventricular ejection fraction and hypertension or coronary artery disease results in adverse outcomes and suggests that the opposite may be beneficial. Namely, shortening the diastolic filling time with a higher heart rate might normalize the elevated filling pressures that are the sine qua non of HFpEF. Initial clinical studies that assessed the effects of accelerated heart rates in pacemaker patients with preclinical and overt HFpEF provide support for this latter hypothesis, having shown improvements in quality of life, natriuretic peptide and activity levels, and atrial fibrillation burden. Objective: The study sought to determine the effects of continued resting heart rate elevation with and without superimposed nocturnal pacing in HFpEF patients without standard pacing indication. Methods: The physiologic accelerated pacing as treatment for heart failure with preserved ejection fraction (PACE HFpEF) trial is an investigator-initiated, prospective, patient-blinded multiple crossover pilot study that assesses the impact of accelerated pacing on quality of life, physical activity, N-terminal pro-B-type natriuretic peptide, and echocardiographic measures of cardiac structure and function. Results: Twenty patients were enrolled and underwent dual-chamber pacemaker implantation under U.S. Food and Drug Administration investigational device exemption with both atrial and ventricular physiologic lead placement targeting the Bachmann bundle and the His bundle. Conclusion: This manuscript describes the rationale and design of the PACE HFpEF trial, which tests the safety and feasibility of continuous accelerated physiological pacing as a treatment strategy in HFpEF.

Effects of Continuous Accelerated Pacing on Cardiac Structure and Function in Patients With Heart Failure With Preserved Ejection Fraction: Insights From the myPACE Randomized Clinical Trial.

BACKGROUND: Heart failure with preserved ejection fraction ≥50% is prevalent with few evidence-based therapies. In a trial of patients with heart failure with preserved ejection fraction with specialized pacemakers, treatment with accelerated personalized pacing averaging 75 bpm (myPACE) markedly improved quality of life, NT-proBNP (N-terminal pro-brain natriuretic peptide), physical activity, and atrial fibrillation burden compared with the standard lower rate setting of 60 bpm (usual care). METHODS AND RESULTS: In this exploratory study, provider-initiated echocardiographic studies obtained before and after the trial were assessed for changes in left ventricular (LV) structure and function among participants who continued their pacing assignment. The analytic approach aimed to detect differences in standard and advanced echocardiographic parameters within and between study arms. Of the 100 participants, 16 myPACE and 20 usual care arm had a qualifying set of echocardiograms performed a mean (SD) 3 (2.0) years apart. Despite similar baseline echocardiogram measures, sustained exposure to moderately accelerated pacing resulted in reduced septal wall thickness (in cm: myPACE 1.1 [0.2] versus usual care 1.2 [0.2], P=0.008) and lower LV mass to systolic volume ratio (in g/mL: myPACE 4.8 [1.9] versus usual care 6.8 [3.1], P=0.038) accompanied by a minor reduction in LV ejection fraction (in %: myPACE 55 [5] versus usual care 60 [5], P=0.015). These changes were paralleled by improvements in heart failure-related quality of life (myPACE Minnesota Living with Heart Failure Questionnaire improved by 16.1 [13.9] points, whereas usual care worsened by 6.9 [11.6] points, P<0.001). Markers of diastolic function and LV performance were not affected. CONCLUSIONS: Exposure to continuous accelerated pacing in heart failure with preserved ejection fraction is associated with a reduced LV wall thickness and a small amount of LV dilation with small reduction in ejection fraction.

Personalized accelerated physiologic pacing.

Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent with a high socioeconomic burden. Pharmacological heart rate lowering was recommended to improve ventricular filling in HFpEF. This article discusses the misperceptions that have resulted in an overprescription of beta-blockers, which in all likelihood have untoward effects on patients with HFpEF, even if they have atrial fibrillation or coronary artery disease as a comorbidity. Directly contradicting the lower heart rate paradigm, faster heart rates provide haemodynamic and structural benefits, amongst which lower cardiac filling pressures and improved ventricular capacitance may be most important. Safe delivery of this therapeutic approach is feasible with atrial and ventricular conduction system pacing that aims to emulate or enhance cardiac excitation to maximize the haemodynamic benefits of accelerated pacing. This conceptual framework was first tested in the myPACE randomized controlled trial of patients with pre-existing pacemakers and preclinical or overt HFpEF. This article provides the background and path towards this treatment approach.

Result of the Physiologic Pacing Registry, an international multicenter prospective observational study of conduction system pacing.

BACKGROUND: Conduction system pacing (CSP), including both left bundle branch area pacing (LBBAP) and His-bundle pacing (HBP) has been proposed as an alternative therapy option for patients with indication for cardiac pacing to treat bradycardia or heart failure. OBJECTIVE: The purpose of this study was to evaluate implant success, safety, and electrical performances of HBP and LBBAP in the multinational Physiological Pacing Registry. METHODS: The international prospective observational registry included 44 sites from 16 countries globally between November 2018 and May 2021. RESULTS: Of 870 subjects enrolled, CSP lead implantation was attempted in 849 patients. Subjects with successful CSP lead implantation were followed for 6 months (5 ± 2 months). CSP lead implantation was successful in 768 patients (90.4%). Implant success was 95.2% (239/251) for LBBAP and 88.5% (529/598) for HBP (P = .002). Procedural duration and fluoroscopy duration were comparable between LBBAP and HBP (P = .537). Capture threshold at implant was 0.69 ± 0.39 V at 0.46 ± 0.15 ms in LBBAP and 1.44 ± 1.03 V at 0.71 ± 0.33 ms in HBP (P <.001). Capture threshold at 6 months was 0.79 ± 0.33 V at 0.44 ± 0.13 ms in LBBAP and 1.59 ± 0.97 V at 0.67 ± 0.31 ms in HBP (P <.001). Pacing threshold rise ≥1 V was observed at 6 months in 3 of 208 (1.4%) of LBBAP and 55 of 418 (13.2%) of HBP (P <.001). Serious adverse events related to implant procedure or CSP lead occurred in 5 of 251 (2.0%) with LBBAP and 25 of 598 (4.2%) with HBP (P = .115). CONCLUSION: This large prospective multicenter study demonstrates that CSP is technically feasible in most patients with relatively higher implant success and suggests that, with current technology, LBBAP may have better pacing parameters than HBP.

Lower heart rates and beta-blockers are associated with new-onset atrial fibrillation.

Background: Lower heart rates (HRs) prolong diastole, which increases filling pressures and wall stress. As a result, lower HRs may be associated with higher brain natriuretic peptide (BNP) levels and incident atrial fibrillation (AF). Beta-blockers may increase the risk for AF due to suppression of resting HRs. Objective: Examine the relationships of HR, BNP, beta-blockers and new-onset AF in the REVEAL-AF and SPRINT cohort of subjects at risk for developing AF. Methods: In REVEAL-AF, 383 subjects without a history of AF and a mean CHA2DS2VASC score of 4.4 ± 1.3 received an insertable cardiac monitor and were followed up to 30 months. In SPRINT, 7595 patients without prior history of AF and a mean CHA2DS2VASC score of 2.3 ± 1.2 were followed up to 60 months. Results: The median daytime HR in the REVEAL-AF cohort was 75bpm [IQR 68-83]. Subjects with below-median HRs had 2.4-fold higher BNP levels compared to subjects with above-median HRs (median BNP [IQR]: 62 pg/dl [37-112] vs. 26 pg/dl [13-53], p < 0.001). HRs <75bpm were associated with a higher incidence of AF: 37% vs. 27%, p < 0.05. This was validated in the SPRINT cohort after adjusting for AF risk factors. Both a HR < 75bpm and beta-blocker use were associated with a higher rate of AF: 1.9 vs 0.7% (p < 0.001) and 2.5% vs. 0.6% (p < 0.001), respectively. The hazard ratio for patients on beta-blockers to develop AF was 3.72 [CI 2.32, 5.96], p < 0.001. Conclusions: Lower HRs are associated with higher BNP levels and incident AF, mimicking the hemodynamic effects of diastolic dysfunction. Suppression of resting HR by beta-blockers could explain their association with incident AF.

Beta-blockers in atrial fibrillation-trying to make sense of unsettling results.

Atrial fibrillation is closely associated with heart failure and adversely affects outcomes. Beta-blockers are strongly recommended to avoid rapid ventricular conduction and tachycardia-induced cardiomyopathy. In this Viewpoint article, we discuss an emerging body of evidence that questions beta-blockers as a preferred rate-control therapy in patients with atrial fibrillation.

Effect of Personalized Accelerated Pacing on Quality of Life, Physical Activity, and Atrial Fibrillation in Patients With Preclinical and Overt Heart Failure With Preserved Ejection Fraction: The myPACE Randomized Clinical Trial.

Importance: Patients with heart failure with preserved ejection fraction (HFpEF) with a pacemaker may benefit from a higher, more physiologic backup heart rate than the nominal 60 beats per minute (bpm) setting. Objective: To assess the effects of a moderately accelerated personalized backup heart rate compared with 60 bpm (usual care) in patients with preexisting pacemaker systems that limit pacemaker-mediated dyssynchrony. Design, Setting, and Participants: This blinded randomized clinical trial enrolled patients with stage B and C HFpEF from the University of Vermont Medical Center pacemaker clinic between June 2019 and November 2020. Analysis was modified intention to treat. Interventions: Participants were randomly assigned to personalized accelerated pacing or usual care and were followed up for 1 year. The personalized accelerated pacing heart rate was calculated using a resting heart rate algorithm based on height and modified by ejection fraction. Main Outcomes and Measures: The primary outcome was the serial change in Minnesota Living with Heart Failure Questionnaire (MLHFQ) score. Secondary end points were changes in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, pacemaker-detected physical activity, atrial fibrillation from baseline, and adverse clinical events. Results: Overall, 107 participants were randomly assigned to the personalized accelerated pacing (n = 50) or usual care (n = 57) groups. The median (IQR) age was 75 (69-81) years, and 48 (48%) were female. Over 1-year follow-up, the median (IQR) pacemaker-detected heart rate was 75 (75-80) bpm in the personalized accelerated pacing arm and 65 (63-68) bpm in usual care. MLHFQ scores improved in the personalized accelerated pacing group (median [IQR] baseline MLHFQ score, 26 [8-45]; at 1 month, 15 [2-25]; at 1 year, 9 [4-21]; P < .001) and worsened with usual care (median [IQR] baseline MLHFQ score, 19 [6-42]; at 1 month, 23 [5-39]; at 1 year, 27 [7-52]; P = .03). In addition, personalized accelerated pacing led to improved changes in NT-proBNP levels (mean [SD] decrease of 109 [498] pg/dL vs increase of 128 [537] pg/dL with usual care; P = .02), activity levels (mean [SD], +47 [67] minutes per day vs -22 [35] minutes per day with usual care; P < .001), and device-detected atrial fibrillation (27% relative risk reduction compared with usual care; P = .04) over 1-year of follow-up. Adverse clinical events occurred in 4 patients in the personalized accelerated pacing group and 11 patients in usual care. Conclusions and Relevance: In this study, among patients with HFpEF and pacemakers, treatment with a moderately accelerated, personalized pacing rate was safe and improved quality of life, NT-proBNP levels, physical activity, and atrial fibrillation compared with the usual 60 bpm setting. Trial Registration: ClinicalTrials.gov Identifier: NCT04721314.

Heart rate changes and myocardial sodium.

Historic studies with sodium ion (Na+ ) micropipettes and first-generation fluorescent probes suggested that an increase in heart rate results in higher intracellular Na+ -levels. Using a dual fluorescence indicator approach, we simultaneously assessed the dynamic changes in intracellular Na+ and calcium (Ca2+ ) with measures of force development in isolated excitable myocardial strip preparations from rat and human left ventricular myocardium at different stimulation rates and modeled the Na+ -effects on the sodium-calcium exchanger (NCX). To gain further insight into the effects of heart rate on intracellular Na+ -regulation and sodium/potassium ATPase (NKA) function, Na+ , and potassium ion (K+ ) levels were assessed in the coronary effluent (CE) of paced human subjects. Increasing the stimulation rate from 60/min to 180/min led to a transient Na+ -peak followed by a lower Na+ -level, whereas the return to 60/min had the opposite effect leading to a transient Na+ -trough followed by a higher Na+ -level. The presence of the Na+ -peak and trough suggests a delayed regulation of NKA activity in response to changes in heart rate. This was clinically confirmed in the pacing study where CE-K+ levels were raised above steady-state levels with rapid pacing and reduced after pacing cessation. Despite an initial Na+ peak that is due to a delayed increase in NKA activity, an increase in heart rate was associated with lower, and not higher, Na+ -levels in the myocardium. The dynamic changes in Na+ unveil the adaptive role of NKA to maintain Na+ and K+ -gradients that preserve membrane potential and cellular Ca2+ -hemostasis.

Personalized pacing for diastolic dysfunction and heart failure with preserved ejection fraction: Design and rationale for the myPACE randomized controlled trial.

BACKGROUND: Patients with pacemakers and heart failure with preserved ejection fraction (HFpEF) or isolated diastolic dysfunction (DD) may benefit from a higher backup heart rate (HR) setting compared with the standard setting of 60 bpm. OBJECTIVE: The purpose of this study was to assess the effects of a personalized backup HR setting (myPACE group) compared with 60 bpm (control group). METHODS: In this prospective, blinded, randomized controlled study, pacemaker patients with DD or HFpEF and atrial pacing with intrinsic ventricular conduction or conduction system or biventricular pacing are randomized to the myPACE group or control group for 1 year. The primary outcome is the change in Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores. Secondary endpoints include changes in N-terminal pro-brain natriuretic peptide levels, physical and emotional MLHFQ subscores, and pacemaker-detected atrial arrhythmia burden, patient activity levels, and thoracic impedance; hospitalization for heart failure, atrial fibrillation, cerebrovascular accident, or myocardial infarction; and loop diuretic or antiarrhythmic medication initiation or up-titration. A sample size of 118 subjects is expected to allow detection of a 5-point change in MLHFQ score in an intention-to-treat analysis and allow initial assessment of clinical outcomes and subgroup analyses. RESULTS: Enrollment began in July 2019. As of November 2020, 107 subjects have been enrolled. It is projected that the 1-year follow-up will be completed by December 2021. CONCLUSION: Atrial pacing with intrinsic ventricular conduction or advanced ventricular pacing at a higher, personalized backup HR may be a therapeutic target for patients with isolated DD or HFpEF. The myPACE trial is designed to test this hypothesis.

Clinical impact of Bachmann's bundle pacing defined by electrocardiographic criteria on atrial arrhythmia outcomes.

AIMS: Evaluate whether Bachmann's bundle pacing (BBp) defined by electrocardiographic (ECG) criteria is associated with less atrial fibrillation/tachycardia (AF/AT) compared with anatomically defined right atrial septal pacing (RASp) and right atrial appendage pacing (RAAp). METHODS AND RESULTS: This is a retrospective study comparing BBp with non-specific RASp and RAAp on new incidence, burden, and recurrence of AF/AT. We included patients who underwent atrial lead placement between 2006 and 2019 and received > 20% atrial pacing. BBp was defined by paced P-wave morphology and fluoroscopic lead position. Compared with RASp (n = 107) and RAAp (n = 108), AF/AT burden was lower in the BBp (n = 134) group by repeated measures ANOVA (P < 0.001). Over 2-year follow-up, AF/AT burden increased in the RASp (P < 0.01) and RAAp (P < 0.01) groups but did not significantly change in the BBp group (P = 0.91). Atrial arrhythmia burden was lower in the BBp group than the RASp and RAAp groups at 12-15, 18-21, and 24-27 months (P < 0.05) after pacemaker placement. Risk of AF/AT recurrence was lower in BBp than RASp (HR 0.43; P < 0.01) and RAAp patients (HR 0.29, P < 0.01). Risk of de novo AF/AT was also lower in BBp than in RASp (OR 0.12; P < 0.01) and RAAp patients (OR 0.20, P < 0.01). CONCLUSION: Bachmann's bundle pacing defined using P-wave criteria was associated with decreased atrial arrhythmia burden, recurrence, and de novo incidence compared with right atrial septal pacing and right atrial appendage pacing.

Heart Rate-Induced Myocardial Ca2+ Retention and Left Ventricular Volume Loss in Patients With Heart Failure With Preserved Ejection Fraction.

Background Increases in heart rate are thought to result in incomplete left ventricular (LV) relaxation and elevated filling pressures in patients with heart failure with preserved ejection fraction (HFpEF). Experimental studies in isolated human myocardium have suggested that incomplete relaxation is a result of cellular Ca2+ overload caused by increased myocardial Na+ levels. We tested these heart rate paradigms in patients with HFpEF and referent controls without hypertension. Methods and Results In 22 fully sedated and instrumented patients (12 controls and 10 patients with HFpEF) in sinus rhythm with a preserved ejection fraction (≥50%) we assessed left-sided filling pressures and volumes in sinus rhythm and with atrial pacing (95 beats per minute and 125 beats per minute) before atrial fibrillation ablation. Coronary sinus blood samples and flow measurements were also obtained. Seven women and 15 men were studied (aged 59±10 years, ejection fraction 61%±4%). Patients with HFpEF had a history of hypertension, dyspnea on exertion, concentric LV remodeling and a dilated left atrium, whereas controls did not. Pacing at 125 beats per minute lowered the mean LV end-diastolic pressure in both groups (controls -4.3±4.1 mm Hg versus patients with HFpEF -8.5±6.0 mm Hg, P=0.08). Pacing also reduced LV end-diastolic volumes. The volume loss was about twice as much in the HFpEF group (controls -15%±14% versus patients with HFpEF -32%±11%, P=0.009). Coronary venous [Ca2+] increased after pacing at 125 beats per minute in patients with HFpEF but not in controls. [Na+] did not change. Conclusions Higher resting heart rates are associated with lower filling pressures in patients with and without HFpEF. Incomplete relaxation and LV filling at high heart rates lead to a reduction in LV volumes that is more pronounced in patients with HFpEF and may be associated with myocardial Ca2+ retention.

Premature ventricular contraction detection for long-term monitoring in an implantable cardiac monitor.

BACKGROUND: Premature ventricular complexes (PVCs) are an important therapeutic target in symptomatic patients and in the setting of PVC-induced cardiomyopathy; however, measuring burden and therapeutic response is challenging. We developed and validated an algorithm for continuous long-term monitoring of PVC burden in an insertable cardiac monitor (ICM). METHODS: A high-specificity PVC detection algorithm was developed using real-world ICM data and validated using simultaneous Holter data and real-world ICM data. The PVC algorithm uses long-short-long RR interval sequence and morphology characteristics for three consecutive beats to detect the occurrence of single PVC beats. Data are expressed as gross incidence, patient average, and generalized estimating equation estimates, which were used to determine sensitivity, specificity, positive and negative predictive value (PPV, NPV). RESULTS: The PVC detection algorithm was developed on eighty-seven 2-min EGM strips recorded by an ICM to obtain a sensitivity and specificity of 75.9% and 98.8%. The ICM validation data cohort consisted of 787 ICM recorded ECG strips 7-16 min in duration from 134 patients, in which the algorithm detected PVC beats with a sensitivity, specificity, PPV, and NPV of 75.2%, 99.6%, 75.9%, and 99.5%, respectively. In the Holter validation dataset with continuous 2-h snippets from 20 patients, the algorithm sensitivity, specificity, PPV, and NPV were 74.4%, 99.6%, 68.8%, and 99.7%, respectively, for detecting PVC beats. CONCLUSIONS: The PVC detection algorithm was able to achieve a high specificity with only 0.4% of the normal events being incorrectly identified as PVCs, while detecting around three of four PVCs on a continuous long-term basis in ICMs.

Effects of a Higher Heart Rate on Quality of Life and Functional Capacity in Patients With Left Ventricular Diastolic Dysfunction.

There is no evidence-based treatment for heart failure with preserved ejection fraction. Although lower heart rates (HRs) provide an unequivocal benefit for patients with HF with reduced ejection fraction, higher HR might convey important hemodynamic and substrate-modifying benefits in patients with diastolic dysfunction. In a prospective study of 20 stable outpatients with diastolic dysfunction and pacemakers, we evaluated the effects of a 4-week increase in the lower pacemaker rate to 80 beats/min followed by reversal to the previous lower HR setting from weeks 4 to 6. We assessed quality of life (Minnesota Living with Heart Failure Questionnaire), 6-minute walk test and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Pacing at 80 beats/min significantly improved quality of life and the 6-minute walk test (p ≤0.05). There was a strong positive correlation between the pacing-induced changes in NT-proBNP and baseline QRS intervals (r2 = 0.31, p <0.01). Stratification by QRS duration revealed that pacing at 80 beats/min led to -21 ± 26% reduction in NT-proBNP in patients with QRS ≤150 ms, whereas QRS >150 ms was associated with a 26 ± 35% increase in NT-proBNP (p <0.01). Patients physiologically paced from the conduction system had a -46 ± 26% reduction in NT-proBNP at 80 beats/min as compared with 4 ± 26% and 13 ± 26% change with pacing from the right atrial appendage and right ventricular apical septum (pinteraction = 0.04). In conclusion, increasing the lower rate setting of pacemakers to 80 beats/min in patients with diastolic dysfunction improves quality of life, functional capacity, and NT-proBNP for those patients with a baseline QRS ≤150 ms. These findings suggest that higher HRs may provide meaningful benefits to patients with left ventricular diastolic dysfunction and heart failure with preserved ejection fraction.

Troubleshooting and programming considerations for His bundle pacing.

Interest in permanent His bundle pacing as a means of both preventing pacing-induced cardiomyopathy and providing physiological resynchronization by normalization of His-Purkinje activation is steadily growing. However, there are differences in atrioventricular timing cycles, sensing, and tissue capture that distinguish His bundle pacing from right ventricular pacing, and hence it is of utmost importance to bear these differences in mind when implanting a His pacing lead and programming the His pacing system. This article focuses on critical considerations and troubleshooting options available to the implanter and follow-up clinic personnel.