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.

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.

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.

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.

Prospectively quantifying the propensity for atrial fibrillation: a mechanistic formulation.

The goal of this study was to determine quantitative relationships between electrophysiologic parameters and the propensity of cardiac tissue to undergo atrial fibrillation. We used a computational model to simulate episodes of fibrillation, which we then characterized in terms of both their duration and the population dynamics of the electrical waves which drove them. Monte Carlo sampling revealed that episode durations followed an exponential decay distribution and wave population sizes followed a normal distribution. Half-lives of reentrant episodes increased exponentially with either increasing tissue area to boundary length ratio (A/BL) or decreasing action potential duration (APD), resistance (R) or capacitance (C). We found that the qualitative form of fibrillatory activity (e.g., multi-wavelet reentry (MWR) vs. rotors) was dependent on the ratio of resistance and capacitance to APD; MWR was reliably produced below a ratio of 0.18. We found that a composite of these electrophysiologic parameters, which we term the fibrillogenicity index (Fb = A/(BL*APD*R*C)), reliably predicted the duration of MWR episodes (r2 = 0.93). Given that some of the quantities comprising Fb are amenable to manipulation (via either pharmacologic treatment or catheter ablation), these findings provide a theoretical basis for the development of titrated therapies of atrial fibrillation.

Mapping multi-wavelet reentry without isochrones: an electrogram-guided approach to define substrate distribution.

AIMS: A key mechanism responsible for atrial fibrillation is multi-wavelet reentry (MWR). We have previously demonstrated that ablation in regions of increased circuit density reduces the duration of, and decreases the inducibility of MWR. In this study, we demonstrate a method for identifying local circuit density using electrogram frequency and validated its effectiveness for map-guided ablation in a computer model of MWR. METHODS AND RESULTS: We simulated MWR in tissues with variation of action potential duration and intercellular resistance. Electrograms were calculated using various electrode sizes and configurations. We measured and compared the number of circuits to the tissue activation frequency and electrogram frequency using three recording configurations [unipolar, contact bipolar, orthogonal closed unipolar (OCU)] and two frequency measurements (dominant frequency, centroid frequency). We then used the highest resolution electrogram frequency map (OCU centroid frequency) to guide the placement of lesions to high frequency regions. Map-guided ablation was compared with no ablation and random/blind ablation lesions of equal length. Electrogram frequency correlated with tissue frequency and circuit density as a function of electrode spatial resolution. Map-guided ablation resulted in a significant reduction in MWR duration (142 ± 174 vs. 41 ± 63 s). CONCLUSION: Electrogram frequency correlates with circuit density in MWR provided electrodes have high spatial resolution. Map-guided ablation is superior to no ablation and to blind/random ablation.

Principles of differential diagnostic pacing maneuvers: serial versus parallel conduction.

In this article we will review differential diagnostic pacing maneuvers. It is not meant to be an exhaustive review of all such maneuvers. Rather, we offer some general analytic principles as they apply to electrophysiology (EP) and illustrate their use through several examples. Our hope is to provide a framework for thinking about electrogram data that acts more like a compass and map than like a specific set of directions. Amongst the most helpful pieces of advice that we can offer the EP trainee is to actively try to picture the waves of electricity spreading through the heart, passing beneath the recording electrodes and generating the electrograms you seek to interpret. Digest the fact that more than one propagation pattern can result in the same electrogram pattern and that differential diagnostic pacing is aimed at distinguishing between these possibilities. A fundamental tenet of differential diagnostic maneuvers of any kind (not simply pacing) is to choose a test that maximizes the difference between possible explanations. This perspective and a careful and meticulous cataloguing of what you can unambiguously conclude from the electrograms versus what remains to be determined via pacing offers the best approach to succeeding at EP. We will discuss pacing maneuvers in three contexts: differential diagnosis of narrow complex tachycardia, mapping of accessory pathways, and Para-Hisian pacing.

Improved spatial resolution and electrogram wave direction independence with the use of an orthogonal electrode configuration.

To improve spatial resolution in recordings of intra-cardiac electrograms we characterized the utility of a novel configuration of two recording electrodes arranged perpendicularly to the endocardial surface. We hypothesized that this configuration denoted as orthogonal close unipolar (OCU) would combine advantages of conventional unipolar and contact bipolar (CBP) configurations. Electrical excitation was simulated in a computational model as arising from dipole current or from multi-wavelet reentry sources. Recordings were calculated for electrode tips 1 mm above the plane of the heart. Analogous recordings were obtained from swine hearts. Electrograms recorded with CBP showed strong dependence on orientation of the electrode pair with respect to the direction of spread of tissue excitation. By contrast, OCU recordings exhibited no directional dependence. OCU was significantly superior to CBP with respect to avoidance of far-field confounding of local tissue activity; the average far-field/near-field ratios for CBP and OCU were 0.09 and 0.05, respectively, for the simulated dipole current sources. In the swine hearts the ratios of ventricular to atrial signals for CBP and OCU were 0.15 ± 0.07 and 0.08 ± 0.09, respectively (p < 0.001). The difference between the actual dominant frequency in the tissue and that recorded by the electrodes was 0.44 ± 0.33 Hz for OCU, 0.58 ± 0.40 Hz for unipolar, and 0.62 ± 0.46 Hz for CBP. OCU confers improved spatial resolution compared with both unipolar and CBP electrode configurations. Unlike the case with CBP, OCU recordings are independent of excitation wave-front direction.

Ablation of multiwavelet re-entry guided by circuit-density and distribution: maximizing the probability of circuit annihilation.

BACKGROUND: A key mechanism responsible for atrial fibrillation is multiwavelet re-entry (MWR). We have previously demonstrated improved efficiency of ablation when lesions were placed in regions of high circuit-density. In this study, we undertook a quantitative assessment of the relative effect of ablation on the probability of MWR termination and the inducibility of MWR, as a function of lesion length and circuit-density overlap. METHODS AND RESULTS: We used a computational model to simulate MWR in tissues with (and without) localized regions of decreased action potential duration and increased intercellular resistance. We measured baseline circuit-density and distribution. We then assessed the effect of various ablation lesion sets on the inducibility and duration of MWR as a function of ablation lesion length and overlap with circuit-density. Higher circuit-density reproducibly localized to regions of shorter wavelength. Ablation lines with high circuit-density overlap showed maximum decreases in duration of MWR at lengths equal to the distance from the tissue boundary to the far side of the high circuit-density region (high-overlap, -43.5% [confidence interval, -22.0% to -65.1%] versus low-overlap, -4.4% [confidence interval, 7.3% to -16.0%]). Further ablation (beyond the length required to cross the high circuit-density region) provided minimal further reductions in duration and increased inducibility. CONCLUSIONS: Ablation at sites of high circuit-density most efficiently decreased re-entrant duration while minimally increasing inducibility. Ablation lines delivered at sites of low circuit-density minimally decreased duration yet increased inducibility of MWR.

Ablation of multi-wavelet re-entry: general principles and in silico analyses.

AIMS: Catheter ablation strategies for treatment of cardiac arrhythmias are quite successful when targeting spatially constrained substrates. Complex, dynamic, and spatially varying substrates, however, pose a significant challenge for ablation, which delivers spatially fixed lesions. We describe tissue excitation using concepts of surface topology which provides a framework for addressing this challenge. The aim of this study was to test the efficacy of mechanism-based ablation strategies in the setting of complex dynamic substrates. METHODS AND RESULTS: We used a computational model of propagation through electrically excitable tissue to test the effects of ablation on excitation patterns of progressively greater complexity, from fixed rotors to multi-wavelet re-entry. Our results indicate that (i) focal ablation at a spiral-wave core does not result in termination; (ii) termination requires linear lesions from the tissue edge to the spiral-wave core; (iii) meandering spiral-waves terminate upon collision with a boundary (linear lesion or tissue edge); (iv) the probability of terminating multi-wavelet re-entry is proportional to the ratio of total boundary length to tissue area; (v) the efficacy of linear lesions varies directly with the regional density of spiral-waves. CONCLUSION: We establish a theoretical framework for re-entrant arrhythmias that explains the requirements for their successful treatment. We demonstrate the inadequacy of focal ablation for spatially fixed spiral-waves. Mechanistically guided principles for ablating multi-wavelet re-entry are provided. The potential to capitalize upon regional heterogeneity of spiral-wave density for improved ablation efficacy is described.

Effects of electrode size and spacing on the resolution of intracardiac electrograms.

BACKGROUND: Electrogram fractionation can result when multiple groups of cardiac cells are excited asynchronously within the recording region of a mapping electrode. The spatial resolution of an electrode thus plays an important role in mapping complex rhythms. METHODS: We used a computational model, validated against experimental measurements in vitro, to determine how spatial resolution is affected by electrode diameter, electrode length, interelectrode distance (in the case of bipolar recordings), and height of the electrode above a dipole current source. RESULTS: We found that increases in all these quantities caused progressive degradation in two independent measures of spatial resolution, with the strongest effect being due to changes in height above the tissue. CONCLUSION: Our calculations suggest that if electrodes could be constructed to have negligible dimensions compared with those in use today, we would increase resolution by about one order of magnitude at most.

Electrogram fractionation: the relationship between spatiotemporal variation of tissue excitation and electrode spatial resolution.

BACKGROUND: Fractionated electrograms are used by some as targets for ablation in atrial and ventricular arrhythmias. Fractionation has been demonstrated to result when there is repetitive or asynchronous activation of separate groups of cells within the recording region of a mapping electrode(s). METHODS AND RESULTS: Using a computer model, we generated tissue activation patterns with increasing spatiotemporal variation and calculated virtual electrograms from electrodes with decreasing resolution. We then quantified electrogram fractionation. In addition, we recorded unipolar electrograms during atrial fibrillation in 20 patients undergoing atrial fibrillation ablation. From these we constructed bipolar electrograms with increasing interelectrode spacing and quantified fractionation. During modeling of spatiotemporal variation, fractionation varied directly with electrode length, diameter, height, and interelectrode spacing. When resolution was held constant, fractionation increased with increasing spatiotemporal variation. In the absence of spatial variation, fractionation was independent of resolution and proportional to excitation frequency. In patients with atrial fibrillation, fractionation increased as interelectrode spacing increased. CONCLUSIONS: We created a model for distinguishing the roles of spatial and temporal electric variation and electrode resolution in producing electrogram fractionation. Spatial resolution affects fractionation attributable to spatiotemporal variation but not temporal variation alone. Electrogram fractionation was directly proportional to spatiotemporal variation and inversely proportional to spatial resolution. Spatial resolution limits the ability to distinguish high-frequency excitation from overcounting. In patients with atrial fibrillation, complex fractionated atrial electrogram detection varies with spatial resolution. Electrode resolution must therefore be considered when interpreting and comparing studies of fractionation.