Evidence supporting medications that slow the heart rate (HR), notably beta-blockers, is overwhelming in heart failure (HF) with reduced ejection fraction. Underwhelming, however, is clinical trial support for such agents in patients with HF with preserved ejection fraction (HFpEF).

Indeed, at least for some such patients, a treatment that modestly accelerates resting HR may be a more promising strategy, suggests an early line of research that challenges current thinking about HFpEF therapy.

In a small, randomized test of the idea, patients with HFpEF and standard pacemakers set to a backup resting HR a bit higher than a standard-of-care 60 bpm, usually to about 75 bpm, reaped important quality of life benefits.

More strikingly, their natriuretic peptide levels and burden of atrial fibrillation (AF) fell significantly, the latter by 27% over 1 year.

The trial enrolled only HFpEF patients with pacemakers previously implanted for sick sinus syndrome or atrioventricular block. But researchers say their 107-patient study called myPACE — if confirmed in larger, multicenter trials — lays the groundwork for a device therapy that is broadly useful, potentially, in patients with “preclinical or overt” HFpEF.

Indeed, some of the intervention’s “quite substantial” benefits rivaled or surpassed what his group has observed with available HFpEF drug therapies, including the SGLT2 inhibitors, observed Markus Meyer, MD, PhD, University of Minnesota College of Medicine, Minneapolis.

Moreover, the study may be “the first to show that, with this approach, we can actually also reduce atrial fibrillation,” he told theheart.org | Medscape Cardiology.

Meyer said his group is “confident” that the HR-modulation strategy will be successful in appropriate clinical trials and that “pacemakers, in the end, will become a treatment modality for HFpEF.”

Meyer is senior author on the trial’s February 1 publication in JAMA Cardiology, with lead author Margaret Infeld, MD, University of Vermont, Burlington.

The trial entered pacemaker patients with HFpEF of stage B or C — that is, either asymptomatic with structural disease or fully symptomatic. But, Meyer said, “We saw that the treatment effect was much more pronounced in the patients who had overt heart failure with preserved ejection fraction.”

Challenging Beta-Blocker Dogma

The study, the report states, “contradicts canonical thinking” by suggesting HFpEF patients may benefit from a higher resting heart rate, which would presumably shorten diastolic filling time. It also “may help reduce the overprescription of beta-blockers to allow higher heart rates in this population.”

Indeed, Meyer observed, no one really knows whether beta-blockers work in HFpEF, “because they really have never been studied in a sufficiently powered randomized controlled trial.”

The current study “basically rewrites what we know about the pathophysiology of this form of clinical heart failure,” said Michael R. Zile, MD, Medical University of South Carolina and Veterans Affairs Medical Center, Charleston, who was not part of the trial or report.

Previously in HFpEF, Zile told theheart.org | Medscape Cardiology, “everybody thought you needed to make diastole longer to give the ventricle a longer time to fill. And none of that really made any sense. It was just sort of accepted as dogma.”

The idea led to widespread use of beta-blockers in HFpEF but “turned out just not to be true.” Indeed, European and North American guidelines, Zile observed, “have all taken beta-blockers out of the equation for HFpEF” except for treating comorbidities that can be associated with HFpEF, like hypertension or AF.

Many patients with HFpEF and chronotropic incompetence could be provided with standard pacemakers with primarily conduction-system pacing but are not getting them, he observed.

The current study might help change that. No one is suggesting, based on the current study, “that we start putting pacemakers in every single patient with HFpEF,” Zile said. Still, for HFpEF patients already with a pacemaker, the study provides “reasonable assurance” that its criteria for elevated resting HR may well improve symptoms.

Moreover, he added, it suggests such pacemakers, programmed as in the study, might potentially give a boost to HFpEF patients without chronotropic incompetence but with persisting symptoms despite guideline-directed drug therapy. That’s certainly worth exploring in further trials, Zile said.

How the Study Worked

The single-center trial entered 107 participants with HFpEF and pacemakers set, at baseline, to a backup resting HR of 60 bpm; their age averaged 75 and 48% were women. Only patients with devices for atrial pacing, conduction-system pacing, or biventricular pacing — which are unlikely to promote ventricular dyssynchrony — were included.

They were randomly assigned, double-blind, to have their devices set to an accelerated backup rate or to be continued at 60 bpm. The backup resting rate set for the intervention group’s 50 patients was individualized based on height and other factors; the median was 75 bpm.

Scores on the Minnesota Living with Heart Failure Questionnaire (MLHFQ), the primary endpoint, improved in the intervention group, compared with baseline, by about 11 points after 1 month and by 15 points after 1 year (P < .001).

The scores in the usual-care group deteriorated by half a point and by 3.5 points at 1 month and 1 year (P = .03), respectively.

Consistent advantages for the accelerated-HR strategy were evident throughout the major secondary endpoints. For example, levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) fell an average 109 pg/dL after 1 month in the accelerated-HR group and rose a mean of 128 pg/dL in the usual-care group (P = .02).

Mean daily pacemaker-monitored activity level rose by 47 minutes by 1 year in the accelerated-HR group, compared with a drop of 22 minutes for those assigned to the standard-care rate (P < .001).

AF was detected in 18% of intervention patients at the 1-year follow-up, down from 31% at baseline. Their risk ratio for AF at 1 year was 0.73 (95% CI, 0.55 – 0.99, P = .04) compared with the control group.

In other patients with HFpEF “we have done pacing studies where we just ramped up the pacing rate, and we see that these pressures in the left atrium actually drop immediately,” Meyer said. It’s that “unburdening of the atria,” he added, that probably leads to the reduction in AF.

Meyer reports holding a patent for pacemakers for HFpEF licensed to Medtronic. Disclosures for the other authors are in the report. Zile said he consults for Medtronic and has no other relevant financial relationships.

JAMA Cardiol. Published online February 1, 2023. Abstract

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