# A New Pacing Approach for Cardioprotection and Repair in Heart Failure

> **NIH NIH R21** · UNIVERSITY OF IOWA · 2020 · $195,899

## Abstract

Heart failure is a major public health challenge. Exercise is increasingly recognized as a powerful tool
to mitigate adverse outcomes in heart failure. One key component of exercise is episodic heart rate
acceleration interspersed with periods of rest. Although slower average heart rates have been consistently
associated with improved cardiovascular outcomes, preliminary results indicate that exercise-similar episodes
of heart rate acceleration above the baseline heart rate can serve as a trigger for upregulation of
cardioprotective molecules and pathways associated with myocardial conditioning and remodeling. This
stimulus, paired with much longer intervening periods of slower HRs to provide the opportunity and resources
for adaptation, could be harnessed for therapeutic use. Specifically, an “exercise-inspired” pattern of heart rate
acceleration is delivered by a pacing protocol specially designed to be maximally physiologic and to confer
positive myocardial adaptive stimuli while carefully avoiding known detrimental consequences of pacing. In
mice, this pacing approach results in significant upregulation of cardioprotective ATP-sensitive potassium
channels and inhibition of basal calcium/calmodulin-dependent protein kinase II activation. These molecular
findings are coupled with improved resistance to ischemia/reperfusion injury and, in hearts recovering from
infarct, less fibrosis. In 8 human subjects with chronic, medically treated but refractory systolic heart failure and
left ventricular ejection fraction <=35%, reproduction of the pacing pattern, delivered through manual
programming of the subjects’ already-implanted pacing devices, transiently raises blood pressure and cardiac
output and is both hemodynamically and symptomatically well-tolerated. In a pre-pilot, five such subjects were
randomized in a single-blind fashion to the same pacing, or to sham pacing, performed daily for 3-5 days/week
over 4 weeks. The pacing group reported significantly improved symptoms/quality of life over their baseline
while improvement in the sham-treated group was not significant. Direct comparison between the groups
showed a trend toward greater improvement with pacing vs. sham. These initial human studies support the
safety and feasibility of the approach. Assessment of the impact on other functional and structural outcome
measures will require greater cohort sizes. The proposed project will further investigate the molecular
mechanisms of these observations in a mouse model of cardiomyopathy and in a human pilot study. Data
obtained under this exploratory project, if supportive of the impact of the proposed pacing approach, will be
used as preliminary data for a more intensive investigation for which NIH R01 funding will be sought. These
studies have the potential to identify novel targets and strategies to promote cardioprotection and outcomes in
heart failure. The approach has potential for high impact given that it may have broad applicability in an ...

## Key facts

- **NIH application ID:** 9849132
- **Project number:** 5R21HL144199-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Denice Hodgson-Zingman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,899
- **Award type:** 5
- **Project period:** 2019-01-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849132

## Citation

> US National Institutes of Health, RePORTER application 9849132, A New Pacing Approach for Cardioprotection and Repair in Heart Failure (5R21HL144199-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9849132. Licensed CC0.

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