# Integrative analysis of electrophysiology in the healed myocardial infarction scar

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $688,575

## Abstract

ABSTRACT
 In the United States, several hundred thousand people experience cardiac arrest each year, with the vast
majority dying from this condition. Approximately two-thirds of cardiac arrest victims have previously suffered a
myocardial infarction (MI), and death results from maladaptive responses to infarct healing. The healed infarct
scar creates a substrate that supports malignant ventricular arrhythmias, and death results from ventricular
tachycardia (VT) originating in the border zone around the infarct scar. The underlying cellular and tissue
electrophysiology that allow the reentrant VT to exist is unknown. Histology studies support a role for surviving
ribbons of myocardial tissue traversing the borderzone region, and immunohistochemical studies show
decreased connexin expression, implicating impaired electrical conduction as a component of the arrhythmia
mechanism. A problem with ascribing causation of VT entirely to these electrical conduction factors is that
they occur diffusely throughout the borderzone, but VT exists in discrete circuits. If impaired conduction were
sufficient to cause VT, it would come from everywhere within the infarct scar and borderzone, but it does not.
Additional factors must be required for existence of VT in the discrete areas where it is found. Our goal is to
define the mechanism of post-infarct VT. We have preliminary data showing alterations in KCNE3 expression
and action potential duration that are unique to VT circuits. We hypothesize that these repolarization effects
combine with the more broadly present alterations in conduction to create conditions that support reentry. To
test our hypothesis, we use an integrative, patient-oriented approach with preclinical testing in a clinically
relevant large mammalian model of post-infarct VT that we have previously validated for mechanistic and
translational studies. We compare the animal model findings to clinical study of patients with post-infarct VT.
In that way, we can perform in-depth mechanistic studies in the animal model and then compare the results to
the human observations to prove relevance. We will focus on 3 aims: (1) to define the unique anatomical and
electrophysiological elements of VT circuits within healed infarct scar in a preclinical model of post-infarction
VT, (2) to reverse the maladaptive electrophysiological changes in the healed infarct scar and assess the
effects on VT, and (3) to define the unique electrophysiological elements of VT circuits within healed infarct
scar in humans. Successful completion of these aims will further our understanding of the mechanism
responsible for infarct-related VT, ultimately allowing translation of these findings into novel drug, gene or
ablative therapies.

## Key facts

- **NIH application ID:** 9868319
- **Project number:** 5R01HL134185-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** J Kevin Donahue
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $688,575
- **Award type:** 5
- **Project period:** 2017-04-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868319

## Citation

> US National Institutes of Health, RePORTER application 9868319, Integrative analysis of electrophysiology in the healed myocardial infarction scar (5R01HL134185-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9868319. Licensed CC0.

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