# Autophagy in Myocardial Recovery and Remission

> **NIH VA I01** · ST. LOUIS VA MEDICAL CENTER · 2022 · —

## Abstract

ABSTRACT
Therapeutic interventions that favorably impact the untoward natural history of heart failure (HF) either slow or
reverse left ventricular (LV) remodeling. In some patients with HF with a reduced ejection fraction (HFrEF)
reverse LV remodeling is associated with freedom from future clinical HF events (“myocardial recovery”),
whereas in the great majority of patients the initial stabilization of LV structure/function is followed by
progressive LV remodeling and untoward clinical outcomes (“myocardial remission”). Thus, although recovery
of LV structure and function are associated with stabilization of the clinical course of HF, as well as reversal of
many aspects of the HF phenotype, it is not associated with freedom from future HF events. Understanding the
clinical and biological features of “compensated” HF patients, who have normalized or partially normalized LV
structure and function, but remain vulnerable to hemodynamic/neurohormonal stress, represents a major unmet
need in the field of heart failure. The long term goal of this research initiative is to delineate the
mechanisms responsible for the functional instability of hearts that have undergone reverse LV
remodeling with recovery of LV function, and to develop new therapies that will address this unmet
clinical need. To explore the biological basis for the clinical phenomenon of “myocardial remission,” we have
developed a clinically relevant pre-clinical model of “reversible heart failure” that combines moderate aortic
constriction (TAC) and distal LAD ligation (MI), which are the major comorbidities that cause HFrEF in
industrialized nations. To “reverse” the HF phenotype, the TAC + MI mice are hemodynamically unloaded by
surgically removing the aortic constriction, resulting in the normalization of LV structure and function. Germane
to the present proposal, when the de-banded TAC + MI mice (“HF-DB” mice) are exposed to a neurohormone
stress, they develop increased LV hypertrophy and increased LV dysfunction, analogous to what is observed in
HFrEF patients who develop functional instability following recovery of LV structure and function. Based on our
preliminary observations that the autophagy-lysosome system is dysregulated during the development and
recovery from HF, we prose to test the following three hypotheses: (1) autophagic flux is impaired during
the development of HF and, although flux is relatively improved following hemodynamic unloading, flux
remains “inefficient” (Aim1); (2) autophagic flux is required for effective reverse LV remodeling (Aim 2);
and (3) insufficient autophagic flux is responsible, at least in part, for the functional instability that
develops in reverse LV remodeled hearts that are exposed to neurohormonal stress (Aim 3). Specific
Aims 1-3 will provide definitive information with respect to the potential role of autophagy in the recovery
of LV structure and LV function following hemodynamic unloading, as well as the functional instability
of rev...

## Key facts

- **NIH application ID:** 10477219
- **Project number:** 5I01BX005065-03
- **Recipient organization:** ST. LOUIS VA MEDICAL CENTER
- **Principal Investigator:** Douglas L Mann
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477219

## Citation

> US National Institutes of Health, RePORTER application 10477219, Autophagy in Myocardial Recovery and Remission (5I01BX005065-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10477219. Licensed CC0.

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