# Cellular Remodeling in Heart Failure and after LVAD Unloading

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $381,250

## Abstract

Project Summary/Abstract
The applicants' long-term aim is to gain insights into mechanisms and therapies of heart failure (HF). In this
study, we will examine the way that cellular architecture and calcium (Ca) handling proteins involved in
excitation-contraction coupling are modified in human HF. Further studies will be performed on patients that
undergo implantation of left ventricular assist devices (LVADs) to establish (1) a microstructural basis for
functional remodeling in HF cells, and (2) if microstructure of HF cells can predict long-term sustainability of
cardiac recovery by LVAD unloading. Our studies are motivated by the finding that nearly 20% of our patients
respond to unloading with cardiac recovery and that recovery in patients required integrity of the transverse
tubular system (t-system) before unloading. In Specific Aim 1, three-dimensional reconstructions of the t-
system and associated ryanodine receptor (RyR) clusters will be obtained with scanning confocal microscopy.
We will investigate ventricular tissues from normal donor hearts and hearts from patients in end stage HF. The
studies are based on the hypothesis that structures in control myocytes are altered in HF cells. We found that
human cells exhibit a very different phenotype in HF than previously described in animal models. In particular,
we found that the t-system remodels to axial, sheet-like invaginations of the sarcolemma in HF. We will then
establish the extent to which RyR clusters are not associated with sarcolemma (primarily t-system) for control
and HF cells. Findings in intact tissue will be compared with isolated cells. In Specific Aim 2, we will study the
changes in Ca transients that produce contractions as a consequence of alterations in the t-system and
proteins associated with EC coupling. This includes measuring Ca movements in normal and HF cells with
rapid two-dimensional confocal microscopy. We will test the hypothesis that Ca transients in HF are
disorganized compared to control. We will measure L-type Ca currents and calculate the gain of EC coupling.
We expect that remodeling of the t-system leads to decreased gain in HF cells. Also, we will measure Ca
extrusion from the cell and Ca uptake into the sarcoplasmic reticulum, and relate those to t-system remodeling.
In Specific Aim 3, we will test the hypothesis that alterations that we observe at the time of LVAD implantation
predict cardiac recovery. Integrity of t-system and improvement of functional properties induced by LVAD
unloading are expected to underlie cardiac recovery. We will investigate whether LVAD unloading can reverse
effects of HF on protein densities, t-system, Ca release, gain of EC coupling and decline of Ca transients.
Finally, we will test the hypothesis that microstructural alterations observed at time of LVAD implantation
predict long-term sustainability of recovery in patients undergoing LVAD explantation. Together, the proposed
studies constitute a crucial step towards u...

## Key facts

- **NIH application ID:** 9838775
- **Project number:** 5R01HL132067-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Stavros George Drakos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2016-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838775

## Citation

> US National Institutes of Health, RePORTER application 9838775, Cellular Remodeling in Heart Failure and after LVAD Unloading (5R01HL132067-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9838775. Licensed CC0.

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