# Defining New Pathways in Heart Failure and Arrhythmia

> **NIH NIH K08** · OHIO STATE UNIVERSITY · 2020 · $149,744

## Abstract

Project Summary
 Dilated cardiomyopathies, heart failure (HF), and arrhythmias are a significant health burden. Despite
the improving medical therapies, cardiac resynchronization therapies, and left ventricular assist devices, HF
remains a global epidemic. The lifetime risk of developing HF is 20% with a 5 year age-adjusted mortality at
59% and 45% for men and women, respectively. Thus, the identification of pathways underlying development
and progression of HF and arrhythmias is essential for the creation of improved diagnostics and treatments.
Over the past two decades, the cardiac cytoskeleton has emerged as a central governing factor in the control
of cardiac membrane integrity, and dysfunction in cytoskeleton and cytoskeletal-associated proteins has been
directly linked with a host of human cardiac pathologies, most notably cardiac myopathies and dystrophies. In
fact, human loss-of-function variants in cardiac cytoskeletal or cytoskeletal-associated genes that alter myocyte
signal transduction, myocardial mechanics, and force transmission are now directly linked with dilated
cardiomyopathy, muscular dystrophy, and arrhythmogenic cardiomyopathy.
 In contrast to myopathy and dystrophy fields, the role of the cytoskeleton in normal electrical function is
not well resolved. Further, until only recently, human arrhythmia mechanisms were limited to mutations in ion
channels. However, our group and now others have defined a second class of arrhythmias due to mutations in
channel-associated proteins. Dysfunction in these proteins is linked with diverse pathologies including defects
in channel synthesis and targeting, gating, and post-translational modifications. While this information has
been important for new disease diagnosis and fundamental cardiac cell biology, there remain large cohorts of
phenotype positive/genotype negative patients with familial forms of HF and arrhythmia. Further, there remain
large knowledge gaps regarding the pathways underlying more common forms of acquired HF and arrhythmia.
The overall goal of my program is to define new cell and molecular pathways underlying HF and arrhythmia.
 Based on clinical and genetic findings, we uncovered a new and essential cytoskeletal-based pathway
critical for cardiac electrical function. Our preliminary data, that spans human to molecule, utilizes new in vivo
mouse models and targeting strategies and innovative technologies supports our central hypothesis that the
cytoskeletal protein II spectrin serves as an unexpected and integral regulatory node for the organization of
critical myocyte membrane and membrane-associated proteins. Further, our data support that dysfunction in
this pathway is an underlying factor for cardiac electrical and structural remodeling in HF and arrhythmia. Our
proposal will test the new roles of the II spectrin pathway in HF and arrhythmia as well as the molecular
mechanisms underlying II spectrin regulation in disease: We will 1) Define the in vivo role of ...

## Key facts

- **NIH application ID:** 9850280
- **Project number:** 5K08HL135437-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Sakima Ahmad Smith
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $149,744
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850280

## Citation

> US National Institutes of Health, RePORTER application 9850280, Defining New Pathways in Heart Failure and Arrhythmia (5K08HL135437-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9850280. Licensed CC0.

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