Evidence map›Paper›PMID 41277423›Full record

ArticleCirculation. Heart failure2025

Global Proteoform Alterations Across Multiple Cellular Compartments Underlie Obstructive Hypertrophic Cardiomyopathy.

Zhan Gao, Kalina J Rossler, Holden T Rogers, Zachery R Gregorich, Timothy J Aballo, Emily A Chapman, Scott J Price, Joshua Hermsen, Willem J de Lange, Yanlong Zhu and 5 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation. Heart failure, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
  2. Article
  3. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors.

Zhan Gao *Department of Cell and Regenerative Biology (Z.G., K.J.R., T.J.A., Y.Z., Y.G.), University of Wisconsin-Madison.ORCID 0009-0009-0677-9653
Kalina J Rossler *Department of Cell and Regenerative Biology (Z.G., K.J.R., T.J.A., Y.Z., Y.G.), University of Wisconsin-Madison.ORCID 0000-0003-0353-1774
Holden T RogersDepartment of Chemistry (H.T.R., E.A.C., B.Z., J.C., Y.G.), University of Wisconsin-Madison.ORCID 0000-0003-0870-0127
Zachery R GregorichDepartment of Animal and Dairy Sciences (Z.R.G.), University of Wisconsin-Madison.ORCID 0000-0002-4013-4869
Timothy J AballoDepartment of Cell and Regenerative Biology (Z.G., K.J.R., T.J.A., Y.Z., Y.G.), University of Wisconsin-Madison.
Emily A ChapmanDepartment of Chemistry (H.T.R., E.A.C., B.Z., J.C., Y.G.), University of Wisconsin-Madison.ORCID 0000-0003-1110-8984
Scott J PriceDepartment of Medicine (S.J.P., J.H., T.J.K.), University of Wisconsin-Madison.
Joshua HermsenDepartment of Medicine (S.J.P., J.H., T.J.K.), University of Wisconsin-Madison.
Willem J de LangeDepartment of Pediatrics (W.J.d.L., J.C.R.), University of Wisconsin-Madison.ORCID 0000-0001-7296-8924
Yanlong ZhuDepartment of Cell and Regenerative Biology (Z.G., K.J.R., T.J.A., Y.Z., Y.G.), University of Wisconsin-Madison.ORCID 0000-0003-4909-7336
Boqian ZhangDepartment of Animal and Dairy Sciences (Z.R.G.), University of Wisconsin-Madison.
Jiaqi ChenDepartment of Chemistry (H.T.R., E.A.C., B.Z., J.C., Y.G.), University of Wisconsin-Madison.
J Carter RalpheDepartment of Pediatrics (W.J.d.L., J.C.R.), University of Wisconsin-Madison.ORCID 0000-0001-8116-2324
Timothy J KampDepartment of Medicine (S.J.P., J.H., T.J.K.), University of Wisconsin-Madison.ORCID 0000-0003-2103-7876
Ying GeDepartment of Cell and Regenerative Biology (Z.G., K.J.R., T.J.A., Y.Z., Y.G.), University of Wisconsin-Madison.ORCID 0000-0001-5211-6812

Funding

Project 3 - Role of Proline Metabolism in Regulation of Mammalian Cardiomyocyte ProliferationP01HL160476 · NHLBI · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI Hesham Sadek · 2022 to 2026
$13.1M
Training Program in Translational Cardiovascular Science (TPTCS)T32HL007936 · NHLBI · UNIVERSITY OF WISCONSIN-MADISON · PI Lee Lochbaum Eckhardt, Gail A Robertson · 2001 to 2026
$11.6M
Integrated Cellular and Tissue Engineering for Ischemic Heart DiseaseU01HL134764 · NHLBI · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI BURSAC, NENAD, KAMP, TIMOTHY J. · 2016 to 2022
$7.7M
Deciphering Myofilament Modifications in Ischemic CardiomyopathyR01HL109810 · NHLBI · UNIVERSITY OF WISCONSIN-MADISON · PI GE, YING · 2013 to 2024
$3.5M
Top Down Proteomics Of Myofilaments In Heart FailureR01HL096971 · NHLBI · UNIVERSITY OF WISCONSIN-MADISON · PI GE, YING · 2011 to 2021
$3.3M
Multiomics and Functional Characterization Establish Druggable Targets for PVC-Driven Idiopathic VFR01HL170521 · NHLBI · UNIVERSITY OF WISCONSIN-MADISON · PI Lee Lochbaum Eckhardt, Eleonora Grandi · 2023 to 2026
$3.1M
Ultra High Resolution Mass Spectrometer for Biomedical ResearchS10OD018475 · OD · UNIVERSITY OF WISCONSIN-MADISON · PI GE, YING · 2015 to 2015
$2.0M
Chemistry-Biology Interface Training ProgramT32GM152341 · NIGMS · UNIVERSITY OF WISCONSIN-MADISON · PI Helen E. Blackwell · 2024 to 2026
$1.6M
MASH Explorer, a Comprehensive Software Environment for Top-Down ProteomicsR01GM125085 · NIGMS · UNIVERSITY OF WISCONSIN-MADISON · PI GE, YING · 2018 to 2021
$1.2M
NHLBI NIH HHS P01 HL160476NHLBI NIH HHS R01 HL096971NHLBI NIH HHS R01 HL109810NHLBI NIH HHS R01 HL170521NHLBI NIH HHS T32 HL007936NHLBI NIH HHS U01 HL134764NIGMS NIH HHS R01 GM125085NIGMS NIH HHS T32 GM152341NIH HHS S10 OD018475
6 · The paper itself

Abstract

backgroundHypertrophic cardiomyopathy (HCM) has traditionally been regarded as a disease of the sarcomere; however, it is in the midst of a paradigm shift with growing recognition of contributions beyond the sarcomere to the heterogeneity of HCM phenotypes. Innovative approaches are essential to uncover novel determinants and mechanisms underlying this heterogeneity. Top-down proteomics has emerged as a powerful method for analysis of proteoforms-the myriad protein products arising from genetic variants, posttranslational modifications, and splicing isoforms from a single gene-offering a more precise lens to understand the disease heterogeneity in HCM. Yet, how proteoforms are altered on a global scale in HCM has not been investigated.

methodsGlobal top-down proteomics was performed on myocardial samples from patients with advanced obstructive HCM and nonfailing controls. Specifically, serial protein extraction enabled by the photocleavable surfactant, 4-hexylphenylazosulfonate (Azo), was utilized to solubilize diverse categories of proteins from minimal tissue, including membrane proteins. Subsequently, high-sensitivity top-down mass spectrometry was used to detect and quantify proteoforms across various cellular compartments.

resultsUsing this global top-down proteomics approach, we have detected ≈2000 proteoforms across disparate cellular compartments, including the sarcoplasmic reticulum, cytoskeleton, mitochondria, and nucleus, in advanced obstructive HCM tissues. Quantitative analysis uncovered significant alterations not only in sarcomeric but also cytoskeletal, mitochondrial, nucleosome, and sarcoplasmic reticulum proteoforms in HCM as compared with nonfailing controls. Notably, we have discovered a significant proteoform crosstalk among the sarcomere, sarcoplasmic reticulum, and cytoskeleton. Moreover, we have identified a previously unrecognized decrease in succinylated mitochondrial proteoforms as a critical feature of the advanced obstructive HCM proteoform landscape, alongside a marked reduction in acetylation of nucleosome proteins.

conclusionsThis study represents the most comprehensive analysis of the proteoform landscape in HCM to date, uncovering pathways beyond the sarcomere that may contribute to HCM pathophysiology and identifying potential targets for development of therapeutic interventions.

Indexed as

Cardiomyopathy, HypertrophicMyocardiumProteomeProteomicsAdultFemaleHumansMaleMiddle AgedMitochondria, HeartSarcomeresProteomecardiomyopathy, hypertrophiccytoskeletonproteomicssarcomeressarcoplasmic reticulum

Identifiers

PMID41277423
PMCPMC12958135

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.