Dataset Information

Proteomic profiling of a large cohort of HCM patients: genotype-specific protein changes

ABSTRACT: Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular (LV) hypertrophy and diastolic dysfunction, which leads to LV outflow tract obstruction (LVOTO) in the majority of cases. Mutations in genes encoding sarcomeric proteins cause HCM and are identified in more than half of the patients (sarcomere-mutation positive, SMP). Currently, more than 1500 HCM-causing mutations are known. Approximately 80% of mutations are located in the MYH7 and MYBPC3 genes, encoding for the thick filament proteins β-myosin heavy chain (β-MHC) and cardiac myosin-binding protein C (cMyBP-C), respectively. Less frequent are mutations in the TNNT2 and TNNI3 genes, encoding for the thin filament proteins cardiac troponin T (cTnT) and I (cTnI). Here, we applied an unbiased proteomics approach in a large number of myectomy samples from a clinically well-characterized HCM patient group to define HCM-specific derailments as well as genotype-specific changes at protein level. Our study shows that the downregulation of metabolic pathways and the upregulation of extracellular matrix proteins are the most prominent HCM-specific disease characteristics that are present in all samples independent of their genotype.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Sander Piersma

LAB HEAD: Connie Ramona Jimenez

PROVIDER: PXD012467 | Pride | 2021-01-14

REPOSITORIES: Pride

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	QE1_170502_OPL3018_MS_DK_CVON_DOSIS_A4_170502163320.raw	Raw
	QE1_170502_OPL3018_MS_DK_CVON_DOSIS_A5_170513000650.raw	Raw
	QE1_170502_OPL3018_MS_DK_CVON_DOSIS_AA4.raw	Raw
	QE1_170502_OPL3018_MS_DK_CVON_DOSIS_AA5.raw	Raw
	QE1_170502_OPL3018_MS_DK_CVON_DOSIS_AB4.raw	Raw

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Publications

Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy.

Schuldt Maike M Pei Jiayi J Harakalova Magdalena M Dorsch Larissa M LM Schlossarek Saskia S Mokry Michal M Knol Jaco C JC Pham Thang V TV Schelfhorst Tim T Piersma Sander R SR Dos Remedios Cris C Dalinghaus Michiel M Michels Michelle M Asselbergs Folkert W FW Moutin Marie-Jo MJ Carrier Lucie L Jimenez Connie R CR van der Velden Jolanda J Kuster Diederik W D DWD

Circulation. Heart failure 20210112 1

<h4>Background</h4>Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. While ≈50% of patients with HCM carry a sarcomere gene mutation (sarcomere mutation-positive, HCM<sub>SMP</sub>), the genetic background is unknown in the other half of the patients (sarcomere mutation-negative, HCM<sub>SMN</sub>). Genotype-specific differences have been reported in cardiac function. Moreover, HCM<sub>SMN</sub> patients have later disease onset and a better prognosis than HCM<sub>SMP</ ...[more]

PMID: 33430602

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Project description:Rationale There is a need for new and better biomarkers for hypertrophic cardiomyopathy (HCM) which correlate more closely with disease progression as determined by clinical imaging and biohumoral information. We have used a combination of heart tissue and plasma proteomics to identify potential biomarkers for HCM and developed them into an exploratory targeted proteomic assay. Objective To identify informative staging biomarkers for HCM and develop them into a blood test. The test using 10 µl of plasma, was developed into a 10 min liquid chromatography-tandem/mass spectrometry (LC-MS/MS) assay to analyze multiple candidate biomarkers and evaluate their association with clinical phenotypes in patients with HCM. Methods and Results Myocardial tissue and plasma samples from patients with HCM and healthy volunteers (controls) were screened using a combined gel- and nano-LC quadrupole time of flight MS approach. Twenty-six potential biomarkers were identified from the proteomics screens and developed into a multiplexed targeted proteomic assay. Their association with clinical phenotypes was tested in plasma samples collected from 207 prospectively recruited participants: 110 patients with HCM (50.1 ± 15.0 years, 70% male; 48 [44%] with identified genetic mutations) and 97 controls (49.6 ± 13.4 years, 58% male), randomly split into training (80 HCM, 67 controls) and validation datasets (30 HCM, 30 controls). Six markers (Aldolase Fructose-Bisphosphate A, Complement C3, Glutathione S-Transferase Omega 1, Ras Suppressor Protein 1, Talin 1, and Thrombospondin 1) were significantly increased (P<0.006) in the plasma of HCM patients compared to controls in the training dataset. These markers correlated with left ventricular (LV) wall thickness, LV mass and % myocardial scar on cardiovascular magnetic resonance imaging. Using supervized machine learning (ML) this panel differentiated HCM from controls (area under the curve: 0.89 in the training dataset, sensitivity 96%, 95% confidence interval [CI] 77–93; specificity 87%, 95%CI 77–94; and 0.87 in the validation dataset, sensitivity 97%, 95%CI 83–100; specificity 77%, 95%CI 58–90). Four of the biomarkers as well as the composite ML score of the plasma proteome correlated with the presence of nonsustained ventricular tachycardia and the estimated 5-year risk of sudden cardiac death. Conclusion By developing a high-throughput, multiplex, and targeted proteomic plasma assay we identified 6 biomarkers that correlate with the presence of disease and with clinical risk score for sudden cardiac death.