Identification of Disease Specific Pathways and Modifiers in Phospholamban R14del Cardiomyopathy (DECIPHER-PLN)

Background

A specific mutation in phospholamban (the PLN R14del mutation), has its origin in the northern parts of the Netherlands (Figure) and causes a severe lethal dilated and/or an arrhythmogenic cardiomyopathy. A large proportion of the population of Groningen (1:1000) carries this mutation. Until now, there is no specific treatment available for patients with PLN cardiomyopathy. Patients are treated like any other type of heart failure patients, although PLN cardiomyopathy has a different etiology from "usual" heart failure. Treatment is therefore insufficient; malignant ventricular arrhythmias and end-stage heart failure at a young age are very prevalent. To develop treatment options, the investigators aim to study the following knowledge gaps:

• Pathophysiology. The clinical phenotype of PLN R14del cardiomyopathy bears characteristics of both arrhythmogenic and dilated cardiomyopathy (ACM and DCM). Using an "omics" approach of plasma, cardiac and skeletal muscle of patients and controls, the investigators aim to reveal distinct pathways affected by the mutant PLN, unique to the PLN R14del cardiomyopathy. This will be related to clinical data and mutant PLN expression levels in both cardiac and skeletal muscle biopsies. Using this extensive profiling, the investigators aim to identify disease mechanisms and provide the context for future risk stratification and disease progression monitoring.
• Penetrance. Subjects with a heterozygous PLN R14del mutation show a wide variety in phenotype. Within the same family, patients can present either with over heart failure in their 20's or completely asymptomatic until at least their 70's. So far, no modifiers have been identified. The investigators will study cardiomyocytes derived from induced pluripotent stem cells from patients who are severely affected versus family members who are unaffected but carry the mutation.
• Treatment response. The investigators have identified potential treatments, and confirmed their efficacy in in vivo models of PLN cardiomyopathy. To establish their efficacy in a human setting, the investigators will generate 3D cardiac tissues of cardiomyocytes gathered from induced pluripotent stem cells of patients affected in varying degrees and subject these tissues to the treatment.

Methods:

For the above purposes, the investigators will collect and analyze the following data/materials:

• Serum and plasma of 90 PLN R14del carriers: 30 unaffected, 30 early affected and 30 end stage.
• Skin biopsy of 20 PLN R14del carriers: 10 unaffected, 10 end stage.
• Cardiac muscle biopsy (obtained during left ventricular assist device [LVAD]/ heart transplant [HTx] surgery) of 30 patients: 10 R14del, 10 arrhythmogenic cardiomyopathy, 10 dilating cardiomyopathy.
• Skeletal muscle biopsy of 10 patients: 5 R14del, 5 non R14del family members

Study Overview

• Status: Completed
• Conditions: Heart Failure; Cardiomyopathy, Familial; Phospholamban R14del Cardiomyopathy

• Study Type: Observational
• Enrollment (Actual): 103

Contacts and Locations

• Study Contact: Name: Niels Grote Beverborg, MD/PhD; Phone Number: 0031-50 361 323; Email: n.grote.beverborg@umcg.nl

Study Locations

• Netherlands
  • Groningen, Netherlands, 9700 RB
    • University Medical Center Groningen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The population consists of patients with PLN R14del, end-stage ACM or DCM, and non-R14del family members of the PLN r14del patients. For this study, we will include 90 PLN R14del carriers, subdivided in 30 end-stage R14del patients, 30 early abnormal and 30 unaffected family members with the PLN R14del mutation and 10 ACM, 10 DCM and 10 PLN R14del cardiomyopathy patients undergoing LVAD or HTx surgery. Finally, we will recruit a total of 5 PLN R14del cardiomyopathy patients and 5 unaffected (non-R14del) family members for the skeletal muscle biopsy collection alone.

Description

Inclusion Criteria:

• A minimum age of 18.
• Of adequate communication.
• Informed consent is obtained.
• Genetically confirmed r14del mutation in PLN, family member or other DCM/ACM

Exclusion Criteria:

• Known allergy for local anaesthetics.
• Other subgroup specific exclusion criteria.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The level of proteins in circulating blood and cardiac- and skeletal muscle tissue	An in-dept analyses of an extensive set of proteins assessed using large scale proteomic techniques to assess differences in individual protein levels and the total proteome of the circulating blood, cardiac tissue and skeletal muscle tissue of patients clinically differentially affected by the PLN R14del mutant protein.	At baseline visit
The level of metabolites in circulating blood and cardiac- and skeletal muscle tissue	An in-dept analyses of an extensive set of metabolites assessed using large scale metabolomic techniques to assess differences in individual metabolite levels and the total metabolome of the circulating blood, cardiac tissue and skeletal muscle tissue of patients clinically differentially affected by the PLN R14del mutant protein	At baseline visit
The level of mRNA in circulating blood and cardiac- and skeletal muscle tissue	An in-dept analyses of an extensive set of mRNA transcripts assessed using large scale transcriptomic techniques to assess differences in individual mRNA levels and the total transcriptome of the circulating blood, cardiac tissue and skeletal muscle tissue of patients clinically differentially affected by the PLN R14del mutant protein	At baseline visit
The level of DNA methylation in cardiac muscle tissue	An in-dept analyses of differences in individual DNA methylation levels and patterns of cardiac tissue of patients clinically differentially affected by the PLN R14del mutant protein	At baseline visit

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2020
• Primary Completion (Actual): May 1, 2023
• Study Completion (Actual): May 1, 2023

Study Registration Dates

• First Submitted: January 18, 2021
• First Submitted That Met QC Criteria: July 23, 2021
• First Posted (Actual): July 27, 2021

Study Record Updates

• Last Update Posted (Actual): August 25, 2023
• Last Update Submitted That Met QC Criteria: August 23, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Cardiomyopathies
• Other Study ID Numbers: 202000350 / 202000351

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No