NCT04978987: DECIPHER-PLN

Identification of Disease Specific Pathways and Modifiers in Phospholamban R14del Cardiomyopathy

Completed Last updated 25 August 2023

What this trial tests

trial in Phospholamban R14del Cardiomyopathy in 103 participants. Completed in 1 May 2023.

Timeline

1 November 2020

Primary endpoint
1 May 2023

1 May 2023

Quick facts

Lead sponsor	University Medical Center Groningen
Status	Completed
Study type	OBSERVATIONAL
Enrollment	103
Start date	1 November 2020
Primary completion	1 May 2023
Estimated completion	1 May 2023
Sites	1 location across Netherlands

Conditions studied

• Phospholamban R14del Cardiomyopathy — all drugs for Phospholamban R14del Cardiomyopathy →
• Heart Failure — all drugs for Heart Failure →
• Cardiomyopathy, Familial — all drugs for Cardiomyopathy, Familial →

Sponsor

University Medical Center Groningen

Who can join

18 and older, any sex, with Phospholamban R14del Cardiomyopathy or Heart Failure. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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

Publications & conference data

3 peer-reviewed publications reference this trial (live from Europe PMC):

1. Clinical trials in-a-dish for cardiovascular medicine.
   Wu X, Swanson K, Yildirim Z, Liu W, et al · · 2024 · cited 17× · PMID 39270727 · DOI 10.1093/eurheartj/ehae519
2. Identification of disease-specific pathways and modifiers in phospholamban R14del cardiomyopathy: rationale, design and baseline characteristics of DECIPHER-PLN cohort.
   Deiman FE, de Brouwer R, Baumhove L, Bomer N, et al · · 2025 · cited 4× · PMID 40048085 · DOI 10.1007/s12471-025-01941-8
3. Plasma proteomics stratification identifies phospholamban R14del carriers at risk for disease progression.
   Deiman FE, Arslan T, de Brouwer R, Henry I, et al · · 2026 · PMID 42033765 · DOI 10.1093/cvr/cvag089