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Open Access 25-07-2023 | Pro-Con Statement – Con

Should we offer preventive treatment to all carriers of PLN p.(Arg14del) variant?

Con: Do no harm to asymptomatic carriers

Auteur: Pieter A. Doevendans

Gepubliceerd in: Netherlands Heart Journal | Uitgave 7-8/2023

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Assuming the term ‘preventive treatment’ indicates treatment of carriers of a severe inherited disease before they develop any symptoms, early intervention may become feasible but may not be desirable. The justification for preventive treatment would have to be found in disease penetrance. If a mutation will definitely cause disease, the decision is relatively simple if the side effects of the treatment are mild or absent.
We also would have to define ‘asymptomatic’ very clearly. Let us use the phospholamban (PLN) p.(Arg14del) cardiomyopathy as an example, in which penetrance of the disease is highly variable, with an arrhythmogenic phenotype presenting at a younger age than the dilated cardiomyopathy phenotype [1]. Yet, many (> 50%) carriers reach the age of 75 years without ever developing symptoms severe enough to seek medical attention. In addition, we are identifying more and more carriers through screening existing datasets (Lifelines Groningen, Blood Bank Amsterdam) in whom no overt disease is found. Therefore, just treating all carriers is against the primary principle of physicians: do no harm.
In the meantime, our diagnostic skills are improving. Using electrocardiography, echocardiography and magnetic resonance imaging, we can see the initiation of a cardiomyopathy. Beautiful studies have been completed by Van der Leur et al., who employed artificial intelligence to detect early changes in the PLN p.(Arg14del) electrocardiogram (ECG) [2]. In addition Taha et al. showed where and how echocardiographic strain patterns are changing and should be considered as early disease parameters [3]. Furthermore, by implanting loop recorders and modernising Holter recordings, more arrhythmias can be detected.
But do these early hints always result in symptoms? Not in a 100% of carriers. However, there is a group with early disease signs but no complaints we would like to treat. Does that entail pre-emptive treatment? Probably not, as the first signs of disease are already present as indicated by changed ECG patterns, abnormal strain analysis results and nonsustained ventricular tachycardias. The path to symptoms is then relatively short.
Therefore, I propose not to treat all carriers with devices or drugs. However, we can start treatment in patients who show onset of cardiomyopathy, not to prevent the disease but to delay the onset of symptoms. The next problem then is to choose an appropriate evidence-based therapy. The work by Eijgenraam et al. clearly showed that in mouse models, pharmacological treatment is not effective in reducing mortality [4]. In addition, the well-designed clinical trial iPHORECAST indicated eplerenone had no effect on delaying the disease either [5]. The team from the University Medical Centre Groningen in the Netherlands clearly showed that pre-emptive pharmacological intervention is currently not a realistic option. The only alternative left is to switch to gene therapy, which has been shown to be effective in mice [6] but is not yet an option for patients, although that is likely to change within 1–2 years. At the moment, 4 US-based gene therapy companies are looking into the PLN p.(Arg14del) models to find a treatment or even a cure. The options are overexpressing the normal gene, reducing the endogenous expression level of PLN (both alleles) or cutting and pasting the chromosomal DNA. The cut-and-paste option is based on viral delivery of the CRISPR/Cas-based tools and is currently being studied. The gene editing approach disrupting the defective allele in heterozygous mice was successful, as reported by Dave et al. [7] Tenaya (San Francisco, CA, USA) recently showed that by reducing PLN expression in the homozygous R14Del mouse model, life expectancy increased. Alternatively, the defective gene can be corrected by introducing the missing triplet in cardiomyocytes [810].
Nevertheless, these therapeutic steps are experimental and not ready to be offered to patients. Hence, they are no options for asymptomatic carriers. Maybe, in contrast to the author of the Pro article, I consider myself a realist by nature.

Conflict of interest

P.A. Doevendans declares that he has no competing interests.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creativecommons.​org/​licenses/​by/​4.​0/​.
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Literatuur
9.
go back to reference Van der Meer P, van Rooij E, Doevendans PA. Cardiomyopathy due to a mutation in the phospholamban gene: a high-impact genetic abnormality] (Dutch). Ned Tijdschr Geneeskd. 2023;167:D7274.PubMed Van der Meer P, van Rooij E, Doevendans PA. Cardiomyopathy due to a mutation in the phospholamban gene: a high-impact genetic abnormality] (Dutch). Ned Tijdschr Geneeskd. 2023;167:D7274.PubMed
Metagegevens
Titel
Should we offer preventive treatment to all carriers of PLN p.(Arg14del) variant?
Con: Do no harm to asymptomatic carriers
Auteur
Pieter A. Doevendans
Publicatiedatum
25-07-2023
Uitgeverij
Bohn Stafleu van Loghum
Gepubliceerd in
Netherlands Heart Journal / Uitgave 7-8/2023
Print ISSN: 1568-5888
Elektronisch ISSN: 1876-6250
DOI
https://doi.org/10.1007/s12471-023-01794-z

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