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Treatment of Barth Syndrome by Cardiolipin Manipulation (CARDIOMAN) With Bezafibrate: Protocol for a Randomized
Lucy Dabner1, Guido E Pieles2,3, Colin G Steward4
1Bristol Trials Centre (Clinical Trials and Evaluation Unit), Bristol Medical School, University of Bristol, Bristol, United Kingdom.
Insights
Barth syndrome, a rare genetic disease, is being studied for bezafibrate treatment efficacy. The CARDIOMAN trial investigates bezafibrate
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Barth syndrome is a rare, life-threatening X-linked genetic disorder affecting mitochondrial lipid metabolism.
- Current treatments only manage acute symptoms; no definitive cure exists.
- Bezafibrate, a lipid-lowering drug, shows promise but requires human trials.
Purpose of the Study:
- To evaluate bezafibrate's efficacy in treating Barth syndrome.
- To determine if bezafibrate enhances mitochondrial biogenesis.
- To assess bezafibrate's effect on the cardiolipin profile (MLCL/L4-CL ratio).
Main Methods:
- The CARDIOMAN study is a UK-based, double-blind, randomized, placebo-controlled crossover trial.
- 11 participants with Barth syndrome were enrolled.
- Primary outcome: peak oxygen consumption (VO2 peak); secondary outcomes: cardiolipin profile, cardiac function, neutrophil count, quality of life.
Main Results:
- Data analysis is ongoing; publication is expected in 2021.
- 11 participants completed the study, with follow-up concluding in January 2020.
Conclusions:
- The CARDIOMAN study's feasibility will inform future rare disease RCTs.
- It will test bezafibrate's efficacy and advance understanding of Barth syndrome mechanisms.
Background:
Barth syndrome is a rare, life-threatening, X-linked recessive genetic disease that predominantly affects young males and is caused by abnormal mitochondrial lipid metabolism. Currently, there is no definitive treatment for Barth syndrome other than interventions to ameliorate acute symptoms, such as heart failure, cardiac arrhythmias, neutropenia, and severe muscle fatigue. Previous mechanistic studies have identified the lipid-lowering drug bezafibrate as a promising potential treatment; however, to date, no human trials have been performed in this population.
Objective:
The aim of this study is to determine whether bezafibrate (and resveratrol in vitro) will increase mitochondrial biogenesis and potentially modify the cellular ratio of monolysocardiolipin (MLCL) to tetralinoleoyl-cardiolipin (L4-CL), ameliorating the disease phenotype in those living with the disease.
Methods:
The CARDIOMAN (Cardiolipin Manipulation) study is a UK single-center, double-blinded, randomized, placebo-controlled crossover study investigating the efficacy of bezafibrate in participants with Barth syndrome. Treatment was administered in two 15-week phases with a minimum washout period of 1 month between the phases where no treatment was administered. The primary outcome is peak oxygen consumption (VO2 peak). Secondary outcomes include MLCL/L4-CL ratio and CL profile in blood cells, amino acid expression, phosphocreatine to adenosine triphosphate ratio in cardiac muscle and skeletal muscle oxidative function on phosphorus-31 magnetic resonance spectroscopy, quality of life using the Pediatric Quality of Life Inventory questionnaire, absolute neutrophil count, cardiac function and rhythm profiles at rest and during exercise, and mitochondrial organization and function assessments. Outcomes were assessed at baseline and during the final week of each treatment phase.
Results:
A total of 12 patients were scheduled to participate across three consecutive research clinics between March and April 2019. In total, 11 participants were recruited, and the follow-up was completed in January 2020. Data analysis is ongoing, with publication expected in 2021.
Conclusions:
This trial was approved by the United Kingdom National Research Ethics Service Committee and the Medicines and Healthcare products Regulatory Agency. The feasibility of the CARDIOMAN study will help to inform the future conduct of randomized controlled trials in rare disease populations as well as testing the efficacy of bezafibrate as a potential treatment for the disease and advancing the mechanistic understanding of Barth syndrome.
Trial Registration:
International Standard Randomized Controlled Trial Number (ISRCTN): 58006579; https://www.isrctn.com/ISRCTN58006579.
International Registered Report Identifier (Irrid):
DERR1-10.2196/22533.
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