{
  "abstract": "Dilated cardiomyopathy (DCM) has an estimated prevalence of 1 in 200 in the UK and is the most common form of cardiomyopathy in children. DCM is characterised by ventricular dilation and impaired systolic function, leading to reduced contractility of the heart and affecting its ability to pump blood normally, resulting in a left ventricular ejection fraction of less than 40%. Efficient energy metabolism is a fundamental process in cardiac maintenance, and as the most metabolically demanding organ in the body, the heart requires a high ATP turnover to achieve optimal contractile function of the myocardium. Given that mitochondrial function is closely linked to the development of DCM, disruption to energy metabolism pathways can impair cardiomyocyte function.A homozygous pathogenic variant, p.Arg203Trp SLC5A6, was identified in a family where two siblings presented with DCM. SLC5A6 encodes the Sodium-dependent Multivitamin Transporter, a transmembrane protein that is crucial for facilitating the active transport of three vitamins: biotin, pantothenic acid and lipoic acid; all of which are critical, organic enzyme cofactors required for energy metabolism in the mitochondria. Although many gene mutations have been implicated in DCM, the underlying pathophysiological mechanisms of this disease are not well understood and there is little known about the function of SLC5A6 in the heart. Therefore, a conditional cardiac-specific mouse model of Slc5a6 (Slc5a6cKO) was engineered to study disease progression and phenotype rescue using vitamin supplementation.Cardiomyocyte-specific deletion of Slc5a6 resulted in a cardiomyopathy phenotype and sudden death from 20 weeks. Slc5a6cKO mice displayed abnormal ECG parameters from 6 weeks, and the hearts showed fibrosis and abnormal mitochondrial morphology. Proteomic analysis revealed dysregulated pathways associated with mitochondrial energy metabolism, particularly fatty acid-beta oxidation, prior to disease presentation. Dietary supplementation with biotin and pantothenic acid prevented premature death and improved both cardiac conduction and function. Mitochondrial abnormalities were also restored as assessed by morphology and proteomic expression profiles were normalised.These findings demonstrate that a lethal mouse model of DCM can be successfully treated with vitamin supplementation that prevents mitochondrial defects, and progression to cardiomyopathy.",
  "authors": [
    {
      "affiliations": [
        "Newcastle University, Newcastle, United Kingdom"
      ],
      "name": "Millie Fullerton"
    },
    {
      "affiliations": [
        "Newcastle University, Newcastle, United Kingdom"
      ],
      "name": "Simon Bamforth"
    },
    {
      "affiliations": [
        "Newcastle University, Newcastle, United Kingdom"
      ],
      "name": "Helen Phillips"
    }
  ],
  "title": "322 Investigating a novel genetic cause of dilated cardiomyopathy and therapeutic rescue of mitochondrial abnormalities by vitamin supplementation",
  "uid": "944b1149-3235-5880-a023-10d150c48bd6"
}