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A retooled drug that restores ionic balance and cardiac function in dystrophin deficient hearts

  • Ryan D. Wuebbles
    Affiliations
    Department of Pharmacology, University of Nevada, Reno School of Medicine, 1664 N. Virginia St., Reno, NV 89557, USA
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  • Dean J. Burkin
    Correspondence
    Corresponding author at: Department of Pharmacology, University of Nevada, Reno School of Medicine, 1664 N. Virginia St., Reno, NV 89557, USA.
    Affiliations
    Department of Pharmacology, University of Nevada, Reno School of Medicine, 1664 N. Virginia St., Reno, NV 89557, USA
    Search for articles by this author
      Duchenne muscular dystrophy (DMD) is a devastating and fatal disease affecting ~1 in 3500 boys with dystrophin gene mutations [
      • Meyers T.A.
      • Townsend D.
      Cardiac pathophysiology and the future of cardiac therapies in duchenne muscular dystrophy.
      ,
      • Finsterer J.
      • Stollberger C.
      • Maeztu C.
      Sudden cardiac death in neuromuscular disorders.
      ]. Dystrophin plays important roles in sarcolemma stability and cell signaling in skeletal, smooth, and cardiac muscles [
      • Meyers T.A.
      • Townsend D.
      Cardiac pathophysiology and the future of cardiac therapies in duchenne muscular dystrophy.
      ,
      • Finsterer J.
      • Stollberger C.
      • Maeztu C.
      Sudden cardiac death in neuromuscular disorders.
      ]. DMD patients often die at a young age from dilated cardiomyopathy (DCM) or respiratory dysfunction. The use of ventilators has reduced respiratory failure in DMD patients and DCM associated heart failure (HF) is now a major cause of DMD patient death [
      • Meyers T.A.
      • Townsend D.
      Cardiac pathophysiology and the future of cardiac therapies in duchenne muscular dystrophy.
      ,
      • Finsterer J.
      • Stollberger C.
      • Maeztu C.
      Sudden cardiac death in neuromuscular disorders.
      ]. Electrocardiograms have shown cardiac dysfunction in DMD boys as young as 9 years-of-age, with an increase in left ventricular end-diastolic diameter >55 mm a strong predictor of mortality which often occurs in the third or fourth decade of life [
      • Finsterer J.
      • Stollberger C.
      • Maeztu C.
      Sudden cardiac death in neuromuscular disorders.
      ,
      • Segawa K.
      • Sugawara N.
      • Maruo K.
      • Kimura K.
      • Komaki H.
      • Takahashi Y.
      • et al.
      Left ventricular end-diastolic diameter and cardiac mortality in Duchenne muscular dystrophy.
      ]. While it remains unclear the precise role the absence of dystrophin plays in DCM development, the loss of cardiomyocyte sarcolemma integrity and proton, sodium, and calcium homeostasis occurs early in the process [
      • Bkaily G.
      • Jacques D.
      Na(+)-H(+) exchanger and proton channel in heart failure associated with Becker and Duchenne muscular dystrophies.
      ]. In this issue of IJC, Ghaleh et al. describe the use of an exciting therapeutic that targets the downstream effects of dystrophin deficient cardiac dysfunction: “Protective effects of rimeporide on left ventricular function in golden retriever muscular dystrophy dogs” [
      • Ghaleh B.
      • Barthelemy I.
      • Wojcik J.
      • Sambin L.
      • Bize A.
      • Hittinger L.
      • et al.
      Protective effects of rimeporide on left ventricular function in golden retriever muscular dystrophy dogs.
      ].
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      Linked Article

      • Protective effects of rimeporide on left ventricular function in golden retriever muscular dystrophy dogs
        International Journal of CardiologyVol. 312
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          Alterations in intracellular Na+ and Ca2+ have been observed in patients with Duchenne muscular dystrophy (DMD) and in animal models of DMD, and inhibition of Na+-H+ exchanger 1 (NHE1) by rimeporide has previously demonstrated cardioprotective effects in animal models of myocardial ischemia and heart failure. Since heart failure is becoming a predominant cause of death in DMD patients, this study aimed to demonstrate a cardioprotective effect of chronic administration of rimeporide in a canine model of DMD.
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