Na⁺–H⁺ exchanger inhibitor prevents early death in hereditary cardiomyopathy

Abstract

Using the UM-X7.1 hereditary cardiomyopathic and muscular dystrophy hamsters (HCMH), we tested the effects of lifelong preventive or curative treatments during the heart failure phase with the NHE-1 inhibitor EMD 87580 (EMD) or with the angiotensin-converting enzyme inhibitor cilazapril on the intracellular Na + and Ca 2+ overloads, elevated level of NHE-1, necrosis, hypertrophy, heart failure, and early death. Our results showed that 310-day pretreatment of 30-day-old HCMHs with EMD significantly prevented cardiac necrosis, cardiomyocyte hypertrophy, and reduced the heart to body mass ratio. This treatment significantly prevented Na + and Ca 2+ overloads and the increase in NHE-1 protein level observed in HCMHs. Importantly, this lifelong preventive treatment significantly decreased the levels of creatine kinase and prevented early death of HCMHs. Curative treatment of hypertrophic 275-day-old HCMHs for 85 days with EMD significantly prevented hypertrophy and early death of HCMHs. However, treatments with cilazapril did not have any significant effects on the cardiac parameters studied or on early death of HCMHs. Our results suggest that the increase in the NHE-1 level and the consequent Na + and Ca 2+ overloads are implicated in the pathological process leading to heart failure and early death in HCMHs, and treatment with the NHE-1 inhibitor is promising for preventing early death in hereditary cardiomyopathy.

Na+–H+exchanger and proton channel in heart failure associated with Becker and Duchenne muscular dystrophies

“…The latter was found to be, in part, a consequence of the development of intracellular acidosis and the resulting sodium influx via the Na + -H + exchanger NHE-1 (Fig. 2) (Bkaily et al 2015(Bkaily et al , 2017. Treatment with an NHE-1 blocker, EMD87580, not only prevented intracellular sodium overload, but also prevented the increase of circulating creatine kinase and early death due to HF (Bkaily et al 2015).…”

“…In fact, hereditary muscular dystrophy and its associated cardiomyopathy in the UM-X7.1 hamsters is characterized by a slow progression towards cardiac failure and early death following well-defined phases, and by its uniform and predicted nature with respect to morphological, biochemical, and electrophysiological anomalies (Bajusz 1969;Jasmin et al 1991;Hatem et al 1994;Honoré et al 2008;Chahine et al 2005;Bkaily et al 2015) (Fig. 1).…”

“…The muscular dystrophy and X-linked DCM of the hereditary cardiomyopathic hamster, like other forms of muscular dystrophy and HF, is characterized by an intracellular calcium overload at the level of skeletal muscle fibers and cardiomyocytes Proschek 1984, 1994;Bkaily and Jacques 1994;Minamisawa et al 2004;Chahine et al 2005;Bkaily et al 2015).…”

“…2) (Bkaily et al 2015(Bkaily et al , 2017. Treatment with an NHE-1 blocker, EMD87580, not only prevented intracellular sodium overload, but also prevented the increase of circulating creatine kinase and early death due to HF (Bkaily et al 2015). Consequently, a treatment that prevents intracellular sodium overload via NHE-1 and (or) prevents the development of acidosis, probably by increasing H + efflux via the proton channel may represent an excellent therapeutic approach to prevent early death due to HF (Figs.…”

“…2) awaits elucidation. For further information concerning sodium overload and NHE-1 in DMD and BMD, the reader should refer to key references (Bkaily et al 1990(Bkaily et al , 2015(Bkaily et al , 2017Al-Khoury et al 2006;Chahine et al 2005;Jacques et al 1997Jacques et al , 2003Honoré et al 2008). …”