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Primessnig, U; Bracic, T; Levijoki, J; Otsomaa, L; Pollesello, P; Falcke, M; Pieske, B; Heinzel, FR.
Long-term effects of Na⁺ /Ca²⁺ exchanger inhibition with ORM-11035 improves cardiac function and remodelling without lowering blood pressure in a model of heart failure with preserved ejection fraction.
Eur J Heart Fail. 2019; 21(12):1543-1552 Doi: 10.1002/ejhf.1619 [OPEN ACCESS]
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Leading authors Med Uni Graz: Heinzel Frank; Primessnig Uwe
Co-authors Med Uni Graz: Bracic Taja; Pieske Burkert Mathias
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Abstract:: Heart failure with preserved ejection fraction (HFpEF) is increasingly common but there is currently no established pharmacological therapy. We hypothesized that ORM-11035, a novel specific Na⁺ /Ca²⁺ exchanger (NCX) inhibitor, improves cardiac function and remodelling independent of effects on arterial blood pressure in a model of cardiorenal HFpEF. Rats were subjected to subtotal nephrectomy (NXT) or sham operation. Eight weeks after intervention, treatment for 16 weeks with ORM-11035 (1 mg/kg body weight) or vehicle was initiated. At 24 weeks, blood pressure measurements, echocardiography and pressure-volume loops were performed. Contractile function, Ca²⁺ transients and NCX-mediated Ca²⁺ extrusion were measured in isolated ventricular cardiomyocytes. NXT rats (untreated) showed a HFpEF phenotype with left ventricular (LV) hypertrophy, LV end-diastolic pressure (LVEDP) elevation, increased brain natriuretic peptide (BNP) levels, preserved ejection fraction and pulmonary congestion. In cardiomyocytes from untreated NXT rats, early relaxation was prolonged and NCX-mediated Ca²⁺ extrusion was decreased. Chronic treatment with ORM-11035 significantly reduced LV hypertrophy and cardiac remodelling without lowering systolic blood pressure. LVEDP [14 ± 3 vs. 9 ± 2 mmHg; NXT (n = 12) vs. NXT + ORM (n = 12); P = 0.0002] and BNP levels [71 ± 12 vs. 49 ± 11 pg/mL; NXT (n = 12) vs. NXT + ORM (n = 12); P < 0.0001] were reduced after ORM treatment. LV cardiomyocytes from ORM-treated rats showed improved active relaxation and diastolic cytosolic Ca²⁺ decay as well as restored NCX-mediated Ca²⁺ removal, indicating NCX modulation with ORM-11035 as a promising target in the treatment of HFpEF. Chronic inhibition of NCX with ORM-11035 significantly attenuated cardiac remodelling and diastolic dysfunction without lowering systemic blood pressure in this model of HFpEF. Therefore, long-term treatment with selective NCX inhibitors such as ORM-11035 should be evaluated further in the treatment of heart failure. © 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
Find related publications in this database (using NLM MeSH Indexing): Aniline Compounds - pharmacology; Animals -; Diastole -; Disease Models, Animal -; Echocardiography -; Heart Failure - drug therapy; Heart Failure - physiopathology; Heart Ventricles - physiopathology; Male -; Phenyl Ethers - pharmacology; Rats -; Rats, Wistar -; Sodium-Calcium Exchanger - antagonists & inhibitors; Stroke Volume - physiology; Ventricular Remodeling - drug effects
Find related publications in this database (Keywords): Na+; Ca2+ exchanger; ORM-11035; Heart failure with preserved ejection fraction; Cardiomyocyte; Calcium