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| Item Type: | Article |
|---|---|
| Title: | Long-term effects of Na(+)/Ca(2+) exchanger inhibition with ORM-11035 improves cardiac function and remodelling without lowering blood pressure in a model of heart failure with preserved ejection fraction |
| Creators Name: | Primessnig, U., Bracic, T., Levijoki, J., Otsomaa, L., Pollesello, P., Falcke, M., Pieske, B. and Heinzel, F.R. |
| Abstract: | AIMS: 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(+)/Ca(2+) exchanger (NCX) inhibitor, improves cardiac function and remodelling independent of effects on arterial blood pressure in a model of cardiorenal HFpEF. METHODS AND RESULTS: 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, Ca(2+) transients and NCX-mediated Ca(2+) 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 Ca(2+) 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 Ca(2+) decay as well as restored NCX-mediated Ca(2+) removal, indicating NCX modulation with ORM-11035 as a promising target in the treatment of HFpEF. CONCLUSION: 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. |
| Keywords: | Na(+)/Ca(2+) Exchanger, ORM-11035, Heart Failure with Preserved Ejection Fraction, Cardiomyocyte, Calcium, Animals, Rats |
| Source: | European Journal of Heart Failure |
| ISSN: | 1388-9842 |
| Publisher: | Wiley |
| Volume: | 21 |
| Number: | 12 |
| Page Range: | 1543-1552 |
| Date: | December 2019 |
| Official Publication: | https://doi.org/10.1002/ejhf.1619 |
| PubMed: | View item in PubMed |
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