dc.contributor.author
Primessnig, Uwe
dc.contributor.author
Bracic, Taja
dc.contributor.author
Levijoki, Jouko
dc.contributor.author
Otsomaa, Leena
dc.contributor.author
Pollesello, Piero
dc.contributor.author
Falcke, Martin
dc.contributor.author
Pieske, Burkert
dc.contributor.author
Heinzel, Frank R.
dc.date.accessioned
2022-02-01T13:47:42Z
dc.date.available
2022-02-01T13:47:42Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/33836
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-33555
dc.description.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+/Ca2+ 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, 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.
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.
en
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject
Na+/Ca2+ exchanger
en
dc.subject
Heart failure with preserved ejection fraction
en
dc.subject
Cardiomyocyte
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
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
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.doi
10.1002/ejhf.1619
dcterms.bibliographicCitation.journaltitle
European Journal of Heart Failure
dcterms.bibliographicCitation.number
12
dcterms.bibliographicCitation.originalpublishername
Wiley
dcterms.bibliographicCitation.pagestart
1543
dcterms.bibliographicCitation.pageend
1552
dcterms.bibliographicCitation.volume
21
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.funding
DEAL Wiley
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
31762174
dcterms.isPartOf.issn
1388-9842
dcterms.isPartOf.eissn
1879-0844