Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Primessnig, U.
Cardiomyocyte Dysfunction in a Model of Heart Failure with Preserved Ejection Fraction
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2018. pp. 143
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Heinemann Akos
- Heinzel Frank
- Olschewski Horst
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- Abstract:
- Introduction: Heart failure with preserved ejection fraction (HFpEF) is increasingly common but there is no special treatment available yet, most likely because underlying pathomechanisms are not well understood. To investigate cardiomyocyte function and calcium handling we established an animal model of chronic kidney disease (CKD) and HFpEF. Furthermore, the role of SEA0400, a Na+/Ca2+ exchanger (NCX) inhibitor was evaluated in this animal model. Material and Methods: Young male Wistar rats were subjected to subtotal nephrectomy (NXT) or sham operation (Sham). In vivo (hemodynamics, echocardiography) and in vitro function (left ventricular (LV) cardiomyocyte cell shortening (CS) and Ca2+ transients (CaT)) were determined after 8 and 24 weeks. Furthermore, SEA0400 was investigated after 24 weeks acutely in vivo and in vitro. In a subgroup of rats SEA0400 or vehicle was given p.o. (1 mg/kg b.w.) between week 8 and 24. Results: Subtotal nephrectomy in rats resulted in stable chronic kidney disease and the clinically relevant HFpEF phenotype with LV hypertrophy, a prolongation of the isovolumetric relaxation constant TAU (IVRc TAU), an elevation in end diastolic pressure (EDP), an increase in lung weight (pulmonary congestion) and a preserved LV systolic function (EF). Cardiomyocytes amplitude of cell shortening and calcium transients were unchanged in NXT vs. Sham at 8 and 24 weeks. Relaxation and CaT decay in NXT cardiomyocytes were progressively prolonged at 8 and 24 weeks vs. Sham, individually correlating with diastolic dysfunction in vivo. In NXT rats the sodium/calcium exchanger was modulated. While NCX protein expression was upregulated at 24 weeks, NCX forward mode activity – measured via caffeine induced calcium response was progressively reduced suggesting an increased NCX reverse mode activity in the subtotal nephrectomy heart failure rats. The NCX inhibitor, SEA0400, acutely improved LV relaxation in vivo and cardiomyocyte relaxation in vitro in NXT rats. Furthermore, chronic treatment with SEA0400 reversed cardiac remodeling and improved diastolic function in NXT rats. Conclusions: Subtotal nephrectomy in rats induced the clinically relevant HFpEF phenotype and stable compensated CKD. Impaired LV relaxation was associated with slowed relaxation in cardiomyocytes from NXT. In NXT rats, the NCX was shifted to increased reverse mode activity and the treatment with the NCX inhibitor SEA0400 improved LV relaxation and cardiomyocyte relaxation acutely. Chronical treatment with SEA0400 reversed cardiac remodeling and diastolic dysfunction in HFpEF rats and therefore could be an interesting treatment option in the future for HFpEF patients with associated renal impairment.