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Research Cardiology Internal Medicine University departments Medical University of Graz

Molecular and cellular mechanisms of heart failure

Our research focuses on the fundamental mechanisms of cardiac aging and heart failure with preserved ejection fraction (HFpEF) – the most common and still growing chronic cardiovascular disease in the elderly. We aim to validate caloric restriction mimetics as effective molecular candidates and therapeutic interventions against cardiovascular aging, cardiometabolic syndrome, and HFpEF. We combine whole body physiological and cell-/tissue-specific molecular approaches by using aged or appropriate transgenic animal models and human liquid and myocardial biopsies from failing and non-failing donors.

Our team pioneered the application of caloric restriction mimetics in cardiovascular medicine by demonstrating the cardioprotective effects of the natural autophagy-inducer, spermidine, which is currently being tested in hypertensive patients.

Our group made a significant contribution to the international fight against HFpEF by demonstrating that boosting NAD⁺ metabolism with nicotinamide or other NAD⁺precursors might become a viable therapy for HFpEF.

We found that the relationship between cardiac insulin/insulin-like growth factor-1 (IGF-1) receptor signaling and healthspan is not linear as currently viewed, but rather biphasic and age-dependent. This finding reveals how fine regulation of the cardiac IGF1 receptor signaling in the course of aging can promote health and longevity.

Going forward, our new flagship projects INTERACD⁺ and VASC-HEALTH, respectively, focus on the mechanisms responsible for exercise- and NAD⁺-mediated protection from cardiometabolic risk and aim at defining actionable mechanistic targets based on autophagy and vascular attrition, which are until now not amenable to therapeutic interventions.

Contact

Assoz. Prof. Priv.-Doz. Dr. rer. nat.
Simon Sedej

T: +43 316 385 72742

E: simon.sedej@medunigraz.at

Research profile

Team

Mahmoud Abdellatif, MD, PhD (Assistant Professor)
Alina Stockner, PhD student
Her project focuses on the regulation of lipid alterations in heart failure with preserved ejection fraction.
Verma Daksh, PhD student
His project focuses on heart-specific effects of exercise and NAD⁺ metabolism in the setting of cardiometabolic risk.
Viktoria Trummer-Herbst, biomedical assistant

Alumni

Nika Barbara Pravica, MD (BioTechMed lab rotation)
Jan Schafmeister, MD
Hendrik Jöst, MD
Simon Kraler, MD
Jan Esser, MD
Alina Humnig, MSc
Julia Voglhuber, MSC (BioTechMed lab rotation)
Felix Renneberg, MD
Martin Wernhart, MD
Marinko Matovina, MD
Clemens Reiter, MD
Corinna Simonini, MD
Isabella Windhager, MD
Georg Arnstein, MD
Eva Thon-Gutschi, MSc

National collaborations

Frank Madeo (University of Graz)
Tobias Eisenberg (University of Graz)
Renate Schreiber (University of Graz)
Rolf Breinbauer (Technical University of Graz)
Kathrin Thedieck (University of Innsbruck)
Andreas Koeberle (University of Innsbruck)
Stefan Kiechl (Medical University of Innsbruck)
Manuel Mayr (Medical University Wien/King’s College London)

International collaborations

Guido Kroemer (University of Sorbonne, France)
Christian Mühlfeld (Medical School Hannover, Germany)
Junichi Sadoshima (New Jersey Medical School, USA)
Abhinav Diwan (Washington University, USA)
Jorge Alegre-Cebollada (CNIC, Spain)
Wolfgang Linke (University of Münster, Germany)
Julie McMullen (Baker Heart Institute, Australia)

Leuchtturmprojekt INTERACD+

VASC-HEALTH - Flagship Projekt

VASC-HEALTH - neue Therapien

VASC-HEALTH - ORF wissenswert

Ten most important publications

1. Abdellatif M, […], Kroemer G, and Sedej S (2022). Fine-tuning cardiac insulin-like growth factor 1 receptor signaling to promote health and longevity. Circulation. 145(25): 1853-1866. doi:10.1161/CIRCULATIONAHA.122.059863.

2. Abdellatif M, […], Kroemer G, and Sedej S (2021). Nicotinamide for the treatment of heart failure with preserved ejection fraction. Science Translational Medicine. 13 (580), eabd7064. doi:10.1126/scitranslmed.abd7064.

3. Eisenberg T, Abdellatif M, […], Kroemer G, Sedej S, and Madeo F (2016). Cardioprotection and life span extension by the natural polyamine spermidine. Nature Medicine. 22(12): 1428–1438. doi:10.1038/nm.4222. #equally contributed and corresponding authors.

4. Abdellatif M, Sedej S, and Kroemer G (2021). NAD⁺ metabolism in cardiac health, aging and disease. Circulation. 144(22):1795-1817. doi:10.1161/CIRCULATIONAHA.121.056589.

5. Ljubojevic-Holzer S and Kraler S, […], Sedej S (2021). Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca²⁺ cycling. Cardiovascular Research. cvab112. doi:10.1093/cvr/cvab112.

6. Abdellatif M and Sedej S (2022).Metabolic therapy for managing heart failure with preserved ejection fraction. Journal of Molecular and Cellular Cardiology. 168:68-69. doi: 10.1016/j.yjmcc.2022.04.009.

7. Abdellatif M, Sedej S, Carmona-Gutierrez D, Madeo F, and Kroemer G (2018). Autophagy in Cardiovascular Aging. Circulation Research. 123(7): 803–824. doi:10.1161/CIRCRESAHA.118.312208.

8. Abdellatif M, […], and Sedej S. (2020) Autophagy in cardiovascular health and disease. Progress in Molecular Biology and Translational Science. 172:87-106. doi:10.1016/bs.pmbts.2020.04.022.

9. Sedej S, […], and Pieske B. (2014). Subclinical abnormalities in sarcoplasmic reticulum Ca²⁺ release promote eccentric myocardial remodeling and pump failure death in response to pressure overload. Journal of the American College of Cardiology. 63(15):1569-79. doi:10.1016/j.jacc.2013.11.010.

10. Sedej S, […], and Pieske B. (2010). Na⁺-dependent SR Ca²⁺ overload induces arrhythmogenic events in mouse cardiomyocytes with a human CPVT mutation. Cardiovascular Research. 87(1):50-9. doi: 10.1093/cvr/cvq007

Full publications list (Pubmed): https://pubmed.ncbi.nlm.nih.gov/?term=sedej+s&sort=date

Nicotinamide for the treatment of heart failure with preserved ejection fraction

in Science Translational Medicine, 2021