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A01 - Ventricular compartmentalization and functional reserve in cardiomyocytes in HFpEF

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Project summary

HFpEF is a multifactorial systemic disease, characterized by cardiac structural remodeling and an inadequate augmentation of cardiac contractile function upon physiological stress. CM contractile function at baseline and its functional contractile reserve are regulated by compartmentalization of the main second messengers, cAMP and Ca2+, in highly controlled intracellular functional microdomains. We hypothesize that HFpEF is associated with molecular-level alterations in intracellular cAMP- and Ca2+ signaling microdomains, which limit the functional reserve of the CM. We aim at establishing alterations of β-adrenoreceptor -subtype /cAMP- and Ca2+ dynamics and the impact on the functional reserve with physiological inotropic stimuli (adrenergic, frequency, stretch) in metabolic vs non-metabolic HFpEF. In addition, we investigate the effects of acute metabolic stress on the cardiomyocyte functional reserve in HFpEF and explore underlying mechanisms.


Graphical Abstract Murine cardiomyocytes isolated from HFpEF wt and HFpEF hearts, with and without stimulation by exercise, will be phenotyped. New fluorescent compounds and advanced fluorescence microscopy will allow assessing changes to subcellular compartmentalization of cAMP and intracellular calcium handling. Mass spectrometry will bes used to reveal alterations of the relevant proteome.


Prof. Dr. med. Ph. Frank R Heinzel

Project leader A01

CVK: Campus Virchow-Klinikum

Dr. Paolo Annibale

Project leader A01

Additional team members

PhD students: Rashin Roshan Bin, Konstantina Georgoula
Postdoc: Judith Hüttemeister, Paulina Sander




Gmach P, Bathe-Peters M, Telugu N, Miller DC, Annibale P. Fluorescence Spectroscopy of Low-Level Endogenous β-Adrenergic Receptor Expression at the Plasma Membrane of Differentiating Human iPSC-Derived Cardiomyocytes. Int J Mol Sci. 2022 Sep 8;23(18):10405. doi: 10.3390/ijms231810405. PMID: 36142320; PMCID: PMC9499492.

Boltz HH, Sirbu A, Stelzer N, de Lanerolle P, Winkelmann S, Annibale P. The Impact of Membrane Protein Diffusion on GPCR Signaling. Cells. 2022 May 17;11(10):1660. doi: 10.3390/cells11101660. PMID: 35626696; PMCID: PMC9139411.

Primessnig U, Deißler PM, Wakula P, Tran KL, Hohendanner F, von Lewinski D, Blaschke F, Knosalla C, Falk V, Pieske B, Grubitzsch H, Heinzel FR. Effects of BNP and Sacubitrilat/Valsartan on Atrial Functional Reserve and Arrhythmogenesis in Human Myocardium. Front Cardiovasc Med. 2022 Jul 5;9:859014. doi: 10.3389/fcvm.2022.859014. PMID: 35865376; PMCID: PMC9294287.

Heinzel FR, Shah SJ. The future of heart failure with preserved ejection fraction : Deep phenotyping for targeted therapeutics. Herz. 2022 Aug;47(4):308-323. doi: 10.1007/s00059-022-05124-8. Epub 2022 Jun 29. PMID: 35767073; PMCID: PMC9244058.