Myocardial remodeling and reverse remodeling in pressure overload

Tønnessen group

Our group is conducting experimental/translational research studying cardiac pathophysiology related to aortic stenosis and pressure overload.

About the group

Aortic stenosis is the most common valvular lesion in the western world. In patients with aortic stenosis, excessive myocardial remodeling (hypertrophy, fibrosis and expression of fetal genes) leads to increased operative risk during aortic valve replacement (AVR). There is currently no effective treatment for postoperative low-output syndrome due to diastolic dysfunction, making this a major challenge in cardiac surgery. Incomplete reverse remodeling after AVR for aortic stenosis is associated with persisting symptoms and increased mortality. Hence, studies addressing myocardial remodeling and reverse myocardial remodeling are warranted.

We have established a mouse model of reversible left ventricular pressure overload mimicking AVR for aortic stenosis and found novel extracellular matrix (ECM) changes during reverse remodeling. To extend these findings we have planned further studies including a “loss of function” approach.

We will use a genetically modified mice to examine the importance of specific extracellular matrix constituents in remodeling and reverse remodeling after relief of pressure overload.

Specifically we want to reveal the importance of the SMAD signalling system in pressure overload. We have found that inhibition of SMAD2 by a small peptide inhibitor (SM16) improves cardiac function, possibly due to effects on SERCA2 and intracellular calcium handling.

Moreover, we have recently focused on the role of proteoglycans (especially lumican and fibromodulin) in myocardial remodeling and function, and their role in whether a pressure overloaded or ischemic heart is transformed from compensated to decompensated heart failure.

Professor Theis Tønnessen is group leader of this associated group.

Group Leader

Group members

Kine Andenæs

Doctoral Research Fellow

Mina Maria Gundersen

Medical Research Curriculum Student

Latest publications

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Rypdal KB, Erusappan PM, Melleby AO, Seifert DE, Palmero S, Strand ME, Tønnessen T, Dahl CP, Almaas V, Hubmacher D, Apte SS, Christensen G, Lunde IG (2021)
The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts
Sci Rep, 11 (1), 19757
PubMed 34611183 DOI 10.1038/s41598-021-99032-2
Frisk M, Le C, Shen X, Røe ÅT, Hou Y, Manfra O, Silva GJJ, van Hout I, Norden ES, Aronsen JM, Laasmaa M, Espe EKS, Zouein FA, Lambert RR, Dahl CP, Sjaastad I, Lunde IG, Coffey S, Cataliotti A, Gullestad L, Tønnessen T, Jones PP, Altara R, Louch WE (2021)
Etiology-Dependent Impairment of Diastolic Cardiomyocyte Calcium Homeostasis in Heart Failure With Preserved Ejection Fraction
J Am Coll Cardiol, 77 (4), 405-419
PubMed 33509397 DOI 10.1016/j.jacc.2020.11.044
Herum KM, Romaine A, Wang A, Melleby AO, Strand ME, Pacheco J, Braathen B, Dunér P, Tønnessen T, Lunde IG, Sjaastad I, Brakebusch C, McCulloch AD, Gomez MF, Carlson CR, Christensen G (2020)
Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin
J Am Heart Assoc, 9 (3), e013518
PubMed 32000579 DOI 10.1161/JAHA.119.013518
Mohammadzadeh N, Melleby AO, Palmero S, Sjaastad I, Chakravarti S, Engebretsen KVT, Christensen G, Lunde IG, Tønnessen T (2020)
Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload
Cardiology, 145 (3), 187-198
PubMed 31968347 DOI 10.1159/000505318
Mohammadzadeh N, Lunde IG, Andenæs K, Strand ME, Aronsen JM, Skrbic B, Marstein HS, Bandlien C, Nygård S, Gorham J, Sjaastad I, Chakravarti S, Christensen G, Engebretsen KVT, Tønnessen T (2019)
The extracellular matrix proteoglycan lumican improves survival and counteracts cardiac dilatation and failure in mice subjected to pressure overload
Sci Rep, 9 (1), 9206
PubMed 31235849 DOI 10.1038/s41598-019-45651-9
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