PS146
Titin phosphorylation by protein kinase G as a novel mechanism of diastolic adaptation to acute load
R. Rocha1,, , J. Almeida-Coelho1, A.M. Leite-Moreira1, J.S. Neves1,2, N. Hamdani3, I. Falcão-Pires1, A.P. Lourenço1,4, W.J. Paulus5, W.A. Linke3, A.F. Leite-Moreira1,6
1 Department of Physiology and Cardiothoracic Surgery & Cardiovascular Research Center, Faculty of Medicine, University of Porto, Portugal
2 Department of Endocrinology, São João Hospital Center, Porto, Portugal
3 Department of Cardiovascular Physiology, Ruhr University Bochum, Germany
4 Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands
5 Department of Anesthesiology, São João Hospital Center, Porto, Portugal
6 Department of Cardiothoracic Surgery, São João Hospital Center, Porto, Portugal

Aim: To evaluate acute adaptions of myocardial stiffness to acute stretch and characterize the underlying mechanisms.

Introduction: Systolic adaption to myocardial stretch/volume overload is known, but whether the heart is also able to modulate its stiffness following such challenges remains unknown.

Methods: Left ventricle (LV) of intact rat Langendorff hearts, rabbit papillary muscles and myocardial strips from cardiac surgery patients were acutely stretched. Skinned cardiomyocytes from Stretched and Non-stretched myocardium were studied. Stretch by increased venous return or volume loading was assessed by echocardiography in healthy volunteers; pressure-volume hemodynamics in cardiac surgery patients and in a rat model of LV hypertrophy. Myocardial cGMP, phosphorylated vasodilator-stimulated phosphoprotein (VASP) and titin phosphorylation were quantified. Pharmacological studies assessed the role of NO and natriuretic peptides (NP).

Results: After stretch, end-diastolic pressure (EDP) or passive tension (PT) decreased over 15min in all preparations. Skinned cardiomyocytes from Stretched hearts showed decreased PT – abrogated by protein phosphatase incubation – those from Non-stretched hearts showed decreased PT after protein kinase (PKG) incubation. Stretched samples showed increased cGMP levels and phosphorylation of VASP. Titin phosphorylation was increased in Stretched samples – attenuated by PKG inhibition (PKGi). PT decay after stretch was blunted by PKGi or by joint NP antagonism, NO synthase inhibition and NO scavenging. Moreover, it was remarkably attenuated in hypertrophic rat hearts which showed reduced titin phosphorylation and no increase with stretch. Healthy volunteers and cardiac surgery patients showed E/E’ and EDP decrease after sustained stretch maneuvers, respectively.

Conclusion: We describe a novel physiological mechanism whereby myocardial compliance is increased in response to stretch/volume overload, by titin phosphorylation through cGMP-PKG signaling. The mechanism was translated to human physiology and may be abolished in the hypertrophic heart (potential role in the pathophysiology of heart failure with preserved ejection fraction).


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