Abstract 8754: cGMP Enhancing Therapy Improves LV Diastolic Distensibility by Phosphorylating Titin
Background: In vitro studies suggest that phosphorylation of titin reduces myocyte/myofiber stiffness. Titin can be phosphorylated by cGMP activated protein kinase (PKG). cGMP production is increased by B-type natriuretic peptide (BNP) and degraded by phosphodiesterases (PDE) including PDE-5A. We hypothesized that a PDE-5A inhibitor (sildenafil) alone or in combination with BNP increases LV diastolic distensibility through titin phosphorylation.
Methods: 8 elderly dogs with experimental hypertension (OH) and 4 young normal (YN) dogs underwent measurement of the end-diastolic pressure (EDP) volume (EDV) relationship (EDPVR) during caval occlusion at baseline, after sildenafil and after BNP infusion. To assess diastolic distensibility independent of load/extrinsic forces, the EDV at a common EDP on sequential EDPVRs was measured (LV capacitance). In a separate group of dogs (n=4), serial full thickness LV biopsies were harvested from the beating heart during identical infusions to measure myofilament protein phosphorylation.
Results: Plasma cGMP increased with sildenafil and further with BNP (7.3±2.4 to 26.9±10.3 to 70.3±8.1 pmol/ml, p<0.001). LV diastolic capacitance increased with sildenafil and further with BNP (51.4±16.9 to 53.7±16.8 to 60.0±19.4 ml, p<0.001). (Figure) Changes were similar in OH and YN dogs. Titin phosphorylation increased with sildenafil and BNP (p-titin:total titin, 0.5±0.1 at baseline, 0.7±0.1 after sildenafil and 0.7±0.1 after BNP, p=0.007) with preferential increase in N2B titin isoform phosphorylation (p-N2B:p-N2BA, 1.06±0.03 at baseline, 1.30 ±0.03 after sildenafil and 1.46±1.03 after BNP, p=0.02). There was no effect on phosphorylation of other myofilament proteins (troponin I, troponin T, myosin binding protein C, phospholamban, myosin light chains -1 or -2).
Conclusions: Acute cGMP enhancing therapy with sildenafil and BNP improves LV diastolic distensibility in vivo, in part, through titin phosphorylation.
- © 2010 by American Heart Association, Inc.