title: Molecular and cellular basis for diastolic dysfunction.
abstract: Heart failure with preserved ejection fraction (HFpEF) is highly prevalent and is frequently associated with metabolic risk factors. Patients with HFpEF have only a slightly lower mortality than patients with HF and reduced EF. The pathophysiology of HFpEF is currently incompletely understood, which precludes specific therapy. Both HF phenotypes demonstrate distinct cardiac remodeling processes at the macroscopic, microscopic, and ultrastructural levels. Increased diastolic left-ventricular (LV) stiffness and impaired LV relaxation are important features of HFpEF, which can be explained by changes in the extracellular matrix and the cardiomyocytes. In HFpEF, elevated intrinsic cardiomyocyte stiffness contributes to high diastolic LV stiffness. Posttranslational changes in the sarcomeric protein titin, affecting titin isoform expression and phosphorylation, contribute to elevated cardiomyocyte stiffness. Increased nitrosative/oxidative stress, impaired nitric oxide bioavailability, and down-regulation of myocardial cyclic guanosine monophosphate and protein kinase G signaling could trigger posttranslational modifications of titin, thereby augmenting cardiomyocyte and LV diastolic stiffness.
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Loek
authors.initials: L
authors.lastname: van Heerebeek
authors.forename: Constantijn P M
authors.initials: CP
authors.lastname: Franssen
authors.forename: Nazha
authors.initials: N
authors.lastname: Hamdani
authors.forename: Freek W A
authors.initials: FW
authors.lastname: Verheugt
authors.forename: G Aernout
authors.initials: GA
authors.lastname: Somsen
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Paulus
mesh_terms: D006152:Cyclic GMP / Q000502:physiology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology; D054144:Heart Failure, Diastolic / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D032383:Myocytes, Cardiac / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D016277:Ventricular Function, Left / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP