title: The Frank-Starling mechanism involves deceleration of cross-bridge kinetics and is preserved in failing human right ventricular myocardium.
abstract: Cross-bridge cycling rate is an important determinant of cardiac output, and its alteration can potentially contribute to reduced output in heart failure patients. Additionally, animal studies suggest that this rate can be regulated by muscle length. The purpose of this study was to investigate cross-bridge cycling rate and its regulation by muscle length under near-physiological conditions in intact right ventricular muscles of nonfailing and failing human hearts. We acquired freshly explanted nonfailing (n = 9) and failing (n = 10) human hearts. All experiments were performed on intact right ventricular cardiac trabeculae (n = 40) at physiological temperature and near the normal heart rate range. The failing myocardium showed the typical heart failure phenotype: a negative force-frequency relationship and β-adrenergic desensitization (P < 0.05), indicating the expected pathological myocardium in the right ventricles. We found that there exists a length-dependent regulation of cross-bridge cycling kinetics in human myocardium. Decreasing muscle length accelerated the rate of cross-bridge reattachment (ktr) in both nonfailing and failing myocardium (P < 0.05) equally; there were no major differences between nonfailing and failing myocardium at each respective length (P > 0.05), indicating that this regulatory mechanism is preserved in heart failure. Length-dependent assessment of twitch kinetics mirrored these findings; normalized dF/dt slowed down with increasing length of the muscle and was virtually identical in diseased tissue. This study shows for the first time that muscle length regulates cross-bridge kinetics in human myocardium under near-physiological conditions and that those kinetics are preserved in the right ventricular tissues of heart failure patients.
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; Medical Scientist Training Program and Biomedical Sciences Graduate Program, The Ohio State University Wexner Medical Center, Columbus, Ohio;
authors.forename: Nima
authors.initials: N
authors.lastname: Milani-Nejad
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio;
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Canan
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
authors.forename: Mohammad T
authors.initials: MT
authors.lastname: Elnakish
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio;
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Davis
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio; Medical Scientist Training Program and Biomedical Sciences Graduate Program, The Ohio State University Wexner Medical Center, Columbus, Ohio;
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Chung
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio;
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Fedorov
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio; and.
authors.forename: Philip F
authors.initials: PF
authors.lastname: Binkley
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio;
authors.forename: Robert S D
authors.initials: RS
authors.lastname: Higgins
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio;
authors.forename: Ahmet
authors.initials: A
authors.lastname: Kilic
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio; and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio; and janssen.10@osu.edu.
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
mesh_terms: D000328:Adult; D000368:Aged; D001831:Body Temperature; D002302:Cardiac Output; D005260:Female; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology*; D006334:Heart Function Tests / Q000379:methods*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000503:physiopathology; D009200:Myocardial Contraction; D009206:Myocardium / Q000473:pathology; D011943:Receptors, Adrenergic, beta; D014129:Trabecular Meshwork / Q000503:physiopathology; D018497:Ventricular Dysfunction, Right / Q000473:pathology / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D011943:Receptors, Adrenergic, beta
keywords: cross-bridge cycling kinetics; heart failure; muscle length; relaxation; trabeculae