Mohammed A Mashali1, Nancy S Saad2, Benjamin D Canan3, Mohammad T Elnakish2, Nima Milani-Nejad3, Jae-Hoon Chung3, Eric J Schultz3, Salome A Kiduko3, Amanda W Huang3, Austin N Hare3, Kyra K Peczkowski3, Farbod Fazlollahi3, Brit L Martin3, Jason D Murray3, Courtney M Campbell4, Ahmet Kilic5, Bryan A Whitson5, Nahush A Mokadam5, Peter J Mohler4, Paul M L Janssen6. 1. Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, United States; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, United States; Department of Surgery, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt. 2. Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, United States; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, United States; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt. 3. Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, United States; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, United States. 4. Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, United States; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, United States; Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, United States. 5. Division of Cardiac Surgery, College of Medicine, The Ohio State University, Columbus, OH, United States. 6. Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, United States; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, United States; Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, United States. Electronic address: janssen.10@osu.edu.
Abstract
BACKGROUND: Heart failure (HF) is associated with highly significant morbidity, mortality, and health care costs. Despite the significant advances in therapies and prevention, HF remains associated with poor clinical outcomes. Understanding the contractile force and kinetic changes at the level of cardiac muscle during end-stage HF in consideration of underlying etiology would be beneficial in developing targeted therapies that can help improve cardiac performance. OBJECTIVE: Investigate the impact of the primary etiology of HF (ischemic or non-ischemic) on left ventricular (LV) human myocardium force and kinetics of contraction and relaxation under near-physiological conditions. METHODS AND RESULTS: Contractile and kinetic parameters were assessed in LV intact trabeculae isolated from control non-failing (NF; n = 58) and end-stage failing ischemic (FI; n = 16) and non-ischemic (FNI; n = 38) human myocardium under baseline conditions, length-dependent activation, frequency-dependent activation, and response to the β-adrenergic stimulation. At baseline, there were no significant differences in contractile force between the three groups; however, kinetics were impaired in failing myocardium with significant slowing down of relaxation kinetics in FNI compared to NF myocardium. Length-dependent activation was preserved and virtually identical in all groups. Frequency-dependent activation was clearly seen in NF myocardium (positive force frequency relationship [FFR]), while significantly impaired in both FI and FNI myocardium (negative FFR). Likewise, β-adrenergic regulation of contraction was significantly impaired in both HF groups. CONCLUSIONS: End-stage failing myocardium exhibited impaired kinetics under baseline conditions as well as with the three contractile regulatory mechanisms. The pattern of these kinetic impairments in relation to NF myocardium was mainly impacted by etiology with a marked slowing down of kinetics in FNI myocardium. These findings suggest that not only force development, but also kinetics should be considered as a therapeutic target for improving cardiac performance and thus treatment of HF.
BACKGROUND: Heart failure (HF) is associated with highly significant morbidity, mortality, and health care costs. Despite the significant advances in therapies and prevention, HF remains associated with poor clinical outcomes. Understanding the contractile force and kinetic changes at the level of cardiac muscle during end-stage HF in consideration of underlying etiology would be beneficial in developing targeted therapies that can help improve cardiac performance. OBJECTIVE: Investigate the impact of the primary etiology of HF (ischemic or non-ischemic) on left ventricular (LV) human myocardium force and kinetics of contraction and relaxation under near-physiological conditions. METHODS AND RESULTS: Contractile and kinetic parameters were assessed in LV intact trabeculae isolated from control non-failing (NF; n = 58) and end-stage failing ischemic (FI; n = 16) and non-ischemic (FNI; n = 38) human myocardium under baseline conditions, length-dependent activation, frequency-dependent activation, and response to the β-adrenergic stimulation. At baseline, there were no significant differences in contractile force between the three groups; however, kinetics were impaired in failing myocardium with significant slowing down of relaxation kinetics in FNI compared to NF myocardium. Length-dependent activation was preserved and virtually identical in all groups. Frequency-dependent activation was clearly seen in NF myocardium (positive force frequency relationship [FFR]), while significantly impaired in both FI and FNI myocardium (negative FFR). Likewise, β-adrenergic regulation of contraction was significantly impaired in both HF groups. CONCLUSIONS: End-stage failing myocardium exhibited impaired kinetics under baseline conditions as well as with the three contractile regulatory mechanisms. The pattern of these kinetic impairments in relation to NF myocardium was mainly impacted by etiology with a marked slowing down of kinetics in FNI myocardium. These findings suggest that not only force development, but also kinetics should be considered as a therapeutic target for improving cardiac performance and thus treatment of HF.
Authors: Nancy S Saad; Kyle Floyd; Amany A E Ahmed; Peter J Mohler; Paul M L Janssen; Mohammad T Elnakish Journal: PLoS One Date: 2016-04-15 Impact factor: 3.240
Authors: Nancy S Saad; Mohammad T Elnakish; Elizabeth A Brundage; Brandon J Biesiadecki; Ahmet Kilic; Amany A E Ahmed; Peter J Mohler; Paul M L Janssen Journal: Life Sci Date: 2018-11-03 Impact factor: 5.037
Authors: Nancy S Saad; Mohammed A Mashali; Mohammad T Elnakish; Austin Hare; Courtney M Campbell; Salome A Kiduko; Kyra K Peczkowski; Amanda W Huang; Farbod Fazlollahi; Gina S Torres Matias; Amany A E Ahmed; Bryan A Whitson; Nahush A Mokadam; Paul M L Janssen Journal: PLoS One Date: 2022-04-11 Impact factor: 3.240
Authors: Kyra K Peczkowski; Mohammed A Mashali; Nancy S Saad; Austin Hare; Courtney M Campbell; Bryan A Whitson; Nahush A Mokadam; Paul M L Janssen Journal: J Am Heart Assoc Date: 2022-06-22 Impact factor: 6.106