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.
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.
J Mol Cell Cardiol. 2021 Jul;156:7-19. doi: 10.1016/j.yjmcc.2021.03.007. Epub 2021 Mar 22.
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.
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.
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.
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.
心力衰竭（HF）与极高的发病率、死亡率和医疗保健成本相关。尽管在治疗和预防方面取得了重大进展，但 HF 仍然与不良临床结局相关。了解末期 HF 中心肌的收缩力和动力学变化，并考虑潜在病因，将有助于开发靶向治疗方法，以帮助改善心脏功能。
研究 HF 的主要病因（缺血性或非缺血性）对左心室（LV）人类心肌在接近生理条件下收缩和舒张的力和动力学的影响。
在基线条件下、长度依赖性激活、频率依赖性激活以及对β-肾上腺素能刺激的反应下，评估了从对照非衰竭（NF；n=58）和末期衰竭缺血性（FI；n=16）和非缺血性（FNI；n=38）人类心肌中分离的 LV 完整小梁的收缩和动力学参数。在基线时，三组之间的收缩力没有显著差异；然而，衰竭心肌的动力学受损，与 NF 心肌相比，FNI 心肌的舒张动力学明显减慢。长度依赖性激活在所有组中均得到保留，几乎相同。NF 心肌中明显可见频率依赖性激活（正力频率关系[FFR]），而 FI 和 FNI 心肌中则明显受损（负 FFR）。同样，β-肾上腺素能对收缩的调节在两个 HF 组中均显著受损。
末期衰竭的心肌在基线条件以及三种收缩调节机制下均表现出动力学受损。这些动力学损伤与 NF 心肌的关系主要受病因影响，FNI 心肌的动力学明显减慢。这些发现表明，不仅要考虑力的发展，还要考虑动力学作为改善心脏功能和治疗 HF 的治疗靶点。
