Mei-Pian Chen1,2, Salome A Kiduko1,2, Nancy S Saad1,2,3, Benjamin D Canan1,2, Ahmet Kilic4, Peter J Mohler1,2,5, Paul M L Janssen1,2,5. 1. Department of Physiology and Cell Biology, The Ohio State University, Hamilton Hall 207a, 1645 Neil Avenue, Columbus, OH 43210, USA. 2. Dorothy M. Davis Heart and Lung Research Institute, 473 W 12th Ave, Columbus, OH 43210 USA. 3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt. 4. Division of Cardiothoracic Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, 410 W 10th Ave, Columbus, OH 43210, USA. 5. Department of Internal Medicine, The Ohio State University Wexner Medical Center, 395 W 12th Ave, Columbus, OH 43210, USA.
Abstract
AIMS: Heart failure (HF) patients commonly experience symptoms primarily during elevated heart rates, as a result of physical activities or stress. A main determinant of diastolic passive tension, the elastic sarcomeric protein titin, has been shown to be associated with HF, with unresolved involvement regarding its role at different heart rates. To determine whether titin is playing a role in the heart rate (frequency-) dependent acceleration of relaxation (FDAR). W, we studied the FDAR responses in live human left ventricular cardiomyocytes and the corresponding titin-based passive tension (TPT) from failing and non-failing human hearts. METHODS AND RESULTS: Using atomic force, we developed a novel single-molecule force spectroscopy approach to detect TPT based on the frequency-modulated cardiac cycle. Mean TPT reduced upon an increased heart rate in non-failing human hearts, while this reduction was significantly blunted in failing human hearts. These mechanical changes in the titin distal Ig domain significantly correlated with the frequency-dependent relaxation kinetics of human cardiomyocytes obtained from the corresponding hearts. Furthermore, the data suggested that the higher the TPT, the faster the cardiomyocytes relaxed, but the lower the potential of myocytes to speed up relaxation at a higher heart rate. Such poorer FDAR response was also associated with a lesser reduction or a bigger increase in TPT upon elevated heart rate. CONCLUSIONS: Our study established a novel approach in detecting dynamic heart rate relevant tension changes physiologically on native titin domains. Using this approach, the data suggested that the regulation of kinetic reserve in cardiac relaxation and its pathological changes were associated with the intensity and dynamic changes of passive tension by titin. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Heart failure (HF) patients commonly experience symptoms primarily during elevated heart rates, as a result of physical activities or stress. A main determinant of diastolic passive tension, the elastic sarcomeric protein titin, has been shown to be associated with HF, with unresolved involvement regarding its role at different heart rates. To determine whether titin is playing a role in the heart rate (frequency-) dependent acceleration of relaxation (FDAR). W, we studied the FDAR responses in live human left ventricular cardiomyocytes and the corresponding titin-based passive tension (TPT) from failing and non-failing human hearts. METHODS AND RESULTS: Using atomic force, we developed a novel single-molecule force spectroscopy approach to detect TPT based on the frequency-modulated cardiac cycle. Mean TPT reduced upon an increased heart rate in non-failing human hearts, while this reduction was significantly blunted in failing human hearts. These mechanical changes in the titin distal Ig domain significantly correlated with the frequency-dependent relaxation kinetics of human cardiomyocytes obtained from the corresponding hearts. Furthermore, the data suggested that the higher the TPT, the faster the cardiomyocytes relaxed, but the lower the potential of myocytes to speed up relaxation at a higher heart rate. Such poorer FDAR response was also associated with a lesser reduction or a bigger increase in TPT upon elevated heart rate. CONCLUSIONS: Our study established a novel approach in detecting dynamic heart rate relevant tension changes physiologically on native titin domains. Using this approach, the data suggested that the regulation of kinetic reserve in cardiac relaxation and its pathological changes were associated with the intensity and dynamic changes of passive tension by titin. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Sudipta Chattopadhyay; Mohammed F Alamgir; Nikolay P Nikitin; Alan S Rigby; Andrew L Clark; John G F Cleland Journal: Circ Heart Fail Date: 2009-10-22 Impact factor: 8.790
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Authors: Henk L Granzier; Kirk R Hutchinson; Paola Tonino; Mei Methawasin; Frank W Li; Rebecca E Slater; Mathew M Bull; Chandra Saripalli; Christopher T Pappas; Carol C Gregorio; John E Smith Journal: Proc Natl Acad Sci U S A Date: 2014-09-22 Impact factor: 11.205