Stretching Single Titin Molecules from Failing Human Hearts at Cardiac Cycle Reveals Titin's Role in Cardiac Kinetic Reserve

Abstract

Diastolic dysfunction occurs not only in diastolic heart failure, but also ubiquitously in systolic heart failure. A main determinant of diastolic passive tension, the elastic sarcomeric protein titin, has been shown to be associated with heart failure, with unresolved mechanisms. Heart failure patients commonly experience symptoms only during physical activities or stress. To determine whether titin is playing a role in the mechanisms of heart failure in terms of its known impaired property of frequency‐dependent acceleration of relaxation (FDAR), we studied the FDAR responses in live left ventricular cardiomyocytes and single‐molecule force spectroscopy (SMFS) of titin elastic domains (PEVK‐distal Ig, distal Ig) from failing (n=11) and non‐failing (n=7) human hearts. To access SMFS on native titin, we developed a novel approach using atomic force microscopy to detect titin passive tension (TPT) based on frequency‐modulated cardiac cycle. Mean TPT was shown to be reduced upon an increased heart rate, which was significantly blunted in failing human hearts. The results from titin distal Ig domain were significantly correlated with the frequency‐dependent relaxation kinetics of human cardiomyocytes from the corresponding hearts, which was shown to be impaired in failing hearts. Correlation studies suggested that the higher the TPT, the faster the cardiomyocytes relaxed, but lower the potential of myocytes to speed up relaxation at a higher heart rate; such poorer FDAR response was also associated with a less reduction or a bigger increase in TPT upon a raised heart rate. Our study established a novel approach in detecting tension physiologically on native titin domains. The data from human hearts suggested that the regulation of kinetic reserve in cardiac relaxation and its pathological changes are associated with the intensity and dynamic changes of passive tension on titin.Support or Funding InformationThis project is supported by RO1HL113084 to Janssen PML, and T32NS779844 to Chen MPThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.