TY - JOUR
T1 - Sarcomere length affects Ca2+ sensitivity of contraction in ischemic but not non-ischemic myocardium
AU - Tanner, Bertrand C.W.
AU - Awinda, Peter O.
AU - Agonias, Keinan B.
AU - Attili, Seetharamaiah
AU - Blair, Cheavar A.
AU - Thompson, Mindy S.
AU - Walker, Lori A.
AU - Kampourakis, Thomas
AU - Campbell, Kenneth S.
N1 - Funding Information:
This work was supported by grants from the American Heart Association (19TPA34860008 to B.C.W. Tanner and K.S. Campbell, and GRNT25460003 to K.S. Campbell), the National Science Foundation (1656450 to B.C.W. Tanner), and the National Institutes of Health (HL149164 to B.C.W. Tanner and K.S. Campbell, and TR001988 to K.S. Campbell).
Funding Information:
This work is part of a special issue on Myofilament Function 2022.Henk L. Granzier served as editor. The authors appreciate helpful comments and advice from Brandon Biesiadecki, Kerry McDonald, and Ivanka Sevrieva. This work was supported by grants from the American Heart Association (19TPA34860008 to B.C.W. Tanner and K.S. Campbell, and GRNT25460003 to K.S. Campbell), the National Science Foundation (1656450 to B.C.W. Tanner), and the National Institutes of Health (HL149164 to B.C.W. Tanner and K.S. Campbell, and TR001988 to K.S. Campbell).
Publisher Copyright:
© 2023 Tanner et al.
PY - 2023/3/6
Y1 - 2023/3/6
N2 - In healthy hearts, myofilaments become more sensitive to Ca2+ as the myocardium is stretched. This effect is known as length-dependent activation and is an important cellular-level component of the Frank-Starling mechanism. Few studies have measured length-dependent activation in the myocardium from failing human hearts. We investigated whether ischemic and non-ischemic heart failure results in different length-dependent activation responses at physiological temperature (37°C). Myocardial strips from the left ventricular free wall were chemically permeabilized and Ca2+-activated at sarcomere lengths (SLs) of 1.9 and 2.3 µm. Data were acquired from 12 hearts that were explanted from patients receiving cardiac transplants; 6 had ischemic heart failure and 6 had non-ischemic heart failure. Another 6 hearts were obtained from organ donors. Maximal Ca2+-activated force increased at longer SL for all groups. Ca2+ sensitivity increased with SL in samples from donors (P < 0.001) and patients with ischemic heart failure (P = 0.003) but did not change with SL in samples from patients with non-ischemic heart failure. Compared with donors, troponin I phosphorylation decreased in ischemic samples and even more so in non-ischemic samples; cardiac myosin binding protein-C (cMyBP-C) phosphorylation also decreased with heart failure. These findings support the idea that troponin I and cMyBP-C phosphorylation promote length-dependent activation and show that length-dependent activation of contraction is blunted, yet extant, in the myocardium from patients with ischemic heart failure and further reduced in the myocardium from patients with non-ischemic heart failure. Patients who have a non-ischemic disease may exhibit a diminished contractile response to increased ventricular filling.
AB - In healthy hearts, myofilaments become more sensitive to Ca2+ as the myocardium is stretched. This effect is known as length-dependent activation and is an important cellular-level component of the Frank-Starling mechanism. Few studies have measured length-dependent activation in the myocardium from failing human hearts. We investigated whether ischemic and non-ischemic heart failure results in different length-dependent activation responses at physiological temperature (37°C). Myocardial strips from the left ventricular free wall were chemically permeabilized and Ca2+-activated at sarcomere lengths (SLs) of 1.9 and 2.3 µm. Data were acquired from 12 hearts that were explanted from patients receiving cardiac transplants; 6 had ischemic heart failure and 6 had non-ischemic heart failure. Another 6 hearts were obtained from organ donors. Maximal Ca2+-activated force increased at longer SL for all groups. Ca2+ sensitivity increased with SL in samples from donors (P < 0.001) and patients with ischemic heart failure (P = 0.003) but did not change with SL in samples from patients with non-ischemic heart failure. Compared with donors, troponin I phosphorylation decreased in ischemic samples and even more so in non-ischemic samples; cardiac myosin binding protein-C (cMyBP-C) phosphorylation also decreased with heart failure. These findings support the idea that troponin I and cMyBP-C phosphorylation promote length-dependent activation and show that length-dependent activation of contraction is blunted, yet extant, in the myocardium from patients with ischemic heart failure and further reduced in the myocardium from patients with non-ischemic heart failure. Patients who have a non-ischemic disease may exhibit a diminished contractile response to increased ventricular filling.
KW - Humans
KW - Sarcomeres/metabolism
KW - Calcium/metabolism
KW - Troponin I/metabolism
KW - Myocardial Contraction/physiology
KW - Myocardium/metabolism
KW - Heart Failure/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85146364869&partnerID=8YFLogxK
U2 - 10.1085/jgp.202213200
DO - 10.1085/jgp.202213200
M3 - Article
C2 - 36633584
AN - SCOPUS:85146364869
SN - 0022-1295
VL - 155
JO - Journal of General Physiology
JF - Journal of General Physiology
IS - 3
M1 - e202213200
ER -
