Etiology-dependent impairment of relaxation kinetics in right ventricular end-stage failing human myocardium

Jae Hoon Chung, Brit L. Martin, Benjamin D. Canan, Mohammad T. Elnakish, Nima Milani-Nejad, Nancy S. Saad, Steven J. Repas, J. Eric J. Schultz, Jason D. Murray, Jessica L. Slabaugh, Rachel L. Gearinger, Jennifer Conkle, Tallib Karaze, Neha Rastogi, Mei Pian Chen, Will Crecelius, Kyra K. Peczkowski, Mark T. Ziolo, Vadim V. Fedorov, Ahmet KilicBryan A. Whitson, Robert Higgins, Sakima A. Smith, Peter J. Mohler, Philip F. Binkley, Paul M.L. Janssen

Research output: Contribution to journalArticle

Abstract

Background: In patients with end-stage heart failure, the primary etiology often originates in the left ventricle, and eventually the contractile function of the right ventricle (RV) also becomes compromised. RV tissue-level deficits in contractile force and/or kinetics need quantification to understand involvement in ischemic and non-ischemic failing human myocardium. Methods and results: The human population suffering from heart failure is diverse, requiring many subjects to be studied in order to perform an adequately powered statistical analysis. From 2009-present we assessed live tissue-level contractile force and kinetics in isolated myocardial RV trabeculae from 44 non-failing and 41 failing human hearts. At 1 Hz stimulation rate (in vivo resting state) the developed active force was not different in non-failing compared to failing ischemic nor non-ischemic failing trabeculae. In sharp contrast, the kinetics of relaxation were significantly impacted by disease, with 50% relaxation time being significantly shorter in non-failing vs. non-ischemic failing, while the latter was still significantly shorter than ischemic failing. Gender did not significantly impact kinetics. Length-dependent activation was not impacted. Although baseline force was not impacted, contractile reserve was critically blunted. The force-frequency relation was positive in non-failing myocardium, but negative in both ischemic and non-ischemic myocardium, while the β-adrenergic response to isoproterenol was depressed in both pathologies. Conclusions: Force development at resting heart rate is not impacted by cardiac pathology, but kinetics are impaired and the magnitude of the impairment depends on the underlying etiology. Focusing on restoration of myocardial kinetics will likely have greater therapeutic potential than targeting force of contraction.

Original languageEnglish (US)
Pages (from-to)81-93
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Volume121
DOIs
StatePublished - Aug 1 2018
Externally publishedYes

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Myocardium
Heart Ventricles
Heart Failure
Pathology
Isoproterenol
Adrenergic Agents
Heart Rate
Population
Therapeutics

Keywords

  • Excitation-contraction coupling
  • Heart failure
  • Myocardial biology

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Chung, J. H., Martin, B. L., Canan, B. D., Elnakish, M. T., Milani-Nejad, N., Saad, N. S., ... Janssen, P. M. L. (2018). Etiology-dependent impairment of relaxation kinetics in right ventricular end-stage failing human myocardium. Journal of Molecular and Cellular Cardiology, 121, 81-93. https://doi.org/10.1016/j.yjmcc.2018.07.005

Etiology-dependent impairment of relaxation kinetics in right ventricular end-stage failing human myocardium. / Chung, Jae Hoon; Martin, Brit L.; Canan, Benjamin D.; Elnakish, Mohammad T.; Milani-Nejad, Nima; Saad, Nancy S.; Repas, Steven J.; Schultz, J. Eric J.; Murray, Jason D.; Slabaugh, Jessica L.; Gearinger, Rachel L.; Conkle, Jennifer; Karaze, Tallib; Rastogi, Neha; Chen, Mei Pian; Crecelius, Will; Peczkowski, Kyra K.; Ziolo, Mark T.; Fedorov, Vadim V.; Kilic, Ahmet; Whitson, Bryan A.; Higgins, Robert; Smith, Sakima A.; Mohler, Peter J.; Binkley, Philip F.; Janssen, Paul M.L.

In: Journal of Molecular and Cellular Cardiology, Vol. 121, 01.08.2018, p. 81-93.

Research output: Contribution to journalArticle

Chung, JH, Martin, BL, Canan, BD, Elnakish, MT, Milani-Nejad, N, Saad, NS, Repas, SJ, Schultz, JEJ, Murray, JD, Slabaugh, JL, Gearinger, RL, Conkle, J, Karaze, T, Rastogi, N, Chen, MP, Crecelius, W, Peczkowski, KK, Ziolo, MT, Fedorov, VV, Kilic, A, Whitson, BA, Higgins, R, Smith, SA, Mohler, PJ, Binkley, PF & Janssen, PML 2018, 'Etiology-dependent impairment of relaxation kinetics in right ventricular end-stage failing human myocardium', Journal of Molecular and Cellular Cardiology, vol. 121, pp. 81-93. https://doi.org/10.1016/j.yjmcc.2018.07.005
Chung, Jae Hoon ; Martin, Brit L. ; Canan, Benjamin D. ; Elnakish, Mohammad T. ; Milani-Nejad, Nima ; Saad, Nancy S. ; Repas, Steven J. ; Schultz, J. Eric J. ; Murray, Jason D. ; Slabaugh, Jessica L. ; Gearinger, Rachel L. ; Conkle, Jennifer ; Karaze, Tallib ; Rastogi, Neha ; Chen, Mei Pian ; Crecelius, Will ; Peczkowski, Kyra K. ; Ziolo, Mark T. ; Fedorov, Vadim V. ; Kilic, Ahmet ; Whitson, Bryan A. ; Higgins, Robert ; Smith, Sakima A. ; Mohler, Peter J. ; Binkley, Philip F. ; Janssen, Paul M.L. / Etiology-dependent impairment of relaxation kinetics in right ventricular end-stage failing human myocardium. In: Journal of Molecular and Cellular Cardiology. 2018 ; Vol. 121. pp. 81-93.
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T1 - Etiology-dependent impairment of relaxation kinetics in right ventricular end-stage failing human myocardium

AU - Chung, Jae Hoon

AU - Martin, Brit L.

AU - Canan, Benjamin D.

AU - Elnakish, Mohammad T.

AU - Milani-Nejad, Nima

AU - Saad, Nancy S.

AU - Repas, Steven J.

AU - Schultz, J. Eric J.

AU - Murray, Jason D.

AU - Slabaugh, Jessica L.

AU - Gearinger, Rachel L.

AU - Conkle, Jennifer

AU - Karaze, Tallib

AU - Rastogi, Neha

AU - Chen, Mei Pian

AU - Crecelius, Will

AU - Peczkowski, Kyra K.

AU - Ziolo, Mark T.

AU - Fedorov, Vadim V.

AU - Kilic, Ahmet

AU - Whitson, Bryan A.

AU - Higgins, Robert

AU - Smith, Sakima A.

AU - Mohler, Peter J.

AU - Binkley, Philip F.

AU - Janssen, Paul M.L.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Background: In patients with end-stage heart failure, the primary etiology often originates in the left ventricle, and eventually the contractile function of the right ventricle (RV) also becomes compromised. RV tissue-level deficits in contractile force and/or kinetics need quantification to understand involvement in ischemic and non-ischemic failing human myocardium. Methods and results: The human population suffering from heart failure is diverse, requiring many subjects to be studied in order to perform an adequately powered statistical analysis. From 2009-present we assessed live tissue-level contractile force and kinetics in isolated myocardial RV trabeculae from 44 non-failing and 41 failing human hearts. At 1 Hz stimulation rate (in vivo resting state) the developed active force was not different in non-failing compared to failing ischemic nor non-ischemic failing trabeculae. In sharp contrast, the kinetics of relaxation were significantly impacted by disease, with 50% relaxation time being significantly shorter in non-failing vs. non-ischemic failing, while the latter was still significantly shorter than ischemic failing. Gender did not significantly impact kinetics. Length-dependent activation was not impacted. Although baseline force was not impacted, contractile reserve was critically blunted. The force-frequency relation was positive in non-failing myocardium, but negative in both ischemic and non-ischemic myocardium, while the β-adrenergic response to isoproterenol was depressed in both pathologies. Conclusions: Force development at resting heart rate is not impacted by cardiac pathology, but kinetics are impaired and the magnitude of the impairment depends on the underlying etiology. Focusing on restoration of myocardial kinetics will likely have greater therapeutic potential than targeting force of contraction.

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KW - Excitation-contraction coupling

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KW - Myocardial biology

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