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; 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 S.D.; Smith, Sakima A.; Mohler, Peter J.; Binkley, Philip F.; Janssen, Paul M.L.

doi:10.1016/j.yjmcc.2018.07.005

Cited by 25 publications

(42 citation statements)

References 32 publications

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“…; Chung et al. ), nonfailing trabeculae typically display a positive FFR, as developed force increases at increased stimulation frequencies. Failing trabeculae typically have a negative FFR as developed force decreases at increased stimulation frequencies.…”

Section: Discussionmentioning

confidence: 98%

Force-frequency relationship and early relaxation kinetics are preserved upon sarcoplasmic blockade in human myocardium

et al. 2018

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In this study, we investigated the quantitative and qualitative role of the sarcoplasmic reticulum (SR) in the regulation of the force‐frequency relationship (FFR). We blocked the function of SR with cyclopiazonic acid (CPA) and ryanodine and measured twitch kinetics and developed force at various stimulation frequencies in nonfailing and failing intact human right ventricular trabeculae. We found that developed forces are only slightly reduced upon SR blockade, while the positive FFR in nonfailing trabeculae and negative FFR in failing trabeculae were both preserved. The contraction kinetics (dF/dt, dF/dt/F, and time to peak), however, were significantly slower at all frequencies tested. Kinetics of first 50% of relaxation (RT50) was not affected by SR blockade. Kinetics of entire relaxation process (RT90) was overall slower at low frequencies, but not at high frequencies. From our findings, we conclude that the SR is not essential for FFR, and its role in regulation of FFR lies mostly in contraction kinetics. Unlike small rodents, human myocardium contractile function is near‐normal in absence of a functional SR with little changes in contractile force, and with preservation with the main regulation of FFR.

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Section: Discussionmentioning

confidence: 98%

Force-frequency relationship and early relaxation kinetics are preserved upon sarcoplasmic blockade in human myocardium

et al. 2018

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“…However, on average these previous studies found no or little difference in developed contractile strength of viable myocardium at rest. A recent study conducted over 6 years (10) on >80 human hearts confirmed that there was indeed no significant difference inactive developed force of viable right ventricular trabeculae between failing and non-failing myocardium at rest. This may seem at odds with our view of heart failure as predominantly a weak heart, but this outcome is actually expected given the fact that the failing heart at rest, and the non-failing heart at rest, produce a very similar cardiac output.…”

Section: Introductionmentioning

confidence: 94%

“…When human myocardium in vitro is subject to the conditions of exercise, causing an elevation in heart rate, contractile deficits clearly become obvious in the end-stage failing myocardium. Healthy human myocardium increases developed force when heart rate is elevated, failing myocardium either increases less, but more often does not increase at all or even decreases when heart rate is elevated (10, 16, 40). …”

Section: Introductionmentioning

confidence: 99%

“…Our recent study on 80+ human hearts determined that in end-stage heart failure, at least in the right ventricular myocardium of end-stage failing hearts, a significant deficit in relaxation kinetics is indeed present. This impaired relaxation is present at a resting heart rate, and this impaired relaxation was more prominent in myocardium of ischemic etiological origin compared to failing myocardium from non-ischemic etiology(10). …”

Section: Introductionmentioning

confidence: 99%

“…Lastly, the external and internal loads that the sarcomere both carries and generates resulting in sarcomere length changes impacts TnC-Ca 2+ binding as well as cross-bridge cycling properties. In human heart failure, the kinetic rate of contraction and relaxation are prominently involved in the manifestation of dysfunction, even at rest(10), possibly more often so than a weak contraction, and a further understanding of the sarcomere as an integrated system will be needed to strategize sarcomere-based treatment for this sarcomere-based dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Myocardial relaxation in human heart failure: Why sarcomere kinetics should be center-stage

Janssen

2019

Archives of Biochemistry and Biophysics

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Myocardial relaxation is critical for the heart to allow for adequate filling of the ventricles prior to the next contraction. In human heart failure, impairment of myocardial relaxation is a major problem, and impacts most patients suffering from end-stage failure. Furthering our understanding of myocardial relaxation is critical in developing future treatment strategies. This review highlights processes involved in myocardial relaxation, as well as governing processes that modulate myocardial relaxation, with a focus on impairment of myocardium-level relaxation in human end-stage heart failure.

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Distributed synthesis of sarcolemmal and sarcoplasmic reticulum membrane proteins in cardiac myocytes

et al. 2021

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It is widely assumed that synthesis of membrane proteins, particularly in the heart, follows the classical secretory pathway with mRNA translation occurring in perinuclear regions followed by protein trafficking to sites of deployment. However, this view is based on studies conducted in less-specialized cells, and has not been experimentally addressed in cardiac myocytes. Therefore, we undertook direct experimental investigation of protein synthesis in cardiac tissue and isolated myocytes using single-molecule visualization techniques and a novel proximity-ligated in situ hybridization approach for visualizing ribosome-associated mRNA molecules for a specific protein species, indicative of translation sites. We identify here, for the first time, that the molecular machinery for membrane protein synthesis occurs throughout the cardiac myocyte, and enables distributed synthesis of membrane proteins within sub-cellular niches where the synthesized protein functions using local mRNA pools trafficked, in part, by microtubules. We also observed cell-wide distribution of membrane protein mRNA in myocardial tissue from both non-failing and hypertrophied (failing) human hearts, demonstrating an evolutionarily conserved distributed mechanism from mouse to human. Our results identify previously unanticipated aspects of local control of cardiac myocyte biology and highlight local protein synthesis in cardiac myocytes as an important potential determinant of the heart’s biology in health and disease.

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

Cited by 25 publications

References 32 publications

Force-frequency relationship and early relaxation kinetics are preserved upon sarcoplasmic blockade in human myocardium

Force-frequency relationship and early relaxation kinetics are preserved upon sarcoplasmic blockade in human myocardium

Myocardial relaxation in human heart failure: Why sarcomere kinetics should be center-stage

Distributed synthesis of sarcolemmal and sarcoplasmic reticulum membrane proteins in cardiac myocytes

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