Impaired isotonic contractility and structural abnormalities in the diaphragm of congestive heart failure rats

Hees, Hieronymus W. H. van; Heijden, Erik H F M van der; Hafmans, T.G.M.; Ennen, Leo; Heunks, Leo; Verheugt, Freek W.A.; Dekhuijzen, P.N.R.

doi:10.1016/j.ijcard.2007.06.080

Cited by 24 publications

(32 citation statements)

References 37 publications

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“…Inspiratory muscle weakness is noted in 30-50% of heart failure patients (Meyer et al, 2001;Ribeiro et al, 2012), and indices of diaphragm dysfunction and structural abnormalities have been noted in both patients and animal models of heart failure (Meyer et al, 2001;van Hees et al, 2008;Wong et al, 2011). LAD-HF rats in this study exhibited significant diaphragm atrophy and decreased sarcomeric Ca 21 sensitivity.…”

Section: Discussionmentioning

confidence: 57%

“…Respiratory muscle weakness has been highlighted as a specific contributor to dyspnea and exercise intolerance in heart failure patients (Meyer et al, 2001). The diaphragm is a primary muscle involved in respiration, and dysfunction of this muscle is specifically a noted complication of heart failure (Meyer et al, 2001;van Hees et al, 2008). In this study, the LAD-HF diaphragm myofiber area was significantly smaller than that of sham diaphragms (1534 6 114.7 versus 1141 6 77.9 mm 2 ; P , 0.05; Fig.…”

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confidence: 52%

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The Small-Molecule Fast Skeletal Troponin Activator, CK-2127107, Improves Exercise Tolerance in a Rat Model of Heart Failure

Hwee

Kennedy

Hartman

et al. 2015

J Pharmacol Exp Ther

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Heart failure-mediated skeletal myopathy, which is characterized by muscle atrophy and muscle metabolism dysfunction, often manifests as dyspnea and limb muscle fatigue. We have previously demonstrated that increasing Ca 21 sensitivity of the sarcomere by a small-molecule fast skeletal troponin activator improves skeletal muscle force and exercise performance in healthy rats and models of neuromuscular disease. The objective of this study was to investigate the effect of a novel fast skeletal troponin activator, CK-2127107 (2-aminoalkyl-5-N-heteroarylpyrimidine), on skeletal muscle function and exercise performance in rats exhibiting heart failure-mediated skeletal myopathy. Rats underwent a left anterior descending coronary artery ligation, resulting in myocardial infarction and a progressive decline in cardiac function [left anterior descending coronary artery heart failure (LAD-HF)]. Compared with sham-operated control rats, LAD-HF rat hindlimb and diaphragm muscles exhibited significant muscle atrophy. Fatigability was increased during repeated in situ isokinetic plantar flexor muscle contractions. CK-2127107 produced a leftward shift in the force-Ca 21 relationship of skinned, single diaphragm, and extensor digitorum longus fibers. Exercise performance, which was assessed by rotarod running, was lower in vehicle-treated LAD-HF rats than in sham controls (116 6 22 versus 193 6 31 seconds, respectively; mean 6 S.E.M.; P 5 0.04). In the LAD-HF rats, a single oral dose of CK-2127107 (10 mg/kg p.o.) increased running time compared with vehicle treatment (283 6 47 versus 116 6 22 seconds; P 5 0.0004). In summary, CK-2127107 substantially increases exercise performance in this heart failure model, suggesting that modulation of skeletal muscle function by a fast skeletal troponin activator may be a useful therapeutic in heart failure-associated exercise intolerance.

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Section: Discussionmentioning

confidence: 57%

mentioning

confidence: 52%

The Small-Molecule Fast Skeletal Troponin Activator, CK-2127107, Improves Exercise Tolerance in a Rat Model of Heart Failure

Hwee

Kennedy

Hartman

et al. 2015

J Pharmacol Exp Ther

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“…In the present experiments contraction was evoked in almost zero load conditions in the unconstrained diaphragm. In this condition the contraction velocity approaches V max and the force expressed by the muscle ought to be lower than the expected isometric force and fell on the flat portion of the diaphragmatic skeletal muscle force/velocity curve (7,34,39,42), where small changes in shortening speed may give rise to larger changes in force, which is generated. Therefore, one may reasonably expect the expressed force, and therefore the impact on lymph flow velocity, to be higher in the in situ-in vivo condition, when diaphragmatic fibers are held at a length closer to their resting one by the thoracic and crural physiological anatomical connection.…”

Section: Ajp-heart Circ Physiolmentioning

confidence: 98%

Lymph flow pattern in pleural diaphragmatic lymphatics during intrinsic and extrinsic isotonic contraction

Moriondo

Solari

Marcozzi

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Moriondo A, Solari E, Marcozzi C, Negrini D. Lymph flow pattern in pleural diaphragmatic lymphatics during intrinsic and extrinsic isotonic contraction. Am J Physiol Heart Circ Physiol 310: H60 -H70, 2016. First published October 29, 2015 doi:10.1152/ajpheart.00640.2015.-Peripheral rat diaphragmatic lymphatic vessels, endowed with intrinsic spontaneous contractility, were in vivo filled with fluorescent dextrans and microspheres and subsequently studied ex vivo in excised diaphragmatic samples. Changes in diameter and lymph velocity were detected, in a vessel segment, during spontaneous lymphatic smooth muscle contraction and upon activation, through electrical whole-field stimulation, of diaphragmatic skeletal muscle fibers. During intrinsic contraction lymph flowed both forward and backward, with a net forward propulsion of 14.1 Ϯ 2.9 m at an average net forward speed of 18.0 Ϯ 3.6 m/s. Each skeletal muscle contraction sustained a net forward-lymph displacement of 441.9 Ϯ 159.2 m at an average velocity of 339.9 Ϯ 122.7 m/s, values significantly higher than those documented during spontaneous contraction. The flow velocity profile was parabolic during both spontaneous and skeletal muscle contraction, and the shear stress calculated at the vessel wall at the highest instantaneous velocity never exceeded 0.25 dyne/cm 2 . Therefore, we propose that the synchronous contraction of diaphragmatic skeletal muscle fibers recruited at every inspiratory act dramatically enhances diaphragmatic lymph propulsion, whereas the spontaneous lymphatic contractility might, at least in the diaphragm, be essential in organizing the pattern of flow redistribution within the diaphragmatic lymphatic circuit. Moreover, the very low shear stress values observed in diaphragmatic lymphatics suggest that, in contrast with other contractile lymphatic networks, a likely interplay between intrinsic and extrinsic mechanisms be based on a mechanical and/or electrical connection rather than on nitric oxide release. lymph propulsion; tissue stress; spontaneous lymphatic contractility NEW AND NOTEWORTHYIn diaphragmatic lymphatics, flow velocity and lymph flow were more than two order of magnitude greater during contraction of diaphragmatic skeletal muscle than during spontaneous contraction of lymphatic smooth muscles, suggesting a marginal role of the latter in setting lymph flow in rhythmically moving, thoracic tissues.THE PLEURAL DIAPHRAGMATIC lymphatic system is composed of linear lymphatic vessels preferentially located in the tendineous and the medial muscular portion of the diaphragm, and of a more complex net of loop-like structures interconnected by short linear tracts and preferentially located at the most peripheral diaphragmatic rim (18). Given the strategic role played by pleural lymphatics in setting the correct pleural fluid volume and subatmospheric pressure required to maintain the normal lung chest wall coupling (29), much effort has been spent in the study of the inner regulatory mechanisms of lymph drainage and propulsion in th...

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“…In addition, there is a shift from fast to slow myosin heavy-chain isoforms, probably induced by myogenic regulatory factors as a likely adaptation to the increased effort of breathing [40,41]. These abnormalities may contribute to the reduction of inspiratory muscle contractility, as demonstrated in experimental studies [42]. Despite the fact that PI max is reduced after maximal exercise in CHF [8••], studies have not been able to demonstrate low-frequency fatigue of the diaphragm in response to bilateral magnetic phrenic nerve stimulation [13,43].…”

Section: Putative Mechanisms By Which Imt May Improve Exercise Capacimentioning

confidence: 99%

Respiratory muscle function and exercise intolerance in heart failure

Ribeiro

Chiappa²,

Neder³

et al. 2009

Curr Heart Fail Rep

106

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Inspiratory muscle weakness (IMW) is prevalent in patients with chronic heart failure (CHF) caused by left ventricular systolic dysfunction, which contributes to reduced exercise capacity and the presence of dyspnea during daily activities. Inspiratory muscle strength (estimated by maximal inspiratory pressure) has independent prognostic value in CHF. Overall, the results of trials with inspiratory muscle training (IMT) indicate that this intervention improves exercise capacity and quality of life, particularly in patients with CHF and IMW. Some benefit from IMT may be accounted for by the attenuation of the inspiratory muscle metaboreflex. Moreover, IMT results in improved cardiovascular responses to exercise and to those obtained with standard aerobic training. These findings suggest that routine screening for IMW is advisable in patients with CHF, and specific IMT and/or aerobic training are of practical value in the management of these patients.

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Impaired isotonic contractility and structural abnormalities in the diaphragm of congestive heart failure rats

Cited by 24 publications

References 37 publications

The Small-Molecule Fast Skeletal Troponin Activator, CK-2127107, Improves Exercise Tolerance in a Rat Model of Heart Failure

The Small-Molecule Fast Skeletal Troponin Activator, CK-2127107, Improves Exercise Tolerance in a Rat Model of Heart Failure

Lymph flow pattern in pleural diaphragmatic lymphatics during intrinsic and extrinsic isotonic contraction

Respiratory muscle function and exercise intolerance in heart failure

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