Force-frequency relationship and inotropic stimulation in the nonfailing and failing human myocardium: implications for the medical treatment of heart failure

Levosimendan has been reported to increase cardiac Ca2+ sensitivity, thereby not enhancing intracellular Ca2+ or diastolic tension. This may be advantageous for the treatment of heart failure patients. Therefore, the present study investigates the mode of action of levosimendan in both failing and nonfailing (NF) human myocardium. The effects of levosimendan on contractile force, Ca2+ transient (fura 2), and the force-frequency relationship (0.5–3 Hz) were studied in left ventricular terminally failing [dilated cardiomyopathy (DCM; n = 18)] and nonfailing (NF) myocardium (donor hearts, n = 6). Levosimendan (0.03–10 μmol/l) increased contractile force in NF (EC50: 0.38 μmol/l). In left ventricular failing myocardium, levosimendan only increased force after prestimulation with isoprenaline (0.1 μmol/l, EC50levosimendan: 0.062 μmol/l) or after elevation of the extracellular Ca2+ concentration from 1.8 to 3.2 mmol/l. After application of isoprenaline, levosimendan shortened relaxation and contraction kinetics. Levosimendan did not change the systolic Ca2+ transient but it improved the force-frequency relationship in DCM. In conclusion, levosimendan improves contraction in failing human myocardium under conditions with already increased intracellular Ca2+.

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The Frank-Starling mechanism involves deceleration of cross-bridge kinetics and is preserved in failing human right ventricular myocardium

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00685.2015 ◽

2015 ◽

Vol 309 (12) ◽

pp. H2077-H2086 ◽

Cited By ~ 26

Author(s):

Nima Milani-Nejad ◽

Benjamin D. Canan ◽

Mohammad T. Elnakish ◽

Jonathan P. Davis ◽

Jae-Hoon Chung ◽

...

Keyword(s):

Heart Failure ◽

Right Ventricular ◽

Muscle Length ◽

Human Myocardium ◽

Force Frequency ◽

Heart Failure Patients ◽

Cycling Rate ◽

Physiological Conditions ◽

Cross Bridge ◽

The Right

Cross-bridge cycling rate is an important determinant of cardiac output, and its alteration can potentially contribute to reduced output in heart failure patients. Additionally, animal studies suggest that this rate can be regulated by muscle length. The purpose of this study was to investigate cross-bridge cycling rate and its regulation by muscle length under near-physiological conditions in intact right ventricular muscles of nonfailing and failing human hearts. We acquired freshly explanted nonfailing ( n = 9) and failing ( n = 10) human hearts. All experiments were performed on intact right ventricular cardiac trabeculae ( n = 40) at physiological temperature and near the normal heart rate range. The failing myocardium showed the typical heart failure phenotype: a negative force-frequency relationship and β-adrenergic desensitization ( P < 0.05), indicating the expected pathological myocardium in the right ventricles. We found that there exists a length-dependent regulation of cross-bridge cycling kinetics in human myocardium. Decreasing muscle length accelerated the rate of cross-bridge reattachment ( ktr) in both nonfailing and failing myocardium ( P < 0.05) equally; there were no major differences between nonfailing and failing myocardium at each respective length ( P > 0.05), indicating that this regulatory mechanism is preserved in heart failure. Length-dependent assessment of twitch kinetics mirrored these findings; normalized dF/d t slowed down with increasing length of the muscle and was virtually identical in diseased tissue. This study shows for the first time that muscle length regulates cross-bridge kinetics in human myocardium under near-physiological conditions and that those kinetics are preserved in the right ventricular tissues of heart failure patients.

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Diaphragmatic free radical generation increases in an animal model of heart failure

Journal of Applied Physiology ◽

10.1152/japplphysiol.01145.2004 ◽

2005 ◽

Vol 99 (3) ◽

pp. 1078-1084 ◽

Cited By ~ 29

Author(s):

Gerald S. Supinski ◽

Leigh A. Callahan

Keyword(s):

Heart Failure ◽

Free Radicals ◽

Free Radical ◽

Protein Carbonyl ◽

Protein Carbonyls ◽

Force Frequency ◽

Free Radical Generation ◽

Coronary Ligation ◽

Radical Generation ◽

Frequency Relationship

Heart failure evokes diaphragm weakness, but the mechanism(s) by which this occurs are not known. We postulated that heart failure increases diaphragm free radical generation and that free radicals trigger diaphragm dysfunction in this condition. The purpose of the present study was to test this hypothesis. Experiments were performed using halothane-anesthetized sham-operated control rats and rats in which myocardial infarction was induced by ligation of the left anterior descending coronary artery. Animals were killed 6 wk after surgery, the diaphragms were removed, and the following were assessed: 1) mitochondrial hydrogen peroxide (H2O2) generation, 2) free radical generation in resting and contracting intact diaphragm using a fluorescent-indicator technique, 3) 8-isoprostane and protein carbonyls (indexes of free radical-induced lipid and protein oxidation), and 4) the diaphragm force-frequency relationship. In additional experiments, a group of coronary ligation animals were treated with polyethylene glycol-superoxide dismutase (PEG-SOD, 2,000 units·kg−1·day−1) for 4 wk. We found that coronary ligation evoked an increase in free radical formation by the intact diaphragm, increased diaphragm mitochondrial H2O2 generation, increased diaphragm protein carbonyl levels, and increased diaphragm 8-isoprostane levels compared with controls ( P < 0.001 for the first 3 comparisons, P < 0.05 for 8-isoprostane levels). Force generated in response to 20-Hz stimulation was reduced by coronary ligation ( P < 0.05); PEG-SOD administration restored force to control levels ( P < 0.03). These findings indicate that cardiac dysfunction due to coronary ligation increases diaphragm free radical generation and that free radicals evoke reductions in diaphragm force generation.

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Force-frequency relationship in patients with chronic heart failure

Journal of Cardiac Failure ◽

10.1016/s1071-9164(99)91280-0 ◽

1999 ◽

Vol 5 (3) ◽

pp. 80

Author(s):

Makoto Kodama ◽

Kiminori Kato ◽

Satoru Hirono ◽

Masahiro Ito ◽

Koichi Fuse ◽

...

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Force Frequency ◽

Frequency Relationship

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Halothane Restores the Altered Force-Frequency Relationship in Failing Human Myocardium

Anesthesiology ◽

10.1097/00000542-199506000-00017 ◽

1995 ◽

Vol 82 (6) ◽

pp. 1456-1462. ◽

Cited By ~ 6

Author(s):

Ulrich Schmidt ◽

Robert H. G. Schwinger ◽

Michael Bohm

Keyword(s):

Cardiac Surgery ◽

Human Heart ◽

Positive Inotropic Effect ◽

Negative Inotropic Effect ◽

Human Myocardium ◽

Inotropic Effect ◽

Force Frequency ◽

Beta Adrenoceptors ◽

Frequency Relationship

Background The terminally failing human myocardium exerts a negative force-frequency relationship (FFR), whereas a positive FFR occurs in nonfailing myocardium. To study the possibility of pharmacologically influencing this defect of the failing human heart, the effect of halothane on the basal FFR and the FFR in the presence of isoproterenol and ouabain was investigated. Methods Experiments were performed on isolated, electrically driven (0.5-2 Hz, 37 degrees C, Ca2+ 1.8 mmol/l) ventricular preparations. Myocardium from human failing and nonfailing hearts was obtained at cardiac surgery. To further characterize the studied myocardium, the positive inotropic effect of isoproterenol and the density of beta-adrenoceptors were measured using the radioligand 125I-CYP. Results Halothane produced a negative inotropic effect. The anesthetic (0.38 mmol/l) reversed the negative FFR in failing myocardium, antagonized the effect of isoproterenol (0.1 mumol/l) on FFR, and restored the FFR in the presence of ouabain. Conclusions Halothane restores the FFR in human failing myocardium possibly by influencing the intracellular Ca2+ homeostasis. These findings provide evidence that pharmacologic interventions, e.g., during anesthesia, may influence contractility also as a result of a depressed or enhanced FFR.

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

Physiological Reports ◽

10.14814/phy2.13898 ◽

2018 ◽

Vol 6 (20) ◽

pp. e13898 ◽

Cited By ~ 4

Author(s):

Jae-Hoon Chung ◽

Benjamin D. Canan ◽

Bryan A. Whitson ◽

Ahmet Kilic ◽

Paul M. L. Janssen

Keyword(s):

Human Myocardium ◽

Force Frequency ◽

Relaxation Kinetics ◽

Frequency Relationship

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Dantrolene sodium improves the force-frequency relationship and β-adrenergic responsiveness in failing human myocardium

European Journal of Heart Failure ◽

10.1016/s1388-9842(99)00017-3 ◽

1999 ◽

Vol 1 (2) ◽

pp. 177-186 ◽

Cited By ~ 10

Author(s):

Achim Meissner ◽

Jiang-Yong Min ◽

Nils Haake ◽

Stephan Hirt ◽

Rüdiger Simon

Keyword(s):

Human Myocardium ◽

Force Frequency ◽

Dantrolene Sodium ◽

Frequency Relationship

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SERCA2a activity correlates with the force-frequency relationship in human myocardium

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.278.6.h1924 ◽

2000 ◽

Vol 278 (6) ◽

pp. H1924-H1932 ◽

Cited By ~ 12

Author(s):

Götz Münch ◽

Birgit Bölck ◽

Klara Brixius ◽

Hannes Reuter ◽

Uwe Mehlhorn ◽

...

Keyword(s):

Left Ventricle ◽

Protein Expression ◽

Right Atrium ◽

Turnover Rate ◽

Human Myocardium ◽

Force Frequency ◽

Unknown Mechanism ◽

Plasmic Reticulum ◽

Frequency Relationship ◽

And Function

The present investigation addresses whether protein expression and function of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) and phospholamban (PLB) correlate in failing and nonfailing human myocardium. SERCA2a activity and protein expression, PLB phosphorylation, and the force-frequency relationship (FFR) have been determined in right atrium (RA) and left ventricle (LV) from nonfailing (NF, n = 12) and terminally failing [dilated cardiomyopathy (DCM), n = 12] human hearts. Only in LV of DCM hearts was SERCA2a activity significantly decreased [maximal turnover rate ( V max) = 196 ± 11 and 396 ± 30 nmol ⋅ mg− 1 ⋅ min− 1in LV and RA, respectively], whereas protein expression of SERCA2a in the different chambers was unchanged in NF (3.9 ± 0.3 and 3.2 ± 0.4 densitometric units in LV and RA, respectively) and DCM hearts (4.8 ± 0.8 and 3.4 ± 0.1 densitometric units in LV and RA, respectively). Phosphorylation of PLB was higher in LV than in RA in NF (Ser16: 180.5 ± 19.0 vs. 56.8 ± 6.0 densitometric units; Thr17: 174.6 ± 11.2 vs. 37.4 ± 8.9 densitometric units) and DCM hearts (Ser16: 132.0 ± 5.4 vs. 22.4 ± 3.5 densitometric units; Thr17: 131.2 ± 10.9 vs. 9.2 ± 2.4 densitometric units). SERCA2a function, but not protein expression, correlated well with the functional parameters of the FFR in DCM and NF human hearts. Regulation of SERCA2a function depends on the phosphorylation of PLB at Ser16 and Thr17. However, direct SERCA2a regulation might also be affected by an unknown mechanism.

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Impact of heart rate on cross-bridge cycling kinetics in failing and nonfailing human myocardium

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00163.2019 ◽

2019 ◽

Vol 317 (3) ◽

pp. H640-H647

Author(s):

Jae-Hoon Chung ◽

Nima Milani-Nejad ◽

Jonathan P. Davis ◽

Noah Weisleder ◽

Bryan A. Whitson ◽

...

Keyword(s):

Heart Failure ◽

Heart Rate ◽

Human Myocardium ◽

Force Frequency ◽

Human Heart Failure ◽

Relaxation Kinetics ◽

Heart Rates ◽

Cross Bridge ◽

Maximal Activation

The force-frequency relationship (FFR) is an important regulatory mechanism that increases the force-generating capacity as well as the contraction and relaxation kinetics in human cardiac muscle as the heart rate increases. In human heart failure, the normally positive FFR often becomes flat, or even negative. The rate of cross-bridge cycling, which has been reported to affect cardiac output, could be potentially dysregulated and contribute to blunted or negative FFR in heart failure. We recently developed and herein use a novel method for measuring the rate of tension redevelopment. This method allows us to obtain an index of the rate of cross-bridge cycling in intact contracting cardiac trabeculae at physiological temperature and assess physiological properties of cardiac muscles while preserving posttranslational modifications representative of those that occur in vivo. We observed that trabeculae from failing human hearts indeed exhibit an impaired FFR and a reduced speed of relaxation kinetics. However, stimulation frequencies in the lower spectrum did not majorly affect cross-bridge cycling kinetics in nonfailing and failing trabeculae when assessed at maximal activation. Trabeculae from failing human hearts had slightly slower cross-bridge kinetics at 3 Hz as well as reduced capacity to generate force upon K+ contracture at this frequency. We conclude that cross-bridge kinetics at maximal activation in the prevailing in vivo heart rates are not majorly impacted by frequency and are not majorly impacted by disease. NEW & NOTEWORTHY In this study, we confirm that cardiac relaxation kinetics are impaired in filing human myocardium and that cross-bridge cycling rate at resting heart rates does not contribute to this impaired relaxation. At high heart rates, failing myocardium cross-bridge rates are slower than in nonfailing myocardium.

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