Force and Calcium Transients Analysis in Human Engineered Heart Tissues Reveals Positive Force-Frequency Relation at Physiological Frequency

One hypothesis to explain increased contraction strength with increased stimulation rate in heart muscle requires that stimulation increase intracellular Na+ activity(aiNa). This is proposed to increase intracellular Ca2+ activity (aiCa) via the Na-Ca exchange mechanism. Several indirect studies have supported the idea that aiNa is increased with stimulation, and more recently we have directly demonstrated aiNa elevation with Na+-sensitive microelectrodes. We now report aiCa to be elevated after trains of stimuli at different rates in sheep cardiac Purkinje strands. The resting level of aiCa in six strands was 93 +/- 15 (SE) nM, and it increased to 162 +/- 20 nM after stimulation at 3 Hz. The recovery of aiCa was exponential, and the time constants of 80-120 s were similar to those previously found for aiNa. A positive force-frequency relation was found in sheep Purkinje fibers that correlated with the increased aiCa. The results support the hypothesis that the Na-Ca exchange system plays an important role in the force-frequency phenomenon.

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Levosimendan restores the positive force-frequency relation in heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01116.2010 ◽

2011 ◽

Vol 301 (2) ◽

pp. H488-H496 ◽

Cited By ~ 6

Author(s):

Satoshi Masutani ◽

Heng-Jie Cheng ◽

Hideo Tachibana ◽

William C. Little ◽

Che-Ping Cheng

Keyword(s):

Heart Failure ◽

Contractile Function ◽

Mechanical Efficiency ◽

Left Ventricular ◽

Force Frequency ◽

Stroke Work ◽

Arterial Elastance ◽

Major Mechanism ◽

Frequency Relation ◽

Positive Force

Frequency potentiation of contractile function is a major mechanism of the increase in myocardial performance during exercise. In heart failure (HF), this positive force-frequency relation is impaired, and the abnormal left ventricular (LV)-arterial coupling is exacerbated by tachycardia. A myofilament Ca2+ sensitizer, levosimendan, has been shown to improve exercise tolerance in HF. This may be due to its beneficial actions on the force-frequency relation and LV-arterial coupling (end-systolic elastance/arterial elastance, EES/ EA). We assessed the effects of therapeutic doses of levosimendan on the force-frequency relation and EES/ EA in nine conscious dogs after pacing-induced HF using pressure-volume analysis. Before HF, pacing tachycardia increased EES, shortened τ, and did not impair EES/ EA and mechanical efficiency (stroke work/pressure-volume area, SW/PVA). In contrast, after HF, pacing at 140, 160, 180, and 200 beat/min (bpm) produced smaller a increase of EES or less shortening of τ, whereas EES/ EA (from 0.56 at baseline to 0.42 at 200 bpm) and SW/PVA (from 0.52 at baseline to 0.43 at 200 bpm) progressively decreased. With levosimendan, basal EES increased 27% (6.2 mmHg/ml), τ decreased 11% (40.8 ms), EES/ EA increased 34% (0.75), and SW/PVA improved by 15% (0.60). During tachycardia, EES further increased by 23%, 37%, 68%, and 89%; τ decreased by 9%, 12%, 15%, and 17%; and EES/ EA was augmented by 11%, 16%, 31%, and 33%, incrementally, with pacing rate. SW/PVA was improved (0.61 to 0.64). In conclusion, in HF, treatment with levosimendan restores the normal positive LV systolic and diastolic force-frequency relation and prevents tachycardia-induced adverse effect on LV-arterial coupling and mechanical efficiency.

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Force-frequency relation and myofilament Ca2+ sensitivity

10.36866/pn.71.39 ◽

2008 ◽

pp. 39-41

Author(s):

Regis Lamberts ◽

Jolanda van der Velden ◽

Ger Stienen

Keyword(s):

Force Frequency ◽

Frequency Relation

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Adrenergic Control of the Force-Frequency Relation

Circulation ◽

10.1161/01.cir.92.8.2327 ◽

1995 ◽

Vol 92 (8) ◽

pp. 2327-2332 ◽

Cited By ~ 92

Author(s):

John Ross ◽

Toshiro Miura ◽

Masashi Kambayashi ◽

Gregory P. Eising ◽

Kyu-Hyung Ryu

Keyword(s):

Force Frequency ◽

Adrenergic Control ◽

Frequency Relation

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Heart rate as a determinant of L-type Ca2+ channel activity: Mechanisms and implication in force-frequency relation

Basic Research in Cardiology ◽

10.1007/pl00007389 ◽

1998 ◽

Vol 93 (S1) ◽

pp. s051-s059 ◽

Cited By ~ 10

Author(s):

S. Lemaire ◽

C. Piot ◽

F. Leclercq ◽

V. Leuranguer ◽

J. Nargeot ◽

...

Keyword(s):

Heart Rate ◽

Force Frequency ◽

Channel Activity ◽

Frequency Relation

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Abstract 15596: Maturation of Hipsc-cm Electrophysiological and Contractile Function for Enhanced Sensitivity of Cardiac Safety Assays

Circulation ◽

10.1161/circ.142.suppl_3.15596 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Heather B Hayes ◽

Anthony M Nicolini ◽

Colin Arrowood ◽

Daniel Millard

Keyword(s):

Contractile Function ◽

Induced Pluripotent Stem Cell ◽

Force Frequency ◽

Cardiac Safety ◽

Electrophysiological Response ◽

Mechanical Conditioning ◽

Enhanced Sensitivity ◽

Frequency Relationship ◽

Positive Force

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have significantly advanced in vitro cardiac safety and disese modeling, yet remain an immature representation of human myocytes. Electrical or mechanical conditioning of hiPSC-CMs facilitates functional maturation, as measured by a positive force-frequency relationship, but current in vitro protocols require 2-4 weeks of conditioning. Using array-based contractility and local electrical stimulation, we detected functionally mature phenotypes and compound responses in hiPSC-CMs after only 48 hours of chronic pacing. To mature cardiomyocytes, hiPSC-CMs were cultured on 24- and 96-well MEA plates with a dedicated stimulation electrodes. Later, hiPSC-CMs were electrically or optically paced at 2Hz for 48 hours. Multimodal measures quantified contractile and electrophysiological responses to varied pacing rates and compound addition. After 48 hours of pacing, hiPSC-CMs displayed shortened repolarization timing compared to before chronic pacing (baseline: 423 +/- 21 ms; matured: 316 +/- 15 ms), without significant beat period changes (baseline: 1255 +/- 40 ms; matured: 1314 +/- 84 ms). Contractile beat amplitude was measured using array-based impedance during spontaneous beating and at increasing pacing rates (1, 1.2, 1.5, 2, and 2.5 Hz). Before chronic pacing, beat amplitude decreased with increasing pacing rate; after chronic pacing, the same wells displayed increased beat amplitudes with increasing pacing rate. The matured wells also showed enhanced sensitivity to positive inotropes, such as isoproterenol, digoxin, omecamtiv mecarbil, and dobutamine. Local extracellular action potentials (LEAP) further revealed altered electrophysiological response to ranolazine, a multichannel blocker. Unpaced control wells exhibited dose-dependent APD90 prolongation in response to ranolazine, whereas matured wells showed no APD90 change. Similar results were seen with 48 hour of optogenetic pacing at 2 Hz. Overall, hiPSC-CMs chronically paced for only 48 hours exhibited more mature functional phenotypes, including a positive force-frequnecy relationship, enhanced ionotrope sensitivity, and altered compound response.

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Dynamic control of maximal ventricular elastance via the baroreflex and force-frequency relation in awake dogs before and after pacing-induced heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00922.2009 ◽

2010 ◽

Vol 299 (1) ◽

pp. H62-H69 ◽

Cited By ~ 5

Author(s):

Xiaoxiao Chen ◽

Javier A. Sala-Mercado ◽

Robert L. Hammond ◽

Masashi Ichinose ◽

Soroor Soltani ◽

...

Keyword(s):

Heart Failure ◽

Transfer Function ◽

Transfer Functions ◽

Dynamic Properties ◽

System Response ◽

Force Frequency ◽

Arterial Baroreflex ◽

Ventricular Elastance ◽

Arterial Blood ◽

Frequency Relation

We investigated to what extent maximal ventricular elastance ( Emax) is dynamically controlled by the arterial baroreflex and force-frequency relation in conscious dogs and to what extent these mechanisms are attenuated after the induction of heart failure (HF). We mathematically analyzed spontaneous beat-to-beat hemodynamic variability. First, we estimated Emax for each beat during a baseline period using the ventricular unstressed volume determined with the traditional multiple beat method during vena cava occlusion. We then jointly identified the transfer functions (system gain value and time delay per frequency) relating beat-to-beat fluctuations in arterial blood pressure (ABP) to Emax (ABP→ Emax) and beat-to-beat fluctuations in heart rate (HR) to Emax (HR→ Emax) to characterize the dynamic properties of the arterial baroreflex and force-frequency relation, respectively. During the control condition, the ABP→ Emax transfer function revealed that ABP perturbations caused opposite direction Emax changes with a gain value of −0.023 ± 0.012 ml−1, whereas the HR→ Emax transfer function indicated that HR alterations caused same direction Emax changes with a gain value of 0.013 ± 0.005 mmHg·ml−1·(beats/min)−1. Both transfer functions behaved as low-pass filters. However, the ABP→ Emax transfer function was more sluggish than the HR→ Emax transfer function with overall time constants (indicator of full system response time to a sudden input change) of 11.2 ± 2.8 and 1.7 ± 0.5 s ( P < 0.05), respectively. During the HF condition, the ABP→ Emax and HR→ Emax transfer functions were markedly depressed with gain values reduced to −0.0002 ± 0.007 ml−1 and −0.001 ± 0.004 mmHg·ml−1·(beats/min)−1 ( P < 0.1). Emax is rapidly and significantly controlled at rest, but this modulation is virtually abolished in HF.

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