Feed Forward Modeling: an efficient approach for mathematical modeling of the force frequency relationship in the rabbit isolated ventricular myocyte.

Background and Objective. This study addresses the Force-Frequency relationship, a fundamental characteristic of cardiac muscle influenced byß1-adrenergic stimulation. This relationship reveals that heart rate (HR) changes at the sinoatrial node lead to alterations in ventricular cell contractility, increasing the force and decreasing relaxation time for higher beat rates. Traditional models lacking this relationship offer an incomplete physiological depiction, impacting the interpretation of in silico experiment results. To improve this, we propose a new mathematical model for ventricular myocytes, named 'Feed Forward Modeling' (FFM).Methods. FFM adjusts model parameters like channel conductance and Ca2+pump affinity according to stimulation frequency, in contrast to fixed parameter values. An empirical sigmoid curve guided the adaptation of each parameter, integrated into a rabbit ventricular cell electromechanical model. Model validation was achieved by comparing simulated data with experimental current-voltage (I-V) curves for L-type Calcium and slow Potassium currents.Results. FFM-enhanced simulations align more closely with physiological behaviors, accurately reflecting inotropic and lusitropic responses. For instance, action potential duration at 90% repolarization (APD90) decreased from 206 ms at 1 Hz to 173 ms at 4 Hz using FFM, contrary to the conventional model, where APD90 increased, limiting high-frequency heartbeats. Peak force also showed an increase with FFM, from 8.5 mN mm-2at 1 Hz to 11.9 mN mm-2at 4 Hz, while it barely changed without FFM. Relaxation time at 50% of maximum force (t50) similarly improved, dropping from 114 ms at 1 Hz to 75.9 ms at 4 Hz with FFM, a change not observed without the model.Conclusion. The FFM approach offers computational efficiency, bypassing the need to model all beta-adrenergic pathways, thus facilitating large-scale simulations. The study recommends that frequency change experiments include fractional dosing of isoproterenol to better replicate heart conditionsin vivo.

The Force-Frequency Characteristics of Quartz Wafers under a Cantilever Beam Structure.

This study investigated the force-frequency characteristics of quartz wafers inside a cantilever beam frame. Firstly, the force-frequency coefficient formula of quartz wafers with fixed ends under axial force was analyzed. Firstly, the formula for the force-frequency coefficient of quartz wafers with fixed ends under axial force was analyzed. A force-frequency coefficient formula suitable for cantilever beam structures was derived by considering the changes in surface stress and stiffness of quartz wafers with fixed ends and one end under force on the other. Subsequently, the formula's accuracy was verified by experiments, and the accuracy was more than 92%. In addition, strain simulation analysis was performed on three different shapes of quartz wafers, and experimental verification was carried out on two of them. The results revealed that trapezoidal quartz wafers and cantilever beam structures exhibited superior stress distribution to rectangular chips. Furthermore, by positioning electrodes at various locations on the surface of the quartz chip, it was observed that, as the electrodes moved closer to the fixed end, the force-frequency coefficient of the rectangular quartz chip increased, along with an increase in chip strain under the cantilever structure. In summary, this study provides a new approach for designing cantilever quartz resonator sensors in the future.

Influence of stimulation frequency on early and late phase rate of torque and velocity development.

The early (≤50 ms) rate of torque development (RTD) is dependent upon the speed of neuromuscular activation; however, few studies have evaluated the determinants of rate of velocity development (RVD), which may be load-dependent. The purpose here was to explore the relationship between stimulation frequency with the early and late (≥100 ms) phase isometric RTD and isotonic RVD. The knee extensors of 16 (five female) young recreationally active participants were stimulated using 14 frequencies from 1 to 100 Hz during isometric and isotonic ("unloaded" and 7.5% of the isometric maximal voluntary contraction [MVC]) contractions. Isometric RTD and isotonic RVD were evaluated for the early (0-50 ms) and late (0-100 ms) phases from torque and velocity onset, respectively. Sigmoid functions were fit and bilinear regressions were used to examine the slopes of the steep portion of the curve and the plateau frequency. RTD- and RVD-frequency relationships were well described by a sigmoid function (all r2 > 0.96). Compared with the late phase, early isometric RTD, and unloaded RVD displayed lower slopes (all P ≤ 0.001) and higher plateau frequencies (all P < 0.001). In contrast, early and late RVD of a moderately loaded isotonic contraction did not display different slopes (P = 0.055) or plateau frequencies (P = 0.690). Early isometric RTD and unloaded isotonic RVD are more dependent on changes in stimulation frequency compared with late phases. However, RVD for a moderately loaded isotonic contraction displayed similar responses for the early and late phases. Therefore, a high frequency of activation is critical for early torque and velocity generation but dependent upon the load for isotonic contractions.NEW & NOTEWORTHY We show that during an "unloaded" isotonic contraction, the early phase rate of velocity development is more dependent upon a high electrical activation frequency compared with the late phase, similar to isometric torque. However, early and late phase rates of velocity development of moderately loaded isotonic contractions display similar responses. These results indicate that the determinants of isotonic shortening function are dependent on the externally applied load, highlighting the importance of task-specificity of contraction.

Differential effects of stimulation frequency on isometric and concentric isotonic contractile function in human quadriceps.

Electrically evoked contractions are used to assess the relationship between frequency input and contractile output to characterize inherent muscle function, and these have been done mostly with isometric contractions (i.e., no joint rotation). The purpose was to compare the electrically stimulated frequency and contractile function relationship during isometric (i.e., torque) with isotonic (i.e., concentric torque, angular velocity, and mechanical power) contractions. The knee extensors of 16 (5 female) young recreationally active participants were stimulated (∼1-2.5 s) at 14 frequencies from 1 to 100 Hz. This was done during four conditions, which were isometric and isotonic at loads of 0 (unloaded), 7.5%, and 15% isometric maximal voluntary contraction (MVC), and repeated on separate days. Comparisons across contractile parameters were made as a % of 100 Hz. Independent of the load, the mechanical power-frequency relationship was rightward shifted compared with isometric torque-frequency, concentric torque-frequency, and velocity-frequency relationships (all P ≤ 0.04). With increasing load (0%-15% MVC), the isotonic concentric torque-frequency relationship was shifted leftward systematically from 15 to 30 Hz (all P ≤ 0.04). Conversely, the same changes in load caused a rightward shift in the velocity-frequency relationship from 1 to 40 Hz (all P ≤ 0.03). Velocity was leftward shifted of concentric torque in the unloaded isotonic condition from 10 to 25 Hz (all P ≤ 0.03), but concentric torque was leftward shifted of velocity at 15% MVC isotonic condition from 10 to 50 Hz (all P ≤ 0.03). Therefore, isometric torque is not a surrogate to evaluate dynamic contractile function. Interpretations of evoked contractile function differ depending on contraction type, load, and frequency, which should be considered relative to the specific task.NEW & NOTEWORTHY In whole human muscle, we showed that the electrically stimulated power-frequency relationship was rightward shifted of the stimulated isometric torque-frequency relationship independent of isotonic load, indicating that higher stimulation frequencies are needed to achieve tetanus. Therefore, interpretations of evoked contractile function differ depending on contraction type (isometric vs. dynamic), load, and frequency. And thus, isometric measures may not be appropriate as a surrogate assessment when evaluating dynamic isotonic contractile function.

The effects of nickel chloride on papillary muscle contractility under normothermic and hypothermic conditions: Comparison of active and hibernating ground squirrels (Urocitellus undulatus) with Wistar rats.

Extracellular Ca2+ plays a pivotal role in the regulation of cardiac contractility under normal and extreme conditions. Here, by using nickel chloride (NiCl2), a non-specific blocker of extracellular Ca2+ influx, we studied the input of extracellular Ca2+ on the regulation of papillary muscle (PM) contractility under normal and hypothermic conditions in ground squirrels (GS), and rats. By measuring isometric force of contraction, we studied how NiCl2 affects force-frequency relationship and the rest effect in PM of these species at 30 °C and 10 °C. We found that at 30 °C 1.5 mM NiCl2 significantly reduced force of contraction across entire frequency range in active GS and rats, whereas in hibernating GS force of contraction was reduced at low and high frequency range. Additionally, NiCl2 evoked spontaneous contractility in rats but not GS PM. The rest effect was significantly reduced by NiCl2 for active GS and rats but not hibernating GS. At 10 °C, NiCl2 fully reduced contractility in active GS and, to a lesser extent, in rats, whereas in hibernating GS it was significant only at 0.3 Hz. The rest effect was significantly reduced by NiCl2 in both active and hibernating GS, whereas it was unmasked in rats that had high contractility under hypothermic conditions in control. Our results show a significant contribution of extracellular Ca2+ to myocardial contractility in GS not only in active but also in hibernating states, especially under hypothermic conditions, whereas limitation of extracellular Ca2+ influx in rats under hypothermia can play protective role for myocardial contractility.

The effect of low-frequency fatigue on the torque-velocity relationship in human quadriceps.

Low-frequency fatigue (LFF) is usually defined as the decline in low:high-frequency force of electrically evoked isometric muscle contractions. The influence of LFF on dynamic muscle function is not well studied. Our aim was to assess the effect of LFF on the electrically evoked torque-velocity relationship in humans. Sixteen participants underwent a series of electrically evoked knee extensions in an isokinetic dynamometer to establish torque-velocity relationships at 15 and 50 Hz using isokinetic contractions. Hereafter, fatigue was induced by five sets of 10 repetitions of maximal voluntary dynamic knee extensions. After 30 min of rest, torque-velocity tests were repeated. Maximal torque (Fmax) was measured, whereas maximal contraction velocity (Vmax) and maximal power (Pmax) were estimated using Hill's force-velocity equation, 15:50 Hz ratios were calculated for Fmax, Vmax, and Pmax as markers of LFF. Fmax decreased by 40% at 15 Hz (P = 0.001) and by 15% at 50 Hz (P = 0.001) in the fatigued state. No significant change was detected for Vmax at 15 Hz [-2%, (P = 0.349)] or 50 Hz [+3% (P = 0.763)], whereas 15 and 50 Hz Pmax decreased by 30% (P = 0.004) and 10% (P = 0.008), respectively. Following the fatigue protocol, the 15:50 Hz Fmax ratio decreased by 31% (P < 0.001), indicating LFF. The 15:50 Hz Pmax ratio also decreased by 23% (P = 0.002), whereas the 15:50 Hz Vmax ratio was unchanged (P = 0.313). In conclusion, fatiguing contractions decreased Fmax and Pmax at both high and low stimulation frequencies, whereas Vmax appeared unaffected. Nevertheless, LFF influences power production during human dynamic contractions at a range of submaximal velocities.NEW & NOTEWORTHY Force-velocity relationships were established using either low- or high-frequency electrical stimulation before and after fatiguing voluntary eccentric/concentric contractions of the knee extensors. Low-frequency fatigue was assessed by the relative decrease in low- and high-frequency maximal torque, maximal shortening velocity, and maximal power estimated by the force-velocity relationship. Low-frequency fatigue manifests itself as a large decrease in low-frequency maximal force and power with a modest decrease in high-frequency maximal force and power. Contraction velocity does not seem to decrease in the same manner.

Single-Cell Analysis of Contractile Forces in iPSC-Derived Cardiomyocytes: Paving the Way for Precision Medicine in Cardiovascular Disease.

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold enormous potential in cardiac disease modeling, drug screening, and regenerative medicine. Furthermore, patient-specific iPSC-CMS can be tested for personalized medicine. To provide a deeper understanding of the contractile force dynamics of iPSC-CMs, we employed Atomic Force Microscopy (AFM) as an advanced detection tool to distinguish the characteristics of force dynamics at a single cell level. We measured normal (vertical) and lateral (axial) force at different pacing frequencies. We found a significant correlation between normal and lateral force. We also observed a significant force-frequency relationship for both types of forces. This work represents the first demonstration of the correlation of normal and lateral force from individual iPSC-CMs. The identification of this correlation is relevant because it validates the comparison across systems and models that can only account for either normal or lateral force. These findings enhance our understanding of iPSC-CM properties, thereby paving the way for the development of therapeutic strategies in cardiovascular medicine.

Study of Force-Frequency Characteristics in AT-Cut Strip Quartz Crystal Resonators with Different Rotation Angles.

This paper investigated the force-frequency characteristics of AT-cut strip quartz crystal resonator (QCR) employing finite element analysis methods and experiments. We used the finite element analysis software COMSOL Multiphysics to calculate the stress distribution and particle displacement of the QCR. Moreover, we analyzed the impact of these opposing forces on the frequency shift and strains of the QCR. Meanwhile, the resonant frequency shifts, conductance, and quality factor (Q value) of three AT-cut strip QCRs with rotation angles of 30°, 40°, and 50° under different force-applying positions were tested experimentally. The results showed that the frequency shifts of the QCRs were proportional to the magnitude of the force. The highest force sensitivity was QCR with a rotation angle of 30°, followed by 40°, and 50° was the lowest. And the distance of the force-applying position from the X-axis also affected the frequency shift, conductance, and Q value of the QCR. The results of this paper are instructive for understanding the force-frequency characteristics of strip QCRs with different rotation angles.

Understanding altered contractile properties in advanced age: insights from a systematic muscle modelling approach.

Age-related alterations of skeletal muscle are numerous and present inconsistently, and the effect of their interaction on contractile performance can be nonintuitive. Hill-type muscle models predict muscle force according to well-characterised contractile phenomena. Coupled with simple, yet reasonably realistic activation dynamics, such models consist of parameters that are meaningfully linked to fundamental aspects of muscle excitation and contraction. We aimed to illustrate the utility of a muscle model for elucidating relevant mechanisms and predicting changes in output by simulating the individual and combined effects on isometric force of several known ageing-related adaptations. Simulating literature-informed reductions in free Ca2+ concentration and Ca2+ sensitivity generated predictions at odds qualitatively with the characteristic slowing of contraction speed. Conversely, incorporating slower Ca2+ removal or a fractional increase in type I fibre area emulated expected changes; the former was required to simulate slowing of the twitch measured experimentally. Slower Ca2+ removal more than compensated for force loss arising from a large reduction in Ca2+ sensitivity or moderate reduction in Ca2+ release, producing realistic age-related shifts in the force-frequency relationship. Consistent with empirical data, reductions in free Ca2+ concentration and Ca2+ sensitivity reduced maximum tetanic force only slightly, even when acting in concert, suggesting a modest contribution to lower specific force. Lower tendon stiffness and slower intrinsic shortening speed slowed and prolonged force development in a compliance-dependent manner without affecting force decay. This work demonstrates the advantages of muscle modelling for exploring sources of variation and identifying mechanisms underpinning the altered contractile properties of aged muscle.

The Role of Ca2+ Sparks in Force Frequency Relationships in Guinea Pig Ventricular Myocytes.

Calcium sparks are the elementary Ca2+ release events in excitation-contraction coupling that underlie the Ca2+ transient. The frequency-dependent contractile force generated by cardiac myocytes depends upon the characteristics of the Ca2+ transients. A stochastic computational local control model of a guinea pig ventricular cardiomyocyte was developed, to gain insight into mechanisms of force-frequency relationship (FFR). This required the creation of a new three-state RyR2 model that reproduced the adaptive behavior of RyR2, in which the RyR2 channels transition into a different state when exposed to prolonged elevated subspace [Ca2+]. The model simulations agree with previous experimental and modeling studies on interval-force relations. Unlike previous common pool models, this local control model displayed stable action potential trains at 7 Hz. The duration and the amplitude of the [Ca2+]myo transients increase in pacing rates consistent with the experiments. The [Ca2+]myo transient reaches its peak value at 4 Hz and decreases afterward, consistent with experimental force-frequency curves. The model predicts, in agreement with previous modeling studies of Jafri and co-workers, diastolic sarcoplasmic reticulum, [Ca2+]sr, and RyR2 adaptation increase with the increased stimulation frequency, producing rising, rather than falling, amplitude of the myoplasmic [Ca2+] transients. However, the local control model also suggests that the reduction of the L-type Ca2+ current, with an increase in pacing frequency due to Ca2+-dependent inactivation, also plays a role in the negative slope of the FFR. In the simulations, the peak Ca2+ transient in the FFR correlated with the highest numbers of SR Ca2+ sparks: the larger average amplitudes of those sparks, and the longer duration of the Ca2+ sparks.

Physiological calcium combined with electrical pacing accelerates maturation of human engineered heart tissue.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have wide potential application in basic research, drug discovery, and regenerative medicine, but functional maturation remains challenging. Here, we present a method whereby maturation of hiPSC-CMs can be accelerated by simultaneous application of physiological Ca2+ and frequency-ramped electrical pacing in culture. This combination produces positive force-frequency behavior, physiological twitch kinetics, robust ß-adrenergic response, improved Ca2+ handling, and cardiac troponin I expression within 25 days. This study provides insights into the role of Ca2+ in hiPSC-CM maturation and offers a scalable platform for translational and clinical research.

Inhibitory and stimulatory micropeptides preferentially bind to different conformations of the cardiac calcium pump.

The ATP-dependent ion pump sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) sequesters Ca2+ in the endoplasmic reticulum to establish a reservoir for cell signaling. Because of its central importance in physiology, the activity of this transporter is tightly controlled via direct interactions with tissue-specific regulatory micropeptides that tune SERCA function to match changing physiological conditions. In the heart, the micropeptide phospholamban (PLB) inhibits SERCA, while dwarf open reading frame (DWORF) stimulates SERCA. These competing interactions determine cardiac performance by modulating the amplitude of Ca2+ signals that drive the contraction/relaxation cycle. We hypothesized that the functions of these peptides may relate to their reciprocal preferences for SERCA binding; SERCA binds PLB more avidly at low cytoplasmic [Ca2+] but binds DWORF better when [Ca2+] is high. In the present study, we demonstrated this opposing Ca2+ sensitivity is due to preferential binding of DWORF and PLB to different intermediate states that SERCA samples during the Ca2+ transport cycle. We show PLB binds best to the SERCA E1-ATP state, which prevails at low [Ca2+]. In contrast, DWORF binds most avidly to E1P and E2P states that are more populated when Ca2+ is elevated. Moreover, FRET microscopy revealed dynamic shifts in SERCA-micropeptide binding equilibria during cellular Ca2+ elevations. A computational model showed that DWORF exaggerates changes in PLB-SERCA binding during the cardiac cycle. These results suggest a mechanistic basis for inhibitory versus stimulatory micropeptide function, as well as a new role for DWORF as a modulator of dynamic oscillations of PLB-SERCA regulatory interactions.

Influence of heart rate on right ventricular function assessed by right heart catheterization and echocardiography in healthy anesthetized dogs.

BACKGROUND: Right ventricular (RV) functional assessment has received considerable attention in veterinary medicine since various diseases, such as cardiovascular, respiratory, endocrine, and neoplastic disease, may affect RV function. Heart rate (HR) is an important factor that can influence RV function through changes in loading condition and contractility. However, no study has yet evaluated the association between HR and RV function in the same individuals. This study aimed to evaluate the influence of elevated HR on RV function using right heart catheterization and echocardiography, and investigate the association between right heart catheterization and echocardiographic indices. RESULTS: Right atrial pacing was performed in eight dogs at 120, 140, 160, and 180 bpm. With an increase in HR, the RV systolic volume, RV diastolic volume, and stroke volume significantly decreased; however, the cardiac output, end-systolic elastance (Ees), and effective arterial elastance (Ea) significantly increased. Significant changes were not observed in RV pressure and Ees/Ea. The RV area normalized by body weight, RV fractional area change normalized by body weight (RV FACn), and tricuspid annular plane systolic excursion normalized by body weight (TAPSEn) significantly decreased with increased HR. Peak systolic myocardial velocity of the lateral tricuspid annulus (RV s'), RV strain, and RV strain rate of only the RV free wall analysis (RV-SrL3seg) showed no significant changes with the increase in HR; however, there was an increase in the RV strain rate of the RV global analysis (RV-SrL6seg). Multiple regression analysis revealed that HR, RV FACn, and RV- SrL6seg had significant associations with the Ees, and the TAPSEn and RV-SrL3seg with Ees/Ea. CONCLUSIONS: Decreased venous return and shortened relaxation time decreased the RV FAC, TAPSE, RV s', and RV strain, and might underestimate the RV function. Ees increased with the increase in HR, reflecting the myocardial force-frequency relation; as a result, RV-SrL6seg could be a useful tool for Ees estimation. Additionally, the RV-SrL3seg could detect RV performance, reflecting the balance between RV contractility and RV afterload.

The air-breathing Alaska blackfish (Dallia pectoralis) remodels ventricular Ca2+ cycling with chronic hypoxic submergence to maintain ventricular contractility.

The Alaska blackfish (Dallia pectoralis) is a facultative air-breather endemic to northern latitudes where it remains active in winter under ice cover in cold hypoxic waters. To understand the changes in cellular Ca2+ cycling that allow the heart to function in cold hypoxic water, we acclimated Alaska blackfish to cold (5 °C) normoxia or cold hypoxia (2.1-4.2 kPa; no air access) for 5-8 weeks. We then assessed the impact of the acclimation conditions on intracellular Ca2+ transients (Δ[Ca2+]i) of isolated ventricular myocytes and contractile performance of isometrically-contracting ventricular strips. Measurements were obtained at various contractile frequencies (0.2-0.6 Hz) in normoxia, during acute exposure to hypoxia, and reoxygenation at 5 °C. The results show that hypoxia-acclimated Alaska blackfish compensate against the depressive effects of hypoxia on excitation-contraction coupling by remodelling cellular Δ[Ca2+]i to maintain ventricular contractility. When measured at 0.2 Hz in normoxia, hypoxia-acclimated ventricular myocytes had a 3.8-fold larger Δ[Ca2+]i peak amplitude with a 4.1-fold faster rate of rise, compared to normoxia-acclimated ventricular myocytes. At the tissue level, maximal developed force was 2.1-fold greater in preparations from hypoxia-acclimated animals. However, maximal attainable contraction frequencies in hypoxia were lower in hypoxia-acclimated myocytes and strips than preparations from normoxic animals. Moreover, the inability of hypoxia-acclimated ventricular myocytes and strips to contract at high frequency persisted upon reoxygenation. Overall, the findings indicate that hypoxia alters aspects of Alaska blackfish cardiac myocyte Ca2+ cycling, and that there may be consequences for heart rate elevation during hypoxia, which may impact cardiac output in vivo.

Intracellular taurine deficiency impairs cardiac contractility in rainbow trout (Oncorhynchus mykiss) without affecting aerobic performance.

Taurine is a non-proteinogenic sulfonic acid found in high concentrations inside vertebrate cardiomyocytes and its movement across the sarcolemmal membrane is critical for cell volume regulation. Taurine deficiency is rare in mammals, where it impairs cardiac contractility and leads to congestive heart failure. In fish, cardiac taurine levels vary substantially between species and can decrease by up to 60% in response to environmental change but its contribution to cardiac function is understudied. We addressed this gap in knowledge by generating a taurine-deficient rainbow trout (Oncorhynchus mykiss) model using a feed enriched with 3% ß-alanine to inhibit cellular taurine uptake. Cardiac taurine was reduced by 17% after 4 weeks with no effect on growth or condition factor. Taurine deficiency did not affect routine or maximum rates of O2 consumption, aerobic scope, or critical swimming speed in whole animals but cardiac contractility was significantly impaired. In isometrically contracting ventricular strip preparations, the force-frequency and extracellular Ca2+-sensitivity relationships were both shifted downward and maximum pacing frequency was significantly lower in ß-alanine fed trout. Cardiac taurine deficiency reduces sarcoplasmic reticular Ca2+-ATPase activity in mammals and our results are consistent with such an effect in rainbow trout. Our data indicate that intracellular taurine contributes to the regulation of cardiac contractility in rainbow trout. Aerobic performance was unaffected in ß-alanine-fed animals, but further study is needed to determine if more significant natural reductions in taurine may constrain performance under certain environmental conditions.

Cardiac contractility of the African sharptooth catfish, Clarias gariepinus: role of extracellular Ca2+, sarcoplasmic reticulum, and ß-adrenergic stimulation.

This study investigated the dependence of contraction from extracellular Ca2+, the presence of a functional sarcoplasmic reticulum (SR), and the effects of ß-adrenergic stimulation using isometric cardiac muscle preparations. Moreover, the expression of Ca2+-handling proteins such as SR-Ca2+-ATPase (SERCA), phospholamban (PLN), and Na+/Ca2+ exchanger (NCX) were also evaluated in the ventricular tissue of adult African sharptooth catfish, Clarias gariepinus, a facultative air-breathing fish. In summary, we observed that (1) contractility was strongly regulated by extracellular Ca2+; (2) inhibition of SR Ca2+-release by application of ryanodine reduced steady-state force production; (3) ventricular myocardium exhibited clear post-rest decay, even in the presence of ryanodine, indicating a decrease in SR Ca2+ content and NCX as the main pathway for Ca2+ extrusion; (4) a positive force-frequency relationship was observed above 60 bpm (1.0 Hz); (5) ventricular tissue was responsive to ß-adrenergic stimulation, which caused significant increases in twitch force, kept a linear force-frequency relationship from 12 to 96 bpm (0.2 to Hz), and improved the cardiac pumping capacity (CPC); and (6) African catfish myocardium exhibited similar expression patterns of NCX, SERCA, and PLN, corroborating our findings that both mechanisms for Ca2+ transport across the SR and sarcolemma contribute to Ca2+ activator. In conclusion, this fish species displays great physiological plasticity of E-C coupling, able to improve the ability to maintain cardiac performance under physiological conditions to ecological and/or adverse environmental conditions, such as hypoxic air-breathing activity.

The effect of temperature acclimation on the force-frequency relationship and adrenergic sensitivity of the ventricle of two populations of juvenile sockeye salmon.

We tested the hypothesis that cardiorespiratory differences known to exist among adult sockeye salmon populations also exist in the juveniles. To test this hypothesis, we compared cardiac contractility and adrenergic responsiveness of juvenile sockeye salmon from two geographically isolated populations that were reared from eggs under common garden conditions and at two acclimation temperatures (5 °C and 14 °C). However, we found no substantive differences in the force-frequency response (FFR) and the cardiac pumping capacity of juveniles from Weaver Creek and Chilko River populations, even when we considered wild-reared juveniles from one of the populations. An unexpected discovery for all fish groups at 5 °C was a rather flat FFR during tonic ß-adrenergic stimulation (ßAR) stimulation. Curiously, while active tension nearly doubled with maximum ßAR stimulation at low pacing frequencies for all fish groups, a negative FFR with maximum ßAR stimulation meant that this inotropic benefit was lost at the highest pacing frequency (0.8 Hz). Active tension with tonic ßAR stimulation was similar at 14 °C, but maximum pacing frequency doubled and all fish groups displayed a modest negative FFR. Maximum ßAR stimulation again doubled active tension and this benefit was retained even at the highest pacing frequency (1.6 Hz) at 14 °C. Even though subtle population differences were apparent for the FFR and pumping capacity, their biological significance is unclear. What is clear, however, is that the cardiac pumping capacity of juvenile sockeye would benefit more from ßAR stimulation swimming at 15 °C than when swimming at 5 °C.

The Degree of t-System Remodeling Predicts Negative Force-Frequency Relationship and Prolonged Relaxation Time in Failing Human Myocardium.

The normally positive cardiac force-frequency relationship (FFR) becomes flat or negative in chronic heart failure (HF). Here we explored if remodeling of the cardiomyocyte transverse tubular system (t-system) is associated with alterations in FFR and contractile kinetics in failing human myocardium. Left-ventricular myocardial slices from 13 failing human hearts were mounted into a biomimetic culture setup. Maximum twitch force (F), 90% contraction duration (CD90), time to peak force (TTP) and time to relaxation (TTR) were determined at 37°C and 0.2-2 Hz pacing frequency. F1 Hz/F0.5 Hz and F2 Hz/F0.5 Hz served as measures of FFR, intracellular cardiomyocyte t-tubule distance (ΔTT) as measure of t-system remodeling. Protein levels of SERCA2, NCX1, and PLB were quantified by immunoblotting. F1 Hz/F0.5 Hz (R 2 = 0.82) and F2 Hz/F0.5 Hz (R 2 = 0.5) correlated negatively with ΔTT, i.e., samples with severe t-system loss exhibited a negative FFR and reduced myocardial wall tension at high pacing rates. PLB levels also predicted F1 Hz/F0.5 Hz, but to a lesser degree (R 2 = 0.49), whereas NCX1 was not correlated (R 2 = 0.02). CD90 correlated positively with ΔTT (R 2 = 0.39) and negatively with SERCA2/PLB (R 2 = 0.42), indicating that both the t-system and SERCA activity are important for contraction kinetics. Surprisingly, ΔTT was not associated with TTP (R 2 = 0) but rather with TTR (R 2 = 0.5). This became even more pronounced when interaction with NCX1 expression was added to the model (R 2 = 0.79), suggesting that t-system loss impairs myocardial relaxation especially when NCX1 expression is low. The degree of t-system remodeling predicts FFR inversion and contraction slowing in failing human myocardium. Moreover, together with NCX, the t-system may be important for myocardial relaxation.

Effects of extremely low-frequency electromagnetic field exposure on the skeletal muscle functions in rats.

The aim of the present study was to systematically investigate the effects of chronic exposure to extremely low-frequency electromagnetic field (ELF-EMF) on electrophysiological, histological and biochemical properties of the diaphragm muscle in rats. Twenty-nine newly weaned (24 days old, 23-80 g) female (n = 15) and male (n = 14) Wistar Albino rats were used in this study. The animals were randomly divided into two groups: the control group and the electromagnetic field (EMF) group. The control group was also randomly divided into two groups: the control female group and the control male group. The EMF exposure group was also randomly divided into two groups: the ELF-EMF female group and the ELF-EMF male group. The rats in the ELF-EMF groups were exposed for 4 h daily for up to 7 months to 50 Hz frequency, 1.5 mT magnetic flux density. Under these experimental conditions, electrophysiological parameters (muscle bioelectrical activity parameters: intracellular action potential and resting membrane potential and muscle mechanical activity parameter: force-frequency relationship), biochemical parameters (Na+, K+, Cl- and Ca+2 levels in the blood serum of rats; Na+-K+ ATPase enzyme-specific activities in muscle tissue; and free radical metabolism in both muscle tissue and serum) and transmission electron microscopic morphometric parameters of the diaphragm muscle were determined. We found that chronic exposure to ELF-EMF had no significant effect on the histological structure and mechanical activity of the muscle and on the majority of muscle bioelectrical activity parameters, with the exception of some parameters of muscle bioelectrical activity. However, the changes in some bioelectrical activity parameters were relatively small and unlikely to be clinically relevant.

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

Force measurements in ex vivo and engineered heart tissues are well established. Analysis of calcium transients (CaT) is complementary to force, and the combined analysis is meaningful to the study of cardiomyocyte biology and disease. This article describes a model of human induced pluripotent stem cell cardiomyocyte-derived engineered heart tissues (hiPSC-CM EHTs) transduced with the calcium sensor GCaMP6f followed by sequential analysis of force and CaT. Average peak analysis demonstrated the temporal sequence of the CaT preceding the contraction twitch. The pharmacological relevance of the test system was demonstrated with inotropic indicator compounds. Force-frequency relationship was analyzed in the presence of ivabradine (300 nM), which reduced spontaneous frequency and unmasked a positive correlation of force and CaT at physiological human heart beating frequency with stimulation frequency between 0.75 and 2.5 Hz (force +96%; CaT +102%). This work demonstrates the usefulness of combined force/CaT analysis and demonstrates a positive force-frequency relationship in hiPSC-CM EHTs.