Lower diastolic tension may be indicative of higher proarrhythmic propensity in failing human cardiomyocytes

Chronic heart failure is one of the most common reasons for hospitalization. Current risk stratification is based on ejection fraction, whereas many arrhythmic events occur in patients with relatively preserved ejection fraction. We aim to investigate the mechanistic link between proarrhythmic abnormalities, reduced contractility and diastolic dysfunction in heart failure, using electromechanical modelling and simulations of human failing cardiomyocytes. We constructed, calibrated and validated populations of human electromechanical models of failing cardiomyocytes, that were able to reproduce the prolonged action potential, reduced contractility and diastolic dysfunction as observed in human data, as well as increased propensity to proarrhythmic incidents such as early afterdepolarization and beat-to-beat alternans. Our simulation data reveal that proarrhythmic incidents tend to occur in failing myocytes with lower diastolic tension, rather than with lower contractility, due to the relative preserved SERCA and sodium calcium exchanger current. These results support the inclusion of end-diastolic volume to be potentially beneficial in the risk stratifications of heart failure patients.


Baseline healthy human ventricular cell model of electromechanics
The latest ToR-ORd model of human ventricular electrophysiology 11 was coupled with the Land human contractility model 12 as the baseline model, as in Margara et al. 13 .To enable the reproduction of enhanced calciumactivated potassium current (I KCa ), and junctional sarcoplasmic reticulum calcium leak (J leak_JSR ), new components of I KCa and J leak_JSR were introduced to the baseline model as illustrated in the Supplementary Material SM1.
With the coupling of the Land model, the calcium buffering was weaker than in the ToR-ORd model, leading to faster calcium transient kinetics and lower diastolic calcium level when SERCA was inhibited (Supplementary Material SM2, Supplementary Fig. S1).Based on the features of troponin C in the electromechanical coupling (Supplementary Material SM2, Supplementary Fig. S2), two modifications were made in the electromechanical model: (1) the effect of troponin C high affinity C-domain was included with K D = 3 nM (Supplementary Material SM2, Supplementary Fig. S3); (2) K D value for the binding of calcium and the N-domain of troponin C was decreased from 0.805 to 0.5 µM (Supplementary Material SM2, Supplementary Fig. S4).However, these changes also led to increased peak active tension and slower time to peak for active tension.The MatLab function ga was used to optimise the amplitude and kinetics of active tension (Ta) in both the healthy normal zone (NZ) and under SERCA inhibition (Supplementary Material SM2, Supplementary Fig. S5).This new ToR-ORd-Land model produced similar action potential as the ToR-ORd model and was able to produce early afterdepolarization (EAD), alternans, and predict drug responses in range with experimental data (Supplementary Material SM3, Supplementary Figs.S6-S9).

Construction of the electromechanical models of human failing cardiomyocytes
Following myocardial infarction, ionic current remodelling occurs both in infarct border zone around the scar and in the remote myocardium.In our study, post-infarction border zone (BZ) and remote zone (RZ) were modelled separately for the investigation of electromechanical heterogeneity in the failing hearts.We considered two models of ionic current remodeling in the post-infarction border zone (BZ1-2) and one type of remote zone (RZ1) based on post-infarction minipig failing myocyte data as well as some failing human myocyte measurements [14][15][16] .Another type of RZ remodeling (RZ2) was established based on multiple experimental references of ischemic or dilated human cardiomyopathic failure 14,15,[17][18][19][20][21] .The two types of BZs and RZs have different extents of SERCA inhibition based on the experimental reports that elevated wall stress adjacent to scars can result in down-regulation of SERCA 22 .HF ionic current remodeling (Table 1) leads to the reduction of the fast sodium current conductance (G Na ), the L-type calcium current conductance (G CaL ), the transient outward potassium current conductance (G to ), the rapid/slow delayed rectifier potassium current conductances (G Kr , G Ks ), the inward rectifier potassium current conductance (G K1 ), the sodium/potassium pump permeability (G NaK ) and the SERCA activity (P Jup ), as well as the increase in the late sodium current conductance (G NaL ), the calciumactivated potassium and chloride current conductances (G KCa , G ClCa ), the increase in CaMKII phosphorylation G KCa 2 16 2 16 2 16 3.75 20 G ClCa 1.25 16 1.25 16 1.25 16 1.25 16 aCaMK 1.5 25 1.5 25 1.5 25 1.5 25 Tau_relp 6 26 6 26 6 26 6 26 G JSR_Leak 4 27 4 27 4 27 4 27

Simulation platform, protocol and calculation of biomarkers
Cellular electromechanical simulations, Latin hypercube sampling, two-sided Wilcoxon rank sum tests (alpha = 0.05) and Pearson partial correlation analysis were performed using MATLAB codes.All the electromechanical myocyte models were paced at 1 Hz, 2 Hz, 2.5 Hz and 3 Hz for 300 beats to detect EAD and alternans generation.Action potential and calcium transient durations at 90% or 50% recovery were computed as APD 90 , APD 50 , CaTD 90 and CaTD 50 , which reflect the length from excitation-contraction to recovery-relaxation for action potential and calcium transients.In addition, the peaks of action potential, calcium transient and active tension were computed as V max , CaT max and Ta max , while their diastolic values were calculated as the resting membrane potential (RMP), CaT min and Ta min .Calcium and active tension amplitudes were defined as the difference between their peak and diastolic values.Time to peak (TTP), and peak time to 50%, 90% and 95% of decay (RT50, RT90 and RT95) were also calculated for active tension as measurements of relaxation speed.A ΔAPD 90 greater than 3 ms between the last two beats at steady state was defined as alternans.

Validation of the HF electromechanical myocyte models
As illustrated in Fig. 1A, the HF ionic remodeling induced longer action potential duration (APD), weaker calcium transient and reduced peak active tension than healthy myocytes.The activation and decay were slower in the HF calcium transient and active tension.Diastolic calcium and active tension tended to be elevated, corresponding to diastolic dysfunction and slower relaxation in HF.While all four subtypes of HF remodelling led to longer action potential than the healthy model, the RZ2 caused the most severe action potential prolongation, as a result of the strongest potassium current inhibitions in the four types of HF remodelling.The two RZs had larger peaks of calcium transient and active tension than the two BZs due to the lack of I CaL inhibition in the RZs.BZ1 tended to have stronger and earlier peaks of calcium transient and active tension than the corresponding BZ2, suggesting the crucial role of SERCA difference in the regulation of calcium dynamics.Simulated action potential, calcium transient and active tension biomarkers from the HF models were validated against experimental data ranges as shown in Fig. 1B.Prolongation of action potentials, calcium transients, and active tension kinetics (as biomarker changes in APD 90 , APD 50 , CaTD 50 , TaTTP, TaRTs) observed in failing cardiomyocytes were reproduced in the simulations, and the reduction in amplitudes of calcium transient and active tension as well as the enhanced diastolic tension reported in HF were also generated in the simulations.Due to the scarcity of the human heart tissue samples, the calculation of experimental ranges may be limited since only a few studies were included and the number of cells involved in the data was small, especially for APD 90 , APD 50 , TaTTP, TaRTs, and Ta min , with details listed in Supplementary Material SM4, Supplementary Table S2 18,21,[28][29][30][31][32] .Nevertheless, quantitative agreements were observed in the comparison of APD 90 , APD 50 , CaT amp , CaT min , Ta max , TaRT 50 and Ta min for all or some subpopulations of HF models, with most experimental data considered in this validation step not used for model construction and calibration.

Enhanced I NaL and suppressed I Kr are the main drivers of action potential prolongation in HF myocytes
After the evaluation of the HF biomarkers, the contribution of each ionic current remodelling on the alteration of biomarkers was analyzed in Fig. 2. The inhibited I Na contributed most to the loss of action potential peak.The augmentation of I NaL and the weaker I Kr contributed most to the prolongation of action potential in failing cardiomyocytes, while the weaker I NaK , and the I KCa enhancement mildly counteracted the action potential prolongation in HF (Fig. 2A).

Remodeling of both sarcoplasmic reticulum calcium dynamics and sarcolemmal currents contribute to the loss of contractility and the slower relaxation in failing myocytes
Similar analysis was conducted to the calcium transient and active tension of HF models.As illustrated in Fig. 2B, HF remodeling of different ionic currents and fluxes contributed to the alteration of calcium transient in HF.SERCA inhibition and the augmented junctional sarcoplasmic reticulum calcium leak through ryanodine receptors (RyR) were the biggest sources for the loss of calcium amplitude, and similar trend was observed in active tension (Supplementary Material SM5, Supplementary Fig. S12A).While the enhanced I KCa and weaker I to also contributed to weaker contractility, stronger I NaL , weaker I Na , I Kr and I NaK , as well as increased CaMKII activity all prevented the loss of contractility (Fig. 2B, Supplementary Fig. S12).SERCA inhibition was the biggest contributor to the slower decay and diastolic elevation of calcium transient and active tension.While I NaL enhancement and I Kr inhibition mildly contributed to the slower relaxation, stronger I KCa and CaMKII both promoted faster relaxation (Fig. 2B, Supplementary Fig. S12A).The modulation of calcium dynamics by I KCa ,

Contribution of current variability to HF biomarkers
Partial correlation analysis was conducted to investigate the sensitivity of HF biomarkers to the ionic current conductances in the population of models.As shown in Supplementary Material SM5, Supplementary Fig. S13, stronger G NaL , G NCX and weaker G Kr were correlated to longer APD 90 and APD 50 in HF, while G Na , G to and G CaL may influence peak action potential (V max ).Strong G NaL , weak G Kr , G NCX and SERCA(P Jup ) contributed to long CaTDs.Increased G NaL , G CaL , weaker G NCX , G Kr promoted larger calcium transient and active tension amplitude, whereas suppressed G NCX and SERCA led to diastolic calcium elevation (Supplementary Fig. S13).Weaker SERCA and stronger G NCX contributed to longer activation time for active tension, while weaker SERCA was also related to longer active tension recovery time (Supplementary Fig. S13).As HF patients often suffer from higher risk of ventricular arrhythmias, repolarization abnormalities, such as EADs, were assessed in the population of HF models.In the midmyocardial population of HF model, only one or two EADs were observed in the BZ populations at 1 Hz pacing.In the RZs, EADs were observed more frequently as illustrated in Fig. 3A.To demonstrate the effects of the individual HF ionic remodeling on the inducibility of EADs, a representative model was chosen from the RZ1 population with EAD (Fig. 3B).Removing the I NaL www.nature.com/scientificreports/remodeling did not eliminate the EAD (the orange dashed trace), and similarly when I Kr inhibition was removed, EAD was still maintained (the yellow dashed trace).However, when both I NaL enhancement and I Kr suppression were absent, the EAD was eliminated (the purple dashed trace).Although I NaL and I Kr remodeling promoted EAD generation in HF, the initiation of EAD would not proceed without the re-activation of I CaL (the green dashed trace).Similar mechanisms were also observed in RZ2 population as shown in the Supplementary Material SM6, Supplementary Fig. S14, where removing either I NaL or I Kr remodeling was enough to eliminate EAD.In addition to I NaL and I Kr remodeling, variability in the population of models also contributes to the generation of EADs and other repolarization abnormalities (RA) such as repolarization failure.EAD and RA models tended to have stronger G CaL , G NCX and weaker repolarization currents (Supplementary Material SM6, Supplementary Figs.S15-S16).Due to the stronger G CaL and G NCX (Fig. 3C), the corresponding endocardial and epicardial models of the RZ1 midmyocardial EAD models had similar amplitudes of calcium transient and active tension as the HF models without EADs (Fig. 3D).On the other hand, the stronger G NCX in the EAD models also led to lower diastolic calcium and tension levels, as well as faster decay of the diastolic tension.(Fig. 3E,F).Similar findings were observed in the epicardial and RZ2 populations (Supplementary Material SM6, Supplementary Figs.S17-S19).HF models with EAD generation did not have more compromised contractility comparing to the non-EAD models, but they tended to have lower diastolic calcium and active tension, as well as faster recovery in tension due to the relative stronger sodium-calcium exchanger current.Therefore, a lower diastolic tension and larger diastolic volume in HF may contribute to higher arrhythmic risk.

SERCA remodelling and CaMKII activation promote alternans generation in HF models with lower diastolic tension
In addition to 1 Hz pacing, fast pacing of 2 Hz, 2.5 Hz and 3 Hz were applied to HF population of models to assess the generation of proarrhythmic abnormalities.Only one endocardial model in the healthy NZ calibrated population produced alternans.On the other hand, the HF populations developed repolarization abnormalities (RA) such as repolarization failure due to action potential prolongation, as well as beat-to-beat alternans at different pacing frequencies (Fig. 4A).The RZ populations of models tended to generate more alternans and repolarization abnormalities than the BZ populations, suggesting the role of preserved I CaL in the initiation of RA and alternans.
To illustrate the contribution of HF ionic current remodelling, the biggest alternans at 2.5 Hz pacing from the RZ1 epicardial population was chosen as an example in Fig. 4. At CL = 400 ms, simulations exhibited alternations of long and short action potentials in the odd and even beats (blue solid traces), and it was clear that alternans was associated with the insufficient calcium re-uptake and slow calcium recovery in junctional sarcoplasmic reticulum (JSR).When the inhibition of SERCA pump (J up ) was switched off (the magenta dashed traces), alternans disappeared along with a significant increase of the calcium level in the junctional sarcoplasmic reticulum (CaJSR, Fig. 4B).In addition to the insufficient calcium re-uptake, enhanced CaMKII and slower calcium release further contributed to the alternans.When CaMKII activation and calcium release (Jrel) kinetics were switched back to normal (the red dashed traces), the duration of calcium release was shorter, giving more time for junctional sarcoplasmic reticulum calcium to recover before the next beat, leading to the elimination of alternans (Fig. 4C).
Further analysis was conducted to assess the contractility of the alternans models at 1 Hz.For the BZ1 midmyocardial population and the RZ1 epicardial population, which generated most alternans at fast pacing with the size of alternans and normal populations comparable, the calcium amplitudes tended to be higher in the alternans models than in the non-alternans HF models at 1 Hz pacing (Fig. 5A, Supplementary Material SM6, Supplementary Fig. S20A), yielding similar or larger amplitude in the active tension (Fig. 5A, Supplementary Material SM6, Supplementary Fig. S20A).Alternans models consistently displayed lower diastolic calcium and tension levels, as well as shorter calcium and active tension durations than the non-alternans HF models (Fig. 5B,C, Supplementary Material SM6, Supplementary Fig. S20B,C).These phenomena were caused by the more preserved SERCA function in the alternans models (Fig. 5D, Supplementary Material SM6, Supplementary Fig. S20D).As illustrated in the Fig. 5E, when SERCA was further inhibited by 20% in the same alternans example of Fig. 4, the weaker calcium re-uptake led to lower initial calcium level in the sarcoplasmic reticulum (CaJSR) at the start of a beat, leading to a smaller calcium release and milder decrease of the junctional sarcoplasmic reticulum calcium level that was easier to refill before the start of the next beat (the green dashed traces).These results demonstrate that alternans models in the HF population could have more preserved SERCA function than the non-alternans HF models, corresponding to lower diastolic calcium and tension, which also suggests that the relatively faster diastolic relaxation and larger diastolic volume in HF may be associated with higher arrhythmic risk.

Discussions
In this study, we systematically constructed, calibrated and validated populations of human electromechanical models of failing cardiomyocytes, and investigated the relationship between the contractility and the proarrhythmic abnormalities in the failing human electromechanical models.Our results show that proarrhythmic triggers tend to occur in failing myocyte models with lower diastolic tension and faster relaxation.Our simulation results provide digital evidence supporting the consideration of end-diastolic volume biomarkers in the improvement of current arrhythmic risk stratifications.
Both systolic and diastolic dysfunctions are typical conditions of HF, which sometimes coincide in a same patient.A clinical study which enrolled more than 200 patients revealed that severe diastolic dysfunction was associated with increased arrhythmic risk regardless of the degree of LVEF reduction 33 .In our HF cellular models, the augmentation of I NaL , and the inhibition of I Kr and SERCA contribute to both diastolic dysfunction and cellular pro-arrhythmic EADs or alternans.On the other hand, we also observe that the cellular models with EADs or alternans were not the ones with the most severe elevation of diastolic tension, which suggests that other factors such as the presence of scars and fibrotic tissue favoring reentrant circuits may be the main contributors to arrhythmic risk in grade III diastolic dysfunction 33 .A significant number of patients who suffer sudden cardiac death have relatively preserved LVEF 3 .As the increase of the end-diastolic volume and the decrease of the end-systolic volume both contribute to larger LVEF, the lower diastolic tension in the EAD and alternans models could be a factor contributing to higher end-diastolic volume in HF.The effect on LVEF however may be counteracted by the increase of end-systolic volume in clinical practice.In addition to the lower end-diastolic tension, the remaining blood volume in the ventricles caused by the compromised systolic contraction may contribute to further enlargement of the end-diastolic volume and trigger stretch-activated ectopic activity 34 (Fig. 6).Larger end-diastolic volume was reported as an independent risk factor for cardiovascular events 4 , and increased mortality 5,6 .Our simulation results provide support for the consideration of end-diastolic volume biomarkers in the improvement of current arrhythmic risk stratifications.
In addition to the ionic current remodelling observed in ischemic or dilated cardiomyopathies, other factors also play roles in the pathogenesis of failing myocytes.For example, females tend to have lower expression of potassium channels and higher expression of calmodulin and calcium ATPase than males 35 , which may contribute  www.nature.com/scientificreports/ to sex-specific differences in pro-arrhythmia as well as contraction and relaxation in HF.The elevation of diastolic tension seems to coincide with the rise of reactive oxygen species (ROS) and inflammation level 36,37 .Proinflammatory cytokines are known to promote ROS production, which leads to reduced nitric oxide bioavailability and protein kinase G activity which results in hypo-phosphorylation of titin and elevated resting tension 38 .On the other hand, HF induces inflammation via wall stress, and inflammatory cytokines can be induced in stretched myocytes/cardiac fibroblasts and in overloaded myocardium 39 .Future studies could be conducted to explore the effects of different therapeutic targets to break the vicious cycle.
In this study, we investigated the contributions of different ionic current remodelling and current variability on action potential prolongation, loss of contractility and diastolic dysfunction.Table 2 summarizes the roles of individual currents on action potential duration, peak calcium and active tension, diastolic calcium and active tension, EAD, and alternans.The results showed: (1) I Kr inhibition and I NaL enhancement played crucial roles in the prolongation of action potential and generation of EAD in HF; (2) SERCA(P Jup ) inhibition and J leak_JSR contributed most to the loss of calcium and active tension amplitudes in HF; (3) SERCA suppression was the biggest cause for the diastolic calcium and tension elevation; (4) SERCA remodelling and CaMKII activation induced alternans generation in failing myocytes.
Based on the simulation results, I Kr enhancement or I NaL inhibition should be considered for the prevention of excessive action potential prolongation and EAD generation.Restoration of SERCA expression and function will improve both the contractility and relaxation of failing myocytes.CaMKII augmentation tended to promote higher calcium amplitude through its regulation on I CaL , however it also had the effect of inducing larger J leak_JSR

HF remodelling Action potential duration Peak calcium and tension Diastolic calcium and tension EAD Alternans
to lower JSR calcium content which then led to reduced calcium release 40 .The higher inducibility of alternans by stronger CaMKII activity also prevented it from being an ideal treatment target for HF.
In addition to the above remodelling, another two key currents also played important roles in the regulation of HF phenotypes with some existing controversies: I CaL and I NCX .One controversy related to the remodelling of I CaL in HF.Most studies reported no change in its current density in animal and human cardiomyocytes 18,28,41,42 .However, some experiments in smaller mammal species showed a reduction in I CaL density 43 .Since I CaL reduction was reported only in the BZ rather than the RZ of post-infarction heart failure minipigs 16 , we only applied I CaL inhibition in the HF BZ models.As shown in Fig. 4A, the BZ models with I CaL suppression tended to generate less alternans than the RZ models, which suggested that I CaL reduction can be relevant for the inhibition of beat-to-beat alternans, consistent with previous research 44 .Due to the potential roles of I CaL on the promotion of alternans and EADs, the augmentation of I CaL is unlikely to be a safe strategy to recover contractility in HF without proarrhythmic risk, as shown by previous studies on calcium channel agonists 45 .
The remodelling of sodium-calcium exchanger in HF is also debatable.Some studies reported the increased expression of NCX in HF 42 , others argued the altered NCX activity could be the consequence of intracellular calcium and sodium variations 46,47 .Human and minipig studies reported no change in the rate of calcium removal from NCX, and no differences in I NCX density 16,28 .As reviewed by Bers et al. 7 , an increase of NCX could compensate for a decrease of SERCA function, contributing to the maintenance of relative normal rates of calcium decline and relaxation.In this study, when we introduced SERCA inhibition without NCX enhancement, elevation of diastolic calcium and slower calcium decay was observed in the HF models, consistent with the group of HF patients who had reduced SERCA function but little alteration in NCX expression 48 .Although higher activity of NCX can contribute to normal diastolic function in HF, it can jeopardize systolic function and also increase the risk of action potential prolongation and EAD.
The restoration of SERCA expression and function is regarded as an effective strategy for the recovery of normal systolic and diastolic function.Efforts have been made to increase SERCA activity in treatment of HF, including with gene therapy in HF patients.Clinical trials of adeno-associated vector type 1 (AAV1)-mediated transgenic therapy of SERCA2a have improved cardiac function and prevented expansion of left ventricular volume 49 .However, larger clinical trial of AAV1-SERCA2a (CUPID2) did not show significant gains in the secondary endpoints, probably due to low gene delivery rate of SERCA2a 50 .Other regulatory strategies of SERCA function involve the direct post-translational modifications such as SUMOylation 51 , acetylation 52 , and phosphorylation 53 , as well as indirect regulations through phospholamban 54 .Our simulation results show that mild SERCA restoration in HF myocytes could maintain the risk of alternans generation.Wet-lab experiments and whole ventricular simulations could be conducted in future work to verify the phenomenon at the cellular and the organ level.
The regulation of diastolic calcium is less understood compared to changes in systolic calcium in HF.As reviewed by Eisner et al. 55 , the diastolic and systolic calcium regulations are closely linked.In addition to SERCA which takes up ~ 70% of the calcium, nearly 30% is extruded via I NCX in the relaxation process 7 .In addition to SERCA, we show additional ionic current remodelling contributed to diastolic calcium elevation, such as the increased RyR leakage (J leak_JSR ) and I NaL , and the inhibition of I Kr .Further studies can explore the interplay between increased intracellular sodium ions in HF and NCX activity, as well as the role of cytoplasmic calcium buffering in the regulation of systolic and diastolic functions.
To conclude, we systematically constructed, calibrated and validated population of human electromechanical models of failing cardiomyocytes.The simulation results demonstrated that proarrhythmic abnormalities can occur in failing myocytes with lower diastolic tension, suggesting the role of end-diastolic volume in risk stratifications.

Figure 1 .
Figure 1.HF ionic current remodelling reproduced action potential, calcium transient and active tension biomarkers in range with experimental observations.(A) Effects of 4 types of HF ionic current remodelling on the membrane potential (Vm), calcium transient (CaT) and active tension (Ta) traces of endocardial, midmyocardial and epicardial baseline models.(B) Validation of the relative biomarker changes of action potential, calcium transient and active tension (HF/NZ) against experimental observations.The black bars cover the experimental ranges of biomarker variations, while the grey bars are distributions of biomarker changes from the population of models.The baseline model biomarkers are labelled as circles (BZ1), squares (BZ2), diamonds (RZ1), and asterisks (RZ2).

Figure 2 .
Figure 2. Contribution of individual HF ionic current remodelling to the morphology and duration of membrane potential (A), the loss of calcium transient peak and the elevation of diastolic calcium (B).

FFigure 3 .
Figure 3. HF models with EAD generation in the midmyocardial layer tend to have similar contractility but lower diastolic calcium and tension.(A) Population of RZ1 midmyocardial models with EADs at 1 Hz pacing.(B) Removing I NaL enhancement and I Kr suppression eliminates EAD, whereas terminating I CaL reactivation achieves the same.EAD models tend to have stronger G CaL and G NCX .Comparison of the amplitudes (D), diastolic levels (E) and durations (F) of the calcium and active tension in the corresponding endocardial models with and without EAD generation in the RZ1 midmyocardial layer.(***p < 0.001, **p < 0.01). https://doi.org/10.1038/s41598-024-65249-0

Figure 4 .Figure 5 .
Figure 4. HF remodelling induced RA and alternans at fast pacing rates.(A) HF remodelling promoted alternans and RA in different population of HF models.(B,C) SERCA inhibition and CaMKII augmentation promoted alternans generation in HF models.

Figure 6 .
Figure 6.Effects of reduced peak and diastolic tension on ejection fraction, end-diastolic volume and arrhythmic risk.

Table 1 .
BZ and RZ ionic remodeling of individual currents in HF remodelling. )

Table 2 .
Summary of individual ionic current remodelling on the electromechanical properties of HF myocytes: red arrows indicate the ionic current remodelling caused maladaptive changes whereas the blue arrows mean the remodeling relieved adverse HF symptoms.'-' means unaltered or insignificant effects.Purple arrows indicate currents which favored the abnormality generation if they were augmented.