Danicamtiv Enhances Systolic Function and Frank-Starling Behavior at Minimal Diastolic Cost in Engineered Human Myocardium.
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ABSTRACT:
SUBMITTER: Shen S
PROVIDER: S-EPMC8477869 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The Frank-Starling mechanism allows the amount of blood entering the heart from the veins to be precisely matched with the amount pumped out to the arterial circulation. As the heart fills with blood during diastole, the myocardium is stretched and oxidants are produced. Here we show that protein kinase G Iα (PKGIα) is oxidant-activated during stretch and this form of the kinase selectively phosphorylates cardiac phospholamban Ser16-a site important for diastolic relaxation. We find that hearts of Cys42Ser PKGIα knock-in (KI) mice, which are resistant to PKGIα oxidation, have diastolic dysfunction and a diminished ability to couple ventricular filling with cardiac output on a beat-to-beat basis. Intracellular calcium dynamics of ventricular myocytes isolated from KI hearts are altered in a manner consistent with impaired relaxation and contractile function. We conclude that oxidation of PKGIα during myocardial stretch is crucial for diastolic relaxation and fine-tunes the Frank-Starling response.
| S-EPMC5095173 | biostudies-literature
Project description:This paper briefly recapitulates the Frank-Starling law of the heart, reviews approaches to establishing diastolic and systolic force-length behaviour in intact isolated cardiomyocytes, and introduces a dimensionless index called 'Frank-Starling Gain', calculated as the ratio of slopes of end-systolic and end-diastolic force-length relations. The benefits and limitations of this index are illustrated on the example of regional differences in Guinea pig intact ventricular cardiomyocyte mechanics. Potential applicability of the Frank-Starling Gain for the comparison of cell contractility changes upon stretch will be discussed in the context of intra- and inter-individual variability of cardiomyocyte properties.
| S-EPMC3114067 | biostudies-literature
Project description:Previous work suggests that titin-based passive tension is a factor in the Frank-Starling mechanism of the heart, by increasing length-dependent activation (LDA) through an increase in calcium sensitivity at long sarcomere length. We tested this hypothesis in a mouse model (N2B KO model) in which titin-based passive tension is elevated as a result of the excision of the N2B element, one of cardiac titin's spring elements. LDA was assessed by measuring the active tension-pCa (-log[Ca(2+)]) relationship at sarcomere length (SLs) of 1.95, 2.10, and 2.30 microm in WT and N2B KO skinned myocardium. LDA was positively correlated with titin-based passive tension due to an increase in calcium sensitivity at the longer SLs in the KO. For example, at pCa 6.0, the KO:WT tension ratio was 1.28+/-0.07 and 1.42+/-0.04 at SLs of 2.1 and 2.3 microm, respectively. There was no difference in protein expression or total phosphorylation of sarcomeric proteins. We also measured the calcium sensitivity after PKA treating the skinned muscle and found that titin-based passive tension was also now correlated with LDA, with a slope that was significantly increased compared to no PKA treatment. Finally, we performed isolated heart experiments and measured the Frank-Starling relation (slope of developed wall stress-LV volume relation) as well as diastolic stiffness (slope of diastolic wall stress-volume relation). The FSM was more pronounced in the N2B KO hearts and the slope of the FSM correlated with diastolic stiffness. These findings support that titin-based passive tension triggers an increase in calcium sensitivity at long sarcomere length, thereby playing an important role in the Frank-Starling mechanism of the heart.
| S-EPMC2917497 | biostudies-literature
Project description:The Frank-Starling mechanism is a fundamental regulatory property which underlies the cardiac output adaptation to venous filling. Length-dependent activation is generally assumed to be the cellular origin of this mechanism. At the heart scale, it is commonly admitted that an increase in preload (ventricular filling) leads to an increased cellular force and an increased volume of ejected blood. This explanation also forms the basis for vascular filling therapy. It is actually difficult to unravel the exact nature of the relationship between length-dependent activation and the Frank-Starling mechanism, as three different scales (cellular, ventricular and cardiovascular) are involved. Mathematical models are powerful tools to overcome these limitations. In this study, we use a multiscale model of the cardiovascular system to untangle the three concepts (length-dependent activation, Frank-Starling, and vascular filling). We first show that length-dependent activation is required to observe both the Frank-Starling mechanism and a positive response to high vascular fillings. Our results reveal a dynamical length dependent activation-driven response to changes in preload, which involves interactions between the cellular, ventricular and cardiovascular levels and thus highlights fundamentally multiscale behaviors. We show however that the cellular force increase is not enough to explain the cardiac response to rapid changes in preload. We also show that the absence of fluid responsiveness is not related to a saturating Frank-Starling effect. As it is challenging to study those multiscale phenomena experimentally, this computational approach contributes to a more comprehensive knowledge of the sophisticated length-dependent properties of cardiac muscle.
| S-EPMC8504729 | biostudies-literature
Project description:AimsBlood pressure (BP) is a crucial factor in cardiovascular health and can affect cardiac imaging assessments. However, standard outpatient cardiovascular MR (CMR) imaging procedures do not typically include BP measurements prior to image acquisition. This study proposes that brachial systolic BP (SBP) and diastolic BP (DBP) can be modelled using patient characteristics and CMR data.MethodsIn this multicentre study, 57 patients from the PREFER-CMR registry and 163 patients from other registries were used as the derivation cohort. All subjects had their brachial SBP and DBP measured using a sphygmomanometer. Multivariate linear regression analysis was applied to predict brachial BP. The model was subsequently validated in a cohort of 169 healthy individuals.ResultsAge and left ventricular ejection fraction were associated with SBP. Aortic forward flow, body surface area and left ventricular mass index were associated with DBP. When applied to the validation cohort, the correlation coefficient between CMR-derived SBP and brachial SBP was (r=0.16, 95% CI 0.011 to 0.305, p=0.03), and CMR-derived DBP and brachial DBP was (r=0.27, 95% CI 0.122 to 0.403, p=0.0004). The area under the curve (AUC) for CMR-derived SBP to predict SBP>120 mmHg was 0.59, p=0.038. Moreover, CMR-derived DBP to predict DBP>80 mmHg had an AUC of 0.64, p=0.002.ConclusionCMR-derived SBP and DBP models can estimate brachial SBP and DBP. Such models may allow efficient prospective collection, as well as retrospective estimation of BP, which should be incorporated into assessments due to its critical effect on load-dependent parameters.
| S-EPMC10749049 | biostudies-literature
Project description:Flocks of starlings exhibit a remarkable ability to maintain cohesion as a group in highly uncertain environments and with limited, noisy information. Recent work demonstrated that individual starlings within large flocks respond to a fixed number of nearest neighbors, but until now it was not understood why this number is seven. We analyze robustness to uncertainty of consensus in empirical data from multiple starling flocks and show that the flock interaction networks with six or seven neighbors optimize the trade-off between group cohesion and individual effort. We can distinguish these numbers of neighbors from fewer or greater numbers using our systems-theoretic approach to measuring robustness of interaction networks as a function of the network structure, i.e., who is sensing whom. The metric quantifies the disagreement within the network due to disturbances and noise during consensus behavior and can be evaluated over a parameterized family of hypothesized sensing strategies (here the parameter is number of neighbors). We use this approach to further show that for the range of flocks studied the optimal number of neighbors does not depend on the number of birds within a flock; rather, it depends on the shape, notably the thickness, of the flock. The results suggest that robustness to uncertainty may have been a factor in the evolution of flocking for starlings. More generally, our results elucidate the role of the interaction network on uncertainty management in collective behavior, and motivate the application of our approach to other biological networks.
| S-EPMC3561045 | biostudies-literature
Project description:Experimentally upregulating compliant titins has been suggested as a therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study. We investigate the effect of upregulating compliant titins in a novel mouse model with a genetically altered titin splicing factor; integrative approaches were used from intact cardiomyocyte mechanics to pressure-volume analysis and Doppler echocardiography.Compliant titins were upregulated through deletion of the RNA Recognition Motif of the splicing factor RBM20 (Rbm20(?RRM)mice). A genome-wide exon expression analysis and a candidate approach revealed that the phenotype is likely to be dominated by greatly increased lengths of titin's spring elements. At both cardiomyocyte and left ventricular chamber levels, diastolic stiffness was reduced in heterozygous (+/-) Rbm20(?RRM)mice with a further reduction in homozygous (-/-) mice at only the intact myocyte level. Fibrosis was present in only -/- Rbm20(?RRM) hearts. The Frank-Starling Mechanism was reduced in a graded fashion in Rbm20(?RRM) mice, at both the cardiomyocyte and left ventricular chamber levels. Exercise tests revealed an increase in exercise capacity in +/- mice.Titin is not only important in diastolic but also in systolic cardiac function. Upregulating compliant titins reduces diastolic chamber stiffness owing to the increased compliance of myocytes, but it depresses end-systolic elastance; under conditions of exercise, the beneficial effects on diastolic function dominate. Therapeutic manipulation of the RBM20-based splicing system might be able to minimize effects on fibrosis and systolic function while improving the diastolic function in patients with heart failure.
| S-EPMC4032222 | biostudies-literature
Project description:For the heart to function as a pump, intracellular calcium concentration ([Ca2+ ]i ) must increase during systole to activate contraction and then fall, during diastole, to allow the myofilaments to relax and the heart to refill with blood. The present study investigates the control of diastolic [Ca2+ ]i in rat ventricular myocytes. We show that diastolic [Ca2+ ]i is increased by manoeuvres that decrease sarcoplasmic reticulum function. This is accompanied by a decrease of systolic [Ca2+ ]i such that the time-averaged [Ca2+ ]i remains constant. We report that diastolic [Ca2+ ]i is controlled by the balance between Ca2+ entry and Ca2+ efflux during systole. The results of the present study identify a novel mechanism by which changes of the amplitude of the systolic Ca transient control diastolic [Ca2+ ]i .The intracellular Ca concentration ([Ca2+ ]i ) must be sufficently low in diastole so that the ventricle is relaxed and can refill with blood. Interference with this will impair relaxation. The factors responsible for regulation of diastolic [Ca2+ ]i , in particular the relative roles of the sarcoplasmic reticulum (SR) and surface membrane, are unclear. We investigated the effects on diastolic [Ca2+ ]i that result from the changes of Ca cycling known to occur in heart failure. Experiments were performed using Fluo-3 in voltage clamped rat ventricular myocytes. Increasing stimulation frequency increased diastolic [Ca2+ ]i . This increase of [Ca2+ ]i was larger when SR function was impaired either by making the ryanodine receptor leaky (with caffeine or ryanodine) or by decreasing sarco/endoplasmic reticulum Ca-ATPase activity with thapsigargin. The increase of diastolic [Ca2+ ]i produced by interfering with the SR was accompanied by a decrease of the amplitude of the systolic Ca transient, such that there was no change of time-averaged [Ca2+ ]i . Time-averaged [Ca2+ ]i was increased by β-adrenergic stimulation with isoprenaline and increased in a saturating manner with increased stimulation frequency; average [Ca2+ ]i was a linear function of Ca entry per unit time. Diastolic and time-averaged [Ca2+ ]i were decreased by decreasing the L-type Ca current (with 50 μm cadmium chloride). We conclude that diastolic [Ca2+ ]i is controlled by the balance between Ca entry and efflux during systole. Furthermore, manoeuvres that decrease the amplitude of the Ca transient (without decreasing Ca influx) will therefore increase diastolic [Ca2+ ]i . This identifies a novel mechanism by which changes of the amplitude of the systolic Ca transient control diastolic [Ca2+ ]i .
| S-EPMC5556151 | biostudies-other
Project description:Cardiolipin (CL) is a major cardiac mitochondrial phospholipid maintaining regular mitochondrial morphology and function in cardiomyocytes. Cardiac CL production includes its biosynthesis and a CL remodeling process. Here we studied the impact of CL biosynthesis and the enzyme cardiolipin synthase (CLS) on cardiac function. CLS and cardiac CL species were significantly downregulated in cardiomyocytes following catecholamine-induced cardiac damage in mice, accompanied by increased oxygen consumption rates, signs of oxidative stress, and mitochondrial uncoupling. RNAi-mediated cardiomyocyte-specific knockdown of CLS in Drosophila melanogaster resulted in marked cardiac dilatation, severe impairment of systolic performance, and slower diastolic filling velocity assessed by fluorescence-based heart imaging. Finally, we showed that CL72:8 is significantly decreased in cardiac samples from patients with heart failure with reduced ejection fraction (HFrEF). In summary, we identified CLS as a regulator of cardiac function. Considering the cardiac depletion of CL species in HFrEF, pharmacological targeting of CLS may be a promising therapeutic approach.
| S-EPMC8581512 | biostudies-literature
Project description:The Frank-Starling mechanism of the heart is due, in part, to modulation of myofilament Ca(2+) sensitivity by sarcomere length (SL) [length-dependent activation (LDA)]. The molecular mechanism(s) that underlie LDA are unknown. Recent evidence has implicated the giant protein titin in this cellular process, possibly by positioning the myosin head closer to actin. To clarify the role of titin strain in LDA, we isolated myocardium from either WT or homozygous mutant (HM) rats that express a giant splice isoform of titin, and subjected the muscles to stretch from 2.0 to 2.4 μm of SL. Upon stretch, HM compared with WT muscles displayed reduced passive force, twitch force, and myofilament LDA. Time-resolved small-angle X-ray diffraction measurements of WT twitching muscles during diastole revealed stretch-induced increases in the intensity of myosin (M2 and M6) and troponin (Tn3) reflections, as well as a reduction in cross-bridge radial spacing. Independent fluorescent probe analyses in relaxed permeabilized myocytes corroborated these findings. X-ray electron density reconstruction revealed increased mass/ordering in both thick and thin filaments. The SL-dependent changes in structure observed in WT myocardium were absent in HM myocardium. Overall, our results reveal a correlation between titin strain and the Frank-Starling mechanism. The molecular basis underlying this phenomenon appears not to involve interfilament spacing or movement of myosin toward actin but, rather, sarcomere stretch-induced simultaneous structural rearrangements within both thin and thick filaments that correlate with titin strain and myofilament LDA.
| S-EPMC4776536 | biostudies-other