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The cellular basis for enhanced volume-modulated cardiac output in fish hearts.

ABSTRACT: During vertebrate evolution there has been a shift in the way in which the heart varies cardiac output (the product of heart rate and stroke volume). While mammals, birds, and amphibians increase cardiac output through large increases in heart rate and only modest increases (approximately 30%) in stroke volume, fish and some reptiles use modest increases in heart rate and very large increases in stroke volume (up to 300%). The cellular mechanisms underlying these fundamentally different approaches to cardiac output modulation are unknown. We hypothesized that the divergence between volume modulation and frequency modulation lies in the response of different vertebrate myocardium to stretch. We tested this by progressively stretching individual cardiac myocytes from the fish heart while measuring sarcomere length (SL), developed tension, and intracellular Ca2+ ([Ca2+]i) transients. We show that in fish cardiac myocytes, active tension increases at SLs greater than those previously demonstrated for intact mammalian myocytes, representing a twofold increase in the functional ascending limb of the length-tension relationship. The mechanism of action is a length-dependent increase in myofilament Ca2+ sensitivity, rather than changes in the [Ca2+]i transient or actin filament length in the fish cell. The capacity for greater sarcomere extension in fish myocardium may be linked to the low resting tension that is developed during stretch. These adaptations allow the fish heart to volume modulate and thus underpin the fundamental difference between the way fish and higher vertebrates vary cardiac output.

SUBMITTER: Shiels HA

PROVIDER: S-EPMC2151555 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Ketone body 3-hydroxybutyrate elevates cardiac output through peripheral vasorelaxation and enhanced cardiac contractility.

Project description:The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output and myocardial perfusion without affecting blood pressure in humans, but the cardiovascular sites of action remain obscure. Here, we test the hypothesis in rats that 3-OHB acts directly on the heart to increase cardiac contractility and directly on blood vessels to lower systemic vascular resistance. We investigate effects of 3-OHB on (a) in vivo hemodynamics using echocardiography and invasive blood pressure measurements, (b) isolated perfused hearts in Langendorff systems, and (c) isolated arteries and veins in isometric myographs. We compare Na-3-OHB to equimolar NaCl added to physiological buffers or injection solutions. At plasma concentrations of 2-4 mM in vivo, 3-OHB increases cardiac output (by 28.3±7.8%), stroke volume (by 22.4±6.0%), left ventricular ejection fraction (by 13.3±4.6%), and arterial dP/dtmax (by 31.9±11.2%) and lowers systemic vascular resistance (by 30.6±11.2%) without substantially affecting heart rate or blood pressure. Applied to isolated perfused hearts at 3-10 mM, 3-OHB increases left ventricular developed pressure by up to 26.3±7.4 mmHg and coronary perfusion by up to 20.2±9.5%. Beginning at 1-3 mM, 3-OHB relaxes isolated coronary (EC50=12.4 mM), cerebral, femoral, mesenteric, and renal arteries as well as brachial, femoral, and mesenteric veins by up to 60% of pre-contraction within the pathophysiological concentration range. Of the two enantiomers that constitute racemic 3-OHB, D-3-OHB dominates endogenously; but tested separately, the enantiomers induce similar vasorelaxation. We conclude that increased cardiac contractility and generalized systemic vasorelaxation can explain the elevated cardiac output during 3-OHB administration. These actions strengthen the therapeutic rationale for 3-OHB in heart failure management.

| S-EPMC10492777 | biostudies-literature

Evaluating corrected carotid flow time as a non-invasive parameter for trending cardiac output and stroke volume in cardiac surgery patients.

Project description:PurposeThe corrected carotid flow time (ccFT) is derived from a pulsed-wave Doppler signal at the common carotid artery. Several equations are currently used to calculate ccFT. Its ability to assess the intravascular volume status non-invasively has recently been investigated. The purpose of this study was to evaluate the correlation and trending ability of ccFT with invasive cardiac output (CO) and stroke volume (SV) measurements.MethodsEighteen cardiac surgery patients were included in this prospective observational study. ccFT measurements were obtained at three time points: after induction of anesthesia (T1), after a passive leg raise (T2), and post-bypass (T3). Simultaneously, CO and SV were measured by calibrated pulse contour analysis. Three different equations (Bazett, Chambers, and Wodey) were used to calculate ccFT. The correlation and percentage change in time (concordance) between ccFT and CO and between ccFT and SV were evaluated.ResultsMean ccFT values differed significantly for the three equations (p < 0.001). The correlation between ccFT and CO and between ccFT and SV was highest for Bazett's (ρ = 0.43, p < 0.0001) and Wodey's (ρ = 0.33, p < 0.0001) equations, respectively. Concordance between ΔccFT and ΔCO and between ΔccFT and ΔSV was highest for Bazett's (100%) and Wodey's (82%) equations, respectively. Subgroup analysis demonstrated that correlation and concordance between SV and ccFT improved when assessed within limited heart rate (HR) ranges.ConclusionThe use of different ccFT equations leads to variable correlation and concordance rates between ccFT and CO/SV measurements. Bazett's equation acceptably tracked CO changes in time, while the trending capability of SV was poor.

| S-EPMC10063698 | biostudies-literature

Enhanced desumoylation in murine hearts by overexpressed SENP2 leads to congenital heart defects and cardiac dysfunction.

Project description:Sumoylation is a posttranslational modification implicated in a variety of cellular activities, and its role in a number of human pathogeneses such as cleft lip/palate has been well documented. However, the importance of the SUMO conjugation pathway in cardiac development and functional disorders is newly emerging. We previously reported that knockout of SUMO-1 in mice led to congenital heart diseases (CHDs). To further investigate the effects of imbalanced SUMO conjugation on heart development and function and its underlying mechanisms, we generated transgenic (Tg) mice with cardiac-specific expression of SENP2, a SUMO-specific protease that deconjugates sumoylated proteins, to evaluate the impact of desumoylation on heart development and function. Overexpression of SENP2 resulted in premature death of mice with CHDs-atrial septal defects (ASDs) and/or ventricular septal defects (VSDs). Immunobiochemistry revealed diminished cardiomyocyte proliferation in SENP2-Tg mouse hearts compared with that in wild type (WT) hearts. Surviving SENP2-Tg mice showed growth retardation, and developed cardiomyopathy with impaired cardiac function with aging. Cardiac-specific overexpression of the SUMO-1 transgene reduced the incidence of cardiac structural phenotypes in the sumoylation defective mice. Moreover, cardiac overexpression of SENP2 in the mice with Nkx2.5 haploinsufficiency promoted embryonic lethality and severity of CHDs, indicating the functional interaction between SENP2 and Nkx2.5 in vivo. Our findings indicate the indispensability of a balanced SUMO pathway for proper cardiac development and function. This article is part of a Special Issue entitled 'Post-translational Modification SI'.

| S-EPMC3294171 | biostudies-literature

Output-Sensitive Filtering of Streaming Volume Data.

Project description:Real-time volume data acquisition poses substantial challenges for the traditional visualization pipeline where data enhancement is typically seen as a pre-processing step. In the case of 4D ultrasound data, for instance, costly processing operations to reduce noise and to remove artefacts need to be executed for every frame. To enable the use of high-quality filtering operations in such scenarios, we propose an output-sensitive approach to the visualization of streaming volume data. Our method evaluates the potential contribution of all voxels to the final image, allowing us to skip expensive processing operations that have little or no effect on the visualization. As filtering operations modify the data values which may affect the visibility, our main contribution is a fast scheme to predict their maximum effect on the final image. Our approach prioritizes filtering of voxels with high contribution to the final visualization based on a maximal permissible error per pixel. With zero permissible error, the optimized filtering will yield a result that is identical to filtering of the entire volume. We provide a thorough technical evaluation of the approach and demonstrate it on several typical scenarios that require on-the-fly processing.

| S-EPMC5349295 | biostudies-literature

RedquorinXS Mutants with Enhanced Calcium Sensitivity and Bioluminescence Output Efficiently Report Cellular and Neuronal Network Activities.

Project description:Considerable efforts have been focused on shifting the wavelength of aequorin Ca2+-dependent blue bioluminescence through fusion with fluorescent proteins. This approach has notably yielded the widely used GFP-aequorin (GA) Ca2+ sensor emitting green light, and tdTomato-aequorin (Redquorin), whose bioluminescence is completely shifted to red, but whose Ca2+ sensitivity is low. In the present study, the screening of aequorin mutants generated at twenty-four amino acid positions in and around EF-hand Ca2+-binding domains resulted in the isolation of six aequorin single or double mutants (AequorinXS) in EF2, EF3, and C-terminal tail, which exhibited markedly higher Ca2+ sensitivity than wild-type aequorin in vitro. The corresponding Redquorin mutants all showed higher Ca2+ sensitivity than wild-type Redquorin, and four of them (RedquorinXS) matched the Ca2+ sensitivity of GA in vitro. RedquorinXS mutants exhibited unaltered thermostability and peak emission wavelengths. Upon stable expression in mammalian cell line, all RedquorinXS mutants reported the activation of the P2Y2 receptor by ATP with higher sensitivity and assay robustness than wt-Redquorin, and one, RedquorinXS-Q159T, outperformed GA. Finally, wide-field bioluminescence imaging in mouse neocortical slices showed that RedquorinXS-Q159T and GA similarly reported neuronal network activities elicited by the removal of extracellular Mg2+. Our results indicate that RedquorinXS-Q159T is a red light-emitting Ca2+ sensor suitable for the monitoring of intracellular signaling in a variety of applications in cells and tissues, and is a promising candidate for the transcranial monitoring of brain activities in living mice.

| S-EPMC7660078 | biostudies-literature

A comparison of ClearSight noninvasive cardiac output and pulmonary artery bolus thermodilution cardiac output in cardiac surgery patients.

Project description:BackgroundThe ClearSight system measures blood pressure non-invasively and determines cardiac output by analyzing the continuous pressure waveform. We performed a multi-center clinical study in China to test the equivalence of cardiac output measured with the ClearSight system (CSCO) and cardiac output measured with the pulmonary artery catheter bolus thermodilution (TDCO) method.MethodsWe included adult patients undergoing cardiac surgery in three Chinese hospitals and measured TDCO and CSCO simultaneously after induction of anesthesia. Hemodynamic stability was required during measurement of TDCO and CSCO. At least four TDCO determinations were performed. The corresponding CSCO was determined as the average over a 30-s period following the injection of each bolus. A data pair for the comparison included the average of three or four accepted TDCO values and the average of the matching CSCO values. Main outcomes included Bland-Altman analysis of bias and standard deviation (SD) and the percentage error (PE).ResultsOne hundred twenty-five subjects were enrolled, and 122 TDCO and CSCO data pairs were available for analysis. Ninety-five (75.4%) data pairs were collected in hemodynamically stable conditions, mean (SD) CSCO was 4.21 (0.78) l/min, and mean TDCO was 3.90 (0.67) l/min. Bias was 0.32 (0.51) l/min, and PE was 25.2%. Analyzing all 122 data pairs resulted in a mean CSCO of 4.19 (0.82) l/min and a mean TDCO of 3.83 (0.71) l/min. Resulting bias was 0.36 (0.53) l/min, and PE was 26.4%.ConclusionsCSCO and TDCO agreed with a low systematic bias. Besides, mean PE was well below the pre-defined 30%. Hemodynamic stability only had a small impact on the analysis. We conclude that CSCO is equivalent to TDCO in cardiac surgery patients. The trial was retrospectively registered in ClinicalTrials.gov, identifier NCT03807622 ; January 17, 2019.

| S-EPMC9178897 | biostudies-literature

Fetal cardiac ventricular volume, cardiac output, and ejection fraction determined with 4-dimensional ultrasound using spatiotemporal image correlation and virtual organ computer-aided analysis.

Project description:ObjectiveThe objective of this study was to quantify fetal cardiovascular parameters using spatiotemporal image correlation (STIC) and virtual organ computer-aided analysis (VOCAL).Study designA cross-sectional study was performed in normal pregnancies (19-42 weeks) to evaluate ventricular volume, stroke volume (SV), cardiac output (CO), and ejection fraction (EF). The CO was also expressed as a function of estimated fetal weight and biometric parameters.ResultsThe following results were found: (1) 184 STIC datasets; (2) with advancing gestation, ventricular volume, SV, CO, and adjusted CO increased, whereas EF decreased; (3) right ventricular (RV) volume was larger than the left ventricular (LV) volume in systole (0.50 vs 0.27 mL; P < .001) and diastole (1.20 vs 1.03 mL; P < .001); (4) there were no differences between the LV and RV in SV, CO, or adjusted CO; and (5) LV EF was greater than the RV EF (72.2 vs 62.4%; P < .001).ConclusionNormal fetal cardiovascular physiology is characterized by a larger RV volume and a greater LV EF, resulting in similar LV and RV SV and CO.

| S-EPMC3175283 | biostudies-literature

Drug effects on the CVS in conscious rats: separating cardiac output into heart rate and stroke volume using PKPD modelling.

Project description:Background and purposePreviously, a systems pharmacology model was developed characterizing drug effects on the interrelationship between mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR). The present investigation aims to (i) extend the previously developed model by parsing CO into heart rate (HR) and stroke volume (SV) and (ii) evaluate if the mechanism of action (MoA) of new compounds can be elucidated using only HR and MAP measurements.Experimental approachCardiovascular effects of eight drugs with diverse MoAs (amiloride, amlodipine, atropine, enalapril, fasudil, hydrochlorothiazide, prazosin and propranolol) were characterized in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats following single administrations of a range of doses. Rats were instrumented with ascending aortic flow probes and aortic catheters/radiotransmitters for continuous recording of MAP, HR and CO throughout the experiments. Data were analysed in conjunction with independent information on the time course of the drug concentration following a mechanism-based pharmacokinetic-pharmacodynamic modelling approach.Key resultsThe extended model, which quantified changes in TPR, HR and SV with negative feedback through MAP, adequately described the cardiovascular effects of the drugs while accounting for circadian variations and handling effects.Conclusions and implicationsA systems pharmacology model characterizing the interrelationship between MAP, CO, HR, SV and TPR was obtained in hypertensive and normotensive rats. This extended model can quantify dynamic changes in the CVS and elucidate the MoA for novel compounds, with one site of action, using only HR and MAP measurements. Whether the model can be applied for compounds with a more complex MoA remains to be established.

| S-EPMC4253457 | biostudies-literature

Structural Basis of Enhanced Facilitated Diffusion of DNA-Binding Protein in Crowded Cellular Milieu.

Project description:Although the fast association between DNA-binding proteins (DBPs) and DNA is explained by a facilitated diffusion mechanism, in which DBPs adopt a weighted combination of three-dimensional diffusion and one-dimensional (1D) sliding and hopping modes of transportation, the role of cellular environment that contains many nonspecifically interacting proteins and other biomolecules is mostly overlooked. By performing large-scale computational simulations with an appropriately tuned model of protein and DNA in the presence of nonspecifically interacting bulk and DNA-bound crowders (genomic crowders), we demonstrate the structural basis of the enhanced facilitated diffusion of DBPs inside a crowded cellular milieu through, to our knowledge, novel 1D scanning mechanisms. In this one-dimensional scanning mode, the protein can float along the DNA under the influence of nonspecific interactions of bulk crowder molecules. The search mode is distinctly different compared to usual 1D sliding and hopping dynamics in which protein diffusion is regulated by the DNA electrostatics. In contrast, the presence of genomic crowders expedites the target search process by transporting the protein over DNA segments through the formation of a transient protein-crowder bridged complex. By analyzing the ruggedness of the associated potential energy landscape, we underpin the molecular origin of the kinetic advantages of these search modes and show that they successfully explain the experimentally observed acceleration of facilitated diffusion of DBPs by molecular crowding agents and crowder-concentration-dependent enzymatic activity of transcription factors. Our findings provide crucial insights into gene regulation kinetics inside the crowded cellular milieu.

| S-EPMC6976804 | biostudies-literature

Stroke volume and cardiac output during 6 minute-walk tests are strong predictors of maximal oxygen uptake in people after stroke.

Project description:Background and objectivesThe 6-minute walk test (6MWT) is a field test commonly used to predict peak oxygen consumption (VO2peak) in people after stroke. Inclusion of cardiodynamic variables measured by impedance cardiography (ICG) during a 6MWT has been shown to improve prediction of VO2peak in healthy adults but these data have not been considered in people after stroke. This study investigates whether the prediction of VO2peak can be improved by the inclusion of cardiovascular indices derived by impedance cardiography (ICG) during the 6MWT in people after stroke.MethodsThis was a cross-sectional study. Patients diagnosed with stroke underwent in random order, a maximal cardiopulmonary exercise test (CPET) and 6MWT in separate dates. Heart rate (HR), stroke volume (SV) and cardiac output (CO) were measured by ICG during all tests. Oxygen consumption was recorded by a metabolic cart during the CPET. Recorded data were subjected to multiple regression analyses to generate VO2peak prediction equations.ResultsFifty-nine patients, mean age 50.0±11.7 years were included in the analysis. The mean distance covered in the 6MWT (6MWD) was 294±13 m, VO2peak was 19.2±3.2 ml/min/kg. Mean peak HR, SV and CO recorded during 6MWT were 109±6 bpm, 86.3±8.8 ml, 9.4±1.2 L/min and during CPET were 135±14 bpm, 86.6±9 ml, 11.7±2 L/min respectively. The prediction equation with inclusion of cardiodynamic variables: 16.855 + (-0.060 x age) + (0.196 x BMI) + (0.01 x 6MWD) + (-0.416 x SV6MWT) + (3.587 x CO 6MWT) has a higher squared multiple correlation (R2) and a lower standard error of estimate (SEE) and SEE% compared to the equation using 6MWD as the only predictor.ConclusionInclusion of SV and CO measured during the 6MWT in stroke patients further improved the VO2peak prediction power compared to using 6MWD as a lone predictor.

| S-EPMC9426911 | biostudies-literature

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