Time Constant Tau Research Articles

Abstract Tu067: ROCK2 Specific Inhibition Prevents Isoproterenol Induced Takotsubo Cardiomyopathy in Mice

Takotsubo Cardiomyopathy (TCM) is an acute, life-threatening condition characterized by a drop in ejection fraction (EF) and apical ballooning of the left ventricle (LV). TCM is most frequently observed in women and is associated with an emotional or physical stressor. Recent work has demonstrated that the Rho kinase ROCK2 contributes to heart failure phenotypes in mice in other models of heart failure. The role of ROCK2 in TCM is unknown. We tested the hypothesis that ROCK2 inhibition attenuates isoproterenol (ISO)-induced TCM in mice. To induce TCM, male and female mice were given a single dose of 200mg/kg ISO, i.p. and cardiac function was assessed by conscious echocardiography. The effect of ISO overdose on acute heart failure over a 7-day time course was determined followed by an intervention study in which mice were treated with the ROCK2 specific inhibitor KD025/belumosudil (50mg/kg, i.p.) concurrent with heart failure induction. Though ISO induced a drop in EF in both sexes after 24 hours, females exhibited lower EF (46.64±3.11%) than males (68.36±2.62, p<0.0001) mirroring the increased prevalence of clinically defined TCM in females in humans. Female mice were used for the remaining experiments. Invasive hemodynamics revealed reduced contraction and relaxation (dp/dt max and dp/dt min) as well as an increased relaxation time constant Tau 24 hours after ISO injection. A time course study demonstrated that EF begins to normalize by Day 3 and is restored to baseline levels by Day 7. Importantly, ROCK2-specific inhibition prevented ISO-induced drop in EF, thinning of the LV wall, and LV volume expansion. Here, we demonstrate that female mice are more susceptible to ISO-induced cardiac dysfunction. Furthermore, we show that ROCK2 activation is necessary for the development of TCM in mice. These results suggest that FDA-approved KD025/belumosudil could potentially be repurposed for treatment in TCM.

The effect of self-identified arm dominance on exercising forearm hemodynamics and skeletal muscle desaturation.

The human forearm model is commonly employed in physiological investigations exploring local vascular function and oxygen delivery; however, the effect of arm dominance on exercising forearm hemodynamics and skeletal muscle oxygen saturation (SmO2) in untrained individuals is poorly understood. Therefore, the purpose of this study was to explore the effect of self-identified arm dominance on forearm hemodynamics and SmO2 in untrained individuals during submaximal, non-ischemic forearm exercise. Twenty healthy individuals (23±4 years, 50% female; 80% right-handed) completed three-minute bouts of supine rhythmic (1 second contraction: 2 second relaxation duty cycle) forearm handgrip exercise at both absolute (10kg; 98N) and relative (30% of maximal voluntary contraction) intensities in each forearm. Beat-by-beat measures of forearm blood flow (FBF; ml/min), mean arterial blood pressure (MAP; mmHg) and flexor digitorum superficialis SmO2 (%) were obtained throughout and averaged during the final 30 seconds of rest, exercise, and recovery while forearm vascular conductance was calculated (FVC; ml/min/100mmHg). Data are Δ from rest (mean±SD). Absolute force production did not differ between non-dominant and dominant arms (97±11 vs. 98±13 N, p = 0.606) whereas relative force production in females did (69±24 vs. 82±25 N, p = 0.001). At both exercise intensities, FBFRELAX, FVCRELAX, MAPRELAX, and the time constant tau for FBF and SmO2 were unaffected by arm dominance (all p>0.05). While arm dominance did not influence SmO2 during absolute intensity exercise (p = 0.506), the non-dominant arm in females experienced an attenuated reduction in SmO2 during relative intensity exercise (-14±10 vs. -19±8%, p = 0.026)-though exercise intensity was also reduced (p = 0.001). The present investigation has demonstrated that arm dominance in untrained individuals does not impact forearm hemodynamics or SmO2 during handgrip exercise.

Sex Dependent Exacerbation of Salt Sensitive Hypertension and Cardiac Dysfunction Is Associated With Upregulation of miRNA Targeting ADAM17 and ACE2 in the Brain

Background: The DOCA-salt model has been widely used to study salt-sensitive hypertension and we previously reported that it is associated with ADAM17-mediated ACE2 shedding in the central nervous system. However, previously reported data are mainly from male mice, and it is unclear whether female mice exhibit the same phenotypes. Objective: We aimed to compare sex specific development of salt sensitive hypertension and cardiac dysfunction and investigate miRNA regulation associated with these changes. Methods: C57 mice (male and females, n = 8 -15) underwent uninephrectomy and telemetry implantation (DSI Inc.) for blood pressure (BP) conscious recording. After baseline recording, a DOCA pellet (50 mg, 21 days, Innovative Research of America) was implanted subcutaneously and drinking water was replaced by 1% NaCl solution to induce salt sensitive hypertension. Cerebral Spinal fluid (CSF) was collected at baseline and after 3 weeks of DOCA-salt treatment for exosome miRNA sequencing (Creative Biolab). In another set of mice, cardiac function was assessed by echocardiography (Visualsonics Vevo F2) and invasive left ventricular hemodynamics (Transonic). Mortality from each group was analyzed as well. Results: Baseline BP was not different between male and female mice. Following DOCA-salt treatment for 3 weeks, BP was increased in both sexes, with higher systolic BP observed in males compared to females (active phase: 173.0 ± 19.6 vs. 154.2 ± 19.1 mmHg, p<0.05). Although ejection fraction was not changed in either male or female mice, mitral peak early diastolic filling velocity and tissue doppler showed that E/E’ was increased in both sexes compared to baselines (Male: 33.4 ± 4 vs. 26.6 ± 1.9; Female: 30.3 ± 5.0 vs. 26.4 ± 4), with a greater increase in males (25.3% vs. 14.4%). In addition, hemodynamics revealed increased left ventricular end-diastolic pressure (11.1 ± 1.9 vs. 4.5 ± 0.5 mmHg, p<0.01) and relaxation time constant Tau (6.7 ± 1.0 vs. 4.9 ± 0.5 msec, p<0.01) in DOCA-salt treated males compared to non-treated controls, with no changes shown in female mice. These data suggest worsened cardiac diastolic function in males compared to females following DOCA-salt treatment. Moreover, a 20% mortality was observed in males while no death occured in females, confirming a more severe phenotype in males. Furthermore, miRNAseq analysis of CSF exosomes showed several upregulated miRNA in males but not in females following DOCA-salt treatment. Notably, miR206 associated with increased ADAM17 activity was increased by 8-fold in males but only 3-fold n females. Conclusion: DOCA-salt treatment promotes exacerbated hypertension, impaired cardiac function and mortality in a sex dependent manner, associated with upregulation of key miRNA targeting the brain renin-angiotensin system. The changes of ADAM17 and ACE2 targeted exosome miRNAs in the central nervous system might contribute to the sex difference in the cardiovascular dysfunction phenotypes in this model. This work was supported in part by a research grant from the National Institutes of Health (HL163588). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Exponential modelling of heart rate recovery after a maximal exercise

Objectives: Heart rate recovery (HRR) after exercise is clinically important as a predictor of mortality. In addition, HRR is an indicator of cardiac autonomic activity, since increased vagal activity and diminished sympathetic activity return the heart rate to resting conditions after exercise. The previous attempts to model HRR using polynomial, first-order and second-order modelling have produced mixed results. In this study, we hypothesised that the double-exponential fit would model the HRR more accurately than the single-exponential fit as it would capture the activity of both autonomic arms responsible for heart rate decay and investigated the outcome of these two models on the HRR data following a maximal exercise. Materials and Methods: Exponential curve fitting was done on a set of previously published data from our laboratory. The HRR data were acquired from 40 male participants (19–38 years) after a maximal treadmill exercise. The normalised HRR data from a 5-min time window from maximal heart rate were fitted using single and double-exponential curves, to obtain, respectively, the time constants Tau and, Tau 1 and Tau 2. The goodness-of-fit of the model was assessed with Chi-square values computed for each participant data set with both models. Considering that Chi-square of zero is a perfect fit, and therefore, smaller Chi-square values indicate a better fit than larger values, we computed the difference in the Chi-square values (Δχ2) between the models by subtracting the Chi-square value of the double-exponential fit from the Chi-square value of the single-exponential fit. This was based on the premise that if the calculated Δχ2 is positive, it would indicate a better fit with double-exponential than single-exponential decay model. The data are presented as mean ± standard deviation. Comparisons were made with Student’s t-test. Results: Data from four participants were excluded for technical reasons. The Tau of the single-exponential fit was 65.50 ± 12.13 s, while Tau 1 and Tau 2 of the double-exponential fit were 43.75 ± 18.96 s and 120.30 ± 91.32 s, respectively, the Tau 1 value being significantly lower than the Tau 2 value (P < 0.0001). Remarkably among the 36 participants, the difference in the Chi-square value was positive (127.2 ± 171.04) in 22 subjects and zero or marginally negative (−0.17 ± 0.31) in 14 subjects. Conclusion: Our results indicate that the double-exponential model fitted the HRR data better than the single-exponential model in almost two-thirds (61%) of our study population. In the remaining participants, the goodness-of-fit was nearly equivalent for both fits with no evidence of superior modelling with the single-exponential fit. Our data show that while the single-exponential fit is sufficient for modelling the HRR of 14 subjects, it was less efficient for fitting the data of most participants. In comparison, the double-exponential curve fit effectively modelled 100% of our study population. Given our findings, we conclude that the double-exponential model is more inclusive and better represented the HRR data of our study population than the single-exponential model.

Comparison of two measurement devices for obtaining horizontal force-velocity profile variables during sprint running

This study established the magnitude of systematic bias and random error of horizontal force-velocity (F-v) profile variables obtained from a 1080 Sprint compared to that obtained from a Stalker ATS II radar device. Twenty high-school athletes from an American football training group completed a 30 m sprint while the two devices simultaneously measured velocity-time data. The velocity-time data were modelled by an exponential equation fitting process and then used to calculate individual F-v profiles and related variables (theoretical maximum velocity, theoretical maximum horizontal force, slope of the linear F-v profile, peak power, time constant tau, and horizontal maximal velocity). The devices were compared by determining the systematic bias and the 95% limits of agreement (random error) for all variables, both of which were expressed as percentages of the mean radar value. All bias values were within 6.32%, with the 1080 Sprint reporting higher values for tau, horizontal maximal velocity, and theoretical maximum velocity. Random error was lowest for velocity-based variables but exceeded 7% for all others, with slope of the F-v profile being greatest at ±12.3%. These results provide practitioners with the information necessary to determine if the agreement between the devices and the magnitude of random error is acceptable within the context of their specific application.

Desert Hedgehog-related endothelial dysfunction is sufficient to induce diastolic dysfunction

Heart Failure with Preserved Ejection Fraction is proposed to be caused by endothelial dysfunction in cardiac small vessels. Our goal is to demonstrate that endothelial dysfunction is sufficient to induce diastolic dysfunction by using a mouse model with genetically-induced endothelial dysfunction. We used Desert Hedgehog (Dhh) endothelial deficient mice as such a model. Indeed, we recently demonstrated that Dhh is a downstream target of Klf2 critical for endothelial integrity. Practically, Cdh5-Cre/ERT2; Dhh flox/flox (Dhh ECKO ) and their control (Dhh flox/flox ) littermates were administered with tamoxifen at 8 weeks of age to induce Dhh KO and endothelial dysfunction. Cardiac function was assessed one month later via echocardiography and hemodynamic measurements. Immediately after, mice were sacrificed for gene expression and histological analyses. As expected, Dhh ECKO mice exhibited phenotypic changes in their cardiac small vessels characterized by a pro-inflammatory and a pro-thrombotic phenotype, an increased endothelium permeability to albumin, IgG and fibrinogen and perivascular fibrosis. Notably, we found that these changes are sufficient to induce diastolic dysfunction since Dhh ECKO mice presented significantly increased end-diastolic pressures (8.05 ± 1.11 mmHg vs. 4.69 ± 1.69 in control mice, P = 0.02) while their left ventricular ejection fraction was comparable to that of control mice. Moreover, Dhh ECKO had a reduced exercise tolerance in the treadmill test, (running time: 13.28 ± 4.62 min vs. 24.97 ± 4.27 in control mice, P = 0.01) suggesting that they do present heart failure. Diastolic dysfunction in these mice is more likely due to an increased cardiomyocyte passive stiffness since Dhh ECKO heart display an increased Tcap mRNA expression while the minimum dP/dt and the relaxation time constant Tau were not modified. Altogether, these results strongly support that endothelial dysfunction is sufficient to HFPEF.

David Annetts’ best of Exploration Geophysics

When airborne electromagnetic (AEM) data is acquired as a streamed or time-series data set, the great redundancy in the data favours compression as a first step in processing. Traditional data compression schemes are time windowing and spatial averaging. An alternative, more efficient data compression scheme is to transform time or frequency domain data to time-constant tau space, which has the effect of removing the waveform dependence of the AEM response.When there are many local anomalies and a variable background, the next stage of rapid processing is to transform the response to a conductivity-depth image (CDI) to facilitate geological interpretation of the background response. Use of the full time range of recorded data, particularly the inclusion of on-time data, improves the stability of the CDI process.The final AEM data processing step for mineral exploration is to assess the likelihood that any local anomaly corresponds to a desired economic target. This step involves the extraction of target geometry and conductivity information from the AEM data. The only economically feasible route at the present time is to parameterise both the data (using inductive and resistive limits) and the model to allow inversion of the local anomalies. A fit to one or two platelike conductors can be achieved in seconds; fits to a blocklike body take minutes on a fast PC. A significant research challenge remains to speed up and stabilise this process.

Abstract 244: Post- But Not Pre-menopausal Female Smoothelin-like 1 Deficient Mice Develop Diastolic Dysfunction Unlike Their Male Counterparts

Diastolic dysfunction is a core characteristic of heart failure with preserved ejection fraction (HFpEF), which accounts for half of all HF cases. Our group revealed a novel impact of the smoothelin-like 1 (SMTNL1) protein which when subjected to genetic deletion drives alterations in endothelial and cardiovascular performances. Of note, previous cardiac hemodynamic profiling showed that young male SMTNL1 knockout (KO) mice developed diastolic dysfunction as evidenced by increased end diastolic pressure (EDP), left ventricular relaxation time constant (Tau) and steeper end diastolic pressure-volume relationship (EDPVR). A majority of HFpEF patients are post-menopausal women, so this study examined the impact of SMTNL1 silencing on endothelial and cardiac function with increasing age in a novel female murine model. The cardiac function of SMTNL1 global KO mice (3-, 12- and 18-month old, male and female) was assessed by echocardiography and pressure-volume loop. Unlike young males, 3-month old female KO mice did not develop diastolic dysfunction. However, ageing provided progressive impairment of diastolic function in female KO mice with increased EDP (8.4±1.1 vs 12.2±0.8 mmHg, p<0.02) and EDPVR (0.22±0.05 vs 0.51±0.05, p=0.02) at 18 months; an elevated E/E′ (20.8±1.6 vs 28.3±2.2, p=0.02) and decreased E′/A′ (1.49±0.19 vs 0.97±0.14, p<0.05) at 12 months in comparison to their WT counterparts, along with a normal ejection fraction (>60%) for all age groups. Furthermore, while flow-mediated dilation was continuously impaired in male KO cohorts from 3-month age, female KO showed impairment only at 12-months. Aging was also associated with altered cardiac morphology and fibrotic levels in the aged female KO cohort. Taken together, we have identified pathophysiologic effects of SMTNL1 silencing on vascular and cardiac function with ageing in female mice. The SMTNL1 KO model for the first time recapitulates the sex dimorphic onset of diastolic dysfunction that is central to HFpEF clinical phenotypes and represents a novel preclinical model to study the etiology of the HFpEF condition. Furthermore, the absence of diastolic dysfunction in KO female mice until post-menopausal age reveals a protective role of female sex hormones and warrants further study.

Cardiorespiratory function and VO2 kinetics after sleeve gastrectomy: a follow-up analysis.

Although poor cardiorespiratory function is a powerful predictor of mortality in patients with obesity, functional evaluation has been given little attention after laparoscopic sleeve gastrectomy (LSG). The aim of this study was thus to investigate the impact of LSG on functional capacity analysing a shorter and longer post-surgical follow-up. In this observational study, 24 patients with severe obesity (BMI 44.04 ± 5.84kg/m2, age 47.0 ± 9.0years) performed cardiopulmonary exercise testing 7months pre-, 6 and 16months post-LSG. Exercise capacity, oxygen uptake and VO2 kinetics were analysed during treadmill exercise testing. Although patients showed an improved peak work capacity after LSG, parameters of maximal absolute aerobic capacity demonstrated a significant decrease, which was confirmed also in the follow-up analysis. Furthermore, the time constant Tau (τ) of the fundamental component of VO2 kinetics was altered by LSG, however, within the 16months of follow-up it returned towards baseline values.It can thusbe concluded that LSG improved peak work capacity along with a lower maximal absolute aerobic capacity, which might be due to a loss of muscle mass and potentially impaired peripheral oxidative muscle metabolism. However, VO2 kinetics might suggest an initial restoration of peripheral oxidative muscle capacity after a longer follow-up.

Electro-optic sensor for static fields

A sensor has been developed for low frequency and DC electric fields E. The device is capable of measuring fields with varDelta mathrm{E}= 4 (1) V/cm resolution. It is based on a Y-cut Z-propagation lithium niobate electro-optic crystal. For a particular commercially available bare crystal, we achieved an in air time constant tau _mathrm{c}(mathrm air)= 6.4(1.8) h for the decay of the electro-optic signal. This enables field monitoring for several hours. As an application, we demonstrated that a constant electric field E^{mathrm{ext}} = 640 V/cm applied via external electrodes to a particular spherical glass container holding an Xe/He gas mixture decays inside this cell with a time constant tau _{E}^{mathrm{glass}} = 2.5(5) h. This is sufficient for the needs of experiments searching for a permanent electric dipole moment in ^{129}Xe. An integrated electric field sensor has been constructed which is coupled to a light source and light detectors via optical fibers. The sensor head does not contain any electrically conducting material.

Abstract P1117: Dissimilarities Between and Carotid and Forearm Pressure-Decay and Windkessel Parameters: Implications for Circulatory Models

We studied whether: 1) the carotid and forearm diastolic pressure-decay time constants (tau) are similar and 2) the associated Windkessel (WK)-derived compliance and stiffness values are also similar and are related to arterial stiffness. Ambulatory normotensive and hypertensive subjects were studied after 30 minutes of supine rest with radial and carotid arterial tonometry (Sphygmocor), standard oscillometric cuff BP, and central (heart-femoral, hf) and peripheral (femoral-ankle, fa) pulse wave velocity (PWV, Colin VP1000). Brachial and carotid Doppler flow studies were performed in a subset. Tonograms were photo-digitized and the pressure in late diastole was modeled as an exponential decay to an asymptote A with time constant tau and start-decay time t0. [Resistance = mean pressure/flow; WK compliance = tau/resistance and WK stiffness = 1/WK compliance.] Tonometry and PWV data were available in 98 individuals; carotid and forearm blood flow in 22: (mean[SD]) age 50[20] years, weight 81[17] kg, BP 134/77[17/12] mmHg, resting HR 66[12], 38% female. Data are presented in the Table; hfPWV and faPWV were well correlated (p<0.001) but neither was correlated with carotid or forearm tau or the corresponding regional WK stiffness. We conclude that diastolic pressure decay (tau) and WK stiffness (or compliance) are not systemic indicators but rather unique regional characteristics not related to central or peripheral large artery stiffness. These findings suggest that single-WK models do not adequately represent the arterial circulation.

Intact DNA Repair in Differentiated Cardiomyocytes is Essential for Maintaining Cardiac Function in Response to Physiological Stimulus

IntroductionDNA in every cell is continuously damaged and DNA repair mechanisms are essential for protection against DNA damage‐induced aging‐related diseases. Evidence indicates that DNA damage is associated with heart failure. We have shown that unrepaired endogenously generated DNA damage drives the early onset of progressive heart failure (de Boer et al. Cardiovasc Res, 2018;114:S105). Here we studied the effects of a physiological stimulus on cardiac function in a mouse model with deficient DNA repair.MethodsTo increase the burden of spontaneous DNA damage, we generated mice with cardiomyocyte‐restricted inactivation of DNA repair endonuclease XPG (αMHC‐Xpgc/−). To induce physiological left ventricular (LV) hypertrophy, mice were exposed to 11 weeks of voluntary wheel running. Subsequently, LV geometry, function and structure were studied at age 16 weeks.ResultsCardiomyocyte‐restricted inactivation of Xpg resulted in systolic as well as diastolic LV dysfunction, demonstrated by decreases in fractional shortening, LVdP/dtP40 and LVdP/dtmin and increases in LV end‐diastolic lumen diameter (LVEDD) and relaxation time constant tau compared to WT (Table). In addition, expression level of hypertrophy maker gene β‐myosin heavy chain (β‐MHC) was elevated. Physical activity has been shown to be beneficial for maintaining and improving cardiac function in mice after myocardial infarction (de Waard et al. Circ Res, 2007;100:1097). In contrast, exercise failed to ameliorate LV remodeling and dysfunction in αMHC‐Xpgc/−, as it produced further increases in LVEDD, tau and β‐MHC compared to sedentary αMHC‐Xpgc/− (Table). Moreover, myocardial collagen content and the number of γH2A. X positive nuclei, a marker for DNA damage, were increased, suggesting that αMHC‐Xpgc/− showed increased susceptibility to exercise.ConclusionCardiomyocyte‐restricted loss of DNA repair protein Xpg increases cardiac vulnerability to develop heart failure in response to exercise training. These findings underscore the importance of genomic stability for maintenance of cardiac function, not only during basal conditions, but also in response to a physiological stimulus.Support or Funding InformationSupported by a NHF Grant 2007B024 and CVON‐ARENA (CVON2011‐11).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Relationship between dynamic expiratory time constant tau(edyn) and parameters of breathing cycle in pressure support ventilation mode.

Study of the relationship between ventilation parameters: monitored expiratory time constant - tau(edyn) and breathing - trigger frequency (f(trig)) and time of breathing cycle (T(cy)) are main goals of this article. Parameters were analyzed during last 4+/-2 h before weaning from ventilation in 66 patients ventilated in pressure support mode (PSV). We have found out, that there exist mathematical relationships, observed during adequate gas exchange, yet not described. Monitored parameters are represented by tau(edyn), f(trig) and T(cy). The analysis showed close negative correlation between T(cy) and f(trig) (R(2)=0.903). This implies that each increasing of tau(edyn) causes decreasing of f(trig) and vice versa. The calculation of regression equation between tau(edyn) and T(cy) outlined that T(cy) = 5.2625 * tau(edyn) + 0.1242 (R(2)=0.85). Regulation of respiratory cycles by the respiratory center in the brain is probably based on evaluation of tau(edyn) as the tau(edyn) probably represents a regulatory element and T(cy) regulated element. It can be assumed, that respiratory center can optimize the work of breathing in order to minimize energy in system patient + ventilator. The unique relationship, described above could be useful in clinical practice for development of new ventilation modes.

Inferring neural circuit properties from optogenetic stimulation.

Optogenetics has become an important tool for perturbing neural circuitry with unparalleled temporal precision and cell-type specificity. However, direct activation of a specific subpopulation of neurons can rapidly modulate the activity of other neurons within the network and may lead to unexpected and complex downstream effects. Here, we have developed a biologically-constrained computational model that exploits these non-intuitive network responses in order to gain insight into underlying properties of the network. We apply this model to data recorded during optogenetic stimulation in the primary visual cortex of the alert macaque. In these experiments, we found that optogenetic depolarization of excitatory neurons often suppressed neuronal responses, consistent with engagement of normalization circuitry. Our model suggests that the suppression seen in these responses may be mediated by slow excitatory and inhibitory conductance channels. Furthermore, the model predicted that the response of the network to optogenetic perturbation depends critically on the relationship between inherent temporal properties of the network and the temporal properties of the opsin. Consistent with model predictions, stimulation of the C1V1TT opsin, an opsin with a fast time constant (tau = 45 ms), caused faster and stronger suppressive effects after laser offset, as compared to stimulation of the slower C1V1T opsin (tau = 60ms). This work illustrates how the non-intuitive network responses that result from optogenetic stimulation can be exploited to gain insight regarding network properties that underlie fundamental neuronal computations, such as normalization. This novel hybrid opto-theoretical approach can thus enhance the power of optogenetics to dissect complex neural circuits.

Abstract 20900: Exercise Training Fails to Improve Cardiac Dysfunction in DNA Repair-Deficient Xpg Mice

Background & Hypothesis: The exact molecular mechanisms underlying the pathogenesis of heart failure (HF) remain incompletely understood hampering a more mechanism-based approach to effective treatment and prevention. Every cell contains DNA repair systems to protect against DNA damage-induced cancer and aging-related diseases. Evidence indicates that DNA damage is associated with heart failure. Physical activity is beneficial for maintaining and improving cardiac function. Therefore we hypothesized that voluntary wheel running (EX) would ameliorate cardiac function in cardiomyocyte-specific DNA repair-deficient Xpg mice. Methods: αMHC-Xpg c/- and wildtype (WT) mice were exposed to 11 wks of sedentary housing (SED) or EX, resulting in 4 groups; αMHC-Xpg c/- SED (n=12), WT SED (n=10), αMHC-Xpg c/- EX (n=16) and WT EX (n=13). At age 16 wks, left ventricular (LV) function was assessed using echocardiography and hemodynamic measurements. Results: Cardiomyocyte-specific inactivation of Xpg resulted in systolic as well as diastolic dysfunction, demonstrated by decreases in fractional shortening (23±2 vs. 39±2 %), LV systolic pressure (82±4 vs. 91±3 mmHg), LV dP/dt at 30 mmHg (5240±350 vs. 7480±440 mmHg/s) and LV dP/dtmin (-6740±830 vs. -10890±780 mmHg/s; all p<0.05). In addition, LV end-diastolic lumen diameter (LVEDD) was markedly increased (3.9±0.1 vs. 3.0±0.1 mm; p<0.05). Total running distance was indistinguishable between αMHC-Xpg c/- EX and WT EX (881±61 vs. 856±39 km resp.). Global LV function was unaffected by EX in WT mice. Contrary to our hypothesis, LV remodeling and dysfunction tended to aggravate by EX in αMHC-Xpg c/- mice, as evidenced by further increases in LVEDD (4.2±0.1 vs. 3.9±0.1 mm; p<0.05) and relaxation time constant tau (19.2±2.6 vs. 13.6±2.9 ms; p<0.06). Conclusion: Although, αMHC-Xpg c/- mice display a cardiac phenotype which is largely similar to mice subjected to MI and we have previously shown exercise improves LV remodeling and dysfunction after MI, exercise failed to ameliorate LV remodeling and dysfunction associated with cardiomyocyte-restricted loss of DNA-repair protein Xpg.

Tetrahydrobiopterin improves left ventricular diastolic function possibly through upregulating phosphorylated protein kinase B expression in hypertensive mice induced by deoxycorticosterone acetate

Objective: To investigate whether tetrahydrobiopterin (BH4) could improve left ventricular diastolic function through phosphoinositide-3 kinase/protein kinase B (PI3K/Akt) signaling pathway in hypertensive mice. Methods: Ten-week-old male C57BL/6 mice were used to establish the deoxycorticosterone acetate (DOCA)-salt hypertensive model, age matched Sham mice serve as the controls. Mice were divided into four groups: Sham(n=20), Sham+ BH4 (n=20), DOCA (n=22), and DOCA+ BH4 (n=22). On the 14 days after surgery, mice in Sham+ BH4 and DOCA+ BH4 groups received BH4 (0.1 ml/10 g) supplement for 7 days, while mice in Sham and DOCA groups were given equal volume of normal saline.The blood pressure measurements were performed 7 days later.Hemodynamic and echocardiographic parameters were used to assess left ventricular functions.High performance liquid chromatography (HPLC) analysis was used to measure cardiac biopterins BH4 and BH2.The phosphorylated phospholamban (p-PLB) was detected by immunohistochemical staining. PI3K, Akt and phosphorylated Akt were assayed with Western blot analysis. Results: (1) The systolic and diastolic blood pressure of DOCA group were significantly higher than control group (P<0.05). Compared with DOCA group, the systolic blood pressure was lower in DOCA+ BH4 mice (P=0.027). Diastolic blood pressure was similar between the groups. (2) Compared with Sham group, the left ventricular diastolic function indexes such as mitral annulus velocity (E') and E'/A'ratio were significantly lower, while the E/ E'ratio was significantly higher(P<0.05)in DOCA mice. The E/ E'ratio of DOCA+ BH4 group was significantly lower than that of DOCA group (P<0.05). Compared with Sham group, the left ventricular end-diastolic pressure (LVEDP), left ventricular end-diastolic pressure volumetric coefficient (EDPVR) and left ventricular relaxation time constant Tau index were significantly higher in DOCA mice (P=0.002, 0.011 and 0.016, respectively). The EDPVR and Tau index were significantly lower in DOCA+ BH4 group than in DOCA group (P<0.05). (3) Compared with Sham group, the myocardial contents of BH4 and BH2 were significantly lower in DOCA mice (P<0.05). The BH4 levels and BH4/BH2 ratio were significantly higher in Sham+ BH4 and DOCA+ BH4 groups than in the DOCA group (P<0.05), but the BH2 levels were similar between groups. (4) The cGMP content, SOD activity and NO content in the left ventricular myocardial tissue were significantly lower (P<0.05), while the MDA content was significantly higher in DOCA mice than in Sham mice.The NO content and SOD activity in DOCA+ BH4 groups were significantly higher than in the DOCA group (P<0.05). (5) Compared with DOCA group, the expression of p-PLB was significantly higher in Sham mice and lower in DOCA+ BH4 mice (P<0.05). (6) The expression of PI3K, Akt and p-Akt (Ser473 and Thr308) in DOCA mice were significantly lower than in Sham group (P<0.05). The expression of PI3K, Akt and p-Akt (Ser473) was significantly higher in DOCA+ BH4 group than in DOCA group (P<0.05). p-Akt (Thr308) expression was similar between DOCA + BH4 group and DOCA group (all P>0.05). Conclusion: Our results suggest that BH4 could improve left ventricular diastolic function in hypertensive mice, this effect might be mediated by reducing the oxidative stress in ventricular myocardium through modlating the expression of Akt and PLB phosphorylation.

A influência de variáveis aeróbias e anaeróbias no teste de “sprints” repetidos

Resumo O objetivo deste estudo foi determinar o modo e o grau com que variáveis aeróbias e anaeróbias influenciam o desempenho e a fadiga em “sprints” repetidos (RS) na corrida. Para este fim, participaram do estudo 24 homens, sendo oito corredores velocistas, oito corredores fundistas e oito sujeitos ativos. Em uma pista sintética de atletismo estes sujeitos foram submetidos aos seguintes testes: 1) teste incremental para determinação do VO2max e da velocidade aeróbia máxima (VAM); 2) teste de velocidade constante realizado a 110%VAM para determinar a cinética do VO2 durante exercício e o máximo déficit acumulado de oxigênio (MAOD); 3) teste de “sprints” repetidos (10 “sprints” de 35 m, intercalados com 20 s de recuperação) para determinar o tempo total dos “sprints” (TT), tempo do melhor sprint (TM) e a queda do desempenho em percentual (Sdec). Para analisar a diferença entre os grupos e as relações entre as variáveis foram utilizadas a análise de variância ANOVA “one-way”, complementada pelo teste de Tukey, e a correlação de Pearson, respectivamente. O TT em RS foi diferente significativamente entre todos os grupos (velocistas, 49,5 ± 0,8 s; fundistas, 52,6 ± 3,1 s; ativos, 55,5 ± 2,6 s) e Sdec foi significativamente inferior em fundistas comparado aos outros grupos (velocistas, 8,9 ± 2,1%; fundistas, 4,0 ± 2,0%; ativos, 8,4 ± 4,4%). O TT foi correlacionado significativamente com o TM (r = 0,85, p &lt; 0,01) e com o MAOD (r = −0,54, p &lt; 0,01). Além disso, Sdec foi correlacionado significativamente com variáveis aeróbias (VO2max, r = −0,58, p &lt; 0,01; VAM, r = −0,59, p &lt; 0,01; constante de tempo “tau”, r = 0,45, p = 0,03). Portanto, conclui-se que apesar de índices aeróbios influenciarem na redução da fadiga em RS, o desempenho em RS é principalmente influenciado por características anaeróbias.

Abstract 262: A Rat Model of Heart Failure With Preserved Ejection Fraction Induced by Pressure Overload

The absence of animal models displaying clinical phenotypes of HFpEF represents a challenge to the pharmaceutical industry in the hope of identifying novel treatments that would benefit patients with this syndrome. We, at Merck, examined the supracoronary aortic banding (SAB) in rats as a potential model and set out to characterize its phenotypes. Juvenile Sprague-Dawley rats were used; a hemostatic clip with an opening of 0.7 mm was placed around the ascending aorta to elicit a pressure overload to the LV. Echocardiography was performed every 3 weeks and invasive hemodynamics was measured at week 9 to evaluate cardiac structural and functional effects; heart and lungs were harvested at the end for morphological and histological analysis. Nine weeks after SAB, LV hypertrophy and dysfunction were apparent, as manifested by increases in LVEDP, left atrial pressure, plasma BNP, LV and lung weights; LV relaxation time constant (Tau) and mitral early to late inflow ratio (E/A) were also increased; while EF and FS were preserved (see table, mean ± SEM). In addition, SAB rats had elevated mean pulmonary pressure (sham 14 ± 1.7 vs. SAB 37 ± 4.4 mm Hg, p&lt;0.05) with an abnormal transpulmonary gradient (sham 12 ± 2.5 vs. SAB 23 ± 0.1 mm Hg, p&lt;0.05), indicating comorbidity of pulmonary hypertension. Finally, piloerection, dyspnea and loss of muscle mass were evident and exercise tolerance measured by treadmill test was decreased in SAB rats. In summary, rats undergoing SAB exhibit many of the clinical phenotypes of HFpEF. Further work includes examining the effects of novel therapies in SAB rats on improving these clinical phenotypes of HFpEF and expanding the model to study morbidity and mortality.

The effect of hydrate promoter SDS on methane dissolution rates at the three phase (H-Lw-V) equilibrium condition

Clathrate hydrate promotion research has often focused on hydrate growth rate differentiation, however little work has been done to understand the kinetics of dissolution. The dissolution of gas into the bulk liquid phase is of great importance to hydrate growth, as it is the first step in hydrate formation. Furthermore, understanding the influence of additives on hydrate systems may provide significant insight into the mechanisms of their function. The effect of the hydrate promoter sodium dodecyl sulphate (SDS) on methane dissolution was thus investigated at the three-phase (H-Lw-V) equilibrium condition of 275.1 K and 3145 kPa. Experiments with concentrations of SDS ranging from 0.01 mM to 4 mM were conducted. The purpose of this study was to investigate the effects on the methane equilibrium saturation values as well as the kinetics of dissolution. The effects on saturation were found to be negligible. The rate of dissolution was measured using a first-order response model and the time constant tau (τ). It was found that the values of τ for SDS increased with an increasing loading of 0.01 mM–0.75 mM and then plateaued for concentrations ranging between 0.75 and 4 mM producing a sigmoidal trend.

Reproducibility of axon reflex-related vasodilation assessed by dynamic thermal imaging in healthy subjects

IntroductionSmall nerve fiber dysfunction is an early feature of diabetic neuropathy. There is a strong clinical need for a non-invasive method to assess small nerve fiber function. Small nerve fibers mediate axon reflex-related vasodilation and play an important role in thermoregulation. Assessing the reflex vasodilation after local heating might elucidate some aspects of small fiber functioning. In this study, we determined the reproducibility of the reflex vasodilation after short local heating in healthy subjects, assessed with thermal imaging and laser Doppler imaging. MethodsHealthy subjects underwent six heating rounds in one session (protocol I, N=10) or spread over two visits (protocol II, N=20). Reflex vasodilation was elicited by heating the skin to 42°C with an infrared lamp. Skin temperature and skin blood flow were recorded during heating and recovery with a thermal imaging camera and a laser Doppler imager. Skin temperature curves were fitted with a mathematical model to describe the heating and recovery phase with time constant tau (tauHeat and tauCool1). ResultsThe reproducibility of tau within a session was moderate to excellent (intra-class correlation coefficient 0.42–0.86) and good (0.71–0.72) between different sessions. Within one session the differences in tauHeat were small (bias±SD −1.3±18.9s); the bias between two visits was −1.2±12.2s. For tauCool1 the differences were also small, 1.4±6.6s within a session and between visits −1.4±11.6s. ConclusionsThe heat induced axon reflex-related vasodilation, assessed with thermal imaging and laser Doppler imaging, was reproducible both within a session and between different sessions. Tau describes the temporal profile in one parameter and represents the effects of all changes including blood flow and as such, is an indicator of the vasodilator function. TauHeat and tauCool1 can accurately describe the dynamics of the axon reflex-related vasodilator response in the heating and recovery phase respectively.