bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac Hypertrophy and Ventricular Contractility in Rats Exposed to Neonatal Supplemental Oxygen and High Fat Diet
Authors: Chandrasekar Shreya , Vellookunnel Shilpa , Hoover Michael , Sturgeon Madison , Murphy Austin , Bates Melissa
Published: November 2023

Premature birth represents about 13% of live births each year. Since lungs of these infants are underdeveloped, they receive supplemental oxygen right after birth, but little is known about its effects on the development of normal physiological responses and whether it impacts long‐term cardio‐metabolic function. Based on previous studies from our lab that showed increased pulse wave velocity in 12 month old rats exposed to neonatal supplemental oxygen, we hypothesized that neonatal exposure to supplemental oxygen causes cardiac hypertrophy and decreased left ventricular contractility. We also hypothesized that these effects to supplemental oxygen would be enhanced by 10 weeks on a high fat diet. To test the hypothesis, we used our rat model of OXY and CON rats exposed to FlO2=0.80 and 0.21 respectively, for 8 days post‐birth. Two months after birth, these OXY and CON rats were randomly assigned to either a high fat diet (60% of calories from animal fat) or low fat diet for 10 weeks during which their weights and caloric consumptions were monitored. After 10 weeks, a Miller conductance catheter was inserted into the left ventricle to obtain pressure volume loops and end‐systolic pressure volume relationship, which was used to evaluate contractility. OXY rats tended to have larger left ventricles (1.40±0.24 g vs 1.18±0.08g) and OXY rats fed a high fat diet showed greater average weight gain than CON rats on the same diet. There was no difference in contractility. These data suggest that neonatal supplemental oxygen may promote left ventricular hypertrophy and weight gain.

Support or Funding Information

The University of Iowa Start‐Up Fund
Left Ventricular Remodeling and Cardiac Dysfunction in Long‐Term Burn Survivors
Authors: Nasirian Aida , Nelson Michael , Kouda Ken , Romero Steven , Adams Amy , Jaffery Manall , Cramer Matthew , Moralez Gilbert , Kowalske Karen , Phelan Herb , Wolf Steven , Merz Noel Bairey , Crandall Craig
Published: November 2023

Burn injury is characterized by increased morbidity and mortality and decreased quality of life. Our group has shown that ~75% of burn survivors (beyond 2 years post‐recovery), having 15 to 75% of their body surface area (BSA) grafted, have a maximal oxygen uptake (VO2max) in the lowest 20th percentile rankings, relative to sex and age adjusted non‐burned individuals. The exact mechanism responsible for this impairment remains unclear but may be related to adverse cardiac remodeling and left ventricular dysfunction. To address this knowledge gap, we recruited 16 burn survivors (age: 40 ± 20 years; female/male: 8/8), with burns ≥ 20% BSA. Left ventricular (LV) morphology and global function were assessed by cardiac magnetic resonance imaging (cMRI). Additionally, myocardial strain analysis, a more sensitive indicator of LV function, was assessed by novel MR tissue tracking of conventional CINE images. The major novel findings of this investigation are twofold. First, the burned subjects' LV mass was ≥ 2 standard deviations less than published normative values (105.8 ± 12.4 vs. 147 ± 20, burn vs. published norm, respectively). Second, all three principal strains (radial, circumferential, longitudinal) were impaired in burn survivors compared to a group of healthy reference controls (radial: 40.0 ± 1.5% vs. 52.4 ± 1.8%; circumferential: −19.8 ± 0.6% vs. −23.8 ± 0.5%; longitudinal: −20.2 ± 0.5% vs. −23.1 ± 0.6%, burn vs. control, respectively; all P<0.05). Taken together, these novel and innovative findings suggest that burn‐injuries lead to severe cardiac atrophy and impaired LV systolic function, which persist well beyond the recovery period. More work is needed to define mechanisms contributing to this adverse response, with a goal to attenuate/eliminate these adverse changes.

Support or Funding Information

This work is supported by: NIH – R01GM068865
Environmental Enrichment Alters the Impact of Social Stress on the Cardiovascular System
Authors: Normann Marigny , McNeal Neal , Colburn William , Dagner Ashley , Ihm Elliott , Toghraee Amir , Woodbury Matthew , Grippo Angela J
Published: November 2023

Stress has been linked to negative cardiovascular consequences in both humans and non‐human animals, such as an increased risk of cardiovascular disease (CVD) and mortality, as well as an increase in depressive and anxiety related behaviors. To combat the effects of stress, research has incorporated environmental enrichment (EE) into animal models of stress. EE involves exposure to novel items and other species‐relevant engaging stimuli such as nesting material and toys. EE has cognitive benefits, such as improving recognition, acquisition and retention of information; as well as psychological benefits, such as reducing anxiety‐related behaviors. This study utilized the prairie vole to investigate the potential protective effects of EE on behavior and cardiovascular function. Prairie voles have a social structure similar to humans, including social monogamy and co‐parenting of offspring, which are rare characteristics in rodents. In this study, female prairie voles were surgically implanted with radiotelemetry transmitters to measure continuous heart rate and heart rate variability [using standard deviation of normal‐to‐normal intervals (SDNN Index) and respiratory sinus arrhythmia (RSA)]. Each female was paired with a male partner for five days followed by a period of isolation for an additional five days. The females were subsequently placed into one of three conditions for ten days: (a) isolation in a standard cage, (b) isolation in an EE cage, or (c) re‐paired with their male partner. The females were then tested in the forced swim test (FST) for five minutes as an index of depressive behavior. Cardiovascular measures were recorded during all phases of the experiment. All animals experienced negative cardiovascular effects of isolation. During exposure to the various treatment conditions, heart rate in the EE and re‐paired groups returned to baseline, but remained elevated in the prolonged isolation group. Similar effects were found for RSA. SDNN Index was increased in the EE group (relative to baseline and isolation), but remained similar to the isolation phase under both the prolonged isolation and re‐paired conditions. In the FST, the animals in the prolonged isolation group spent twice as much time immobile than the EE or repaired groups, which were comparable, indicating lower levels of depressive behaviors in the EE and re‐paired groups. These results suggest that EE may be as beneficial for an animal's behavioral and cardiovascular health as being re‐paired with a previously socially‐bonded partner. EE or a similar non‐social experience may attenuate psychological and physiological consequences of social stress in humans.

Support or Funding Information

HL112350
Exposure to PM2.5 In Utero Contributes to Early Adult Cardiac Dysfunction
Authors: Tanwar Vineeta , Adelstein Jeremy , Grimmer Jacob , Youtz Dane , Wold Loren
Published: November 2023

Objective

Fine particulate matter (PM2.5) exposure during developmental is strongly associated with adverse cardiovascular outcomes at adulthood. The present study was designed to investigate the effects of in utero exposure to PM2.5 on cardiac function in 14 day old pups.

Methods

Female FVB mice were exposed either to filtered air (FA) or PM2.5 at an average concentration of 73.61μg/m3 for 6h/day, 7days/wk (mimicking exposure in a large industrial area) throughout pregnancy. To examine cardiac function, male offspring at 14 days of age underwent baseline echocardiographic assessment. Following sacrifice, cardiomyocytes were isolated to assess in vitro cardiomyocyte sarcomere function using the IonOptix system. LV tissue from a separate group of mice was used to isolate protein for western blot analyses.

Results

Mice exposed to PM2.5 during the in utero period demonstrated decreased percentage fractional shortening (%FS). Isolated cardiomyocyte function illustrated reduced peak shortening (%PS), decreased 360/380 ratio of fura 2 fluorescence and increased fluorescence decay time constant (tau). Western Blot analyses showed increased expression of SERCA and p‐PLN and decreased expression of CaV1.2 and NCX in 14 day old in utero PM2.5 exposed mouse hearts compared to FA exposed hearts.

Conclusion

Exposure to PM2.5 during the in utero period caused adverse effects on the developing fetus by modifying expression of Ca2+ signaling proteins leading to cardiac dysfunction, which is evident during the very early stages (14 days) of the postnatal period.

Support or Funding Information

Funding for the project was provided by a grant from the National Institutes of Health (RO1ES019923) to LEW.
Specific Afferent Renal Denervation Improves Reduced nNOS in the Paraventricular Nucleus in Rats with Heart Failure
Authors: Zheng Hong , Liu Xuefei , Knuepfer Mark M , Patel Kaushik P
Published: November 2023

Renal denervation (RDN) has been shown to restore endogenous neuronal nitric oxide synthase (nNOS) in the paraventricular nucleus (PVN), and at the same time reduce sympathetic drive during heart failure (HF), however the role of afferent versus efferent renal nerves in this response remains to be determined. The purpose of the present study was to assess the contribution of afferent renal nerves (ARN) in the nNOS within the PVN mediated sympathetic outflow in rats with HF. HF was induced in rats by ligation of the left coronary artery. Four weeks after surgery, selective afferent RDN (A‐RDN) was performed by bilateral perivascular application of capsaicin on the renal arteries. Seven days after intervention, A‐RDN was verified by lack of calcitonin gene‐related peptide in renal pelvic wall. A‐RDN reduced basal lumbar sympathetic nerve activity (LSNA) in rats with HF (8.5 ± 0.5 vs 17.0 ± 1.2 % of Max). nNOS‐positive cells immunostaining and ‐diaphorase staining were significantly decreased in the PVN of HF rats, findings that were ameliorated by A‐RDN. Microinjection of nNOS inhibitor L‐NMMA into the PVN resulted in a blunted increase in LSNA in HF, this response was improved after A‐RDN (ΔLSNA: 25.7 ± 2.4 vs 11.2 ± 0.9%). Resting ARN activity, expressed as a percent of peak ARN activity, was substantially increased in HF compared to sham rats (60.9 ± 2.2 vs 27.7 ± 4.4 %Amax). These results suggest that intact ARN contribute to the reduction of nNOS in the PVN, resulting in activation of the neurons in the PVN of rats with HF. Specific A‐RDN restores nNOS and thus attenuates the sympathoexcitation. Also, resting ARN activity is elevated in HF rats, which may highlight a crucial neural mechanism initiated from the kidney in the maintenance of enhanced sympathetic drive in HF.

Support or Funding Information

This work was supported by NIH grant P01 HL62222.
Insulin‐Like Growth Factor 1 Preserves Cardiac Function after Myocardial Infarction without Affecting Initial Ischemia and Reperfusion Injury
Authors: Heinen Andre , Nederlof Rianne , Raupach Annika , Reffelt Heiko , Gödecke Stefanie , Gödecke Axel
Published: November 2023

Insulin‐like growth factor 1 (IGF1) preserves cardiac function after myocardial infarction (MI). The remodeling process after myocardial infarction is influenced by the extend of the initial infarction and regulated by multiple cardiac and non‐cardiac cell types. It is unknown whether the beneficial effect of IGF1 on cardiac function is the consequence of a reduction in early myocardial necrosis due to IGF1 receptor (IGF1R) signalling in cardiomyocytes.

Inducible cardiomyocyte specific IGF1R KO and wild type mice (WT) underwent 45 min regional myocardial ischemia followed by 4 weeks of reperfusion. At reperfusion, mice received vehicle (Con) or IGF1 as bolus (40 ng/g, ip) followed by continuous infusion over 3 days using osmotic mini pumps (1 μg/g/d, sc). At baseline, there were no differences between WT and KO animals in left ventricular function (end diastolic (EDV), end systolic volume (ESV), and ejection fraction (EF)). IGF1 treatment improved cardiac function not only in WT mice (EF, week 4: 49±4% (IGF1) vs 36±8% (Con)), but also in KO mice (48±5% (IGF1) vs 35±5% (Con)). To investigate the effect of IGF1 on early ischemia and reperfusion injury, C57Bl6 mice underwent 45 min regional myocardial ischemia followed by 2 hours of reperfusion with and without IGF1 treatment. Infarct size staining showed no effect of IGF1 on infarct size (38±10% (IGF1) vs. 39±11% (Con)). In addition, IGF1 did not affect left ventricular function and myocardial damage in isolated perfused mouse hearts after global ischemia.

Exogenous IGF1 treatment preserves cardiac function after myocardial infarction independent of cardiomyocyte specific signaling. The preserved function after IGF1 treatment is not caused by an effect on early ischemia and reperfusion injury indicating that IGF1 modulates the cardiac remodeling process in the subacute phase after MI.

Support or Funding Information

Funded by the German Research Foundation (SFB1116/A06)
Impact of Methamphetamine on the Ischemic Hearts of Three Generations of Rats
Authors: Rorabaugh Boyd R. , Seeley Sarah L. , Stoops Thorne , Sprague Lisanne , Bui Albert D. , D'Souza Manoranjan
Published: November 2023

Approximately 5 % of the United States population has used methamphetamine at some point in their lifetime. Methamphetamine is known to increase the risk of a myocardial infarction, but it is unclear whether methamphetamine alters the extent of myocardial injury. The first goal of this study was to determine whether repeated methamphetamine exposure alters the extent of injury in the ischemic heart. Adult rats received daily subcutaneous injections of methamphetamine (5 mg/kg) or saline for 10 days, and their hearts were subjected to an ischemic insult on day 11 using a Langendorff isolated heart apparatus. Hearts from methamphetamine‐treated female rats exhibited significantly larger infarcts and significantly suppressed postischemic recovery of contractile function compared to hearts from saline‐treated females. In contrast, infarct size and postischemic recovery of contractile function were unaffected by methamphetamine in males. The second goal was to determine whether prenatal methamphetamine exposure alters myocardial sensitivity to ischemic injury during adulthood. Pregnant rats (F0 generation) received daily injections of methamphetamine (5 mg/kg) or saline throughout the duration of their pregnancy. When the F1 pups reached 8 weeks of age, their hearts were subjected to an ischemic insult. Infarcts were significantly larger in adult female hearts that had been prenatally exposed to methamphetamine compared to control females that were prenatally exposed to saline. In addition, protein kinase C‐ɛ expression and Akt phosphorylation were decreased in hearts from methamphetamine‐exposed females. In contrast, methamphetamine had no impact on infarct size, PKC‐ɛ, or Akt phosphorylation in their male littermates. Others have reported that rat pups (F2) born to parents (F1) that were prenatally exposed to methamphetamine exhibit deficits in sensory‐motor coordination. Thus, F1 rats that had been prenatally exposed to methamphetamine were used as breeders to produce the F2 generation of rats. Hearts from F2 rats were subjected to an ischemic insult when they reached 8 weeks of age. We found no evidence for myocardial hypersensitivity to ischemic injury in the F2 generation that was not directly exposed to methamphetamine. These data provide evidence that a history of adult or prenatal exposure to methamphetamine worsens ischemic injury in the adult heart. This could have significant implications for people who have both ischemic heart disease and a history of adult or prenatal exposure to methamphetamine.

Support or Funding Information

This work was supported by an Ohio Northern University Bower and Bennet Endowment Award to BRR.
Retinoic Acid Regulates Cardiac Progenitor Cell Proliferation and Differentiation
Authors: Favreau‐Lessard Amanda J , Rath Rutwik , Duarte Samantha , Pinz Ilka , Ryzhov Sergey , Asson‐Batres Mary Ann , Sawyer Douglas B.
Published: November 2023

Vitamin A (retinol) and its metabolite retinoic acid (RA) are crucial for heart development; however their role in the adult heart is less understood. Lecithin retinol acyltransferase (LRAT) null mice lack the ability to store retinoic acid precursors in the liver, and thus cannot release RA in response to cardiac injury. This unique mouse model allows us to examine the role of RA in myocardial ischemia. We reported that LRAT null mice have improved recovery after myocardial infarction compared to wild type (WT) mice. Further investigation of this result showed that hearts of LRAT null mice have higher numbers of Sca1posCD31neg cardiac progenitor cells and that they have an increased proliferative phenotype. These findings suggest a role for RA in regulating this cardiac progenitor cell population. We hypothesized that hepatic retinol release post‐cardiac injury will alter Sca1posCD31neg cell proliferation and differentiation. Thus, in this study, we examined how RA regulates this cell population in vitro. We found that Sca1posCD31neg cells express retinoic acid receptor gamma (RARγ) and retinaldehyde dehydrogenase enzyme 1 (RALDH1) measured by qPCR, indicating they are responsive to RA signaling and have the ability to convert retinol to RA. We then examined the effect of RA on proliferation (Ki67) of Sca1posCD31neg cells and expression of the anti‐fibrotic marker, Sca1 and the pro‐fibrotic marker, alpha smooth muscle actin (αSMA). We found that RA treatment reduces Sca1 expression, which is associated with cell differentiation. Consequently, we performed flow cytometry using αSMA and CD31 as myofibroblast and endothelial cell markers. CD31 expression was unchanged across treatment groups, suggesting that RA does not promote the endothelial lineage. However, RA treatment caused an 11% increase in αSMA compared to untreated cells (unpaired t test, p<0.05), suggesting that RA exposure promotes myofibroblast differentiation. This myofibroblast subpopulation is Ki67 positive and was further tested for its response to RA. Untreated Ki67pos cells were 29% αSMApos while RA exposure increased αSMA to 41% (unpaired t test, p<0.05). This suggests that RA determines Sca1posCD31neg cell fate by specifically inducing proliferative myofibroblasts. Overall, our study identified a novel role of RA in the regulation of cardiac Sca1posCD31neg cells by demonstrating that they are retinoid responsive cells that preferentially differentiate into a proliferative myofibroblast lineage. Future work on the mechanism of RA‐induced αSMA expression will determine whether targeting RA‐dependent signaling in Sca1posCD31neg cells provides a new therapeutic option in preventing left ventricular remodeling after ischemic myocardial injury.
Deficiency of Ataxia‐telangiectasia Mutated Kinase Induces Autophagic Impairment Following Myocardial Infarction
Authors: Thrasher Patsy R. , Scofield Stephanie L.C. , Dalal Suman , Singh Mahipal , Singh Krishna
Published: November 2023

Autophagy, a conserved physiological process, is typically triggered by nutritional stress and/or growth factor deprivation and ultimately results in the packaging of cellular components into autophagosomes. These autophagosomes then fuse to lysosomes to be degraded. Although often associated with nutrient deprivation, autophagy is suggested to play a significant role in cardiac remodeling, particularly following myocardial infarction (MI). Ataxia‐telangiectasia mutated kinase (ATM) is a 370 kDa threonine/serine kinase. Mutations in ATM cause a multisystemic disease known as Ataxia‐telangiectasia (AT). Although the role of ATM in cell cycle progression is well known, its role in autophagy is not yet completely understood. The present study tested the hypothesis that deficiency of ATM impairs autophagic response in the heart post‐MI. MI was induced in ~4 month old wild‐type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. The mice were sacrificed 4 hours following MI. Levels of microtubule‐associated protein light chain 3 (LC3), sequestosome 1 (p62), cathepsin D, and phosphorylation of Akt and glycogen synthase kinase 3β (GSK3‐β) were analyzed in the heart lysates using western blots. Ratio of LC3II/LC3I, marker of autophagy induction and autophagosome formation, was significantly lower in hKO‐sham when compared to WT‐sham group (P<0.05 vs WT‐sham; n=7). MI decreased LC3II/LC3I ratio in both groups with no significant difference between the two genotypes. Expression of p62, a marker of autophagic clearance, was significantly higher in hKO‐MI group when compared to hKO‐sham and WT‐MI groups (P<0.05 vs hKO‐sham and WT‐MI; n=6–7). Expression of mature cathepsin D, a lysosomal endopeptidase involved in autophagic clearance, was lower in hKO‐MI group when compared to hKO‐sham. Activation of Akt was lower, while activation of GSK3β was higher in hKO‐MI group when compared to hKO‐sham (P<0.05 vs hKO‐sham; n=6–7). These data suggest that 1) ATM deficiency down‐regulates autophagy in the heart at basal levels; 2) MI down‐regulates autophagy in both genotypes 4 h post‐injury as assessed by the ratio of LCII/LC3I; 3) ATM deficiency impairs autophagic response as indicated by the accumulation of p62 and decreased cathepsin D levels in ATM deficient hearts post‐MI; and 4) autophagic impairment during ATM deficiency involves Akt/GSK3β pathway. Thus, ATM deficiency results in impaired autophagic activity in the heart post‐MI via the involvement of Akt/GSK3β signaling.

Support or Funding Information

Supported by Department of Veterans Affairs (BX002332), NIH R15HL129140 (NHLBI) and Institutional Research and Improvement account.
Bolus ghrelin administration ameliorates the inflamatory response and oxidative stress during precutaneous cardiopulmonary support in a rat model
Authors: SUKUMARAN VIJAYAKUMAR , Fujii Yutaka , Tsuchimochi Hirotsugu , Shirai Mikiyasu , Tatsumi Eisuke , Pearson James T
Published: November 2023

Background

Percutaneous cardiopulmonary support (PCPS) induced inflammation significantly contributes to the development of postoperative complications, including respiratory failure, myocardial, renal and neurological dysfunction and ultimately leads to multiple organ failure. Ghrelin is a small endogenous peptide with wide ranging physiological effects on metabolism and cardiovascular regulation. We investigated the protective effects of ghrelin against the PCPS‐induced inflammatory reactions, oxidative stress and acute organ damage.

Methods

Adult male Sprague Dawley rats were subjected to PCPS for 4 hours and randomly received vehicle (n=6) or a bolus of ghrelin (150μg/kg, sc, n=6). Rats were euthanized and heart, lung, kidney and brain samples were harvested for further histopathological analysis. Blood samples were taken before starting, after 2 hrs and 4 hrs of PCPS. We measured the plasma cytokine levels of (tumor necrosis factor (TNF)‐α and interleukin (IL)‐6), catecholamines (norepinephrine, epinephrine and dopamine) and organ damage markers (lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Oxidative stress markers (3‐nitrotyrosine) were measured by western blot.

Results

PCPS‐induced leucocytosis and increased plasma levels of TNF‐α, IL‐6 indicating an inflammatory response. In addition, organ damage markers and catecholamines were also elevated. Ghrelin treatment attenuated the inflammatory response, as evidenced by reduced inflammatory cytokines, organ damage markers and protein levels of 3‐nitrotyrosin. Importantly, ghrelin dramatically suppressed the plasma catecholamines concentration when compared to the PCPS group.

Conclusions

These results suggest that ghrelin inhibits the inflammatory response and oxidative stress. One bolus of ghrelin might provide an effective approach for reducing widespread PCPS‐induced organ injury.

Support or Funding Information

Japan society for the promotion of science
Effects of Sanguinate™ on Systemic and Microcirculatory Variables in a Model of Prolonged Ischemic Shock
Authors: Nugent William H , Cestero Ramon F , Jubin Ronald , Abuchowski Abe , Song Bjorn K
Published: November 2023

Hemorrhage after trauma is the leading cause of preventable death in young adults. In cases of severe blood loss, outcomes are dependent on prompt hemorrhage control and restoration of volume and oxygen carrying capacity. There is a dire need for oxygen carrying resuscitants that overcome the perishability, compatibility, and bioreactivity issues of blood.

To study the effects of prolonged hypoxia and the effects of resuscitative fluids, a new model of prolonged ischemic shock (PIS) was developed by subjecting 17 male Sprague Dawley rats to a controlled, stepwise blood withdrawal (45% by volume), which mimicked conditions of post‐injury progressive hemorrhage control. Animals were then maintained in a state of untreated ischemic shock for at least 60 minutes and then received a 20% hypovolemic resuscitation with one of three test solutions: a crystalloid (Lactated Ringer's Solution; LRS), a colloid (Hextend™), or a novel PEGylated carboxyhemoglobin‐based oxygen carrier (Sanguinate™). Measurements of post‐resuscitative survival, spinotrapezius muscle interstitial oxygenation (PISFO2), arteriolar diameters, and systemic cardiovascular parameters were obtained throughout the experimental time course.

The PIS hemorrhage protocol produced peripheral tissue hypoxia as measured by phosphorescence quenching microscopy and was lethal in sham (untreated) animals after 90 min. Survival was significantly different among treatment groups (p < 0.01), where LRS, Hextend™ and Sanguinate™‐treated animals survived 16 ± 3.4, 76 ± 11.1 and 193 ± 33.4 mins, respectively. Only Sanguinate™ produced a significant rise in tissue PISFO2 by two hours post‐resuscitation (p < 0.01). Mean arterial pressure (MAP) was significantly increased in Sanguinate™ versus LRS (p < 0.05) post‐resuscitation, and higher than Hextend™ by 60 min post‐resuscitation (p < 0.0001). Post‐resuscitative increases in MAP and PISFO2 correlated with increased survival times.

We present a new model of evaluating prolonged tissue ischemia in the setting of hemorrhagic shock. Using this PIS model, we have shown that resuscitation with a carboxyhemoglobin‐based oxygen carrier (Sanguinate™) results in improved survival compared to standard resuscitation fluids. The PIS model provides a platform to investigate outcomes due to prolonged ischemia as opposed to acute hemorrhagic shock, and may therefore be more clinically applicable to current resuscitation protocols. Additionally, the PIS model may be useful in studies of reperfusion injury.

Support or Funding Information

Support: Song Biotechnologies, LLC & Prolong Pharmaceuticals, LLC
Taurine Supplementation Improves Cardiac Ischemia/Reperfusion Injury by Inhibiting Intra‐Cardiac Renin‐Angiotensin System Overactivity in Adult Female Rats Perinatally Depleted of Taurine
Authors: Kulthinee Supaporn , Navar L. Gabriel , Roysommuti Sanya
Published: November 2023

Perinatal taurine depletion particularly followed by a high sugar diet exacerbates cardiac injury, sympathoexcitation, and arterial pressure dysregulation after ischemia/reperfusion (IR) in adult male rats, while taurine treatment before and after cardiac IR prevents or reduces the adverse effects of IR. This study tested the hypothesis that in adult female rats perinatally depleted of taurine followed by a high sugar diet, taurine supplementation mitigates the cardiac IR injury by inhibiting intra‐cardiac renin‐angiotensin system overactivity. Female Sprague‐Dawley rats were fed normal rat chow with tap water alone (control, C) or tap water containing 3% beta‐alanine (taurine depletion, TD) from conception to weaning. Female offspring were fed the normal rat chow and drank 5% glucose in tap water (CG and TDG) or tap water alone (TDW and CW) throughout the study. One week before surgery, half of the rats in each treatment were supplemented with 3% taurine in tap water (CW+T, CG+T, TDW+T, and TDG+T). At 7–8 weeks of age, cardiac angiotensin II content and plasma cardiac injury markers were studied in anesthetized rats after cardiac IR induction and in untreated Sham control rats. Body, heart, and heart to body weight ratios were not significantly different among the nine groups. While plasma cardiac injury markers significantly increased in all IR groups compared to Sham control, the marked cardiac damage was observed in the TDG group (creatine kinase MB: Sham 211 ± 2 u/l, CW 300 ± 7 u/l, CW+T 245 ± 5 u/l, CG 313 ± 7 u/l, CG+T 251 ± 9 u/l, TDW 330 ± 6 u/l, TDW+T 318 ± 7 u/l, TDG 367 ± 3 u/l, TDG+T 334 ± 8 u/l; cardiac troponin C: TDG 0.9 ± 0.1 ng/ml, TDG+T 0.4 ± 0.1 ng/ml, other groups < 0.01 ng/ml; N‐terminal prohormone brain natriuretic peptide: TDG 8.8 ± 0.3 pg/ml, TDG+T 6.3 ± 0.2 pg/ml, other groups < 5.0 pg/ml). Further, cardiac angiotensin II levels significantly increased in CG, TDW, and TDG compared to Sham and CW groups (Sham 32.3 ± 1.5 pg/ml, CW 43.6 ± 3.0 pg/ml, CW+T 43.3 ± 2.6 pg/ml, CG 75.9 ± 8.41 pg/ml, CG+T 46.3 ± 2.5 pg/ml, TDW 80.3 ± 5.7 pg/ml, TDW+T 53.2 ± 2.4 pg/ml, TDG 139.0 ± 8.1 pg/ml, TDG+T 82.4 ± 3.7 pg/ml). The adverse effects of IR on cardiac injury and angiotensin II content were similarly attenuated, at least in part, by taurine supplementation. The present study demonstrates that perinatal taurine depletion particularly followed by a high sugar diet exacerbates cardiac IR injury via intra‐cardiac renin‐angiotensin system overactivity in adult female rats, and this adverse effect can be reduced by short‐term taurine supplementation.

Support or Funding Information

This work was supported by Khon Kaen University, Khon Kaen, Thailand.
Cardioprotective Role of Regulator of G Protein Signaling 6 in the Ischemic Heart
Authors: Rorabaugh Boyd R. , Chakravarti Bandana , Seeley Sarah L. , Bui Albert D. , Yang Jianqi , Watts Stephanie W , Neubig Richard R. , Fisher Rory A
Published: November 2023

Gαi‐coupled receptors play important roles in protecting the heart from ischemic injury. Regulator of G protein signaling (RGS) proteins suppress Gαi signaling by accelerating the GTPase activity of Gαi subunits. However, the roles of individual RGS proteins in modulating ischemic injury are unknown. In the present study, we investigated the impact of RGS6 deletion on myocardial sensitivity to ischemic injury. Hearts from RGS6 knockout (RGS6−/−) and wildtype (RGS6+/+) mice were subjected to 30 min ischemia and 2 hr reperfusion on a Langendorff heart apparatus. Infarcts in RGS6−/− hearts were significantly larger than infarcts in RGS6+/+ hearts. RGS6−/− hearts also exhibited increased phosphorylation of β2‐adrenergic receptors, ERK, and GRK2. Mitochondrial GRK2 as well as caspase‐3 cleavage were increased significantly in RGS6−/− hearts compared to RGS6+/+ hearts following ischemia. Chronic propranolol treatment of mice prevented the observed increases in ischemic injury and phosphorylation of ERK and GRK2 observed in RGS6−/− hearts. Our findings suggest that loss of RGS6 predisposes the ventricle to pro‐death signaling through the β2AR‐ERK‐GRK2 signaling axis and provide evidence for a protective role of RGS6 in the ischemic heart. Individuals expressing genetic polymorphisms that suppress the activity of RGS6 may be at increased risk of cardiac ischemic injury. Furthermore, the development of agents that increase RGS6 expression or activity might provide a novel strategy for the treatment of ischemic heart disease.

Support or Funding Information

This work was supported by the National Institute of General Medicine [GM39561 to RRN], National Cancer institute [CA161882 to RAF], the American Heart Association [14GRNT20460208 to RAF], and an Ohio Northern University Bower and Bennet Endowment Award to BRR
Effect of arterial stiffness on hemodynamic responses to the cold pressor test in men and women
Authors: Tucker Matthew A. , Looney Jacob , Lyon Matthew , Layman Lawrence C. , Pollock David M. , Harris Ryan A.
Published: November 2023

Differences in arterial stiffness between men and women have been described and may partly explain the sex‐related disparity in cardiovascular disease risk. Sex differences in the hemodynamic response to a cold pressor test (CPT) have also been described. However, it is unknown if arterial stiffness influences the hemodynamic response to a CPT and whether sex differences in this relationship exist.

PURPOSE

To investigate the relationship between arterial stiffness and hemodynamic responses to CPT in healthy men and women.

METHODS

18 men (age 29 ± 6 y, BMI = 26.4 ± 4.8 kg/m2) and 10 women (age 28 ± 6 y, BMI = 24.9 ± 5.1 kg/m2) participated in this study. Arterial stiffness was assessed via automated analyses of brachial and estimated aortic pressure waveforms to determine AIx75 (an indirect marker of arterial stiffness, corrected for a heart rate of 75 bpm). The CPT protocol consisted of a 5 min baseline followed by immersion of the right hand up to the wrist in ice water (~2°C) for 3 min. Hemodynamic parameters including total peripheral resistance index (TPRI), cardiac index (CI), and diastolic/systolic blood pressure (DBP/SBP) were measured throughout the protocol using beat‐to‐beat monitoring of the ‐ finger arterial pressure (Finapres NOVA).

RESULTS

Baseline measures of AIx75, TPRI, CI, DBP, and SBP were not statistically different between sexes (all p>0.05). Independent of sex, TPRI, CI, DBP, and SBP all increased in response to CPT (all p<0.001). Overall, AIx75 was significantly correlated with the change (Δ) in TPRI (r=0.406, p=0.032) and ΔCI (r=−0.438, p=0.020). However, AIx75 was positively associated with ΔTPRI in men (r=0.536, p=0.022) but not women (r=0.092, p=0.801). Similarly, there was a trend towards significance in the relationship between AIx75 and ΔCI (r=−0.462, p=0.054) and ΔSBP (r=0.401, p=0.099) in men, but not in women (r=−0.456, p=0.186 and r=−0.402, p=0.249, respectively).

CONCLUSION

These data suggest that arterial stiffness is associated with an increased vascular resistance response to CPT in men but not women. The sex‐dependent disparity in the observed relationships between arterial stiffness and ΔTPRI suggests that basal arterial stiffness influences the hemodynamic response to sympathoexcitation differently between sexes. Further evaluation of the exact mechanisms are warranted.

Support or Funding Information

NIH/NHLBI P01HL06999 (R.A.H.)
IMPACT OF ANGIOTENSIN CONVERTING ENZYME (ACE) GENE LEVELS ON BAROREFLEX IMPAIRMENT AND SYMPATHETIC HYPERACTIVITY AFTER A HIGH FRUCTOSE DIET
Authors: Moraes‐Silva Ivana C , de Souza Leandro E , Casarini Dulce E. , Irigoyen Maria‐Claudia
Published: November 2023

ACE gene polymorphism may influence in pathologically‐induced adaptations. We investigated whether mice harbouring 1, 2 or 3 copies of the ACE gene are distinctly impaired after a high fructose diet (F) regarding cardiovascular autonomic control, vascular reactivity, and metabolic parameters.

Male mice received F (100g/l) or tap water (C) for 8 weeks. Glucose tolerance (0–120 min after glucose load=1.5 g/Kg ip), total cholesterol and triglycerides were measured. Blood pressure (BP) was directly recorded (Windaq, 4kHz) and baroreflex sensitivity was evaluated by heart rate (HR) responses to vasoactive drugs. HR and BP variabilities were analyzed in frequency domain by FFT. Mesenteric resistance artery reactivity to noradrenaline (Nor;0.1nM‐1μM), and acetylcholine (Ach;1nM‐10μM) was studied in an isometric myograph (DMT,620M). Results in mean±SEM, statistical analysis: ANOVA, p<0.05.

No differences were found among C. F induced glucose intolerance vs. C (1 copy: 100±3 vs. F=198±5; 2 copies: 121±4 vs. F=201±8; 3 copies: 86±4 vs. F=212±5 mg/dl at 120th min) without differences among F mice. Total cholesterol and triglycerides were not significantly altered. Systolic BP increased after F vs. C with an additional augment in 3‐copy mice (15±1mmHg vs. 1copy:6±1; 2copies:9±1; mean C:112±2 mmHg), while diastolic BP increased ~8±1mmHg in all F‐fed groups vs. C (mean C:80±2mmHg). Bradycardic responses reduced 40%, 44% and 56% in F‐fed 1, 2 and 3‐copy mice, respectively, as well as tachycardic responses (decreases of 50%, 37% and 60%, respectively). Once more, 3‐copy mice was the most impaired (p<0.05 vs. 1 and 2). While sympathovagal balance increased ~40% in 1 and 2‐copy mice, it increased 130% in 3‐ copy. Similarly, BP variability was higher in 3‐copy (+33%) vs. other groups (p<0.05), and its sympathetic component (LF) had a more pronounced augment in 3‐copy vs. 1 and 2‐copy (31±3; 11±2 and 20±5 %, respectively, p<0.05). Moreover, F‐fed 3‐copy mice arterial reactivity to Nor was superior than the others (mean C:102±4; F:1 copy:170±5; 2 copies:190±7; 3 copies:214±10 %) while Ach‐induced relaxation was more reduced in 3‐copy mice than 1 and 2 copies (mean C:76±5; F:1 copy:58±8, 2 copies:47±6, 3 copies:36±5 %). A negative correlation was observed between BP variability and Ach‐induced maximal relaxation (r2=0.75), and a positive correlation was seen for Nor‐induced maximal constriction (r2=0.78). Similarly, LF component of BP was negatively correlated with Ach maximal relaxation (r2=0.75), and positively correlated with Nor maximal constriction (r2=0.72).

Concluding, the F‐induced magnitude of autonomic and vascular dysfunctions are modulated by ACE gene levels. The association of these mechanisms can respond for BP increase and for a more increased cardiovascular risk in 3‐copy mice.

Support or Funding Information

FAPESP and PNPD‐CAPES
Identification of open‐loop baroreflex gain from continuous arterial pressure monitoring
Authors: Mannoji Hiroshi , Saku Keita , Nishikawa Takuya , Tohyama Takeshi , Oga Yasuhiro , Abe Kiyokazu , Kishi Takuya , Tsutsui Hiroyuki , Sunagawa Kenji
Published: November 2023

Background

Although the importance of arterial baroreflex function in cardiovascular disease is well established, the lack of practical methods to identify the open‐loop baroreflex transfer function (H) makes it difficult to serve as a clinical tool. We repeatedly demonstrated that the H approximates a first‐order low pass filter with the corner frequency of 0.05 Hz in rats. In theory, a feedback system with H attenuates disturbance (D) to D/(1+H). We hypothesized that the baroreflex attenuates the power spectrum density (PSD) of arterial pressure (AP) in its operating frequency range (<0.1Hz), thereby H can be identified from the attenuation of PSD as long as D remains unchanged irrespective of baroreflex function.

Methods

We used 9 Wister‐Kyoto rats. We created graded baroreflex dysfunction by sinoaortic denervation (SAD) (partial: denervation only in right side, n=3 and total: bilateral denervation). One week after SAD, we calculated PSD from continuous AP recording (telemetry, 12hours). To estimate the baroreflex gain, we took the ratio of PSD at 2 frequencies (0.01 Hz/0.1 Hz) and normalized the value by PSD of total SAD. At the end of each experiment, we isolated baroreceptors and measured the open‐loop baroreflex gain.

Results

Partial SAD increased the lability (standard deviation of AP), and total SAD increased more (sham: 6.41 ± 0.79, partial SAD: 9.16 ± 0.58, total SAD: 20.1 ± 5.00 mmHg, p<0.001). SAD increased PSD below 0.1Hz, whereas did not affect above 0.1 Hz indicating that D remains unchanged regardless of SAD (Fig. 1). Estimated open loop baroreflex gain linearly correlated with that experimentally determined (y = 0.24x + 0.11, R2 = 0.87) (Fig. 2).

Conclusion

Power spectrum anaysis of AP time series allows us to identify broreflex function. The proposed framework may faclitate the noninvasive estimation of baroreflex function in clinial setting.
Wavelet Analysis of Cardiac Baroreflex Sensitivity during Stepwise Blood Pressure Changes
Authors: Tarumi Takashi , Tian Fenghua , Xing Chang‐Yang , Turner Marcel , Repshas Justin , Zhang Rong
Published: November 2023

Background

Cardiac baroreflex regulates short‐term fluctuations in blood pressure (BP) via controlling heart rate (HR). The objective of this study was to determine the effect of steady‐state BP changes on cardiac baroreflex sensitivity (BRS) using wavelet analysis.

Methods

Thirteen subjects (67±7 years, 8 women) were tested during intravenous infusions of sodium nitroprusside (SNP) and phenylephrine (PE). Drug dosage was increased stepwise after achieving steady‐state BP in each stage. BRS was calculated from the beat‐by‐beat changes in systolic BP and RR interval within the frequency band of 0.02–0.20 Hz. Linear mixed model was used to analyze the effect of steady‐state BP changes on BRS.

Results

SNP infusion decreased mean arterial pressure (MAP) by 15% and increased HR by 12%. In contrast, PE infusion increased MAP by 23% and decreased HR by 3%. Representative wavelet map of BRS estimation during drug infusions is shown below. During SNP and PE infusions, there was a positive association between changes in steady‐state MAP and BRS (P<0.001). Furthermore, the slope of BRS reduction with decreasing MAP during SNP infusion was greater than that during PE infusion (0.085±0.014 vs. 0.042±0.011 ms/mmHg per 1 mmHg change in MAP, P=0.004).

Conclusions

Steady‐state decrease in BP is associated with elevation of HR and marked reduction of BRS. These findings suggest that dynamic short‐term regulation of BP during hypotension may be impaired and elevate the risk of fall or syncope.

Support or Funding Information

This study was supported by the NIH (R01AG033106 and K99HL133449) and the Americann Heart Association (14POST20140013).
Tractographic analysis of the medulla oblongata necessitates partial re‐wiring of the contemporary neural circuit for baroreflex‐mediated sympathetic vasomotor tone
Authors: Chan Samuel H.H.
Published: November 2023

Contemporary dogma stipulates that the caudal ventrolateral medulla (CVLM) participates in baroreflex‐mediated sympathetic vasomotor tone by acting as a synaptic relay that connects the nucleus tractus solitarii (NTS) to the rostral ventrolateral medulla (RVLM). Functionally, CVLM exerts an inhibitory action on RVLM neurons that are involved in tonic and reflex control of sympathetic vasomotor tone. Whether neuronal traffic in the above‐mentioned circuit actually takes place in the brain stem during the execution of baroreflex has never been visualized. This study was undertaken to fill this void. In male adult C57BL/6 mice instrumented for physiological measurements by radiotelemetry, intracerebroventricular (i.c.v.) infusion of angiotensin (7.5 μg/h at 0.5 μL/h) by osmotic minipump for 7 days elicited a significant elevation in mean arterial pressure (MAP) that returned to basal levels over time. Determined by the power density of the low‐frequency component of systolic blood pressure, the baroreflex‐mediated sympathetic vasomotor tone exhibited a significant increase that paralleled temporally the elevation in MAP. Tractographic analysis based on magnetic resonance imaing/diffusion tensor imaging (DTI) of the medulla oblongata using a 9.4T scanner further revealed that under basal MAP, there was robust connectivity between the NTS and RVLM. This NTS‐RVLM connectivity was substantially reduced when visualized during sustained hypertension and elevated baroreflex‐mediated sympathetic vasomotor tone. More importantly, the connectivity between the NTS and RVLM was re‐established when MAP or low‐frequency power returned to their basal levels. Quantification of the magnitude of NTS‐RVLM connectivity by two DTI indices, fractional anisotropy (FA) and number of fiber tracts, yielded comparable results. Interestingly, in an anterior‐posterior presentation of the FA map of the medulla oblongata, we rarely (P < 0.0001, Chi‐square analysis) detected the obligatory presence of connectivity between NTS and CVLM under basal conditions (3 out of 56 observations) or during neurogenic hypertension (1 out of 28 observations). Our visualization of the baroreflex at work therefore necessitates partial re‐wiring of the circuit for baroreflex‐mediated sympathetic vasomotor tone.
Gonadal Hormone Receptors Underlie The Resistance Of Female Rats To Cardiovascular Complications Of Endotoxemia
Authors: El‐Lakany Mohammed A , El‐Gowelli Hanan M , Fouda Mohamed A , El‐Gowilly Sahar M , El‐Mas Mahmoud M
Published: November 2023

Gender differences exist in the immunological and cardiovascular complications of sepsis, with the male gender being more vulnerable to these conditions. The current study tested the hypotheses that female rats are protected against the endotoxemia‐evoked hypotension and cardiac autonomic dysfunction, and that the presence of functional gonadal hormone receptors is a prerequisite for such protection. Changes in blood pressure (BP), heart rate (HR) and cardiac sympathovagal balance, as indexed by the analysis of heart rate variability (HRV), caused by a single i.v. dose of lipopolysaccharide (LPS, 10 mg/kg) were determined in conscious male and female rats. In male rats, LPS caused significant falls in BP and increases in HR. The spectral index of the cardiac sympathovagal balance (low‐frequency/high‐frequency ratio (LF/HF) of interbeat intervals was reduced by LPS, suggesting a shift in cardiac autonomic control towards parasympathetic dominance. Remarkably, none of the above cardiovascular effects of LPS was evident in female rats. We also report that pretreatment of female rats with fulvestrant (nonselective estrogen receptor blocker), PHTPP (estrogen receptor‐β blocker), mifepristone (progesterone receptor blocker) or formestane (aromatase inhibitor) uncovered clear hypotensive and tachycardic responses to LPS. Moreover, these female rats, unlike their male counterparts, exhibited increases, rather than decreases, in LF/HF ratio in response to LPS. Alternatively, LPS failed to modify the cardiovascular function in female rats pretreated with MPP, a selective blocker of estrogen receptor‐α. These findings highlight important roles for estrogen receptor‐β and progesterone receptors in guarding against cardiovascular derangements caused by endotoxemia in female rats.

Support or Funding Information

Supported by the Science and Technology Development Fund, Egypt (STDF Grant No. 14895)