bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelial hyper‐permeability and cardiomyocyte dysfunction following Coronary Artery Bypass Grafting
Authors: Velten Markus , Duerr Georg Daniel , Hamiko Marwan , Frede Stilla , Rogers Lynette K , Baumgarten Georg , Hoeft Andreas , Hilbert Tobias 
Published: November 2023

ObjectiveIschemia Reperfusion Injury (IRI) is contributing to morbidity and mortality in various cardiac diseases including coronary artery bypass graft surgery (CABG). We hypothesized that CABG induced IRI is resulting in capillary leakage due to Angiopoietins (ANG) and cardiomyocytes dysfunction affecting perioperative morbidity after CABG.ApproachAfter institutional revenue board approval and informed consent, serum samples (n = 28) were collected pre CABG surgery, 1, 6, and 24 h after aortic de‐clamping. ANG1, ANG2, sTIE2, HMGB1, sRAGE and IL‐6 serum concentrations were analyzed by ELISA. Endothelial cells (HPMECs) and primary murine cardiomyocytes were incubated with human serum to assess the impact of IRI on endothelial permeability and myocardial contractility after CABG.ResultsCABG induced an early and sustained increase of ratio of ANG2/ANG1 (7‐fold change in ANG2/ANG1 ratio after 24 h compared to pre‐surgery). These changes correlated with elevated serum lactate levels, postoperative fluid balance, as well as the duration of mechanical ventilation. Permeability of ECs significantly increased after incubation with post‐surgery patient serum showing a marked shift of ANG2/ANG1 balance (18‐fold) compared to serum with a less pronounced increase (6‐fold). Furthermore, CABG resulted in increased IL‐6, HMGB1, and sRAGE serum content. Pre‐incubation with serum containing high levels of IL‐6 amplified the ANG2 secretion by HPMECs however this was not influenced by blocking IL‐6. Moreover, contractility of murine cardiomyocytes was significantly reduced after incubation with human serum 1h after aortic de‐clamping. These changes correlated with increased HMGB1 and sRAGE levels.ConclusionCABG induced IRI altered the relative levels of serum ANG2 to ANG1, increased HMBG1 and sRAGE concentrations, resulting in endothelial hyper‐permeability and impaired cardiomyocytes contractility. This influences perioperative morbidity, leading to changes in clinical surrogate parameters of tissue hypo‐perfusion, vascular leakage, and pulmonary dysfunction.
Thermoregulatory and Ventilatory Responses in Humans with a Patent Foramen Ovale During Passive Cooling While Immersed in 20 °C Water
Authors: Davis James T , Hay Madeline W , Hardin Alyssa M , Lovering Andrew T 
Published: November 2023

Approximately 35% of the general healthy population has a patent foramen ovale (PFO). People without a PFO (PFO−) have a lower esophageal temperature (Tesoph) under resting conditions and during exercise. Additionally, while breathing super cooled (−2.0 °C) air at the end of a 10‐minute exercise bout (2:30 stages at 25, 50, 75 and 90% of VO2MAX), PFO− subjects did not increase Tesoph as much as subjects with a PFO (PFO+). These data suggest blunted respiratory system cooling in PFO+ subjects. Taken together, these data suggest differences between PFO− and PFO+ subjects in thermoregulatory and ventilatory responses at rest and during exercise. However, to our knowledge it has not been prospectively determined if a PFO has any role on thermoregulatory and ventilatory responses to passive cooling.Fourteen males matched for height, weight and age participated in this study (9 PFO−; age: 26 ± 6 yrs, height: 180.1 ± 7.2 cm, weight: 83.3 ± 12.3 kg, BSA: 2.0 ± 0.2 m2; 5 PFO+; age: 28 ± 6 yrs, height: 175.8 ± 7.3 cm, weight: 77.7 ± 6.0 kg, BSA: 2.0 ± 0.1 m2). Subjects came to the lab at the same time each morning and laid in a reclined position, immersed to the nipple line in a water bath (19.6 ± 0.7 °C) until 1) 60 minutes elapsed, 2) Tesoph decreased to 35.5 °C, 3) sustained shivering occurred (oxygen uptake [VO2] > 25% of resting values for 5 consecutive minutes), or 4) subjects asked to get out of the water.We measured Tesoph, VO2 and minute ventilation (VE) every 5 minutes. At rest before immersion PFO− subjects had a lower Tesoph than PFO+ subjects (PFO−: 36.5 ± 0.2, PFO+: 36.8 ± 0.2, p = .04). At the end of immersion PFO− subjects also had a lower Tesoph than PFO+ subjects (PFO− : 36.0 ± 0.4, PFO+: 36.5 ± 0.3, p = .04). There were no differences in VO2 or VE at any time point. Furthermore, after the initial increase in Tesoph upon immersion, PFO− subjects decreased Tesoph throughout the remainder of the trial; while PFO+ subjects drop in Tesoph plateaued after 50 minutes of immersion. These data suggest that PFO− subjects are unable to retain heat as effectively as PFO+ subjects during passive cooling. This may be due to the possibility that PFO− subjects have greater respiratory system heat loss than PFO+ subjects.Support or Funding Information2015 Eugene and Clarissa Evonuk Memorial Graduate Fellowship
Sex Differences in the Expression of Cardiac miR‐29 Family microRNAs in Diabetic Male and Female Rats and its Correlation with Increased Risk for Coronary Artery Disease in Diabetic Females
Authors: Lum‐Naihe Kelly , Pulakat Lakshmi 
Published: November 2023

Diabetic females are at increased risk of heart failure (HF) and coronary artery disease (CAD) than age‐matched diabetic males and non‐diabetic females. Factors contributing to this sex difference in diabetic heart disease are not understood. We have previously shown that progression of diabetes mellitus (DM) in male rats correlates with increased expression of cardiac miR‐29 family of microRNAs. The miR‐29 family is composed of three members who share an identical seed sequence, however, they exhibit different roles in vivo: miR‐29a is a biomarker of hypertrophy and fibrosis, miR‐29b is involved in aneurysm formation in Marfan's syndrome, and miR‐29c is a marker of hyperglycemia. Here we investigated whether sex differences exist in the expression of cardiac miR‐29 family in 5‐month old Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats, and examined whether overexpression of the miR‐29 family miRNAs is detrimental to human male and female coronary artery vascular smooth muscle cells (hCAVSMCs). Cardiac miR‐29 expression was assessed by qRT‐PCR and cardiac structure was examined by histological analysis. Expression of miR‐29a, b and c were elevated in both diabetic female (ZDF‐F) and male (ZDF‐M) rats when compared to lean female (ZL‐F) and male (ZL‐M) rats (p‐values for ZDF‐F vs. ZL‐F: miR‐29a, 0.054, miR‐29b, 0.03, miR‐29c, 0.02; for ZDF‐M vs. ZL‐M: miR‐29a, 0.0001, miR‐29b, 0.0015, miR‐29c, 0.0001), however, relative to lean controls, miR‐29a and miR‐29c were increased to a greater extent in ZDF‐M (~10.3‐ and 26.3‐fold greater, respectively) than in ZDF‐F (~4.8‐ and 8.8‐fold, respectively). In contrast, in ZDF‐F, miR‐29b was ~18.1‐fold greater than ZL‐F, while in ZDF‐M, miR‐29b was ~4.7‐fold higher than ZL‐M. Examination of cardiac sections stained with H&E or Masson's trichrome revealed structural damage in ZDF‐F, which was not observed in any other group. Transfection of primary cultures of male and female hCAVSMCS with miR‐29 mimics individually showed that 48‐hour post‐transfection, loss of cell membrane integrity, as assessed by propidium iodide (PI) exclusion assay, was highest in cells transfected with miR‐29b compared to those transfected with miR‐29a or miR‐29c. TUNEL assay further confirmed this detrimental effect of miR‐29b in hCAVSMCs. Since miR‐29b expression was higher in heart tissues of ZDF‐F compared to all other groups, and miR‐29b was most effective in inducing cell death compared to other miR‐29 family miRNAs in human CAVSMCs, we conclude that the sex difference in miR‐29b expression may underlie higher risk for CAD in diabetic females.Support or Funding InformationLSME, UM‐Columbia(LP), NIH 1R01HL118376‐01(LP)
Increasing Muscle Mass Improves Cavernosal Function in Obesity
Authors: MicKinac Nathan K. , Larion Sebastian , Mintz James D. , Fulton David J. , Stepp David W. 
Published: November 2023

Obesity is a known risk factor for erectile dysfunction but the causal mechanisms remain poorly understood. Moreover, exercise is known to improve erectile function but the components of exercise (weight loss, aerobic capacity, or muscle mass) that contribute are unclear. The purpose of our study was to investigate whether increased muscle mass in an obese mouse model improves the erectile function of the corpus cavernosum.Lean mice heterozygous for db, the leptin receptor, were bred to mice lacking myostatin, a myokine the limits muscle growth. Four groups were studied. Lean controls, lean myostatin‐null mice, obese control and obese myostatin‐null mice. All mice were phenotyped using metabolic cages and analysis of plasma chemistry. Responses of cavernosal strips were assessed in vitro in response to phenylephrine and acetylcholine.Obese mice compared to lean were characterized by a two‐fold increase in body weight, marked adiposity, low oxygen consumption, muscle atrophy, dyslipidemia and hyperglycemia. Deletion of myostatin in lean mice markedly increased muscle mass (35%, p<0.05) but otherwise produced no phenotypic alterations. Deletion of myostatin increased muscle mass to a similar degree as lean mice and improved glucose control in obese mice with no effect on lipids, body weight or body composition.Despite similar cavernosal mass, obese mice showed increased vasoconstrictor force generation (which would restrain erection) to phenylephrine when compared to the lean controls (102%, p<0.05). Deletion of myostatin had no effect in lean mice but reduced constriction to normal values in obese mice. Vasodilation to acetylcholine tended to be reduced in obese mice but no significant differences emerged among the four groups.Overall, these results support the hypothesis that increased muscle tone can improve erectile function in obese mice. This effect, potentially due to improved glucose tolerance by the larger muscle mass, may explain to some degree how exercise improves erectile function in obesity.Support or Funding InformationWork supported by NHLBI 092446 and 124773 and the Dean's Summer Research Program
Helium induces Caveolin Secretion and decreases Permeability in Human Umbilical Vein Endothelial Cells
Authors: Landau Maximilian Alexander , Smit Kirsten Fernande , Warmbrunn Moritz , Preckel Benedikt , Hollmann Markus Werner , Patel Hemal H , Albrecht Martin , Weber Nina Claudia 
Published: November 2023

Caveolins are structural proteins essential for the formation of caveolae, small lipid enriched membrane invaginations. Caveolins have been shown to be involved in anesthetic‐induced cardioprotection and play an important role in signal transduction in various cell types. The noble gas helium, a potent cardioprotectant, leads to decreased protein levels of caveolin‐1 and caveolin‐3 in mice hearts, whereas higher levels of these caveolins were found in the serum of mice. These data suggest that caveolins are secreted into the bloodstream after helium inhalation. As actin filaments are an integral part of the cytoskeleton and are located in close connection to caveolins in the plasma membrane we hypothesized that helium might affect the cytoskeleton and thereby induce secretion of caveolins. To investigate this hypothesis we used human umbilical vein endothelial cells (HUVEC), as the endothelium is considered the first target organ that gets in contact with circulating blood.HUVEC were isolated from fresh umbilical cords, pooled and grown upon a confluent monolayer in passage 3–5. Cells were exposed for 20 minutes to either helium (5% CO2, 25% O2, 70% He) or control gas (5% CO2, 25% O2, 70% N2) in a specialized gas chamber. Cells and supernatant were collected after 0 minutes, 2, 4, 6, 12 and 24 hours for Western blot analysis, RT‐PCR, immunofluorescence staining and permeability measurements.In the helium group, protein analysis showed a significantly lower expression of caveolin‐1 at 6 hours in cell lysate (13.35±1.30 in controls vs. 8.02±1.29 in helium treated cells, average light intensity (AVI), p<0.05) and a higher expression in supernatant starting at 6h (1.42±0.25 in controls vs. 8.26±4.5 in helium treated cells, AVI, p<0.05) Actin staining demonstrated a significant increase of the border/inner ratio of the filaments at 12 hours after helium exposure. Cell permeability measurement revealed a significantly lower flow‐through of FITC‐BSA at 6 (p<0.05) and 12 hours (p<0.05) in the helium group. RT‐PCR of Cav‐1 did not show significant differences.These findings suggest that caveolin‐1 is secreted after helium exposure in vitro and that the actin cytoskeleton filaments are regulated by helium. This mechanism might finally lead to a decreased permeability of the endothelium after helium inhalation.Support or Funding InformationThis project was in part funded by the IARS (International Anesthesia Research Society) and the SCA (Society of Cardiovascular Anesthesiologists).
Ventilatory Efficiency and Oscillatory Breathing As Clinical Markers of Surgical Outcomes in Heart Failure
Authors: Jesse Nicholas , Raichlin Eugenia , Schultz Harold 
Published: November 2023

BackgroundVentilatory efficiency (Ve/VCO2) and oscillatory breathing (OB) during exercise have been shown to be important predictors of long‐term survival in patients with chronic systolic heart failure (CHF). However, the status of Ve/VCO2 and OB in patients after undergoing heart transplant (HT) or left ventricular assist device (LVAD) implant is less clear. The aim of this study was to assess the outcomes of HT or LVAD implantation on Ve/VCO2 and OB. We hypothesized that Ve/VCO2 and OB are improved (i.e. decreases in Ve/VCO2 slope and breathing interval variability) after HT and LVAD and that these changes correlate with improved exercise tolerance (6 minute walk).MethodsCardiopulmonary exercise test (CPET) data were retroactively analyzed for Ve/VCO2 slope and OB (coefficient of variability of breath interval) during progressive treadmill exercise from eight CHF patients: HT (n=4), and LVAD (n=4). Sample size was restricted due to insufficient CPET data in most HT/LVAD patient records at the time of analysis.ResultsWe found that Ve/VCO2 was reduced in three patients in each group after the intervention [LVAD: 38 ± 6.1(SD) before vs. 34 ± 3 after (6 % improvement) n =4] [HT: 45 ± 17 before vs. 35 ± 6 after (12 % improvement) n= 4]. The reduction in Ve/VCO2 in the three patients from each group correlated with a reduction in exercise OB. One patient in each group exhibited increased Ve/VCO2 and OB after the intervention. Overall, the direction and magnitude of the change in Ve/VCO2 correlated well with changes in OB for all patients (r2 = 0.70). There also was a correlation between improved VE/CO2 or OB and improved exercise tolerance (increased distance walked in 6 min).ConclusionsVe/VCO2 and OB were improved after LVAD or HT implant in the majority of CHF patients tested and correlated with improved exercise tolerance. Patients will be followed to determine long‐term survivability. Further analysis as additional CPET data becomes available will give a more complete picture of the efficacy of these measurements as diagnostically relevant markers of improved ventilatory function and long‐term outcomes in LVAD and HT patients.Support or Funding InformationNIH PO1‐HL62222
Doxorubicin Decreases Cyclooxygense‐2 Levels in Heart, Brain, and Pial Arteries from Ovariectomized Female Rats
Authors: Gonzales Rayna , Raman Puneet , Vijayavel Nirmal , Kerrigan Colleen , Hale Taben , Carroll Chad , Dickinson Jared , Angadi Sidartha 
Published: November 2023

Doxorubicin (DOX) is a highly effective chemotherapy agent. Its use is hampered however owing to severe dose‐dependent cardiovascular toxicity in cancer survivors. Multiple mechanisms have been implicated in the pathogenesis of DOX cardiotoxicity, one of which involves inflammation mediated by activation of the NFκB/TLR4/COX‐2 pathway in the heart. Knowledge regarding the toxic effects of DOX‐induced inflammation in other organ systems such as the brain has not been thoroughly investigated. Therefore, we explored the inflammatory potential of DOX by assessing TLR4 and COX‐2 levels in cortex and pial arteries isolated from ovariectomized (OVX) female Sprague‐Dawley rats. We hypothesized that DOX would promote inflammation by increasing COX‐2 expression along with expression of its upstream innate immune receptor, TLR4, both of which are under the transcriptional regulation of NFκB. OVX rats were treated with three, bi‐weekly, i.p. injections of DOX (4 mg/kg; cumulative dose 12 mg/kg) or vehicle (saline) and euthanized 5 days after the last dose. Tissues were isolated, snap frozen, homogenized, and analyzed for COX‐2, TLR4 and NFκBp65 levels using standard western blotting. Although COX‐2 is typically considered an inducible enzyme, it has been shown to be expressed under basal conditions. In cortex and pial arteries from vehicle‐treated rats, measurable levels of COX‐2 and TLR4 protein were detected. However, contrary to our hypothesis, levels of COX‐2 and TLR4 were decreased following DOX. In pial arteries, DOX elicited a reduction in both the COX‐2 72 kDa band 74 kDa band with the greatest reduction observed in the 72 kDa. The 72 kDa band corresponds to the partially glycosylated inactive form of enzyme, while the 74 kDa band has been shown to represent the fully glycosylated active form. Cytosolic levels of NFκBp65 levels were detected in brain and pial vessel lysate, however levels were not altered by DOX. Similar to brain and pial arteries, basal expression of COX‐2 and TLR4 were detected in left ventricle and DOX treatment attenuated expression. In conclusion, although others have suggested the involvement of the NFκB pathway during the development and progression of DOX‐induced cardiomyopathy, our studies demonstrate a possible novel action for the anticancer agent implicating anti‐inflammatory mechanisms, particularly in female cohorts with low circulating levels of gonadal hormones.Support or Funding InformationArizona State University Intramural Funds (SA and JD), Midwestern University Intramural Funds (CC), Sarver Heart Center (RG)
Chronic inhibition of endoplasmic reticulum (ER) stress attenuates cardiovascular but not appetite responses to MC3/4R antagonism in SHR
Authors: do Carmo Jussara Marcia , da Silva Alexandre A. , Wang Zhen , Hall John E. 
Published: November 2023

We previously demonstrated that activation of the central nervous system (CNS) melanocortin system plays a key role in modulating sympathetic nerve activity (SNA) and blood pressure (BP) in spontaneous hypertensive rats (SHR). Previous studies also suggest that endoplasmic reticulum (ER) stress may contribute to cardiovascular pathophysiology and hypertension in SHR. However, whether there is a major interaction of ER stress and melanocortin‐4 receptor (MC4R) activation in contributing to hypertension and appetite regulation in SHR is still unknown. In this study we examined the role of ER stress alone or in combination with MC3/4R antagonism in controlling BP and metabolic functions in SHR. Male SHR (n=7) were implanted with BP telemetry transmitters and an intracerebroventricular (ICV) cannula was inserted into the lateral ventricle at 12 weeks of age. After 10 days of recovery, food intake, BP and heart rate (HR) were measured 24‐hrs/day. After stable baseline measurements for 5 days, tauroursodeoxycholic (TUDCA, 100 mg/kg, IP) was injected daily for 22 consecutive days to inhibit ER stress, which was followed by a 10‐day combined treatment with the MC3/4R antagonist (SHU‐9119, 1 nmol/h, ICV) for 10 days. Chronic ER stress inhibition alone did not alter food intake (16±1 vs. 14±3g), body weight (293±4 vs. 301±4 g), MAP (166±2 vs. 169±3 mmHg) or HR (335±6 vs. 338±2 bpm). Combined treatment with MC3/4R antagonist significantly increased food intake by 120% and body weight by 19%, while reducing BP by 9±2 mmHg and HR by 28±5 bpm when compared to −25 mmHg and −45 bpm with MC3/4R antagonist alone. No changes were observed in blood glucose levels. These results indicate that chronic inhibition of ER stress did not alter appetite, HR or BP, but attenuated BP and HR responses to MC3/4R antagonist in SHR.Support or Funding Information(NHLBI‐PO1HL51971, NIGMS‐P20GM104357 and AHA SDG5680016)
Severe Sleep Apnea Is Associated with Telomere Lengthening
Authors: Polonis Katarzyna , Singh Prachi , Becari Christiane , Covassin Naima , Druliner Brooke , Johnson Ruth , Boardman Lisa , Somers Virend K 
Published: November 2023

BackgroundObstructive sleep apnea (OSA) increases the risk for metabolic and cardiovascular disease. Telomere shortening has been linked to hypertension, diabetes mellitus, and cardiovascular diseases such as stroke and myocardial infarction. Because these conditions are highly prevalent in sleep apnea, we hypothesized that telomere length (TL) would be reduced in patients with OSA.MethodsGenomic DNA was isolated from circulating leukocytes in 176 subjects (42.8 ± 13.8 years, 22.7 % women) who had undergone overnight polysomnographic evaluation. Of these individuals, 92 subjects had an Apnea Hypopnea Index (AHI) >5 events/hour and were classified as OSA patients. TL was measured using a quantitative PCR where a telomere to single copy gene ratio is determined and represented as number of base pairs (bp). The effect of OSA on TL was determined by comparing a control group (no OSA) (AHI<5, n=92) with patients with mild OSA (≥ 5 AHI <15, n=25), and those with moderate to severe OSA (AHI ≥15, n=59) in unadjusted and age‐adjusted models.ResultsCompared to control subjects, mild and moderate to severe OSA subjects were older: 48.9 ± 11.2 vs. 36.0 ± 11.2 years (p<0.001) and 50.8 ± 13.1 vs. 36.0 ± 11.2 years (p<0.001), respectively. Statistical models examining the effects of OSA severity on TL showed a J‐shaped curve : longer TL in moderate to severe OSA (4867 ± 221 bp) and controls (4820 ± 160 bp), and the shortest TL in mild OSA (4742 ± 155 bp). The mean TL in moderate to severe OSA was significantly longer than in mild OSA (p=0.0048). These effects were more pronounced after adjustment for age, when we observed significant differences in mean TL between moderate to severe OSA and mild OSA (p=0.0036) and between moderate to severe OSA and the control group (p=0.0379) (Fig. 1). However, the mean TL between control subjects and subjects with mild OSA was not different.ConclusionModerate to severe OSA patients had longer TL compared with mild OSA and control group. This association was independent of age. Even though OSA is associated with increased cardiovascular risk, telomere lengthening in subjects with moderate to severe OSA suggests the presence of protective compensatory mechanisms to prevent telomere shortening in OSA. On the other hand, the existence of longer telomere in subjects with moderate and severe OSA may also indicate triggering of molecular mechanisms which may contribute to cancer development. Further studies are needed to explain the role of hypoxia in telomere dynamics in OSA, and the interactions between telomere length and increased longevity reported in older patients with OSA.Support or Funding InformationNIH R01 grant (#HL65176); Singh P. is supported by AHA scientist development grant (11SDG7260046). Becari C. is supported by grant from CNPq‐Brazil (# 203802/2014‐4).