bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of cardiac function during the progression of heart failure induced by intracoronary embolizations in the canine model: monitoring in conscious and anesthetized states.
Authors: Krishnan Abhinav C , Lovelace Abe , Senador Danielle , Kaur Jasdeep , Alvarez Alberto , Hanna Hanna W , Levanovich Peter E , Dombrowski Mary D , Mannozzi Joseph T , Aung Kimberly , Haddad Samuel , Sala‐Mercado Javier , Levy Phillip D , O'Leary Donal S
Published: November 2023

Various animal models of acute and chronic heart failure exist including coronary artery occlusion via ligation or microembolization, rapid‐ventricular pacing, aortic banding, and fluid challenge. However, to our knowledge, no study has investigated whether anesthesia alters conclusions regarding hemodynamic effects associated with heart failure development. In this study, global ischemic cardiomyopathy, via repeated coronary artery microembolizations, (range: 5–15 embolization procedures per animal) was induced to lower ejection fraction to < 40% in ten chronically instrumented canines. We measured the progression of myocardial dysfunction over time, with each animal serving as its own control in conscious and anesthetized states to elucidate the effect of anesthesia on cardiovascular parameters. Hemodynamic measurements were taken in three conditions: anesthetized, immediately prior to each embolization, anesthetized 1.25 minutes after each embolization, and in a conscious, non‐anesthetized state at rest, 1 week after each embolization. We observed that anesthesia lowered arterial pressure (Δ−31.8 ±3.7%) and cardiac output (Δ−22.2 ±3.4%) when compared with the conscious state and that the effect of the embolization on ventricular function was better revealed in conscious animals. Thus, anesthesia affects the conclusions drawn regarding the extent of cardiovascular impairment induced via the embolization model.

Support or Funding Information

Supported by Novartis Pharmaceuticals CRLX030AUSNC01T and NIH HL55473 and HL126706.
The Roles of Flanking DNA and Transcriptional Activators in Regulating SAGA‐Mediated Nucleosome Acetylation
Authors: Olson Sannie J. , Mittal Chitvan , Shogren‐Knaak Michael A.
Published: November 2023

The SAGA family of transcriptional coactivators are prototypical nucleosome acetyltransferase complexes that regulate multiple steps of gene transcription. The size and complexity of both the SAGA enzyme and the chromatin substrate provide opportunities to regulate the acetylation process. To better probe this regulation, we have characterized the binding interactions and kinetics of acetylation using different nucleosomal substrates and the full SAGA complex purified from budding yeast. We find that SAGA‐mediated nucleosome acetylation proceeds through a multiple‐turnover burst phase, suggesting rapid nucleosome acetylation at multiple sites prior to nucleosome release. The rate of nucleosome acetylation is affected by DNA flanking the nucleosome, both by facilitating the binding of SAGA and by accelerating acetylation turnover. This stimulation requires flanking DNA on both sides of the nucleosome, where one side needs to be longer than 15 base pairs. Gal4‐VP16 activator can also augment nucleosome acetylation. However, contrary to our expectations, this stimulation does not appear to occur by stabilizing the binding of SAGA toward nucleosomes containing an activator binding site. Instead, stimulation of nucleosome acetylation occurs by increasing acetylation turnover by SAGA. Altogether, these studies uncover several novel mechanisms of SAGA regulation by chromatin substrates.

Support or Funding Information

This work was supported by American Cancer Society Research Scholar Grant 1206501 to M. A. S.‐K. Work by S. J. O. was supported in part by a Gary Roewe Faculty Research Award.
Mitofilin knockdown in Rat H9c2 Myoblasts Induces Cell Death by Apoptosis Via an AIF‐PARP‐Dependent Mechanism and Cell Cycle Arrest
Authors: Lie Mihaela , Madungwe Ngonidzashe Benson , Feng Yansheng , Bopassa Jean C.
Published: November 2023

Introduction

Mitochondrial activity plays an essential role in the efficient function of cardiomyocytes. Mitofilin is an inner membrane protein that has been defined as a mitochondria‐shaping protein in controlling and maintaining mitochondrial cristae structure and remodeling. In this study, we determined the role of mitofilin in the H9c2 myoblast survival by investigating the mechanism underlying mitofilin knockdown‐induced cell death by apoptosis.

Methods

H9c2 cells were cultured and treated with mitofilin siRNA or scramble siRNA for 24 hours. Cell death (apoptosis), caspase 3 activity, and cell cycle phases were assessed by flow‐cytometry, cytochrome C release and intracellular ATP production were measured by ELISA. Mitofilin, AIF and PARP expression was measured by Western blot analysis and calpain activity assessed using calpain kit. Mitochondria images were taken using electron microscopy.

Results

We found that mitofilin knockdown increases cell death by apoptosis mainly via activation of AIF pathway leading to nuclear fragmentation and subsequent PARP1 activation in the nucleus that is correlated with S phase arrest of the cell cycle. Knockdown of mitofilin in H9c2 myoblasts with siRNA led to mitochondrial swelling and damage of mitochondrial cristae that is associated with the increase in ROS production, decrease in intracellular ATP production and a marked decrease in mitochondrial membrane potential. Moreover, cells treated with mitofilin siRNA displayed an increase in calpain activity versus scramble siRNA.

Conclusion

Together, these results indicate that mitofilin knockdown by siRNA increases calpain activity that presumably leads to mitochondrial structural degradation resulting in a critical reduction of mitochondrial function that is responsible for the increase in cell death by apoptosis via AIF‐PARP mechanism which is associated with nuclear fragmentation and S phase arrest of cell cycle.

Support or Funding Information

Voelcker Fund and American Heart Association.
Vaping to Vascular Damage: The Role of E‐Cigarettes on Vascular Function
Authors: Clayton Stuart , DeVallance Evan , Branyan Kayla , Pitzer Christopher , Breit Matthew , Hoskinson Hannah , Klinkhachorn Powsiri , Erdreich Brett , Chantler Paul , Olfert Mark
Published: November 2023

Background

Electronic cigarettes (E‐cigs) have exponentially increased in popularity and usage due to the perception that e‐cigs are safe, their usefulness as a cigarette‐smoking cessation tool, and the appeal of heavily marketed flavors. There is little known about the long‐term effects of E‐cig vapor exposure, particularly in the context of vascular dysfunction. We hypothesize that the long‐term use of E‐cig vapor decreased aortic function, and increase aortic stiffness.

Methods

Data were obtained from C57BL/6 female mice exposed to 3R4F reference cigarette (N=5–7), cappuccino flavored E‐vapor (18 mg/ml nicotine, N=7), or filtered air (N=7–8) for 4 h/day, 5 d/wk for 8 months. Food and water were administered ad libitum. Before and after the exposure, in‐vivo aortic stiffness (pulse wave velocity) was measured using B‐mode and Doppler ultrasound by obtain blood flow signals at the aortic arch and before the carotid bifurcation from a single image, which were gated to the EKG. At the end of the exposure the thoracic aorta was dissected, sectioned into rings and mounted onto an ex‐vivo wire tension myograph system. Force transduction was used to measure the changes in aortic tension in response to methacholine, or sodium nitroprusside.

Results

Aortic stiffness increased (0.45±0.20 m/s) in the air‐exposed group, reflecting the normal aging process. However, an accelerated age‐associated aortic stiffness was noted in the cigarette (1.28±0.27 m/s) and E‐cig (1.14±0.24 m/s) groups (ANOVA, p<0.05). In animals exposed to filtered air, the maximal aortic relaxation achieved to methacholine was 90%, compared to 60% and 70% in the cigarette and E‐cig groups, respectively (p<0.05). No differences were noted in sodium nitroprusside dilation between groups.

Conclusion

Our data suggests that 8 months of E‐cig significantly accelerated the age‐associated increase in aortic stiffness, and significantly impaired aortic endothelial‐dependent but not endothelial‐independent dilation. These data show the E‐cigs induce similar vascular dysfunction to cigarette smoke exposure suggesting that E‐cig have similar risk to develop accelerated cardiovascular aging and disease.

Support or Funding Information

National Institutes of Health Grant: 1P20 GM‐109098

West Virginia University – Marshall University Collaborative Health Research Grants
Critical role of smooth muscle Rac1 in neointimal formation following vascular injury
Authors: Lennon Frances E , Li Yuxin , Hong Zhigang , Liao James K
Published: November 2023

Background

Rac1 is a small GTPase, which plays a critical role in cell movement, spreading, proliferation, transformation, and production of reactive oxygen species (ROS). Because smooth muscle cell (SMC) migration and proliferation are important for vascular remodeling after injury, we hypothesized that SMC Rac1 may play an important role in neointima formation.

Methods and Results

To investigate the role of SMC Rac1 in neointimal formation, we used global haploinsufficient Rac1 knock out mice (Rac1+/−) and also generated SMC‐specific Rac1+/− (smRac1+/−) mice by crossing smMHC‐Cre mice with Rac1 flox/flox mice. Four weeks after carotid artery ligation, neointimal formation in Rac1+/− and smRac1+/− mice was substantially reduced compared to wild‐type (WT) or Rac1 flox/+ (control) mice (intima area, WT vs. Rac1+/−: 59.59±12.43 vs. 27.72±5.97 103 μm2; control vs. smRac1+/−: 50.69±9.75 vs. 14.32±2.43 103 μm2). Aortic SMC isolated from smRac1+/− mice exhibited normal cytoskeletal architecture, and similar migratory and adherent function as WT SMCs. However, smRac1+/− SMCs showed decreased chemotaxis, and proliferation compared with WT SMCs. Furthermore, SMCs from smRac1+/− mice showed decreased phosphorylation of PAK1 and ERK, and reduced ROS production in response to mechanical stretch compared to that of SMCs from WT mice. Inhibition of Rac1 in vitro using NSC23766 lead to decreases in vascular SMC migration and proliferation and significantly reduced SMC glycolytic metabolism measured via changes in ECAR and lactate production. The effects of Rac1 inhibition on migration and proliferation could be rescued via supplementation with the glycolytic end products lactate or pyruvate.

Conclusion

These findings indicate that Rac1 regulation of SMC migration and proliferation is mediated in part via control of glycolytic metabolism in these cells. These findings illustrate the critical role of Rac1 and glycolysis in neointimal formation after vascular injury. Therapeutic modalities, which target Rac1 in SMCs, therefore, may be beneficial in preventing vascular proliferative diseases.

Support or Funding Information

Project funded by NIH R01 HL052233 to James K Liao
Perinatal Taurine Supplementation Prevents Metabolic and Cardiovascular Effects of Maternal Dyslipidemia in Adult Rat Offspring
Authors: Thaeomor Atcharaporn , Tangnoi Chonticha , Chaisakul Janeyuth , Seanthaweesuk Suphaket , Somparn Nuntiya , Roysommuti Sanya
Published: November 2023

Maternal obesity predisposes metabolic and cardiovascular disorders in adult offspring. This study tests the hypothesis that perinatal taurine supplementation prevents dyslipidemia and hypertension in adult offspring of dyslipidemic rat mothers. Female Wistar rats were fed normal rat chow and water with (Dyslipidemia group) or without dyslipidemic induction by intraperitoneal Triton WR‐1339 injection (Control group). After confirmed pregnancy, they were supplemented with (Control+T and Dyslipidemia+T) or without 3% taurine in water from conception to weaning. After weaning, male offspring were fed normal rat chow and water throughout the study. At 16 weeks of age, body weight, epididymis fat size, fasting blood glucose (Control, 84 ± 2 mg/dl; Control+T, 85 ± 3 mg/dl; Dyslipidemia, 96 ± 2 mg/dl; Dyslipidemia+T, 82 ± 2 mg/dl; P < 0.05), plasma low‐density lipoprotein (Control, 102 ± 6 mg/dl; Control+T, 100 ± 6 mg/dl; Dyslipidemia, 137 ± 7 mg/dl; Dyslipidemia+T, 107 ± 5 mg/dl; P < 0.05) and cholesterol (Control, 81 ± 5 mg/dl; Control+T, 81 ± 3 mg/dl; Dyslipidemia, 95 ± 3 mg/dl; Dyslipidemia+T, 81 ± 2 mg/dl; P < 0.05), mean arterial pressure, and heart rate increased but baroreflex sensitivity decreased significantly in Dyslipidemia compared to Control groups. While perinatal taurine supplementation did not affect these parameters in the Control, this treatment normalized, at least in part, the metabolic and cardiovascular effects of maternal dyslipidemia in adult offspring. In addition, plasma high‐density lipoprotein, triglyceride, leptin, alanine aminotransferase, aspartate aminotransferase, creatinine, and blood urea nitrogen were not significantly different among the four groups, irrespective of maternal dyslipidemia or taurine supplementation. These data demonstrate that perinatal taurine supplementation prevents the adverse effects of maternal dyslipidemia on metabolic and cardiovascular defects in adult male offspring.

Support or Funding Information

Suranaree University of Technology
Young healthy men and women are protected from prolonged sitting and postprandial hyperglycemia‐induced brachial artery endothelial dysfunction
Authors: Walsh Lauren K , Restaino Robert M , Jones Chelsea A , Winn Nathan C , Padilla Jaume
Published: November 2023

Previous studies have shown that postprandial hyperglycemia and prolonged sitting are predictors of cardiovascular disease (CVD), potentially due to the detrimental effects of glycemic excursions on the artery wall and reductions in shear stress, respectively. It is possible that prolonged sitting, when combined with consumption of high sugar drinks, may lead to severe endothelial dysfunction. Herein, we hypothesized that sitting exacerbates postprandial hyperglycemia‐induced endothelial dysfunction. In twelve young healthy subjects (six men, six women), brachial artery flow‐mediated dilation (FMD) was assessed at baseline, 1 hour, and 2 hours post oral administration of a 75g glucose load (oral glucose tolerance test, OGTT). Subjects were tested on two separate visits in a randomized, crossover design: after either accumulating 15,000 steps or remaining seated, each throughout an eight‐hour period. The average number of steps during the walking and sitting conditions were 15,972 ± 189 and 315 ± 37 (p<0.0001), respectively. FMD was not reduced during hyperglycemia in either the walking (baseline: 5.98± 0.8%, 1hr: 4.99± 1.01%, 2hr: 6.40 ± 1.12%) or sitting (baseline: 5.24 ± 0.8%, 1hr: 4.84± 0.65%, 2hr: 5.97± 0.94%) condition. However, plasma glucose levels were elevated in the final hour of the OGTT in the walking, but not sitting, condition (p<0.01). Additionally, non‐esterified fatty acid (NEFA) levels were also elevated in response to hyperglycemia in the walking condition, supporting the tenet that prior walking promotes a substrate shift towards increased lipid utilization. These preliminary results suggest that young, healthy subjects may be protected against acute hyperglycemia–induced endothelial dysfunction. This effect is associated with increased plasma glucose and NEFAs following the glucose drink, potentially suggesting a difference in substrate utilization between conditions.

Support or Funding Information

NIH R21DK105368 (JP)
Protective Respiratory Effect of Beta‐Blockade Therapy in Heart Failure Patients
Authors: Uithoven Katelyn E , Snyder Eric M , Olson Thomas P
Published: November 2023

INTRODUCTION

Treatment with β‐antagonists in heart failure (HF) elicits known cardioprotective benefits. Recent work has suggested that administration of a β‐agonist can induce lung fluid clearance in healthy subjects and HF patients. However, the impact of β‐antagonists on the diffusing capacity of the lungs for carbon monoxide (DLCO, to assess lung fluid changes) remains unclear.

PURPOSE

To examine the relationship between β‐antagonist use and lung diffusion in HF patients.

METHODS

A retrospective analysis was performed on 102 HF patients seen at Mayo Clinic between 1995–2010. Patients were divided into two groups: BB=patients prescribed β‐antagonists (n=70) and NB=patients not prescribed β‐antagonists (n=32). Medical records were examined ±1 year from the time of the most recent exercise stress test for age (yrs), sex, height (cm), weight (kg), body mass index (BMI) and β‐antagonist status. Outcome variables included DLCO, left ventricular ejection fraction (LVEF), cardiac output (Q), and cardiac output corrected for body surface area (CI). Independent‐samples t‐test compared age, height, weight, and BMI between BB and NB. A Chi‐Squared test compared New York Heart Association (NYHA) classification and sex between NB and BB. Comparison of DLCO, LVEF, Q, CI, DLCO corrected for CI (DLCO/CI), and DLCO corrected for Q (DLCO/Q) between NB and BB was performed with an independent‐samples t‐test. Data are reported as mean ± standard deviation (SD) or frequency (percentage) where applicable.

RESULTS

There were no differences in age (75±12 vs. 76±13yrs), height (172±10 vs. 173±9cm), weight (84±20 vs. 86±18kg), or BMI (28±6 vs. 29±5kg/m2) between NB vs. BB, respectively. Neither NYHA classification (χ2=0.159; p=0.98) or sex (χ2=0.066; p=0.80) were different between NB and BB groups. No differences were found for LVEF (36.8±17.3 vs. 31.6±15.6%) or DLCO (20.32±7.6 vs. 19.35±5.7ml/min/mmHg) for NB vs. BB, respectively. Compared to NB, the BB group demonstrated lower CI (0.72±0.3 vs. 0.56±0.3, p=0.006) and Q (1.47±0.6 vs. 1.15±0.6, p=0.01), while both DLCO/CI and DLCO/Q were higher in BB (31.32±14.1 vs. 43.84±29.5, p=0.005 and 15.84±7.5 vs. 21.93±16.2, p=0.01, respectively).

CONCLUSIONS

These data suggest that HF patients prescribed β‐antagonist therapy demonstrate better lung diffusion for a given cardiac output compared to HF patients not prescribed β‐antagonist therapy.
Peak Aortic Acceleration as a Noninvasive Index of Left Ventricular Contractility
Authors: Reddy Anilkumar , Heredia Celia Pena , Coulthard Tonya , Pham Thuy T , Taffet George E
Published: November 2023

Peak left ventricular (LV) pressure derivative (+dP/dtmax) is considered to be the gold standard in the assessment of left ventricular contractility. The measurement of left ventricular pressure with an intravascular pressure catheter is an invasive procedure and is usually done as a terminal procedure in mice and other small animals. In patients mean acceleration derived from aortic outflow velocity which is measured noninvasively by echocardiography was shown to be a good surrogate of left ventricular contractility. In rats peak acceleration of aortic flow whic is measured with invasive extravascular flow probe was shown to be correlated well with dP/dtmax. We believe that echocardiography measurement of aortic outflow in mice may not be sensitive enough (due to angle correction) for serial measurements of left ventricular contractility. We undertook this study to evaluate the utility of peak acceleration of aortic flow velocity measured with a single crystal pulsed Doppler probe (no angle correction needed) as a noninvasive surrogate measurement of left ventricular contractility. In this study we made simultaneous measurements of left ventricular pressure using an invasive pressure catheter and aortic flow velocity using a noninvasive 20 MHz pulsed Doppler probe in normal mice. Measurements were made at baseline and at several time intervals after a single intraperitoneal injection of dobutamine (1μg/g BW). Peak dP/dt and peak aortic acceleration values were calculated at several heart rates (range: 387 to 701 beats/minute) obtained from the 4 wild‐type male mice (5 months old). Linear regression of peak aortic acceleration (y) versus peak dP/dt (x) showed a high correlation between the two measurements (y = 2.8x + 1617; p<0.0001; r2 = 0.896; n=18 data points). The preliminary findings obtained from this limited study suggest that peak aortic acceleration may be used as a noninvasive index of LV contractility. We expect to further evaluate this relationship between peak aortic acceleration and peak dP/dt under conditions of vasoconstriction and vasodilation along with responses to positive and negative ionotropic agents to validate the potential use of this noninvasive index in mice and other small animals.
High Salt Diet Plus Fructose Water Intake Induces Hypertension
Authors: Hahka Taija M. , Fan Yuanyuan , Jiang Enshe Marie , Chen Qinghui , Shan Zhiying
Published: November 2023

Evidence in prior studies have indicated that a high salt (HS) diet in combination with high fructose intake results in hypertension. Detailed metabolic parameters have not measured. This study aims to test the metabolism of rats with either a HS diet or a normal salt (NS) diet with and without fructose drinking water. Seven‐week‐old, Sprague‐Dawley (SD), male rats were divided into four groups (n=6 per group). The SD rats were then fed the following diets: NS diet as the control, HS (4% NaCl) diet, NS diet with 20% fructose in drinking water (F), and HS (4% NaCl) diet with 20% fructose in drinking water (HS+F), respectively. Blood pressures of all the rats were then measured twice a week via non‐invasive tail cuff method. Two weeks after the blood pressure measurements, all the rats were then transferred into metabolic cages and housed individually. In the metabolic cages, the rats received the same diet and drinking water as they have had throughout the entire blood pressure study. SD rats were given twenty‐four hours to acclimate to their environment in the metabolic cages and then their water intake, food intake, feces and urine output was measured for three consecutive days. At the beginning of the experiment, results have indicated that there is no significant difference in baseline blood pressure among the four groups. However, A three‐week diet of a HS+F treatment has demonstrated an increase in mean arterial pressure (MAP) by 37 mmHg (p < 0.05) compared to the NS control group. No significant increases were observed in the other two groups (C: 89 ± 5; HS: 97 ± 4; F: 97± 7; HS+F: 126 ± 9 mmHg). Metabolic measurements have shown that there was a significant increase in water intake (C: 27.9 ± 2.0; HS: 59.2 ± 6.4; F: 35.1 ± 5.2; HS+F: 54.8 ± 6.0, mL/24 hours) and urine output (C: 13.5 ± 1.7; HS: 39.7 ± 2.2; F: 13.3± 1.6; HS+F: 28.1 ± 1.4, mL/24 hours) for HS alone and HS+F groups in comparison to the control group. Food intake had substantially decreased in the HS+F group compared to the other three groups (P<0.05) (C: 36.1 ± 3.6, HS: 25.1± 0.9, F: 21.7 ± 0.7, HS+F: 14.5 ± 1.0, mL/24 hours); the feces output data was diverse and does not show significant differences among groups (data not shown). Our results suggest that high salt plus high fructose diet dramatically changes metabolism which alters cardiovascular function.

Support or Funding Information

Grant Support: NIH R15HL129213, Shan
Sirtuin‐1 deacetylation of p53 plays a role in shear stress‐induced autophagy in endothelial cells
Authors: Ting Pei‐Ching , Wu Li‐Hong , Wang Danny Ling
Published: November 2023

Blood flow‐induced shear stress acted on endothelial cells (ECs) is essential for maintaining normal vascular function. Autophagy represents a homeostatic mechanism crucial for cell survival. In our current study, we demonstrate that shear stress to ECs increases autophagy and Sirtuin‐1 (SIRT1, a NAD+‐dependent deacetylase) deacetylation of tumor suppressor protein p53 may play a role. Human ECs subjected to shear stress (12 dynes/cm2) increased SIRT1 expression as well as NAD+/NADH ratio. ECs under shear stress stimulated autophagy as demonstrated by 1) an increase of LC3‐II/LC3‐I ratio and 2) a decrease of p62 level. Decrease or inhibition of p53 has been shown to induce autophagy and p53 degradation is facilitated with deacetylation by SIRT1. This study was aimed to understand whether p53 levels regulated by SIRT1 mediate shear stress‐induced autophagy. Shear stress to ECs induced SIRT1 expression whereas p53 acetylation (K382) and p53 levels were decreased. ECs treated with siRNA to knockdown SIRT1 or Sirt inhibitor (EX527) increased p53 acetylation and p53 level coupled with decreased autophagy. ECs treated with an activator (CTBP) of P300 (an acetyltransferase) to increase p53 acetylation resulted in an increase of p53 level and then lead to a decreased autophagy. ECs treated with SIRT1 activator (SRT1720) also decreased p53 acetylation and increased autophagy. Therefore, p53 level regulated by SIRT1 activity may at least partially play a role in shear stress‐induced autophagy in ECs. In conclusion, ECs under shear stress increase SIRT1 expression and the consequent decrease of p53 promotes autophagy and thus enhances endothelial homeostasis.
Time‐dependent effects of training on cardiac renin angiotensin system (RAS): Protection against oxidative stress, inflammation and pathological cardiac remodeling.
Authors: Silva Sebastiao Donato , Jara Zaira , Moreira Roseli , Casarini Dulce , Michelini Lisete
Published: November 2023

Goals

To investigate the time course effects of aerobic training on the cardiac injurious axis of the renin angiotensin system (RAS) (Ang II) and its counter regulatory and protective axis (Ang‐(1–7)), as well their relationship with oxidative stress, inflammation and cardiac remodeling in spontaneously hypertensive rats (SHR).

Methods

Adult male SHR and age‐matched WKY controls were trained on treadmill (T) or kept sedentary (S) for 2 months. Resting arterial blood pressure (AP) and heart rate (HR) were measured at weeks 0 (S0), 1 (T1), 2 (T2), 4 (T4) e 8 (S8 and T8) followed by euthanasia and heart harvesting. Ang II and Ang (1–7) (HPLC), oxidative stress (DHE staining), NF‐kB (Electrophoretic Mobility Shift Assay) and expression of pro‐inflammatory genes were measured in the left ventricle (LV).

Results

SHR‐S0 vs. WKY‐S0 had higher AP and HR (169±1 vs 115±1 mmHg; 358±7 vs 330±8 b/mim), LV hypertrophy (+27% in LV/BW ratio), increased ROS levels (+19%), elevated TNF‐α expression (2.8‐fold) and higher collagen volume (+20%) in LV, which were all kept in higher levels up to the end of protocols. At the beginning of protocols NF‐kB activity, IL‐1β expression, and Ang II and Ang‐(1–7) content (~87±3 and 54±3 pmol/g tissue, respectively) were similar in both strains, butt Nfkb activity, IL‐1β expression (~1,2 fold), and Ang II (+27%) were increased in SHR kept sedentary for 8 weeks. In SHR, T reduced LV Ang II content (−71%, T1), increased Ang‐(1–7) content (+30%, T2) and reduced and normalized DHE fluorescence (T2), which were maintained in lower levels until the end of protocols (T8). A transitory increase (T1–T2) in Nfkb, IL‐1β and TNF‐α (~5, 1.5, 1.8, fold) were observed in SHR. However, from T4 up to T8, NF‐kB activity was reduced and TNF‐α and IL‐1β expression were back to control levels. At the end of protocols LV/BW still higher in SHR vs WKY without differences between T and S groups, but collagen volume was normalized in SHR T8 to similar levels presented by WKY. Training was accompanied by reductions in HR (−15%, T4–T8) and AP (−10%, T8).

Conclusion

Training in SHR reduced cardiac Ang II and increased Ang‐(1–7) content, indicating a shift from the injurious axis of the RAS to the protective axis. This was associated with reduced oxidative stress and decreased inflammation. Although no changes were observed in LV hypertrophy, collagen volume was reduced in SHR T. Our findings suggest that training has a cardioprotective effect in hypertension and prevents the deleterious cardiac remodeling.

Support or Funding Information

FAPESP: 2011/15681‐8; CAPES
Sevoflurane Increases Mobilization of Endothelial Progenitor Cells in Rats and Coronary Artery Disease Patients
Authors: Vlad Adelina , Popescu Mihaela , Stanca Ionut , Corneci Dan , Stancu Camelia , Niculescu Loredan , Isvoranu Gheorghita , Ceafalan Laura , Popescu Andreea Catarina , Dimulescu Doina
Published: November 2023

Plasma levels of endothelial progenitor cells (EPCs) correlate to the cardiovascular outcomes, while basic science suggest that preconditioning with volatile anesthetics (APC) may improve stem cells biology. Thus, we tested in rodents and on patients with coronary artery disease (CAD) the effects of sevoflurane on the mobilization of these angiogenic cells. EPCs plasma levels were evaluated by flow‐cytometry before exposure to sevoflurane (baseline) and 24 hrs afterwards, in blood samples collected from Wistar rats or CAD patients scheduled for elective percutaneous coronary intervention (PCI). Sevoflurane (1 MAC in air for the animal model, and in 50% O2 in the clinical study) was administered prior a myocardial ischemia/reperfusion procedure (I/R) in rats (3 cycles of 5 min) or before PCI in CAD patients (2 cycles of 15 min); control subjects received only air, or oxygen (50% in air) respectively. Values are means ± SEM, compared by ANOVA. In the animal study quantification was performed by flow cytometry at baseline, 12h, 24h, 48h and 72 h after sevoflurane administration, and an important increase of CD34+ (n=3, 7‐fold increase versus control, p = 0.031) and CD34+/Flk1+ cells (n = 3, 2.3‐fold increase versus control values, p < 0.001) was observed only at 24 hrs after treatment. In CAD patients, plasma CD45dim/CD34+/KDR+, CD45dim/CD34+/KDR+/CD133+ and CD45dim/CD34+/CD309+/CXCR4+ mononuclear cell populations were increased 1.45‐fold (p = 0,006), 1,67‐fold (p < 0,001) and 1.36‐fold (p = 0.005) respectively in sevoflurane treated patients (n = 16) at 24 h postexposure versus baseline, whereas in the control group (n = 10) the values where relatively the same at 24 hrs and at baseline. In conclusion, sevoflurane administered in a discontinuous manner increases the levels of plasma EPCs in the late window of APC in Wistar rats and CAD patients, indicating EPCs mobilization as a potential mechanism for the regenerative and anti‐ischemic processes of APC. Although preliminary, our results sustain the initiative of using preconditioning protocols with volatile anesthetics in cardiovascular and non‐cardiovascular surgery, or for reducing the in‐stent restenosis following angioplasty.

Support or Funding Information

Research grant PN‐II‐RU‐TE‐2012‐3‐0463, UEFISCDI Romania
Endothelial dysfunction occurs independently of adipose tissue inflammation and insulin resistance in ovariectomized Yucatan swine
Authors: Jurrissen Thomas Jacob , Olver T. Dylan , Lin Gabriela S , Winn Nathan C , Gastecki Michelle L , Welly Rebecca J , Grunewald Zachary I , Emter Craig A , Vieira‐Potter Victoria J , Padilla Jaume
Published: November 2023

Ovarian hormone deficiency is associated with increased adiposity, inflammation, and impaired vascular function, which are contributing factors to cardiovascular disease. In rodents, ovariectomy causes white adipose tissue (AT) inflammation and insulin resistance (IR), potentially contributing to vascular dysfunction; however, whether this occurs in a more translationally‐relevant large animal model remains unknown. We tested the hypothesis that ovariectomy would promote white AT inflammation, IR and peripheral vascular dysfunction in female swine. At sexual maturity (7 months of age), female Yucatan swine were either ovariectomized (OVX, n=7) or kept ovary‐intact (CON, n=9). All pigs were fed equal amounts of standard chow, and were euthanized 6 months post‐surgery. Body mass, spontaneous (cage) physical activity, fasting blood glucose, insulin, and non‐esterified fatty acids were not significantly different between groups; however, triglycerides were elevated in OVX vs CON (29%, P<0.05). Circulating cytokines (eg. IL‐1β, IL‐6, IL‐10, and TNFα) were not significantly different between groups, whereas, circulating leptin levels were decreased in OVX vs Con (−21%, P<0.05). Adipocyte size in omental (visceral) AT was greater in OVX vs CON (27%; P<0.05); however, no differences in omental AT inflammation were noted between groups. In contrast, ex vivo brachial artery endothelial‐dependent vasorelaxation was reduced in OVX vs CON (−30%, P<0.05) and rescued with blockade of endothelin receptor A via BQ123. In conclusion, loss of ovarian hormones perturbs endothelial function independent of systemic and visceral AT inflammation or IR in Yucatan swine.
Effects of Swimming Training and Estrogen Terapy on C‐Type Natriuretic Peptide‐induced Relaxation in aorta of ovariectomized Hypertensive Rats
Authors: Abreu Glaucia Rodrigues , Claudio Erick R , Almeida Simone A , Silva Fabricio B , Menezes Lais A
Published: November 2023

Estrogen deficiency is detrimental to vascular function. On the other hand, the practice of exercise training and estrogen therapy improve vascular function. However, the effects of swimming training (SW) and estrogen therapy (ET) on the relaxation induced by C‐type natriuretic peptide (CNP) is unclear. Our aim was to investigate the effects of chronic SW and ET on CNP‐induced vascular relaxation in the aorta of ovariectomized hypertensive rats. The groups were randomly divided into sham (S), sham+SW (SSW), ovariectomized (OVX), ovariectomized+ET (OET), ovariectomized+SW (OSW) and ovariectomized+ET+SW (OET+SW). ET (5 mg of 17β‐Estradiol, s.c.) and SW (60 min – 5x/wk) were performed during eight weeks. Systolic blood pressure was measured before and after the training and treatment period. Aorta reactivity was performed in response to increased concentration of CNP. Ovariectomy significantly impairs the systolic blood pressure, while ET, SW and the association of both prevents this impairment. OVX reduces significantly the CNP‐induced vasorelaxation in the aorta of hypertensive animals. However, ET and SW were able to prevent the reduction caused by OVX, being able to maintain the relaxation at the same level as observed in sham animals. The association of ET and SW can also prevent the decrease in relaxation induced by CNP, but it did not show any additive effects. SW and ET prevent the ovariectomy‐induced worsening in vascular relaxation to CNP in hypertensive animals. Therefore, the practice of chronic exercise training can play a major role in the cardioprotection in hypertensive postmenopausal women.

Support or Funding Information

UFES‐CApes‐CNPq‐Fapes
Gender Differences of Heart Rate Variability in College Age Students
Authors: Toth Abigail , Melton Sheri
Published: November 2023

Heart Rate variability (HRV) is the beat‐to‐beat time interval of a heart rate, also known as a R‐R interval. HRV can be used to suggest health related problems. Too high of a HRV could suggest an arrhythmia or another sort of neurological issue, while too low of a HRV could suggest chronic stress, pathology, or regression due to age to name a few. Prior research has suggested healthy males have a higher HRV when compared to healthy females. However, no study to date has investigated the day‐to‐day gender differences of heart rate variability in college age students.

The purpose of this study is to examine the day‐to‐day differences in HRV for both male and female college age students. College age males and females (n=30) were recruited to participate in this study. Students who were not currently under doctor's care were included. Each subject underwent two electrocardiograms (ECG) administered on two different days within 48 hours. Subjects were positioned in a supine position for both resting single lead ECG's. Two minutes of cardiac cycles were used to evaluate cardiac rhythms. HRV was measured utilizing Power Lab/ECG Analysis Add‐On for LabChart 8 (ADInstruments). Statistical analysis included an ANOVA to compare subgroups for day one and day two, and a Wilcoxon matched pairs test to compare day one to day two as a whole. Statistical significance was set at P < 0.05. Based on the current results, we conclude there is no difference for day‐to‐day HRV in college‐aged students as a whole. Additionally, there is also no significant difference in HRV between gender subgroups.

Support or Funding Information

No grants were obtained
Low Flow‐mediated constriction in Peri‐menopausal Women
Authors: Kuczmarski Andrew , Sebzda Kelly N , Wenner Megan M
Published: November 2023

Impairments in vascular function are evident early in the menopausal transition, as previously demonstrated by a reduced brachial artery flow‐mediated dilation (FMD) in peri‐menopausal women compared to premenopausal women. Recently, low flow mediated constriction (L‐FMC) has been used as a complementary measure of vascular health, and has been shown to be reduced with aging and in diseased populations. Therefore, the purpose of this study is to test the hypothesis that peri‐menopausal women have decreased L‐FMC compared to young women. We measured changes in brachial artery diameter via ultrasound in seven young (24±1 years, 23±1 kg/m2) and five peri‐menopausal women (50±1 years, 24±1 kg/m2). A blood pressure cuff was placed just distal to the olecranon process and inflated to suprasystolic pressure for five minutes. Images were recorded continuously at baseline (1‐minute), during a five minute occlusion, and for a remaining 2‐minutes after cuff deflation. FMD was calculated as a percent change from baseline to peak diameter after cuff deflation. L‐FMC was calculated from the last 30 seconds of cuff inflation using the lowest average value and was reported as percent change from baseline. Total vessel reactivity was calculated by adding the absolute value of FMD and L‐FMC. FMD values were comparable between peri‐menopausal (6.75±0.36%) and young women (7.88±0.33%). L‐FMC was similar between peri‐menopausal (−2.32±0.47%) and young women (−2.95±0.36%). Total vessel reactivity was also similar between young (10.82±0.56) and peri‐menopausal women (9.46±0.49). In conclusion, these preliminary data suggest that L‐FMC is preserved in peri‐menopausal women. Additional data are needed to further examine whether L‐FMC is altered across the menopausal transition or in postmenopausal women.

Support or Funding Information

Supported by NIH Grant P20 GM 103446, U54 GM 104941, and University of Delaware Research Foundation.
Endurance Exercise Training Improves Functional Sympatholysis in Postmenopausal Women
Authors: Kruse Nicholas , Hughes William , Hochstedler Reginald , Bock Joshua , Iwamoto Erika , Ueda Kenichi , Casey Darren
Published: November 2023

The ability to reduce sympathetic vasoconstriction during exercise and thus, optimize blood flow proportional to the metabolic demand of the working muscle is termed functional sympatholysis. While regular exercise has been shown to offset the age‐related decline in functional sympatholysis in older males, the effect of exercise training on functional sympatholysis in older postmenopausal women (PMW) remains unknown. The purpose of the present study was to examine whether aerobic exercise training can offset the impaired functional sympatholysis in contracting skeletal muscle in PMW (>12 months since last menstrual cycle). Nineteen PMW (untrained, n=9 vs. trained, n=10) performed 5‐minutes of steady state (SS) forearm exercise at 10 and 20% of maximal voluntary contraction and an absolute contraction intensity of 5kg. Trained status consisted of those PMW who completed aerobic or high intensity interval training >2 years prior to the study and involved >30‐minutes/day and >4 days/week. Global increases in SNS activity were performed via application of lower body negative pressure (i.e. LBNP, −30 mmHg) during SS‐exercise. Non‐invasive measures of forearm blood flow (FBF), mean arterial pressure (MAP), cardiac output (CO) and heart rate (HR) were continuously recorded before and during exercise. Muscle oxygen consumption (VO2m) across the forearm was estimated (via venous blood sampling) during SS‐exercise and SS‐exercise with LBNP. Forearm vascular conductance (FVC; ml·min−1·100 mmHg−1) was calculated from blood flow (ml·min−1) and blood pressure (mmHg). Vasoconstrictor responsiveness was then determined as the % change in FVC (between SS‐exercise and SS‐exercise with LBNP). The reduction in FVC (% change FVC) during LBNP was attenuated in trained vs. untrained PMW at 10% MVC (−7.3±1.2% vs. −13.0±1.1%; P<0.05), 20% MVC (−4.5±0.8% vs. −8.6±1.4%; P<0.05) and 5kg (−5.3±0.8% vs. −8.9±1.4%; P<0.05) conditions, whereas there was no difference at rest (−32.7±4.4% vs. 33.7±4.0%). Forearm VO2m and the magnitude of change in systemic hemodynamics (HR, CO and MAP) did not differ between groups during exercise. Lastly, age and years PM did not differ between trained PMW vs. untrained PMW, suggesting that training factors were influential in the training‐induced blunting of vasoconstrictor restraint during acute exercise. Collectively, these findings suggest that long‐term endurance exercise training in PMW blunts sympathetically induced vasoconstriction (i.e. improved functional sympatholysis) during relative and absolute mild‐to‐moderate intensity forearm exercise.

Support or Funding Information

Funded by NIH HL‐105467 (DPC) and NIH Abboud Cardiovascular Center Interdisciplinary Fellowship (NTK)
TRPV4 deletion improves cardiac function, structure and remodeling following myocardial infarction
Authors: Adapala Ravi Kumar , Minasyan Ashot , Kanugula Anantha K , Cappelli Holly C , Paruchuri Sailaja , Meszaros Gary J , Thodeti Charles K
Published: November 2023

Ischemic heart disease (IHD) is the major underlying cause of myocardial infarction (MI), scarring, and hypertrophy leading to heart failure. The prevention of ischemic damage due to MI involves scar formation by synthesis and reorganization of ECM. Cardiac fibroblasts are the primary mediators of cardiac repair as they secrete and remodel extracellular matrix in the heart. We have recently demonstrated that mechanosensitive ion channel, TRPV4 (Transient Receptor Potential Vanilloid 4) mediates cardiac fibroblast differentiation into myofibroblasts in vitro. However, the physiological significance of TRPV4 in cardiac remodeling in vivo is not known. In the present study, we explored the role of TRPV4 in cardiac remodeling following MI. We subjected WT and TRPV4KO mice to MI (permanent occlusion of LAD) and measured cardiac function for 8 weeks by serial echocardiographic assessment. We found significant time‐dependent preservation of cardiac function (ejection fraction and fractional shortening) post‐MI in TRPV4KO mice compared to WT counterparts. Further, picro‐sirius red and Masson's trichrome staining revealed reduced collagen deposition in infarcted and remote zones of TRPV4KO hearts, 8 weeks post‐MI. Mechanistically, we found decreased cardiomyocyte apoptosis (TUNEL assay) and increased capillary density (CD31 staining) in TRPV4KO hearts compared to WT hearts, 1 week post‐MI. Taken together, these results suggest that absence of TRPV4 preserves cardiac function and structure post‐MI by reducing myocyte apoptosis and cardiac fibrosis probably by increasing revascularization.

Support or Funding Information

NIH(1RO1HL119705)NIH(1R15CA202847‐01), AHA Grant in Aid(14GRNT20380935)
Age‐Related Left Ventricular Systolic Dysfunction in a Mouse Model of Hypertrophic Cardiomyopathy
Authors: Larson Robert A. , Purnell Benton S. , Davis Melissa K. , Weiss Robert M. , Cicha Michael Z. , Sabharwal Rasna , Chapleau Mark W.
Published: November 2023

Familial hypertrophic cardiomyopathy (HCM) is a devastating disease caused by mutations in cardiac sarcomeric proteins that result in myocyte disarray, cardiac fibrosis and hypertrophy. A hallmark of HCM is cardiac diastolic dysfunction. Systolic function is generally preserved or even enhanced; however, some patients develop systolic dysfunction over time. In this study we tested the hypothesis that left ventricular (LV) systolic dysfunction increases with age in transgenic mice with cardiac‐specific expression of mutated alpha tropomyosin (Glu180Gly), an established model of human HCM. Cardiac function was assessed by echocardiography (Vevo 2100, Visualsonics) in HCM and control wild type (WT) mice over a wide range of age (3–47 weeks). Mice were lightly sedated with midazolam (0.15 mg, SC) to avoid anesthesia‐induced decreases in heart rate, myocardial contractility and sympathetic tone. LV end diastolic volume (EDV) was not significantly different in HCM vs. WT mice at any age (see Table). LV end systolic volume (ESV) and ejection fraction (EF) did not differ between very young, 3‐week old WT and HCM mice. In contrast, at 7 weeks of age, ESV was higher and EF was lower in HCM vs. WT mice (P<0.05). Systolic dysfunction was most pronounced in middle‐aged HCM mice between 36 and 47 weeks of age (Table, P<0.05). We conclude that alpha tropomyosin mutant mice with HCM exhibit age‐dependent LV systolic dysfunction.

Support or Funding Information

AAS‐Lundbeck Fellowship & HL14388

3 Weeks
7 Weeks
43±1 Weeks

WT (n=8)
HCM (n=9)
WT (n=8)
HCM (n=9)
WT (n=5)
HCM (n=12)

EDV (μL)
24.2±2.4
28.8±2.0
37.4±4.8
45.4±4.3
41.6±7.3
54.0±3.7

ESV (μL)
6.7±1.1
9.5±0.9
9.1+1.5
18.0±2.8 *
10.1±2.0
21.3±1.7*

EF (%)
73±2
67±1
76±2
62±3*
76±3
61±2*

p<0.05 WT vs. HCM
Depressed State of Cardiac Energetics Following Cardiopulmonary Bypass in Pigs
Authors: Jaimes Rafael , Sarkislali Kamil , Sherman Meredith , Swift Luther , Ishibashi Nobuyuki , Posnack Nikki
Published: November 2023

Objective

The objective of this work is to determine the state of cardiac energetics after hypoxia due to cross‐clamping of the aorta during cardiopulmonary bypass in an open‐heart, pig model.

Methods

Blood samples and apical, left‐ventricular biopsies (~1g) were taken after 2 hours of cardiopulmonary bypass. Blood samples were measured for lactate dehydrogenase (LDH) activity. The key modulating enzyme for glucose oxidation, pyruvate dehydrogenase (PDH), was assessed for activity using isolated mitochondria from the myocardium. Biopsies were incubated with sodium fluoride and phenylmethylsulfonyl fluoride, then homogenized and underwent a series of centrifugation to isolate mitochondria. Mitochondrial membranes were permeated using Triton‐X and then mixed with PDH substrates (thiamine tri‐phosphate, MgCl2, NAD+, CoA, and pyruvate). PDH kinetics were assessed by monitoring NADH absorbance at 340nm with a spectrophotometer. The sub‐maximal PDH activity was determined by using 2mM pyruvate and maximal activity was determined with 20mM pyruvate. The ratio of sub‐maximal to maximal activity provided the activated fraction.

Summary of Results

PDH was found to be 42.3% ± 7.8 activated in bypass pigs (n=3), compared to 71% ± 12.4 activated in control pigs (n=2). Lactate dehydrogenase level was 444±123 IU/L in bypass pigs compared to the reference range of 105–333 IU/L.

Conclusion

PDH is inactivated by the buildup of the electron carrier NADH and ATP, which occurs in hypoxic conditions. Lack of post‐ischemic, re‐activation of PDH results in an accumulation of pyruvate and activation of LDH, which is associated with decreased functional recovery (previously shown in isolated rodent hearts). This work shows that aortic‐cross clamping causes inactivation of PDH due to hypoxia. Reduced PDH activity can inhibit electrical and mechanical cardiac performance during the vulnerable post‐operative period.

Support or Funding Information

This study was supported by the National Institutes of Health (R00ES023477 to NGP, UL1TR000075, KL2TR000076), Children's Research Institute: Divisions of Cardiology and Cardiac Surgery.