bluuebunny/crossref_metadata_2025 huggingface dataset:
Continuous Use of Intrathoracic Pressure Regulation Device Improved Cardiac Output in Porcine Peritonitis
Authors: Goldfarb Roy David , Jaffe J. Douglas , Torjman Marc C , Mitrev Ludmil , Jasti Purnachandra , Knob Christopher , Metzger Anja , Lurie Keith , Parrillo Joseph E. , Dellinger R. Phillip
Published: June 2021

Septic shock initiates multiple pathophysiologic pathways manifesting characterized by reduced cardiac output. We tested an Intrathoracic Pressure Regulator (IPR) a device which decreases intrathoracic pressure during passive exhalation creating more negative intrathoracic pressure enhancing venous return and cardiac output. We hypothesized that continuous IPR therapy would improve cardiac output without fluid resuscitation during porcine peritonitis.

Six Yorkshire pigs (30–40kg) were anesthetized with isofluorane, intubated, mechanically ventilated, instrumented with a Swan‐ Ganz and a femoral artery catheter. Animals were assigned to a treatment or control group. After a basal period, peritonitis was induced by implanting a fibrin clot containing 4×109 cfu·kg−1 E. coli O11.B4. At 2 hours IPR was applied for 4 hrs or until the animal met euthanasia criteria. The primary outcome measurement was cardiac index.

Continuous IPR augmented cardiac index and mean arterial blood pressure for duration therapy, becoming larger as time increased while pulmonary vascular resistance declined. This study demonstrated that IPR treatment for peritonitis caused significant cardiovascular support in this model. Further studies are needed to determine the potential clinical benefit of this non‐invasive circulatory enhancement technology.
N‐acetylcysteine Ameliorates Infarction‐induced Myocardial Fibrosis
Authors: Lee Tsung-Ming , Chen Chien-Chang
Published: June 2021

Excessive production and deposition of extracellular matrix proteins is a feature after myocardial infarction. Reactive oxygen species contributes to collagen synthesis through the activation of RhoA. We assessed whether N‐acetylcysteine could attenuate myocardial fibrosis after myocardial infarction. Male Wistar rats after ligating coronary artery were randomized to either vehicle, or N‐acetylcysteine for 4 weeks. Post‐infarction was associated with increased oxidant release, as measured by myocardial glutathione and superoxide, and dihydroethidium fluorescent staining. RhoA/ROCK activation after infarction was observed by increasing RhoA localization from the cytosol to the membrane and phosphorylating the ROCK substrate myosin phosphatase target subunit 1. N‐acetylcysteine diminished myocardial fibrosis by inhibiting RhoA/ROCK activation without alteration of TGF‐β1 proteins. A Rho inhibitor, C3 exoenzyme, and 2 ROCK inhibitors, fasudil and Y‐27632, significantly attenuated connective tissue growth factor expression. Furthermore, the effects of N‐acetylcysteine on connective tissue growth factor were abolished by administering L‐buthionine sulfoximinem. These results indicate that N‐acetylcysteine as a glutathione precursor can expedite the attenuation of infarction‐induced myocardial fibrosis probably through the inhibition of TGF‐β1‐indepdent RhoA/ROCK activity.
Anti‐Inflammatory Effects of ACE Inhibition Persist Following Withdrawal of Treatment
Authors: Hale Taben Mary , Tu Danni , Shahid Wafa , Biwer Lauren A
Published: June 2021

Transient (2‐wk tx + 2‐wk washout) angiotensin converting enzyme (ACE) inhibition induces persistent changes that result in a preservation of cardiac function and fewer infiltrating macrophages after 10 days of nitric oxide synthase inhibition (L‐NAME) – despite evidence of infarction. In the present study we investigated whether prior ACE inhibition (enalapril) would yield a modified immune response during L‐NAME‐induced pathological remodeling. We performed a time course analysis of left ventricular (LV) inflammatory cytokines and macrophage infiltration during L‐NAME (L) treatment in SHR that were previously treated with placebo (C+L) or enalapril (E+L) for 2wks followed by 2‐wk washout. L‐NAME equivalently increased arterial pressure, regardless of pre‐treatment. Distinct patterns of cytokine levels were observed in C+L vs E+L. In C+L, but not E+L LV there was an early (day 3) and sustained increase in monocyte chemoattractant protein‐1 and granulocyte macrophage colony stimulating factor that resulted in a significant increase in macrophage infiltration on day 7 of L‐NAME treatment.

This is the first evidence that transient pre‐treatment with an ACE inhibitor can produce long‐term changes in L‐NAME‐induced immune responses. Further studies will determine whether this reduced macrophage recruitment will result in attenuation of post‐infarct remodeling.
Impact of Hyperhomocysteinemia on Cardiac Gene Expression in Pregnant Rats
Authors: Song Su , Ojaimi Caroline , Kertowidjojo Elizabeth , Zhang Su Hua , Huang Harer , Kandhi Sharath , Wolin Michael , Hintze Thomas H
Published: June 2021

Hyperhomocysteinemia (HHcy) causes cardiovascular dysfunction during pregnancy. We have previously shown that HHcy disrupts the regulation of O2 consumption in the heart by lowering NO bioavailability through the generation of superoxide. Presently, we explored the molecular effects of HHcy during pregnancy. Pregnant SD rats were fed with 10g/L methionine in drinking water for 20 days to increase plasma homocysteine (Hcy) (3.0±1.2 to 14.6±8.9 uM). mRNA microarray analysis of left ventricle tissue revealed significant changes in 242 genes (p<0.05, > ±1.5). We grouped differentially expressed genes into different functional categories, and the results showed a wide range of distribution of expression patterns within the functional groups. For example, some cell structure/motility genes were upregulated, including Kruppel‐like factor, histone deacetylase 1, myosin 1b, and ARP2 actin‐related protein 2. We have also seen several oxidative stress‐related genes, such as hypoxia up‐regulated 1 and ischemia related factor up‐regulated. Metabolism genes such as pyruvate dehydrogenase phosphatase isoenzyme 2 and fatty acid transporter 4 were differentially regulated.

Conclusion

HHcy triggers cardiac gene expression changes during pregnancy, suggesting an underlying mechanism behind the effects of HHcy.
Thyroid hormone preserves myocytes in the border zone of myocardial Infarction
Authors: Chen Yuefeng , Youmans Steven , Weltman Nathan Y. , Li Xiang , Crause David , Gerdes Anthony Martin
Published: June 2021

Introduction

Thyroid hormone (TH) improves left ventricular (LV) remodeling and function after myocardial infarction (MI); however, the cellular basis is unknown.

Methods

MI was produced by ligation of the LAD in female SD rats. Rats were divided into the following groups: (1) Sham MI, (2) MI, and (3) MI+T4 treatment (T4 pellet 3.3mg, 60 days release, implanted subcutaneously immediately following MI). Each group was further divided into two subgroups (n=9 per subgroup) for myocytes isolation and whole heart tissues collection eight weeks after surgery.

Results

MI resulted in LV chamber dilatation and functional impairment, with LV myocyte lengthening. T4 treatment after MI improved LV function, increased LV weight by 37%, increased LV myocyte volume and cross‐sectional area (CSA) by 13%, and increased non‐infarcted tissue area by 41%, but did not change the infarct perimeter or LV dimension (Table 1). The increase in LV myocyte volume accounted for only 1/3 of the increase in non‐infarcted tissue area, indicating an increased number of surviving myocytes accounted for the remaining portion. Based on our previously published paper, T4 treatment might help to preserve myocytes in the border zone after MI via its anti‐apoptotic effect.

Conclusions

These results suggest T4 treatment after MI can improve LV myocyte remodeling and preserve myocytes in the border zone.
The metabolic mechanisms involved in the heart protection from myocardial infarction induced by diabetes
Authors: Malfitano Christiane , Carbonaro M , de Souza AL , Alba-Loureiro TC , Souza LE , Figueroa D , Silva K , Curi R , Irigoyen MC
Published: June 2021

Metabolic mechanisms involved in heart protection of myocardial infarction (control = C, diabetic = D, myocardial infracted = MI and diabetic myocardial infarcted = DI) rats were investigated. After 30 days of diabetes and 15 days of MI, the left ventricle (LV) function and energy substrate levels were evaluated by echocardiogram and biochemistry methods. The infarcted area in DI was 36% lower than in MI and the ejection (DI: 82  3 vs 55 3% in MI) and shortening (DI: 48  2 vs MI: 25  2%) fractions were improved. Plasma levels (mg/dl) of free fatty acids (21 ± 3) and triglycerides (252 ± 44) were increased in D vs DI (12 ± 0.9; 110 ± 19), respectively. In the LV, the contents of free fatty acids (mg/g of tissue) and glycogen (mg of glucosyl unit/mg of tissue) were reduced in D (0.45 ± 0.09 and 91± 12) vs DI (1.1 ± 0.2 and 31 ± 2), respectively. LV activities (umol/min/mg protein) of citrate synthase in the MI were reduced (3.6 ± 0.2) and in D were similar (D: 5 ± 0.9; DI: 4.3 ± 0.6) to C (6.2 ± 0.3); CPT 1 content in DI was 46% lower than in the D; hexokinase activity was 50% reduced in D vs C. The phosphofructokinase and glucose‐6‐phosphate dehydrogenase activities were not changed. The content of coenzyme A (μmol/ g tissue) was increased in DI (4.2 ± 2.9) vs MI (3.6 ± 0.1). These findings suggest an increase in the heart capacity for ATP generation maintaining the cardiac function in infarction. Support: CAPES, CNPq, FAPESP, UNEMAT
Fibroblast Growth Factor 8 (FGF8) Inhibits Apoptosis mediated by PTEN and Akt pathway in the Infarcted Myocardium
Authors: Singla Dinender , Abdelli Latifa
Published: June 2021

FGF8 enhances embryonic cardiogenesis; however, its role in the adult cardiac repair following myocardial infarction (MI) remains unknown. We injected FGF8 into post‐myocardial infarcted hearts and investigated its effect on cardiac apoptosis. Animals were divided into three groups: Sham, MI, and MI+FGF8. MI was induced by coronary artery ligation. MI+FGF8 group received two intramyocardial injections of FGF8 (1ug/20ul) into the peri‐infarct region of the heart. At day 14 post‐MI, cardiac function was assessed, mice were sacrificed, hearts were harvested, and apoptosis was evaluated. Our data reveals that apoptosis was significantly (p<0.05) increased in MI group. This increase was significantly (p<0.05) attenuated following FGF8 injection as demonstrated by a decrease in apoptotic nuclei confirmed with TUNEL staining, and caspase3 activity. Our data also show a significant decrease in Bax, a pro‐apoptotic protein, and an increase in Bcl‐2, an anti‐apoptotic factor and inhibitor of Bax. Additionally, we have shown an increase in pAkt, a cell survival protein, and a decrease in levels of PTEN, a negative regulator of Akt pathway in hearts injected with FGF8. Furthermore, functional data showed a significant (p<0.05) improvement in both fractional shortening and ejection fraction after FGF8 treatment. Our data suggests FGF8 inhibits apoptosis following MI mediated through Bax/Bcl‐2 and Akt pathways.
The Role of MicroRNA in Anesthetic‐Induced Cardiac Preconditioning
Authors: Olson Jessica , Yan Yasheng , Bai Xiaowen , Kriegel Alison , Canfield Scott , Liang Mingyu , Bosnjak Zeljko J
Published: June 2021

Anesthetic preconditioning has been reported to decrease myocardial infarct size after ischemia‐reperfusion injury. However, the underlying mechanisms are not fully understood. MicroRNAs (miRNAs) are short nucleotide sequences that have been implicated in many different cell signaling pathways via suppression of messenger RNA. In this study, we investigated the effect of anesthetic exposure on miRNA expression in the left ventricle of the rat heart. Male Wistar rats were exposed to 30 min of one minimum alveolar concentration of isoflurane. Total RNA was extracted from the left ventricle of the heart and converted to cDNA. Using real‐time PCR, microarray‐based analyses of 88 miRNAs were performed, revealing twenty upregulated miRNAs. One microRNA, miR‐21, has consistently shown a twofold upregulation in hearts exposed to anesthetic. This microRNA has been demonstrated to decrease infarct size in hearts exposed to ischemic preconditioning via its action on heat shock protein 70, endothelial nitric oxide synthase, and inducible nitric oxide synthase. Further investigation into the isoflurane‐induced upregulation of miR‐21 may reveal that miR‐21‐mediated pathways contribute to the preconditioning effect of anesthetics. This work is supported by NIH Grants R01HL034708 and P01GM066730 for Z. Bosnjak.
Effect of Cd36 on cardiac ischemic tolerance and adrenergic signaling in spontaneously hypertensive rats
Authors: Neckar Jan , Silhavy Jan , Papousek Frantisek , Klevstig Martina , Manakov Dmitry , Novotny Jiri , Novakova Olga , Novak Frantisek , Pravenec Michal , Kolar Frantisek
Published: June 2021

CD36 fatty acid translocase plays a key role in supplying heart with its major energy substrate, long‐chain fatty acids (FA). Spontaneously hypertensive rat (SHR) harbors a deletion variant of Cd36 gene. We analyzed the effects of mutant Cd36 on cardiac susceptibility to ischemia‐reperfusion injury in adult SHR‐Cd36 transgenic rats with wild type Cd36 compared to age‐matched SHR controls. Using an open‐chest model of coronary artery occlusion, we found that SHR‐Cd36 showed profound ischemic arrhythmogenesis resulting in significantly increased total number of premature ventricular complexes (2623±517 vs. 849±250) in SHR controls. On the other hand, transgenic SHR showed significantly reduced infarct size (52.6±4.3% vs. 72.4±2.9% of area at risk). Similar differences were observed in isolated perfused hearts and the increased incidence of arrhythmias in transgenic SHR was abolished by reserpine suggesting the involvement of catecholamines. Furthermore, forskolin‐stimulated activity of adenylyl cyclase was increased in the SHR‐Cd36. It can be concluded that Cd36 plays an important role in modulating cardiac susceptibility to ischemia‐reperfusion injury. The proarrhythmic effect of Cd36 transgene appears to be related to increased adrenergic stimulation. Supported by grants: GAAV IAAX01110901, GAUK 429611
Novel magnetic field system: Application to micropropagation of Phalaenopsis Gallant Beau ′George Vazquez′
Authors: Van Pham T , Teixeira da Silva Jaime A. , Tanaka Michio
Published: June 2021

This is the first study with the purpose of creating a new system for moderate permanent magnetic fields (MF) which is simple, safe, easy to set up and saves space in a tissue culture room or greenhouse. We applied this system to investigate the effects of different MF intensities (0.1 Tesla (T), 0.15 T and 0.2 T) and different durations of exposure to 0.15 T MF, at both North (N) and South (S) poles on the micropropagation of Phalaenopsis Gallant Beau ‘George Vazquez’ at 2 development stages: protocorm‐like bodies (PLBs) proliferation and shoot development. The control exposed to naturally occurring geo‐MF and not to any induced MF. The MF of 0.1 T ‐ S resulted in the greatest fresh weight of regenerated PLBs and also the greatest influence on specific Phalaenopsis plantlet growth parameters: maximum leaf length, root length, fresh and dry weight of shoots and roots, and leaf width. The S pole of MF had stronger effects on Phalaenopsis PLBs proliferation than the N pole did in all treatments.

Constant exposure to a MF of 0.15 T for 3 months, independent of polarity, significantly enhanced the development of plantlets when compared with the shorter duration of exposed plants (i.e. 1, 2 months). The longer duration of exposure to an MF of 0.15 T (7 weeks vs. 2 weeks), regardless of the polarity, resulted in greater biomass of newly formed PLBs and smaller average number of newly formed PLBs.

The results obtained in this study indicate that MFs have the potential to be applied in practical plant culture room for fundamental physiological studies.
Tetrahydrobiopterin (BH4) attenuates extracorporeal shock wave lithrotripsy (ESWL) induced blood nitric oxide (NO) level reduction in the renal vein
Authors: Deiling Brittany Leigh , Iames Edward , Perkins Kerry-Anne , Chen Qian , Young Lindon H
Published: June 2021

ESWL, a therapy for kidney stone ablation clinically, may lead to hypertension. This may be due to kidney vascular endothelial dysfunction, which is characterized as increased oxidative stress and decreased endothelial NO synthase (eNOS)‐derived NO bioavailability. We hypothesized that ESWL would decrease NO in rat renal veins. By contrast, rats given BH4, the essential cofactor of eNOS, would attenuate ESWL‐induced decrease in NO. Blood NO was directly measured in real‐real time by inserting a NO microsensor (100μm diameter) into the left renal vein in the anesthetized rat. ESWL treatment consisted of 1,000 shocks with a 16kV shock wave for approximately 13 minutes. Saline or BH4 was injected via the jugular vein immediately post‐ ESWL and at the same time point for the non‐ESWL control rats. Our preliminary data showed that saline ESWL‐treated rats (n=3) reduced blood NO by 107–203 nM, which is significantly reduced compared to non‐ESWL controls (n=6, p< 0.05) during the 30 min post‐ESWL. By contrast, blood NO level in rats given BH4 under ESWL conditions (6.5 mg/kg, n=4, p<0.05) only decreased by 15–19 nM post‐ESWL compared to saline ESWL. This data supports that ESWL treatment decreases NO bioavailability, which may be due to decreased BH4 content. Future studies are aimed at evaluating blood oxidative stress levels (i.e. hydrogen peroxide) when given ESWL or ESWL+BH4.
Sickle mouse red cells activate endothelium by heme‐mediated peroxide generation and promote red cell and leukocyte adhesion
Authors: Kaul Dhananjay K. , Shah Janki , Suzuka Sandra , Fabry Mary E.
Published: June 2021

Sickle red blood cells (SS RBCs) are known to generate reactive oxygen species due to autoxidation of hemoglobin S (HbS). We hypothesize that HbS autoxidation and peroxide generation in SS mouse RBCs will result in activation of quiescent endothelium. We, therefore, infused BERK SS RBCs into congenic C57BL mice. BERK mice RBCs express exclusively HbS. A bolus of 150 μl of FITC‐labeled or unlabeled RBCs (Hct 30%) was infused iv into C57BL mice, and intravital observations made in the cremaster microcirculation. Infusion of FITC‐labeled C57BL RBCs into C57BL mice resulted in rare or no RBC adhesion, suggesting no endothelial activation. In contrast, infusion of BERK RBCs into C57BL mice caused marked increase in adhesion of infused RBCs in venules, accompanied by leukocyte recruitment. When the cremaster preparation was suffused with dihydrorhodamine (DHR), an H2O2‐sensitive probe, infusion of BERK RBCs, but not C57BL RBCs, resulted in increased endothelial fluorescence intensity. Infusion of BERK RBCs treated with catalase (100 U) to quench RBC‐generated peroxide inhibited DHR fluorescence, and adhesion of RBCs and leukocyte. Superoxide dismutase was relatively ineffective. These results suggest an obligatory role of heme‐mediated peroxide generation by SS RBC in endothelial activation, SS RBC adhesion and inflammatory effects in sickle cell disease. Supported by grants from American Heart Association and NIH (HL070047).
Effects of Lifelong Endurance Exercise on Cardiovascular Response to Orthostatic Stress in The Elderly Athletes
Authors: Fujimoto Naoki , Carrick-Ranson Graeme , Bhella Paul S , Hastings Jeffrey L , Shibata Shigeki , Palmer Dean , Benjamin Levine D
Published: June 2021

Background

Young endurance athletes have a greater decrease in stroke volume (SV) during orthostatic stress than age‐matched controls, due to a more compliant left ventricle (LV). Elderly athletes with lifelong training (EA) also have more compliant LV compared to elderly controls (C). However, it is unclear if the decrease in SV during orthostatic stress is greater in EA relative to C.

Methods

Fifty five subjects (EA 27, C 28) underwent right heart catheterization to measure pulmonary capillary wedge (PCWP) and right atrial (RAP) pressures, and SV at baseline and −15 and −30 mmHg lower body negative pressures (LBNP). To minimize the effect of external constraint on the LV, transmural pressure (TMP), which is the true preload for the LV, was calculated as PCWP‐RAP.

Results

At baseline, SV index was larger in EA than C. PCWP appeared to be lower in EA, while TMP was similar between EA and C (3.4±1.4 vs. 3.5±1.4 mmHg, p=0.87). LBNP similarly lowered PCWP and TMP in EA and C (interaction p ≥ 0.56), while a greater decrease in SV index from baseline was observed in EA than C at −30 mmHg LBNP (17 vs. 12 ml/m2, p <0.01).

Conclusion

TMP was similarly regulated in EA and C at all loading conditions. EA had greater decrease in SV during orthostatic stress, probably due to a more compliant LV. Thus, similar to young athletes, EA may be more susceptible to orthostatic intolerance.
Reductions in nitric oxide (NO) production within the nucleus tractus solitarius (NTS) contributes to exercise pressor reflex (EPR) overactivity in hypertension
Authors: Murphy Megan Nicole , Mizuno Masaki , Downey Ryan , Smith Scott A
Published: June 2021

In hypertension, activation of the skeletal muscle EPR elicits an exaggerated blood pressure (BP) response. Neural input from the EPR is processed within the NTS of the brainstem. Normally, NO produced within the NTS buffers the BP response to EPR activation. Thus, we hypothesized that EPR overactivity in hypertension is mediated by a decrease in NO production within the NTS. To test this hypothesis, NO production within the NTS was assessed during stimulation of the EPR in normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Diaminoanthraquinone (DAA), an immunofluorescent molecule that irreversibly binds to NO, was dialyzed into the NTS. The integrated density of DAA fluorescence is directly related to the production of NO. Basal NO production (F0) was measured in WKY and SHR. In separate animals, the EPR was stimulated intermittently for 15 min by electrically‐inducing hindlimb muscle contraction. During this 15 min period, DAA was concomitantly dialyzed into the NTS and subsequently measured (F1). The F1/F0 ratio was used to evaluate NO production during muscle contraction. DAA fluorescence was greater in WKY than SHR after EPR activation (WKY F1/F0 5.8 ± 1.4 A.U.; SHR F1/F01.9 ± 0.7 A.U.;p<0.01). The data suggest that NO production is reduced within the NTS of SHR during muscle contraction and likely contributes to the EPR overactivity manifest in hypertension. Supported by NIH HL‐088422.
Blunted exercise‐induced vasodilation in familial hypercholesterolemic swine does not involve enhanced ET‐1‐mediated vasoconstriction
Authors: Bender Shawn B , de Beer Vincent J , Tharp Darla L , Bowles Douglas K , Duncker Dirk J , Laughlin M Harold , Merkus Daphne
Published: June 2021

Hypercholesterolemia causes endothelial dysfunction and activation of the vascular endothelin‐1 (ET‐1) system. The procontractile effect of ET‐1 action on resistance vessels would therefore be expected to limit exercise‐induced vasodilation. To assess the role of hypercholesterolemia on ET‐1 activation and exercise‐induced vasodilation, we compared the effects of ET receptor blockade in instrumented Yucatan (Y) and familial hypercholesterolemic (FH) swine, at rest and during exercise. Exercise induced systemic vasodilation, measured as systemic vascular conductance index (SVCi = SVC/kg bodyweight), that was reduced in FH swine (36%) compared to Y swine (91%). Unexpectedly, the ETA/ETB receptor blocker tezosentan did not enhance exercise‐induced vasodilation in FH swine and the vasodilator effect of tezosentan at rest was reduced in FH swine (16%) versus Y swine (48%). Isolated skeletal muscle 2A arterioles from FH swine demonstrated enhanced sensitivity to ET‐1; however, plasma ET‐1 levels tended to be lower in conscious FH swine compared to Y swine (p=0.08). Thus, our data suggest that although the skeletal muscle vasculature of FH swine exhibits enhanced sensitivity to ET‐1, an ET‐1‐mediated enhancement of systemic vascular tone does not account for the reduced exercise‐induced dilation in FH swine, possibly as a result of reduced production/release of ET‐1 in FH swine. Supported by NIH‐HL52490.
Effects of prior endurance exercise on postprandial lipemia‐induced changes in circulating angiogenic cytokines in young men
Authors: Landers-Ramos Rian Quinn , Jenkins Nathan T , Spangenburg Espen E , Hagberg James M , Prior Steven J
Published: June 2021

We examined the effect of prior endurance exercise on plasma angiogenic cytokine responses to a high fat meal as these may contribute to pathologic angiogenesis in atherosclerosis. Blood samples were obtained from 10 healthy men at baseline and 4 h postprandial with or without ~50 min of endurance exercise at 70% of VO2max the day before. Plasma levels of VEGF, basic fibroblast growth factor (bFGF), placental growth factor (PlGF), and soluble VEGF receptor (sFlt‐1) were measured by multiplex ELISA. Postprandial lipemia (PPL) significantly increased VEGF (~23%, P<0.05) in each group (with and without prior exercise) as well as bFGF with (45%, P<0.05) and without prior exercise (56%, P<0.05). PlGF level decreased by 11% (P<0.05) in the control trial but this effect of PPL was absent with prior exercise. sFlt‐1 level decreased (12%, P<0.05) in the control trial but this difference was reduced to only a 4% decrease with prior exercise (P>0.05). These findings indicate that PPL increases plasma VEGF and bFGF regardless of prior endurance exercise; however, PPL‐induced decreases in PlGF and sFlt‐1 were present only without prior endurance exercise. We speculate that prior exercise may reduce the pro‐atherogenic effects of PPL by attenuating the PPL‐induced changes in PlGF and sFLT‐1 to potentially inhibit pathological angiogenesis.

Supported by NIH AGT3200068 and the American College of Sports Medicine Foundation.
Effect of a cold pressor test (CPT) on the cardiovascular (CV) responses to static handgrip exercise and peak force production
Authors: Kimmerly Derek , Chisholm-Drane Rory
Published: June 2021

The transition from an inverted to upright position results in greater maximal voluntary contraction (MVC) force and greater CV response to exercise. It is unclear whether these results are due to the postural change per se or the heightened sympathetic state associated with the upright posture. We tested the hypothesis that elevated baseline sympathetic activity, elicited using a CPT, produces greater MVC handgrip force and a larger CV response to isometric handgrip exercise (IHG). 13 (8F/5M) normotensive subjects (22 ± 2 years) were randomized between cold (~10ºC) and thermoneutral (~24ºC) conditions. During each condition, their foot was submerged for 6 minutes. Non‐dominant MVC handgrip force (kg) was recorded then followed by a 150s rest period, 90s of IHG (40% MVC), and 120s of post‐exercise ischemia (no exercise). Heart rate (HR), mean arterial pressure (MAP) and calf blood flow (CBF) were measured throughout. Calf vascular resistance (CVR) was calculated. At rest, MAP (+4 ± 1 mmHg) and CVR (+5 ± 3 PRU) were increased in the cold condition. Handgrip MVC was greater (24 ± 10 vs. 22 ± 8 kg) in the thermoneutral condition. MAP during IHG was higher in the cold condition (93 ± 12 vs. 86 ± 7 mmHg). Application of a cold stimulus augmented resting MAP and CVR. This heightened sympathetic state resulted in a lower handgrip MVC force but an exaggerated MAP response to IHG
Impact of endothelial nitric oxide synthase gene polymorphisms on hemodynamic after a bout of maximal dynamic exercise
Authors: Silva Bruno Moreira , Pereira Felipe S. , Neves Fabricia J. , Rocha Natalia G. , Sales Allan R. , Medeiros Renata F. , Pereira Fabiane T. , Nóbrega Antonio C.
Published: June 2021

Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene (NOS3) have been associated with lower eNOS expression and activation, which can lead to impairment in eNOS related traits. Thus, we investigated the individual (genotype analysis) and combined (haplotype analysis) impact of three polymorphisms in the NOS3 (−786T>C, 4b4a and 894G>T) on hemodynamic variables. Sedentary, non‐obese, healthy subjects were enrolled [n = 93, age 31 ± 9 years (mean ± SD)]. Genotypes were determined by PCR‐RFLP and haplotypes were inferred by a Bayesian based algorithm. Heart rate (ECG) and blood pressure (BP; finger photoplethismography) were continuously measured during 10 min in the supine position before [baseline (BL)], 10, 60 and 120 min after a maximal cardiopulmonary exercise test. Stroke volume was estimated by the Model Flow method. Then, cardiac output (CO) and total peripheral resistance (TPR) were calculated. There was no difference between subjects in genotype analysis. However, subjects with haplotype containing the polymorphisms −786T>C and 4b4a had higher systolic BP at 10, 60 and 120 min after exercise than subjects with wild haplotype (P < 0.05), which occurred due to higher CO (P < 0.05), while TPR was similar between groups (P > 0.05). In conclusion, NOS3 haplotype containing the polymorphisms −786T>C and 4b4a was associated with impaired hemodynamic response after a bout of maximal dynamic exercise.
Voluntary exercise induces chromatin remodelling in the heart
Authors: Medford Heidi M , Hall Kyla E , Cox Emily J , Porter Karen , Marsh Susan A
Published: June 2021

Chromatin remodelling regulates skeletal muscle adaptations to exercise and the development of pathological cardiac hypertrophy by interactions between repressor element 1‐silencing transcription factor (REST), mSin3A and histone deacetylases (HDAC). It is not known if chromatin remodelling regulates exercise‐induced physiological hypertrophy in the heart. Young male mice exercised on voluntary running wheels for 7 days. Heart weight:body weight and actin protein were not different compared to sedentary controls as overt cardiac hypertrophy does not occur until at least 14 days of exercise. mSin3A was higher in trained hearts but REST was not different between groups. HDAC 3, a pro‐hypertrophic class I HDAC, was higher in exercise‐trained hearts whereas HDAC 4, an anti‐hypertrophic class IIa HDAC, was lower in exercised hearts. To determine if chromatin remodelling is initiated during acute exercise, mice underwent a single bout of treadmill running for either 15 or 30 minutes and hearts were harvested immediately following exercise. Examination of the nuclear fractions revealed that REST, mSin3A and HDAC proteins were not different between groups. These data suggest that 7 days of voluntary exercise induces cardiac chromatin remodelling but that this does not occur immediately following a single exercise bout.
A useful, innovative, and visual method to quantify fitness and heart failure
Authors: Hansen James Edward , Sun Xing-Guo , Stringer Williiam W
Published: June 2021

We have reported that the highest ratios of O2 uptake and CO2 output to ventilation (VO2/VE and VCO2/VE) occur during moderate rather than maximal exercise and that lower ratios better predict early cardiac death than lower peak VO2 or anaerobic threshold values. Therefore we postulated that plotting simultaneous VO2/VE‐vs‐VCO2/VE values of incremental exercise studies against each other on X‐Y axes would give an easy‐to‐understand single display that might quantify cardiovascular performance exceptionally well. Plots of 90‐s rolling averages of VO2/VE‐vs‐VCO2/VE were optimal. The diagonal oval racetrack patterns of VO2/VE‐vs‐VCO2/VE in normal subjects were distinctive. In over 300 normal subjects, reference formulas in mL (STPD)/L (BTPS) for highest VO2/VE = 42.2 – 0.189yrs +0.036cm less 3.0 for women and for highest VCO2/VE = 38.9 – 0.155yrs + 0.038cm less 1.9 for women. The patterns and highest values for patients with left or right heart failure were also examined. Patients with more severe heart failure had lower VO2/VE‐vs‐VCO2/VE values at rest with exercise values moving in an abnormal direction. We conclude that highest VO2/VE and VCO2/VE values, elicited without maximal exercise, are important parameters. Further, plots of VO2/VE‐vs‐VCO2/VE yield distinctive patterns that alone well assess cardiac performance and disease. No government, industry, or institutional support.
Carbonic Anhydrase XIV Bound to and Increases the AE3‐mediated Cl−/HCO3− Exchange Activity in the Hypertrophic Heart
Authors: Alvarez Bernardo V. , Vargas Lorena A.
Published: June 2021

AE3fl and AE3c anion exchangers catalyze Cl−/HCO3−exchange across cardiomyocyte sarcolemma, to regulate cardiac contractility. AE1 and AE3 proteins associate with carbonic anhydrases (CAII and CAIV), forming a HCO3− transport metabolon (BTM), regulating cardiomyocytes intracellular pH (pHi). Transmembrane CAXIV is also expressed in the myocardium. AE3/CAXIV physical association was examined by coimmunoprecipitation (CoIP) using mouse heart lysates. Both AE3fl and AE3c were IP using anti‐CAXIV Ab, indicating AE3fl‐AE3c/CAXIV interaction in the myocardium. CoIP experiments on heart lysates from an ae3−/− null mouse, failed to pull‐down AE3 with the CAXIV Ab. AE1 protein was also IP by CAXIV Ab from heart lysates. Functional association of AE3fl and CAXIV was examined in hypertrophic rat cardiomyocytes (HRC), monitoring pHi by epifluorescence. HRC presented elevated AE‐mediated Cl−/HCO3−exchange activity compared to normal cardiomyocytes (7.5±1.3 versus 2.9±0.1 mM/min, n=4–6); accompanied by twofold increase of CAXIV protein expression in hypertrophic hearts (HH) (n=11). Benzolamide, a CA‐inhibitor, neutralized the stimulatory effect of extracellular CA on AE3 transport activity (3.7±1.5, n=3), in the HH. CAXIV/AE3 interaction constitutes an extracellular component of a BTM. Increased CAXIV expression and consequent AE3/CAXIV complex formation would render AE3 hyperactive in the HH.

Supported by Agencia Nacional de Promoción Científica y Tecnológica (PICT2007 01011, SECyT, Argentina)
Intermittent dobutamine administration mimicked exercise‐induced cardiac phenotype and protected against left ventricular acute pressure overload
Authors: Gonçalves Daniel , Henriques-Coelho Tiago , Fonseca Hélder , Ferreira Rita , Padrão Ana Isabel , Santa Cátia , Vieira Sara , Amado Francisco , Leite-Moreira Adelino , Duarte José Alberto
Published: June 2021

The aim of the present study was to address if the submission to a stimuli that mimicked the intermittent cardiac overload imposed by exercise training, would result in a comparable cardioprotective phenotype. Male Wistar rats were submitted to treadmill running (Ex,n=20), dobutamine (Dob; 2mg/kg,s.c.,n=20) or placebo administration (Cont,n=20) for 5 days/week during 8 weeks. After that, half were sacrificed for histological and biochemical analysis and half were submitted to hemodynamic evaluation at baseline and during 2 hours of left ventricular acute pressure (LVP) overload (35% increase in LVPmax). Both Ex and Dob showed cardiac hypertrophy with normal MHC isoforms, fibrosis, osteopontin‐1 and calcineurin protein levels. Moreover, they presented increased SERCA2a and phospho Akt/mTOR protein levels. Both Ex and Dob protected from cardiac dysfunction induced by acute LVP overload. These data suggest that chronic submission to intermittent cardiac overload induced by dobutamine provides a cardioprotective phenotype resembling exercise training.
α‐Dystrobrevin functions to reinforce the interaction between dystrophin and the membrane, loss of α‐dystrobrevin results in significant loss of cardiac reserve
Authors: Townsend DeWayne , Dean Jon , Sharpe Katharine
Published: June 2021

The C‐terminal region of dystrophin is highly conserved across vertebrates, but its function is largely unknown. α‐Dystrobrevin (DB) is one of several proteins that bind to this region of dystrophin. Mice lacking α‐DB demonstrate a mild myopathy in skeletal muscle, but the phenotype of the heart has not been fully characterized. Here we demonstrate that the loss of α‐DB significantly weakens the association of cardiac dystrophin with membrane glycoproteins. In the absence of α‐DB, wheat germ agglutinin pull down assay reveals a dystrophin:α‐dystroglycan ratio only 13% of that observed in wildtype mice. The physiological importance of the disruption of this interaction is evident in the marked pathology induced by chronic isoproterenol administration. This challenge protocol results in significant myocardial damage and mortality >60% in mice lacking α‐DB, in contrast wild type mice survived with minimal injury. The lesions and mortality observed in the α‐DB null mice were not different from mice lacking dystrophin. These findings have significant implications on the design of truncated dystrophin constructs suitable for delivery via gene therapy, as many of these constructs lack the binding domain for α‐DB.
Rate of force recovery immediately following lengthening contractions for various mouse models of muscular dystrophy
Authors: Rader Erik Paul , Han Renzhi , Levy Jennifer R. , Bansal Dimple , Campbell Kevin P.
Published: June 2021

Mutations in genes encoding distinct proteins of the dystrophin‐glycoprotein complex (DGC) or dysferlin are associated with various forms of muscular dystrophy. Dystrophin, β‐sarcoglycan, and glycosylated α‐dystroglycan are essential components of the DGC which links the extracellular matrix to the cytoskeleton and prevents extreme sarcolemma damage. Dysferlin also helps to maintain sarcolemma integrity but by a different mechanism – membrane repair. Muscle fibers with either hypoglycosylated α‐dystroglycan or dysferlin deficiency have an inability to reseal laser‐induced sarcolemma damage. To what extent compromised resealing correlates with force generation after contraction‐induced injury is unclear. We tested the hypothesis that hypoglycosylated α‐dystroglycan or deficiency in dysferlin, dystrophin, or β‐sarcoglycan is associated with a slow rate of force recovery immediately following a lengthening contraction protocol (LCP). The extensor digitorum longus muscle was isolated, exposed to a LCP, and monitored at various time points for up to 45 minutes post‐LCP. Muscles with hypoglycosylated α‐dystroglycan or deficiency in dystrophin or β‐sarcoglycan sustained slow rates of force recovery. Muscles of dysferlin‐null mice exhibited wild‐type recovery rates. Interestingly, muscles of mice deficient in both dystrophin and dysferlin exhibited rate constants of recovery (0.032 ± 0.012 min−1) significantly lower than those for muscles null for dystrophin alone (0.080 ± 0.006 min−1). This indicated that a disrupted DGC unmasks the function of dysferlin in force recovery. Determining the rate of force recovery may be a useful method for evaluating the physiological consequences of impaired sarcolemma resealing in various mouse models of muscular dystrophy.
Effects of Endurance Exercise Training, Metformin, and Their Combination on Adipose Tissue Cytokine Secretion in a Rat Model of Type 2 Diabetes (T2D)
Authors: Jenkins Nathan T , Padilla Jaume , Martin Jeffrey S , Rector R. Scott , Thyfault John P , Booth Frank W. , Laughlin M. Harold
Published: June 2021

Otsuka Long Evans Tokushima Fatty (OLETF) rats are a hyperphagic and obese rodent model of T2D. We randomly assigned OLETF rats (age 20 wks, the onset of insulin resistance) to sedentary (SED), endurance exercise training (TR; 20 m/min, 60 min/d, 5 d/wk running), metformin (MET; 300 mg/kg/d in drinking water), or TR + MET groups. Age‐matched SED Long‐Evans Tokushima Otsuka (LETO) rats served as controls. At sacrifice (age 30–32 wks), retroperitoneal (RP) fat pads were harvested and incubated in Krebs solution for 60 min at 37°C. RP fat‐conditioned buffers were assayed for interleukin‐6 (IL‐6), leptin, monocyte chemoattractant protein‐1 (MCP‐1), and tumor necrosis factor‐α (TNF‐α). Compared to LETO RP fat, sedentary OLETF RP fat secreted ~30%, ~200%, ~15%, and ~50% more IL‐6, leptin, MCP‐1, and TNF‐α, respectively. Preliminary analysis of treatment effects revealed that: (i) MET alone or TR + MET, but not TR alone, normalized differences between OLETF and LETO groups in IL‐6 and TNF‐α secretion; (ii) only MET, but neither TR nor TR + MET, normalized MCP‐1 secretion; (iii) TR and TR + MET, but not MET alone, normalized leptin secretion. Leptin levels in RP fat‐conditioned buffer correlated with plasma leptin across all groups (r2 = 0.78, P < 0.01). These data suggest that MET decreases adipose tissue inflammatory cytokine release and that TR decreases adipose tissue leptin secretion in T2D.
Can diabetes prevention program increase resting leg blood flow and antegrade shear rate in patients with metabolic syndrome?
Authors: Johansson Rebecca E , Limberg Jacqueline K , McBride Patrick E , Schrage William G
Published: June 2021

No studies have tested whether healthy lifestyle changes can alter blood flow (BF) and shear patterns in adults with metabolic syndrome (MS). We hypothesized limb BF and conduit artery antegrade shear rate (ASR) would increase in the arm and leg of patients with MS after participation in a Diabetes Prevention Program (DPP). We also hypothesized DPP would reduce retrograde shear rate (RSR) and oscillatory shear index (OSI). Resting BF and shear rates (Doppler ultrasound of brachial and femoral arteries) were measured in MS patients (n=16, 51±2 yrs) before and after a 12‐week DPP. DPP reduced weight, waist circumference, blood pressure (BP) (p all<0.05), and glucose (p=0.06). Resting leg BF (38±22%, p=0.05) and ASR (12±6%, p=0.04) increased, and OSI tended to be lower (p=0.09). RSR did not change (p=0.30) in the leg. In contrast, DPP did not alter arm BF (p=0.29) or ASR (p=0.35), and RSR (32±15%, p=0.02) and OSI (52±30%, p=0.05) increased. We conclude resting leg BF and femoral artery ASR increases in response to a 12‐week DPP. These limb‐specific vascular adaptations may contribute to improvements in BP and blood glucose, and limit the progression of atherosclerosis in the leg circulation. Support: NIH R21 HL091397
Impact of short‐term aerobic and resistance training on acute post‐exercise blood glucose in Type 1 diabetic rodents
Authors: McDonald Matthew W , Hall Katharine E , Melling C.W. James
Published: June 2021

Despite the benefits of exercise (EX), physical activity levels are lower in Type 1 diabetics (T1D) due to the frequency of EX‐induced hypoglycemia. The objective of this study was to examine T1D post‐EX blood glucose (BG) levels in response to different EX modalities and to determine if short‐term training can modulate these responses. Forty rats were randomly divided into 4 groups; sedentary T1D (CD), T1D high intensity EX (DH), T1D low intensity EX (DL) and T1D resistance EX (DR). For 6 weeks, DH and DL rats ran on a treadmill at 27m/min and 15m/min, respectively, whereas DR climbed a vertical ladder while weighted. BG was measured for 2hrs post‐EX at week 3 and week 6. At week 3, DH had a significant fall in BG post‐EX, which sustained for 75min (p<0.05). DH demonstrated similar immediate reductions in BG at week 6; however, BG returned to pre‐EX values by 45min (p<0.05). DL had a significant drop in BG post‐ EX for >2hrs (p<0.05) at week 3; while at week 6, no immediate reductions in BG were evident up to 2hrs post‐EX. In contrast to aerobically trained animals, DR exhibited a post‐EX BG time course that was not significantly different from the BG regulation of CD animals throughout the 6 week study. To conclude, different EX modalities lead to differential regulation of BG following EX. In DH and DL, there appears to be a glucoregulatory adaptation to training that was not evident in DR rats. Supported by CIHR Grant #CCT‐ 83029.
Exercise blood pressures are lower after aquatic compared to land treadmill training
Authors: Crouse Stephen F , Lambert Brad S , Greene Nicolas P , Constanzo Travis W , Martin Steven E
Published: June 2021

We tested blood pressure responses to the Bruce treadmill protocol PRE and POST 12‐wks of matched volume training on a land treadmill (LTM, n= 9♂,13♀, age=43±3 yrs, weight=88.1±3.6 kg) or aquatic treadmill (ATM, n=18♂, 17♀, age=45±2 yrs, weight=90.6±3.0 kg). Systolic (SBP), diastolic (DBP), pulse pressure (PP) and mean arterial pressure (MAP) were analyzed using a 2 (ATM or LTM) x 2 (PRE & POST) ANOVA repeated for the training time at rest, 3 stages of the exercise protocol, and 1 and 5 minutes of recovery; Tukeyˈs post hoc tests were used as follow‐up for significant interactions, α=0.05. VO2max increased significantly 11–15% with training in both groups. Significant training changes for MAP shown in Table (mmHg, mean±SE); SBP and PP paralleled these results. Significance remained after covarying for BMI, %body fat, and age.

Data suggest ATM may provide superior benefits over LTM for promoting reductions in exercise blood pressure.

Funding provided by HydroWorx International, Inc.
Prevalence of fracture and low bone mineral density in competitive road cyclists
Authors: METGHALCHI SHIVA , Medelli Jean , Campion Frédéric , Karlsson Magnus , Nevill Alan , Leslie Bill , Cordero-MacIntyre Zaida
Published: June 2021

Low bone density is considered a risk factor for fracture. Recent studies have shown that competitive road cyclists have significantly lower bone mineral density (BMD) than matched controls.

Objective

The aim of this study was to evaluate the possible association between BMD and fracture in competitive cyclists.

Method

This was a case‐control study design including 101 professional road cyclists as cases and 30 healthy males as controls.

Results

The age‐adjusted relative risk of fracture in cyclists was 4.24 (P = 0.002). Cyclists had lower BMD Z‐scores at the femur (−0.8 SD 0.95, P < 0.001), lumbar (−0.9 SD 0.75, P < 0.001), and radius UD (−0.5 SD 1.1, P = 0.063) compared to controls. Amongst professional cyclists, 53% had a low lumbar BMD (−1.54 SD 0.35) while the proportion was 32% in elite (−1.49 SD 0.49) and 13% in controls. The number of fracture in cyclists was significantly though weakly correlated with Femoral neck BMD (r = −0.28, P = 0.02).

Conclusion

While a high prevalence of fracture could be observed in competitive road cyclists as well as a widespread low BMD especially among professional cyclists, no clear relationship could be detected between fracture and low BMD in these well trained endurance athletes.
Sex differences in bone mineral density after resistance training in growing rats
Authors: Joo Woojin , Singh Harpreet , Ahles Cammie P , Colazas William , Lee Lucy , Lee Yvonne , Jaque S Victoria , Sumida Ken D
Published: June 2021

The purpose of this study was to determine if there was a sex difference in the resistance training‐induced elevation in bone mineral density (BMD) during the growth period in rats. Sixteen male and 16 female rats (~8wks old) were randomly divided into Control (MC=8, FC=8), and resistance trained (RT) groups (M‐RT= 8, F‐RT=8). The RT groups were conditioned to climb a vertical ladder 4 consecutive times (per exercise session) with weights appended to their tail 3 days/wk for a total of 6 wks. After 6 wks, left tibial BMD (in g/cm2) was significantly greater for M‐RT (0.240 ± 0.005) compared to MC (0.211 ± 0.005). Further, bone strength (force to failure in Newtons) from the right tibia was significantly greater for M‐RT (144.4 ± 8.0) compared to MC (118.3 ± 2.7). In contrast, while the BMD for F‐RT (0.226 ± 0.006) was elevated compared to FC (0.214 ± 0.005), statistical significance was not achieved (P=0.09) whereas bone strength was significantly greater (P=0.04) for F‐RT (97.4 ± 3.5) compared to FC (82.3 ± 3.1). While the impact of resistance training demonstrated anticipated trends for BMD and bone strength among males and females, the training‐induced elevations were greater for M‐RT compared to F‐RT. The results indicate that the resistance training program was more effective for elevating BMD and bone strength in males compared to females during the growth period in rats.