bluuebunny/crossref_metadata_2025 huggingface dataset:
COMBINED EXERCISE TRAINING (AEROBIC PLUS RESISTANCE) PROMOTES ADDITIONAL CARDIOVASCULAR BENEFITS IN RELATION TO AEROBIC OR RESISTANCE ALONE IN EXPERIMENTAL MODEL OF MENOPAUSE
Authors: Sanches Iris Callado , dos Santos Costa Gabrielly Minguta , Freitas Sarah Cristina , Bernardes Nathalia , Doro Marcio , Irigoyen Maria‐Cláudia , De Angelis Kátia
Published: November 2023

Introduction

The cardiovascular benefits of exercise training (ET) after menopause are mainly due to the aerobic training, getting to doubt whether the association of aerobic with resistance exercise could bring different effects.

Objectives

To compare the effects of aerobic, resistance and combined (aerobic + resistance) exercise training on hemodynamic parameters and baroreflex sensitivity in an experimental model of menopause.

Methods

For this, 35 female Wistar rats (200–220g) were divided into (n=7 each group): 1 sedentary control group (C); and 4 ovariectomized groups (bilateral removal of ovaries): sedentary (SO), underwent to aerobic (AET), resistance (RET) and to combined ET (CET). After 8 weeks of ET, the animals were cannulated in the carotid artery for direct recording of arterial pressure (AP) (CODAS, 2kHz). Increasing doses of phenylephrine and sodium nitroprusside were used to test the baroreflex sensitivity (BS).

Results

The ovarian hormone deprivation induced an increase in mean AP (MAP) in the SO group (119.8±2.5 vs. 114.5±1.5 mmHg in C) associated with reduced BS for both tachycardic responses (TR) (2.67±0.55 vs. 4.29±0.41 bpm/mmHg in C) and for bradycardic responses (BR) (−0.61±0.36 vs. −1.17±0.16 bpm/mmHg in C). All trained animals presented a normalization of MAP (AET: 111.7±1.5, RET: 108.9±2.4, CET: 107.6±3.0 mmHg vs. SO), which was associated with reduction of diastolic AP (vs. SO). The group underwent to combined ET presented a reduction in systolic AP compared with the other groups (CET: 115.7±2.3 vs. C: 131.6±2.1; SO: 135.5±3.8, AET: 130.9±1.8; RET: 131.9±2.6 mmHg). The trained groups showed normalization of baroreflex sensitivity for BR (AET: −0.97±0.16; RET: −1.29±0.20; CET: −1.34±0.04 vs. SO), and only resistance ET was not able to normalize RT (AET: 4.12±21; RET: 3.59±0.62; CET: 3.95±0.38 bpm/mmHg vs. SO). All trained groups showed resting bradycardia (C: 368.4±5.5; SO: 382.9±8.9; AET: 335.5±6.9; RET: 353.0±8.2; CET: 345.7±8.1 vs. SO: 382.9 ± 8.9 bpm).

Conclusions

The 3 modalities of ET were effective in cardiovascular improvement after ovarian hormone deprivation. However, the combined ET promoted additional benefits in relation to aerobic ET (reduction in SAP) and resistance ET (improved baroreflex sensitivity ‐ TR) isolated.
The Effect of Protease‐Activated Receptor 2 on Cutaneous Vasodilation and Sweating in Young Males During Exercise in the Heat
Authors: Halili Lyra , Danquah Mercy , Fujii Naoto , McNeely Brendan , Kenny Glen
Published: November 2023

Protease‐activated receptor 2 (PAR‐2) is a G protein‐coupled receptor stimulated by the enzyme trypsin and is responsible for modulating the inflammatory response. It has been localized ‐on both the eccrine sweat glands and cutaneous vascular endothelial cells. In particular, activation of PAR‐2 contributes to the degranulation of secretory cells in the eccrine sweat glands and may therefore play a role in modulating the sweating response in humans. However, it is unknown if activation of PAR‐2 augments cutaneous vasodilation and sweating during exercise in the heat. Therefore, the purpose of the present study was to investigate these heat loss responses in young adults exercising in the heat. Five healthy, habitually active, young males (25 ± 6 years) performed 50‐min of moderate intensity (~55% VO2peak) cycling in the heat (35°C, 20% relative humidity) followed by a 30‐min recovery period. Local forearm sweat rate (ventilated capsule) and cutaneous vascular conductance (CVC, laser‐Doppler perfusion units/mean arterial pressure) were recorded at four skin sites, continuously perfused with: 1) Lactated Ringer's (Control), 2) 0.05 mM, 3) 0.5 mM, or 4) 5 mM SLIGKV‐NH2 (PAR‐2 agonist) via intradermal microdialysis. There were two baseline measurements conducted at different ambient temperatures. The first baseline (Baseline 1) was measured at 25°C, 20% relative humidity and the second baseline (Baseline 2) depicted the onset of heat stress and was measured at 35°C, 20% relative humidity. During Baseline 1, there was a tendency for an increase in CVC at both the 0.5 mM (14 ± 3% CVCmax, P = 0.078) and 5 mM (21 ± 7% CVCmax, P = 0.067) SLIGKV‐NH2 site relative to Control. At the end of the 50‐min exercise bout, there were no significant differences in CVC between all sites (Control: 71 ± 4% CVCmax; 0.05 mM: 69 ± 8% CVC max; 0.5 mM: 68 ± 5% CVCmax; 5 mM: 74 ± 9% CVCmax; P > 0.05) Further, we also show that activation of PAR‐2 at all concentrations of SLIGKV‐NH2 did not elicit significant changes in sweat rate at the end of exercise (Control: 1.31 ± 0.24; 0.05 mM: 1.52 ± 0.21; 0.5 mM: 1.55 ± 0.12; 5 mM: 1.51 ± 0.13 mg·min−1·cm−2; P > 0.05). In summary, our preliminary findings demonstrate that PAR‐2 activation exhibits a tendency to increase CVC at higher concentrations (0.5 and 5 mM) of SLIGKV‐NH2 relative to Control during baseline conditions. However, this increase is not present at the onset of and during heat stress, thereby indicating that PAR‐2 does not contribute to the modulation of sweating and cutaneous vasodilation during moderate intensity exercise in the heat.

Support or Funding Information

This study was supported by the Natural Sciences and Engineering Research Council of Canada (Discovery grant, RGPIN‐06313‐2014; Discovery Grants Program ‐ Accelerator Supplement, RGPAS‐462252‐2014; funds held by Dr. Glen P. Kenny).
Carotid Chemoreceptor Control of Muscle Sympathetic Nerve Activity in Hypobaric Hypoxia
Authors: Fisher James P , Flück Daniela , Hilty Matthias P , Lundby Carsten
Published: November 2023

High altitude hypoxia causes sympathoexcitation in humans, but the underlying mechanisms remain unclear. In this study we tested the hypothesis that muscle sympathetic nerve activity (MSNA) would be lowered at high altitude when carotid chemoreceptor activity is reduced by intravenous dopamine infusion.

Nine healthy individuals (mean [SD]; 26 [4] yr, 179 [9] cm, 75 [10] kg, 1 women) were studied at sea level (Zurich) and at the Jungfraujoch research station (3454 m), 15–17 days after arrival. Intravenous infusions of a placebo (saline) and dopamine (3 μg/(kg*min)) were administered on both study days, according to a single blind design. Minute ventilation (VE) and the partial pressure of end‐tidal oxygen (PETO2) and carbon dioxide (PETCO2) were measured breath‐by‐breath (Cosmed). Mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR) were recorded on a beat‐to‐beat basis via finger photoplethysmography (Nexfin) and multi‐unit recordings of MSNA were obtained using peroneal microneurography (ADInstruments).

Sojourn to high altitude decreased PETO2 (mean±SE; saline, 93±1 to 60±1; dopamine, 91±1 to 57±1 mmHg), PETCO2 (saline, 40±1 to 31±0.4; dopamine, 41±1 to 32±1 mmHg) and increased VE (saline, 8.6±0.5 to 11.3±0.6; dopamine, 8.2±0.5 to 10.6±0.8 L· min−1) (P<0.05). MAP (saline, 82±4 to 91±3; dopamine, 82±4 to 91±3 mmHg) and MSNA burst frequency (saline, 16±3 to 28±4; dopamine, 16±4 to 31±4 bursts· min−1) were also increased at altitude, while CO (saline, 7.4±0.5 to 7.7±0.4; dopamine, 8.3±0.5 to 8.3±0.3 L· min−1) was unchanged, and TPR was decreased (saline, 15.1±1 to 14.7±1; dopamine, 14.7±1 to 12.7±1 L· min−1) (P<0.05). Dopamine infusion increased CO, decreased TPR, but had no effect on either MAP or MSNA burst frequency (P<0.05).

These data suggest that high altitude‐mediated increases in MSNA are not attributable to a dopaminergic mechanism.
Chemoreflexes : A Major Component of Adaptation to High Altitude/Hypoxic Environment
Authors: Richalet Jean‐Paul , Voituron Nicolas , Hermand Eric , Jeton Florine , Lhuissier François J
Published: November 2023

The decrease in O2 pressure in hypoxia, either at high altitude or in disease, induces physiological responses mediated through oxygen sensing systems. Among those responses, chemoreflexes play a major role, especially during the initial phase of exposure to hypoxia. Peripheral chemoreceptors (carotid bodies) and central receptors (retrotrapezoid nucleus) are sensitive to hypoxia and hypercapnia and modulate the activity of the Respiratory rhythm generator. Our aim was to determine the role of erythropoietin (Epo) on those mechanisms in two animal models: transgenic anemic mice under‐expressing Epo (EpoTagh), and the Pika (Ochotona curzoniae) a lagomorph genetically adapted to high altitude on the Tibetan plateau. We showed that Epo are necessary for ventilatory acclimatization in EpoTagh mice and that nNOS and NMDA receptors are overexpressed in the medulla of Pikas. In humans, the sensitivity to hypoxia is a determinant factor for acclimatization to high altitude. A prospective cohort study on 1017 subjects has shown that the ventilatory response to hypoxia at exercise is predictive of the occurrence of severe high altitude illnesses (SHAI). From clinical evaluation and physiological response to hypoxia measured during a hypoxia exercise test, a predictive score of SHAI was calculated, which allowed the detection of high‐risk subjects. Instability of the control of ventilation has been evidenced during exercise in hypoxia, with oscillations of ventilation with a period of 11–12 seconds. The mechanisms of this instability is linked to the gain of the O2 and CO2 response, as well as other factors such as dead space and cardiac output.

Support or Funding Information

Laboratory of Excellence GrEx
Cerebral and peripheral circulation and progression of Alzheimer's disease
Authors: Pedrinolla Anna , Venturelli Massimo , Fonte Cristina , Galazzo Ilaria Boscolo , Crispoltoni Lucia , Benetti Maria Vittoria , Stabile Anna , Pistilli Alessandra , Rende Mario , Pizzini Fracesca Benedetta , Smania Nicola , Schena Federico
Published: November 2023

Background

In aging, cerebral and systemic circulation decline likewise to cognitive decline. Also, reduced availability of nitric oxide (NO) in both cerebral and peripheral blood vessels results in further alterations of circulation. Therefore, changes in circulation and NO availability may contribute to the development of Alzheimer's disease (AD). However, current literature lacks of evidence about the progression of AD and circulation impairment at both cerebral and peripheral level.

Aims

First aim of the study was to verify if circulation at cerebral and peripheral level is significantly reduced in AD patients compared with age‐matched healthy counterparts. Second aim was to verify if circulation at cerebral and peripheral level declines further with the severity of AD. Potential correlation between circulation and NO availability was also assessed.

Methods

In 55 AD patients (severity of dementia distribution: 12 MCI, 15 AD1, 19 AD2, 9 AD3), 13 healthy elderly (OLD), and 10 young (YG) subjects, cerebral blood flow (CBF) with partial volume correction, blood flow of carotid (CB) and femoral (FB) arteries were assessed. In addition, systemic vascular function was assessed by means of passive limb movement (PLM). NO availability was determined via plasma NO metabolites (NO−3 +NO−2).

Results

CBF was 57 ml/min/100gr, 48.6 ml/min/100gr, 44 ml/min/100gr, 40 ml/min/100gr, 34 ml/min/100gr, 30 ml/min/100gr in YG, OLD, MCI, AD1, AD2, and AD3 respectively. CF was 613 ml/min, 535 ml/min, 479 ml/min, 450 ml/min, 348 ml/min, 309 ml/min in YG, OLD, MCI, AD1, AD2, and AD3 respectively. FB was 403 l/min, 325 ml/min, 288 ml/min, 253 ml/min, 224 ml/min in YG, OLD, MCI, AD1, AD2, and AD3 respectively. Δpeak PLM was 739 ml/min, 284 ml/min, 227, 182 ml/min, 166 ml/min, 155 ml/min in YG, OLD, MCI, AD1, AD2, and AD3 respectively. NO−3 +NO−2 was 53 μM, 47 μM, 42 μM, 40 μM, 38 μM, 35 μM in YG, OLD, MCI, AD1, AD2, and AD3 respectively. Correlation between CBF and Δpeak PLM was r=0.677 (p<.01). Correlation between Δpeak PLM and NO−3+NO−2 was r=0.9765 (p<.01).

Conclusion

Our results confirm that CBF as well as CB, FB, Δpeak PLM and NO−3 +NO−2 are reduced in aging. AD patients exhibited a further reduction of all these parameters compared with healthy age‐matched counterparts. Moreover, circulation and NO availability were progressively declined with the progression of dementia, implicating that AD and its progression might be the result of an intertwined decline of both neural and vascular functions, likely related to the NO availability.

Support or Funding Information

No funding was received.
Exercise Ameliorated Cognitive Dysfunction through Mitochondrial Remodeling in Alcohol Administrated C57BL/6 Mice
Authors: Kelly Kimberly E. , George Akash K. , Behera Jyotirmaya , Tyagi Neetu
Published: November 2023

Alcohol consumption is a potent inducer of oxidative stress. Previous data indicate that alcohol consumption induces mitochondrial dysfunction and free radical production in mouse cerebral cortex. Exercise has been recommended by clinicians as a secondary protective therapy; however, its effect on brain functions through mitochondrial interventions has not been fully explored. Therefore, we hypothesized that exercise mitigates alcohol‐induced neurodegeneration and decline in cognitive function through mitochondrial remodeling. To test this hypothesis, we selected 10–12 weeks old male wild‐type mice (C57BL/6, WT), grouped as follows: 1) WT, 2) WT+ Alcohol, 3) WT+ Exercise, 4) WT+ Alcohol+ Exercise. Mice were given an intraperitoneal injection of EtOH (1.5g/kg BW) or saline solution every day for 12 weeks. The mice were exercised for 12 weeks on a treadmill with a controlled speed of 7 meters/min for the first week, the speed of 10 meters/min for the second week and 11 meters/min in the following weeks and a total of 330 meters every day. After each 110 meters mice were given rest of 10 minutes. Cognitive and behavior alterations were assessed by Novel Object Recognition, Passive Avoidance, and Y‐maze tests. Mitochondrial membrane potential and mitochondrial permeability changes were evaluated by flow cytometry. Our results suggest significant improvement in cognitive functions in exercised alcohol administrated group, as compared to non‐exercised alcohol administrated group. The involvement of mitochondrial remodeling in mice following exercise was further confirmed and we found there was a significant increase in ATP production, membrane potential, oxygen consumption, copy‐number as well as a decrease in reactive oxygen species when compared with non‐exercised alcoholic mice. Furthermore, a considerable reduction in TUNEL reactivity was determined in intact mitochondria isolated from the exercised group as compared to non‐exercised alcoholic mice. In addition, the effect of exercise on neuronal survival in the alcoholic brain was confirmed by Fluoro‐Jade C reactivity. Taken together, our results indicate a myriad of beneficiary effects of exercise over mitochondrial pathology during alcoholism. Furthermore, our findings suggest exercise mitigates neurodegeneration and cognitive dysfunction and thereby improving total mitochondrial function.

Support or Funding Information

This work was supported by NIH grant HL107640‐NT.
The dipeptidyl peptidase IV inhibitor saxagliptin prevents angiotensin II‐induced cardiac diastolic dysfunction: potential involvement of cardiac lymphocytes?
Authors: Brown Scott M , Smith Cassandra E , Khan Maloree , Meuth Alex I , Sowers James R , Chandrasekar Bysani , DeMarco Vincent G , Nistala Ravi , Bender Shawn B
Published: November 2023

Activation of the renin‐angiotensin‐aldosterone system (RAAS) is common in subjects with obesity, insulin resistance, and cardiovascular dysfunction. Recently, the anti‐hyperglycemia drugs dipeptidyl peptidase‐IV (DPPIV) inhibitors have been shown to exert cardioprotective effects in these patients; however, the impact of DPPIV inhibition on RAAS‐dependent cardiac injury and the underlying molecular mechanisms have not been investigated. Here, we hypothesized that DPPIV inhibition with saxagliptin (Saxa) attenuates angiotensin II (Ang II)‐induced cardiac dysfunction. Male C57BL/6J mice (13 weeks of age) underwent Ang II (sc, 500 ng/kg/min) or vehicle infusion for 3 wks. Animals received Saxa (po, 10 mg/kg/d) or placebo during the final 2 weeks of Ang II infusion. Echocardiography revealed diastolic dysfunction with Ang II infusion, indicated by reduced E′/A′ ratio, coincident with aortic stiffening (i.e., increased pulse wave velocity). Further, Ang II induced cardiac hypertrophy and periarterial, but not interstitial, fibrosis. Ang II also increased pro‐fibrotic (collagen I, CTGF), oxidative stress (NOX2), and macrophage‐specific (CD11c, CD163, CD86) gene expression. In fact, flow cytometry revealed increased CD45+F4/80+CD11b+ macrophages and a tendency for increased CD45+CD4+ lymphocytes in the heart. Treatment with Saxa significantly reduced plasma DPPIV activity by ~60% and abrogated Ang II‐induced cardiac diastolic dysfunction, but not aortic stiffening. Moreover, Saxa inhibited Ang II‐induced upregulation of cardiac Collagen 1 gene expression and periarterial fibrosis. Interestingly, Saxa failed to modulate the hypertrophic response. Saxa also failed to alter cardiac CD45+F4/80+CD11b+ macrophage recruitment. It did however elevate cardiac memory/effector CD45+CD8+CD44+ lymphocytes. Taken together, these results demonstrate that DPPIV inhibition with Saxa can prevent Ang II‐induced cardiac fibrosis and diastolic dysfunction. Furthermore, the benefit of Saxa treatment may involve a recently described anti‐fibrotic role of memory/effector CD8+ lymphocytes. DPPIV inhibition with Saxa may therefore represent a novel therapeutic approach for cardiac diastolic dysfunction in states associated with RAAS activation.

Support or Funding Information

Supported by funding from AstraZeneca (SBB and RN) and VA BLR&D CDA‐2 BX002030 (SBB).
Assessing cardiac function during simulated activities of daily living: A magnetic resonance imaging study
Authors: Beaudry Rhys I , Samuel Thomas J , Tucker Wesley , Zaha Vlad G , Singhavi Monika , Haykowsky Mark J , Nelson Michael D
Published: November 2023

Cardiac magnetic resonance imaging (cMRI) is the clinical gold‐standard imaging tool for evaluation of left ventricular morphology and function. Increasing cardiac demand through stress testing improves prognostic value of cardiac imaging; however, current MR stress testing approaches remain limited to pharmaceutical agents (e.g. dobutamine, adenosine) which only partially mimic the metabolic demands of activities of daily living. With the advent of MR‐compatible exercise equipment, we can now simulate the metabolic cost associated with activities of daily living during a single standardized cMRI exam. To demonstrate this, we first established the association between supine work rate and metabolic equivalents (METs) in ten healthy subjects (age: 25 ± 4 years; female/male: 5/5; BMI: 22.8 ± 3.2 kg/m2). We used four incremental workloads on a commercially available, MR compatible leg ergometer (Ergospect, Tirol, Austria), at a cadence of 60 steps per minute until steady state VO2 and measured METs using expired gas analysis (ParvoMedics TrueOne 2400). We then examined left ventricular volumes and global systolic function by cMRI in 6 subjects (age: 23 ± 1 years; female/male: 3/3; BMI: 25.5 ± 3.7 kg/m2) at rest, and at a workload equivalent to 3 METS—near the minimum threshold for independent living—using standardized, vendor provided, imaging sequences (GE Healthcare, Waukesha, Wisconsin, USA). As expected, heart rate increased significantly with exercise (67 ± 10 bpm rest vs. 122 ± 7 bpm 3 METS, p<0.05). LV end‐diastolic volumes, normalized to body surface area (BSA), decreased with exercise (80.2 ± 17.4 ml/m2 rest vs. 63.9 ± 24.8 ml/m2 3 METS), in parallel with reductions in end‐systolic volumes/BSA (26.6 ± 8.9 ml/m2 rest vs. 18.6 ± 8.7 ml/m2 3 METS). A slight decrease in stroke volume (51.1 ± 11.4 ml/m2 rest vs. 45.2 ± 18.7 ml/m2 3 METS) coupled with the drop in end‐diastolic volume preserved ejection fraction during exercise (67 ± 8% rest vs. 71 ± 6% 3 METS), and increased cardiac output (Δcardiac output: 1.3 ± 1.1 l/min/m2, 24 ± 19%). Taken together, these preliminary data demonstrate our ability assess the cardiac functional reserve required for activities of daily living using cMRI. More work is needed to include regional measures of myocardial tissue deformation, and to extend this work to clinical populations.

Support or Funding Information

This work was supported by AHA 16SDG27260115 and the Harry S. Moss Heart Trust.
Cervicothoracic Transcutaneous Electrical Nerve Stimulation Attenuates Cardiac Sympathetic Overdrive in Heart Failure: A 123l‐MIBG Myocardial Scintigraphy, Randomized Double‐Blind Crossover Trial
Authors: Fernandes Igor Alexandre , Campos Monique Opuszcka , Miranda Sandra Marina , Ribeiro Mario Claudio Lucas , Braghiroll Ana Maria Silveira , Mesquita Claudio Tinoco , Nóbrega Antonio Claudio Lucas
Published: November 2023

Introduction

Cardiac sympathetic drive provides inotropic support to the failing heart and preserves cardiovascular homeostasis. Nonetheless, as myocardial insult evolves, this compensatory response leads to a progressive decline in contractile function, increases the vulnerability to arrhythmias and constitutes an independent mortality predictor. Despite advanced pharmacological therapies, side effects and persistent cardiac sympathetic overdrive highlights the modulation of the adrenergic system as a primary target for non‐pharmacological strategies in the heart failure (HF) treatment. In this scenario, we propose cervicothoracic transcutaneous electrical nerve stimulation (TENS) as a non‐pharmacological therapy to attenuate cardiac sympathetic overdrive in patients with heart failure.

Methods

In this prospective, randomized, sham‐controlled, double‐blind crossover trial, seven HF patients (6 men and 1 women, 54 ± 6 years of age, and body mass of 61 ± 11 kg, NYHA class II–III, ejection fraction 28.1 ± 2.5%,) were randomly assigned to either an in‐home cervicothoracic transcutaneous electrical nerve stimulation therapy (TENS: 30 min twice a day with 80 Hz frequency and pulse duration of 150 μs) or a sham control intervention (SHCI) for two weeks. Following a two‐month washout phase from TENS/SHCI, patients crossed over and started the opposite condition. Washout rate and heart‐to‐mediastinum ratio, indexes of cardiac sympathetic activity and innervation density, were obtained from planar 123l‐metaiodobenzylguanidine myocardial scintigraphy images at the beginning and end of each condition.

Results

Baseline washout rate (TENS 27.1 ± 4.4% vs. SHCI 25.2 ± 6.8%, p = 0.657), early (TENS 1.78 ± 0.1 vs. SHCI 1.78 ± 0.05, p = 0.916) and late (TENS 1.74 ± 0.19 vs. SHCI 1.68 ± 0.16, p = 0.222) heart‐to‐mediastinum ratios were similar between both conditions. While early and late heart‐to‐mediastinum ratio did not change throughout the study (p > 0.05), TENS, but not SHCI, promoted a significant reduction in the washout rate (TENS ‐ 12.8 ± 4.3 vs. STHI + 8.0 ± 8.9%, p = 0.03).

Conclusion

These findings indicate that short‐term TENS therapy attenuates cardiac sympathetic overdrive in patients with heart failure with no impact on myocardial innervation density.

Support or Funding Information

Grant Funding Source: CAPES, CNPq, FAPERJ, FINEP and IEN
Reduced Sensory Nerve Fiber Density in Ventricular Myocardium in a Rat Myocardial Infarction Heart Failure Model
Authors: Siano John , Li Ying , Dedkov Eduard I , Zhang Youhua
Published: November 2023

Introduction

Heart failure (HF) results in autonomic dysfunction, characterized by sympathetic activation and vagal withdrawal, which in turn contributes to HF progression. The cardiac afferent sensory nerves play a critical role in mediating cardiovascular reflexes and in the neural regulation of cardiovascular function. However, the role of cardiac sensory nerves in mediating autonomic dysfunction in HF is less studied and it is unknown whether HF causes cardiac sensory nerve remodeling.

Methods

Myocardial infarction (MI) was induced by left anterior coronary artery ligation in 9 rats, with 8 sham‐operated animals serving as controls. Two months after MI surgery, HF was confirmed in post‐MI rats (MI‐HF) by echocardiography and hemodynamic measurements. Sensory nerve fibers in ventricular myocardium were visualized on frozen histological sections by immunostaining with anti‐calcitonin gene related peptide (CGRP) antibody. The density of CGRP‐positive nerve fibers was determined on digitized images of non‐infarcted ventricular myocardium (remote from the infarction area) by using Image‐Pro Analyzer v.7.0 software.

Results

Compared to controls, the sensory nerve fiber density in non‐infarcted ventricular myocardium was significantly decreased in MI‐HF animals (see figure).

Conclusions

The development of HF in post‐MI rats is associated with a significant sensory nerve fiber remodeling with reduced sensory nerve fiber density.
Interaction Between Lipid and β‐Carotene Metabolism in the Maternal Heart in Mice
Authors: Holloway Chelsee T.L , Kim Youn‐kyung , Quadro Loredana
Published: November 2023

The heart uses large amounts of fatty acids as energy‐providing substrates, and alterations in various lipid metabolic pathways have been shown to affect cardiac function. Little is known regarding the consequences of disruption of cardiac lipid metabolism during pregnancy, when the maternal heart becomes hypertrophic. Interestingly, there is an abundance of evidence for interactions between β‐carotene and lipid metabolism. Recently, Lee and colleagues (Am J Physiol Heart Circ Physiol 2014) show that male mice lacking β‐carotene 15,15′‐oxygenase (BCO1), the main enzyme that generates vitamin A from dietary β‐carotene, have altered cardiac lipid and retinoid metabolism accompanied by impaired cardiac function. Here we examine the effects of the lack of the β‐carotene cleavage enzyme (Bco1−/−) on lipid metabolism in the maternal heart during pregnancy. We analyzed the mRNA expression levels of key genes involved in the synthesis and oxidation of fatty acids in the hearts of wild‐type (WT) and Bco1−/− mice (n=5/group) at mid gestation. During pregnancy, fatty acid synthase (Fas) mRNA levels were decreased in the WT heart, likely to favor fatty acid oxidation and thus meet the higher energy demand of the enlarged heart. In the heart of Bco1−/− mice, Cd36 mRNA expression, important for fatty acid uptake, was reduced compared to WT. This reduction in Cd36 was accompanied by increased Fas (p<0.05), and reduced expression of genes involved in triglyceride synthesis (Dgat2) and fatty acid oxidation (Pgc1α). Overall, these data suggest the existence of a compensatory mechanism in hearts of Bco1−/− mice that may negatively impact their ability to maintain proper maternal cardiac functions. Notably, we observed that the hearts of Bco1−/− dams failed to enlarge. Ongoing works aim to elucidate the molecular mechanisms of the interaction between carotenoid and lipid metabolism and its role in maintaining proper maternal cardiac functions during pregnancy.
Ginger Treatment Ameliorates Alcohol‐Induced Myocardial Damage by Suppression of Hyperlipidemia and Cardiac Biomarkers in Rats
Authors: Kesireddy Sathyavelu Reddy , Ganjikunta Venkatasubbaiah , Bhasha Shanmugam , Sahukaru Ravi
Published: November 2023

Background

Alcohol‐induced hyperlipidemia is positively correlated with cardiovascular diseases. Several herbal extracts are reported to protect the cardiac injury and suppress the hyperlipidemia. However, the effect of ginger on alcohol‐induced hyperlipidaemia and myocardial damage remains unclear.

Objective

This study investigated the cardio protective properties of ginger ethanolic extract (Gt) on alcohol‐induced myocardial damage, and further distinguished the association between hyperlipidemia and occurrence of myocardial damage in rats.

Materials and Methods

Twenty four Wistar male albino rats weighing 250 ± 20 g were divided into four groups includes, Normal control (NC) (0.9% NaCl), Ginger treated (Gt) (200 mg/Kg b.w.), Alcohol treated (At) (20%, 6 g/Kg b.w.) and Alcohol along with Ginger treatment(At+Gt). In this study, lipid profiles such as fatty acids, triglycerides, total cholesterol, phospholipids, low density lipoprotein and high density lipoproteins and Cardiac biomarkers includes LDH, AST, CK‐MB, cTn‐T and cTn‐I were examined in rats. In addition, histopathological studies were also conducted.

Results

We found alcohol‐induced myocardial damage was associated with increased lipid profile except high density lipoprotein in alcohol treated (6 g/kg b.w.) rats compared to control rats while ginger treatment (200 mg/kg b.w.) reduced the lipid profiles except high density lipoproteins. Furthermore, elevated cardiac biomarkers activities with alcohol intoxication were significantly suppressed by ginger treatment. In addition, ginger treatment significantly minimized the myocardial damage induced by alcohol.

Conclusion

Our results conclude that ginger could protect from alcohol ‐ induced myocardial damage by suppression of hyperlipidemia and cardiac biomarkers.

Support or Funding Information

UGC‐MRP‐F.No43‐586/2014(SR) dated 30‐10‐2015
Remodeling of Glucose Metabolism by HIF‐1α in Hypoxic Heart
Authors: Li Ying , Lin Penghui , Peterson Jonathan M , Wright Gary L
Published: November 2023

Hypoxia inducible‐1α (HIF‐1α) is a transcription factor that directs multiple cellular changes in response to low oxygen conditions. Previously we have shown that hearts derived from mice with the cardiac‐restricted expression of a stabilized form of HIF‐1α are remarkably ischemia stress‐tolerant. The current studies are designed to further probe the metabolic rearrangements directed by HIF‐1α, particularly as they relate to glucose metabolism. Wild‐type (WT) and HIF‐1α expressing hearts were perfused with U‐13C6 glucose for 30min, ex vivo. Subsequently the hearts were subjected to global ischemia (for 0, 5, 10, 15 and 30 min), flash frozen and polar metabolites were extracted. The incorporation of 13C in the metabolome reservoir of the heart was determined by NMR spectroscopy. Total glycogen (12C, PRESAT) was depleted by 5–10 min in WT hearts while glycogen reserves were maintained at 30min of ischemia in HIF‐1α hearts. 13C‐Glucose incorporation into glycogen ceased within 5min of ischemia in WT hearts, but unexpectedly continued to rise in HIF‐1α hearts for up 30min of ischemia. Indicating enhanced glycolytic flux 13C‐lactate production was elevated in the HIF‐1α as compared to WT hearts, especially after 15min of ischemia where lactate levels continued to rise in the HIF‐1α hearts while peaking within 5–10min of ischemia in WT hearts. Concomitant with these metabolic changes, the total adenine nucleotide pool (AXP) was maintained in HIF‐1α hearts at 30 min of ischemia while reduced by ~50% in WT. In conclusion, HIF‐1α hearts have increased glycolytic flux that is maintained longer into ischemia. The data also suggests that glucose:glycogen turnover is maintained for up 30 min in HIF‐1α hearts during zero‐flow ischemia. Finally, it is important to mention that many additional 12C and 13C‐containing metabolites, not discussed here, were observed to be significantly different between WT and HIF‐1α hearts during ischemia. Clearly, HIF‐1α is directing broad and profound metabolic rearrangements within the heart with the goal to situate it to survive ischemic insult.
Cardiac ischemic tolerance of spontaneously hypertensive rats with increased expression of C‐reactive protein
Authors: Neckar Jan , Papousek Frantisek , Silhavy Jan , Pravenec Michal , Kolar Frantisek
Published: November 2023

C‐reactive protein (CRP) is a major acute‐phase inflammatory reactant produced in the liver. It has been reported that increased CRP level is a risk factor for cardiovascular disease, including myocardial infarction, hypertension, and heart failure. However, it is not clear whether CPR is just a marker or an active mediator of any of these cardiovascular disorders. Therefore, the aim of this study was to analyze the effects of CRP overexpression on myocardial contractility and cardiac susceptibility to ischemia‐reperfusion injury in adult spontaneously hypertensive rats expressing human CRP transgene in the liver (SHR‐CRP) and age‐matched SHR controls. Echocardiographic assessment of systolic function revealed significantly lower fractional shortening in SHR‐CRP as compared to SHR (by 6–8 %) both at baseline and after the stimulation with increasing infusion rates of dobutamine. Using an open‐chest model of coronary artery occlusion, we found significantly smaller infarct size normalized to the area at risk in SHR‐CRP (48.5 ± 5.1 %) compared to SHR (66.5 ± 4.9 %). However, profound ischemic arrhythmogenesis resulting in significantly increased duration of ventricular tachyarrhythmias and the total number of premature ventricular complexes was observed in SHR‐CRP (340 ± 56 s and 3299 ± 498, respectively) compared to SHR (103 ± 49 s and 1316 ± 511, respectively). In SHR‐CRP, concentration of thromboxane B2, the inactive product of proarrythmogenic thromboxane A2, increased by 185 % in ischemized compared to non‐ischemized myocardium while it was not affected by ischemia in SHR controls. It can be concluded that transgenic CRP‐SHR have opposite effects on two major end‐points of cardiac ischemia‐reperfusion injury (arrhythmias vs. infarction). The proarrhythmogenic effect of CRP overexpression can be related to increased thromboxane A2 level.
Muscle Metaboreflex Activation in Young Healthy Men with a Family History of Hypertension
Authors: Kaur Jasdeep , Vranish Jennifer R. , Patik Jordan C. , Young Benjamin E. , Keller David M. , Fadel Paul J.
Published: November 2023

Activation of metabolically sensitive skeletal muscle afferents (i.e., the muscle metaboreflex) contributes importantly to the muscle sympathetic nerve activity (MSNA) and pressor responses evoked by static handgrip exercise. Individuals with a positive family history of hypertension (+FHH) have been shown to evoke greater pressor responses to static handgrip exercise however, whether this is due to an exaggerated muscle metaboreflex remains unclear. A recent study demonstrated that young, healthy women with +FHH have an exaggerated muscle metaboreflex activation compared to women with no family history (‐FHH). However, whether men with +FHH also exhibit an augmented muscle metaboreflex response has not been investigated. Therefore, we tested the hypothesis that muscle metaboreflex activation is exaggerated in young men with +FHH. Young, healthy men (+FHH, n=7 and ‐FHH, n=13) performed 2 min of static handgrip exercise at 40% of maximal voluntary contraction followed by a 2 min period of post‐exercise ischemia (PEI) to isolate skeletal muscle metaboreflex activation. In addition, a cold pressor test (CPT) was performed as a generalized, sympathoexcitatory stimulus. Beat‐to‐beat arterial blood pressure (finger photoplethysmography), heart rate (ECG) and MSNA (peroneal nerve microneurography) were measured. Resting mean arterial pressure (MAP; +FHH: 99±3 vs. ‐FHH: 95±2 mmHg, p=0.34) and MSNA (+FHH: 12±1 vs. ‐FHH: 15±3 bursts/min, p=0.56) were similar between groups. The increase in MAP during PEI following 40% handgrip was not different between groups (+FHH: Δ22±3 vs. ‐FHH: Δ23±1 mmHg, p=0.52). However, the MSNA response during PEI was greater in +FHH (Δ20±1 bursts/min) compared to ‐FHH (Δ10±2 bursts/min, p=0.01). No difference was observed in MAP (+FHH: Δ20±5 vs. ‐FHH: Δ19±3 mmHg, p=0.82) or MSNA (+FHH: Δ14±4 vs. ‐FHH: Δ16±5 bursts/min, p=0.75) response to CPT between groups. These preliminary data suggest that a heightened muscle metaboreflex mediated sympatho‐excitation is present in young healthy men with a family history of hypertension.

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NIH R15‐HL‐130906
Effect of Exercise Training on Neurovascular Control During Mental Stress in Patients with Acute Coronary Syndrome
Authors: Ferreira‐Santos Larissa , Martinez Daniel Godoy , Nicolau José Carlos , Moreira Humberto Graner , Alves Maria Janieire NN , Trombetta Ivani Credidio , Negrão Carlos Eduardo , Rondon Maria Urbana PB
Published: November 2023

Patients with myocardial infarction present abnormal neurovascular control at rest and during physiological conditions. On the other hand, exercise training (ET) restores the autonomic control in these patients. However, the effect of ET on neurovascular control during a defense reaction of mental stress in patients with acute coronary syndrome (ACS) remains unknown. We tested the hypothesis that long‐term ET would decrease muscle sympathetic nerve activity (MSNA) and would increase the skeletal muscle vasodilatation during mental stress in ACS patients. Thirty‐four patients with ACS with preserved ventricular function were allocated in two groups: 1) ET (ACS‐ET, n=17) and 2) Untrained (ACS‐U, n=17). MSNA was recorded directly from the peroneal nerve by microneurography and forearm blood flow was measured by venous occlusion plethysmography. The six‐month ET program was supervised and consisted of three 60‐min exercise sessions/week. Mental stress was elicited by a mental challenge of Stroop Color Word Test during 3 minutes. MSNA significantly decreased during mental stress in the ACS‐ET group (P=0.002), but not in the ACS‐U group. In addition, in the post‐intervention period, the levels of MSNA during mental stress were significantly lower in the ACS‐ET group in compared with ACS‐U group (P=0.04). ET did not significantly change the forearm vascular conductance during mental stress. However, in the post‐intervention period, the forearm vascular conductance response was significantly higher in the ACS‐ET group compared with ACS‐U group (P<0.001). In conclusion, ET improves neurovascular control during a defense reaction of mental stress in patients with ACS. Therefore, these results emphasize the importance of prescribing ET in the treatment of these patients.

Support or Funding Information

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP #2010/50048‐1); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq#475911/2013‐0, #309821/2014‐2 and #308068/2011‐4) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior‐ CAPES
Inspiratory Muscle Strength Training for Sleep‐related Breathing Disorders
Authors: Barrera Guadalupe Ramos , De Asis Roxanne , Bailey E. Fiona
Published: November 2023

We have shown previously that inspiratory muscle strength training (IMST) lowers blood pressure in healthy, college‐aged adults (Vranish and Bailey 2015) and in adults with mild and moderate obstructive sleep apnea (OSA) (Vranish and Bailey 2016). The mechanism underlying IMST‐related declines in blood pressure remains unclear moreover, it is unclear if individuals with more severe forms of OSA can benefit from the intervention. Here, we explore the potential for IMST to modulate blood pressure, baroreflex sensitivity (BRS) and heart rate in normotensive and hypertensive adults who have been diagnosed with moderate and severe OSA and who are unable or unwilling to comply with standard CPAP therapy.

Nine adults (5 men, 4 women) ages 54–80 years (68.5± 9.37 years) with an average AHI of 29±9.35 have been recruited to the study. Pre‐ and post‐ assessment measures include in‐home sleep studies (ApneaLink Air, ResMed), 24 hour non invasive blood pressure monitoring (SOMNOtouch, Germany), ECG, resting BRS, muscle sympathetic nerve activity (MSNA) and spirometry. Additionally, all subjects complete the Pittsburgh Sleep Quality Index. Following pre assessment, subjects are randomly assigned to IMST (n=4; 75% maximal inspiratory pressure) or sham training (n=5; 15% maximal inspiratory pressure) groups and performed in home training (30 breaths/day, 7 days/week for 6 weeks) using the K3 Series POWERbreathe trainer (Warwickshire, UK). Each subject's pulmonary function, maximal inspiratory pressure (PImax), resting blood pressure and BRS are reassessed at the beginning of each training week (1–6).

Preliminary findings show decreases in resting systolic (128.33± 19.66 mmHg vs. 118± 19.67 mmHg) and diastolic blood pressures (74 ± 8.56 mmHg vs. 69.91 ±9.39 mmHg) pre vs. post for the IMST group. Blood pressures in sham trained subjects are unchanged (systolic 131.66 ± 8.79 mmHg vs. 136.16 ± 16.93 mmHg and diastolic 69.66 ± 7.72 mmHg vs. 72.33 ± 15.34 mmHg pre vs. post). Surprisingly, we see no effect of the intervention on either heart rate, BRS or MSNA. Our preliminary data indicate that whereas 6 weeks of IMST is effective in lowering blood pressure in adults with moderate to severe OSA however, the improvement in blood pressure cannot be attributed to increases in baroreflex sensitivity or to decreases in sympathetic outflow. Data collection is ongoing with target recruitment of 15 subjects for IMST and sham training groups.

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AHA 16GRNT26700007
The α7/α4β2 nAChRs Alleviate The Hypotension And Altered Cardiac Sympathovagal Balance Evoked By Endotoxemia In Male Rats
Authors: Sallam Marwa Y , El‐Gowilly Sahar M , El‐Gowelli Hanan M , El‐Mas Mahmoud M
Published: November 2023

Nicotine favorably influences inflammatory conditions such as endotoxemia and ulcerative colitis through the activation of the cholinergic antiinflammatory pathway. In this communication, we hypothesized that α7 and/or α4β2 nicotinic acetylcholine receptors (nAChRs) protect against the cardiovascular and autonomic imbalances caused by endotoxemia. Experiments were performed in conscious male rats to assess the dose‐effect relationships for i.v. nicotine (25, 50, or 100 μg/kg), PHA‐543613 (selective α7 nAChR agonist; 0.2 or 2.0 mg/kg), or 5‐iodo‐A‐85380 (5IA, selective α4β2 nAChRs agonist; 0.01 or 0.1 mg/kg) on cardiovascular responses elicited by lipopolysaccharide (LPS, 10 mg/kg i.v.). The two lower doses of nicotine (25 and 50 mg/kg) caused significant and dose‐dependent attenuation of the hypotensive and tachycardic responses caused by prior LPS administration. The effects of the 100 mg/kg dose of nicotine were comparable to those caused by the 25 mg/kg dose. The reductions in the time‐ domain indices of heart rate variability (HRV) and spectral measure of cardiac sympathovagal balance (ratio of the low‐frequency to high‐frequency power) induced by LPS were similarly reversed by nicotine. Alternatively, the hypotensive and tachycardic effects of LPS were (i) partly and dose‐dependently reversed after selective activation of α7 or α4β2 nAChRs by PHA or 5IA, respectively, and (ii) completely eliminated after treatment with a mixture of the smaller doses of the two agonists. By contrast, the individual or combined use of PHA or 5IA fully abolished the LPS‐evoked reductions in the low‐frequency/high‐frequency ratio, indicating the normalization of the cardiac sympathovagal balance. Together, the data implicate monomeric (α7) and heteromeric (α4β2) nAChRs in the nicotine counteraction of the adverse cardiovascular effects of endotoxemia.

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Supported by the Science and Technology Development Fund, Egypt (STDF Grant No. 14895).
A Reduction in SK Channel Function Contributes to Increased Excitability of Hypothalamic Magnocellular Neurons During Heart Failure
Authors: Neto Hildebrando Candido Ferreira , Biancardi Vinicia , Stern Javier
Published: November 2023

Neurohumoral activation, which includes elevated plasma levels of vasopressin, is a hallmark of heart failure (HF) and contributes to morbidity and mortality in this disease. Here, we evaluated whether changes in Ca2+‐activated K+ (SK) channels contribute to enhanced hypothalamic magnocellular neurosecretory cell (MNCs) activity in HF rats. Whole‐cell patch clamp recordings obtained from MNCs in slices from Sham and HF rats showed that the spike frequency evoked by direct current injection was significantly higher in the HF rats compared to Sham rats (Sham 16±0.9 vs HF 24±1.2 spikes, p<0.001). Bath application of the SK channel blocker apamin significantly increased the evoked firing frequency in MNCs from Sham rats, but no effect was observed in HF rats (Sham 23±0.9, p< 0.05 vs control; HF 26±0.7 spikes, p>0.05 vs control). The medium afterhyperpolarization potential (mAHP) following a train of spikes was significantly smaller in MNCs from HF rats compared to Sham rats (Sham 9.7±1.1 vs HF 6.6±0.6 mV, p<0.05) and apamin reduced the mAHP in both groups (Sham 2.9±0.5 vs HF 1.6±1.1 mV). Voltage‐clamp recordings of SK tail currents revealed that the apamin‐sensitive current amplitude and area were significantly smaller in MNCs from HF rats (amplitude: Sham 0.2±0.03 vs HF 0.09±0.03 nA, p<0.05; area: Sham 15.4±2.5 vs HF 7.2±1.2 nA.ms, p<0.01) whereas intracellular dialysis of MNCs with BAPTA reduced the currents in both groups to the same extent. No significant differences were observed in cell capacitance (Sham 30±2 vs HF 26±3 pF, p>0.05) or input resistance (Sham 960±87 vs HF 945±167 MΩ, p>0.05) between groups. Taken together, our data indicates that a decrease in SK channel function/activity and/or expression contributes to the increased excitability of MNCs in HF rats.

Support or Funding Information

NIH R01HL090948
Water deprivation does not enhance sympathetic and pressor responses to sciatic nerve stimulation or chemical activation of RVLM neurons
Authors: Stocker Sean D , Wenner Megan M , Farquhar William B
Published: November 2023

Water deprivation produces a volume contraction and elevation in plasma sodium concentrations and osmolality. Together, these changes activate the sympathetic nerve activity (SNA) to support arterial blood pressure (ABP). Prior studies suggest that dietary salt intake raises plasma sodium concentrations to sensitize central autonomic networks including the rostral ventrolateral medulla (RVLM), exaggerate sympathetic reflexes, and increase blood pressure variability. The purpose of the present study was to examine whether water deprivation produced similar changes in RVLM neurons and enhanced sympathetic responses from activation of sciatic afferent nerves. Male Sprague‐Dawley rats (300–450g) were deprived of water but not food for 48h. Control rats were given free access to both. Then, animals were anesthetized with Inactin (120mg/kg, IV), artificially‐ventilated, and prepared for recording brachial ABP and SNA. Sciatic afferents were electrically stimulated (500uA, 1s pulse, 5s duration) at various frequencies (2, 5, 10, and 20 Hz). Water deprivation (H2OD) vs control rats significantly elevated plasma sodium concentrations (143±1 vs 137±1 mM, respectively; P<0.01) and osmolality (310±4 vs 294±2 mOsm/L, respectively; P<0.01). Activation of sciatic afferents produced frequency‐dependent increases in all variables in both control and water‐deprived animals. However, there were no statistical differences at any frequency between groups in mean ABP (5Hz ‐ control: 18±3 mmHg vs H2OD: 21±2 mmHg; n=6–8), lumbar SNA (5Hz – control: 139±11% vs H2OD: 129±10%, n=6–8), renal SNA (5Hz – control: 169±20% vs H2OD: 178±18%, n=6–8 per group), or splanchnic SNA (5Hz – control: 163±17% vs H2OD: 162±5%, n=6–8 per group). In a second set of experiments, chemical stimulation of RVLM neurons by microinjection of L‐glutamate (10mM, 35nL) produced significant increases in SNA and ABP in control and water‐deprived groups; however, there were no significant differences in mean ABP (control: 15±4mmHg vs H2OD: 11±2mmHg; n=4 per group), lumbar SNA (control: 124±4% vs H2OD: 131±10%), renal SNA (control: 133±5% vs H2OD: 131±4%), or splanchnic SNA (control: 131±3% vs H2OD: 140±17%). Inhibition of RVLM by unilateral injection of GABA (100mM, 35nL) produced similar decreases in mean ABP (control: ‐31±3mmHg vs H2OD: −29±2mmHg; n=3–4 per group), lumbar SNA (control: −26±1% vs H2O: −27±8%), renal SNA (control: −41±8% vs H2OD: −30±7%), and splanchnic SNA (control: −39±11% vs H2OD: −43±7%). Collectively, these findings suggest that water deprivation raises plasma sodium concentrations and osmolality but does not alter sympathetic reflexes or alter the excitability of RVLM neurons.

Support or Funding Information

AHA Established Investigator Award (SDS), NIH R01 HL113270 (SDS), NIH R01 HL128388 (SDS, WBF)