Effect of different intensities of physical activity on cardiometabolic markers and vascular and cardiac function in adult rats fed with a high-fat high-carbohydrate diet

Background: Physical activity (PA) and diet are 2 lifestyle factors that affect cardiometabolic risk. However, data on how a high-fat high-carbohydrate (HFHC) diet influences the effect of different intensities of PA on cardiometabolic health and cardiovascular function in a controlled setting are yet to be fully established. This study investigated the effect of sedentary behavior, light-intensity training (LIT), and high-intensity interval training (HIIT) on cardiometabolic markers and vascular and cardiac function in HFHC-fed adult rats. Methods: Twelve-week-old Wistar rats were randomly allocated to 4 groups (12 rats/group): control (CTL), sedentary (SED), LIT, and HIIT. Biometric indices, glucose and lipid control, inflammatory and oxidative stress markers, vascular reactivity, and cardiac electrophysiology of the experimental groups were examined after 12 weeks of HFHC-diet feeding and PA interventions. Results: The SED group had slower cardiac conduction (p = 0.0426) and greater thoracic aortic contractile responses (p < 0.05) compared with the CTL group. The LIT group showed improved cardiac conduction compared with the SED group (p = 0.0003), and the HIIT group showed decreased mesenteric artery contractile responses compared with all other groups and improved endothelium-dependent mesenteric artery relaxation compared with the LIT group (both p < 0.05). The LIT and HIIT groups had lower visceral (p = 0.0057 for LIT, p = 0.0120 for HIIT) and epididymal fat (p < 0.0001 for LIT, p = 0.0002 for HIIT) compared with the CTL group. Conclusion: LIT induced positive adaptations on fat accumulation and cardiac conduction, and HIIT induced a positive effect on fat accumulation, mesenteric artery contraction, and endothelium-dependent relaxation. No other differences were observed between groups. These findings suggest that few positive health effects can be achieved through LIT and HIIT when consuming a chronic and sustained HFHC diet

Increased calcium influx mediates increased cardiac stiffness in hyperthyroid rats

Cardiac remodeling (hypertrophy and fibrosis) and an increased left ventricular diastolic stiffness characterize models of hypertension such as the SHR and DOCA-salt hypertensive rats. By contrast, hyperthyroidism induces hypertrophy and hypertension, yet collagen expression and deposition is unchanged or decreased, whereas diastolic stiffness is increased. We determined the possible role of increased calcium influx in the development of increased diastolic stiffness in hyperthyroidism by administering verapamil (15 mg/[kg·d] orally) to rats given triiodothyronine (T3) (0.5 mg/[kg·d] subcutaneously for 14 d). Administration of T3 significantly increased body temperature (control: 36.7 ± 0.2°C; T3: 39.6 ± 0.2°C), left ventricular wet weight (control: 2.09 ± 0.02 mg/kg; T3 3.07 ± 0.07 mg/kg), systolic blood pressure (control: 128 ± 5 mmHg; T3: 156 ± 4 mmHg), and left ventricular diastolic stiffness (control: 20.6 ± 2.0; T3: 28.8 ± 1.4). Collagen content of the left ventricle was unchanged. Contractile response to noradrenaline in thoracic aortic rings was reduced. Relaxation in response to acetylcholine (ACh) was also reduced in T3- reated rats, whereas sodium nitroprusside response was unchanged. Verapamil treatment of hyperthyroid rats completely prevented the increased diastolic stiffness and systolic blood pressure while attenuating the increased body temperature and left ventricular weight; collagen content remained unchanged. ACh response in thoracic aortic rings was restored by verapamil. Thus, in hyperthyroid rats, an increased calcium influx is a potential mediator of the increased diastolic stiffness independent of changes in collagen

Statins with different lipophilic indices exert distinct effects on skeletal, cardiac and vascular smooth muscle

Irwin, JC ORCiD: 0000-0001-9427-6347AIMS: Data concerning the influence of statin lipophilicity on the myotoxic and pleiotropic effects of statins is conflicting, and mechanistic head-to-head comparison studies evaluating this parameter are limited. In order to address the disparity, this mechanistic investigation aimed to assess the effects of two short-acting statins with different lipophilic indices on skeletal, cardiac and vascular smooth muscle physiology. MATERIALS AND METHODS: Young female Wistar rats were randomised to simvastatin (80 mg kg-1 day-1), pravastatin (160 mg kg-1 day-1) or control treatment groups. Changes in functional muscle performance were assessed, as well as mRNA levels of genes relating to atrophy, hypertrophy, mitochondrial function and/or oxidative stress. KEY FINDINGS: There were no significant differences in the mRNA profiles of isolated skeletal muscles amongst the treatment groups. In terms of skeleletal muscle performance, simvastatin reduced functionality but treatment with pravastatin significantly improved force production. Rodents given simvastatin demonstrated comparable myocardial integrity to the control group. Conversely, pravastatin reduced left ventricular action potential duration, diastolic stiffness and Mhc-β expression. Pravastatin improved endothelium-dependent relaxation, particularly in muscular arteries, but this effect was absent in the simvastatin-treated rats. The responsiveness of isolated blood vessels to noradrenaline also differed between the statin groups. The findings of this study support that the effects of statins on skeletal, cardiac and vascular smooth muscle vary with their lipophilic indices. SIGNIFICANCE: The results of this work have important implications for elucidating the mechanisms responsible for the myotoxic and pleiotropic effects of statins

Geranylgeraniol prevents statin-induced skeletal muscle fatigue without causing adverse effects in cardiac or vascular smooth muscle performance

Irwin, JC ORCiD: 0000-0001-9427-6347The administration of geranylgeranyl pyrophosphate (GGPP) (or its precursor, geranylgeraniol [GGOH]) has been shown by several in vitro studies to be capable of abrogating statin-induced myotoxicity. Nonetheless, the potential of GGPP repletion to prevent statin-associated muscle symptoms (SAMS) in vivo is yet to be investigated. Therefore, this study aimed to evaluate the ability of GGOH to prevent SAMS in rodents. Female Wistar rats (12 weeks of age) were randomised to 1 of 4 treatment groups: control, control with GGOH, simvastatin or simvastatin with GGOH. Ex vivo assessment of force production was conducted in skeletal muscles of varying fiber composition. Ex vivo left ventricular performance and blood vessel function was also assessed to determine if the administration of GGOH caused adverse changes in these parameters. Statin administration was associated with reduced force production in fast-twitch glycolytic muscle, but coadministration with GGOH completely abrogated this effect. Additionally, GGOH improved the performance of muscles not adversely affected by simvastatin (ie, those with a greater proportion of slow-twitch oxidative fibers), and increased force production in the control animals. Neither control nor statin-treated rodents given GGOH exhibited adverse changes in cardiac function. Vascular relaxation was also maintained following treatment with GGOH. The findings of this study demonstrate that GGOH can prevent statin-induced skeletal muscle fatigue in rodents without causing adverse changes in cardiovascular function. Further studies to elucidate the exact mechanisms underlying the effects observed in this investigation are warranted. © 2019 Elsevier Inc

Systematic Review of the Diagnostic and Clinical Utility of Salivary microRNAs in Traumatic Brain Injury (TBI)

Research in traumatic brain injury (TBI) is an urgent priority, as there are currently no TBI biomarkers to assess the severity of injury, to predict outcomes, and to monitor recovery. Small non-coding RNAs (sncRNAs) including microRNAs can be measured in saliva following TBI and have been investigated as potential diagnostic markers. The aim of this systematic review was to investigate the diagnostic or prognostic ability of microRNAs extracted from saliva in human subjects. PubMed, Embase, Scopus, PsycINFO and Web of Science were searched for studies that examined the association of saliva microRNAs in TBI. Original studies of any design involving diagnostic capacity of salivary microRNAs for TBI were selected for data extraction. Nine studies met inclusion criteria, with a heterogeneous population involving athletes and hospital patients, children and adults. The studies identified a total of 188 differentially expressed microRNAs, with 30 detected in multiple studies. MicroRNAs in multiple studies involved expression change bidirectionality. The study design and methods involved significant heterogeneity that precluded meta-analysis. Early data indicates salivary microRNAs may assist with TBI diagnosis. Further research with consistent methods and larger patient populations is required to evaluate the diagnostic and prognostic potential of saliva microRNAs

Validation of a clinically-relevant rodent model of statin-associated muscle symptoms for use in pharmacological studies

Irwin, JC ORCiD: 0000-0001-9427-6347; Ryan, KR ORCiD: 0000-0002-5080-4782Various rodent models of statin-associated muscle symptoms (SAMS) have been used to investigate the aetiology of statin myotoxicity. Variability between these models, however, may be contributing to the ambiguity currently surrounding the pathogenesis of SAMS. Furthermore, few studies have assessed the reproducibility of these models. The aim of this study was to compare two established rodent models of statin myotoxicity, differing in treatment duration and dose, to determine which reproducibly caused changes characteristic of SAMS. Isolated skeletal muscle organ bath experiments, biochemical analyses, real-time quantitative-PCR and biometric assessments were used to compare changes in skeletal muscle and renal integrity in statin-treated animals and time-matched control groups. The SIM80 model (80 mg kg −1 day −1 simvastatin for 14 days) produced fibre-selective skeletal muscle damage characteristic of SAMS. Indeed, fast-twitch gastrocnemius muscles showed increased Atrogin-1 expression, reduced peak force of contraction and decreased Myh2 expression while slow-twitch soleus muscles were unaffected. Contrastingly, the SIM50 model (50 mg kg −1 day −1 simvastatin for 30 days) produced little evidence of significant skeletal muscle damage. Neither statin treatment protocol caused significant pathological changes to the kidney. The results of this study indicate that the SIM80 model induces a type of SAMS in rodents that resembles the presentation of statin-induced myalgia in humans. The findings support that the SIM80 model is reproducible and can thus be reliably used as a platform to assess the aetiology and treatment of this condition. © 2018 Elsevier Inc

Epicatechin’s cardiovascular protective effects are mediated via opioid receptors and nitric oxide

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: Cardiovascular disease is the leading cause of mortality globally. Epicatechin has previously been shown to improve vascular responses and possess cardioprotective properties. However, the mechanisms underpinning these cardiotropic outcomes remain unknown. The aim of this study was to further identify epicatechin’s mechanism of action in the cardiovasculature. Methods: The effects of epicatechin on isolated rat conduit arteries, resistance vessels and cardiac electrophysiology were investigated on resting tension and precontracted vessels and cardiac action potential parameters, both in the presence and in the absence of various antagonists. Results: At resting tension, epicatechin alone did not affect the vasoreactivity of either conduit or resistance vessels. In noradrenaline pre-contracted thoracic aortic arteries and potassium chloride pre-contracted mesenteric vessels, epicatechin (10 −9 –10 −4  M) induced significant vasorelaxation. The addition of naloxone (10 −5  M), N G -nitro-L-arginine methyl ester (10 −5 M), 4-aminopyridine (5 mM) and verapamil (10 −5  M) attenuated epicatechin-mediated vasorelaxation. No change in epicatechin-mediated vasorelaxation was observed with the addition of atropine (10 −5  M). Epicatechin significantly improved cardiac electrophysiology by reducing the resting membrane potential, action potential amplitude and force of contraction that was mitigated following the addition of naloxone (10 −5  M). Epicatechin significantly decreased the action potential duration at 20, 50 and 90% duration and time to 90% relaxation of force that was unchanged following the addition of naloxone (10 −5  M). Conclusions: These findings suggest epicatechin’s vascular responses and cardioprotective effects are mediated through opioid receptors, nitric oxide, potassium channel and calcium channel activation and highlight the importance of the endothelium/nitric oxide in epicatechin mediated vasorelaxation

Effects of light intensity activity on CVD risk factors: a systematic review of intervention studies

The effects of light intensity physical activity (LIPA) on cardiovascular disease (CVD) risk factors remain to be established. This review summarizes the effects of LIPA on CVD risk factors and CVD-related markers in adults. A systematic search of four electronic databases (PubMed, Academic Search Complete, SPORTDiscus, and CINAHL) examining LIPA and CVD risk factors (body composition, blood pressure, glucose, insulin, glycosylated hemoglobin, and lipid profile) and CVD-related markers (maximal oxygen uptake, heart rate, C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and tumor necrosis factor receptors 1 and 2) published between 1970 and 2015 was performed on 15 March 2015. A total of 33 intervention studies examining the effect of LIPA on CVD risk factors and markers were included in this review. Results indicated that LIPA did not improve CVD risk factors and CVD-related markers in healthy individuals. LIPA was found to improve systolic and diastolic blood pressure in physically inactive populations with a medical condition. Reviewed studies show little support for the role of LIPA to reduce CVD risk factors. Many of the included studies were of low to fair study quality and used low doses of LIPA. Further studies are needed to establish the value of LIPA in reducing CVD risk

Reversal of cardiac dysfunction by selective ET-A receptor antagonism

1. The effectiveness of a selective endothelin receptor-A (ET-A) antagonist, A-127722 (approximately10 mgkg day as 200 mgkg powdered food), to reverse existing cardiac remodelling and prevent further remodelling was tested in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. 2. Uninephrectomised rats (UNX) administered DOCA (25 mg every fourth day s.c.) and 1% NaClin drinking water for 28 days developed hypertension (systolic blood pressure (BP): UNX12876 mmHg, DOCA-salt 18275* mmHg; *P0.05 vs UNX), left ventricular hypertrophy (UNX1.9970.06 mgkg1 body wt, DOCA-salt 3.3070.08* mgkg body wt), decreased left ventricularinternal diameter (UNX 6.6970.18 mm, DOCA-salt 5.5170.37* mm), an increased left ventricularmonocyte/macrophage infiltration together with an increased interstitial collagen from 2.770.3 to11.771.3%, increased passive diastolic stiffness (UNX 21.170.5, DOCA-salt 30.171.3*), prolongation of the action potential duration at 20 and 90% of repolarisation (APD20–UNX 6.871.1, DOCAsalt10.171.5* ms; APD90–UNX 34.473.5 ms, DOCA-salt 64.3710.4* ms) and vascular dysfunctions (2.6-fold decrease in maximal contractile response to noradrenaline, 3.5-fold decrease in maximalrelaxation response to acetylcholine). 3. Administration of A-127722 for 14 days starting 14 days after surgery attenuated the increases in systolic BP (15076** mmHg, **Po0.05 vs DOCA-salt), left ventricular wet weight (2.6570.06**mg kg body wt) and internal diameter (6.3970.31** mm), prevented left ventricular monocyte/macrophage accumulation, attenuated the increased left ventricular interstitial collagen (7.671.3%**), reversed the increased passive diastolic stiffness (22.171.2**), attenuated the action potential duration prolongation (APD20 – 7 . 671.4**, APD90 – 41.576.9** ms) and normalised changes in vascular function. 4. ET-A receptor antagonism both reverses and prevents the cardiac and vascular remodelling in DOCA-salt hypertension and improves cardiovascular function