Effects In Cardiovascular System Research Articles

#957 The immunometabolic profile of human peritoneal macrophages during peritoneal dialysis and its relation to systemic cardiovascular effects

Abstract Background and Aims Patients with end-stage kidney disease (ESKD) treated with peritoneal dialysis (PD) exhibit a high risk of heart failure (HF). This largely concerns HF with a preserved ejection fraction (HFpEF). Uremic toxins, oxidative stress and systemic inflammation related to ESKD contribute to this HFpEF phenotype, which may be aggravated by the daily administration of glucose-rich PD-fluids. These induce insulin resistance and formation of advanced glycaemic end products, resulting in microvascular injury and arteriosclerosis. A hallmark of HFpEF is the presence of profibrotic cardiac macrophages that aggravate fibrosis. In the peritoneum, the non-physiological high glucose concentrations trigger local oxidative stress, fibrosis and inflammation, processes alike those seen in HFpEF. While the role of macrophages in HFpEF is established, the involvement of human peritoneal macrophages (HPMs) in PD-induced peritoneal injury is largely unknown. We hypothesize that HPMs, chronically exposed to the glucose-rich fluids, exhibit an inflammation-driven immunometabolic profile. This may contribute to cardiovascular (CV)-risk in PD-treated patients. We present preliminary results on the isolation of HPMs from PD effluent (PDE) and a detailed protocol to establish the immunometabolic profile of HPMs. These profiles will subsequently be related to cardiac function (left ventricular global longitudinal strain (LV-GLS), an echocardiographic measure of HFpEF) and parameters of systemic inflammation. Method In 15 adult PD-treated patients we will prospectively perform cardiac echography, draw a blood sample and collect PDE for HPM isolation. To obtain control HPMs a peritoneal saline flush will be collected from 5 adult patients with non-metastasized colon cancer during a routine diagnostic laparoscopy. HPMs will be isolated from the PDE and saline by centrifugation, followed by freezing for storage. We compared fresh and thawed cells of a PDE-sample to evaluate the impact of storage on HPM phenotype and functionality, respectively using flow cytometry and measurement of IL-6 production, with and without a lipopolysaccharide (LPS) challenge. In-depth HPM characterization will be performed by measuring glucose and lactate, conducting metabolic flux analysis, assessing glycolysis and mitochondrial characteristics using Seahorse®, and employing cytometry to evaluate reactive oxygen species and metabolic fuel preference. A phenotypical profile will be established using fluorescent probes and antibodies. To assess functionality, HPMs will be exposed in vitro to “M1” and “M2” inducers and we will use human monocyte-derived macrophages from healthy adult controls as a comparison. We will relate the immunometabolic, phenotypical and functional HPM characteristics to LV-GLS, blood cytokine (obtained with Bio-Plex multiplex) and blood immune profiles (obtained with cytometry) in PD-treated patients. Furthermore, we will compare the HPM characteristics of the PD-treated patients with the control group. Results Preliminary results of 6 patients show that we can isolate HPMs from the PDE with a yield of >5M cells. The phenotype and functionality of HPMs was evaluated both directly after isolation and after a freeze-thaw cycle. Flow cytometry showed high percentages of CD14+HLA-DR+CD64+ macrophages in both fresh and biobanked HPMs. IL-6 production was observed in both fresh and biobanked HPMs even without LPS-stimulation (Figure). Conclusion By successfully isolating and storing HPMs from the easily accessible PDE, we optimized the conditions to assess their immunometabolic characteristics. The proposed protocol not only aims to provide valuable insights into HPM phenotype and functionality, but also allows us to relate these to cardiac function and systemic inflammation. With this strategy, we aim to gain insight in the immunometabolic effects of PD on peritoneal immune cells and how these relate to CV-effects.

Xylazine Test Strips for Drug Checking

Why is this an issue?
 
 The opioid crisis is an ongoing public health concern in Canada. In 2022, a total of 7,328 apparent opioid toxicity deaths were reported, which is an average of 20 deaths per day.
 Xylazine, referred to as tranq, is an animal tranquilizer that has appeared as an adulterant in the unregulated drug supply (particularly in opioids) and is contributing to increasing numbers of drug poisoning (overdose) events and deaths.
 There is no approved drug for humans for reversing the effects of xylazine, so detection is critical.
 
 What is the technology?
 
 The Rapid Response Xylazine Test Strip by BTNX (Pickering, Ontario) is a rapid test for the detection of xylazine that can be used for drug checking in an unregulated drug supply.
 
 What is the potential impact?
 
 Xylazine can have harmful effects, such as severe skin lesions, central nervous system depression, cardiovascular effects, and death.
 The detection of xylazine using a test strip could alter consumption behaviours, such as avoiding the use of contaminated drugs, reducing the quantity consumed, injecting more slowly, or choosing to use at a supervised consumption site.
 
 What else do we need to know?
 
 The strips are currently available in Canada for $349.00 for a box of 100 or $3.49 per strip.
 Although these strips are good at checking for xylazine, they are not designed to anticipate and test for the next adulterant to enter the unregulated drug supply which could be equally or even more dangerous. Therefore, these strips would be useful as part of a robust harm reduction strategy.

A nyiroködéma, a zsírödéma és a vénás lábszárfekélyek kezelési lehetőségeinek legújabb vonatkozásai

This review outlines the novel therapies and their effects in lymphedema, lipedema and chronic wounds. So far compression therapy represents the cornerstone of all treatment modalities in these disoders and recent reports demonstrated compression-related systemic cardiovascular effects. Furthermore, we are able to determine responsiveness of venous leg ulcers to therapy and with application of autologous blood their healing can be ameliorated.

The Different Pathways of Epicardial Adipose Tissue across the Heart Failure Phenotypes: From Pathophysiology to Therapeutic Target.

Epicardial adipose tissue (EAT) is an endocrine and paracrine organ constituted by a layer of adipose tissue directly located between the myocardium and visceral pericardium. Under physiological conditions, EAT exerts protective effects of brown-like fat characteristics, metabolizing excess fatty acids, and secreting anti-inflammatory and anti-fibrotic cytokines. In certain pathological conditions, EAT acquires a proatherogenic transcriptional profile resulting in increased synthesis of biologically active adipocytokines with proinflammatory properties, promoting oxidative stress, and finally causing endothelial damage. The role of EAT in heart failure (HF) has been mainly limited to HF with preserved ejection fraction (HFpEF) and related to the HFpEF obese phenotype. In HFpEF, EAT seems to acquire a proinflammatory profile and higher EAT values have been related to worse outcomes. Less data are available about the role of EAT in HF with reduced ejection fraction (HFrEF). Conversely, in HFrEF, EAT seems to play a nutritive role and lower values may correspond to the expression of a catabolic, adverse phenotype. As of now, there is evidence that the beneficial systemic cardiovascular effects of sodium-glucose cotransporter-2 receptors-inhibitors (SGLT2-i) might be partially mediated by inducing favorable modifications on EAT. As such, EAT may represent a promising target organ for the development of new drugs to improve cardiovascular prognosis. Thus, an approach based on detailed phenotyping of cardiac structural alterations and distinctive biomolecular pathways may change the current scenario, leading towards a precision medicine model with specific therapeutic targets considering different individual profiles. The aim of this review is to summarize the current knowledge about the biomolecular pathway of EAT in HF across the whole spectrum of ejection fraction, and to describe the potential of EAT as a therapeutic target in HF.

Neuropathologic Features in Chronic Methamphetamine Use.

Methamphetamine is a psychostimulant that exerts its euphoric and stimulant effects by increasing cytosolic monoamine concentration at the nerve terminal. In addition to its known systemic cardiovascular effects, there is compelling evidence to suggest a direct neurotoxic effect of methamphetamine; however, the existing body of literature includes very few human tissue studies. This exploratory analysis used postmortem human brain specimens to examine histologic and immunohistochemical features associated with chronic methamphetamine use. This retrospective cohort study included 60 decedents who were autopsied at the University of Iowa Hospitals and Clinics between the years 2015 and 2021. Logistic regression models demonstrated no definite pathologic changes in the hippocampi of individuals with a history of chronic methamphetamine use. Decedents with a history of methamphetamine use had a marginally increased odds of basal ganglia arteriosclerosis, which did not reach statistical significance (odds ratio, 3.33; 95% confidence interval, 0.6-19.2; P = 0.17), which may be independent of the systemic hypertensive effects of methamphetamine. Future studies that include targeted examination of brain regions of interest, such as the basal ganglia and specifically the striatum, may prove revealing.

Repeated dose budesonide/formoterol compared to salbutamol in adult asthma: A randomised cross-over trial.

To determine the comparative bronchodilator, systemic beta2-agonist, cardiovascular and adverse effects of salbutamol 200 µg and budesonide/formoterol 200/6 µg when taken repeatedly in stable asthma. This open-label, cross-over, single-centre, controlled trial, randomised adults with asthma to different orders of two treatment regimens: salbutamol 200 µg via MDI at t=0, 30, 60, 90 min, then salbutamol 2.5 mg via nebuliser at t=120, 140, 160 and 420 min; or budesonide/formoterol 200/6 µg one actuation via Turbuhaler at t=0, 30, 60, 90 min, two actuations at t=120, 140, 160 and 420 min. The primary outcome measure was FEV1 after 180 min. Secondary outcomes included repeat measures of FEV1, serum potassium, heart rate, and adverse events RESULTS: Of 39 patients randomised, two withdrew due to adverse events (QTCF prolongation and T wave abnormalities) after the first intervention with salbutamol. The mean (sd) change from baseline FEV1 180 min after randomisation for salbutamol and budesonide/formoterol regimens was 0.71 (0.46) L, N=38, and 0.58 (0.45) L, N=37, respectively; with a mean (sd) paired difference of -0.10 (0.40) L, N=37, and a model-based estimated difference (95% CI) -0.12 (-0.25 to 0.02) L, p=0.088. In the main secondary analysis, salbutamol resulted in significantly greater FEV1 from 30 to 240 min, but lesser FEV1 at 360 and 420 min. Salbutamol resulted in a significantly lower serum potassium, and a higher heart rate and number of adverse events. The comparative bronchodilator responses of repeated administration of salbutamol 200 µg dose-1 and budesonide/formoterol 200/6 µg differed depending on the time of measurement. Salbutamol caused greater systemic beta2-agonist and cardiovascular effects and more adverse events.

Implementation of the evidence‐based risk assessment for the re‐evaluation of Bisphenol A: preparatory work on cross‐sectional studies.

EFSA is implementing evidence-based risk assessments for the re-evaluation of the safety of bisphenol A (BPA) for human health. The aim of this work was to carry out some preparatory work for the working group on BPA re-evaluation, with particular reference to the preparation of individual summary tables of human studies with cross-sectional design, and a narrative and factual summary of the above studies when grouped by health outcome category and by effect/endpoint. The first stage of the work was conducted using DistillerSR, the web-based systematic review software used by EFSA which enabled direct access/download to the published documents and provided an on-line template for data extraction and reporting. A total of 161 published articles were considered and data extracted from these into the online templates. Using these data, with additional reference back to the published articles, a narrative report was produced that sub-divided the studies into seven key toxicological areas: reproduction, neurotoxicity, immune system toxicity, metabolic effects, cardiovascular effects, carcinogenicity and general toxicity.

Implementation of the evidence‐based risk assessment for the re‐evaluation of Bisphenol A: preparatory work on Mode of Action studies in mammalian, human and/or in vitro models.

EFSA is implementing evidence-based risk assessments for the re-evaluation of the safety of bisphenol A (BPA) for human health. The aim of this project was to carry out preparatory tasks for the working group on BPA re-evaluation, with particular reference to the preparation of individual summary tables from studies relating to BPA's toxicological mode of action or mechanism, and the production of a narrative and factual summary of these studies when grouped by health outcome category and by effect/endpoint. The first stage of the work was conducted using DistillerSR, the web-based systematic review software used by EFSA which enabled direct access/download to the published documents and provided electronic data collection templates for data extraction and reporting. A total of 1193 published articles were considered and, using the pre-established rules defined by EFSA, 581 were selected for inclusion. Data from these were subsequently extracted into the electronic data collection templates. Using these data with additional reference back to the published articles, a narrative report was produced that sub-divided the studies into eight key toxicological areas: reproduction, neurotoxicity, immune system toxicity, metabolic effects, cardiovascular effects, carcinogenicity, general toxicity and genotoxicity as well as smaller groups of studies that did not fall naturally into these health categories. This narrative report briefly summarises the data extracted.

Cardiovascular effects of dose escalating of norepinephrine in healthy dogs anesthetized with isoflurane

ObjectiveTo evaluate the systemic cardiovascular effects of dose escalating administration of norepinephrine in healthy dogs anesthetized with isoflurane. Study designExperimental study. AnimalsA total of six adult laboratory Beagle dogs, 10.5 (9.2–12.0) kg [median (range)]. MethodsEach dog was anesthetized with isoflurane at an end-tidal concentration of 1.7%, mechanically ventilated and administered a continuous rate infusion of rocuronium (0.5 mg kg–1 hour–1). Each dog was administered incremental dose rates of norepinephrine (0.05, 0.125, 0.25, 0.5, 1.0 and 2.0 μg kg–1 minute–1), and each dose was infused for 15 minutes. Cardiovascular variables were recorded before administration and at the end of each infusion period. ResultsNorepinephrine infusion increased mean arterial pressure (MAP), cardiac output (CO) and oxygen delivery in a dose-dependent manner. Systemic vascular resistance did not significantly change during the experiment. Stroke volume increased at the lower dose rates and heart rate increased at the higher dose rates. Oxygen consumption and lactate concentrations did not significantly change during infusions. ConclusionsIn dogs anesthetized with isoflurane, norepinephrine increased MAP by increasing the CO. CO increased with a change in stroke volume at lower dose rates of norepinephrine. At higher dosage, heart rate also contributed to an increase in CO. Norepinephrine did not cause excessive vasoconstriction that interfered with the CO during this study. Clinical relevanceNorepinephrine can be useful for treating hypotension in dogs anesthetized with isoflurane.

Lavandulae aetheroleum Oil: A Review on Phytochemical Screening, Medicinal Applications, and Pharmacological Effects

Lavandulae aetheroleum, the oil, was obtained by vapor condensation from the flower of Lavandula angustifolia Mill. or Lavandula intermedia Loisel (Lamiaceae) plant. Other names of Lavandulae aetheroleum oil are Al birri, common or English lavender. The Lavandula angustifolia Mill. or Lavandula intermedia Loisel plant is spreading in the Mediterranean, southern Europe, Bulgaria, Russia, and USA. The Lavandula angustifolia Mill. or Lavandula intermedia Loisel plant, is an odor shrub with 1-2 m in height. The oil is a clear, colorless, or pale yellow. The gas chromatography studies reported the following percentage of the major chemical constituents in the oil: linalyl acetate (25-46%), linalool (20-45%), terpinen-4-ol (1.2-6.0%), lavendulyl acetate (> 1.0%), 1,8-cineole (1,8-cineol, cineol, cineole, eucalyptol) (< 2.5%), 3-octanone (< 2.5%), camphor (< 1.2%), limonene (< 1.0%), and α-terpineol (< 2.0%). Medicinal applications of the oil include the treatment of restlessness, anxiety, cardiovascular disorders, insomnia, and gastrointestinal disorders, burns, diarrhea, headache, sore throats, and wounds. Pharmacological effects include experimental and clinical pharmacology. Experimental pharmacology includes anesthetic, anticonvulsant, sedative, anti-inflammatory, antimicrobial, antispasmodic, antispasmodic, central nervous system depressant effects. Clinical pharmacology includes anxiolytic, analgesic, and cardiovascular effects. The oil dose by inhalation = 0.06-0.2 ml/ 3 times/day while oil dose internally = 1-4 drops approximately 20-80 mg on a sugar cube per day. In conclusion, Lavandulae aetheroleum oil had an anesthetic, anticonvulsant, sedative, anti-inflammatory, antimicrobial, antispasmodic, antispasmodic, central nervous system depressant, anxiolytic, analgesic, and cardiovascular effects.

Abstract 6239: A novel topical delivery system of carvedilol for skin cancer prevention

Abstract Solar ultraviolet (UV) light-induced non-melanoma skin cancer is the most common type of cancer diagnosed in the United States and remains one of the major public health concerns. There is an urgent need to develop effective and safe skin cancer chemopreventive agents. We have previously demonstrated that carvedilol, an FDA approved β-blocker for cardiovascular diseases, could prevent UV-induced skin cancer in vitro and in vivo. However, the β-adrenergic blockade effects of carvedilol might be a barrier for its repurposing as a cancer chemopreventive agent. In this study, we designed a novel topical formulation, namely carvedilol-loaded transfersomes (T-CAR), to maintain cancer preventive properties of carvedilol while avoiding systemic cardiovascular effects. T-CAR formulations were prepared using different phospholipids and surfactants at various ratios by the thin-film hydration method. The formulations were characterized in terms of particle size, zeta potential, and encapsulation efficiency. An optimal formulation was identified that composes carvedilol, soy phosphatidylcholine (SPC), and Tween 80 at a ratio of 1:3:0.5 with the particle size of 95.84 ± 3.8 nm, the zeta potential of +11.34 ± 0.7 mV, and the encapsulation efficiency of 93.7 ± 5.1%. The in vitro drug release and ex vivo skin permeation studies were performed using Pur-A-Lyzer mini dialysis kit and Franz diffusion cells, respectively. The optimal formulation showed a relative slow in vitro release profile and it could permeate through the porcine ear skin to the same degree as free carvedilol dissolved in acetone. 200 uL of 10 uM carvedilol dissolved in acetone, T-CAR containing the same amount of carvedilol as in acetone group, or the plain transfersome were topically applied to SKH-1 hairless mice 30 minutes before and immediately after single-dose UV irradiation. Compared to carvedilol solution, T-CAR demonstrated the same inhibitory effects against UV-induced epidermis thickening but exhibited increased inhibitory effects against UV-induced cyclobutane pyrimidine dimer (CPD) formation and mRNA expression of pro-inflammatory cytokines IL-1β and IL-6. In addition, carvedilol was not detectable by LC-MS in plasma after topical administration. These findings suggest that T-CAR could be a promising topical carvedilol formulation to prevent UV-associated skin cancer, with enhanced photoprotective effects but neglectable systemic cardiovascular effects. Citation Format: Mengbing Chen, Steven Yeung, Md Abdullah Shamim, Kaitlyn Coronel, Ayaz Shahid, Bradley Andresen, Jeffrey Wang, Ying Huang. A novel topical delivery system of carvedilol for skin cancer prevention [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6239.

AN EXPERIMENTAL TRIAL OF BIOPROPHYLACTIC FORMULA DESIGNED TO MINIMIZE COMBINED TOXICITY OF BOTH LEAD AND CADMIUM

Introduction. The increase in the body resistance to the combined effects of lead and cadmium (including systemic toxicity, cardiovascular effects, and genotoxicity) by using a specific bioprotective formula (based on theoretical knowledge and experimental research) remains a pressing challenge. However, a data search has not yielded any results on either an experimental trial or a theoretical justification of the means of biological protection against a variety of adverse effects caused by Pb and Cd combination. Material and methods. The experiment was conducted on the outbred male rats. The animals received repeated intraperitoneal injections of water solutions of lead acetate and cadmium chloride, 3 times per week for 6 weeks. After the exposition was completed, more than 50 indices of toxic exposure (including biochemical and histo-morphological ones) were estimated in all groups of the tested animals. To assess the genotoxic effect of “in vivo” there was used amplified fragment length polymorphism (AFLP) analysis. Statistical analysis was done using Student’s t-test. Results. We found the administration of the bioprotective formula to improve the indices of general toxicity. Genotoxicity studied using AFLP analysis of blood cells DNA was shown to be mitigated. Histo-morphological indices of Pb+Cd hepato- and nephrotoxicity improved under a bioprotective complex (BPC) administration. Blood Pb and Cd decreased during BPC administration. There was a statistically reliable decrease in the mean diameter of cardiomyocytes associated with Pb+Cd administration. These changes became less apparent with the BPC administration. Conclusion. We developed and tested a strategy to mitigate the toxic effects of Pb and Cd at organ and organ system levels, including general toxicity, target organ toxicity (with cardiotoxicity) and genоtoxicity.

Abstract 2176: Topical delivery of carvedilol-loaded transfersomes for photoprotection and skin cancer prevention

Abstract Ultraviolet (UV)-induced skin cancer is the most common cancer diagnosed in the United States and remains one of major public health concerns. Thus, there is an urgent need for the development of more effective strategies to prevent and treat skin cancer. We have previously demonstrated that carvedilol, an FDA approved β-blocker for cardiovascular diseases, could prevent UV-induced skin cancer both in vitro and in vivo. However, the β-adrenergic blockade effects of carvedilol might be a barrier for its repurposing as a cancer chemopreventive agent due to its cardiovascular side effects. In this work, we aimed to design a novel topical formulation, namely carvedilol-loaded transfersomes, which could maintain anti-cancer activities but avoid systemic cardiovascular effects. Carvedilol-loaded transfersomes were prepared using different phospholipids and surfactants at various ratios by a thin-film hydration method. Following optimization of preparation, the transfersomes were characterized in terms of particle size, zeta potential, and encapsulation efficiency. Skin permeation studies were performed using Franz vertical diffusion cells and skin dissected from SKH-1 hairless mice to examine the permeability of carvedilol. An optimal formulation was identified to compose carvedilol, Soy PC, and Tween-80 at a ratio of 1:3:0.5. The particle size, zeta potential and encapsulation efficiency for this formulation were determined to be 162.9±9.6 nm, 17.1±0.3 mV and 47.9±3.5%, respectively. Skin permeation studies showed that the specific carvedilol-loaded transfersomes could not penetrate through the skin layers in comparison with free carvedilol dissolved in acetone. Taken together, these results suggest that the transfersomal formulations of carvedilol may have desirable physical and biological characteristics for skin retention and local action. Ongoing studies are focused on further improvement of encapsulation efficiency and determination of its effectiveness against skin cancer. Citation Format: Mengbing Chen, Mengbing Chen. Topical delivery of carvedilol-loaded transfersomes for photoprotection and skin cancer prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2176.

Medical Correlates of Chronic Multisymptom Illness in Gulf War Veterans

BackgroundChronic multisymptom illness (CMI) is more prevalent among deployed than nondeployed veterans from the first Gulf War. Objective physiologic markers of CMI are lacking. The purpose of this study is to determine whether measurable abnormalities in the autonomic nervous system or hypothalamic-pituitary adrenal axis would distinguish CMI cases (CMI+) from controls (CMI-) among deployed veterans of the 1990-1991 Gulf War. MethodsThis is a cross-sectional case-control cohort study that examined deployed veterans who participated in the Phase III study: National Health Survey of Gulf War Veterans and Their Families. Autonomic nervous system and hypothalamic-pituitary adrenal axis function-related measures included: 24-hour heart-rate variability, urinary catecholamines and cortisol, hypertension, insulin sensitivity, dyslipidemia, body fat, bone mineral density, and ultrasensitive C-reactive protein. ResultsVeterans of the first Gulf War with CMI (n = 73) and without the condition (n = 111) were studied. Sociodemographic characteristics were similar. Veterans with CMI reported poorer mental and physical functioning, greater use of prescription medications, and more nonroutine clinic visits. These veterans were also more likely to have fibromyalgia syndrome, irritable bowel syndrome, metabolic syndrome, and among males, a larger waist-to-hip ratio. Lower values for a nonlinear heart-rate-variability parameter—the short-term fractal scaling exponent (DFA1), reflecting an increased randomness of beat-to-beat changes in heart rate—were observed in veterans with CMI than those veterans without it (1.28±0.16vs 1.35±0.15; p=0.005). Hypothalamic-pituitary-adrenal axis function measures were similar between the two groups. ConclusionIn this cohort of deployed veterans from the first Gulf War, we identified abnormal heart-rate variability in veterans with CMI compared to veterans without the condition, which suggests abnormal functioning of the autonomic nervous system and possible long-term cardiovascular effects.

Cardiovascular effects of methotrexate in immune-mediated inflammatory diseases.

The cardiovascular effects of disease-modifying antirheumatic drugs and particularly of methotrexate (MTX) are complex and frequently incorrectly understood, which might lead to the unjustified discontinuation of this treatment. MTX, 'the gold standard' and first line treatment in rheumatoid arthritis, psoriatic arthritis, and other immune-mediated inflammatory diseases, has been proven to decrease inflammation, improve cardiovascular risk factors, and reduce mortality. This is supported by both the mechanism of action, as well as a body of clinical data evidence. MTX's cardiovascular effects, although incompletely understood, are explained by its antiproliferative, immunosuppressive, anti-inflammatory, and antiatherogenic effects. Several clinical trials have shown that MTX is associated with improved endothelial function, slower atherosclerosis progression, decreased risk of major cardiovascular adverse events, and benefits on survival. Given its systemic cardiovascular effects, MTX could be regarded as an important therapeutic agent not only to control disease activity in rheumatic diseases, but also to reduce cardiovascular risk and mortality.

Myocardial contrast echocardiography in mice: technical and physiological aspects.

Myocardial contrast echocardiography (MCE) offers the opportunity to study myocardial perfusion defects in mice in detail. The value of MCE compared with single-photon emission computed tomography, positron emission tomography, and computed tomography consists of high spatial resolution, the possibility of quantification of blood volume, and relatively low costs. Nevertheless, a number of technical and physiological aspects should be considered to ensure reproducibility among research groups. The aim of this overview is to describe technical aspects of MCE and the physiological parameters that influence myocardial perfusion data obtained with this technique. First, technical aspects of MCE discussed in this technical review are logarithmic compression of ultrasound data by ultrasound systems, saturation of the contrast signal, and acquisition of images during different phases of the cardiac cycle. Second, physiological aspects of myocardial perfusion that are affected by the experimental design are discussed, including the anesthesia regimen, systemic cardiovascular effects of vasoactive agents used, and fluctuations in body temperature that alter myocardial perfusion. When these technical and physiological aspects of MCE are taken into account and adequately standardized, MCE is an easily accessible technique for mice that can be used to study the control of myocardial perfusion by a wide range of factors.

Cannabinoids in the Cardiovascular System.

Cannabinoids are known to modulate cardiovascular functions including heart rate, vascular tone, and blood pressure in humans and animal models. Essential components of the endocannabinoid system, namely, the production, degradation, and signaling pathways of endocannabinoids have been described not only in the central and peripheral nervous system but also in myocardium, vasculature, platelets, and immune cells. The mechanisms of cardiovascular responses to endocannabinoids are often complex and may involve cannabinoid CB1 and CB2 receptors or non-CB1/2 receptor targets. Preclinical and some clinical studies have suggested that targeting the endocannabinoid system can improve cardiovascular functions in a number of pathophysiological conditions, including hypertension, metabolic syndrome, sepsis, and atherosclerosis. In this chapter, we summarize the local and systemic cardiovascular effects of cannabinoids and highlight our current knowledge regarding the therapeutic potential of endocannabinoid signaling and modulation.

Thyroid dysfunction and kidney disease: An update.

Thyroid hormones influence renal development, kidney hemodynamics, glomerular filtration rate and sodium and water homeostasis. Hypothyroidism and hyperthyroidism affect renal function by direct renal effects as well as systemic hemodynamic, metabolic and cardiovascular effects. Hypothyroidism has been associated with increased serum creatinine and decreased glomerular filtration rate. The reverse effects have been reported in thyrotoxicosis. Most of renal manifestations of thyroid dysfunction are reversible with treatment. Kidney disease may also cause thyroid dysfunction by several mechanisms. Nephrotic syndrome has been associated to changes in serum thyroid hormone concentrations. Different forms of glomerulonephritis and tubulointerstitial disease may be linked to thyroid derangements. A high prevalence of thyroid hormone alteration has been reported in acute kidney injury. Thyroid dysfunction is highly prevalent in chronic kidney disease patients. Subclinical hypothyroidism and low triiodothyronine syndrome are common features in patients with chronic kidney disease. Patients treated by both hemodialysis and peritoneal dialysis, and renal transplantation recipients, exhibit thyroid hormone alterations and thyroid disease with higher frequency than that found in the general population. Drugs used in the therapy of thyroid disease may lead to renal complications and, similarly, drugs used in kidney disorders may be associated to thyroid alterations. Lastly, low thyroid hormones, especially low triiodothyronine levels, in patients with chronic kidney disease have been related to a higher risk of cardiovascular disease and all-cause mortality. Interpretation of the interactions between thyroid and renal function is a challenge for clinicians involved in the treatment of patients with thyroid and kidney disease.

Short-term cardiovascular and autonomic effects of inhaled salbutamol

Asthma independently increases the risk of developing cardiovascular disease. As inhaled β-agonists have systemic cardiovascular effects, and elevations in arterial stiffness and sympathetic nerve activity are associated with increased cardiovascular morbidity/mortality, this study examines the effect of salbutamol use on pulse wave velocity (PWV) and muscle sympathetic nervous activity (MSNA). Healthy men and women (26.2±1.5years) were recruited for: Day 1: 4 inhalations of placebo followed by 4 inhalations of salbutamol (4×100μg); Day 2: placebo only; Day 3: carotid-femoral PWV measurements before/after placebo/salbutamol. Heart rate (HR), mean arterial pressure (MAP), and carotid-radial PWV were obtained on Day 1 and 2. MSNA was obtained on Day 1. Salbutamol increased HR and total MSNA (Baseline1: 2.8±2.8au; Placebo: 2.4±2.1au; Baseline2: 2.7±3.0au; Salbutamol: 3.3±2.9au; p=0.05), with no changes in MAP or PWV. There were no effects of placebo on HR, MSNA, or PWV. Acute salbutamol use increases sympathetic activity suggesting that salbutamol could contribute to cardiovascular morbidity/mortality in individuals using inhaled β-agonists.

Verapamil Inhibits the Pelvic Pressure Increase Corresponding to Flow Perfusion in the Porcine Percutaneous Renal Puncture Model

Purpose: To estimate the effects of verapamil on pelvic pressure and investigate the possible systemic side effects in the porcine model during the procedure of increasing perfusion rates. Materials and Methods: In the experimental group, the pelvic pressure was recorded with increasing perfusion rates of the renal pelvis (0, 2, 4, 6, 8, 10, 14 and 20 ml/min) in response to intraluminal administration of increasing concentrations of verapamil (0, 0.1, 1, 10 and 100 µg/ml) in isotonic saline. In the isotonic saline group, the pressure flow study was also done by increasing perfusion rates of the renal pelvis per animal using isotonic saline without verapamil. Results: Perfusion with 1, 10 and 100 µg/ml verapamil caused a decrease in pelvic pressure as a response to increasing flow rates, whereas perfusion with 0.1 µg/ml verapamil did not obviously inhibit the increase of pelvic pressure at all perfusion rates compared with other concentrations. Importantly, the mean systolic blood pressure and mean heart rate were stable despite the increase of flow rates and verapamil concentrations. In the isotonic saline group, perfusion with isotonic saline resulted in an increase in the pelvic pressure with an increase in flow rates each time. Conclusions: Endoluminal administration of verapamil reduces pelvic pressure significantly without any untoward systemic cardiovascular side effects.