Significant Cardiovascular Effects Research Articles

Acromegaly: The Relationship between Hemodynamic Profiles Assessed via Impedance Cardiography and Left Ventricular Systolic Function Assessed via Echocardiography.

Background/Objectives: Acromegaly-induced prolonged exposure to growth hormone and insulin-like growth factor 1 may have significant cardiovascular effects. The purpose of this study was to assess the relationship between hemodynamic parameters measured via impedance cardiography (ICG) and parameters of systolic left ventricular function measured via echocardiography in patients with acromegaly. Methods: The observational cohort study included 33 patients with newly diagnosed acromegaly, with a mean age of 47 years and without significant comorbidities. Correlation analysis (Spearman's rank correlation coefficient R) was performed on parameters obtained by ICG and left ventricular systolic function parameters obtained by echocardiography. ICG assessment included indices of (1) cardiac function as a pump: stroke volume index (SI), cardiac index (CI), Heather index (HI), velocity index (VI), and acceleration index (ACI); (2) afterload: systemic vascular resistance index (SVRI) and total arterial compliance index (TACI); and (3) thoracic fluid content (TFC). Echocardiographic examinations evaluated left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). Results: A lower LVEF was associated with a lower SI (R = 0.38; p = 0.03) and a higher SVRI (R = -0.35; p = 0.046), whereas lower GLS was associated with lower SI (R = 0.43; p = 0.02), CI (R = 0.62; p < 0.001), VI (R = 0.59; p < 0.001), ACI (R = 0.38; p = 0.048), HI (R = 0.59; p < 0.001), and TACI (R = 0.50; p = 0.006) and a higher SVRI (R = -0.59; p < 0.001). No significant correlation was observed between either LVEF or GLS and TFC. Conclusions: In patients with acromegaly, poorer echocardiographic parameters of left ventricular systolic function are associated with impaired function of the heart as a pump and higher afterload as assessed via ICG.

Comparison of Systemic Exposure Between Epinephrine Delivered via Metered-Dose Inhalation and Intramuscular Injection.

Background: Primatene® MIST, an epinephrine metered-dose inhaler (MDI), has long been questioned by some medical professionals for asthma treatment despite having been approved by the Food and Drug Administration. One of the primary reasons for their concerns stemmed from potential cardiovascular complications following epinephrine administration. However, the majority of documented cardiovascular complications seemed to occur following the injection route of the epinephrine. The aim of this study was to evaluate the systemic exposure of epinephrine delivered through different administration routes and to understand its relationship with cardiovascular effects. Since albuterol inhalers are commonly recommended for asthma, albuterol was also studied as a comparator drug. Method: A randomized, evaluator-blinded, three-arm crossover study was conducted in 28 healthy adult subjects to compare the profiles of systemic exposure for epinephrine delivered by MDI versus epinephrine intramuscular (IM) injection and albuterol MDI. Serially sampled plasma epinephrine and albuterol levels were measured and compared between treatment groups. Safety was assessed by adverse events, serial vital signs, electrocardiograms (ECGs), and clinical laboratory tests obtained at each crossover dosing visit. Results: Systemic exogenous drug exposure for inhaled epinephrine MDI (39 pg/mL × hour) was ∼9 times lower than that of epinephrine IM (435 pg/mL × hour) and 122 times lower than that of albuterol MDI (3453 pg/mL × hour) after dose normalization. The Cmax in epinephrine MDI (345 pg/mL) was approximately half of that of epinephrine IM (816 pg/mL) and that of albuterol MDI (681 pg/mL). Plasma drug concentrations for epinephrine MDI dropped rapidly to baseline (∼0.6 hour), while epinephrine IM took ∼8 hours, and albuterol MDI required more than 24 hours. Epinephrine MDI and albuterol MDI resulted in minimal, clinically insignificant changes in vital signs and ECGs, whereas epinephrine IM led to mild transient increases in systolic blood pressure, heart rate, and corrected QT interval. Conclusion: Epinephrine MDI (Primatene MIST) had ∼9 times lower systemic drug exposure (SDE) than that of epinephrine IM and ∼122 times lower than that of albuterol MDI. The lower SDE of inhaled epinephrine also correlated with reassuring safety findings, with no significant cardiovascular adverse effects found, compared with transient effects seen after IM epinephrine. Clinical trial registration number: NCT04207840.

Curcumin alone not combined with piperine exerts cardioprotective effects in pressure-overload rats by increasing glucagon-like peptide-1 receptor signaling and additional properties

Background and aimCurcumin has shown significant cardiovascular protective effects. However, the low bioavailability limits its practical application. As a natural bioenhancer, piperine is expected to increase the bioavailability of curcumin, and then, enhance its beneficial effects. Meanwhile, glucagon-like peptide-1 receptor (GLP-1R) signaling has been confirmed to be involved in the regulation of cardiovascular events. Herein, this study aimed to investigate whether piperine could enhance the beneficial effects of curcumin in pressure-overload rats and whether GLP-1/GLP-1R signaling is involved in their action mechanism. Methods and resultsMale Sprague-Dawley (SD) adult rats were subjected to abdominal aortic constriction (AAC) surgery to 16 weeks, which elevated blood pressure and induced cardiac hypertrophy. Curcumin (100 mg/kg/day) or/and piperine (20 mg/kg/day) were orally given for 4 weeks from the 17th week after AAC surgery. Curcumin alone treatment significantly lowered blood pressure, ameliorated cardiovascular remodeling, improved left ventricular performance and endothelium-dependent vascular relaxation. Accompanied by these results, GLP-1R expression in the myocardium was up-regulated. Piperine alone also exhibited a certain positive inotropic cardiac activity, but the effect was less significant. The combination of curcumin and piperine didn't show enhanced cardiovascular protective effects relative to curcumin, along with decreased fasting serum GLP-1 level and GLP-1R expression in the myocardium. ConclusionCurcumin exerts cardiovascular protective effects in pressure-overload rats by upregulating GLP-1R, and inhibiting of GLP-1/GLP-1R signaling pathway may be related to the limited beneficial effects of combination of curcumin and piperine. This study provides a new thinking that oral administration of some spices may affect cardiovascular function by modulating the GLP-1/GLP-1R system in a mode of gut-heart axis regulation.

Systemic hypertension with VEGFR inhibitor (axitinib) therapy in cancer patients: A meta-analysis and systematic review of randomized controlled trials

Vascular endothelial growth factor receptor inhibitors (VEGFRi), namely axitinib, are commonly used chemotherapeutic agents in patients with cancer; however, this medication has a significant cardiovascular side effect profile, such as high-grade hypertension. We performed this updated meta-analysis of RCTs to compile cardiovascular adverse events, such as all-grade and high-grade (>3) hypertension, the risk for thrombosis (DVT and PE), and peripheral edema. A systematic search was performed on PubMed, Cochrane, and Embase from inception until October 2023 for studies using axitinib to treat various cancers. Trials with patients randomly allocated for VEGFRi drug therapy with axitinib and reported all-grade hypertension as an outcome were included. Statistical analysis was performed using Cochrane Review Manager to calculate pooled proportions of odds ratios (OR) with a 95 % confidence interval (CI) using the random-effects model, Mantel−Haenszel method. A total of 8 RCTs and 2502 patients were included in the review. Compared with the placebo group, the VEGFRi (Axitinib) therapy group was associated with a higher risk of all-grade and high-grade hypertension, hand–foot syndrome, and fatigue. Furthermore, there was no increased risk of thromboembolism (DVT/PE) or hypothyroidism. However, a lower risk of peripheral edema was noted between the two groups. Screening for patients with preexisting hypertension, identifying risk factors for cardiovascular diseases before the initiation of VEGFRi therapy, and careful monitoring of high-risk patients during VEGFRi therapy, as well as prompt treatment with antihypertensive drugs, will help mitigate the adverse effects. Further evaluation using prospective designs is required to study the clinical significance and develop mitigation strategies.

Comparison of analgesic efficacy of tramadol, morphine and methadone in cats undergoing ovariohysterectomy.

The aim of this study was to compare the analgesic efficacy and the effect on physiological variables and behavior of the use of tramadol, methadone and morphine as preoperative analgesia in healthy cats undergoing elective ovariohysterectomy. Cats undergoing ovariohysterectomy were randomly assigned to receive one of the following premedication treatments intramuscularly: methadone (0.2 mg/kg; n = 10); morphine (0.2 mg/kg; n = 10); or tramadol (3 mg/kg; n = 10). Induction of anesthesia was done with propofol, and maintenance of anesthesia was done with isoflurane. Intraoperative heart rate, arterial blood pressure, respiratory rate, end-tidal isoflurane concentration and frequency of rescue analgesia (fentanyl 2.5 µg/kg) were compared between groups. Postoperative analgesia was assessed using the UNESP-Botucatu Multidimensional Composite Pain Scale, and perioperative serum glucose, cortisol concentrations and postoperative rescue analgesia were evaluated. Intraoperative rescue analgesia was required in 76.5% of cats at some time during surgery, and 27% of cats required postoperative rescue analgesia up to 6 h after extubation. There were no significant differences between groups with respect to intraoperative and postoperative rescue analgesia, pain scale scores and end-tidal isoflurane concentrations. In the immediate postoperative period, after extubation, most of the patients presented with hypothermia; however, 1-6 h postoperatively, hyperthermia was observed in most of the patients, and was most common in the tramadol group. Under the conditions of this study, methadone, morphine and tramadol produced satisfactory postoperative analgesia in most of the cats undergoing ovariohysterectomy, and the effects lasted up to 6 h postoperatively. Intraoperative analgesia was not sufficient in most cases. Significant cardiovascular or respiratory effects contraindicating the use of these drugs were not found. Postanesthetic hyperthermia occurred with all opioids studied and was more frequent in the tramadol group.

Sodium-Glucose Cotransporter 2 Inhibitor Among Patients With Cancer Therapy-Induced Left Ventricular Dysfunction.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently been shown to improve clinical outcomes in patients with left ventricular (LV) dysfunction and heart failure (HF). Originally designed to induce glucosuria in diabetic patients by targeting sodium-glucose cotransporter (SGLT) proteins in the kidney, it has become evident that these drugs possess significant cardiovascular effects beyond their renal effects. However, the optimal application of SGLT-2i in cancer patients receiving cardiotoxic agents to mitigate the risk of adverse cardiac events remains uncertain.

Enhancing Safety in Hyperbaric Environments through Analysis of Autonomic Nervous System Responses: A Comparison of Dry and Humid Conditions.

Diving can have significant cardiovascular effects on the human body and increase the risk of developing cardiac health issues. This study aimed to investigate the autonomic nervous system (ANS) responses of healthy individuals during simulated dives in hyperbaric chambers and explore the effects of the humid environment on these responses. Electrocardiographic- and heart-rate-variability (HRV)-derived indices were analyzed, and their statistical ranges were compared at different depths during simulated immersions under dry and humid conditions. The results showed that humidity significantly affected the ANS responses of the subjects, leading to reduced parasympathetic activity and increased sympathetic dominance. The power of the high-frequency band of the HRV after removing the influence of respiration, PHF⟂¯, and the number of pairs of successive normal-to-normal intervals that differ by more than 50 ms divided by the total number of normal-to-normal intervals, pNN50¯, indices were found to be the most informative in distinguishing the ANS responses of subjects between the two datasets. Additionally, the statistical ranges of the HRV indices were calculated, and the classification of subjects as "normal" or "abnormal" was determined based on these ranges. The results showed that the ranges were effective at identifying abnormal ANS responses, indicating the potential use of these ranges as a reference for monitoring the activity of divers and avoiding future immersions if many indices are out of the normal ranges. The bagging method was also used to include some variability in the datasets' ranges, and the classification results showed that the ranges computed without proper bagging represent reality and its associated variability. Overall, this study provides valuable insights into the ANS responses of healthy individuals during simulated dives in hyperbaric chambers and the effects of humidity on these responses.

Phenylephrine and Ephedrine for Prevention of Hypotension in Women during Lower Segment Caesarean Section under Spinal Anaesthesia: A Randomised Clinical Study

Introduction: Hypotension is the most common serious adverse event associated with Spinal Anaesthesia (SA) and is associated with nausea and vomiting leading to pulmonary aspiration, respiratory depression and cardiac arrest. Phenylephrine (PE) and Ephedrine (EP) are vasopressors commonly used for prevention of hypotension associated with SA. Aim: To compare the efficacy and safety of PE and EP in prevention of hypotension induced by SA in women during Lower Segment Caesarean Section (LSCS) surgery. Materials and Methods: The present randomised clinical study was conducted on 60 women, between 18-36 years of age and a Heart Rate (HR) of 60-100 per minute randomised to receive either 100 mcg Intravenous (i.v.) bolus of PE, or 12 mg i.v. of EP during intrathecal block. Women having intraoperative hypotension were injected additional doses of vasopressor. Cardiovascular parameters were recorded at baseline (before block) and then at 1, 5, 10, 15, 30, 40 and 60 minutes. Further, safety was also assessed based on hypotension events and adverse events reported during immediate postoperative period. Data analysis was done using IBM SPSS 17 and a p-value &lt;0.05 was considered statistically significant. Results: The mean age of the study participants in PE and EP group was 26.67±5.40 and 26.23±4.59 years, respectively. Significant differences were observed between PE and EP groups for change in Systolic Blood Pressure (SBP) after 1, 10, 30, 40 and 60 minutes. Overall, there was a slight fall in SBP with PE, whereas, with EP there was a slight rise in SBP. Also, the Diastolic Blood Pressure (DBP) was maintained with EP throughout the 60 minute period, whereas with PE there was an initial rise in DBP followed by a slight fall in DBP. The Mean Arterial Pressure (MAP) was well maintained with PE throughout, whereas with EP there was a fall in MAP after 15 minutes. However, these changes were not clinically significant. The Pulse Rate (PR) was lower with PE compared to EP group at time points of 1, 5, 15 and 20 minutes. The mean respiratory rates and blood oxygen saturation were similar with PE and EP administration (p&gt;0.05). A total of 13 (43.3%) patients in the PE group and 14 (46%) in the EP group had adverse events excluding hypotensive patients. Conclusion: According to the findings of the present study, the i.v. bolus of 100 mcg PE and 12 mg EP administered immediately after SA are equally effective in prevention of maternal hypotension and do not cause any significant cardiovascular and respiratory effects.

Acute effects of insulin and insulin-induced hypoglycaemia on carotid body chemoreceptor activity and cardiorespiratory responses in dogs.

What is the central question of this study? What are the effects of insulin and insulin-induced hypoglycaemia on carotid body chemoreceptor activity in vivo and how do carotid body chemoreceptor stimulation-mediated cardiorespiratory responses in beagle dogs compare during euglycaemia and insulin-induced hypoglycaemia? What is the main finding and its importance? Intracarotid insulin administration leads to sustained increase in carotid body chemoreceptor activity and respiratory response with significant cardiovascular effects. Insulin-induced hypoglycaemia exacerbated NaCN-mediated carotid body chemoreceptor activity and respiratory response with enhanced cardiovascular reflex response. These findings suggest that insulin-induced hypoglycaemia augments the carotid body chemoreceptors to initiate the adaptive counter-regulatory responses to restore the normoglycaemic condition. The carotid body chemoreceptors (CBC) play an important role in the adaptive counter-regulatory response to hypoglycaemia by evoking the CBC-mediated sympathetic neuronal system to restore normoglycaemia. Ex vivo studies have shown varied responses of insulin-induced hypoglycaemia on CBC function, and several in vivo studies have indirectly established the role of CBCs in restoring normoglycaemia in both animals and humans. However, a direct effect of insulin and/or insulin-induced hypoglycaemia on CBC activity is not established in animal models. Therefore, the aim of this study was to evaluate in vivo effects of insulin and insulin-induced hypoglycaemia on CBC activity and cardiorespiration in a preclinical large animal model. The carotid sinus nerve (CSN) activity and cardiorespiratory responses to sodium cyanide (NaCN; 25µg/kg) were compared before (euglycaemic) and after (hypoglycaemic) intracarotid administration of insulin (12.5-100µU/dogs) in beagle dogs. Insulin administration increased CSN activity and minute ventilation ( E ) with significant (P<0.0001) effects on heart rate and blood pressure. Insulin-mediated effects on CSN and cardiorespiration were sustained and the change in E was driven by tidal volume only. Insulin significantly (P<0.0001) lowered blood glucose level. NaCN-mediated CSN activity and E were significantly (P<0.0001) augmented during insulin-induced hypoglycaemia. The augmented E was primarily driven by respiratory frequency and partially by tidal volume. The cardiovascular reflex response mediated through CBC stimulation was significantly (P<0.0001) exacerbated during insulin-induced hypoglycaemia. Collectively, these results demonstrate direct effects of insulin and insulin-induced hypoglycaemia on CBC chemosensitivity to potentiate CBC-mediated neuroregulatory pathways to initiate adaptive neuroendocrine and cardiorespiratory counter-regulatory responses to restore normoglycaemia.

High rates of the SDHB p.Arg46Gln pathogenic variant predisposes New Zealand Māori to phaeochromocytoma/paraganglioma.

Phaeochromocytomas (PCC) and paragangliomas (PGL; together PPGL) are rare tumours of the adrenal medulla or extra-adrenal paraganglia. They may secrete catecholamines with significant cardiovascular effects. Management of PPGL is predominantly surgical, despite the anaesthetic risks related to potential haemodynamic instability. Meticulous pre-treatment and intra-operative management are required to improve cardiovascular outcomes. There are limited local data regarding the incidence of PPGL and the clinical characteristics of individuals diagnosed with these tumours in New Zealand. We undertook a retrospective study investigating the local practice and patient characteristics with an additional focus on intra-operative haemodynamic stability and post-operative outcomes. Electronic patient records were searched for individuals with a diagnosis of PPGL. Clinical records and electronic databases were interrogated for pre-operative, intra-operative and post-operative data points. Particular attention was paid to rates and types of germline mutations, intra-operative haemodynamic stability and post-operative renal and cardiovascular outcomes. We identified 49 individuals with PPGL, of whom 34 were from the local area. This gave a local incidence of PPGL of around five cases per million people per year. Māori were significantly over-represented in our cohort, with this being in part due to high rates of the SDHB R46Q mutation. Over 95% of our cohort met pre-specified pre-operative blood pressure parameters. Intra-operative monitoring revealed a tendency to hypotension, but this did not translate into adverse post-operative outcomes, which were infrequent. Māori were over-represented due to high rates of germline SDHB R46Q mutations. There were few post-operative adverse outcomes in this contemporary cohort.

Emulating Near-Roadway Exposure to Traffic-Related Air Pollution via Real-Time Emissions from a Major Freeway Tunnel System.

Epidemiological and toxicological studies continue to demonstrate correlative and causal relationships between exposure to traffic-related air pollution and various metrics of adverse pulmonary, cardiovascular, and neurological health effects. The key challenge for in vivo studies is replicating real-world, near-roadway exposure dynamics in laboratory animal models that mimic true human exposures. The advantage of animal models is the accelerated time scales to show statistically significant physiological and/or behavioral response. This work describes a novel exposure facility adjacent to a major freeway tunnel system that provides a platform for real-time chronic exposure studies. The primary conclusion is that particulate matter (PM) concentrations at this facility are routinely well below the National Ambient Air Quality Standards (NAAQS), but studies completed to date still demonstrate significant neurological and cardiovascular effects. Internal combustion engines produce large numbers of ultrafine particles that contribute negligible mass to the atmosphere relative to NAAQS regulated PM2.5 but have high surface area and mobility in the body. It is posited here that current federal and state air quality standards are thus insufficient to fully protect human health, most notably the developing and aging brain, due to regulatory gaps for ultrafine particles.

Abstract 311: Ponatinib loaded leukocyte-based nanoparticles for osteosarcoma treatment in sarcosphere tumor model

Abstract Osteosarcoma (OS) is the most common pediatric bone tumor with a worldwide incidence of 3.4 cases per million people annually. Unfortunately, current treatments are still not sufficient to eradicate OS, due to its ability to resist the upfront standard chemotherapy. Therefore, it is essential to identify and effectively deliver novel therapeutic regimens. Multi-tyrosine kinase inhibitors have been explored as new therapeutics for different sarcomas. Among many, Ponatinib (Pon) demonstrated very potent anti-tumor activity, however, it received a black box warning from the FDA due to significant cardiovascular side effects. Recently, our lab developed novel biomimetic nanoparticles (NPs) called Leukosomes (Leuko) capable of encapsulating and effectively releasing Pon. These NPs are synthesized from activated leukocytes, maintaining leukocytes' tropism towards inflamed endothelium. Leveraging on this technology, we aim to validate the therapeutic potential of Leuko in 3D OS tumor model (sarcospheres) and their ability to target primary murine OS model while concomitantly reducing the detrimental side effects. Given its biological relevance and ability to better recapitulate the tumor structure, a 3D tumor model was chosen to reproduce key properties, such as diffusion limitations and the cellular network of solid tumors that have significant impacts on cancer drug efficacy.In the sarcospheres model, we observed efficient penetration and internalization of NPs in both, murine (RF379, 577) and human PDX derived (PDX94, pPDX202) OS cell lines, where Leuko exhibited a 20% increase in targeting vs the control Liposome (Lipo). This difference was not detected in the control 2D model. Moreover, our data demonstrated a 2-fold increase in the Leuko cytotoxic effect in 3D compared to 2D systems. Murine OS cell viability was 20% lower in sarcospheres after treatment with the IC50 for Pon. In addition, NPs induced complete inhibition of murine sarcosphere formation in the extreme limiting dilution assay (ELDA). These findings were also confirmed using the PDX derived OS cell lines. Subsequently, an in vivo intratibial syngeneic orthotopic mouse model was utilized to determine the targeting and biodistribution of the NPs. Leuko showed an increased targeting and penetration in the tumor 1 and 3h post NPs injection as anticipated by the 3D in vitro studies. By exploiting the inflammatory conditions within the tumor, which increases the Leuko accumulation, these preliminary results advocate the translational potential of this innovative formulation as a new targeted drug delivery approach for OS. This promising platform could improve the clinical therapeutic approaches and lead to improved outcomes and reduced side effects for OS patients. Citation Format: Federica Giordano, Stefania Lenna, Riccardo Rampado, April Ewing, Gherardo Baudo, Matteo Massaro, Assaf Zinger, Enrica De Rosa, Jason T Yustein, Francesca Taraballi. Ponatinib loaded leukocyte-based nanoparticles for osteosarcoma treatment in sarcosphere tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 311.

Effect of maternal oxytocin on umbilical venous and arterial blood flows during physiological-based cord clamping in preterm lambs.

BackgroundDelayed umbilical cord clamping (UCC) after birth is thought to cause placental to infant blood transfusion, but the mechanisms are unknown. It has been suggested that uterine contractions force blood out of the placenta and into the infant during delayed cord clamping. We have investigated the effect of uterine contractions, induced by maternal oxytocin administration, on umbilical artery (UA) and venous (UV) blood flows before and after ventilation onset to determine whether uterine contractions cause placental transfusion in preterm lambs.Methods and findingsAt ~128 days of gestation, UA and UV blood flows, pulmonary arterial blood flow (PBF) and carotid arterial (CA) pressures and blood flows were measured in three groups of fetal sheep during delayed UCC; maternal oxytocin following mifepristone, mifepristone alone, and saline controls. Each successive uterine contraction significantly (p<0.05) decreased UV (26.2±6.0 to 14.1±4.5 mL.min-1.kg-1) and UA (41.2±6.3 to 20.7 ± 4.0 mL.min-1.kg-1) flows and increased CA pressure and flow (47.1±3.4 to 52.8±3.5 mmHg and 29.4±2.6 to 37.3±3.4 mL.min-1.kg-1). These flows and pressures were partially restored between contractions, but did not return to pre-oxytocin administration levels. Ventilation onset during DCC increased the effects of uterine contractions on UA and UV flows, with retrograde UA flow (away from the placenta) commonly occurring during diastole.ConclusionsWe found no evidence that amplification of uterine contractions with oxytocin increase placental transfusion during DCC. Instead they decreased both UA and UV flow and caused a net loss of blood from the lamb. Uterine contractions did, however, have significant cardiovascular effects and reduced systemic and cerebral oxygenation.

The causal role of the amygdala in the autonomic regulation of stress and anxiety

Introduction The amygdala is known to play an important role in the limbic system, which regulates fear and anxiety. Differences in fear and anxiety are associated with changes in autonomic system ie breathing, cardiovascular and urinary function. Although the amygdala has been recognized as an important center within the limbic system, it is not known whether it has any direct causal influence on breathing, cardiovascular or urinary functions. Methods We used both cats and rats for this study. In isoflurane anesthetized, vagi intact, spontaneously breathing cats (n= 4) and in urethane anesthetized vagi-intact spontaneously breathing rats (n = 12), we stereotaxically stimulated the the lateral amygdala (LA) and central amygdala (CeA) with excitatory amino acid [EAA, metabotropic glutamic acid (L-Glut, 500 mM, pH 7.4)], and investigated the changes in diaphragm function, thoracic pressure, blood pressure, heart rate and urodynamic control. EAA technique allows for stimulating only the cell bodies and not the axons or fibers of the passage thus enabling localization of specific areas and neuronal circuits within the amygdala and its causal impact on autonomic (respiratory, cardiovascular and urinary) system. Results from the cat studies Respiratory modulation: In the cat, LA generated hyperpnea and tachypnea while CeA induced dyspnea, bradypnea, inspiratory apneusis and double diaphragm breathing pattern. Apneas were never generated from either of the two regions of the amygdala. Cardiovascular modulation: The cardiovascular effects generated from the cat amygdala were varied and did not show specific topography as respiration. Both LA and CeA induced hypertension as well as hypotension. Micturition: In the cat, stimulation of CeA (but not LA) produced micturition. Results from the rat studies EAA stimulation of CeA induced tachypnea and hypertension. Topical stimulation of the CeL portion of the CeA, produced breath-hold. LA did not induce significant respiratory or cardiovascular effects. CeA however produced both hyper and hypotension. Micturition was not produced from either region of the amygdala. Conclusion 1. Lateral and Central amygdala areas produce distinct autonomic modulation which may define its selection associated with stress, fear and/or anxiety. 2. Species differences between cat and rat exists in terms of autonomic circuitry within the amygdala and their causal effects. These results constitute a variety of autonomic indices that can be translated for clinical determination of stress and anxiety disorders including PTSD and panic disorders in humans. Declaration This work was wholly undertaken in the laboratory of HHS at The University of Queensland between 2015-2017 with full ethics approval provided by the university Animal Ethics Care committee. Both HHS and GH were named investigators on the ethics approvals. None of work described here were undertaken at either of the current work designations of HHS or GH. HHS and GH conceived and designed the project, performed the experiments, analyzed primary data and made figure illustrations. GH curated the final data/figure representation in this presentation/poster. Correspondence to Gert Holstege: holstege23@gmail.com

The Cardiac Effects of Performance-Enhancing Medications: Caffeine vs. Anabolic Androgenic Steroids.

Several performance-enhancing or ergogenic drugs have been linked to both significant adverse cardiovascular effects and increased cardiovascular risk. Even with increased scrutiny on the governance of performance-enhancing drugs (PEDs) in professional sport and heightened awareness of the associated cardiovascular risk, there are some who are prepared to risk their use to gain competitive advantage. Caffeine is the most commonly consumed drug in the world and its ergogenic properties have been reported for decades. Thus, the removal of caffeine from the World Anti-Doping Agency (WADA) list of banned substances, in 2004, has naturally led to an exponential rise in its use amongst athletes. The response to caffeine is complex and influenced by both genetic and environmental factors. Whilst the evidence may be equivocal, the ability of an athlete to train longer or at a greater power output cannot be overlooked. Furthermore, its impact on the myocardium remains unanswered. In contrast, anabolic androgenic steroids are recognised PEDs that improve athletic performance, increase muscle growth and suppress fatigue. Their use, however, comes at a cost, afflicting the individual with several side effects, including those that are detrimental to the cardiovascular system. This review addresses the effects of the two commonest PEDs, one legal, the other prohibited, and their respective effects on the heart, as well as the challenge in defining its long-term implications.

Effect of a phase 2 cardiac rehabilitation program on obese and non-obese patients with stable coronary artery disease

BackgroundObesity is associated with significant cardiovascular morbidity and mortality effects. Cardiac rehabilitation programs cause a significant reduction in cardiovascular mortality and a reduction in all cardiovascular risk factors. Up to 80% of patients referred to cardiac rehabilitation programs are either overweight or obese. This study aimed to compare the effects of a phase 2 cardiac rehabilitation program on obese and non-obese patients with stable coronary artery disease following total revascularization by coronary angioplasty.ResultsThis was a prospective study including 120 patients with stable coronary artery disease. Patients were enrolled in a 12-week phase 2 cardiac rehabilitation program. Patients were classified into two groups based on their body mass index (BMI): those with a BMI < 30 kg/m2 were considered non-obese (n = 58) while those with a BMI ≥ 30 kg/m2 were considered obese (n = 62). At baseline, BMI and blood pressure (BP) were recorded; fasting blood sugar, triglyceride levels, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels were assessed; and echocardiography was used to measure left ventricular ejection fraction (LVEF). These were re-assessed after completion of the program. At baseline, there were more females in the obese group 20 (32.25%) vs 6 (10.13%) (p = 0.04), more hypertensives (p = 0.023), and less smokers 32 (51%) vs 46 (79%) (p = 0.025). Obese patients achieved fewer metabolic equivalent of tasks (METs) 7.97 ± 2.4 vs 9.74 ± 2.47 (p = 0.007) and had higher LDL-C levels 121.63 ± 36.52 mg/dl vs 95.73 ± 31.51 mg/dl (p = 0.005). At the end of the program, obese patients showed more reduction in BMI − 1.78 ± 1.46 kg/m2 vs − 0. 60 ± 0.70 kg/m2 (p < 0.001) and systolic and diastolic BP (p = 0.016 and 0.038, respectively). LDL-C level was more reduced in the obese group − 25.76 ± 14.19 mg/dl vs − 17.37 ± 13.28 mg/dl (p = 0.022). Non-obese patients had more increase in LVEF (p = 0.024). There was no difference between obese and non-obese patients in the magnitude of increase in METs achieved (p = 0.21).ConclusionCardiac rehabilitation programs lead to an improvement in cardiovascular disease risk factors with more reduction in BMI, BP, and LDL-C levels in obese patients compared to non-obese ones. LVEF was more increased in non-obese individuals. Exercise capacity in the form of METs achieved was equally improved in both groups.

Association of ambient air pollution with cardiovascular disease risks in people with type 2 diabetes: a Bayesian spatial survival analysis

BackgroundEvidence is limited on excess risks of cardiovascular diseases (CVDs) associated with ambient air pollution in diabetic populations. Survival analyses without considering the spatial structure and possible spatial correlations in health and environmental data may affect the precision of estimation of adverse environmental pollution effects. We assessed the association between air pollution and CVDs in type 2 diabetes through a Bayesian spatial survival approach.MethodsTaiwan’s national-level health claims and air pollution databases were utilized. Fine individual-level latitude and longitude were used to determine pollution exposure. The exponential spatial correlation between air pollution and CVDs was analyzed in our Bayesian model compared to traditional Weibull and Cox models.ResultsThere were 2072 diabetic patients included in analyses. PM2.5 and SO2 were significant CVD risk factors in our Bayesian model, but such associations were attenuated or underestimated in traditional models; adjusted hazard ratio (HR) and 95% credible interval (CrI) or confidence interval (CI) of CVDs for a 1 μg/m3 increase in the monthly PM2.5 concentration for our model, the Weibull and Cox models was 1.040 (1.004–1.073), 0.994 (0.984–1.004), and 0.994 (0.984–1.004), respectively. With a 1 ppb increase in the monthly SO2 concentration, adjusted HR (95% CrI or CI) was 1.886 (1.642–2.113), 1.092 (1.022–1.168), and 1.091 (1.021–1.166) for these models, respectively.ConclusionsAgainst traditional non-spatial analyses, our Bayesian spatial survival model enhances the assessment precision for environmental research with spatial survival data to reveal significant adverse cardiovascular effects of air pollution among vulnerable diabetic patients.Graphical abstract

Metformin and Chemoprevention: Potential for Heart-Healthy Targeting of Biologically Aggressive Breast Cancer.

Currently, tamoxifen is the only drug approved for reduction of breast cancer risk in premenopausal women. The significant cardiovascular side effects of tamoxifen, coupled with lack of a survival benefit, potential for genotoxicity, and failure to provide a significant risk-reduction for estrogen receptor-negative breast cancer, all contribute to the low acceptance of tamoxifen chemoprevention in premenopausal women at high-risk for breast cancer. While other prevention options exist for postmenopausal women, there is a search for well-tolerated prevention agents that can simultaneously reduce risk of breast cancers, cardiovascular disease, and type-2 diabetes. Metformin is a well-tolerated oral biguanide hypoglycemic agent that is prescribed worldwide to over 120 million individuals with type-2 diabetes. Metformin is inexpensive, safe during pregnancy, and the combination of metformin, healthy lifestyle, and exercise has been shown to be effective in preventing diabetes. There is a growing awareness that prevention drugs and interventions should make the “whole woman healthy.” To this end, current efforts have focused on finding low toxicity alternatives, particularly repurposed drugs for chemoprevention of breast cancer, including metformin. Metformin's mechanisms of actions are complex but clearly involve secondary lowering of circulating insulin. Signaling pathways activated by insulin also drive biologically aggressive breast cancer and predict poor survival in women with breast cancer. The mechanistic rationale for metformin chemoprevention is well-supported by the scientific literature. Metformin is cheap, safe during pregnancy, and has the potential to provide heart-healthy breast cancer prevention. On-going primary and secondary prevention trials will provide evidence whether metformin is effective in preventing breast cancer.

Cardiovascular Protection of Hydroxychloroquine in Patients with Sjögren's Syndrome.

Sjögren’s syndrome (SS) is a chronic systemic inflammation disease with clinical presentation of dry eye, dry mouth, and polyarthralgia. Active inflammation is associated with an increased risk of associated arterial stiffness or subclinical atherosclerosis-related cardiovascular events. We used the longitudinal health insurance database of Taiwan, which includes one million participants, to evaluate the relationship between the clinical medication of hydroxychloroquine (HCQ) and the development of coronary artery disease (CAD). In total, 1674 patients with SS receiving HCQ medication were included after exclusion for previous CAD. Altogether, 1142 SS patients were included for evaluation after follow-up for more than one year. After adjusting for age, gender, medications, and chronic comorbidities, a significantly decreased hazard ratio (HR) for developing CAD was found among SS patients with higher medication possession ratio (MPR) of HCQ (HR = 0.49, 95% confidence interval, CI: 0.26–0.94) when compared with low MPR of HCQ. A low HR for CAD was observed in SS patients with a high cumulative dose of at least 100,267 mg of HCQ (HR = 0.25, 95% CI: 0.09–0.66). Long-term HCQ therapy may decrease the HR of CAD in SS patients. The significant cardiovascular protective effect of HCQ therapy was observed in our study.

Amphetamine-like Neurochemical and Cardiovascular Effects of α-Ethylphenethylamine Analogs Found in Dietary Supplements

Dietary supplements often contain additives not listed on the label, including α-ethyl homologs of amphetamine such as N,α-diethylphenethylamine (DEPEA). Here, we examined the neurochemical and cardiovascular effects of α-ethylphenethylamine (AEPEA), N-methyl-α-ethylphenethylamine (MEPEA), and DEPEA as compared with the effects of amphetamine. All drugs were tested in vitro using uptake inhibition and release assays for monoamine transporters. As expected, amphetamine acted as a potent and efficacious releasing agent at dopamine transporters (DAT) and norepinephrine transporters (NET) in vitro. AEPEA and MEPEA were also releasers at catecholamine transporters, with greater potency at NET than DAT. DEPEA displayed fully efficacious release at NET but weak partial release at DAT (i.e., 40% of maximal effect). In freely moving, conscious male rats fitted with biotelemetry transmitters for physiologic monitoring, amphetamine (0.1–3.0 mg/kg, s.c.) produced robust dose-related increases in blood pressure (BP), heart rate (HR), and motor activity. AEPEA (1–10 mg/kg, s.c.) produced significant increases in BP but not HR or activity, whereas DEPEA and MEPEA (1–10 mg/kg, s.c.) increased BP, HR, and activity. In general, the phenethylamine analogs were approximately 10-fold less potent than amphetamine. Our results show that α-ethylphenethylamine analogs are biologically active. Although less potent than amphetamine, they produce cardiovascular effects that could pose risks to humans. Given that MEPEA and DEPEA increased locomotor activity, these substances may also have significant abuse potential.SIGNIFICANCE STATEMENTThe α-ethyl homologs of amphetamine have significant cardiovascular, behavioral, and neurochemical effects in rats. Given that these compounds are often not listed on the ingredient labels of dietary supplements, these compounds could pose a risk to humans using these products.