Changes In Cardiovascular Function Research Articles

The pro-resolving mediator, annexin A1 regulates blood pressure, and age-associated changes in cardiovascular function and remodeling.

Aging is associated with chronic, low-level inflammation which may contribute to cardiovascular pathologies such as hypertension and atherosclerosis. This chronic inflammation may be opposed by endogenous mechanisms to limit inflammation, for example, by the actions of annexin A1 (ANXA1), an endogenous glucocorticoid-regulated protein that has anti-inflammatory and pro-resolving activity. We hypothesized the pro-resolving mediator ANXA1 protects against age-induced changes in blood pressure (BP), cardiovascular structure and function, and cardiac senescence. BP was measured monthly in conscious mature (4-month) and middle-aged (12-month) ANXA1-deficient (ANXA1-/- ) and wild-type C57BL/6 mice. Body composition was measured using EchoMRI, and both cardiac and vascular function using ultrasound imaging. Cardiac hypertrophy, fibrosis and senescence, vascular fibrosis, elastin, and calcification were assessed histologically. Gene expression relevant to structural remodeling, inflammation, and cardiomyocyte senescence were also quantified. In C57BL/6 mice, progression from 4 to 12 months of age did not affect the majority of cardiovascular parameters measured, with the exception of mild cardiac hypertrophy, vascular calcium, and collagen deposition. Interestingly, ANXA1-/- mice exhibited higher BP, regardless of age. Additionally, age progression had a marked impact in ANXA1-/- mice, with markedly augmented vascular remodeling, impaired vascular distensibility, and body composition. Consistent with vascular dysfunction, cardiac dysfunction, and hypertrophy were also evident, together with markers of senescence and inflammation. These findings suggest that endogenous ANXA1 plays a critical role in regulating BP, cardiovascular function, and remodeling and delays cardiac senescence. Our findings support the development of novel ANXA1-based therapies to prevent age-related cardiovascular pathologies.

Role of corticotropin-releasing factor neurotransmission in the lateral hypothalamus on baroreflex impairment evoked by chronic variable stress in rats.

Despite the importance of physiological responses to stress in a short-term, chronically these adjustments may be harmful and lead to diseases, including cardiovascular diseases. The lateral hypothalamus (LH) has been reported to be involved in expression of physiological and behavioral responses to stress, but the local neurochemical mechanisms involved are not completely described. The corticotropin-releasing factor (CRF) neurotransmission is a prominent brain neurochemical system implicated in the physiological and behavioral changes induced by aversive threats. Furthermore, chronic exposure to aversive situations affects the CRF neurotransmission in brain regions involved in stress responses. Therefore, in this study, we evaluated the influence of CRF neurotransmission in the LH on changes in cardiovascular function and baroreflex activity induced by chronic variable stress (CVS). We identified that CVS enhanced baseline arterial pressure and impaired baroreflex function, which were followed by increased expression of CRF2, but not CRF1, receptor expression within the LH. Local microinjection of either CRF1 or CRF2 receptor antagonist within the LH inhibited the baroreflex impairment caused by CVS, but without affecting the mild hypertension. Taken together, the findings documented in this study suggest that LH CRF neurotransmission participates in the baroreflex impairment related to chronic stress exposure.

Abstract 14225: Cardiovascular Structural and Functional Changes Become Apparent With Increased Waist Circumference in Childhood Obesity

Background: Higher waist circumference (WC) is associated with cardiovascular disease, however, little is known about the association between WC and cardiovascular functional change in children. The purpose of this study is to examine the relationships between numbers of cardiovascular risk factors and left ventricular (LV) geometry and function in children. Methods: Echocardiography was performed in 401 children aged 7 to 13 years. Left atrial (LA) diameter, LV end-diastolic volume, ejection fraction, mass, mass-to-volume ratio, and carotid artery intima media-thickness (IMT) were measured. Transmitral peak flow velocities during early and late diastole and mitral annular myocardial velocities during early (Em) and late diastole (Am) were measured. LA systolic force and aortic stiffness were calculated. Lipids, uric acid, fasting glucose, insulin, high sensitive CRP, and homeostasis model assessment for insulin resistance (HOMA-IR) were also assessed. Subjects were divided into 4 groups: A group, WC within normal range; B group, increased WC; C group, increased WC plus any one of the following individual factors of hypertension, dyslipidemia (low high-density lipoprotein-cholesterol and/or high triglyceride), and raised fasting glucose; D group, metabolic syndrome. Results: Compared with the A group, LA diameter, mass/volume ratio, HOMA-IR, and uric acid were greater in the B group (p<0.05 for all). With increasing number of metabolic syndrome disorders (C and D groups), dyslipidemia, increased Hs-CRP, decreased Em/Am, enhanced LA systolic force, increased IMT, and aortic stiffening were observed (Table). Conclusions: Higher WC is associated with insulin resistance, hyperuricemia, and concentric LV hypertrophy. Cardiovascular structural and functional changes become apparent with increasing number of metabolic syndrome disorders. Our findings suggest that primary prevention programs should be initiated in children with increased WC.

Even periconceptional alcohol consumption can have long-term consequences on heart health in the offspring.

Even periconceptional alcohol consumption can have long-term consequences on heart health in the offspring.

Effects of Upper Body Exercise Training on Aerobic Fitness and Performance in Healthy People: A Systematic Review

Purpose: This systematic review aimed to evaluate the effects of upper body endurance training (UBET) on oxygen uptake (VO2) in healthy persons and derive evidence-based recommendations to improve upper body fitness and performance. Methods: Databases were systematically searched in accordance with PRISMA guidelines until 1 February 2023. Eligibility criteria included healthy male and female adults and older adults who underwent an UBET intervention. Outcomes of interest included physical fitness (VO2peak and/ or VO2 submax) and transfer effects (i.e., effects from trained (VO2peak ARM) to untrained (VO2peak LEG) musculature). Results: The search identified 8293 records, out of which 27 studies reporting on 29 interventions met our eligibility criteria. The average duration of interventions was 6.8 ± 2.6 weeks with 3.2 ± 0.8 training sessions per week. For 21 of 29 interventions, significant increases in VO2peak ARM were reported following UBET (+16.4% ± 8.3%). Three of the nine studies that analyzed transfer effects of untrained legs after upper body training exhibited significant increases in VO2peak LEG (+9.3% ± 2.6%). Conclusions: This review showed that UBET is a beneficial and useful training modality to increase the oxygen utilization in the upper body. Although UBET is an uncommon form of endurance training in healthy individuals, transfer effects to the untrained muscles can be observed in isolated cases only, rendering transfer effects in UBET inconclusive. Further research should focus on the peripheral changes in muscle morphology of the trained muscles and central changes in cardiovascular function as well as when transfer effects can occur after UBET in healthy people.

Potentiated respiratory metaboreflex in older males and females: afferent or efferent mechanisms?

Potentiated respiratory metaboreflex in older males and females: afferent or efferent mechanisms?

PS-B04-3: SHORT-TERM LOW IODINE DIET EXACERBATES VASCULAR REACTIVITY WITHOUT ALTERING THYROID HORMONE PROFILES IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

Objective: Iodine is an essential microelement required for thyroid hormone (TH) synthesis and regulation. Recent evidence links iodine to direct cardiovascular functional changes independent of TH. We aimed to determine the short-term effect of a low iodine diet on cardiovascular parameters in young Wistar Kyoto (WKY) and stroke-prone spontaneously hypertensive (SHRSP) rats. Design and method: 5-week-old WKY and SHRSP males and females (n = 5–7 per group) were assigned a normal (NID) or low iodine (LID) diet for 4 weeks. Iodine content was 1.2 mg/kg for NID and 0.211 mg/kg for LID. Tail cuff blood pressure (BP) and body weight were measured pre-diet and weekly. Transthoracic echocardiography, food intake, water consumption, and urine production were determined pre-diet and fortnightly. At sacrifice, thyroid tissue was weighed and snap-frozen for sodium iodide symporter (NIS) gene expression. Plasma was collected for thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) measurement. Third-order mesenteric arteries were assessed for vascular function using wire myography. Results: Baseline TSH, fT3, and fT4 levels were not significantly different between strains. LID did not influence food intake, body weight, thyroid weight, left ventricular (LV) mass, relative wall thickness (RWT) or BP. TSH levels, but not fT3 or fT4, significantly increased by 63.3% in SHRSP males (p = 0.0002) and 74.5% in females fed LID (p = 0.018) but not in WKY when compared to strain, sex- and age-matched rats fed NID. NIS expression significantly increased by 3.27-fold in WKY males fed LID when compared to WKY males fed NID (p = 0.03) but not in SHRSP males. A similar trend in NIS expression was observed in WKY females fed LID. Water intake/urine output ratio significantly increased by 53.62% in SHRSP females fed LID compared to SHRSP females fed NID (p = 0.04). Trends towards reduced stroke volume (SV) and cardiac output (CO) were observed in males fed LID compared to those fed NID irrespective of strain. Vascular reactivity to U46619 in third-order mesenteric resistance arteries was significantly increased by 24.9% in SHRSP males fed LID compared to SHRSP males fed NID (p = 0.03). A similar trend was evident in SHRSP females fed LID when compared to SHRSP females fed NID. Conclusions: Our results demonstrate that short-term LID increases vascular reactivity in SHRSP male rats and is associated with altered expression of genes that encode iodine transport proteins yet independent of thyroid hormone levels.

Study of the Echocardiographic Changes in Patients with Diabetic Nephropathy

Background: Diabetes mellitus (DM) is a metabolic disorder of multiple etiologies. Cardiovascular changes are one of the important macro vascular complications which are a major cause of mortality in diabetic patients with diabetic nephropathy. The aim of this work was to evaluate the structural and functional cardiovascular changes using echocardiography in diabetic patients with diabetic nephropathy (DN) in comparison with those without diabetic nephropathy. 
 Methods: This observational cross-sectional study was carried out on 60 diabetic patients with type 2 diabetes mellitus (T2DM) only or had T2DM with DN Patients were subdivided in to two equal groups: group A included patients without DN and group B included patients with DN. All patients were subjected to laboratory investigations, echocardiography (tricuspid annular plane systolic excursion (TAPSE), pulmonary artery pressure measuring, left ventricular systolic and diastolic function assessment).
 Results: There was a significantly lower Hb and significantly higher creatinine level and AL/CR ratio in group B in comparison to group A. There was significantly higher number of sclerotic aortic valve patients, higher numbers of low TAPSE, higher estimated systolic pulmonary artery pressure (ESPAP), higher end diastolic diameter (EDD), higher end systolic diameter (ESD), heavier left ventricular mass and thicker posterior wall thickness in group B in comparison to group A (P ≤ 0.05). There was a positive relationship between AL/CR ratio and EDD, left ventricular mass, TAPSE, and posterior wall thickness, while negative relationship between it and ESD in the two studied groups, and it was found that high EPASP and sclerosis of the Aortic valve were more prevalent with DN group.
 Conclusions: Risks of cardiovascular events increase substantially with increasing stage of kidney disease in T2DM patients. Asymptomatic diabetic subjects are at high risk for major adverse cardiovascular events, such as those with, chronic diabetic kidney disease (DKD), or proteinuria.

413 CARDIOVASCULAR CHANGES MICROGRAVITY-RELEATED: SYSTEMATIC REVIEW OF THE LITERATURE

Abstract Introduction Microgravity-relevant space is characterized by different environmental conditions than terrestrial space, including microgravity, vacuum/hypovaria, acceleration, extreme temperature, ionizing radiation, and confinement/isolation. The space environment induces biomechanical and cardiovascular stress during both takeoff and landing, exposing astronauts to the development of cardiovascular disease (CVD). This literature review focuses on cardiovascular changes that can be traced to an aerospace mission. (Baran, R., et All. 2021). Materials and Methods A systematic literature review was conducted to assess the cardiovascular changes that occur on the human body in microgravity. The search was performed using PUBMED as the database. The inclusion criteria established, for an article to be used, was the relevance of the topic. The choice of articles that were subsequently included in the study was based on predetermined questions and inclusion and exclusion criteria in accordance with PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses). The quality of the study was assessed by two reviewers and then discussed with a third reviewer using the DIXONWOOD checklist. Results and Discussion Baran, R. et all studied cardiovascular changes during spaceflight in vivo and related molecular changes in vitro that, were outside the scope of pre-flight cardiovascular disease. These changes are related to several factors, including the absence of orthostatic pressure, and reduced blood pressure, which results in a depletion of cardiac workload, sometimes leading to cardiac atrophy, i.e., reduced ventricular size in cosmonauts following a mission. In the face of these, the scientific community is investigating through pre- and post-flight simulation tests the adaptation and prevention of the cardiovascular system. An exposure to microgravity greater than 6 months cascades numerous physiological adaptations. Indeed, there is a shift in body fluids, arrhythmias, and an increase in systolic output (35-46%) and cardiac output (18-41%). Despite these increases, astronauts may enter a hypovolemic state and cardiogenic shock (10-15% decrease in volaemia). (Baran, R., et All. 2021). In addition to this, prolonged stay in Space, exposes, the cosmonaut to syncopal events of cardiogenic origin in the re-entry and post-landing phase. (Meck, J. V., et All. 2001). Conclusions Exposure to microgravity conditions results in significant changes in cardiovascular function. Further clinical studies in larger samples are, however, needed to understand and prevent microgravity exposure-related CVD. For future applications and theoretical-practical investigations, there also emerges the need, in view of increasingly longer and riskier missions̀ health teleconsultations, for the presence of the health care team on board the shuttle or at the bases alreadỳ present in Earth orbit.

Preeclampsia: Maternal cardiovascular function and optimising outcomes

Preeclampsia is associated with cardiac dysfunction, not only during the clinical phase of the disease, but also after delivery, with long term implications for both maternal and neonatal cardiovascular health. An abnormal cardiovascular phenotype also precedes conception, indicating that pre-existing cardiovascular dysfunction is associated with the development of preeclampsia. This review summarises the changes in cardiovascular function in preeclampsia, examining the evidence for when cardiovascular dysfunction develops and presenting the evidence for two phenotypes – one associated with fetal growth restriction, low cardiac output and high peripheral resistance, and a second associated with normal fetal growth, high cardiac output and low peripheral resistance. The presence of a cardiovascular phenotype that precedes conception demonstrates the potential for prevention of preeclampsia through cardiovascular optimisation at this stage. The two phenotypes mean therapy can be targeted to optimising cardiovascular function. The prevention and effective treatment of preeclampsia are essential aspects of improving maternal and neonatal cardiovascular health in the long term.

Changes in Cardiac Function During a Swallow Exercise Program in Patients with Coronary Artery Disease.

Research regarding risks of swallow treatment suggests that patients with coronary artery disease (CAD) experience changes in heart rate/rhythm when completing the supraglottic swallow and super-supraglottic swallow. The current study evaluated cardiac function during multiple swallowing exercises in patients with dysphagia and CAD. Eligible patients had CAD and confirmed pharyngeal dysphagia from VFS and sufficient cognitive ability to follow direction. The protocol included an a priori concealed randomized order of seven swallowing exercises (supraglottic swallow, super-supraglottic swallow, Mendelsohn and Masako maneuvers, effortful swallow with and without breath hold, and jaw opening exercise). Objective measures of heart rate/rhythm, oxygen saturation, and blood pressure were compared before vs after the overall session and each exercise using the Wilcoxon signed-rank test, and McNemar's and Cochran's Q tests with alpha at 0.05 and power at 0.80. Participants were 20 adults (15 male), aged 28-88 (median 76.5years). 90% were intubated during their hospital stay (44% > 1 intubation) and 20% suffered post-op stroke. Severe dysphagia, marked by NPO status, occurred in 30% of patients. Sessions were 26min long (mean; SD = 2.29). With few exceptions, objective measures were stable pre vs post overall and after each exercise. Potential vulnerability was noted with increased heart rate after the super-supraglottic swallow and increased arrhythmias after the effortful swallow (p < 0.05 for both). The order that swallowing exercises were completed did not significantly impact cardiovascular function. Telemetry and pulse oximetry proved to be feasible tools to monitor for subtle changes in cardiovascular function during completion of swallowing exercises.

Impact of Myocardial Fibrosis on Cardiovascular Structure, Function and Functional Status in Heart Failure with Preserved Ejection Fraction

Myocardial fibrosis, measured using cardiovascular magnetic resonance extracellular volume (ECV), is associated with adverse outcome in heart failure with preserved ejection fraction, but the mechanisms by which myocardial fibrosis exerts this deleterious effect are unclear. We performed mediation analyses of data from the Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction (PIROUETTE) trial to determine whether myocardial fibrotic regression causes changes in cardiovascular function and functional status following antifibrotic therapy. Regression of myocardial fibrosis correlated with improvements in 6-min walk test and KCCQ clinical summary score. The only outcome variable that demonstrated a treatment effect was an increase in left ventricular ejection fraction (LVEF). The estimated average causal mediation effects of myocardial ECV, absolute myocardial extracellular matrix volume and absolute myocardial cellular volume on LVEF were 6.1%, 21.5% and 13.7%, respectively, none of which was significant and therefore not mediated by myocardial fibrosis. (PIROUETTE; NCT02932566).Graphical

Impact of COVID-19 on pathophysiological changes on feto-maternal health and treatment strategies: A literature review

Aim: During the coronavirus disease 2019 (COVID-19) pandemic, physiological changes in pregnancy have placed both the mother and the fetus at potential risk of infection. Particularly, changes in cardiovascular function, the coagulation cascade, the immune system, and the respiratory system may be instrumental in the COVID-19 disease progression. Since this is a novel virus, the management, treatment, and prevention of COVID-19 is still evolving in general and obstetric patients as well. Therefore, it has become very crucial to study its effect on pregnancy and how providers adapted new practices pragmatically without prior scientific data. Our goal is to focus on addressing these issues systematically. Methods: We selected all the peer-reviewed articles on pregnancy-related to COVID-19 infection. Search terms were COVID-19, coronavirus, pregnancy, and maternal health using google scholar, Centers for Disease Control and Prevention (CDC), and PubMed. Results: We demonstrated the direct and indirect impact of COVID-19 on maternal health, including physical, mental, and social effects. We primarily highlighted case series and cohort studies discussing the clinical course, management, pathophysiological (immunological) changes, and the outcomes of COVID-19 infection in pregnant women. Conclusion: We discussed the physiological, pathological, and mental health changes in pregnant women with COVID-19 infection and the current evolving management plans, treatment approaches, and preventive measures to combat the disease. A global effort in further research is essential to determine and minimize the impact of COVID-19 on pregnant women and their outcomes.

Assessment of blood serum renalase in end stage kidney failure patient in Babylon city

End-stage renal disease is associated with significant changes in cardiovascular function, fluid, electrolyte, acid-base balance homeostasis, bone metabolism, erythropoiesis, and blood coagulation. Between October and the end of December 2021, the study recruited (30) patients and (20) healthy control subjects. Several physiological parameters, such as (urea, creatinine, renalase, and glomerular filtration rate). The results of the current study showed that the patient groups have significant statistical significance (P≤ 0.05) levels of RNLS, Urea, GFR, and creatinine in contrast with control groups, resulting insignificantly differences (P≤ 0.05).

Impact of age on microvascular free flap perfusion in head and neck reconstruction

Aging is associated with structural and functional cardiovascular changes that may affect microvascular free flap perfusion, which is a prerequisite for flap viability and flap success. This study is aimed to investigate the impact of age on flap perfusion. Intraoperative and postoperative flap perfusion of 348 patients who underwent successful reconstruction with a radial free forearm flap (RFFF), anterolateral thigh flap (ALTF), or fibular free flap (FFF) was retrospectively analyzed and compared between older (>70 years) and younger patients (≤70 years) using the Mann-Whitney test and linear regression models. Intraoperative flap blood flow and hemoglobin concentration (55.5 arbitrary units [AU] vs 69.3 AU, P=.004; 42.5 AU vs 47.3 AU, P=.016, respectively) were reduced in ALTFs in older patients compared with younger patients. These 2 differences did not persist in multivariable testing (P=.097 and P=.323, respectively). No other differences were observed between the older and younger patients in terms of intraoperative and postoperative flap blood flow, hemoglobin concentration, and hemoglobin oxygen saturation in RFFFs, ALTFs, and FFFs (all P > .05). Age has no impact on microvascular free flap perfusion in RFFFs, ALTFs, and FFFs. This could contribute to the observed equal success of free flaps in older patients.

Daily E‐cigarette Vapor Exposure Does Not Modify Response to 10% Normobaric Hypoxia in Long‐Evans Rats

E‐cigarettes or electronic nicotine delivery systems are devices used to deliver aerosolized liquids often containing nicotine and other chemicals. The short and long term effects of e‐cigarette vapor exposure are still under active investigation with many studies focusing on changes in cardiovascular function, lung tissue morphology, and inflammatory markers. This pilot study aimed to investigate the effects of seven days of e‐cigarette vapor exposure in adult rats on lung function and the physiological response to acute hypoxia. Since the chemicals found in e‐cigarette solutions have been shown to alter properties of the lung tissue, we predicted that response to acute hypoxia may be altered with vape exposure. Using random assignment, ten adult male Long‐Evans rats were assigned to vape (experimental) or air (control) groups. The animals were exposed to either air (n=4) or JUUL 5% nicotine vapor (n=6) using a whole‐body exposure chamber, twice a day for ten minutes for seven consecutive days. Ventilation was recorded on day 0 (baseline, pre‐exposure) and day 8 (post‐exposure) using unrestrained whole‐body plethysmography. Minute ventilation, tidal volume, and breathing frequency were assessed in normoxia and normobaric hypoxia (10% oxygen). Blood was collected on day 8 for cotinine (a nicotine metabolite) detection in serum. Cotinine was found to be present in the serum samples of the vape groups (86.6 ng/ml ± 1.0 ng/mL) but not the air groups (0.0 ng/mL) confirming e‐cigarette vapor exposure in the experimental group only. Baseline ventilation data collected on day 0 and post‐exposure ventilation data collected on day 8 were compared between air and vape groups across three different parameters: minute ventilation, frequency, and tidal volume. These parameters were first compared in normoxic conditions resulting in three distinct two‐way ANOVAs comparing the variables time and treatment. These parameters were also compared in hypoxic conditions resulting in an additional three distinct two‐way ANOVAs comparing the variables time and treatment. No significant difference was found among any of the comparisons (p &gt; 0.05 for all). In this pilot study, a seven day vape exposure in adult rats did not affect the response to acute hypoxia. We plan to repeat this study with modifications to the vape protocol and exposure duration.

Chronic Unpredictable Stress impairs Relaxation Responses to Acetylcholine in Resistance Arteries from Mice

BackgroundExposure to chronic stress is considered a major environmental factor that causes vascular aging, giving rise to the development of cardiovascular diseases. The chronic unpredictable stress (CUS) protocol has emerged as a translationally relevant model for studying the pathophysiology of stress exposure in rodents. The CUS protocol relies on heterotypic, unpredictable, and uncontrollable stressors that prevent adaptation and lead to disrupted stress response systems, mimicking the real‐life situation. CUS induces changes in cardiovascular function that are accompanied by the release of inflammatory cytokines. Indeed, previous studies have reported endothelial dysfunction in humans exposed to chronic stress and experimental animal models of chronic unpredictable stress. However, the mechanisms through which CUS induces cardiovascular injury are still unknown and require investigation.HypothesisThis study tests the hypothesis that mice exposed to CUS will have impaired endothelial function.MethodsVascular function using wire myographs was performed on isolated mesenteric resistance arteries (MRAs) from male and female C57BL/6 mice subjected to CUS for 28 days. The arterial rings were kept in physiological salt solution at 37°C, constantly aerated with 95%O2/5%CO2. Concentration‐response curves to phenylephrine (PE; 10‐9‐3x10‐5M) were performed in some arterial rings, whereas concentration‐response curves to acetylcholine (ACh; 10‐9 – 3x10‐5M) were performed in arterial rings precontracted with phenylephrine (PE 3x10‐6M). Concentration‐response curves were analyzed using non‐linear regression analysis. Data are presented as mean ± S.E.M. Statistical significance set at p&lt;0.05. Data were analyzed with GraphPad Prism 9.2.0.ResultsIn the MRA of both males and females, relaxation responses to ACh were impaired in the animals exposed to CUS when compared to their controls. There were no differences in the contractile responses to PE between controls and mice exposed to CUS.ConclusionOur results show that relaxation responses to acetylcholine are impaired in mesenteric resistance arteries from mice exposed to chronic unpredictable stress. This suggests that exposure to chronic unpredictable stress causes endothelial dysfunction and may have important implications for the role of stress on the development of cardiovascular diseases, particularly, hypertension.

Metformin Exposure in uteroProgrammes Hypertension in a Sex‐Specific Manner in Adult Offspring of Obese Mice

IntroductionMetformin is the first‐line pharmacological treatment for gestational diabetes in many countries. Although effective at improving maternal glycaemia, metformin readily crosses the placenta and could directly affect the fetus. Indeed, metformin exposure in utero increases postnatal adiposity. However, other long‐term effects on offspring exposed to metformin in utero have not been investigated. Here we explored the impact of maternal metformin treatment during obese, glucose‐intolerant pregnancy on offspring cardiovascular function at one year of age using an established mouse model of maternal diet‐induced obesity.MethodsFemale C57Bl/6J mice were fed either a standard chow diet [Control dams (Con)] or an obesogenic diet [Obese (Ob) and Obese‐Metformin (Ob‐Met) dams] from weaning up to and including pregnancy and lactation. Ob‐Met dams received a clinically relevant dose of metformin orally from one week prior to mating until day 19 of gestation. All offspring were weaned onto standard chow fed ad libitum at three weeks of age. At one year of age, systolic blood pressure (SBP) was measured by tail cuff plethysmography in the conscious animal and echocardiography was performed under anaesthesia. Post‐mortem, femoral arteries were isolated and vasomotor reactivity tested using in vitro wire myography. Myography dose‐response curves were analysed using mixed effects models, all other data were analysed by One‐Way ANOVA. Post‐hoc multiple comparisons were performed where appropriate. Significance was accepted when P&lt;0.05.ResultsRelative to controls, female offspring of Ob‐Met dams had increased SBP. However, no differences in SBP were observed in male offspring (Fig.1A). Female offspring of both Ob and Ob‐Met dams had enhanced femoral vasoconstrictor reactivity to K+ (Fig. 1B) but normal cardiac function (Fig. 1C). In contrast, male offspring of both Ob and Ob‐Met dams showed indices of diastolic dysfunction (Fig. 1C) and male offspring of Ob‐Met dams had enhanced femoral vasoconstrictor reactivity to phenylephrine (PE) (Fig.1B).ConclusionsMaternal obesity and metformin exposure in utero caused sex‐specific changes in cardiovascular function in 12‐month‐old offspring. In female offspring, exposure to maternal obesity and metformin programmed hypertension with enhanced peripheral vasoconstrictor reactivity. In male offspring, maternal obesity alone programmed echocardiographic indices of left ventricular restrictive filling which were not corrected by metformin treatment, while combined exposure to maternal obesity and metformin also programmed enhanced peripheral vasoconstrictor reactivity. These findings provide novel insight into the long‐term effects of in utero metformin exposure on the cardiovascular health of the next generation in obese pregnancy, and highlight the importance of considering offspring sex in developmental programming studies.

Impact of Gonadectomy on Sex‐Selective Dysregulation of Cardiovascular Function Resulting From In UteroExposure to Dexamethasone

Prenatal insults leading to increased fetal glucocorticoid exposure can sex‐selectively impact cardiovascular function in adulthood. In support of this, we have shown that when pregnant rat dams are treated with the glucocorticoid, dexamethasone (DEX), for the last 4 days of gestation, female‐specific changes resulting in enhanced pressor and heart rate (HR) responses to stress occur in adult offspring. Moreover, we demonstrated that females exposed to DEX in uteroshow altered autonomic function compared to vehicle‐exposed females. This is characterized by a reduced high frequency (HF) power component of heart rate variability (HRV) in DEX‐exposed rats, suggesting a lower reliance on parasympathetic drive. The present study evaluated the degree to which the sex‐specific changes in autonomically‐driven cardiovascular responses are due to activational effects of gonadal steroid hormones. Pregnant dams were administered DEX (0.4mg/kg per day, s.c.) or vehicle on gestation days 18‐21. This resulted in a significant reduction in birthweight in DEX‐exposed males and females. At 8 weeks, rats underwent a gonadectomy (GDX) or sham surgery, or remained intact, and at 10 weeks rats were instrumented with radiotelemetric transmitters for direct recording of arterial pressure, HR, and HRV in conscious, freely moving male and female rats. At 11‐12 weeks rats were placed in a restraint tube for 20 minutes, followed by a 3‐hour recovery period, to assess whether GDX alters the sex‐specific stress responses in DEX‐exposed offspring. Restraint‐stress testing was performed on diestrus in intact and sham females, and absence of cycling in GDX females was confirmed via cytological analysis. We demonstrate that intact females, but not males, that were exposed to DEX in utero exhibit an exaggerated pressor response to restraint, as compared to vehicle‐exposed females. We found that GDX did not alter stress‐responsive MAP in males regardless of prenatal treatment, suggesting testosterone does not play a role in acute cardiovascular stress responses in adult rats. In vehicle‐exposed females, when compared to intact, both sham and GDX surgery resulted in an exaggerated pressor response to restraint. However, in females that were prenatally exposed to DEX, there was no difference in the pressor response to restraint between intact, sham, and GDX rats. This suggests that the exaggerated pressor response observed in DEX females compared to males is not due to activational effects of estradiol. GDX was shown to have opposing effects on HRV in males and females, with no influence of prior DEX. In females, GDX resulted in a tendency toward reduced HF (p=0.065) and low frequency (LF, p=0.074) power component of HRV, whereas males showed a significant increase in HF (p=0.044) and a tendency toward increased LF (0.051). Taken together, activational effects of gonadal steroids appear to impact HRV, but not acute cardiovascular responses to stress. It may be that gonadal steroids act at an organizational level to mediate the sex difference observed in rats exposed to DEX in utero. Future studies to identify the mechanisms by which prenatal dexamethasone produce long‐term changes in cardiovascular function will be important for better understanding the sex‐specific consequences of prenatal programming over the lifespan.

Cardiovascular responses to high-intensity stair climbing in individuals with coronary artery disease.

Exercise‐based cardiac rehabilitation leads to improvements in cardiovascular function in individuals with coronary artery disease. The cardiac effects of coronary artery disease (CAD) can be quantified using clinical echocardiographic measures, such as ejection fraction (EF). Measures of cardiovascular function typically only used in research settings can provide additional information and maybe more sensitive indices to assess changes after exercise‐based cardiac rehabilitation. These additional measures include endothelial function (measured by flow‐mediated dilation), left ventricular twist, myocardial performance index, and global longitudinal strain. To investigate the cardiovascular response to 12 week of either traditional moderate‐intensity (TRAD) or stair climbing‐based high‐intensity interval (STAIR) exercise‐based cardiac rehabilitation using both clinical and additional measures of cardiovascular function in individuals with CAD. Measurements were made at baseline (BL) and after supervised (4wk) and unsupervised (12 week) of training. This study was registered as a clinical trial at clinicaltrials.gov (NCT03235674). Participants were randomized into either TRAD (n = 9, 8M/1F) and STAIR (n = 9, 8M/1F). There was a training‐associated increase in one component of left ventricular twist: Cardiac apical rotation (TRAD: BL: 5.6 ± 3.3º, 4 week: 8.0 ± 3.9º, 12 week: 6.2 ± 5.1º and STAIR: BL: 5.1 ± 3.6º, 4 week: 7.4 ± 3.9º, 12 week: 7.8 ± 2.8º, p (time) = 0.03, η2 = 0.20; main effect) and post‐hoc analysis revealed a difference between BL and 4 week (p = 0.02). There were no changes in any other clinical or additional measures of cardiovascular function. The small increase in cardiac apical rotation observed after 4 weeks of training may indicate an early change in cardiac function. A larger overall training stimulus may be needed to elicit other cardiovascular function changes.