Cardiovascular
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Item Assessment of Arterial Occlusive Pressures for Blood Flow Restriction Exercise(2017-03-14) Sprick, Justin; Romero, Steven; Rickards, Caroline; Coon, JaceIntroduction: Blood flow restriction exercise is a training technique that involves restricting blood flow to an active limb (i.e. arm or leg) during exercise, and can stimulate muscle hypertrophy. Application of this technique is limited, however, as the optimal occlusive pressure required for physiological benefit has not yet been clearly identified. A cuff pressure of 220 mmHg around the upper thighs has been used in a blood flow restriction exercise study in this laboratory, but the degree of arterial occlusion elicited by this pressure has not been investigated. The aims of this investigation were to 1) quantify the degree of blood flow restriction induced by this cuff pressure (220 mmHg); and, 2) assess the cuff pressure required for complete occlusion of arterial blood flow. We hypothesized that 220 mmHg cuff pressure would not result in complete arterial occlusion of the superficial femoral artery in all subjects. Methods: 3 human subjects (1M/2F) underwent a protocol of progressively increasing cuff pressures applied to both upper thighs from 220 mmHg to 300 mmHg, in 10 mmHg increments every 60 s. Blood velocity and diameter of the superficial femoral artery was measured using duplex ultrasound during each stage. Superficial femoral artery blood flow was calculated as [time averaged mean velocity x [(radius)2 x π]]. Muscle oxygenation (SmO2) of the vastus lateralis was measured using near infrared spectroscopy, and mean arterial pressure (MAP) and stroke volume (SV) were calculated via finger photoplethysmography. Results: 220 mmHg cuff pressure reduced superficial femoral artery blood flow by 30.9 ± 14.8%, accompanied by a 4.2 ± 2.3% reduction in SV, a 0.2 ± 0.3% reduction in SmO2, and a 2.0 ± 1.7 mmHg increase in MAP. Complete occlusion of the superficial femoral artery was not achieved, even at a maximal cuff pressure of 300 mmHg; superficial femoral artery blood flow was reduced by 20.1 ± 7.6%, SV decreased by 21.1 ± 5.8%, SmO2 decreased by 22.3 ± 6.3%, and MAP increased by 3.4 ± 4.2 mmHg. Conclusions: In support of our hypothesis, 220 mmHg cuff pressure did not result in complete occlusion of the superficial femoral artery. This stimulus was sufficient to reduce venous return, however, as evidenced by the reduction in stroke volume. These findings could be relevant to future blood flow restriction exercise studies, as they provide insight into the degree of arterial occlusion achieved at rest by a standard cuff pressure of 220 mmHg.Item Brief Exposure to Intermittent Hypoxia Prolongs QTc in Human Subjects, which is Abrogated with AT1a Receptor Blockade.(2017-03-14) Bysani, Kaethan; Cooley, Daniel; Cutler, Michael; Raven, Peter; Smith, Michael; Jouett, NoahPurpose: Patients with Obstructive Sleep Apnea (OSA) frequently succumb to sudden cardiac death (SCD). Prolongation of the QTc, possibly via intermittent hypoxia (IH) mediated activation of angiotensin II type 1a receptors (ATR1a), predisposes towards SCD. Hence, the present study tested the hypothesis that (1) a brief exposure of IH lengthens QTc which (2) is abrogated with Losartan, an antagonist of ATR1a. Further, we evaluated how Losartan affects the relationship between direct measurements of muscle SNA (MSNA) and QTc via linear regression analyses during IH. Methods: Seven healthy human subjects were recruited with normal 12-lead ECGs. Subjects ingested either placebo or 100 mg of Losartan 1 hour prior to experimentation, and then repeated the study on a separate day in a randomized, repeated measures design. 3-lead ECG and MSNA (peroneal microneurography) were recorded throughout the study. Subjects were exposed to 20 minutes of IH, which was composed of 20 cycles of the following: 2-3 breaths of 95-100% N2, 20-second end-expiratory apnea, and 40-second room-air recovery. QTc (determined by Bazett’s formula) averages were compared statistically using a repeated-measures ANOVA. Results: Losartan did not alter baseline QTc (P = 0.17). IH + Placebo significantly prolonged QTc (baseline: 359.8 ± 4.8 ms vs. IH: 368.3 ± 4.8 ms, P 2 = 0.06, IH + Losartan: R2: 0.22). Conclusions: IH prolongs QTc, which is prevented with Losartan . Furthermore, IH alters the relationship of MSNA and QTc, in part through activation of ATR1a. Future studies should evaluate the possible cardioprotective benefits of ATR1a antagonists in OSA patients.Item Cerebral Blood Flow Changes During Acute Apneic Episodes Simulating Obstructive Sleep Apnea(2017-03-14) Bysani, Kaethan; Griffin, Brandon; Jouett, Noah; Smith, Michael; Cooley, DanielBackground: Obstructive sleep apnea (OSA) has not only been linked to hypertension and increased cardiovascular risk, but it can also result in mental status changes such as memory impairment. Under normal conditions, autoregulation in the cerebral vasculature maintains a constant flow rate to the brain. As such, the observed changes in the mental status may result from altered cerebral blood flow in OSA patients. By simulating apneic conditions using Intermittent Hypoxic Training (IHT), we can approximate the effect of OSA on cerebral blood flow using a Transcranial Doppler (TCD) to monitor middle cerebral artery (MCA) flow velocity. Using these techniques, we tested the hypothesis that IHT would cause alterations in cerebral blood flow in healthy individuals. Methods: Nine healthy subjects were recruited for the study. Subjects were between 18-40 years of age and free of any pre-existing OSA or Cardiovascular disease. The IHT protocol consisted of a series of hypoxic apneas in which subjects inhaled 2-3 breaths of nitrogen, followed by a 20-second apnea and 40 seconds of room air breathing recovery every minute for 20 minutes. TCD was used to record MCA velocity throughout the study and, additionally, ECG and cardiopulmonary perimeters were also recorded. Results: The MCA velocity during 5 minutes baseline and 5 minutes post-IHT was compared. The measured TCD flow velocity was not statistically different (p [greater than] 0.05) between baseline and post-IHT including the following TCD variables: systolic, diastolic, mean, pulsatility, MAP coherence, MAP phase, MAP transfer and vascular resistance (all p [greater than] 0.05). Conclusions: Cerebral blood flow measures were not significantly altered following IHT in these healthy individuals. The data demonstrates that a 20 minute period of simulated sleep apnea does not affect steady-state cerebral blood flow. Thus, it is likely that cerebral autoregulation is sufficient to maintain normal blood flow in healthy subjects and is not affected by this period of IHT. Further studies may need to examine chronic OSA subjects to discern whether altered cerebral blood flow plays a pathophysiologic role in the disease.Item Circulating Cell-free Mitochondrial DNA In Normal Human Pregnancy and In Experimental Preeclampsia(2017-03-14) Phillips, Nicole; Sprouse, Marc; Jarvis, Sara; Okada, Yoshiyuki; Morton, Jude; Davidge, Sandra; Fu, Qi; Goulopoulou, Styliani; Chaudhari, SarikaBackground: Mitochondrial DNA (mtDNA) is a damage-associated molecular pattern (DAMP) with potent immunogenic and inflammatory properties. Circulating cell-free mtDNA is increased in various inflammatory conditions associated with intense cell apoptotic processes. Pregnancy is characterized by systemic inflammation and placental apoptosis, which increase with advancing gestational age. The temporal changes of cell-free mtDNA during healthy pregnancy and in pregnancies with preeclampsia are unknown. Hypothesis: Circulating cell free mtDNA increases with gestational age in pregnant women and these changes positively correlate with maternal cardiovascular responses and neonatal biometrics. In a rat model of preeclampsia, circulating mtDNA is increased compared to normotensive control rats. Methods: Normal Human Pregnancy: Maternal blood samples were collected at early pregnancy (≤ 8 weeks of gestation), late pregnancy (32-36 weeks), and postpartum (6-10 weeks after delivery) in healthy, normotensive, pregnant women (n=21). Experimental Model of Preeclampsia: Reduced uterine perfusion pressure (RUPP) was surgically induced in pregnant rats on gestational day (GD) 14. Maternal blood samples were collected from RUPP rats (n=11) and control rats (Sham, n=11) on GD20. Absolute real-time PCR quantification of mtDNA was performed on whole genomic extracts from maternal human and rat sera using TaqMan® probes and chemistry. Results: Normal Human Pregnancy: Circulating mtDNA in late pregnancy were greater compared to early pregnancy (0.02 ± 1.2 pg/μL vs. 0.04 ± 1.2 pg/μL, p=0.04) and remained elevated post-partum (0.03 ± 1.2 pg/μL). Both blood pressure and heart rate increased from early to late pregnancy and decreased postpartum (pExperimental Model of Preeclampsia: RUPP rats had increased circulating mtDNA as compared to the sham group (0.30 ± 0.04 copy number/µL vs. 0.18 ± 0.04 copy number/µL, p=0.03). Conclusions: In normal pregnant women, circulating mtDNA change with advancing gestational age and may reflect rates of placental cell apoptosis. In a rat model of preeclampsia associated with placental ischemia, circulating cell free mtDNA is elevated in late pregnancy. The temporal changes in mtDNA in preeclampsia and their functional role in normal and preeclamptic pregnancies need to be further evaluated.Item Combined Effects of Remote Ischemic Preconditioning and Aerobic Exercise on Sympathetic Responses: A Novel Adaptation of Blood Flow Restriction Exercise(2017-03-14) Colby, Hannah; Rickards, Caroline; Sprick, JustinPurpose: Remote ischemic preconditioning (RIPC) is an innovative therapy used to attenuate tissue damage sustained by ischemia-reperfusion injury. Blood flow restriction exercise (BFRE) is a training method that also limits blood flow to the active muscles during exercise. We implemented a novel approach to BFRE with cyclical bouts of blood flow restriction and reperfusion, reflecting the RIPC model, which could elicit similar protection against ischemia-reperfusion injury. A concern about the use of BFRE, however, is the potential amplification of the exercise pressor reflex, which could be unsafe in at-risk populations. We hypothesized that cyclical BFRE would elicit a greater increase in sympathetic outflow and arterial pressure than conventional exercise (CE) when performed at the same relative heart rate (HR) intensity. Methods: 11 subjects (6M/5F) performed two 40-min treadmill exercise bouts at 65-70% of maximal HR. In the BFRE condition, cuffs around the upper thighs were inflated to 220 mmHg for 4 cycles of 5-min cuff inflation (occlusion)/5-min cuff deflation (reperfusion). The CE condition was identical, but without application of the cuffs. Mean arterial pressure (MAP), and plasma norepinephrine concentrations [NE] were compared between trials. Results: As hypothesized, BFRE resulted in higher [NE] compared to CE (923±92 vs 782±68 pg/ml; P=0.05). Unexpectedly, however, there were no differences in MAP between conditions during the cuff inflation time periods (BFRE vs. CE; P≥0.12)), and MAP was lower with BFRE during all 4 reperfusion periods compared to the CE trial (Cycle 1: BFRE vs. CE, 103±3 vs 107±2 mmHg; Cycle 2: 98±2 vs 103±2 mmHg; Cycle 3: 96±2 vs 102±2 mmHg; Cycle 4: 95±2 vs 100±2 mmHg; P≤0.04). Conclusion: BFRE elicited an exaggerated sympatho-excitatory response compared to CE as evidenced by higher plasma [NE]. This response was not accompanied by higher arterial pressures, however, most likely due to the cyclical nature of the occlusion/reperfusion protocol. The reactive hyperemia resulting from each cuff deflation may have offset the expected sympathetically-mediated increase in arterial pressure, resulting in an attenuation of the exercise pressor reflex. In conclusion, this novel cyclical BFRE paradigm could be applied to the clinical setting, such as cardiac or stroke-rehabilitation, where patients are already engaged in an exercise program, but where they could also benefit from the protection associated with RIPC.Item Comparison of Time to Tissue Plasminogen Activator in Patients Receiving In-Hospital Vs. Emergency Medical Services Lab Draws(2017-03-14) Hulsizer, Abigail; Gibson, Pharm.D, Caitlin; Gandhi, HiralPurpose: Tissue plasminogen activator (tPA) is beneficial when given within 4.5 hours of acute ischemic stroke onset, giving patients an increased likelihood to recover without any significant disability within a 3-month time period. Delays in diagnosis and laboratory data can place patients outside the tPA window. In an attempt to shorten time to tPA administration, some emergency medical services (EMS) companies have begun drawing blood for labs in the ambulance. The aim of this study is to determine if laboratory draws inside the ambulance shorten the time to tPA administration. Methods: This study is a retrospective chart review of patients admitted to a 348-bed community hospital for acute ischemic stroke who received tPA. Patients were included if they were greater than 18 years of age who have arrived at the hospital via EMS who have had an ischemic stroke with a clearly defined time of onset, a deficit measurable on the NIHSS, and a baseline computed tomographic (CT) scan of the brain that showed no evidence intracranial hemorrhage. Patients were excluded if they arrived with rapidly improving symptoms signaling a TIA, if they did not have a definitive ischemic stroke diagnosis, and/or if they had the stoke on site and did not have the opportunity to have an EMS vehicle transport. The primary outcome was to determine if receiving labs in the EMS significantly reduced door to needle time compared to receiving labs in the Emergency Department (ED). The secondary outcome was to determine if there were better health outcomes, as determined by discharge NIH scores, in patients receiving tPA within a shorter amount of time due to getting labs in an ambulance. Safety outcomes were adverse events related to tPA, such as angioedema, intracranial hemorrhage and anaphylaxis within 24 hours. Descriptive statistics were utilized. Results: Twenty-nine patients met inclusion criteria with one patient making two visits in the past year. The mean age and door to needle time (DTN) were 58.8 years-old and 77.5 minutes respectively. Hypertension, diabetes and smoking history were present in 78.1 percent, 43.7 percent, and 30 percent of patients, respectively. Of those who came by ambulance only 30 percent (n=11) had labs drawn in route to the hospital. The average DTN for those who had labs drawn in the EMS was 77.7 minutes. From the remaining patients, the average DTN time from the who had labs drawn at the hospital was 86.3 minutes. During the study, two patients expired from complications of tPA. One patient suffered a repeat stroke within the year. Conclusions: EMS lab draw in patients suspected of acute ischemic stroke was associated with a 8.6-minute decrease in door to needle time compared to patients who had labs drawn at the hospital. Clinical significance is likely negligible.Item Diastolic Properties in Older Mice: Comparison Between C57Bl6J and C57BL6N.(2017-03-14) Taffet, George; Acharya, Deepak; Reddy, Anilkumar; Yechoor, Poornima; Pham, Thuy; Hermosillo, Jesus; Harley, Craig; Knebl, Janice; Karim, SanaaPurpose: Cardiac aging in both humans and mice is associated with diastolic dysfunction, and impairment of the left ventricle filling. Age-related factors contributing to this filling impairment include fibrosis of the ventricle and impaired calcium handling by cardiomyocytes. Most aging studies use the C57Bl6/J (J mouse), but the C57Bl6/N (N mouse) has similar longevity without extensive cardiac fibrosis at comparable ages. Hence, this study is designed to identify the effect of fibrosis on diastolic function. Methods: We performed Doppler and 2-D echocardiography on fourteen 29 months old C57B16 (J and N’s) mice under 1% Isoflurane. The parameterized diastolic filling (PDF) formalism was used to comprehensively evaluate the diastolic dysfunction modeling the ventricle as a damped spring with spring stiffness (k), damping constant (c), initial stretch (x0). Small doses of Ivabradine were given to control heart rate for this assessment. Results: The N mice showed a c value of 205 ± 15, k of 7940 ± 530 and a xo of -.23 ± .004 in comparison to the J mice that showed a c value of 195 ± 14, a k value of 10,420 ± 800 and a xo value of -.016 ± .001. Conclusions: Though systolic function was preserved in old N’s and J’s, the spring stiffness (k) was significantly higher for the old J’s. This suggests fibrosis stiffens the old heart dramatically, but the larger LV diameter in the N’s suggests that fibrosis may prevent chamber enlargement with aging.Item Differences in Actomyosin Function in the Left and Right Ventricles of Human Hearts(2017-03-14) Nagwekar, Janhavi; Patel, Vipulkumar; Fudala, Rafal; Gryczynski, Zygmunt; Gryczynski, Ignacy; Borejdo, Julian; Requena, SebastianPurpose: In both ventricles of the heart, actin is expressed from the same genes. There are no differences in twitch duration, work performance, and power among the right (RV) and left (LV) ventricles in animals. So there is no expectation that the properties of actin or myosin isolated from either ventricle would be different. Nevertheless, the situation is more complex in human hearts. The LV must pump more powerfully because it has to overcome a larger resistance presented by the systemic system than the RV, which has to overcome a lower resistance offered by the pulmonary system. The question arises whether stronger pumping action of the LV is partially caused by the LV actomyosin developing more force than the RV actomyosin. The goal of this work is too identify if there are any differences in the kinetics rates of the actomyosin mechanochemical cycle in the LV versus the RV. Methods: Such a question is impossible to answer by making macroscopic measurements such as tension or ATPase activity, because the number of molecules involved in these processes is too large, (of the order of 1011) Measurements must be taken from a few molecules. We measured variations in the polarization of fluorescence of a few actomyosin molecules during the contraction cycle using time-resolved single molecule fluorescent microscopy. We obtained molecular kinetic information by calculating its autocorrelation function using R (version 3.3.1). The autocorrelation curve was fitted with a bi-exponential decay model to extract the rate constants using XPFIT (version 1.2.1) The goodness of fit was assessed by chi-squared. Results: The results suggest that actomyosin function is identical in both ventricles. There are no statistically significant differences in the kinetic rates that we obtained. Additionally, the spatial distribution of actomyosin is also the same. Conclusions: Our results suggest that the differences in the LV and RV may not be due to differences at the molecular level between actomyosin from the LV or RV in human hearts. However, our study only involved the use of failing human hearts with a wide variety of clinical parameters. These differences in the type of heart failures and patients may mean that we will not be able to extract statistically different results between kinetic rates. We have begun working on non-failing human hearts and will see if differences are present in that case.Item Does Intermittent Hypoxia Training Augment Antioxidant and Anti-Glycation Enzymes in Rat Brain?(2017-03-14) Cherry, Brandon; Williams, Arthur Jr.; Marianna, Jung; Myoung-Gwi, Ryou; Mallet, Robert T.; Nguyen, JulianHypothesis: Intermittent hypoxia training (IHT) has been found to minimize damage in the brain of rats subjected to ischemic stroke and alcohol intoxication-withdrawal, but the neuroprotective mechanisms are unclear. The finding that antioxidant treatments during IHT blunt the protection identifies a pivotal role of reactive oxygen species (ROS). Because ROS activate expression of antioxidant and anti-glycation enzymes, this study addressed the hypothesis that IHT augments these enzymes in rat brain. Specifically, the cerebral activities of anti-glycation (glyoxalase-1, i.e. GLO1), anti-oxidant (glucose 6-phosphate dehydrogenase, i.e. G6PDH) and hypoxia-inert (lactate dehydrogenase, i.e. LDH) enzymes were analyzed in IHT and non-hypoxic rats. Material and Methods: Ten rats (5 males) completed a 20 day IHT program (5-8 daily cycles of 5-10 min exposures to 9.5-10% O2 followed by 4 min room air exposures), and another 10 rats (5 males) were sham-conditioned by cyclic exposures to 21% O2. One day after completing the IHT or sham programs, the rats were isoflurane-anesthetized and decapitated. The cerebra were harvested, flash-frozen in liquid N2, pulverized in a mortar under liquid N2, homogenized in phosphate buffer, and centrifuged. Enzyme activities in supernatants were analyzed by spectrophotometry, and total protein content by colorimetric Bradford assay. Results: Activities of GLO1 were 78 ± 8 and 62 ± 7 mU/mg protein in the IHT and sham groups, respectively (P = 0.23). G6PDH activities were 21 ± 2 and 24 ± 2 mU/mg protein in the IHT and sham groups (P = 0.32). As expected, LDH activities were similar in the two groups: 899 ± 49 mU/mg protein in the IHT rats, and 940 ± 58 mU/mg protein in the sham rats (P = 0.60). Thus, IHT did not produce a statistically significant treatment effect on these enzymes. Conclusions: The 20 day IHT program, which exerts robust cerebroprotection against ischemia-reperfusion and ethanol intoxication-withdrawal, did not augment activities of selective antioxidant and anti-glycation enzymes. The impact of IHT on other antioxidant (e.g. glutathione peroxidase, superoxide dismutase, catalase) and anti-glycation (e.g. glyoxalase-2) enzymes remains to be evaluated. It also is possible that IHT activates other cytoprotective mechanisms, including signaling cascades that ameliorate mitochondrial permeability transition, oxidative stress and other mechanisms of neural injury. Such alternative mechanisms merit investigation.Item Effectiveness and safety of indomethacin for decreasing chest tube duration after coronary artery bypass graft surgery(2017-03-14) Gibson, Caitlin PharmD BCPS; Howard, Meredith PharmD BCPS; Hall, BrentonPurpose: Early removal of chest tubes in coronary artery bypass graft (CABG) patients is a factor that positively affects length of hospital stay. Indomethacin is sometimes used in one community hospital to reduce chest tube output via reduction in inflammation in an attempt to shorten chest tube duration. Nonsteroidal anti-inflammatory drugs, including indomethacin, are contraindicated in the setting of CABG due to a boxed warning regarding increased risk of cardiovascular thrombotic events. The aim of this study was to determine if the use of indomethacin in CABG patients is safe and effective in shortening the duration of chest tube placement. Methods: This was a retrospective chart review of patients in a 348 bed community hospital receiving indomethacin therapy after CABG surgery. The records of all adult patients receiving CABG surgery between 2010 and 2015 were systematically screened for receipt of at least one dose of indomethacin while chest tubes remained inserted. Charts with admit diagnoses of cardiac arrest or stroke were omitted from review. Identified subjects were individually matched based on demographics, medical history, and concomitant cardiac surgeries. Data collected included patient comorbidities, daily chest tube output, duration of chest tube placement, and concomitant medications. The primary outcome measure was change in time from first dose of indomethacin until removal of chest tubes compared with duration of insertion of chest tubes in control patients. The secondary outcome measure was total duration of chest tube insertion. Safety endpoints included occurrence of thrombotic events, TIMI bleeding in the setting of CABG, or death. Descriptive statistics were utilized. This study was approved by the institutional review board. Results: Sixteen patients received indomethacin and were eligible for inclusion. They were matched 1:1 to 16 patients not receiving indomethacin. Two of the patients in the indomethacin group received heart valve replacement at time of CABG and were able to be matched only on sex and type of valve replaced. The median age was 55 years in the indomethacin group and 56 years in the control group. Twenty-four subjects were male. Indomethacin was associated with a shorter duration of chest tube insertion when comparing time from first dose of indomethacin to chest tube discontinuation with duration of insertion in control. The median decrease in duration of chest tube insertion in the indomethacin group was 14.5 hours. The median total duration of chest tube insertion in indomethacin and control patients was 214.3 and 91.2 hours, respectively. No patients experienced thrombotic events, bleeding, or death during admission. Conclusions: Indomethacin decreased chest tube insertion times, however the clinical impact of this reduction is uncertain. Although it has shown to be safe in this cohort study, more studies are needed to determine if indomethacin has a place in the setting of CABG surgery.Item Effects of Acute Intermittent Hypoxia Training on Markers of Cardiac Autonomic Regulation(2017-03-14) Griffin, Brandon; Cooley, Daniel; Jouett, Noah; Smith, Michael; Bysani, KaethanBackground and Hypothesis: The intermittent episodes of hypoxia observed during apneic events of obstructive sleep apnea (OSA) increase the risk of cardiovascular disease, by altering sympathetic nervous activity (SNA); increased SNA outflow is postulated to be mediated by activation of angiotensin II receptors. Hypoxic apneic episodes were used to simulate short-term OSA with an intermittent hypoxic training (IHT) protocol, while assessing several indices of autonomic control with or without treatment with angiotensin receptor blockers (ARBs). Our hypotheses were: 1)Acute IHT training in healthy patient will increase indices of sympathetic control post-IHT compared to baseline, and 2)blockade of angiotensin II receptors with ARBs will attenuate the change in autonomic control associated with IHT. Materials and Methods: Eight healthy subjects were studied on two days. On day 1, subjects were treated with placebo or Losartan and IHT. On Day 2, the study was repeated with the alternative treatment (ARB or placebo). The IHT protocol consisted of a 5 minute baseline, then 3 breaths of nitrogen followed by 20 second expiratory apneas with a 40 second recovery period between each apnea for a total of 20 apneas, and then followed by a 5 minute post-IHT period. Heart rate (ECG), beat-to-beat blood pressure (Finometer), and O2 saturation (pulse oximeter) recorded continuously. The following autonomic indices were derived from these measures RRI, pNN50, and HF-RRI as indices of parasympathetic control, and LF-MAP, LF-SAP, and LF-RRI as indices of sympathetic control. Results: The IHT conditioning produced significant reductions in parasympathetic control (evidenced by RRI, pNN50 and HF-RRI, p0.05) and increases in sympathetic control (evidenced by LF-MAP, LF-SAP and LF-RRI, p0.05). Treatment with the ARB did not significantly alter the responses of any of these variables (although the a levels for sympathetic indices were near significance ~0.1-0.15). Conclusions: Acute IHT training in healthy individuals significantly enhanced the indices of sympathetic control, and reduced the indices of parasympathetic control. The ARB treatment did not significantly affect these measures although the sympathetic measures trended toward significance. Coupled with our prior finding that ARBs reduced the SNA post-IHT, these data suggest that further investigation is needed that includes a larger subject number and longer stimulus period similar to actual OSA.Item Evidence of Underdiagnosis of Sleep Apnea and Associated Abnormal Blood Pressure Control Among Minority Populations(2017-03-14) Smith, Michael; Jackson, Hillary; Jouett, Noah; Osho, RuthIntroduction: Obstructive sleep apnea (OSA) remains to be grossly underdiagnosed in the general population. We have recently shown that chemoreflex control of sympathetic nerve activity as measured by the pressor response to voluntary breathholding is exaggerated in patients with obstructive sleep apnea (OSA) and is highly sensitive for diagnosing OSA ([greater than] 0.90). In this study, we used the DSAP during volunteer breathholds to determine the pressor responses in a preliminary group of subjects from family medicine clinics who are not diagnosed with OSA. The population included African-Americans (AA), Hispanics (H) or Caucasians (C), and each subject also completed the EPWORTH sleepiness score (ESS) which is a marker of potential risk of OSA. Methods: Standard auscultatory blood pressure was measured in triplicate during quiet rest and immediately following a 20 sec voluntary end-expiratory breath hold (apnea) in 28 AA subjects, 16 H subjects and 48 C subjects who presented to the family medicine clinic without a diagnosis of sleep apnea. In addition, each subject completed the ESS survey and a score was calculated. Results: The entire cohort of subjects had reported to the clinic without a diagnosis of OSA. However, the ESS was significantly greater in both the AA and H groups when compared to the C subjects (p10 (high risk of OSA) was also significantly greater in the AA and H groups compared with the C cohort (p p Conclusions: These data derived from a general group of patients reporting to the primary care clinic support the premise that both AA and H individuals tend to be underdiagnosed for OSA and that the measurement of both the ESS and the pressor response to voluntary apnea can provide insights into both the risk of OSA and potential risk of underlying cardiovascular disease.Item Exaggerated Pressor Response to Voluntary Apneas in Patients with a History of Anxiety(2017-03-14) Jouett, Noah; Winter, Scott; Lopez, Karla; Gill, Jaskirit; Adams, Kathryn; Grimwood, Brian; Franks, Susan; Burton, Mandy; Smith, Michael; Griffin, BrandonBackground and Hypothesis: Patients with anxiety disorders tend to have an increased risk of cardiovascular complications including heart failure,cardiovascular mortality, and coronary heart disease. Knowing that an increase in sympathetic activity is detrimental to cardiovascular health this study was conducted to test the hypothesis that anxiety patients would demonstrate increased sympathetic responses to a voluntary apnea, a recognized physiologic stress that simulates the typical stress response. Methods: Previously, our laboratory has shown that systolic arterial pressure (SAP) changes are a reliable index of sympathetic responses during voluntary apneas. Therefore, we studied the SAP responses to voluntary apneas in 10 patients diagnosed with generalized anxiety disorder and 37 healthy control subjects. Room air voluntary apneas were performed by each subject six times while SAP (Finometer and auscultatory) and heart rate (ECG) responses were measured continuously during each apneic episode. Peak changes in arterial pressure from baseline to end of apnea were quantified. Results: The pressor responses to voluntary apneas in the anxiety patients exhibited a marked increase in SAP (16.962 ± 8.002, P Conclusions: These data demonstrate that anxiety subjects have enhanced sympathetic neural activity responses (as measured by the pressor response) to a mild physiologic stressor that does not provoke a response in non-anxious individuals. These data may explain, in part, the increased cardiovascular complications seen is this population, and suggest that the pressor response to apnea may be a simple tool for assessing altered physiologic function and cardiovascular risk in these patient populations.Item Exposure to Synthetic CpG DNA During Pregnancy Increases Expression and Activity of Cyclooxygenase in Maternal Arteries(2017-03-14) Osikoya, Deborah; Jaini, Paresh; Nguyen, An; Valdes, Melissa; Goulopoulou, Styliani; Dimos, BradfordObjective: Preeclampsia is a pregnancy-associated disorder that is characterized by elevated maternal blood pressure, end organ damage, and/or proteinuria. This pregnancy syndrome affects 2-8% of pregnancies worldwide and has no treatment other than fetal delivery. The mechanisms behind the development of this condition remain unknown and is one of the barriers preventing the development of effective treatment. One of the suggested etiologies behind preeclampsia is activation of the innate immune system. We have previously determined that maternal exposure to CpG DNA (a ligand of Toll-like Receptor-9, TLR-9) causes maternal hypertension and excess vasoconstriction. In cancer cells, CpG DNA/TLR-9 activation leads to upregulation of cyclooxygenase (COX), which is the rate-limiting step in the conversion of arachidonic acid to prostaglandins and thromboxanes. It is unknown whether treatment with CpG DNA during pregnancy affects COX in maternal and fetal tissues. Hypothesis: Treatment of pregnant rats with CpG DNA induces maternal hypertension and increases COX function in maternal and fetal tissues. Methods: Pregnant Sprague-Dawley rats were treated with ODN 2395 (synthetic CpG DNA, 100μg/rat/ i.p. injection) and saline (control group) on gestational days (GD): 14, 16, 18 (term: 21-22 days). Tail cuff blood pressure was measured on GD19. On GD20, rats were euthanatized and maternal liver and arteries as well as fetal tissues were frozen for western blot analysis. Thromboxane B2 (TxB2) was measured in serum and media from maternal arteries by ELISA. Results: ODN 2395 increased systolic BP (Control: 100±4 mmHg vs. ODN2395 119±4 mmHg, p=0.006). Serum TxB2 was greater in the ODN 2395 group compared to control rats (Control: 65.2±8.9 ng/mL vs. ODN2395: 123.6±19.7 ng/mL, p=0.03). ODN2395 also increased release of TxB2 from mesenteric (Control: 28.2±4.3 pg/mg tissue vs ODN 54.5±6.2 pg/mg tissue, p=0.008) but not from uterine arteries (p>0.05). Western Blot analysis revealed greater expression of COX-2 in mesenteric (p=0.002) and uterine arteries (p=0.006) in ODN2395-treated animals. ODN2395 increased COX-1 expression in mesenteric arteries (p=0.006) and showed a moderate effect on uterine arteries (p=0.07). No differences were observed between treatment groups for COX-1 and COX-2 in maternal (p>0.07) and fetal liver (p>0.20). Conclusions: Exposure to CpG DNA during pregnancy induced maternal hypertension and augmented function of COX in maternal arteries.Item For General Health, is Heavy Alcohol Use Related to Heart Disease in Adult Woman Aged 45-64?(2017-03-14) Braithwaite, Alycia; Rutledge, Erin; Tannery, Hayley; Hartos, Jessica; Williams, JamieIntroduction: Heart disease and general alcohol use are leading health concerns in the general population, but little is known about the relationship between heart disease and heavy alcohol use in women aged 45-64. The purpose of this study was to assess the relationship between heavy alcohol use and heart disease in middle-aged women. Methods: This cross sectional analysis used 2014 BRFSS data for females ages 45-64 from Arkansas, Kentucky, Louisiana, and West Virginia. Multiple logistic regression analysis was used to assess the relationship between lifetime heart disease and heavy alcohol use while controlling for age, ethnicity, marital status, income level, exercise, weight status, diabetes, and tobacco use. Results: A small percentage of female participants aged 45-64 reported lifetime heart disease (6-8%) or heavy alcohol use (2-6%). After controlling for demographic factors, heart disease was not significantly related to heavy alcohol use in any of the four states. However, heart disease was significantly related to exercise in AR, KY, and WV, and significantly related to diabetes in KY and LA. Conclusions: In summary, heart disease was not significantly related to heavy alcohol use but was significantly related to exercise and diabetes in general population samples of women aged 45-64. Although this study was limited by poorly defined variable measurements and a lack of direction of influence, it is recommended that primary care providers screen and educate their middle-aged female patients on the relationship between heart disease, exercise and diabetes. Given low prevalence of heart disease in the target population and lack of significant relationship between heart disease and heavy alcohol use, it is not indicated to screen for heart disease and heavy alcohol use in every middle-aged woman. Screening for either is recommended if the patient presents with symptoms.Item For Heart Disease, Do Depression Rates Differ Between Middle-aged and Elderly Males?(2017-03-14) Burchfield, Jenna; Krawietz, Bethany; Raschke, M.; Hartos, Jessica; McCormick, SamanthaPurpose: Depression is a debilitating mental illness that has consistently been linked to heart disease, but depression rates between age groups in people within this population are unknown. Therefore, the purpose of this study was to assess whether depression rates differ between middle-aged and elderly males with cardiac disease. Methods: This cross-sectional analysis utilized 2014 BRFSS data for males 35 and older who have ever been diagnosed with heart disease from Arkansas, Kentucky, Louisiana, and Oklahoma. Multiple logistic regression analysis was used to assess the relationship between depression rates and age while controlling for ethnicity/race, employment status, weight status, exercise, alcohol use, and tobacco use. Results: In this target population, approximately a quarter of the participants reported ever being diagnosed with depression or dysthymia (24-28%) and the majority were 65 and older (63-69%). Depression was about three to four times less likely to be reported in males ages 65 years and older diagnosed with heart disease compared to those 35 to 64 in three out of four states. Conclusions: Overall, this study found that middle-aged males with cardiac disease reported higher rates of depression than their elderly counterparts. The major limitation of this study was the inability to assess the onset of diagnoses or comorbid health conditions over time. General practitioners can expect that roughly a quarter of their male cardiac patients will report depression and that these rates might be higher among unemployed individuals. Primary care providers should assess their male cardiac patients ages 35 and above for depression, especially the younger patients in this group.Item Is Depression a Risk Factor for Cardiovascular Disease in Middle-Aged Women?(2017-03-14) Carpenter, Kelsey; Schwab, Paige; Schaffner, Camille; Hartos, Jessica; Foley, SamanthaIntroduction: Cardiovascular disease (CVD) and depression are prevalent morbidities found in middle aged adults; however, the association between depression and cardiovascular disease remains largely understudied in middle-aged females. The purpose of this study was to assess whether depression is a risk factor for cardiovascular disease in middle-aged women 40-65 years old. Methods: This cross-sectional analysis used 2014 data from the Behavioral Risk Factor Surveillance System (BRFSS) for females ages 40-65 in Alabama (N=2621), Louisiana (N=2025), Mississippi (N=1251), and Tennessee (N=1528). Multiple logistic regression analysis was used to assess the relationship between depression and cardiovascular disease, after adjusting for age, ethnicity/race, exercise, diabetes, alcohol use, tobacco use, and marital status. Results: Few participants in the target population reported they were ever diagnosed with angina or coronary heart disease (5-6%) or ever diagnosed with any form of depression or dysthymia (26-31%). After controlling for demographic, psychosocial, and behavioral factors depression was significantly associated with an increased risk of cardiovascular disease in two of fours states. In addition, diabetes and age (55-65) were related to CVD in two of four states. Conclusions: These findings suggest depression may increase the risk for CVD in middle-aged women in the general population. This cross-sectional study could not determine the direction of the relationship between depression and cardiovascular disease. Although CVD and depression are not prevalent in the general population, it is still recommended that practitioners screen, educate, and provide referral services as necessary.Item Is Kidney Disease Related to Heart Disease in Elderly Males?(2017-03-14) Cox, Jessica; Davis, Kaylee; Hamilton, Cristen; Hartos, Jessica; Florez, VictoriaIntroduction: Kidney disease and heart disease are two common chronic diseases and although a relationship between the two has been found, there is conflicting results regarding which acts as a predisposing risk factor for the other. The purpose of this study was to assess the relationship between kidney disease and heart disease in males aged 65 years old and older, and to determine which acts as the predominating risk factor in the relationship. Methods: Data from the 2014 Behavioral Risk Factor Surveillance System (BRFSS) for Arizona, Nevada, Texas, and Oklahoma for males aged 65 years and older was used in this cross-sectional analysis. Multiple logistic regression analysis was used to assess the relationship between kidney disease and heart disease while controlling for diabetes, weight status, exercise, educational level, tobacco use, and ethnicity/race. Results: For males aged 65 years and older, about one-fifth reported that they had ever been diagnosed with angina or coronary heart disease (16-21%) and about one-tenth of participants reported ever being diagnosed with kidney disease (not stones, UTI, or incontinence) (5-9%). After controlling for comorbidities, behavioral factors, and socioeconomic status, kidney disease and heart disease were found to be related (moderate effect sizes) in Nevada, Arizona, and Texas, and both were found to be related to diabetes (moderate to large effect sizes) in Nevada, Arizona, and Oklahoma. Conclusions: Overall, kidney disease and heart disease were found to be related to one another and to diabetes in population-based samples of males aged 65 years and older; however, this study is unable to establish the direction of influence. Although kidney disease and heart disease would not be very prevalent in men aged 65 years and older with 5-9% and 16-21% in a primary care setting, and diabetes would be somewhat more prevalent with 23-26%, it is recommended that primary care practitioners follow the progression of patients with kidney disease, heart disease, and diabetes as screening for the others may be indicated in some patients depending on their severity and prognosis.Item L-sulforaphane Decreased Contractile Response in Mesenteric Arteries in A Rat Model of Gestational Hypertension(2017-03-14) Osikoya, Oluwatobiloba; Goulopoulou, Styliani PhD; Cushen, SpencerBackground: Maternal hypertension is a state of inflammation characterized by oxidative stress. Exposure of pregnant rats to the Toll-like Receptor 9 activator, ODN2395, induces hypertension and upregulates vascular oxidative stress. The transcription factor, Nuclear Factor Erythroid 2 Like 2 (Nrf2), is a regulator of antioxidant response, is overexpressed in placentas from patients with preeclampsia. However, the role of Nrf2 in maternal vascular dysfunction is unknown. Hypothesis: L-sulforaphane, an Nrf2 activator, will have anti-contractile effects on arteries from pregnant rats treated with CpG oligonucleotides (a model of gestational hypertension). Methods: Pregnant Sprague-Dawley rats were treated with synthetic unmethylated CpG oligonucleotides (ODN2395, 100µg/intraperitoneal injection) or saline (Control) on gestational day 14, 16, and 18 (term=21-22 days). Blood pressure was measured before pregnancy and on gestational day 19 using the tail cuff method. The contractile responses of mesenteric resistance arteries to a thromboxane A2 (TxA2) mimetic, U46619, in the presence or absence of Nrf2 activator, L-sulforaphane (L-S, 40 µM), were assessed by wire myography on gestational day 21. Results: Rats treated with ODN2395 had greater systolic blood pressure on gestational day 19 compared to control rats (Control, n=9: 100±4 mmHg vs. ODN2395, n=7: 119±4 mmHg, p=0.007). Three-hour but not one-hour incubation with L-sulforaphane reduced the contractile response to U46619 in mesenteric arteries from both ODN2395 and control rats (Peak contraction as %Max KCl (120mM), Control Veh: 120.5%±4.85; Control L-S: 39.1%±7.16; ODN2395 Veh: 111.1%±4.19; ODN2395 L-S: 42.6%±2.68). Conclusions: Pregnancy is a state of oxidative stress and this may explain the anti-contractile effects of L-sulforaphane in arteries from normal, healthy rats. In preeclampsia, levels of oxidative stress are greater compared to normotensive pregnancies and thus, systemic treatment with L-sulforaphane or other Nrf2 activators may improve poor cardiovascular outcomes in pregnancies with preeclampsia.Item Magnetic Resonance Angiography to Assess Anomalous Coronary Arteries in Children at 3-Tesla: Diagnosis, Risk Stratification, and Interobserver Reliability.(2017-03-14) Hamby, Tyler; Muyskens, Steve; Olmstead, KeeganBackground: Anomalous aortic origin of the coronary arteries (AAOCA) is the second most common cause of sudden cardiac death (SCD) in young athletes. The prevalence, pathophysiology, and optimal method of evaluating AAOCA are unknown. The reliability of coronary magnetic resonance angiography (MRA) in assessing AAOCA, and the use of contrast enhanced coronary MRA in children at 3-Tesla has not been well described. We present our institutional experience using a 3-dimensional (3D) IR-FLASH sequence with slow gadolinium infusion and respiratory navigation at 3-Tesla to diagnose and risk stratify AAOCA in children. Methods: A retrospective review was conducted of all MRA patients referred for possible AAOCA between January 1, 2011 and May 9, 2016. Patients with complex congenital heart disease were excluded. Coronary anomalies with an intramural or interarterial course were classified as high risk, and a high aortic origin or intraseptal course were classified as low risk. Completed studies were anonymized and evaluated by two blinded independent observers for image quality, diagnosis of AAOCA, intramural course, and interarterial course. Reliability analyses, utilizing kappa, assessed diagnostic agreement between raters. MRA and surgical findings were compared in patients with AAOCA repair. Results: Fifty-nine patients were referred for suspected AAOCA (median age 13.79 years, range 5.19 – 19.84, 73% male). For 58 successfully acquired angiograms, 31 were high risk, 11 were low risk, and 16 were normal. Overall image quality was rated good to excellent. The two raters showed excellent agreement on image quality, κ = .85 (93%), diagnosis of AAOCA, κ = .81 (91%), and diagnosis of proximal interarterial course, κ = .81 (88%). There was moderate agreement about diagnosis of intramural course, κ = .63 (74%). For all 11 cases with surgical repair, the combined MRA ratings correctly diagnosed the presence of AAOCA and interarterial course. The presence of an intramural course was correctly rated in all 9 cases, while the absence of an intramural course was correctly rated in 1 of 2 cases. Conclusions: Coronary MRA using 3D IR-FLASH with slow contrast infusion at 3-Tesla showed high inter-rater reliability for diagnosing and characterizing AAOCA in pediatrics. Furthermore, findings were validated at time of surgical repair. This protocol is an effective means to examine AAOCA in pediatric patients and help stratify those who may be at high risk of SCD.