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    Estrogen Receptor Alpha on Catecholaminergic Neurons in the Nucleus Tractus Solitarius
    (2018-03-14) Horn, Christopher; Wang, Lei; Mifflin, Steve; Nguyen, Dianna
    Purpose: Catecholaminergic neurons in the Nucleus Tractus Solitarius (NTS) are involved in Hypothalamic-Pituitary-Adrenal (HPA) axis and cardiovascular response to stress. While many studies have shown that pre-menopausal females are protected against the hypertensive and sympatho-excitatory effects of stress, very little is known about the location of neurons expressing estrogen receptors within the NTS. Our goal was to elucidate whether estrogen receptor alpha (ERα) is expressed on catecholaminergic neurons in the NTS in male and female rats. Methods: Adult male and female Sprague-Dawley rats were transcardially perfused with 4% paraformaldehyde and hindbrains harvested. In coronal sections containing the NTS (40um thick) immunohistochemistry was performed to determine whether NTS catecholaminergic neurons express ERα using monoclonal anti-tyrosine hydroxylase (TH) antibody (1:1000, Millipore) and secondary antibody Alexa Fluor 488 donkey anti-mouse (1:500, Jackson ImmunoResearch) and polyclonal anti-ERα antibody (1:2000-5000, Millipore) and secondary antibody Cy3 donkey anti-rabbit (1:400, Jackson ImmunoResearch). Sections were captured using an Olympus BX41 Fluorescence Microscope and analyzed using ImageJ. The NTS was divided into 2 regions: sections caudal to the area postrema (caudal CAUD) and sections lying below the area postrema (sub-postrema SP), and the number of immunoreactive neurons in each region counted and expressed as an average number of labeled neurons per section±SEM. The number of sections analyzed ranged from 7-11 in CAUD and 3-7 in SP. Results: In male rats, TH in CAUD NTS (n=6) was observed in 26±4 and ERα in 24±4 neurons/section. Co-localization of ERα and TH was observed in 13±2 neurons/section. TH in SP NTS (n=5) was observed in 54±3 and ERα in 34±2 neurons/section. Co-localization of ERα and TH was observed in 15±2 neurons/section. In female rats, TH in CAUD NTS (n=6) was observed in 27±2 and ERα in 30±3 neurons/section. Co-localization of ERα and TH was observed in 17±2 neurons/section. TH in SP NTS (n=6) was observed in 50±4 and ERα in 52±5 neurons/section. Co-localization of ERα and TH was observed in 27±2 neurons/section. At sacrifice, females were in estrus (1), diestrus (2) or proestrus (3). Conclusions: In both males and females, ERα is expressed on a subset of catecholaminergic NTS neurons, as well as non-catecholaminergic neurons. This could provide a substrate for estrogen-mediated cardiovascular protection in females.
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    An Unusual Case of a Large Left Ventricle Thrombus Presenting as NSTEMI
    (2018-03-14) Ahmed, Shahzad; Khan, Ahsan; Chou, Mark; Johnson, Douglas; Jipescu, Daniel
    Background: Although not common, the Left Ventricle (LV) thrombus can occur within 24 hours post myocardial infarction. Visser et al., showed that about 90% of thrombi are formed at maximum of 2 weeks after the event but can occur as late as 3 months to one year. Thrombus occurs most often with ST-elevation myocardial infarction and it seems to disappear more often in patients with apical akinesia than those with apical aneurysm or dyskinesia. Here we present a case of a large free flowing LV thrombus presenting as an NSTEMI from embolization. Case Report: A 56-year-old Hispanic male with PMHx significant for prosthetic aortic valve replacement, permanent pacemaker, paroxysmal A-fib on coumadin, bilateral femoral arteries thrombectomy, heart failure, HTN was brought in by ambulance for retrosternal chest pain (CP) radiating to the left arm. CP was associated with SOB, nausea, headache. Patient underwent cholecystectomy and appendectomy 2 weeks ago. His family reports that Coumadin was stopped during the admission process and was not restarted. The rest of the review of systems was noncontributory except for recent lower extremity edema. Physical exam was significant for lower extremity edema and positional SOB that was worse with the patient lying down and improved with him sitting up in a very specific position. Cardiac exam was WNL, no S3, S4 noted. During the initial work-up it was noted: BUN is 54, creatinine 1.51. Troponin 0.11. EKG with paced rhythm. The patient was diagnosed with acute kidney injury and NSTEMI. Due to persistent chest pain he was taken to the catheterization lab where he was found to have occluded, PDA and PLV and 85% occlusion of PDA branch with clot, underwent successful manual thrombectomy and PTCA. Due to the clot burden cardiology suspected possible origin of thrombus to be of intracardiac origin. Echocardiogram was ordered an extremely impressive echodense mass was noted. This was 5x5 centimeters with a remarkable and dramatic movement in the left ventricle. It was mostly considered to be a large mural clot. Right and left ventricular function was severely impaired. Cardiothoracic surgery and Interventional Radiology were unable to assist with removing the clot. Palliative services assisted with placing the patient on hospice. Discussion/Conclusion: Would like to have the opportunity to share this case with our colleagues due to the staggering echo imaging, the impressive positional SOB that show one more time that a good history and a physical exam are very important for reaching the appropriate diagnosis, and last but not the least due to the extremely difficult treatment option and ethical challenges in patient like this with severe comorbidities.
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    6-Hydroxydopamine Aggravates Renal Injury and Inflammation in a Murine Model of Systemic Lupus Erythematosus
    (2018-03-14) Osazuwa, Billy; Thomas, Orlexia; Vedantam, Shyam; Fancher, Daniel; Mathis, Keisa W.; Pham, Grace
    Purpose: Renal inflammation is prevalent in the chronic autoimmune disease systemic lupus erythematosus (SLE) and drives the progression of kidney injury. Inflammation in SLE results from a loss of self-tolerance and the production of autoantibodies against nuclear antigens. However, other immunoregulatory mechanisms, such as the cholinergic anti-inflammatory pathway, may also be dysregulated and contribute to aberrant systemic and renal inflammation in the disease. The cholinergic anti-inflammatory pathway is a protective, neuroimmune mechanism thought to involve neurotransmission between the parasympathetic vagus and the sympathetic splenic nerves. In order to confirm the importance of the splenic nerve in this pathway, others have used 6-hydroxydopamine (6OHDA), a neurotoxin that depletes catecholamines, to chemically denervate the spleen and thereby dampen the sympathetic component of the cholinergic anti-inflammatory pathway. We hypothesized that splenic injection of 6OHDA would further disrupt the cholinergic anti-inflammatory pathway in a mouse model of SLE and result in increased renal inflammation and worsened disease severity, which would highlight the importance of the splenic nerve in quelling renal inflammation. Methods: In the current study, female SLE and control mice were injected with 6OHDA (120 µg in 60 μl saline) or vehicle directly into the spleen at 33 weeks of age (n = 6/group). To confirm splenic denervation with 6OHDA, we utilized the glyoxylic acid condensation reaction on 12 μm spleen sections of representative animals and verified that catecholamine histofluorescence was diminished in 6OHDA-treated mice (205 vs. 111 histofluorescent foci). Results: Renal cortical TNF-α (normalized to total protein) was increased in SLE mice compared to controls (3.1e6 ± 1.2e5 vs. 7.8e5 ± 1.6e4 intensity units; p = 0.029), and 6OHDA exacerbated this pro-inflammatory cytokine in SLE mice (7.6e6 ± 2.4 intensity units; p = 0.048) with no effect in controls (2.4e6 ± 6.6e5 intensity units; p = 0.697). Anti-dsDNA autoantibodies were elevated in SLE mice compared to controls (2.1e4 ± 5.7e3 vs. 1.0e4 ± 4.7e3 activity units; p = 0.013), but 6OHDA did not alter this measure of disease severity in SLE mice (1.8e4 ± 5.2e3 activity units; p = 0.692). Albumin excretion rate (AER) was elevated in SLE mice compared to controls (160.7 ± 28.0 vs. 2.7 ± 2.7 mg/dL; p Conclusions: In summary, 6OHDA aggravated renal inflammation and injury in SLE mice indicated by heightened renal cortical TNF-α and AER. This suggests that chemical splenic denervation may disrupt endogenous, sympathetically-mediated anti-inflammatory mechanisms. Further studies are needed to confirm the role of the splenic nerve in regulating renal inflammation.
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    Neurons in the Nucleus Tractus Solitarius show no discernable change in intracellular calcium during acute application of 17β-estradiol
    (2018-03-14) Paundralingga, Obed; Wang, Lei; Mifflin, Steve
    Purpose: Neurons in the Nucleus Tractus Solitarius (NTS) are important regulators of cardiovascular and hormonal responses to stress and a potential site for estrogen modulation of stress responses. Our goal was to elucidate whether acute estrogen receptor activation is associated changes in intracellular calcium in NTS neurons in male and female rats. Methods: Adult male and female Sprague-Dawley rats were anesthetized with isoflurane and the hindbrain removed and cut into 300um thick sections. The NTS slices were then incubated for 50min with 10μM of Fura-2AM, 0.1% F-127 at 40°C and then washed for 20min in aCSF gassed with 95%O2+5%CO2. A single slice was transferred to the recording chamber on an upright epi-fluorescent microscope. The slice was held in place with a nylon mesh and superfused with normal aCSF at a rate of 2.5 ml/min. Application of 100 nM 17β-estradiol or 63 mM KCl dissolved in aCSF solution was done using multi barrel patch pipette positioned close to the neuron so that injection (volume) occurred in the same direction as the flow of aCSF being perfused. Fluorescence of Fura-2AM was excited by epi-illumination with light provided by a 75 W Xenon lamp band-pass filtered alternatively at 340 or 380 nm. Emission light pass through a barrier filter (510 nm). Pairs of 340 and 380 nm images were acquired at intervals of 5s and analyzed off-line with NIS-Elements AR 3.2 software. All images were captured with a charge-coupled device (CCD) camera. Results: A total of 19 sections were examined from 4 female rats and an average of 7 cells/slice were analyzed in each section. In response to superfusion of the slice with 100 nM 17β-estradiol no discernable change in the 340/380 ratio was observed in any cell. In 58 neurons from 10 slices in an additional 2 rats, a higher concentration of 1mM 17β-estradiol still failed to alter the 340/380 ratio. Cell viability was confirmed by application of 63 mM KCl which induced a 14 ± 5.4% increase in the 340/380 ratio relative to baseline in the cells studied. Conclusions: Acute application of 17β-estradiol did not alter intracellular calcium in NTS neurons. This could reflect a true lack of coupling between estrogen receptors and calcium signaling mechanisms in NTS neurons. However, if estrogen receptors are on a subset of NTS neurons, perhaps the fura-2 did not label the relevant population of NTS neurons. Further, perhaps estrogen does not have an acute (non-genomic, membrane bound receptor) effect in NTS and a more prolonged application of 17β-estradiol.
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    Responses of cerebral blood flow and tissue oxygenation to low frequency oscillations during simulated hemorrhagic stress in humans
    (2018-03-14) Park, Flora; Sprick, Justin; Rickards, Caroline; Anderson, Garen K.
    Introduction: Tolerance to both actual and simulated hemorrhage varies between individuals. Low frequency (LF; ~0.1 Hz) oscillations in mean arterial pressure (MAP) and brain blood flow (indexed via middle cerebral artery velocity, MCAv), may play a role in tolerance to reduced central blood volume; subjects with high tolerance to simulated hemorrhage induced via application of lower body negative pressure (LBNP) exhibit greater LF power in MAP and MCAv compared to low tolerant subjects. The mechanism for this association has not been explored. We hypothesized that inducing LF oscillations would attenuate reductions in cerebral blood flow and oxygenation during simulated hemorrhage. Methods: 11 subjects (9M/2F) were exposed to two LBNP profiles with an average chamber pressure of -60 mmHg: 1) 0 Hz - chamber pressure remained at -60 mmHg for 9-min, or 2) 0.1 Hz - chamber pressure oscillated between -30 mmHg and -90 mmHg at a frequency of 0.1 Hz for 9-min. Profiles were separated by a 5-min recovery. Measurements included arterial pressure and stroke volume via finger photoplethysmography, MCAv via transcranial Doppler ultrasound, and cerebral oxygenation of the frontal lobe (ScO2) via near infrared spectroscopy. Hemodynamic data was analyzed using a paired t-test. Tolerance was assessed with a Fischer’s exact test. Results: No differences were observed between profiles for MAP (0 Hz, 79.8±2.5 mmHg vs. 0.1 Hz, 80.0±1.9 mmHg; P=0.93) and MCAv (0 Hz, 42.4±3.3 cm/s vs. 0.1 Hz, 43.5±3.7 cm/s P=0.43). The reduction in ScO2 was attenuated (P=0.05) during the 0.1 Hz profile (-4.1±1.2 %) compared to the 0 Hz profile (-6.1±1.1 %). A similar attenuation was observed in stroke volume (0 Hz, -42.6±2.5 % vs. 0.1 Hz, -30.6±2.5 %; P Discussion:In partial support of our hypothesis, cerebral oxygenation was protected during the 0.1 Hz OLBNP profile. While MCAv was similar between conditions, the oscillatory pattern of cerebral blood flow may elicit a shear-stress induced vasodilation, so assessment of velocity may mask an increase in flow. Importantly, more subjects were able to tolerate the 0.1 Hz profile compared to the static 0 Hz profile, despite similar arterial pressure responses. These findings emphasize the potential importance of hemodynamic oscillations in maintaining perfusion and oxygenation of cerebral tissue during hemorrhagic stress.
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    Acute Effects of Obstructive Sleep Apnea on QT interval
    (2018-03-14) Davis, Tyler; Elias, Christopher; Burk, John; Smith, Michael; Burgess, Lauren
    Over 20 million people in the United States suffer from Obstructive Sleep Apnea (OSA). Compared to the general population, OSA patients are 2.6 times more likely to experience sudden cardiac death (SCD), and it is suspected that this is due, in part, to QT prolongation leading to fatal dysrhythmias. We recently showed that 20 min of simulated OSA in healthy young individuals caused significant increases in QTc, however, it is not known what effect actual OSA events have on QT interval and what factors influence these responses. Thus, the purpose of this study was to evaluate whether obstructive apneic events in OSA patients leads to QT prolongation compared to baseline. Methods: We determined QTc intervals (determined by Bazett’s formula) from the electrocardiograms of 14 patients undergoing polysomnography for diagnosis of OSA and titration of treatment with positive airway pressure. IRB approval was obtained for our protocol (UNTHSC #2018-019). Patients that were selected had an apnea hypopnea index >20/Hr and had no prior myocardial infarction or heart failure. Each patient’s ECG during their sleep study was analyzed to assess QT interval throughout the night. Baseline QT intervals were compared to QT intervals during obstructive apneas before midnight (Early) and apneas after midnight (Late), thus, representing those in which there were few prior apneas (Early) versus those with numerous prior apneas (Late). The QTc intervals were compared between baseline awake and baseline asleep, and between baseline and Late apneas. Statistical comparisons were made with paired t tests. Results: Baseline QTc intervals were not different between awake and sleep (p > 0.60); however, during apneas (whether Early or Late), the QTc intervals were significantly prolonged (p = 0.008). Conclusions: In conclusion, OSA is often associated with acute QTc prolongation with the magnitude ranging from 5-42 msec in this patient cohort. Further analyses will be performed to determine factors that affect the magnitude of QT prolongation accompanying apneas during the night. In addition, future studies will focus on QTc changes in OSA patients with prior heart disease, as these are the patients at greatest risk for developing serious arrhythmias during the night.
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    Peripartum Cardiomyopathy in Neuroblastoma Patient. Pregnancy alone vs Chemotherapy
    (2018-03-14) Patel, Harsh; Patel, Aman; Burkholz, Michael; Jipescu, Daniel
    Background/Abstract: Although known for decades, etiology for peripartum cardiomyopathy (PPCM) is still eluding. It’s not only a challenging disease for physician but also for the patients due to it’s complexity in management and very high recurrence rate with subsequent pregnancies. Several risk factors for PPCM include: age [greater than] 30, multiparity, eclampsia, pre-eclampsia, and prolonged tocolytic therapy with beta agonists. Here we present a case of a young caucasian woman with history of neuroblastoma that developed severe peripartum cardiomyopathy leading to cardiac cirrhosis. Case Report: This is a 22-year-old Caucasian female with past medical history of fetal alcohol syndrome, neuroblastoma at birth status post chemotherapy, portal hypertension status post banding, and recently diagnosed peripartum cardiomyopathy. The patient’s pregnancy was complicated with eclampsia, which resulted in a C-Section emergent birth. 2 weeks after birth, patient started complaining of dyspnea on exertion, productive cough with clear sputum, orthopnea and lower extremity swelling. Initial workup with CXR revealed pulmonary vascular congestion, a TTE with EF 5-10%, diffuse hypokinesis, grade 3 diastolic dysfunction, and pulmonary artery peak pressure of 35-40 mmHg, physical examination revealed: pulmonary rales, 2+ pitting LE edema, dyspnea on exertion. Patient was diagnosed with CHF at the time and discharged on Carvedilol and Furosemide; however, 2 weeks later her LE edema continued, this time presenting with worsening dyspnea and tachycardia. Bilateral LE duplex was negative for DVT, but a CTA Chest with contrast revealed a PE in subsegmental Left Lower lobe for which she was started on Apixaban. Her EF remained the same. CHF medications were optimized with Lisinopril, Metoprolol Succinate, Lasix, and Digoxin. Initial hypercoagulable workup was negative, however, the CTA Chest revealed liver lesions. MRI of abdomen revealed a cirrhotic liver secondary to combination of hepatic venous congestion from RHF, chronic portal vein thrombosis, portal hypertension, gastrohepatic varices. The patient’s current therapy for her CHF is: Digoxin, Furosemide, Betablockers, and Milrinone drip. She will be sent for evaluation for liver and heart transplant. Discussion/Conclusion: PPCM is a rare but serious condition with high maternal and fetal morbidity and mortality. It is idiopathic but many theories implicate potential role of maternal or fetal hormones, immunological, genetic or environmental factors. Early diagnosis is paramount with strong clinical suspicion, lab markers and echocardiography. Management includes treating heart failure symptomatically as well as potential use of newer therapies targeting immunological system as well as anti prolactin therapy with Bromocriptine and in severe cases cardiac transplant. However, no randomized clinical studies are available till date to support newer therapies. Some questions that we proposed during literature reviews are: is there an early lab or imaging marker (either maternal or fetal) that can predict PPCM and thus prevent or slow the severity. More studies are needed to answer these puzzling questions.
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    An Unusual Case of Viral Cardiomyopathy Presenting as Acute Ischemic CVA
    (2018-03-14) Aftabizadeh, Som; Walji, Shaista; Chennupati, Anupama; Nguyen, Thao
    Background/Abstract: HIV HIV-associated cardiomyopathy (HIVAC) is a significant cause of morbidity and mortality among HIV-infected individuals.1 The HIV virus is increasingly becoming recognized as an important cause of cardiomyopathy. While the exact mechanism remains unclear, effects from direct viral burden as well as opportunistic infections are thought to play a key role.2 Here we present a case of severe cardiomyopathy in a patient previously undiagnosed with HIV. Case Report: A 21yo Hispanic male with PMH significant for fatty liver disease and recent Tylenol toxicity presented to the ER for evaluation of sudden onset of left sided weakness and left facial droop. He was found down and noted to be shaking, thus there was also a concern for seizure activity. NIHSS upon arrival was 16, with early changes on CT and visualized clot in M1 distribution of the right MCA with poor collateral flow on CTA. Right MCA syndrome was diagnosed and patient was given tPA. Patient recovered well with rapid resolution of the focal deficits. Prothrombotic workup revealed low protein C activity. Transthoracic echo performed as part of evaluation of ischemic CVA demonstrated a LVEF of 15% and moderately dilated left ventricle.. The etiology of CVA was felt to be thromboembolic secondary to this severe cardiomyopathy. Patient denied any personal or family history of prior cardiac problems as well as cardiac arrhythmias. Due to noted recurrent fevers and pancytopenia throughout the course of his admission, HIV reactivity was checked and revealed him to not only have HIV but also AIDS with a CD4 count of 84 and RNA PCR of 121,000. With this finding, viral cardiomyopathy was felt to be the most reasonable explanation for heart failure in this young patient. He was started on oral anticoagulation to prevent further thromboembolic events and was fitted for a LifeVest. Discussion/Conclusion: HIV- associated cardiomyopathy is a known chronic complication in patients living with HIV/ AIDS, especially in uncontrolled infection as was seen in the patient who presented to our hospital. Uncontrolled infection can lead to both direct and indirect cardiotoxicity from infections associated with low CD4 counts as well as HIV itself. The pathogenesis of HIV- induced cardiomyopathy is often multifactorial including myocarditis, cardiac autoimmunity, micronutrient deficiency, and even antiretroviral therapy (ART) induced.1 Patients living with HIV are at a higher risk than the general population for developing HF. Studies have shown that in HIV-infected individuals, the prevalence of HF was highest among those with CD4 counts References: Lumsden RH, Bloomfield GS. The Causes of HIV-Associated Cardiomyopathy: A Tale of Two Worlds. Biomed Res Int. 2016;2016:8196560. Al-kindi SG, Elamm C, Ginwalla M, et al. Heart failure in patients with human immunodeficiency virus infection: Epidemiology and management disparities. Int J Cardiol. 2016;218:43-46. Ntsekhe M, Mayosi BM Cardiac manifestations of HIV infection: an African perspective. Nat Clin Pract Cardiovasc Med. 2009;6:120–127. Gopal M, Bhaskaran A, Khalife WI, Barbagelata A. Heart Disease in Patients with HIV/AIDS-An Emerging Clinical Problem. Curr Cardiol Rev. 2009;5(2):149-54. Currie PF, Jacob AJ, Foreman AR, Elton RA, Brettle RP, Boon NA. Heart muscle disease related to HIV infection: prognostic implications. BMJ. 1994;309:1605–1607. Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, Baughman KL, KasperEK. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy.N Engl J Med. 2000;342:1077–1084
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    Effect of General Anesthesia on Cardiac Magnetic Resonance Derived Cardiac Function in Tetralogy of Fallot.
    (2018-03-14) Honan, Kevin; Hamby, Tyler; Umejiego, Johnbosco; Muyskens, Steve; Roshan, Tony
    Introduction: Surgical palliation of tetralogy of Fallot (TOF) results in excellent short-term survival, however, residual defects result in increased long-term mortality. Depressed right ventricular (RV) and left ventricular (LV) ejection fractions (EF) are associated with adverse outcomes. While cardiac magnetic resonance (CMR) imaging is the preferred modality to assess these patients, some require sedation for successful data acquisition. General anesthesia (GA) has been shown to depress EF and heart rate (HR) in animal models. The effect in patients with congenital heart disease has not been well described. Case Information: A retrospective review was conducted of all CMR patients referred with TOF between January 2011, and May 2017. Patients with significant aortic or mitral valve disease, history of cardiomyopathy, undergoing conscious sedation, or receiving inotropic support were excluded. The cohort was separated into GA and non-sedated groups. A standard anesthetic regimen using sevoflurane was used in all patients. Propensity score matching (PSM) was utilized to adjust for selection bias. The matching algorithm was used in matched subjects to calculate the mean differences in LVEF, RVEF, HR, and cardiac index (CI). A total of 114 patients met criteria, 31 patients were administered GA (mean age 15 years, range 2 – 45, 48% male), while 83 patients received no sedation (mean age 19 years, range 11 – 53, 53% male). The unmatched analysis showed significant depression in LVEF (49.9 vs 56.8%, p Conclusions: GA with sevoflurane results in myocardial depression and significantly depressed CMR derived LVEF, RVEF, and CI. It may be inappropriate to use this data to determine surgical timing for pulmonary valve replacement. Studies examining the effect of GA and the use of alternative protocols should be conducted.
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    Outcomes of Hypoplastic Left Heart Syndrome with and without Restrictive Atrial Septum
    (2018-03-14) Noblett, Bryan; Hamby, Tyler; Kuo, James; Weston, Jacob
    Abstract – Outcomes of Hypoplastic Left Heart Syndrome with and without Restrictive Atrial Septum Jake Weston, OMS-II, Bryan Noblett, OMS-II, James Kuo, MD Introduction: Hypoplastic Left Heart Syndrome (HLHS) is a congenital heart defect characterized by inadequate development of a functional left ventricle to the point where it is unable to support systemic circulation. Patients often undergo a series of palliative surgeries beginning with the Norwood procedure within several weeks of life, which has greatly improved the mortality rate associated with this condition. However, about 6-22% of these patients also have an intact atrial septum (IAS) or restrictive atrial septum (RAS), which is associated with significantly worse survival rates. Multiple strategies have been developed in order to treat this complication. The Cook Children’s Heart Center tends to perform early Norwood procedures (day 0-1 of life), and one of the goals of this study is to analyze the outcomes of performing early Norwood procedures. It was hypothesized that the Cook Children’s institutional approach of early Norwood procedure for patients with HLHS with RAS is at least comparable, if not superior, to other approaches in terms of survival and long term outcomes. Methods: This was a retrospective study of patients who had a Norwood procedure done at Cook Children’s Hospital from 2014 – 2016; 36 patients met inclusion criteria. Data were collected for variables of significance, including presence of restrictive atrial septal defect (ASD), pre- vs. post-natal diagnosis of HLHS, survival to discharge, and mortality. Using logistic regressions, we examined the effect of ASD and pre- vs. post-natal diagnosis on survival at discharge, and overall mortality. Results: Thirty-one of 36 (86%) patients survived. Those with ASD (4/6) were not statistically significantly less likely to survive than those without ASD (27/30), p=.13, and those born pre-natally (23/26) were not significantly less likely to survive than those born post-natally (8/10), p=.51. Discussion: The survival rates at discharge were slightly higher than published survival rates for patients with and without restrictive ASD. While the results are preliminary, and further research with a larger sample size is needed, we believe our current data shows a trend that supports our hypothesis.
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    Trophoblast cells exposed to hypoxia and oxidative stress release mitochondrial DNA and undergo apoptosis
    (2018-03-14) Blessing, Alexandra; Chaudhari, Sarika; Patil, Shruti; Phillips, Nicole R.; Goulopoulou, Styliani; Cushen, Spencer
    1. Purpose Preeclampsia is a syndrome of high blood pressure with end organ damage diagnosed after the 20th week of pregnancy. This syndrome is associated with placental ischemia, oxidative stress, and exaggerated rates of placental cell death. Mitochondrial DNA (mtDNA) that is released in the extracellular space due to mitochondrial damage or cell death has potent pro-inflammatory and pro-immunogenic properties. Circulating mtDNA is increased in plasma from women with preeclampsia compared to healthy pregnant women; however, the cellular origin of mtDNA is unknown. This leads to our hypothesis that trophoblast cells exposed to hypoxic and oxidative stress release mitochondrial DNA and undergo apoptosis. 2. Methods Human trophoblast cells (BeWo choriocarcinoma cell line) were grown to 80-90% confluency before treatment with: 1) hypoxia (1% O2) vs. normoxia (21% O2) for 6, 15, or 24 h, or 2) an oxidative stress inducer (H2O2, 200 μM for 4 h or 24 h), a mitochondrial complex I inhibitor (Rotenone, 5 μM for 4 h), or untreated control. Absolute real-time PCR quantification of mtDNA was measured on total nucleic acid extracts (Omega Mag-Bind® Blood & Tissue DNA HDQ Kit) from cell culture supernatants using TaqMan® probes and chemistry. Apoptosis was quantified via double staining for Annexin V and propidium iodide using flow cytometry. 3. Results Concentrations of mtDNA were higher in supernatants from BeWo cells exposed to hypoxia than those exposed to normoxia for 15 h (normoxia: 14.2 pg/μL ± 1.2, n = 3 vs. hypoxia: 20.6 pg/μL ± 0.4, n = 3; p = 0.02). BeWo cells treated with H2O2 showed no increase in mtDNA release after 4 or 24 h (p ≥ 0.34). Cells exposed to hypoxia did not exhibit increased apoptosis after 6, 15, or 24 h (p ≥ 0.25). Incubation with H2O2 for 18 h resulted in increased apoptosis (Untreated control: 15.6%, n = 1 vs. H2O2: 32.5%, n = 1). Treatment with rotenone resulted in increased BeWo cell apoptosis (Untreated control: 18.1% ± 2.6, n = 2 vs. Rotenone: 35.5% ± 2.5, n = 2). 4. Conclusions Extracellular mtDNA was increased in a trophoblast cell culture exposed to hypoxia, but not when exposed to H2O2. Apoptosis was not increased when cells were exposed to hypoxia but was increased after exposure to inducers of oxidative stress. Future studies will investigate the mechanism by which hypoxia results in release of mtDNA, with focus on determining whether mtDNA release is independent of apoptosis.
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    (2018-03-14) Kay, Victoria; Rickards, Caroline; Rosenberg, Alexander
    Trauma-induced hemorrhage is a leading cause of disability and death due, in part, to impaired perfusion and oxygenation of the brain. While cerebrovascular function is known to differ between males and females, it is not clear if cerebrovascular responses to blood loss are differentiated based on sex. Purpose: To examine the effect of sex on cerebral blood velocity and oxygenation responses following simulated hemorrhage induced via application of lower body negative pressure (LBNP) to presyncope. Methods: Healthy males (n=11, 25±1 yr) and females (n=7, 27±1 yr) participated in a LBNP ramp protocol (-3 mmHg/min) until presyncope. Middle cerebral artery velocity (MCAv), cerebral oxygen saturation (ScO2), end-tidal CO2 (etCO2), heart rate (HR), arterial pressure (MAP) and stroke volume (SV) were measured continuously. Results: Baseline MCAv was higher in females vs. males (70.3±5.8 vs. 57.8 ± 2.1 cm/s, p=0.03), despite a lower etCO2 (37.9±0.9 vs. 44.4±1.5 mmHg, p=0.02). While LBNP tolerance was higher for males compared with females (1675.5±123.1 vs. 1315.9±140.0 s; p=0.08), the absolute and relative (% change) increases in HR and decreases in MCAv, MAP, SV, and etCO2 were similar between males and females at presyncope (p≥0.11). Males exhibited a lower rate of change in MCAv over LBNP time (-0.56±0.10 vs. -0.92±0.09 cm/s/min, p=0.03) and a greater maximum decrease in ScO2 (-7.6±1.3 vs -5.3±0.9 %, p=0.08) when compared with females, most likely due to the higher tolerance in this group. Conclusions: These findings suggest that sex may influence the cerebral hemodynamic responses to simulated blood loss in young healthy adults.
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    Does General Health Differ by Physical Activity Levels in Females Ages 55 and Older with Cardiovascular Disease?
    (2018-03-14) Davis, Victoria; Smith, Rachel; Reedy, James; Barron, Kirk; Hartos, Jessica; Hacker, James
    Abstract Purpose: For older adults with existing cardiovascular disease (CVD), few studies have examined the benefits of varying levels of physical activity with respect to general health. The purpose of this study was to assess the relationship between general health and physical activity levels in women ages 55 and older with a history of CVD. Methods: This cross-sectional analysis used 2015 BRFSS data for females ages 55 and older with a history of CVD in Alabama, Arkansas, Louisiana, Mississippi, and Oklahoma. This study analyzed data for three separate conditions related to CVD: stroke, heart attack, and coronary heart disease. Adjusted analysis was conducted to determine the relationship between general health and physical activity levels for each condition while controlling for high blood pressure, diabetes, high cholesterol, weight status, alcohol use, tobacco use, and age. Results: Across states, there was a low prevalence of CVD in females ages 55 and older (8-10%). Participants with CVD had a moderate prevalence of good general health (32-61%) and low prevalence of highly active physical activity (16-25%). Results of adjusted analysis for each of the three CVD related conditions determined good general health was significantly related to being highly active (moderate-to-large effect sizes) in four out of five states. Additionally, for participants with a history of coronary heart disease, good general health was significantly related to being active (large effect sizes) in four out of five states. Conclusions: Overall, good general health was found to be significantly related to active and highly active physical activity levels in population based samples for females ages 55 and older with CVD. Limitations of this study include inability to assess the duration and severity of illness over time. Despite the low prevalence of participants with a history of CVD across states, it is recommended that practitioners educate patients with CVD on the importance of engaging in higher levels of physical activity because of its relationship to general health.
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    Interventions for Peripheral Arterial Disease: A Systematic Review
    (2018-03-14) Quiben, Myla Claire; Lorentsen, Jenna
    Purpose: Peripheral Artery Disease (PAD), affecting 1 in 5 older adults, impacts blood flow to the lower extremities causing cramping or claudication that potentially limits walking, cardiorespiratory response, muscle performance, and quality of life. The purpose of this systematic review is to investigate interventions effective in improving function in individuals with PAD and it’s presenting symptoms. Subjects: Studies reviewed n=21 included Randomized Controlled Trials (RCT’s) and Systematic Reviews (SR’s) with a total of 6,195 subjects ages 60 to 84. For the studies that included the specific subject demographics, there were 3,355 men and 2,202 women with and/or without intermittent claudication. Methods: Literature search was performed on two databases (PubMed and Cochrane Reviews) for randomized controlled trials (RCT’s) and systematic reviews (SR’s) published between 2010 and 2017, using the following search terms: “interventions,” “resistance training,” “strength training,” “treadmill walking,” “intensive walking,” “aquatic therapy,” “ergometry,” and “blood flow restriction” or “BFR” and PAD. Inclusion criteria for study selection included sample size [greater than] 20, any language that is translated in English, subjects with an Ankle Brachial Index (ABI) Data Analysis: The full review of articles was completed by two independent reviewers. Results: Of the 21 studies reviewed 12 RCT’s and 9 SR’s used the following interventions: comparison studies (n=7 studies); resistance training (n= 2 studies), supervised or conventional exercise (n=5 studies), intensive walking programs (n=1 studies), home exercise programs (n=4 studies), and BFR (n=2 studies) in patients with PAD. Outcomes measured to determine the effects of interventions include: Walking Impairment Questionnaire (WIQ), 6MWT, SF-36, time to claudication, maximal walking distance, and aerobic capacity. Of the interventions, standard walking programs, are most effective at improving walking time and distance, time to claudication, 6MWD, Walking Impairment Questionnaire (WIQ), and quality of life (3,4,5,6,7,9,10,11,17). Resistance training has proved to be as effective, if not more effective than walking (8,12,14,16,17,18) using the same outcomes. Other interventions reviewed showed statistically significant outcomes, and may also serve as complimentary or alternative treatments for individuals with PAD (1,2,14). Future research can look into the effects of BFR for PAD, as it has been shown to improve muscle performance in older adults, without having an impact on arterial stiffness (19,20). Conclusion: Although methodologies and interventions widely vary, traditional walking programs are considered the gold standard for improved outcomes for individuals with PAD, however, resistance training is just as effective or better in improving the same outcomes and can serve as a component of or alternative intervention (8,12,14,16,17,18). Cycling, home exercise programs, and walking with poles are other interventions that improved outcomes. Interpretation of the results should take into consideration the following limitations: lack of heterogeneity/homogeneity, subject compliance, lack of standardized interventions across the studies, and presence multi-morbidities. Clinical Relevance: The interventions reviewed are effective in improving outcomes in PAD and are more cost effective than surgical interventions. The presence of comorbidities (i.e. diabetes or other cardiovascular conditions) may attenuate the improvement of symptoms (1,2,15,21) and need to be taken into consideration when measuring exercise tolerance.
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    Are waist circumference, sagittal abdominal diameter, and waist-to-height ratio better predictors of cardiovascular risk than BMI?
    (2018-03-14) Nandy, Karabi; Khan, Mahbuba
    Purpose: Diseases of the heart are the leading causes of death in the US for adults. Obesity, having excess body fat, is one of the major risk factors for heart diseases. Body mass index (BMI) is one of the popular surrogate measures of excess body fat, and it is established as a predictor of cardiovascular risk. However, ethnicity, age, and sex may also influence the association of BMI and excess fat. While abdominal obesity is associated with metabolic syndrome (a composite risk factor for heart disease), BMI does not account abdominal fat; rather it accounts for the overall excess fat. The purpose of this study was to evaluate waist circumference, sagittal abdominal diameter, and waist-to-hip ratio as surrogate measures of abdominal obesity, and compare their performance with BMI as a predictor of heart disease risk. Methods: We used data from National Health and Nutrition Examination Survey (NHANES) 2013-2014 for this study. A total of 5,033 adult subjects (mean age 50.85 years and 54% female) participated the survey. We used high-density lipoprotein (HDL) as a risk factor for heart diseases. Univariate analyses were carried out to assess the strength of association between HDL and waist circumference, sagittal abdominal diameter, waist-to-hip ratio, and BMI. We will estimate the strength of different body fat measures separately to predict the heart disease risk (HDL Results: Average HDL was 52.79 mg/dL and nearly one-fifth of the participants were at risk of heart diseases (HDL/dL). Average BMI, waist circumference and sagittal abdominal diameter were 29.05 kg/m2, 98.93 cm, 22.65 cm, respectively. Our preliminary, unadjusted and unweighted, findings suggested that sagittal abdominal diameter was a slightly better predictor of low HDL than waist circumference and BMI; Pearson correlation coefficients were -0.35, -0.34, and -0.27, respectively. We will further estimate the predictability of waist circumference, sagittal abdominal diameter, waist-to-height ratio, and BMI using logistic regression after adjusting for demographic and socioeconomic status. Conclusions: Findings of this study will help health practitioners to use a better predictor to screen people who are at risk of heart diseases.
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    S1Q3T3 Leading to Early Suspicion of Pulmonary Embolism in Low-Risk Patient
    (2018-03-14) Reddy, Prashanth; Patel, Harsh; Machaiah, Madhrira; Thambidorai, Senthil; Mughal, Iqbal; Ahsan, Syed; Aftabizadeh, Som
    Background/Abstract: Acute pulmonary embolism (PE) may prove fatal without early suspicion and subsequent treatment. Many cases go undiagnosed, with one study showing an estimated 70% of post mortem PE cases were undiagnosed at the time of death.1 Young patients are most at risk of being misdiagnosed as suspicion in this population is very low. Even with a variety of diagnostic modalities a high clinical suspicion remains key for diagnosis.2 The varying degree of clinical presentation makes diagnosing PE very difficult. Here we present a case of a patient with no known risk factors and WELLS score of 0 whose electrocardiogram (EKG) findings led to an early investigation, diagnosis, and subsequent treatment of a massive pulmonary embolism. Case Report: A 34 year old AAM with a PMHx of asthma presented to our ED with a chief complaint of substernal chest pain with associated dyspnea. On arrival, the patient was hemodynamically stable with all VS in normal range. CXR showed no acute process. Our team was called to admit the patient from the ED for uptrending troponins and an EKG with inferior lead T-wave inversions. Troponins trended up to 0.255. His EKG showed sinus tachycardia with T-wave inversion in inferior and anterior leads along with S wave in lead I and Q wave in lead III. WELLS score was 0. Though not sensitive, the EKG findings increased our suspicion for PE. D-dimer was ordered and found to be elevated at 6,693. A stat Chest CTA revealed a large saddle pulmonary emboli. LMWH therapy was initiated. Work-up for genetic and acquired factors were negative and patient was discharged on oral anticoagulation. Discussion/Conclusion: EKG findings in patients with PE have been a topic of much debate since first reports of investigation in 1935. Over the years medicine has evolved with ubiquitous access to more effective modalities for diagnosing PE. Despite the advent of these other modalities, the diagnosis of PE remains elusive and the prognosis is variable depending on clinical presentation and appropriate diagnosis and treatment.4 While the S1Q3T3 pattern is commonly taught in medical schools around the world as the pathognomonic ECG pattern associated with pulmonary embolism, its reported incidence in acute PE is highly variable with studies showing its incidence anywhere from 10-50%.5 Non-specific ST elevation and T wave inversion in inferior and anterior precordial leads are the most frequently noted EKG abnormalities in patients presenting with acute PE.6 Acute pulmonary embolism in young males without risk factors is rare. Given the time sensitive nature of appropriate diagnosis and treatment of PE, it is important that health care providers recognize EKG findings characteristic of PE. These findings can incite suspicion in low risk patients and direct subsequent work-up and management in a timely fashion.