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    R21C Mutation in Cardiac Troponin I Imposes Differences in the Degree of Order and Kinetics of Myosin Cross-bridges of Left and Right Ventricles
    (2015-03) Duggal, Divya; Nagwekar, Janhavi; Rich, Ryan; Raut, Sangram; Fudala, Rafal; Das, Hriday; Gryczynski, Zygmunt; Gryczynski, Ignacy; Szczesna-Cordary, Danuta; Borejdo, Julian
    The effect of the TnI R21C mutation in the human cardiac troponin I, the mutation that is linked to hypertrophic cardiomyopathy, on muscles of the left (LV) and right (RV) ventricles was examined in knock-in mice. Experiments probed 3-4 actin molecules in ex-vivo myofibrils prepared from LV and RV muscles. Control anisotropy experiments revealed that the orientation of actin reflected orientation of cross-bridges (XBs). It was found that the mutation imposed significant difference on the XB kinetics cycle of the LV and RV: XBs from RV displayed a 3-fold decrease in the rate of power stroke and a 2-fold decrease in the rate of dissociation from thin filaments as compared to LV. The mutation also imposed significant differences in the distribution of angles that actin makes with thin filament axis: during contraction, actin angles from LV were more tightly distributed compared to actin angles from RV. We speculate that molecular differences between ventricles are caused by inability of XBs to dissociate promptly from thin filaments. This work reveals phenotypic differences of the R21C mutation in the left versus right mouse ventricles even though both ventricles express the same isoform of the cardiac TnI and highlights the importance of functional differences between the two ventricles of cardiac disease.
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    Reproducibility of Near Infrared Spectroscopy (NIRS)-Derived Peripheral Muscle Oxygenation Measurements at Rest and During Central Hypovolemia
    (2015-03) Pham, Grace; Kay, Victoria; Rickards, Caroline
    Background: Noninvasive muscle oxygen saturation (SmO2) measurements from near-infrared spectroscopy (NIRS) sensors have been demonstrated to track the severity of central hypovolemia. The reproducibility of these devices in detecting and tracking reductions in SmO2 during central hypovolemia, however, has not been quantified. Methods: 27 healthy human subjects (11 F, 16 M) were instrumented with a CareGuide 1100 muscle NIRS sensor (Reflectance Medical Inc.) on their right flexor carpi ulnaris muscle for assessment of SmO2, tissue pH, and the microcirculatory index (MCI, an estimate of peripheral resistance). Subjects were exposed to two trials (≥ 4 weeks intervening) of lower body negative pressure (LBNP) applied at a rate of 3 mmHg/min until presyncope or voluntary termination. SmO2, pH, and MCI were compared to stroke volume (SV) responses derived from a non-invasive arterial pressure waveform. Results: SV decreased by ~50% for both trials (p=0.94), and time to LBNP termination was similar (p=0.36). Both baseline and maximal SmO2, pH, and MCI were statistically indistinguishable between the two trials (p≥0.17). Responses of SmO2, pH, and MCI were highly correlated between trials (r≥0.91; p≤0.004; slopes≥0.77), and each parameter tracked the reduction in SV (table). Conclusions: NIRS-derived measurements of SmO2, pH, and MCI were reproducible during central hypovolemia elicited by continuous application of LBNP. These findings support the use of SmO2 to monitor blood loss.
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    N-Acetyl Cysteine Attenuates Hypoxia Induced Sympathoexcitation in Human Subjects
    (2015-03) Jouett, Noah; Moralez, Gilbert; Raven, Ph.D., Peter; Smith, Michael L.
    This investigation tested the hypothesis that central and peripheral reactive oxygen species (ROS) mediate hypoxia induced sympathoexcitation, which is a central feature of the Obstructive Sleep Apnea-Hypopnea Syndrome (OSAS). 10 healthy human subjects were recruited. One hour prior to experimentation, each subject randomly ingested either 70 of N-Acetyl Cysteine (NAC, n=5) or vehicle placebo (n=5). ECG, BP, muscle sympathetic nerve activity (MSNA) and plasma ROS and catecholamines were measured. Subjects underwent a 20 minute intermittent hypoxia training (IHT) protocol consisting of cyclical end-expiratory apneas with 100% N2. Venous blood was analyzed pre/post IHT for ROS by electron paramagnetic spectroscopy and for catecholamines by ELISA. In the placebo group, MSNA was increased between pre vs. post IHT (P=0.01). In the NAC group, however, MSNA was unchanged (P=0.26). NAC reduced the percent change (% ∆) of ROS observed from pre- vs. post-IHT compared to placebo (P=0.02). The % ∆ of ROS was directly related to increasing MSNA (R2=0.83, p=0.01). The % ∆ of norepinephrine was lower in the NAC vs. placebo group after IHT (P=0.05), whereas the % ∆ of epinephrine was unchanged (P=0.40). These data indicate that NAC reduces central sympathetic outflow in response to IHT, and thereby could reduce cardiovascular risk in OSAS patients.
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    The effect of hospital factors on mortality rates after abdominal aortic aneurysm repair
    (2015-03) Sharma, Sneha; Dua, Anahita; Desai, Sapan; Furlough, Courtney L.; Ray, Hunter; Upchurch, Gilbert
    Purpose: Patient factors that contribute to mortality from abdominal aortic aneurysm (AAA) repair have been previously described, but few studies have delineated the hospital factors that may be associated with an increase in patient mortality after AAA. This study used a large national database, the Nationwide Inpatient Sample (NIS), to identify hospital factors that affect mortality rates after open repair (OAR) and endovascular AAA repair (EVAR) of elective and ruptured AAA. Methods: A retrospective analysis was completed using NIS from 1998 to 2011. International Classification of Disease, Ninth Revision codes were used to identify patients who underwent elective or ruptured AAA repair by OAR or EVAR. The association between mortality and hospital covariates, including ownership, bed size, region, and individual hospital volume for these patients was statistically delineated by analysis of variance, χ 2, and Mann-Kendall trend analysis. Results: A total of 128,232 patients were identified over the 14-year period, of which 88.5% were elective procedures and 11.5% were performed acutely for rupture. Most hospitals that complete elective OAR do between one and 50 cases, with mortality between 0% and 40%. Hospitals with mortality >40% uniformly complete fewer than five elective OAR cases annually and fall in the bottom 2.5% of all hospitals for mortality. Most hospitals that complete elective EVAR do between one and 70 cases, with mortality between 0% and 13%. Hospitals with mortality >13% uniformly complete fewer than eight elective EVAR cases annually and fall in the bottom 2.5% of all hospitals for mortality. The majority of hospitals that complete OAR or EVAR for ruptured AAA have between 0% to 100% for mortality, indicative of the high mortality risk associated with rupture. Conclusions: Hospitals that complete fewer than five OARs or eight EVARs annually have significantly greater mortality compared with their counterparts. Improved implementation of best practices, more detailed informed consent to include hospital mortality data, and better regional access to health care may improve survival after elective AAA repair.
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    Spatial Distribution of Actin and Mechanical Cycle of Myosin are Different in Right and Left Ventricles of Healthy Mouse Hearts
    (2015-03) Nagwekar, Janhavi; Duggal, Divya; Rich, Ryan; Raut, Sangram; Fudala, Rafal; Gryczynski, Ignacy; Gryczynski, Zygmunt; Borejdo, Julian
    The contraction of the right ventricle (RV) expels blood into the pulmonary circulation, and the contraction of the left ventricle (LV) pumps blood into the systemic circulation through the aorta. The respective afterloads imposed on the LV and RV by aortic and pulmonary artery pressures create very different mechanical requirements for the two ventricles. In spite of these functional differences, it is commonly believed that the right and left ventricular muscles are identical because there were no differences in stress development, twitch duration, work performance and power among the RV and LV. This report shows that the two ventricles in rigor differ in the degree of orientational disorder of actin within thin filaments, and during contraction they differ in the kinetics of the cross-bridge cycle. Mouse ventricle muscle is the source of sample for experiments in this project. Glycerinated muscle bundles were homogenized and myofibrils were extracted. Myofibrils were labeled with 1 nM rhodamine-phalloidin (RP) + 10 nM unlabeled-phalloidin (UP) in Ca2+-rigor solution in the ratio of 1:1000 fluorescent to non-fluorescent phalloidin to ensure 1 in ~105actin monomers carry a fluorophore. Labeled myofibrils were analyzed for error of the mean of polarized fluorescence to determine kinetic rate constants in the ATPase cycle and distribution of orientations emanating from myosin cross-bridges. Histograms were plotted from the polarized fluorescence data and the Full Width at Half Maximum (FWHM) of the mean was calculated. The mean polarization of a contracting WT LV myofibril power stroke 0.159±0.086 was higher as compared to 0.085±0.035 for RV. Similarly, dissociation of myosin from actin was significantly faster in LV compared to RV. The FWHM of actins of RVs were significantly narrower (better ordered) than those of LVs which shows that the LV and RV of the heart are different. The study suggest that the differences in the rate constants during contraction and orientation of cross bridges during rigor signify the functional differences between left and right ventricles of the healthy mouse heart.
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    Intermittent hypoxic conditioning (ihc) modulates delta opioid receptor (dor) phenotypes
    (2015-03) Estrada, Juan; Caffrey, James L.; Downey, Fred; Mallet, Robert T.
    IHC mediated cardioprotection is dependent on the DOR in dogs. It is predominantly expressed on cholinergic fibers and recruits both vagotonic and vagolytic pathways. Ganglioside GM-1 treatment decreases recruitment vagolytic DOR pathways. Vagal stimulation is cardioprotective, therefore we tested the hypothesis that IHC modulates the receptor phenotype in favor of the vagotonic receptor subtype by changing expression and DOR and GM-1. Dogs were assigned to 3 groups: non-hypoxic sham, IHC, or IHC + N. Atrial tissue was collected for biochemical analysis. Immunoblot densitometry was used to measure DOR protein content and immunocytochemistry followed by line scan intensity analysis of photomicrographs was used to evalaute GM-1. There was an increase in DOR following IHC+N relative to sham (p
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    Universal Cholesterol Screening of all 9 - 11 year old Children in Community Based Ambulatory Pediatric Clinics
    (2015-03) Mou, Margaret; Wilson, Don P.; Davis, Sharon; Matches, Sarah; Shah, Deep; Leung-Pineda, Van; Suzuki, Sumihiro; McNeal, Catherine; Bowman, W. Paul
    Introduction: In the U.S. and in most Western countries, coronary artery disease (CAD) is theleading cause of death, linked to hypercholesterolemia, especially in familial hypercholesterolemia (FH). Early identification and treatment of children with hypercholesterolemia has been shown to be effective and safe in reducing morbidity and mortality, especially in those with FH. However, few children with FH are currently being identified. Thus, the National Heart, Blood and Lung Institute (NHLBI) issued a guideline recommending universal cholesterol screening (UCS) of all 9 – 11 year old children in November 2011. We report a comparison of the number of 9 - 11 year old children screened for hypercholesterolemia 1 year prior to and 1 year following publication of the NHLBI’s screening guidelines in 5 community-based ambulatory pediatric clinics. Methods: Five (5) community-based ambulatory pediatric clinics (4 hospital affiliated and 1 university affiliated) were recruited for this study, with retrospectively obtained data that was de-identified. Cholesterol screening results 1 year prior to publication of the NHLBI’s screening guidelines acted as the baseline for each clinic. Rates and results of lipid screening performed by each clinic in all 9-11 year old children at the time of scheduled or un-scheduled clinic visits was measured. Results: Of all eligible 9–11 year-old children, 489 (17.1%) were screened 1 year prior to publication of recommendations, and 686 (20.1%) were screened 1 year following publication of recommendations for universal cholesterol screening. Specifically, Clinic 1 increased screening from 24.2% to 32.3%, Clinic 2 decreased screening from 19% to 16.1%, Clinic 3 decreased screening from 14.7% to 11.9%, Clinic 4 increased screening from 23.1% to 28.5%, and Clinic 5 increased screening from 8.8% to 14.3% of target population. Conclusion: There was a significant increase in the rates of lipid screening for the five clinics in our study following publication of the NHLBI’s recommendations for universal cholesterol screening compared to the year previous to recommendations. Given the high prevalence of premature CVD associated with familial hypercholesterolemia, additional strategies are needed to improve screening rates. The ability to identify this vulnerable population creates the opportunity for prevention of future cardiovascular disease by encouraging healthy lifestyles and the use of lipid lowering medication.
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    Angiotensin Converting Enzyme 1 (ACE1) Knockdown in the Median Preoptic Nucleus (MnPO) Attenuates Downstream Neural Activation following Chronic Intermittent Hypoxia
    (2015-03) Faulk, Katelynn; Cunningham, Tom
    Sleep apnea is associated with a sustained increase in diurnal blood pressure. Chronic Intermittent Hypoxia (CIH), which simulates the arterial hypoxemia of sleep apnea, also produces a sustained increase in diurnal blood pressure. Several CNS regions that contribute to CIH hypertension have been identified including the MnPO and paraventicular nucleus (PVN). We have shown that viral-mediated shRNA knockdown of ACE1 within MnPO selectively decreases CIH hypertension during normoxia. Our hypothesis is that ACE1 knockdown in the MnPO will decrease FosB, a neuronal activation marker, positive neurons in the PVN which is a downstream target of the MnPO. We tested this hypothesis using a viral vector containing shRNA to ACE1 within the MnPO. Isoflurane anesthetized adult male rats were microinjected in the MnPO with 500nl of an adeno-associated virus containing GFP and either shRNA against ACE1 (shACE1) or scrambled shRNA (shSCM). Mean arterial blood pressure was recorded using radio telemetry. Rats were then exposed to 7 days of CIH (3 minute periods of hypoxia (10% oxygen) and 3 minute periods of normoxia (21% oxygen) for 8 hours/day) or normoxia (room air). Immunohistochemistry was used to assess FosB stained neurons within the MnPO and PVN. FosB positive neurons increased in the MnPO and PVN following CIH in both shSCM and shACE1 groups. However, shACE1 significantly decreased the FosB positive neurons in both MnPO and PVN following CIH. The shACE1 had no effects on FosB staining in normoxic controls. These results suggest that FosB activation within the MnPO and the PVN following CIH is at least partially dependent on MnPO ACE1.
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    Median Preoptic AT1a Receptor Increase Responsible for Sustained Component of Hypertension from Chronic Intermittent Hypoxia
    (2015-03) Shell, Brent; Nedungadi, T. Prashant; Cunningham, J. Thomas
    Sleep apnea sufferers experience repeated bouts of hypoxemia that result in a sustained increase in blood pressure. This hypertension persists despite the cessation of the hypoxic stimulus. Our lab focuses on a model for the hypoxemia experienced during sleep apnea by exposing rodents to chronic intermittent hypoxia (CIH). Previous studies have shown that there is an increase in neuronal activity in regions of the brain associated with sympathetic nerve activity after CIH, but little is known about the specific maladaptive neural changes that occur to drive this pathophysiology. Work from our lab has shown that the Angiotensin II Type 1a Receptor (AT1aR) is up regulated after CIH in the Median Preoptic Nucleus (MnPO). The MnPO receives inputs from circumventricular organs outside the blood brain barrier and synapses on regions controlling sympathetic outflow. This critical location between peripheral sensation neurons and downstream effector neurons makes the MnPO an attractive target for intervention. We hypothesize that CIH results in up-regulation of AT1aRs in the MnPO and results in excessive activation of downstream neurons responsible for sympathetic activation and sustained hypertension. Sprague-Dawley rats receive microinjections of a virus with a short hairpin RNA that binds to the AT1a receptor (AT1ashRNA) RNA or a scramble sequence (SCRshRNA) in the MnPO. After recovery, radio telemetry is implanted for continuous monitoring of cardiovascular variables. Rats proceed through a CIH protocol consisting of a 5 day baseline followed by a 7 days of CIH. On the morning of the 8th day animals are perfused for FosB immunohistochemistry (IHC) or snap frozen for qRT-PCR. Exposure to CIH resulted in a significant increase in AT1aR mRNA in the MnPO which was prevented by of AT1ashRNA.The ability of AT1ashRNA to eliminate the sustained component of hypertension by preventing the increase in AT1aR RNA demonstrates the importance of Ang II MnPO in this type of neurogenic hypertension. The ability of this signaling to influence downstream sympathetic outflow as shown by a lack of FosB IHC in the RVLM provides insight into the mechanism of this disease. These experiments can help us to optimize our current sleep apnea treatment regimen by focusing on blood brain barrier permeable angiotensin receptor blockers as well as provide new therapies for neurogenically derived hypertension.
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    Cardiac Arrest Induces Lung Inflammation 3 days after Cardiac Arrest in Domestic Pigs
    (2015-03) Dietemann, Daniel; Nguyen, Anh Q.; Olivencis-Yurvati, Albert H.; Mallet, Robert T.
    Introduction: Cardiac arrest, a leading cause of death in the United States, is associated with detrimental damages, which includes the lungs. Reperfusion of ischemic tissue following cardiac arrest leads to systemic inflammation inflicted by free radical production. Pyruvate , a cellular metabolite and an antioxidant, has a demonstrated protective anti-oxidative effect on the heart through enhancement of the natural anti-oxidative glutathione system. Purpose: Using Myeloperoxidase activity as a marker for neutrophilic inflammation, we sought to quantify the extent of the inflammation in lung tissue, and to determine pyruvate’s protective effect against ischemia/reperfusion injury in the lung. Methods: Fourteen juvenile male Yorkshire swine were divided into three groups, a sham group(n=3) which underwent no cardiac arrest or CPR protocol, a CPR group(n=5) which received an intravenous infusion of sodium chloride solution, and a CPR + Pyruvate group which instead received an infusion of pyruvate solution(n=6). The CPR groups were placed in cardiac arrest via ventricular fibrillation for six minutes, followed by four minutes of cardiopulmonary compression and subsequent defibrillating counter shocks. The respective infusions were delivered at a rate of 0.1 mmol/kg/min throughout CPR and for 60 minutes following cardioversion. After three days, left lung samples were collected and assayed for protein content and myeloperoxidase activity. Results: Three days following the procedure, Myeloperoxidase (MPO) activity was elevated in animals subjected to cardiac arrest compared to sham, although the result was not statistically significant (P=0.15). Pyruvate did not dampen MPO activity in the left lung.
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    Cardiomyopathy due to Treatment with Anthracyclines
    (2015-03) Polamraju, Tanmayee S.; Bowman, Paul
    This case study illustrates the importance of cardiac monitoring in survivors who have received high dose anthracycline therapy for childhood malignancies. A single case medical file and personal interview were used in obtaining information for the study. MG, a 45 year old woman, was diagnosed with Ewing’s sarcoma of the right femur at 9 years of age, and received over 400 mg/m2 of Doxorubicin. An ECHO performed four weeks into her pregnancy demonstrated a decreased left ventricular ejection fraction (LVEF) of 35.4%, and MG was started on aggressive treatment. Despite appropriate treatment, she was not able to sleep while reclining during the last trimester of pregnancy and progressed to lethargy and shortness of breath on postpartum day 1. She was found to have congestive heart failure with cardiomyopathy; MG was hospitalized and given IV diuretics. Her LVEF has gradually improved since then and is stable at 60%. MG’s cardiomyopathy became evident due to a stressful trigger 22 years after her treatment ended. Without an ECHO performed early in her pregnancy, the cardiomyopathy may not have been diagnosed until she developed symptoms. At that stage in her pregnancy, her condition would have likely progressed significantly endangering her life and possibly resulting in the demise of her child. This case study demonstrates that cardiotoxicity can develop at any time after the completion of treatment. Further, this case study establishes the importance of annual cardiac monitoring for childhood cancer survivors who have been treated with high-dose anthracyclines especially.
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    Neuronal injury from cardiac arrest: aging years in minutes
    (2015-03) Cherry, Brandon H.; Nguyen, Anh Q.; Ryou, Myoung-Gwi; Sumien, Nathalie; Mallet, Robert T.
    Cardiac arrest is a leading cause of death and permanent disability. Most victims succumb to the oxidative and inflammatory damage sustained during arrest/resuscitation, but even survivors typically battle long-term neurocognitive impairment. Although extensive research has delineated the complex mechanisms that culminate in neuronal damage and death, no effective treatments have been developed to interrupt these mechanisms. Of importance, many of these injury cascades are also active in the aging brain. In the aged brain, neurons and other cells are under persistent oxidative and inflammatory stress which eventually damages or kills the cells. With respect to these similarities, it is reasonable to propose that the brain essentially ages the equivalent of several years within the few minutes taken to resuscitate a patient from cardiac arrest. Accordingly, cardiac arrest-resuscitation models may afford an opportunity to study the deleterious mechanisms underlying the aging process, on an accelerated time course. The purpose of this presentation is to highlight parallel mechanisms of brain damage and neuronal death that ensue following cardiac arrest and in the aging brain. Despite their different time courses, mechanistic information gained from studying the two conditions could be harnessed to synergistically advance both fields. Ultimately this could lead to the development of treatments targeting specific components in these neurodegenerative pathways, in order to provide more robust protection of patients from neurocognitive impairment and/or death.
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    Central nuclei activated during long-term facilitation of blood pressure following acute exposures to intermittent hypoxia
    (2015-03) Batliwala, Shehzad; Wu, Qiong; Yamamoto, Kenta; Mifflin, Steve
    Introduction: Acute intermittent hypoxia (AIH) is a protocol used to mimic the arterial hypoxemia that occurs during sleep apnea. AIH involves brief (1 min) exposures to systemic hypoxia (10% FIO2) repeated at 6 min intervals for an hour. Such exposures to AIH induce a phenomenon termed long-term facilitation (LTF). LTF is a long-lasting (at least 3 hr) increase in mean arterial pressure (MAP), heart rate (HR), sympathetic nerve discharge (SND) and phrenic nerve discharge (PND). As LTF represents a form of neuronal plasticity, we were interested in determining what sites within the CNS might be involved in the generation of LTF induced by AIH. Our hypothesis is that AIH will induce activity in central sites typically associated with cardiovascular regulation in the brain. Methods: After rats underwent tracheal intubation and were artificially ventilated, they had femoral artery and venous catheters implanted for measurement of arterial pressure and administration of drugs, respectively. AIH was induced as previously described (Yamamoto et al., 2015). The test rats (n=3) were maintained for 1 hour after the last hypoxic exposure. The control group (n=2) was surgically prepared exactly as the experimental group but was not exposed to hypoxia during the 2-hour experimental period. Following the AIH protocol, rats were sacrificed, transcardially perfused with paraformaldehyde and their brains sectioned on a cryostat and processed for immunohistochemical detection of c-Fos in alternate sections. Cardiovascular parameters were statistically analyzed using 2-way ANOVA. Brain sections containing the central nuclei of interest were examined for the presence of c-Fos. Results: Our protocol of AIH induced a significant increase in all measured cardiovascular parameters (MAP, HR, renal SND and PND) measured 1 hr after cessation of exposure to AIH. This LTF was associated with c-Fos immunoreactivity in neurons located with the NTS and the RVLM but not within the hypothalamic PVN. Conclusions & Future Studies: The generation of LTF appears to be dependent upon medullary sites involved in cardiorespiratory regulation (NTS) and sympathetic outflow (RVLM) but not within hypothalamic cardiorespiratory and sympathetic regulatory nuclei such as the PVN. Future experiments can also use neuronal inhibitors to determine the specific role of each area in AIH-induced LTF, and further clarify the statistical significance of this result. This could provide insights into central areas involved in the persistent sympatho-excitation and hypertension observed in sleep apnea patients.
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    Structural impact of cardiac arrest and resuscitation on right vs. left ventricular myocardium
    (2015-03) Batliwala, Shehzad; Ray, George; Nguyen, Anh Q.; Estrada, Juan; Olivencia-Yurvati, Albert H.; Mallet, Robert T.
    BACKGROUND: Cardiac arrest imposes ischemia on the entire body including the heart itself. Although cardio-cerebral resuscitation and defibrillation are essential to save the cardiac arrest victim, these interventions can damage the heart by initiating reperfusion injury culminating in oxidative stress, inflammation and edema. However, the literature contains a paucity of information on the effects of cardiac arrest, precordial compressions and trans-thoracic countershocks on myocardium structure and the degree of acute inflammation that occurs following cardiac arrest-resuscitation-induced ischemia-reperfusion. Moreover, the specific post-resuscitation structural differences in left vs. right ventricular myocardium have never been reported. The right ventricle is positioned directly beneath the anterior chest wall and receives the initial impact of the forceful precordial chest compressions; furthermore, the right ventricular wall is thinner and less robust than the left ventricular free wall and interventricular septum. Therefore, structural damage resulting from resuscitation efforts may differ in the right vs. left ventricles. Accordingly, this study tested the hypothesis that cardiac arrest, closed-chest cardio-cerebral resuscitation and transthoracic countershocks produce structural injury that is more severe in the right than left ventricular myocardium. METHODS: Isoflurane-anesthetized Yorkshire swine, 25-40 kg of both genders were studied. The heart was arrested by a rapid train of impulses administered with an intravascular pacing wire. After 6 minutes of arrest, precordial compressions were applied at a rate of 100/min for 4 minutes. Transthoracic countershocks (200-300 J) were administered until spontaneous cardiac rhythm was restored. At 72 hours recovery, the heart was excised, and 1 x 1 cm, transmural biopsies of left and right ventricular free wall were collected, formalin-fixed and paraffin-embedded. Non-arrested sham experiments were also performed for comparison with cardiac arrest-resuscitation. Sections were cut, stained with hematoxylin and eosin, and 20 random high power (125 x) fields were examined and scored by an investigator blinded to the protocol. Specific structural endpoints included extracellular expansion, neutrophil invasion and hypercontracted tissue. RESULTS: Sections of left and right ventricular myocardium are currently being analyzed in 6 cardiac arrest and 6 sham experiments for neutrophillic damage and infiltration. It is anticipated that tissue injury will be evident in both ventricles. CONCLUSIONS: The finding of greater extracellular volume, neutrophil count and cardiomyocyte hypercontracture in right vs. left ventricular myocardium will be taken as evidence supporting the hypothesis. Such an outcome would argue for development of interventions to promote post-resuscitation myocardial structural recovery.
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    Cardiovascular Screening in Youth
    (2015-03) Mou, Margaret; Wilson, Don
    The objective of this project is to understand general providers’ screening and treatment processes and treatment options in children with a variety of cardiovascular disease risk factors. Currently, the national standard is to screen for hyperlipidemia and hypercholesterolemia every child within the ranges of 9 to 11 years old. Studies have shown this age to be a critical time that could possibly prevent the development of coronary artery disease as adults. With our study, we aimed to understand current knowledge and the practice patterns of practicing providers for cholesterol screening and treatment in children. Our study created opportunities to understand the knowledge gaps and barriers for universal screening in children ages 9-11 in order to develop improved screening processes and treatment interventions in children with cardiovascular disease risk factors to prevent the future escalation of atherosclerotic heart disease. We created an electronic questionnaire, which was advertised both through the NIH website and through NIH members’ emails, asking what current physicians are doing for cardiovascular screening and follow-up. Results showed that about 80% of providers agreed to screen all children ages 9-11, but there are still barriers to improve screening and treatment, including poor reimbursement and families’ opposition.
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    Effects of Music Therapy on Functional Mobility in Patients with Stroke
    (2015-03) Pittmon, William; Liu, Howe; Ping, Miao; Salem, Yasser
    Abstract Effects of Music Therapy on Functional Mobility in Patients with Stroke Introduction and Purpose: Normally human gait activity is a rhythmic movement of left and right lower extremities, but among patients with stroke, such a movement is often significantly affected or disturbed by the hemiparesis. In last 10-20 years, music therapy (MT) has been introduced to treat patients with stroke for improving mood as well as improving gait pattern. However, no consensus has been reached yet among clinicians on how to best utilize music therapy for patients with stroke. Therefore, the purpose of this review was to evaluate of effectiveness of the music therapy by focusing on: type of music, type of patients with stroke, outcome assessments on functional mobility, and intervention parameters for using music therapy. Methods. PubMed and Scopus were used to search literature in last 15 years. Key words to search were stroke rehab, music rehab, cardiovascular accident, hemi paralysis, hemiparesis, music, rhythmic, auditory stimulation, metronome, and gait. Longitudinal studies included randomized control trial, single group study or case study with music therapy as one of the interventions. Results. Five articles qualified for our literature analysis. It was found that listening to rhythmic auditory stimulus (3) was the most favored intervention, followed by listening to a patient’s familiar music (1), and utilizing a metronome synchronizing que in gait training. (1) All of these studies indicated that patients with sub-acute and chronic stroke could benefit more; no acute patients were reported. It revealed that combined use of MT with regular gait training could provide better results than MT alone. The most notable used intervention parameters were: 30 minutes each time, 5 times a week, for a minimum of 3 weeks. In these studies patients demonstrated improvement in gait velocity, stride length, cadence, symmetry, and standing balance as measured by GaitRite. Also it showed that after MT, patients with stroke could improve their balance and functional mobility as measured by Biodex, and 10 meter walking test respectively. Conclusions. Music therapy is an effective and economical intervention for patients with stroke. Patients whom are more likely to benefit are those: with sub-acute stroke and have a lesion supplied by the middle cerebral artery. The MT intervention should be provided at least 5 times a week for minimal 3 weeks and used with functional gait training. Both temporal and spatial gait parameters, balance, mobility, and could be improved with MT.
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    The Effect of Continuous Positive Airway Pressure Treatment on Cardiovascular Reactivity in Patients with Obstructive Sleep Apnea
    (2015-03) Romano, James J. III; Jouett, Noah P.; Watenpaugh, Don; Smith, Michael L.
    INTRODUCTION: Obstructive sleep apnea (OSA) is commonly associated with significantly elevated sympathetic activity throughout the day and during sleep (a time when sympathetic activity normally decreases). It is also well-known that chronically elevated sympathetic activity profoundly increases risk of cardiovascular disease and contributes to disease progression. Nevertheless, it is not clear whether OSA patients tend to have exaggerated stress responses similar to other patient populations. Despite documented improvements on blood pressure with use of continuous positive airway treatment (CPAP), it is unknown whether CPAP also improves the stress response in these patients. We tested the hypothesis that effective treatment of OSA (with CPAP) would reduce the autonomic-mediated stress response to voluntary apneas. We assessed cardiovascular reactivity as the pressor response to hypoxic apneas and also assessed baseline blood pressure and heart rate variability (indices of basal autonomic function) in treated and untreated OSA patients. METHODS: 22 OSA patients were recruited including 14 who were untreated and 8 who were effectively treated with CPAP for at least 3 months and had demonstrated treatment compliance and efficacy as determined by a high treatment success index. Subjects were fitted with a three lead electrocardiogram to measure the electrical activity of the heart, a pulse oximeter to observe continuous blood oxygen saturation and a Finometer to measure beat to beat arterial pressure through the duration of the study. Following a baseline period, subjects were then instructed to initiate a voluntary apnea (breathhold) lasting 20 sec. Data were collected electronically on to data acquisition system for subsequent analyses. RESULTS: The PAP-treated OSA subjects exhibited a lower BP response to apnea than treated subjects. CONCLUSION: These data demonstrate that CPAP decreases the pressor response to voluntary breathholds which is a form of stress. Previous studies in our lab have shown that these responses are primarily mediated by the sympathetic nervous system, thus these data suggest that the sympathetic response to stress is reduced in well-treated OSA patients. Finally, the decrease in sympathetic activity appears to be independent of any alterations of vagal outflow as no significant differences in the heart rate variability was observed.
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    Effects of pyruvate fortified cardiopulmonary resuscitation on myocardial injury after cardiac arrest
    (2015-03) Ray, George; Batliwala, Shehzad; Nguyen, Anh; Estrada, Juan; Olivencia-Yurvati, Albert H.; Mallet, Robert T.
    Effects of pyruvate fortified cardiopulmonary resuscitation on myocardial injury after cardiac arrest BACKGROUND: Cardiac arrest kills 400,000 Americans annually. Over 90% of victims outside the hospital and 76% of those inside the hospital succumb to the destructive effects of cardiac arrest on the vital organs. To save the victims, forceful precordial chest compressions and trans-thoracic countershocks are applied, but the use of metabolic substrates as adjuvant treatments for cardiac arrest has not been tested clinically. Pyruvate, a natural intermediary metabolite, energy substrate and antioxidant, has been found to be cardioprotective during ischemia. Pyruvate accomplishes this cardioprotection through several mechanisms including enhancement of myocardial energy reserves and antioxidant defenses, and reduction of reactive oxygen species. Pyruvate-fortified cardioplegic solution administered during cardiopulmonary bypass hastened recovery of cardiac function and shortened hospitalization in patients undergoing coronary revascularization. Despite these discoveries, pyruvate’s effects on myocardial structural damage and inflammation after cardiopulmonary resuscitation and defibrillatory countershocks treated cardiac arrest have not been reported. This study tested the hypothesis that intravenous pyruvate administration minimizes left ventricular structural damage and inflammation that result from myocardial ischemia-reperfusion, precordial chest compressions, and trans-thoracic countershocks. METHODS: Isoflurane-anesthetized Yorkshire swine, 25-40 kg of both genders were studied. The heart was arrested by rapid pacing. After 6 minutes of arrest, precordial compressions were applied at a rate of 100/min for 4 minutes while sodium pyruvate or NaCl control was infused iv to a concentration of 4 mM. Transthoracic countershocks (200-300 J) were administered until spontaneous cardiac rhythm was restored, and infusions maintained until 60 min recovery. The pigs were recovered for 72 hours, and then transmural biopsies of left ventricular free wall were collected, formalin-fixed and paraffin-embedded. Non-arrested sham experiments also were performed and compared with pyruvate- and NaCl-treated cardiac arrest-resuscitation. Sections were cut, stained with hematoxylin and eosin, and 20 random high power (100x) fields were examined and scored by an investigator blinded to the protocol. Structural endpoints included extracellular expansion, neutrophil invasion and hypercontracted tissue. RESULTS: Sections of left ventricular myocardium are currently being analyzed from the 6 sham, 6 cardiac arrest, and 6 pyruvate treated cardiac arrest experiments for neutrophil infiltration, edema, hypercontraction and other evidence of structural damage. CONCLUSIONS: Evidence of decreased neutrophil count, extracellular volume and cardiomyocyte hypercontraction in pyruvate-treated vs. control myocardium 72 h after cardiac arrest will be taken as evidence supporting the hypothesis. Such outcomes would argue for the acute use of pyruvate based interventions during initial treatment to promote post-cardiac arrest myocardial structural integrity.
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    Cerebral Blood Flow Regulation Following Inhalation of Nicotine via Electronic Cigarettes
    (2015-03) Colby, Hannah B.; Sprick, Justin D.; Pham, Grace; Cooke, William H.; Fogt, Donovan L.; Rickards, Caroline A.
    Background: The use of electronic cigarettes (e-cigarettes) is growing rapidly but the physiologic effects of vaporized nicotine are relatively unknown. We hypothesized that acute inhalation of vaporized nicotine via e-cigarettes would impair regulation of cerebral blood flow (CBF) in response to variations in arterial pressure (cerebral autoregulation, CA). Methods: 13 subjects (6 F; 7 M) inhaled vapor from an 18 mg nicotine (nicotine) or a 0 mg nicotine (placebo) e-cigarette on separate days (randomized). Heart rate (HR), mean arterial pressure (MAP), mean middle cerebral artery velocity (MCAv), and cerebral oxygen saturation (SCO2) were measured non-invasively. Oscillatory lower body negative pressure (OLBNP) between 0 and -60 mmHg was applied for 20 cycles at 0.05 Hz and 0.10 Hz. Results: Between placebo and nicotine conditions, baseline MAP, MCAv, SCO2, and HR were similar (P≥0.21). MAP and ScO2 very low frequency (VLF; 0.04-0.07 Hz) power with 0.05 Hz OLBNP, and low frequency (LF; 0.07-0.2 Hz) power with 0.1 Hz OLBNP were higher under the placebo condition (P≤0.03-0.06). Cross-spectral analysis in the LF (with 0.1 Hz OLBNP) and VLF (with 0.05 Hz OLBNP) revealed that gain between MAP-MCAv was similar between conditions (P≥0.128). MCAv-ScO2 and MAP-ScO2 coherences wereConclusion: These data suggest that nicotine, when acutely inhaled via e-cigarettes, does not impair the cerebral pressure-flow relationship.
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    Pyruvate’s Neuroprotection in the Brain Following Cardiac Arrest-Resuscitation
    (2015-03) Nguyen, Anh Q.; Valdes, Melissa; Hollrah, Roger A.; Williams, Arthur G. Jr.; Ryou, Myoung-Gwi; Scott, Gary; Olivencia-Yurvati, Albert H.; Mallet, Robert T.
    Introduction: Ischemia and reperfusion as a result of cardiac arrest (CA) imposes detrimental injuries to the brain. Previous studies showed that pyruvate, an antioxidant and a cellular metabolite, was associated with upregulation of cellular defense pathways such as hypoxia induced factor 1α (HIF-1α), erythropoietin (EPO), nuclear factor erythroid 2-related factor (Nrf-2) and downregulation of proteins directly involved with apoptosis. Hypothesis: Pyruvate iv infusion during resuscitation preserves neurons and its supportive cells, and thus fosters post-CA neurocognitive recovery in swine. Methods: Yorkshire swine (25-35 kg; n = 18) were subjected to pacing-induced CA, cardiopulmonary resuscitation (CPR) at approximately 100/min at 10-14 min CA, and transthoracic countershocks to restore sinus rhythm. NaCl or Na-pyruvate was infused iv (0.1 mmol/kg/min) during compressions and the first 60 min recovery. At 4 h reperfusion, brain biopsies were freeze-clamped for biochemical analysis and fixed in 10% formalin for immunohistochemistry. Results: At 4h recovery, pyruvate treatment was correlated with an increase trend in hippocampal and cerebellar HIF-1α, EPO, and heme oxygenase-1 (HO-1), a key player in Nrf-2/HO-1 antioxidant pathway. Pyruvate did not affect brain Nrf-2 content among animals subjected to cardiac arrest. Conclusions: Many cellular pathways may contribute to initial brain injury and protection after CA. Further analyses are being conducted to elucidate pyruvate’s neuroprotection effect on the brain after ischemia-reperfusion by CA. NINDS support: R01 NS076975