Browsing by Author "Tune, Johnathan D."
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Item Characterization of Arterial Pressure and Cerebral Blood Flow Responses To Repeated Thigh Cuff Inflation In Three Experimental Models (Humans, Pigs, Rats)(2022-05) Bhuiyan, Nasrul A.; Rickards, Caroline A.; Tune, Johnathan D.; Cunningham, J. ThomasIn a human model of simulated blood loss, oscillatory patterns of arterial pressure and blood flow, or "pulsatile perfusion", can protect cerebral and peripheral tissue oxygenation, and prolong tolerance to this stress. In this pilot study, we characterize the hemodynamic responses to pulsatile perfusion therapy induced via repeated thigh cuff inflations in humans at rest, and in pig and rat models of actual blood loss. In 2 human participants, 0.1 Hz (10-second cycle) thigh cuff oscillations induced robust 0.1 Hz oscillations in arterial pressure and cerebral blood flow. In the two animal models, all subjects underwent a baseline period, hemorrhage of 55% of total blood volume, then a 30-min period with or without thigh cuff oscillations (0.1 Hz for pigs, and 0.5 Hz for rats). Decreases in mean arterial pressure (MAP) and carotid artery blood flow were observed in response to hemorrhage (P≤0.002) in both pigs and rats. At the end of the PPT period, however, no differences were observed between the oscillation or no oscillation groups for absolute MAP (rats, P=0.44; pigs, P=0.90) or common carotid artery (CCA) peak blood flow (rats, P=0.92; pigs, P=0.93). When examining the frequency power spectrums, there was not a robust increase in 0.5 Hz oscillations for MAP (P=0.23) or CCA flow (P=0.82), but 0.1 Hz oscillations were detected in CCA flow for pigs (P=0.09). While in the human model, large increases in oscillatory power were observed for both arterial pressure and cerebral blood flow, the responses in the two animal models were inconclusive due to high inter-individual variability. These findings indicate the need for further studies and refinement of the thigh cuff approach in the animal models to reliably induce hemodynamic oscillations.Item Hemodynamic Responses to Oscillatory Thigh Cuff Inflations(2023-05) McIntyre, Benjamin J.; Rickards, Caroline A.; Tune, Johnathan D.; Farmer, GeorgeExperimental generation of 0.1 Hz oscillations (~10-s cycle) in arterial pressure and cerebral blood flow (CBF) increases tolerance to simulated hemorrhage, and protects cerebral tissue oxygenation. In this study we evaluated a clinically applicable method of inducing 0.1 Hz oscillations in arterial pressure and CBF via repeated thigh cuff inflations. We also characterized the effect of common carotid artery (CCA) stiffness on the magnitude of cerebral blood flow oscillations, and evaluated the effects of intermittent thigh cuff inflation on several markers of cardiac function. We hypothesized that: 1) the amplitude of arterial pressure and CBF oscillations at 0.1 Hz would increase in response to repeated thigh cuff inflations at 0.1 Hz, 2) the magnitude of 0.1 Hz CBF oscillations would be positively correlated to the stiffness of the CCA, and 3) measurements of cardiac function would increase in response to thigh cuff induced oscillations of arterial pressure at 0.1 Hz. Thirteen healthy human participants were tested (6 male, 7 female; 27.1 ± 4.3 y). In response to 10-min of intermittent thigh cuff inflations at 0.1 Hz, the amplitude of 0.1 Hz oscillations increased for mean arterial pressure (MAP; 24.4 ± 20.1 mmHg2 vs. 932.0 ± 758.1 mmHg2; P<0.01) and middle cerebral artery velocity (MCAv; 17.5 ± 13.8 (cm/s)2 vs. 325.5 ± 279.9 (cm/s)2; P<0.01). There was also a large increase in MAP-MCAv coherence at 0.1 Hz (0.60 ± 0.24 a.u. vs. 0.90 ± 0.11 a.u.; P<0.01) during the oscillatory period compared to baseline. There was a moderate positive relationship between CCA stiffness and amplitude of MCAv power at 0.1 Hz during intermittent thigh cuff inflations (r=0.68, P=0.01), but not at rest (r=-0.08, P=0.80). When compared to baseline, no changes were observed during the oscillatory period for heart rate (P=0.47), stroke volume (P=0.87), cardiac output (P=0.55), MAP (P=0.20), or dP/dTmax (P=0.61). Future studies directly examining sympathetic nerve activity are needed to better elucidate the effects of induced 0.1 Hz hemodynamic oscillations on neural regulation of the cardiovascular system. In conclusion, we have shown that intermittent thigh cuff inflations can be used to increase hemodynamic variability at a target frequency, and therefore could be a therapy for treating tissue hypoperfusion following severe blood loss injuries.Item Interplay between metabolic and myogenic mechanisms in coronary pressure-flow autoregulation(2022-05) Warne, Cooper M.; Tune, Johnathan D.; Dick, Gregory M.; Mallet, Robert T.The local metabolic hypothesis proposes that myocardial oxygen tension, indexed by coronary venous PO2 (CvPO2), determines the degree of coronary pressure-flow autoregulation. Conversely, the myogenic hypothesis proposes that pressure-induced vascular tone, indexed by the pressure at which coronary flow is zero (Pzf), determines autoregulation. My working hypothesis posits that if metabolism predominates, then autoregulation will be directly related to CvPO2, irrespective of reductions in coronary vasomotor tone. Conversely, if a myogenic mechanism predominates, then autoregulation will be directly related to Pzf, regardless of underlying CvPO2. I tested these hypotheses by examining the extent to which exaggeration of the metabolic error signal and attenuation of myogenic tone influences coronary autoregulation. Experiments were performed in anesthetized, open-chest swine in which a coronary artery was cannulated and connected to a servo-controlled roller pump system. This allowed coronary perfusion pressure (CPP) to be incrementally reduced from 140 to 40 mmHg before and during hypoxemia (SO2 ~50%). CvPO2 decreased 13 mmHg and coronary blood flow fell 57% as CPP was reduced. Hypoxemia augmented myocardial oxygen consumption (P < 0.01), increased coronary blood flow (P < 0.0001), and reduced CvPO2 (P < 0.0001) over the same CPP range. Coronary blood flow during hypoxemia maintained myocardial oxygen delivery (P = 0.20). Hypoxemia increased closed-loop autoregulatory gain (Gc) over a CPP range of 120 to 60 mmHg (P = 0.02). Gc was inversely correlated to CvPO2 and Pzf, but the correlation was stronger for CvPO2. These findings support that coronary pressure-flow autoregulation is augmented by hypoxemia-induced increases in the local metabolic error signal, regardless of the myogenic tone.Item The effects of esmolol on the control of coronary blood flow and myocardial oxygen supply-demand balance in sepsis(2023-05) Bradford, Ni' Ja D.; Hodge, Lisa M.; Dick, Gregory M.; Tune, Johnathan D.; Mallet, Robert T.Purpose: Sepsis is life-threatening acute organ dysfunction secondary to infection and a major cause of morbidity and mortality in critically ill patients. Sepsis accounts for ~5% of the U.S.'s hospital costs. Hallmarks of sepsis include cognitive impairment, elevated heart rate, low blood pressure, metabolic acidosis, immune dysfunction, respiratory dysfunction, capillary leakiness, thermal dysregulation, multiple organ dysfunction, and shock. Currently, the standard treatment of care includes fluid therapy, antibiotics, and vasopressors; however, these treatments are not optimal, as the mortality rate approaches 26%. The current standard of care for sepsis does not address increases in heart rate, but recent trials show that esmolol (a short-acting, highly selective beta blocker) reduces mortality. Esmolol effectively controls heart rate without increasing adverse effects. Importantly, the mechanisms of action of esmolol during sepsis are not well understood, particularly regarding the coronary circulation. The purpose of this study is to investigate the effects of esmolol on the control of coronary blood flow and myocardial oxygen supply-demand balance in sepsis. We chose the pig as a model because they closely resemble humans in terms of heart rate, blood pressure, and alveolar ventilation, making it a robust large animal model for translational research. We hypothesize that treatment with esmolol during acute sepsis will increase survival, maintain coronary perfusion pressure, and improve myocardial oxygen delivery. We also predict that esmolol will improve mixed venous oxygen saturation and attenuate lactic acidosis. The following specific aim will be addressed: Identify coronary vascular mechanisms underlying the protective effect of esmolol during acute sepsis. Methods: Yorkshire pigs (61.3 ± 9 kg, n=11) were used. Our model of acute sepsis is an anesthetized, open-chest pig instrumented for measurements of coronary blood flow, arterial pressure, and blood sampling (arterial, mixed venous, and coronary venous). Lipopolysaccharide (LPS; 10 μg/kg) was infused intravenously over 2 h. At the end of LPS infusion, medical intervention was started and lasted 4 h. Three medical interventions were compared: 1) no treatment 2) standard treatment of saline plus norepinephrine (NE, to maintain blood pressure) and 3) experimental treatment of the combination of saline, NE, and esmolol (to maintain blood pressure and reduce heart rate). A sham group where no LPS or treatment was given was compared to the other three medical interventions to account for values affected by the anesthesia. Hemodynamic variables were measured constantly, while blood samples were taken every 30 min. Results: Only the sham and the experimental group treated with esmolol in addition to the standard treatment had a 100% survival rate, whereas the standard treatment group had a 75% survival rate. The control group had a 0% survival rate. The addition of esmolol to standard treatment effectively reduced heart rate in comparison to every other treatment group. Additionally, the addition of esmolol was better able to maintain mean arterial pressure, coronary blood flow, myocardial oxygen delivery, and extraction closer to baseline than the standard treatment or the control groups. Indicating that esmolol improved myocardial oxygen supply and demand balance. Furthermore, esmolol attenuated the reduction of coronary venous PO2 in septic patients. However, esmolol did not attenuate the reduction of mixed venous PO2 or elevated lactic acid in the porcine sepsis model. Conclusions: The outcomes of the study provide greater insight into the coronary vascular mechanisms of esmolol treatment that promote survival in sepsis. The impact of our studies will be a more solid mechanistic foundation upon which to design clinical trials of esmolol patients with sepsis.Item The Effects of Insulin on Myocardial Glucose Metabolism and Contractile Function During Moderate Coronary Hypoperfusion(1997-08-01) Tune, Johnathan D.; Downey, H. Fred; Mallet, Robert T.; Caffrey, James L.Tune, Jonathan David, The Effects on Insulin on Myocardial Glucose Metabolism and Contractile Function during Moderate Coronary Hypoperfusion Doctor of Philosophy (Biomedical Sciences), August, 1997, 98 pp, 3 tables, 11 figures, references, 117 titles. This study was designed to determine the effects of insulin on myocardial metabolism and contractile function during moderate coronary hypoperfusion. Coronary perfusion pressure (CPP) was lowered from 100 to 60, 50, and 40 mmHg in the left anterior descending coronary artery of anesthetized, open chest dogs. Regional glucose uptake, lactate uptake, oxygen consumption (MVO2), and percent segment shortening were determined without (n=12) or with either intravenous insulin (4 U/min, n=12) or intracoronary insulin (4 U/min, n=6). Glucose metabolites, high energy phosphates, and the phosphorylation state of creatine phosphate were determine in freeze clamped biopsies of control (n=6), and of intravenous insulin (n=6) treated hearts at the completion of the protocol (CPP = 40 mmHg). Glucose uptake increased with both intravenous and intracoronary insulin treatments (P0.05). Thus, insulin treatment improved contractile function while myocardial oxygen demand was unchanged, i.e. oxygen utilization efficiency increased. Myocardial glycogen, alanine, lactate, and pyruvate contents were not significantly different in untreated and intravenous insulin treated hearts. Reducing CPP to 40 mmHg produced similar changes in both untreated and insulin treated hearts: ATP content was unchanged, creatine phosphate content decreased 17%, creatine content and inorganic phosphate concentration increased 27% and 124%, respectively, and the phosphorylation potential decreased 80%. We conclude that 1) when the potentially detrimental effects on insulin stimulated glucose metabolism are avoided during moderate ischemia, insulin treatment increases contractile function without significantly elevating myocardial oxygen demand; 2) during moderate ischemia, insulin stimulated glucose metabolism increases oxygen utilization efficiency and prevents a further decline in the energy state of the myocardium.Item The impact of early life stressors on the progression of SLE(2021-08) Hartman, Rusty L.; Mathis, Keisa W.; Cunningham, J. Thomas; Hodge, Lisa M.; Tune, Johnathan D.Our preliminary studies show that an established model of systemic lupus erythematosus (SLE), the female NZBWF1 mouse, had worsened indices of disease later in life when the mice were shipped to our institution at an early age during the summer. We hypothesized that interleukin (IL)-6-induced release of heat shock protein 90 (HSP90) is upregulated in response to this summer early-life stressor, thus accelerating autoimmunity and renal disease in female SLE mice. To begin to study this, we measured renal IL-6 and HSP90 in 6-week-old female NZBWF1 mice that were shipped in winter or summer months and found that both were elevated immediately following summer compared to winter travel. Our findings indicate that the mediators associated with early-life travel/seasonal stressors may predict the progression of autoimmunity in SLE-prone mice. Other findings here within highlight the specificity of this effect in the kidney and describe sex differences in the observed phenomena.Item The Interaction Between Arterial Stiffness, Amplitude of Cerebral Blood Flow Oscillations, and Cerebral Tissue Oxygenation(2024-05) Hudson, Lindsey M.; Rickards, Caroline A.; Tune, Johnathan D.; Dick, Gregory M.Inducing 0.1 Hz (10-s cycle) oscillations in cerebral blood flow attenuates the reduction in cerebral tissue oxygenation during simulated hemorrhage in humans. Our laboratory has developed a potential therapeutic technique called pulsatile perfusion therapy (PPT) which induces 0.1 Hz oscillations in cerebral blood flow. It is unknown, however, how stiffness of the arteries influences the magnitude of cerebral blood flow oscillations, and/or the protection of cerebral tissue oxygenation. When 0.1 Hz oscillations are induced during simulated hemorrhage, we hypothesized that: 1) arterial stiffness of the internal carotid artery (ICA) and common carotid artery (CCA) would increase from rest; 2) the amplitude of 0.1 Hz oscillations in cerebral blood flow would be higher in individuals with stiffer arteries, and; 3) the reduction in cerebral tissue oxygenation would be smaller with higher amplitude of cerebral blood flow oscillations. Two studies using two different techniques of PPT were performed to investigate these hypotheses. Study 1: In a retrospective analysis, 8 healthy human participants (age: 30.1±7.6 y) underwent a 10-min hypovolemic oscillatory lower body negative pressure (OLBNP) protocol, where chamber pressure oscillated every 5-s between -30 mmHg and -90 mmHg (i.e., 0.1 Hz). ICA β-stiffness index was calculated from measurements of ICA diameter (via ultrasound imaging), and arterial pressure (via finger photoplethysmography). Middle cerebral artery velocity (MCAv) was measured using transcranial doppler ultrasound, and cerebral tissue oxygenation (ScO2) was measured with near infrared spectroscopy. Fast Fourier transformation was used to quantify oscillations in mean MCAv at ~0.1 Hz. While mean MCAv 0.1 Hz oscillations increased from baseline to OLBNP (N=8, 34.0±33.9 (cm/s)2 vs. 104.7±58.1 (cm/s)2, p=0.01), ICA β stiffness did not increase (N=5, 6.1±0.7 au vs. 8.2±2.7 au, p=0.21). There was no relationship between baseline ICA β-stiffness and the percent change in mean MCAv 0.1 Hz oscillations (N=5; r=0.44, p=0.46). ScO2 decreased from baseline to OLBNP (N=8, 66.5±2.9 % vs. 64.8±2.9 %, p=0.03), but there was also no relationship between the percent change in mean MCAv 0.1 Hz oscillations and the decrease in ScO2 (r=0.28, p=0.50). Study 2: In a prospective pilot study, 3 participants underwent a 10-min LBNP protocol to a chamber pressure of -60 mmHg, and hemodynamic oscillations were simultaneously induced with bilateral thigh cuffs inflating for 5-s to 230 mmHg then deflating for 5-s in a 10-s cycle (i.e., 0.1 Hz). β-stiffness index of the CCA was measured. In this pilot study, insufficient data were collected to perform statistics for each of the three aims, so descriptive results are presented. Adequate ultrasound measurements were made for assessment of CCA β- stiffness in two participants; in the control condition, CCA β-stiffness was 6.7 ± 2.4 au during baseline and increased to 7.4 ± 1.1 au during LBNP (N=2). With PPT, CCA β-stiffness was 6.6 ± 1.6 au during baseline and increased to 7.8 ± 2.2 au during LBNP (N=2). The amplitude of MCAv 0.1 Hz oscillations increased from 7.9 (cm/s)2 at baseline of the control condition to 179.8 (cm/s)2 (i.e., a ~23-fold increase) during LBNP. The amplitude of MCAv 0.1 Hz oscillations increased from 25.8 (cm/s)2 during baseline of PPT to 210.2 (cm/s)2 (~8-fold increase) during LBNP (N=1). ScO2 decreased from 75.0% to 71.3% during LBNP in the control condition, and from 73.4% to 71.6% in the PPT condition (N=1). Based on the results of Study 1, 0.1 Hz OLBNP does not increase ICA stiffness, and there is no relationship between ICA stiffness, amplitude of induced 0.1 Hz cerebral blood flow oscillations, and the reduction in cerebral tissue oxygenation during simulated hemorrhage. However, as this analysis was performed retrospectively, and arterial stiffness was not initially an outcome measure, there were limited data available for analysis. For Study 2, we were successfully able to induce 0.1 Hz oscillations in cerebral blood flow by combining LBNP with bilateral thigh cuff inflations. However, insufficient data were available to make definitive conclusions about the role of PPT on CCA β-stiffness, 0.1 Hz oscillations in cerebral blood flow, or the relationship in 0.1 Hz oscillations in cerebral blood flow and protection of cerebral tissue oxygenation. This study is currently ongoing, and additional data will provide further insight into these relationships.