Browsing by Subject "Coronary Circulation"
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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.