Cardiovascular
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/30805
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Browsing Cardiovascular by Author "Dick, Gregory"
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Item Hypoxemia Augments the Local Metabolic Error Signal and Improves Coronary Pressure-Flow Autoregulation(2022) Warne, Cooper M.; Essajee, Sal; Dick, Gregory; Tune, JohnathanThe local metabolic hypothesis proposes that myocardial oxygen tension, indexed by coronary venous PO2 (CvPO2), determines the degree of coronary pressure-flow autoregulation by increasing the production of vasodilator metabolites as coronary perfusion pressure (CPP) is reduced. We tested this hypothesis by examining the extent to which exaggeration of the metabolic error signal influences coronary autoregulatory capability. Experiments were performed in anesthetized, open chest swine (n = 8) in which the left anterior descending coronary artery was cannulated and connected to a servo-controlled roller pump system. This allowed CPP to be reduced from 140 to 40 mmHg in increments of 10 mmHg before and during hypoxemia (PaO2 from 138 ± 5 to 34 ± 1 mmHg). Under control-normoxic conditions, CvPO2 decreased from 33 ± 1 to 20 ± 1 mmHg and coronary blood flow fell from 0.81 ± 0.09 to 0.35 ± 0.04 ml/min/g as CPP was reduced from 140 to 40 mmHg. Hypoxemia augmented myocardial oxygen consumption (P < 0.01), increased coronary blood flow (P < 0.0001), and reduced CvPO2 (22 ± 1 to 14 ± 1 mmHg; P < 0.0001) over the same range of CPPs. Increases in coronary blood flow during hypoxemia were sufficient to maintain myocardial oxygen delivery at values equivalent to normoxic conditions (P = 0.20). Calculation of closed-loop autoregulatory gain (Gc) over a CPP range of 120 to 60 mmHg (value of 1 represents perfect autoregulation) demonstrated that Gc was improved from 0.18 ± 0.05 to 0.45 ± 0.14 under normoxic vs. hypoxemic conditions respectively (P = 0.02). Gc was also inversely related to CvPO2 and the slope increased ~4-fold by hypoxemia. These findings support that coronary pressure-flow autoregulatory capability is augmented by hypoxemia-induced increases in the local metabolic error signal.Item Impaired cardiovascular function in obese Ossabaw swine model of heart failure with preserved ejection fraction(2022) Weber, Theodore Van; Dick, Gregory; Gerlt, Deitrich; Bale, Alexander; Warne, CooperPresenter: Ted Weber Authors: Ted Weber, OMS-II; Deitrich Gerlt, Alex Bale, Cooper Warne, Gregory Dick PhD, Johnathan Tune, PhD Title: Impaired cardiovascular function in obese Ossabaw swine model of heart failure with preserved ejection fraction Background: The lack of pre-clinical large animal models of heart failure with preserved ejection fraction (HFpEF) remains a growing, yet unmet obstacle to improving understanding of this complex condition. Objective: The goal of this study was to examine cardiovascular responses to acute reductions in blood pressure in lean-control vs. obese Ossabaw swine with HFpEF (obese HF). Heart failure was induced by chronic tachycardia at 180 beats/min for ~4 weeks. We tested the hypothesis that rapid ventricular pacing would augment left ventricular end diastolic pressure, impair cardiac contractile function, and diminish regional myocardial perfusion. Methods: Following completion of pacing protocol, swine were anesthetized and instrumented for continuous measurements of hemodynamic parameters, left ventricular pressure, volume, and coronary blood flow. After measurements were obtained under baseline conditions, blood was serially removed to lower blood pressure in ~10 mmHg increments down to a mean arterial pressure of ~40 mmHg. Arterial and coronary venous blood samples were obtained at rest and during each reduction in blood pressure. Results: Chronic tachycardia significantly increased left ventricular end diastolic pressure (P < 0.001) but did not affect ejection fraction (P = 0.79) in obese HF (n = 5) vs. lean-control (n = 7) swine. Hemorrhage reduced blood pressure from 106 ± 5 mmHg to 40 ± 1 mmHg vs. 102 ± 4 mmHg to 41 ± 1 mmHg in lean-control and obese HF swine, respectively. Reductions in arterial pressure robustly increased heart rate from 73 ± 8 to 136 ± 19 beats/min in lean swine. In contrast, the reflexive heart rate response was significantly attenuated in obese HF, as evidenced by a 4-fold reduction in the slope of the relationship between heart rate and blood pressure in obese HF vs. lean-control swine (P < 0.01). These changes were associated with significant reductions in the relationship between cardiac index (cardiac output/body weight) and end diastolic volume (P < 0.01), while the ratio of subendocardial to subepicardial blood flow to the left ventricle remained consistent as blood pressure was diminished in lean-control and obese HF (P = 0.53). Conclusions: These findings support that chronic high-rate ventricular pacing of obese Ossabaw swine induces key phenotypic features of HFpEF, including elevated left ventricular end diastolic pressure with normal ejection fraction, chronotropic incompetence, and impaired ventricular contractility.Item Innate immune system stimulation during pregnancy induces upregulation of thromboxane synthesis in rat maternal heart(2022) Tucker, Selina; Cushen, Spencer; Bradshaw, Jessica L.; Gardner, Jennifer; Ricci, Contessa; Dick, Gregory; Tune, Johnathan; Goulopoulou, StylianiPurpose: Infections during pregnancy are associated with adverse clinical outcomes. We previously showed that exposure to immunostimulatory ODN2395 (synthetic Toll-like receptor 9 agonist) during pregnancy induces maternal vascular inflammation and enhances vascular tone in pregnant rats. These outcomes were mediated in part by activation of the cyclooxygenase/thromboxane A2 (COX/TxA2) pathway. The objective of this study was to investigate the impact of ODN2395-induced immune system stimulation on maternal hearts during pregnancy. We hypothesize that exposure to TLR9-mediated immune system activation during pregnancy upregulates the COX/TxA2 signaling pathway in maternal cardiac tissues in rats. Methods: Rats were treated with a synthetic CpG DNA (ODN2395, 1 mg/kg, intraperitoneal injection) or vehicle (saline) in late pregnancy. Fetoplacental biometrics were recorded after euthanasia on gestational day 20 and maternal hearts were collected to assess COX-1 and COX-2 expression and 6-keto PGF1α (PGI2 metabolic byproduct) and TxB2 (TxA2 metabolic byproduct) production. Results: Left ventricular tissues from dams treated with ODN2395 released higher concentrations of TxB2 compared to tissues from vehicle-treated dams (ODN2395: 0.56 ± 0.06 ng/mg protein vs. Vehicle: 0.31 ± 0.04 ng/mg protein, n5, p=0.0041) but there were no differences in cardiac 6-keto PGF1α release between groups (p=0.16). COX-2 expression was lower in left ventricles from ODN2395-treated rats compared to vehicle-treated rats (p=0.009). There were no differences in cardiac COX-1 expression between groups (p=0.27). Exposure to ODN2395 during pregnancy increased fetal-placental weight ratio (ODN2395: 5.3 ± 0.22 vs. Vehicle: 4.7 ± 0.15, p = 0.04). COX-2 expression was greater in placental tissues from ODN2395-treated rats (p=0.004) but there were no differences in placental 6-keto PGF1α (p=0.51) and TxB2 release (p=0.32). Conclusion: TLR9 activation during pregnancy induces upregulation of TxB2 synthesis in maternal cardiac tissues coupled with a reduction in COX-2 expression. Maternal heart may have enhanced sensitivity to bacterial infections during pregnancy.