Clifford R Greyson

University of Colorado, Denver, Colorado, United States

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Publications (32)187.97 Total impact

  • Gregory G. Schwartz · Li Lu · Shuyu Ye · Clifford R. Greyson

    No preview · Article · Mar 2015 · Journal of the American College of Cardiology
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    ABSTRACT: Aim: Metabolic syndrome affects a large proportion of the population and increases cardiovascular disease risk. Because metabolic syndrome often co-exists clinically with atherosclerosis, it is difficult to distinguish the respective contributions of the components to vascular abnormalities. Accordingly, we utilized a porcine dietary model of metabolic syndrome without atherosclerosis to investigate early abnormalities of vascular function and signaling. Methods: Thirty-two Yucatan micropigs were fed either a high-fat, high-simple-sugar, high-calorie (HFHS) or standard chow diet (STD) for 6 months. Neither diet contained added cholesterol. Blood pressure and flow-mediated vasodilatation were assessed at baseline and 6 months. Aortas were harvested at 6 months to assess histology, insulin signaling, and endothelial nitric oxide (eNOS) phosphorylation. Results: HFHS pigs developed characteristics of metabolic syndrome including obesity, dyslipidemia, and insulin resistance, but without histologic evidence of atherosclerosis. Although arterial intima-media thickness did not differ between groups, vascular dysfunction in HFHS was manifest by increased blood pressure and impaired flow-mediated vasodilation of the femoral artery. Compared with STD, aortas from HFHS exhibited increased p85α expression and Ser307 IRS-1 phosphorylation, and blunted insulin-stimulated IRS-1-associated phosphatidylinositol (PI) 3-kinase activity. In the absence of insulin stimulation, aortic Akt Ser473-phosphorylation was greater in HFHS than in STD. With insulin stimulation, Akt phosphorylation increased in STD, but not HFHS. Insulin-induced Ser1177-phosphorylation of eNOS was decreased in HFHS, compared with STD. Conclusions: Pigs with metabolic syndrome develop early vascular dysfunction and aortic insulin signaling abnormalities, and could be a useful model for early human vascular abnormalities in this condition.
    No preview · Article · Apr 2013 · Journal of diabetes and its complications
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    ABSTRACT: Background: Clinical metabolic syndrome conveys a poor prognosis in patients with acute coronary syndrome, not fully accounted for by extent of coronary atherosclerosis. To explain this observation, we determined whether post-ischemic myocardial contractile and metabolic function are impaired in a porcine dietary model of metabolic syndrome without atherosclerosis. Methods: Micropigs (n=28) were assigned to control (low-fat, no added sugars) or intervention diet (high saturated fat and simple sugars, no added cholesterol) for 7 months. Intervention diet produced obesity, hypertension, dyslipidemia, and impaired glucose tolerance, but not atherosclerosis. Under open-chest, anesthetized conditions, pigs underwent 45 min low-flow myocardial ischemia and 120 min reperfusion. Results: In both diet groups, contractile function was similar at baseline and declined similarly during ischemia. However, after 120 min reperfusion, regional work recovered to 21±12% of baseline in metabolic syndrome pigs, compared with 61±13% in controls (p=0.01). Ischemia/reperfusion caused a progressive decline in mechanical/metabolic efficiency (regional work/oxygen consumption) in metabolic syndrome hearts, but not in controls. Metabolic syndrome hearts demonstrated altered fatty acyl composition of cardiolipin and increased Akt phosphorylation in both ischemic and non-ischemic regions, suggesting tonic activation. Metabolic syndrome hearts utilized more fatty acid than controls (p=0.03). When fatty acid availability was restricted by prior insulin exposure, differences between groups in post-ischemic contractile recovery and mechanical/metabolic efficiency were eliminated. Conclusion: Pigs with characteristics of metabolic syndrome demonstrate impaired contractile and metabolic recovery after low-flow myocardial ischemia. Contributory mechanisms may include remodeling of cardiolipin, abnormal activation of Akt, and excessive utilization of fatty acid substrate.
    Preview · Article · Jan 2013 · AJP Heart and Circulatory Physiology
  • Clifford R Greyson
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    ABSTRACT: This review summarizes the approach to and recent developments in the evaluation and treatment of acute right heart failure in the ICU. Right heart failure, defined as failure of the right ventricle to provide sufficient blood flow through the pulmonary circulation at normal central venous pressure, is a common problem caused by a combination of increased right-ventricular afterload and right-ventricular contractile dysfunction. Management of acute right heart failure continues to be challenging because of insufficient understanding of its pathophysiology, a lack of guidelines, and few available tools. Recent research has contributed to an improved understanding of its mechanisms, helping to guide therapy and suggest future options. Right-ventricular assist devices are emerging as a promising approach to treatment when optimization of hemodynamics and conventional medical therapy fail. Right heart failure causes venous congestion and systemic hypoperfusion. Once right heart failure is identified, the primary goal is to alleviate any reversible cause of excessive load or right-ventricular contractile failure. When the underlying abnormalities cannot be alleviated, trials of diuretic, vasodilator, or inotropic therapy may be required. Invasive monitoring helps guide therapy. Medically refractory right heart failure may potentially be treated with right-ventricular assist devices.
    No preview · Article · Aug 2012 · Current opinion in critical care
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    Janice V Huang · Clifford R Greyson · Gregory G Schwartz
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    ABSTRACT: Peroxisome proliferator-activated receptor γ (PPAR-γ) is a key regulator of fatty acid metabolism, promoting its storage in adipose tissue and reducing circulating concentrations of free fatty acids. Activation of PPAR-γ has favorable effects on measures of adipocyte function, insulin sensitivity, lipoprotein metabolism, and vascular structure and function. Despite these effects, clinical trials of thiazolidinedione PPAR-γ activators have not provided conclusive evidence that they reduce cardiovascular morbidity and mortality. The apparent disparity between effects on laboratory measurements and clinical outcomes may be related to limitations of clinical trials, adverse effects of PPAR-γ activation, or off-target effects of thiazolidinedione agents. This review addresses these issues from a clinician's perspective and highlights several ongoing clinical trials that may help to clarify the therapeutic role of PPAR-γ activators in cardiovascular disease.
    Preview · Article · Jun 2012 · The Journal of Lipid Research
  • Hasan A Ahmad · Li Lu · Shuyu Ye · Gregory G Schwartz · Clifford R Greyson
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    ABSTRACT: Right heart failure from right ventricular (RV) pressure overload is a major cause of morbidity and mortality, but its mechanism is incompletely understood. We tested the hypothesis that right heart failure during 4 hours of RV pressure overload is associated with alterations of the focal adhesion protein talin, and that the inhibition of calpain attenuates RV dysfunction and preserves RV talin. Anesthetized open-chest pigs treated with the calpain inhibitor MDL-28170 (n = 20) or inactive vehicle (n = 23) underwent 4 hours of RV pressure overload by pulmonary artery constriction (initial RV systolic pressure, 64 ± 1 and 66 ± 1 mm Hg in MDL-28170 and vehicle-treated pigs, respectively). Progressive RV contractile dysfunction was attenuated by MDL-28170: after 4 hours of RV pressure overload, RV systolic pressure was 44 ± 4 mm Hg versus 49 ± 6 mm Hg (P = 0.011), and RV stroke work was 72 ± 5% of baseline versus 90 ± 5% of baseline, (P = 0.027), in vehicle-treated versus MDL-28170-treated pigs, respectively. MDL-28170 reduced the incidence of hemodynamic instability (death or systolic blood pressure of < 85 mm Hg) by 46% (P = 0.013). RV pressure overload disrupted talin organization. MDL-28170 preserved talin abundance in the RV free wall (P = 0.039), and talin abundance correlated with the maintenance of RV free wall stroke work (r = 0.58, P = 0.0039). α-actinin and vinculin showed similar changes according to immunohistology. Right heart failure from acute RV pressure overload is associated with reduced talin abundance and disrupted talin organization. Calpain inhibition preserves the abundance and organization of talin and RV function. Calpain inhibition may offer clinical utility in treating acute cor pulmonale.
    No preview · Article · May 2012 · American Journal of Respiratory Cell and Molecular Biology
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    ABSTRACT: Despite favorable metabolic and vascular effects, thiazolidinedione (TZD) drugs have not convincingly reduced cardiovascular mortality in clinical trials, raising the possibility of countervailing, off-target effects. We previously showed that TZDs block cardiac ATP-sensitive potassium (K(ATP)) channels in pigs. In this study, we investigated whether TZDs affect onset, spectral characteristics, and mortality of ischemic ventricular fibrillation (VF) and whether such effects are recapitulated by a non-selective K(ATP) blocker (glyburide) or a mitochondrial K(ATP) blocker (5-hydroxydecanoate). A total of 121 anesthetized pigs were pre-treated with TZD (pioglitazone or rosiglitazone, 1 mg/kg IV, resulting in clinically relevant plasma concentrations), glyburide (1 mg/kg IV), 5-hydroxydecanoate (5 mg/kg IV) or inert vehicle. Ischemia was produced by occlusion of the left anterior descending coronary artery. In a subset of pigs treated with rosiglitazone or vehicle, ischemic preconditioning was performed. VF developed in all but 6 pigs. In non-preconditioned pigs, onset of VF occurred sooner with pioglitazone (11±3 min, p<0.05) or rosiglitazone (14±3 min, p=0.06) than with vehicle (20±2 min). Defibrillation of VF was successful in 44% of pigs treated with vehicle, compared with 0% with pioglitazone (p=0.057) and 33% with rosiglitazone (NS). After ischemic preconditioning, defibrillation was successful in 62% of pigs treated with vehicle, compared with 26% treated with rosiglitazone (p=0.03). TZDs attenuated slowing of conduction due to ischemia and shifted ECG power spectra during VF toward higher frequencies. All effects of TZDs were recapitulated by glyburide, but not by 5-hydroxydecanoate, supporting an interaction of TZDs with the sarcolemmal K(ATP) channel. In a porcine model, TZDs promote onset and increase mortality of ischemic VF, associated with alterations of conduction and VF spectral characteristics. Similar effects in a clinical setting might adversely impact cardiovascular mortality.
    No preview · Article · Mar 2012 · Cardiovascular Drugs and Therapy
  • Clifford R Greyson
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    ABSTRACT: Right ventricular (RV) function is a powerful prognostic factor in congestive heart failure and pulmonary hypertension, but assessing RV function is a challenge because of the right ventricle's complex geometry, its extreme sensitivity to loading conditions, and a limited understanding of underlying mechanisms of right heart failure. At present, a single widely accepted and generally applicable index of RV function is not available. Current approaches to assessment of RV function include physical examination, catheterization, conventional contrast and radionuclide angiography, nuclear perfusion scintigraphy, cardiac CT, MRI, echocardiography, and positron emission tomography. This review will discuss assessment of RV function in the context of RV physiology.
    No preview · Article · Feb 2011 · Current Cardiology Reports
  • Clifford R Greyson

    No preview · Article · Jun 2010 · Critical care medicine
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    Preview · Article · Mar 2010 · Journal of the American College of Cardiology
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    Clifford R Greyson
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    ABSTRACT: The primary purpose of the right ventricle and pulmonary circulation is gas exchange. Because gas exchange occurs in thin, highly permeable alveolar membranes, pulmonary pressure must remain low to avoid pulmonary edema; because the right ventricle and the lungs are in series with the left ventricle and the systemic circulation, the entire cardiac output must pass through the lungs. This low pressure, high volume system, makes dramatically different demands on the right ventricle compared with the demands made on the left ventricle by the systemic circulation. Moreover, the right ventricle and pulmonary circulation must buffer dynamic changes in blood volume and flow resulting from respiration, positional changes, and changes in left ventricular cardiac output. The optimizations needed to meet these conflicting demands result in reduced capacity to compensate for increased afterload or pressure. Unfortunately, a large number of pathologic processes can result in acute and or chronic increases in afterload stress. As afterload stress rises, right heart failure may develop, and hemodynamic instability and death can occur abruptly. Several biochemical pathways have been identified that may participate in adaptation or maladaptation to excessive pressure loads.
    Preview · Article · Jan 2010 · Revista Espa de Cardiologia
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    Clifford R. Greyson
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    ABSTRACT: La función principal del ventrículo derecho y de la cir-culación pulmonar es el intercambio de gases. Dado que el intercambio de gases se produce en membranas al-veolares finas y altamente permeables, la presión pulmo-nar debe mantenerse baja para evitar el edema pulmo-nar, debido a que el ventrículo derecho y los pulmones están en serie con el ventrículo izquierdo y la circulación sistémica, y todo el gasto cardiaco debe pasar a través de los pulmones. Este sistema de baja presión y volumen alto somete al ventrículo derecho a exigencias comple-tamente distintas de las que la circulación sistémica im-plica para el ventrículo izquierdo. Además, el ventrículo derecho y la circulación pulmonar deben amortiguar los cambios dinámicos en el volumen y el flujo sanguíneo resultantes de la respiración, los cambios posicionales y los cambios en el gasto cardiaco del ventrículo izquierdo. Las adaptaciones necesarias para satisfacer estas exigencias contrapuestas tienen como consecuencia una capacidad de compensación reducida frente a un aumento de poscarga o presión. Desgraciadamente, un elevado número de procesos patológicos pueden tener como consecuencia aumentos agudos o crónicos en la poscarga. A medida que aumenta tal exceso de pos-carga, puede aparecer insuficiencia cardiaca derecha y pueden sobrevenir repentinamente inestabilidad hemodi-námica y muerte. Se han identificado varias vías bioquí-micas que pueden participar en la adaptación apropiada o inadecuada a las sobrecargas de presión. palabras clave: Ventrículo derecho. Hipertensión pulmo-nar arterial. Insuficiencia cardiaca. Fisiología. the Right Ventricle and pulmonary Circulation: Basic Concepts The primary purpose of the right ventricle and pulmonary circulation is gas exchange. Because gas exchange occurs in thin, highly permeable alveolar membranes, pulmonary pressure must remain low to avoid pulmonary edema; because the right ventricle and the lungs are in series with the left ventricle and the systemic circulation, the entire cardiac output must pass through the lungs. This low pressure, high volume system, makes dramatically different demands on the right ventricle compared with the demands made on the left ventricle by the systemic circulation. Moreover, the right ventricle and pulmonary circulation must buffer dynamic changes in blood volume and flow resulting from respiration, positional changes, and changes in left ventricular cardiac output. The optimizations needed to meet these conflicting demands result in reduced capacity to compensate for increased afterload or pressure. Unfortunately, a large number of pathologic processes can result in acute and or chronic increases in afterload stress. As afterload stress rises, right heart failure may develop, and hemodynamic instability and death can occur abruptly. Several biochemical pathways have been identified that may participate in adaptation or maladaptation to excessive pressure loads.
    Preview · Article · Jan 2010 · Revista Espa de Cardiologia
  • Clifford R. Greyson
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    ABSTRACT: Intravascular pressure measurement is one of the oldest techniques employed in clinical medicine. By 1733, long before accurate external blood pressure measurement had been developed by Korotkoff, Stephen Hales had performed direct measurement of arterial blood pressure by inserting a brass tube into a horse’s artery and observing the height of the resulting blood column. By 1828, Poiseuille had improved on intraarterial blood pressure measurement by using a fluid-filled catheter connected to a mercury manometer. In 1848 Ludwig invented the kymograph, a smoke-covered rotating cylinder that provided the means for graphical recording of dynamic signals for many years to come. By connecting the kymograph to a fluid-filled intraarterial catheter, the first graphical representation of the arterial pulse waveform was obtained.1 Today, intravascular pressure measurement is performed so routinely in intensive care units, operating rooms and catheterization laboratories, that it is easy to forget that numbers and graphical representations of pressure are strongly affected by the measurement system, and indeed, can misrepresent reality. The signal processing techniques commonly used in intravascular and intraventricular pressure measurement are generally quite rudimentary and limited to simple filtering (see Chap. 4), averaging, and peak and trough detection. Less well-appreciated, but equally important, are the alterations in the raw signal introduced by the measurement system itself. In some cases, these artifacts can lead to serious errors in diagnosis. This chapter will provide an overview of how both intended and unintended signal processing affect the appearance and interpretation of data obtained using this nearly universal technique.
    No preview · Chapter · Dec 2009
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    ABSTRACT: Heightened cardiovascular risk among patients with systemic insulin resistance is not fully explained by the extent of atherosclerosis. It is unknown whether myocardial insulin resistance accompanies systemic insulin resistance and contributes to increased cardiovascular risk. This study utilized a porcine model of diet-induced obesity to determine if myocardial insulin resistance develops in parallel with systemic insulin resistance and investigated potential mechanisms for such changes. Micropigs (n = 16) were assigned to control (low fat, no added sugars) or intervention (25% wt/wt coconut oil and 20% high-fructose corn syrup) diet for 7 mo. Intervention diet resulted in obesity, hypertension, and dyslipidemia. Systemic insulin resistance was manifest by elevated fasting glucose and insulin, abnormal response to intravenous glucose tolerance testing, and blunted skeletal muscle phosphatidylinositol-3-kinase (PI 3-kinase) activation and protein kinase B (Akt) phosphorylation in response to insulin. In myocardium, insulin-stimulated glucose uptake, PI 3-kinase activation, and Akt phosphorylation were also blunted in the intervention diet group. These findings were explained by increased myocardial content of p85alpha (regulatory subunit of PI 3-kinase), diminished association of PI 3-kinase with insulin receptor substrate (IRS)-1 in response to insulin, and increased serine-307 phosphorylation of IRS-1. Thus, in a porcine model of diet-induced obesity that recapitulates many characteristics of insulin-resistant patients, myocardial insulin resistance develops along with systemic insulin resistance and is associated with multiple abnormalities of insulin signaling.
    Preview · Article · Nov 2009 · AJP Heart and Circulatory Physiology
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    Li Lu · Michael J. Reiter · Ya Xu · A Chicco · Clifford R. Greyson · Gregory G. Schwartz
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    ABSTRACT: Opening of ATP-sensitive potassium (K(ATP)) channels during myocardial ischaemia shortens action potential duration and is believed to be an adaptive, energy-sparing response. Thiazolidinedione drugs block K(ATP) channels in non-cardiac cells in vitro. This study determined whether thiazolidinedione drugs block cardiac K(ATP) channels in vivo. Experiments in 68 anaesthetised pigs determined: (1) effects of inert vehicle, troglitazone (10 mg/kg i.v.) or rosiglitazone (0.1 or 1.0 mg/kg i.v.) on epicardial monophasic action potential (MAP) during 90 min low-flow ischaemia; (2) effects of troglitazone, rosiglitazone or pioglitazone (1 mg/kg i.v.) on response of MAP to intracoronary infusion of a K(ATP) channel opener, levcromakalim; and (3) effects of inert vehicle, rosiglitazone (1 mg/kg i.v.) or the sarcolemmal K(ATP) blocker HMR-1098 on time to onset of ventricular fibrillation following complete coronary occlusion. With vehicle, epicardial MAP shortened by 44+/-9 ms during ischaemia. This effect was attenuated to 12+/-8 ms with troglitazone and 6+/-6 ms with rosiglitazone (p<0.01 for both vs vehicle), suggesting K(ATP) blockade. Intracoronary levcromakalim shortened MAP by 38+/-10 ms, an effect attenuated to 12+/-8, 13+/-4 and 9+/-5 ms during co-treatment with troglitazone, rosiglitazone or pioglitazone (p<0.05 for each), confirming K(ATP) blockade. During coronary occlusion, median time to ventricular fibrillation was 29 min in pigs treated with vehicle and 6 min in pigs treated with rosiglitazone or HMR-1098 (p<0.05 for both vs vehicle), indicating that K(ATP) blockade promotes ischaemic ventricular fibrillation in this model. Thiazolidinedione drugs block cardiac K(ATP) channels at clinically relevant doses and promote onset of ventricular fibrillation during severe ischaemia.
    Preview · Article · Apr 2008 · Diabetologia
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    Clifford R Greyson · Gregory G Schwartz · Li Lu · Shuyu Ye · Steve Helmke · Ya Xu · Hasan Ahmad
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    ABSTRACT: Right ventricular contractile failure from acute RV pressure overload is an important cause of morbidity and mortality, but the mechanism of RV failure in this setting is incompletely defined. We hypothesized that RV dysfunction from acute RV pressure overload is, in part, due to activation of calpain, and that calpain inhibition would therefore attenuate RV dysfunction. Anesthetized, open chest pigs were treated with the calpain inhibitor MDL-28170 or with inactive vehicle, and then subjected to acute RV pressure overload for 90 min. RV contractile function was assessed by the regional Frank-Starling relation. RV myocardial tissue was analyzed for evidence of calpain activation and calpain-mediated proteolysis. RV pressure overload caused severe contractile dysfunction, along with significant alterations in the endogenous calpain inhibitor calpastatin typical of calpain activation. MDL-28170 attenuated RV free wall dysfunction by more than 50%. However, there were no differences in degradation of spectrin, desmin, troponin-I or SERCA2 between SHAM operated pigs and pigs subjected to acute RV pressure overload, or between vehicle and MDL-28170 treated pigs. Acute RV pressure overload causes calpain activation, and RV contractile dysfunction from acute RV pressure overload is attenuated by the calpain inhibitor MDL-28170; however, the effect is not explained by inhibition of calpain-mediated degradation of spectrin, desmin, troponin-I or SERCA2. Because this is the first report of any agent that can directly attenuate RV contractile dysfunction in acute RV pressure overload, further investigation of the mechanism of action of MDL-28170 in this setting is warranted.
    Full-text · Article · Feb 2008 · Journal of Molecular and Cellular Cardiology
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    Clifford R Greyson
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    ABSTRACT: Right ventricular failure may be defined as the inability of the right ventricle of the heart to provide adequate blood flow through the pulmonary circulation at a normal central venous pressure. Critical care specialists encounter right ventricular failure routinely in their practice, but until recently right ventricular failure as a primary clinical entity received scant consideration. Indeed, there is still not a single published practice guideline focused on right ventricular failure. Right ventricular failure is usually due to a combination of right ventricular pressure overload and contractile abnormalities of the right ventricular free wall. Decompensation may occur abruptly and catastrophically because of unique aspects of right ventricular physiology. This review will focus on the pathophysiology of acute right ventricular failure in the critical care setting and summarize the limited management options available.
    Preview · Article · Feb 2008 · Critical care medicine
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    ABSTRACT: Rodent studies suggest that peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activation reduces myocardial ischemia-reperfusion (I/R) injury and infarct size; however, effects of PPAR-alpha activation in large animal models of myocardial I/R are unknown. We determined whether chronic treatment with the PPAR-alpha activator fenofibrate affects myocardial I/R injury in pigs. Domestic farm pigs were assigned to treatment with fenofibrate 50 mg.kg(-1).day(-1) orally or no drug treatment, and either a low-fat (4% by weight) or a high-fat (20% by weight) diet. After 4 wk, 66 pigs underwent 90 min low-flow regional myocardial ischemia and 120 min reperfusion under anesthetized open-chest conditions, resulting in myocardial stunning. The high-fat group received an infusion of triglyceride emulsion and heparin during this terminal experiment to maintain elevated arterial free fatty acid (FFA) levels. An additional 21 pigs underwent 60 min no-flow ischemia and 180 min reperfusion, resulting in myocardial infarction. Plasma concentration of fenofibric acid was similar to the EC50 for activation of PPAR-alpha in vitro and to maximal concentrations achieved in clinical use. Myocardial expression of PPAR-alpha mRNA was prominent but unaffected by fenofibrate treatment. Fenofibrate increased expression of carnitine palmitoyltransferase (CPT)-I mRNA in liver and decreased arterial FFA and lactate concentrations (each P < 0.01). However, fenofibrate did not affect myocardial CPT-I expression, substrate uptake, lipid accumulation, or contractile function during low-flow I/R in either the low- or high-fat group, nor did it affect myocardial infarct size. Despite expression of PPAR-alpha in porcine myocardium and effects of fenofibrate on systemic metabolism, treatment with this PPAR-alpha activator does not alter myocardial metabolic or contractile responses to I/R in pigs.
    Preview · Article · Jun 2006 · AJP Heart and Circulatory Physiology
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    ABSTRACT: Peroxisome proliferator-activated receptor (PPAR)-gamma modulates substrate metabolism and inflammatory responses. In experimental rats subjected to myocardial ischemia-reperfusion (I/R), thiazolidinedione PPAR-gamma activators reduce infarct size and preserve left ventricular function. Troglitazone is the only PPAR-gamma activator that has been shown to be protective in I/R in large animals. However, because troglitazone contains both alpha-tocopherol and thiazolidinedione moieties, whether PPAR-gamma activation per se is protective in myocardial I/R in large animals remains uncertain. To address this question, 56 pigs were treated orally for 8 wk with troglitazone (75 mg x kg(-1) x day(-1)), rosiglitazone (3 mg x kg(-1) x day(-1)), or alpha-tocopherol (73 mg x kg(-1) x day(-1), equimolar to troglitazone dose) or received no treatment. Pigs were then anesthetized and subjected to 90 min of low-flow regional myocardial ischemia and 90 min of reperfusion. Myocardial expression of PPAR-gamma, determined by ribonuclease protection assay, increased with troglitazone and rosiglitazone compared with no treatment. Rosiglitazone had no significant effect on myocardial contractile function (Frank-Starling relations), substrate uptake, or expression of proinflammatory cytokines during I/R compared with untreated pigs. In contrast, preservation of myocardial contractile function and lactate uptake were greater and cytokine expression was attenuated in pigs treated with troglitazone or alpha-tocopherol compared with untreated pigs. Multivariate analysis indicated that presence of an alpha-tocopherol, but not a thiazolidinedione, moiety in the test compound was significantly related to greater contractile function and lactate uptake and lower cytokine expression during I/R. We conclude that PPAR-gamma activation is not protective in a porcine model of myocardial I/R. Protective effects of troglitazone are attributable to its alpha-tocopherol moiety. These findings, in conjunction with prior rat studies, suggest interspecies differences in the response to PPAR-gamma activation in the heart.
    Preview · Article · Apr 2005 · AJP Heart and Circulatory Physiology
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    Ya Xu · Michael Gen · Li Lu · Clifford Greyson · Carlin S Long · Gregory G Schwartz

    Preview · Article · Mar 2004 · Journal of the American College of Cardiology

Publication Stats

548 Citations
187.97 Total Impact Points

Institutions

  • 2003-2013
    • University of Colorado
      • Section of Cardiology
      Denver, Colorado, United States
  • 2009
    • Spokane VA Medical Center
      Spokane, Washington, United States
  • 2000-2005
    • United States Department of Veterans Affairs
      Бедфорд, Massachusetts, United States
  • 1992-1999
    • University of California, San Francisco
      • Veterans Affairs Medical Center
      San Francisco, California, United States
  • 1997
    • CSU Mentor
      Long Beach, California, United States
  • 1995
    • San Francisco VA Medical Center
      San Francisco, California, United States