Obstetrician & Gynecologist
34 years of experience

8335 Walnut Hill Ln
Ste 200
Dallas, TX 75231
214-766-7488
Locations and availability (2)

Education ?

Medical School
Tulane University (1976)

Affiliations ?

Dr. Yarbrough is affiliated with 1 hospitals.

Hospital Affilations

  • Presbyterian Hosp
  • Publications & Research

    Dr. Yarbrough has contributed to 19 publications.
    Title Caspase Inhibition Modulates Left Ventricular Remodeling Following Myocardial Infarction Through Cellular and Extracellular Mechanisms.
    Date September 2010
    Journal Journal of Cardiovascular Pharmacology
    Excerpt

    Myocyte death occurs by necrosis and caspase-mediated apoptosis in myocardial infarction (MI). In vitro studies suggest caspase activation causes myocardial contractile protein degradation without inducing apoptosis. Thus, caspase activation may evoke left ventricular (LV) remodeling through independent processes post-MI. The effects of caspase activation on LV geometry post-MI remain unclear. This project applied pharmacologic caspase inhibition (CASPI) to a porcine model of MI.

    Title Alternative Technique for Salvage of Donor Lungs with Insufficient Atrial Cuffs.
    Date October 2009
    Journal The Annals of Thoracic Surgery
    Excerpt

    Inadequate left atrial cuff surrounding donor pulmonary veins may present a technical challenge for successful lung transplantation. A simple technique for construction of venous anastomoses during lung transplantation when donor atrial cuff is lacking involves circumferential incorporation of surrounding donor pericardium into the anastomosis without directly suturing or augmenting donor venous structures.

    Title Selective Targeting of Matrix Metalloproteinase Inhibition in Post-infarction Myocardial Remodeling.
    Date July 2006
    Journal Journal of Cardiovascular Pharmacology
    Excerpt

    BACKGROUND: A cause-effect relationship has been established between MMP activation and left ventricular (LV) remodeling following myocardial infarction. The goal of the present study was to examine a selective MMP inhibitor (sMMPi) strategy that effectively spared MMP-1, -3, and -7 with effect to regional and global left ventricular remodeling in a pig model of myocardial infarction. METHODS AND RESULTS: Pigs instrumented with coronary snares and radiopaque markers within the area at risk were randomized to myocardial infarction-only (n = 10) or sMMPi (PGE-530742, 1 mg/kg TID) begun 3 days prior to myocardial infarction. Ten weight-matched noninstrumented pigs served as reference controls. Left ventricular end-diastolic volume in the myocardial infarction-only group was increased from baseline (81 +/- 3 mL versus 55 +/- 4 mL, respectively, P < 0.05) but was attenuated with sMMPi (67 +/- 3 mL, P < 0.05). Fractional area of shortening of marker area was decreased in the myocardial infarction-only group (change from baseline -63 +/- 10%, P < 0.05) but this effect was attenuated with sMMPi (-28 +/- 14%, P < 0.05), indicative of less dyskinesis of the infarct region with sMMPi. Wall stress was reduced within both the septal and posterior wall regions with sMMPi. Myocardial MMP-2 activity was decreased in both remote and border areas of sMMPi-treated samples compared with myocardial infarction-only values, consistent with pharmacologic MMP inhibition. CONCLUSIONS: Selective MMP inhibition favorably affected regional myocardial geometry and decreased left ventricular dilation post-myocardial infarction. This study suggests that a strategy of selective MMP inhibition of a limited array of MMPs may be an achievable goal in preventing pathologic left ventricular remodeling post-myocardial infarction.

    Title Alterations in Cultured Myocardial Fibroblast Function Following the Development of Left Ventricular Failure.
    Date June 2006
    Journal Journal of Molecular and Cellular Cardiology
    Excerpt

    A structural event in the progression of left ventricular (LV) failure is myocardial extracellular matrix (ECM) remodeling. The myocardial fibroblast is a major cell type influencing the ECM, but whether and to what degree specific phenotypic differences in myocardial fibroblasts can be demonstrated to occur in culture with the development of LV failure remains unclear. Adult pigs (25 kg) were used for control myocardial fibroblast preparations (N=5) or following pacing-induced LV failure (N=5; 240 bpm, 3 weeks). LV remodeling occurred with pacing as evidenced by increased LV end diastolic volume (132+/-11 vs. 60+/-4 mL for control; P<0.05). Functional parameters including migration, adhesion, collagen and matrix metalloproteinase release were assessed in fibroblast cultures from passages 1-4. The following findings were consistent with each passage and the results were analyzed with control values set to 100%. Migration of LV failure fibroblasts increased by over 170% (P<0.05). Adhesion to collagen I, laminin and fibronectin was increased by over 160% in LV failure fibroblasts (P<0.05). beta(1) integrin density decreased by 50% in LV failure fibroblasts (P<0.05). Fibrillar collagen release increased by over 130% and matrix metalloproteinase-2 increased by 140% in LV failure fibroblasts (P<0.05). The unique findings of this study are two-fold. First, after a pathological stimulus in-vivo, adult myocardial fibroblasts maintain a consistent phenotype through early passages in-vivo. Second, a differential release of, and response to ECM components occurred in LV failure fibroblasts. Thus, a phenotypic transformation of the myocardial fibroblast occurs with the development of LV failure, which in turn may contribute to matrix remodeling and presents as a potential cellular therapeutic target.

    Title Cardiac Support Device Modifies Left Ventricular Geometry and Myocardial Structure After Myocardial Infarction.
    Date February 2006
    Journal Circulation
    Excerpt

    BACKGROUND: Whether mechanical restraint of the left ventricle (LV) can influence remodeling after myocardial infarction (MI) remains poorly understood. This study surgically placed a cardiac support device (CSD) over the entire LV and examined LV and myocyte geometry and function after MI. METHODS AND RESULTS: Post-MI sheep (35 to 45 kg; MI size, 23+/-2%) were randomized to placement of the CorCap CSD (Acorn Cardiovascular, Inc) (MI+CSD; n=6) or remained untreated (MI only; n=5). Uninstrumented sheep (n=10) served as controls. At 3 months after MI, LV end-diastolic volume (by MRI) was increased in the MI only group compared with controls (98+/-8 versus 43+/-4 mL; P<0.05). In the MI+CSD group, LV end-diastolic volume was lower than MI only values (56+/-7 mL; P<0.05) but remained higher than controls (P<0.05). Isolated LV myocyte shortening velocity was reduced by 35% from control values (P<0.05) in both MI groups. LV myocyte beta-adrenergic response was reduced with MI but normalized in the MI+CSD group. LV myocyte length increased in the MI group and was reduced in the MI+CSD group. Relative collagen content was increased and matrix metalloproteinase-9 was decreased within the MI border region of the CSD group. CONCLUSIONS: A CSD beneficially modified LV and myocyte remodeling after MI through both cellular and extracellular mechanisms. These findings provide evidence that nonpharmacological strategies can interrupt adverse LV remodeling after MI.

    Title Trafficking of the Membrane Type-1 Matrix Metalloproteinase in Ischemia and Reperfusion: Relation to Interstitial Membrane Type-1 Matrix Metalloproteinase Activity.
    Date October 2005
    Journal Circulation
    Excerpt

    BACKGROUND: The matrix metalloproteinases (MMPs) contribute to regional remodeling after prolonged periods of ischemia and reperfusion (I/R), but specific MMP types activated during this process remain poorly understood. A novel class, the membrane-type MMPs (MT-MMPs), has been identified in the myocardium, but activity of these MMP types has not been assessed in vivo, particularly during I/R. METHODS AND RESULTS: Pigs (30 kg, n=8) were instrumented with microdialysis catheters to measure MT1-MMP activity in both ischemic and nonischemic (remote) myocardium. A validated MT1-MMP fluorogenic substrate was infused through the microdialysis system, and changes in fluorescence were reflective of MT1-MMP activity at steady state, during ischemia (90 minutes), and during reperfusion (120 minutes). At peak ischemia, MT1-MMP activity was increased by >40% in the ischemic region, with no change in the remote region, which persisted with reperfusion (P<0.05). After I/R, MT1-MMP abundance was increased by >50% (P<0.05). Differential centrifugation revealed that the endosomal fraction (which contains subcellular organelles) within the ischemic myocardium was associated with a >135% increase in MT1-MMP (P<0.05). Furthermore, in an isolated left ventricular myocyte model of I/R, hypoxia (simulated ischemia) induced a >70% increase in MT1-MMP abundance in myocytes, and confocal microscopy revealed MT1-MMP internalization during this time period and reemergence to the membrane with reperfusion. CONCLUSIONS: These unique results demonstrate that a specific MMP type, MT1-MMP, is increased in abundance and activity with I/R and is likely attributed, at least in part, to changes in intracellular trafficking.

    Title Myocardial Interstitial Matrix Metalloproteinase Activity is Altered by Mechanical Changes in Lv Load: Interaction with the Angiotensin Type 1 Receptor.
    Date October 2005
    Journal Circulation Research
    Excerpt

    LV myocardial remodeling is a structural hallmark of hypertensive hypertrophy, but molecular mechanisms driving this process are not well understood. The matrix metalloproteinases (MMPs) can cause myocardial remodeling in chronic disease states, but how MMP activity is altered with a mechanical load remains unknown. The present study quantified interstitial MMP activity after a discrete increase in LV load and dissected out the contributory role of the angiotensin II Type 1 receptor (AT1R). Pigs (38 kg) were randomized to undergo (1) increased LV load by insertion of an intra-aortic balloon pump (IABP) triggered at systole for 3 hours, then deactivated (n=11); (2) IABP and AT1R blockade (AT1RB; valsartan, 3 ng/kg/hr; n=6). MMP activity was directly measured in the myocardial interstitium using a validated inline digital fluorogenic microdialysis system. IABP engagement increased LV peak pressure from 92+/-3 to 113+/-5 and 123+/-7 mm Hg in the vehicle and AR1RB group, respectively, and remained elevated throughout the IABP period (P<0.05). With IABP disengagement, segmental shortening (% change from baseline of 0) remained depressed in the vehicle group (-32.2+/-11.8%, P<0.05) but returned to baseline in the AT1RB group (2.3+/-12.5%). MMP activity decreased with IABP in both groups. At IABP disengagement, a surge in MMP activity occurred in the vehicle group that was abrogated with AT1RB (3.03+/-0.85 versus 0.07+/-1.55 MMP units/hr, P<0.05). A transient increase in LV load caused a cyclic variation in interstitial MMP activity that is regulated in part by the AT1R. These temporally dynamic changes in MMP activity likely influence myocardial function and structure with increased LV load.

    Title Caspase Inhibition Attenuates Contractile Dysfunction Following Cardioplegic Arrest and Rewarming in the Setting of Left Ventricular Failure.
    Date February 2005
    Journal Journal of Cardiovascular Pharmacology
    Excerpt

    Hyperkalemic cardioplegic arrest (HCA) and rewarming evokes postoperative myocyte contractile dysfunction, a phenomenon of particular importance in settings of preexisting left ventricular (LV) failure. Caspases are intracellular proteolytic enzymes recently demonstrated to degrade myocardial contractile proteins. This study tested the hypothesis that myocyte contractile dysfunction induced by HCA could be ameliorated with caspase inhibition in the setting of compromised myocardial function. LV myocytes were isolated from control pigs (n = 9, 30 kg) or pigs with LV failure induced by rapid pacing (n = 6, 240 bpm for 21 days) and were randomized to the following: (1) normothermia (2003 myocytes), incubation in cell culture medium for 2 hours at 37 degrees C; (2) HCA only (506 myocytes), incubation for 2 hours in hypothermic HCA solution (4 degrees C, 24 mEq K); or (3) HCA + z-VAD, incubation in hypothermic HCA solution supplemented with 10 microM of the caspase inhibitor z-VAD (z-Val-Ala-Asp-fluoromethyl-ketone, 415 myocytes). Inotropic responsiveness was examined using beta-adrenergic stimulation (25 nM isoproterenol). Ambient normothermic myocyte shortening velocity (microm/s) was reduced with LV failure compared with control values (54 +/- 2 versus 75 +/- 2, respectively, P < 0.05). Following HCA, shortening velocity decreased in the LV failure and control groups (27 +/- 5 and 45 +/- 3, P < 0.05). Institution of z-VAD increased myocyte shortening velocity following HCA in both the LV failure and control groups (49 +/- 5 and 65 +/- 5, P < 0.05). Moreover, HCA supplementation with z-VAD increased beta-adrenergic responsiveness in both groups compared with HCA-only values. This study provides proof of concept that caspase activity contributes to myocyte contractile dysfunction following simulated HCA. Pharmacologic caspase inhibition may hold particular relevance in the execution of cardiac surgical procedures requiring HCA in the context of preexisting LV failure.

    Title Myocyte Contractility with Caspase Inhibition and Simulated Hyperkalemic Cardioplegic Arrest.
    Date June 2004
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Exposure of left ventricular (LV) myocytes to simulated hyperkalemic cardioplegic arrest (HCA) has been demonstrated to perturb ionic homeostasis and adversely affect myocyte contractility on rewarming. Altered ionic homeostasis can cause cytosolic activation of the caspases. While caspases participate in apoptosis, these proteases can degrade myocyte contractile proteins, and thereby alter myocyte contractility. Accordingly, this study tested the hypothesis that caspase inhibition during HCA would attenuate the degree of myocyte contractile dysfunction upon rewarming, independent of a loss in myocyte viability. METHODS: Porcine (n = 8) LV myocytes were isolated and assigned to the following treatment groups: normothermic control: incubation in cell culture media for 2 hours at 37 degrees C; HCA only: incubation for 2 hours in hypothermic HCA solution (4 degrees C, 24 mEq K(+)); or incubation in hypothermic HCA solution supplemented with 10 microM of the caspase inhibitor, z-VAD (z-Val-Ala-Asp-fluoromethyl-ketone, HCA+zVAD). Myocyte viability, assayed as a function of mitochondrial function, was determined to be similar in the normothermic and both HCA groups. RESULTS: The HCA caused a significant reduction in myocyte shortening velocity compared with normothermic control values (41 +/- 6 versus 86 +/- 8 microm/s, p < 0.05). The HCA+zVAD group had significantly improved myocyte shortening velocity compared with the HCA only group (63 +/- 7 microm/s, p < 0.05). CONCLUSIONS: Independent of changes in viability, caspase inhibition attenuated myocyte contractile dysfunction after HCA and rewarming. Thus, caspase activation during HCA contributes, at least in part, to impaired myocyte contractility with rewarming. Supplementation of HCA with caspase inhibitors may provide a means to preserve myocyte contractile function after cardioplegic arrest.

    Title Pharmacologic Inhibition of Intracellular Caspases After Myocardial Infarction Attenuates Left Ventricular Remodeling: a Potentially Novel Pathway.
    Date January 2004
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    OBJECTIVE: Myocyte death occurs by necrosis and caspase-mediated apoptosis in the setting of myocardial infarction. In vitro studies suggest that caspase activation within myocytes causes contractile protein degradation without inducing cell death. Thus, caspase activation may evoke left ventricular remodeling through 2 independent processes post-myocardial infarction. However, the effects of caspase activation on left ventricular geometry post-myocardial infarction remain unclear. This project applied broad-spectrum caspase inhibition to a chronic porcine model of myocardial infarction. METHODS: Coronary snares and sonomicrometry crystals in remote and area-at-risk regions were placed in pigs (n = 22, 34 kg). Geometric measurements at end diastole and end systole, including left ventricular area by echocardiography and interregional distance by sonomicrometry, were obtained at baseline. Coronary occlusion was instituted for 60 minutes, followed by reperfusion and repeated geometric measurements at 7 days, including left ventriculography. At reperfusion, pigs were randomized to saline (n = 12) or caspase inhibition (n = 10, IDN6734, 2 mg/kg intravenously, then 2 mg x kg x h for 24 hours) at a dose that achieved desired plasma concentrations (790 +/- 142 ng/mL) as predicted by prior pharmacokinetic studies. RESULTS: Infarct size and 24-hour troponin-I values were not significantly different between the saline and caspase inhibition groups (51% +/- 8% vs 42% +/- 6% and 189 +/- 20 ng/mL vs 152 +/- 26 ng/mL, respectively, P >.10). At 7 days, end-diastole volume was increased in both groups compared with reference control values (47 +/- 1 mL, P <.05), but it was decreased with caspase inhibition (72 +/- 4 mL) compared with saline (84 +/- 4 mL, P <.05). Similarly, end-diastole and end-systole areas increased by 32% +/- 3% and 81% +/- 16% in the saline group but were attenuated with caspase inhibition (19% +/- 3% and 31% +/- 10%, respectively, P <.05). End-diastole interregional distance increased by 30% +/- 7% in the saline group but was attenuated with caspase inhibition (12% +/- 5%, P <.05). CONCLUSION: Despite equivalent degrees of myocardial injury, caspase inhibition reduced post-myocardial infarction left ventricular remodeling as evidenced by multiple, independent assessments of left ventricular dilation. Thus, caspase activation alters left ventricular geometry in the absence of significant effects on myocardial injury.

    Title Modulation of Calcium Transport Improves Myocardial Contractility and Enzyme Profiles After Prolonged Ischemia-reperfusion.
    Date January 2004
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Ischemia-reperfusion (IR) injury causes myocardial dysfunction in part through intracellular calcium overload. A recently described pharmacologic compound, MCC-135 (5-methyl-2-[1-piperazinyl] benzenesulfonic acid monohydrate, Mitsubishi Pharma Corporation), alters intracellular calcium levels. This project tested the hypothesis that MCC-135 would influence regional myocardial contractility when administered at reperfusion and after a prolonged period of ischemia. METHODS: A circumflex snare and sonomicrometry crystals within remote and area-at-risk regions were placed in pigs (n = 18, 32 kg). Coronary occlusion was instituted for 120 minutes followed by 180 minutes of reperfusion. At 105 minutes of ischemia pigs were randomly assigned to IR only (n = 11) or MCC-135 (IR-MCC [300 microg. kg(-1). h(-1), n = 7]) administered intravenously. Regional myocardial contractility was determined by calculation of the regional end-systolic pressure-dimension relation (RESPDR [mm Hg/cm]). Myocardial injury was determined by measurement of plasma levels of myocyte-specific enzymes. RESULTS: At 90 minutes ischemia, mean troponin-I was 35 +/- 8 ng/mL with no significant difference between groups. At 180 minutes reperfusion, heart rate was increased by 18% +/- 5% in the IR only group (p < 0.05) and was reduced by 11% +/- 4% with IR-MCC (p < 0.05). At 90 minutes ischemia RESPDR was reduced from baseline by 51% +/- 6% (p < 0.05). By 30 minutes reperfusion, reductions in RESPDR were attenuated with IR-MCC compared with IR only values. The CK-MB levels were increased at 180 minutes reperfusion in the IR only group (52 +/- 9 ng/mL) compared with baseline (6 +/- 1 ng/mL, p < 0.05) but were attenuated with IR-MCC (24 +/- 4 ng/mL, p < 0.05) compared with IR only values. CONCLUSIONS: Despite similar degrees of injury at 90 minutes ischemia MCC-135 improved regional contractility and reduced the egress of CK-MB. Moreover MCC-135 was associated with decreased heart rate, a determinant of myocardial oxygen demand. Pharmacologic modulation of calcium transport ameliorates myocardial dysfunction in the acute IR period.

    Title Direct Inhibition of the Sodium/hydrogen Exchanger After Prolonged Regional Ischemia Improves Contractility on Reperfusion Independent of Myocardial Viability.
    Date January 2004
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    BACKGROUND: A mechanism for myocardial dysfunction after ischemia and reperfusion is Na(+)/H(+) exchanger activation. Although past in vivo models of limited ischemia and reperfusion intervals demonstrate that Na(+)/H(+) exchanger inhibition confers myocardial protection when administered at the onset of ischemia, the effect of Na(+)/H(+) exchanger inhibition on myocardial function after prolonged ischemia and reperfusion remains unknown. This investigation tested the hypothesis that Na(+)/H(+) exchanger inhibition instituted at reperfusion and after prolonged coronary occlusion in pigs would influence myocardial contractility independent of myocardial viability. METHODS: A coronary snare and sonomicrometry crystals were placed in pigs (n = 21, 32 kg). Coronary occlusion was instituted for 120 minutes followed by reperfusion for 180 minutes. At 105 minutes of ischemia, pigs were randomized to ischemia and reperfusion only (saline solution, n = 11) or Na(+)/H(+) exchanger inhibition (HOE-642, 3 mg/kg intravenously, n = 10). Myocardial injury was determined by tissue staining and measurement of plasma myocyte-specific enzymes. Myocardial contractility was determined by calculation of the regional end-systolic pressure-dimension relation (millimeters of mercury per centimeter) and by assessment of interregional shortening. RESULTS: Infarct size was not different between groups (39% +/- 6%, P =.26). Moreover, at 180 minutes of reperfusion, plasma troponin-I and creatine kinase MB values had increased to identical levels in the ischemia and reperfusion-only and Na(+)/H(+) exchanger inhibition groups (300 +/- 35 and 50 +/- 6 ng/mL, respectively). At 90 minutes of ischemia, regional end-systolic pressure-dimension relation decreased from baseline (5.7 +/- 0.5 versus 2.7 +/- 0.3, P <.05) in the area at risk. By 30 minutes of reperfusion, regional end-systolic pressure-dimension relation decreased further in the ischemia and reperfusion-only group (1.6 +/- 0.2, P <.05), but improved with Na(+)/H(+) exchanger inhibition (4.4 +/- 0.7, P <.05). CONCLUSIONS: Na(+)/H(+) exchanger inhibition instituted at reperfusion improved contractility independent of myocardial viability as assessed by absolute infarct size and myocyte-specific enzyme release. Thus, modulation of Na(+)/H(+) exchanger activity in the setting of prolonged ischemia and reperfusion may hold therapeutic potential.

    Title Selective Targeting and Timing of Matrix Metalloproteinase Inhibition in Post-myocardial Infarction Remodeling.
    Date November 2003
    Journal Circulation
    Excerpt

    BACKGROUND: A cause-and-effect relationship exists between matrix metalloproteinase (MMP) induction and left ventricular (LV) remodeling after myocardial infarction (MI). Whether broad-spectrum MMP inhibition is necessary and the timing at which MMP inhibition should be instituted after MI remain unclear. This study examined the effects of MMP-1 and MMP-7-sparing inhibition (sMMPi) on regional and global LV remodeling when instituted before or after MI. METHODS AND RESULTS: Pigs instrumented with coronary snares and radiopaque markers within the area at risk were randomized to MI only (n=11) or sMMPi (PGE-530742, 10 mg/kg PO TID) begun 3 days before MI (n=11) or 3 days after MI (n=10). Eleven weight-matched noninstrumented pigs served as reference controls. At 10 days after MI, infarct size was similar between groups (47+/-3% of the area at risk). Marker area increased from baseline in the MI-only group (10+/-3%, P<0.05) but was unchanged with sMMPi. LV end-diastolic volume increased in the MI-only group (82+/-3 mL) compared with controls (56+/-3 mL, P<0.05) but was attenuated with pre-MI and post-MI sMMPi (69+/-3 and 69+/-4 mL, respectively, P<0.05). Collagen content increased in the infarct zone of the MI-only group (34+/-5%) compared with control (2+/-1%, P<0.05) but was reduced with pre-MI and post-MI sMMPi (24+/-1% and 23+/-2%, P<0.05). Collagen content increased in the border zone (12+/-2%) and decreased in the remote zone (3+/-1%) of the pre-MI sMMPi group compared with post-MI sMMPi values (7+/-1% and 5+/-1%, P<0.05). CONCLUSIONS: Inhibition of MMP-1 and -7 is not required to favorably influence LV remodeling after MI. Moreover, a temporal difference exists with respect to the timing of sMMPi and regional and global myocardial remodeling patterns after MI.

    Title Large Animal Models of Congestive Heart Failure: a Critical Step in Translating Basic Observations into Clinical Applications.
    Date August 2003
    Journal Journal of Nuclear Cardiology : Official Publication of the American Society of Nuclear Cardiology
    Excerpt

    Congestive heart failure (CHF) is a clinical syndrome in which pathophysiologic underpinnings include left ventricular (LV) dysfunction, remodeling, and increased neurohormonal activation. Accordingly, large animal constructs must be developed that mimic this disease process in order to define new pharmacologic and surgical treatment strategies. Multiple large animal species have been used for these purposes. For instance, canine coronary artery microembolization has been used to generate ischemia-induced LV dilation and dysfunction. Sheep have been subjected to total acute coronary artery occlusion to evaluate ischemia-induced mitral valve insufficiency. Rapid ventricular pacing has been used in both dogs and pigs to reproduce the characteristics of dilated cardiomyopathy. Each model is associated with advantages and disadvantages. Therefore findings derived from the study of large animal models of LV failure must be carefully evaluated. With proper interpretation, important insights into the pathogenesis of CHF may be realized. Furthermore, these models may be used in conjunction with imaging modalities such as magnetic resonance imaging, single photon emission computed tomography, and positron emission tomography to elucidate the identification of cellular and extracellular alterations associated with LV failure. Thus large animal models of CHF are critical components in the effort to translate basic observations into beneficial clinical applications.

    Title Matrix Metalloproteinase Inhibition Modifies Left Ventricular Remodeling After Myocardial Infarction in Pigs.
    Date April 2003
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    BACKGROUND: Global and regional shape changes that occur within the left ventricular wall after myocardial infarction have been termed infarct expansion. A potential mechanism for this postinfarction remodeling is activation of the matrix metalloproteinases. Accordingly, the present study examined the effects of matrix metalloproteinase inhibition on left ventricular global geometry after myocardial infarction in pigs. METHODS: Myocardial infarction was created in pigs by means of occlusion of the first and second obtuse marginal branches of the circumflex coronary artery, resulting in a uniform left ventricular free wall infarct size of 21% +/- 2%. At 5 days after infarction, the pigs were randomized to undergo broad-spectrum matrix metalloproteinase inhibition (n = 9; PD166793, 20 mg. kg(-1). d(-1) by mouth) or myocardial infarction alone (n = 8). Ten pigs served as noninfarction control animals. Left ventricular end-diastolic area, determined by means of echocardiography, was measured 8 weeks after infarction. RESULTS: Left ventricular end-diastolic area increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and myocardial infarction only groups compared to reference control animals (3.7 +/- 0.2 cm(2)), but was reduced with broad-spectrum matrix metalloproteinase inhibition compared to myocardial infarction alone (4.5 +/- 0.2 vs 4.9 +/- 0.2 cm(2), respectively; P <.05). Regional radial stress within the infarct region increased in both infarction groups when compared to values obtained from reference control animals (599 +/- 152 g/cm(2)), but was attenuated in the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition group compared to the myocardial infarction alone group (663 +/- 108 vs 1242 +/- 251 g/cm(2), respectively; P <.05). Similarly, regional myocardial stiffness increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and the myocardial infarction only groups compared with that observed in reference control animals (14 +/- 1 rkm, P <.05) but was lower with broad-spectrum matrix metalloproteinase inhibition than with myocardial infarction alone (42 +/- 6 vs 68 +/- 10 rkm, respectively; P <.05). CONCLUSIONS: Matrix metalloproteinase inhibition reduced postinfarction left ventricular dilation, reduced regional myocardial wall stress, and modified myocardial material properties. These unique findings suggest that increased myocardial matrix metalloproteinase activation after infarction contributes directly to the left ventricular remodeling process.

    Title Myocardial Infarct Expansion and Matrix Metalloproteinase Inhibition.
    Date February 2003
    Journal Circulation
    Excerpt

    BACKGROUND: A potential mechanism for left ventricular (LV) remodeling after myocardial infarction (MI) is activation of the matrix metalloproteinases (MMPs). This study examined the effects of MMP inhibition (MMPi) on regional LV geometry and MMP levels after MI. METHODS AND RESULTS: In pigs instrumented with radiopaque markers to measure regional myocardial geometry, MI was created by ligating the obtuse marginals of the circumflex artery. In the first study, pigs were randomized to MMPi (n=7; PD166793, 20 mg x kg(-1) x d(-1)) or MI only (n=7) at 5 days after MI, and measurements were performed at 2 weeks. Regional MI areas were equivalent at randomization and were increased in the MI-only group at 2 weeks after MI compared with the MMPi group. In the second study, pigs randomized to MMPi (n=9) or MI only (n=8) were serially followed up for 8 weeks. At 8 weeks after MI, LV end-diastolic dimension was lower with MMPi than in the MI-only group (4.7+/-0.1 versus 5.1+/-0.1 cm, P<0.05). Regional MI area was reduced with MMPi at 8 weeks after MI (1.3+/-0.1 versus 1.7+/-0.1 cm2, P<0.05). MMPi reduced ex vivo MMP proteolytic activity. In the MI region, membrane-type MMP levels were normalized and levels of the endogenous tissue inhibitor of MMPs (TIMP-1) were increased compared with normal levels with MMPi. These effects were not observed in the MI-only group. CONCLUSIONS: MMPi attenuated the degree of post-MI LV dilation and expansion of the infarct during the late phase of MI healing. In addition, exogenous MMPi caused region-specific modulation of certain MMP and TIMP species.

    Title Electrocochleography with Retardates.
    Date July 1974
    Journal The Laryngoscope
    Title Bronchofiberscope As an Aid to Endotracheal Intubation and Respiratory Care in Surgical Patients.
    Date January 1974
    Journal Southern Medical Journal
    Title Drugs Containing Halogen Atoms: Toxicity and Lack of Toxicity.
    Date December 1972
    Journal Journal of the Medical Association of Georgia

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