PubMed Health⌕ Search

Biomedical subjects

Francis G Spinale

Publications and source records attributed to Francis G Spinale.

At least 55 records · Page 3Linked to original sources
PubMed2004

Caspase inhibition attenuates contractile dysfunction following cardioplegic arrest and rewarming in the setting of left ventricular failure.

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.

Adrenergic beta-Agonists↗
PubMed2004

The effects of leukocyte reduction on matrix metalloproteinase release in cardiopulmonary bypass.

Matrix metalloproteinases (MMPs) are a family of enzymes responsible for degrading the extracellular matrix, a process that likely contributes to the development of altered vascular permeability. Past studies in patients undergoing cardiopulmonary bypass (CPB) have documented increased levels of MMPs with CPB. The purpose of this study was to evaluate the effect of leukocyte reduction on MMP release during CPB. Patients (n = 17) undergoing elective coronary revascularization requiring CPB were randomly assigned to either a leukocyte-reducing filter (LRF) group (n = 9) or the standard CPB circuit with no LRF (n = 8). White blood cell (WBC) counts, MMP-2, and MMP-9 levels were serially measured at baseline and up to 12 hours post CPB. MMP levels were measured by enzyme-linked immunoassay. ProMMP-2 levels increased in both the non-LRF and LRF groups but to a higher degree in the LRF group. ProMMP-9 levels increased by 40% in the non-LRF group. In contrast, proMMP-9 decreased by 30% in the LRF group. The addition of leukocyte-reducing filters in the CPB circuit attenuated the release of MMP-9 but increased release of MMP-2 post-CPB. Because MMPs can degrade the extracellular matrix, leading to increased vascular permeability, attenuation of MMPs may have decreased the local tissue injury known to occur as a result of these enzymes. However, future prospective studies to test this hypothesis directly are warranted.

Cardiopulmonary Bypass↗
PubMed2003

Targeted overexpression of noncleavable and secreted forms of tumor necrosis factor provokes disparate cardiac phenotypes.

BACKGROUND: Recent studies suggest that posttranslation processing or "shedding" (ie, secretion) of tumor necrosis factor (TNF) by tumor necrosis factor-alpha converting enzyme (TACE) may contribute to the left ventricular (LV) remodeling that occurs in the failing human heart. METHODS AND RESULTS: To address the functional significance of TNF shedding, we generated lines of transgenic mice with targeted overexpression of secreted wild-type (MHCsTNF2) TNF and overexpression of a mutated noncleavable transmembrane form of TNF (MHCmTNF). Both lines of mice had overlapping levels of myocardial TNF protein; however, the phenotypes of the MHCsTNF2 and MHCmTNF mice were strikingly disparate. Whereas the MHCmTNF mice developed a concentric LV hypertrophy phenotype, the MHCsTNF2 mice developed a dilated LV phenotype. The fibrillar collagen weave in MHCmTNF mice with concentric hypertrophy was characterized by thick collagen fibrils and increased collagen content, whereas the fibrillar collagen weave in the MHCsTNF2 mice with LV dilation was characterized by a diminished collagen content. Inhibition of matrix metalloproteinases with a broad-based matrix metalloproteinase inhibitor prevented LV dilation in the MHCsTNF2 mice. CONCLUSIONS: These findings suggest that posttranslational processing of TNF, as opposed to TNF expression per se, is responsible for the adverse cardiac remodeling that occurs after sustained TNF overexpression.

Animals↗
PubMed2003

Myocardial remodeling after discrete radiofrequency injury: effects of tissue inhibitor of matrix metalloproteinase-1 gene deletion.

Discrete myocardial lesions created through the delivery of radiofrequency (RF) energy can expand; however, the mechanisms have not been established. Matrix metalloproteinases (MMPs) play an important role in myocardial remodeling, and MMP activity can be regulated by the tissue inhibitors of the metalloproteinases (TIMPs). This study examined the role of TIMP-1 in postinjury myocardial remodeling. Lesions were created on the left ventricular (LV) epicardium of wild-type (WT, 8-12 wk, 129SVE) and age-matched TIMP-1 gene-deficient (timp-1(-/-)) mice through the delivery of RF current (80 degrees C, 30 s). Heart mass, LV scar volumes, and collagen content were measured at 1 h and 3, 7, and 28 days postinjury (n = 10 each). Age-matched, nonablated mice were used as reference controls (n = 5). Heart mass indexed to tibial length increased in WT and timp-1(-/-) mice but was greater in the timp-1(-/-) mice by 7 days. Scar volumes increased in a time-dependent manner in both groups but were higher in the timp-1(-/-) mice than the WT mice at 7 days (1.48 +/- 0.09 vs. 1.20 +/- 0.11 mm(3).mg(-1).mm, P < 0.05) and remained higher at 28 days. In the remote myocardium, wall thickness was greater and relative collagen content was lower in the timp-1(-/-) mice at 28 days postinjury. Discrete myocardial RF lesions expand in a time-dependent manner associated with myocyte hypertrophy remote to the scar. Moreover, postinjury myocardial remodeling was more extensive with TIMP-1 gene deletion. Thus TIMP-1 either directly or through modulation of MMP activity may regulate myocardial remodeling following infliction of a discrete injury.

Animals↗
PubMed2003

Selective targeting and timing of matrix metalloproteinase inhibition in post-myocardial infarction remodeling.

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.

Animals↗
PubMed2003

Targeted overexpression of transmembrane tumor necrosis factor provokes a concentric cardiac hypertrophic phenotype.

BACKGROUND: Tumor necrosis factor (TNF) is initially synthesized as a 26-kDa transmembrane protein that is enzymatically cleaved by TNF-alpha converting enzyme (TACE) to generate a 17-kDa form of "secreted" TNF. Whereas the effects of secreted TNF in the heart have been characterized extensively, the effects of transmembrane TNF in the heart are unknown. METHODS AND RESULTS: We generated lines of transgenic mice with cardiac-restricted overexpression of a noncleavable, transmembrane form of TNF. We next treated a previously generated transgenic line of mice with cardiac-restricted expression of cleavable TNF (referred to as MHCsTNF mice) with a TACE inhibitor (DPC-IDR1) to determine whether TACE inhibition would prevent the transition from concentric hypertrophy to left ventricular (LV) dilation that occurs in this line of transgenic mice. Two of the founder lines did not have a demonstrable phenotype (M-41 and M-45), whereas a third line developed a concentric hypertrophic cardiac phenotype (M-48). Characterization of the M-48 line at 6 weeks of age showed that this line developed concentric hypertrophy, with an increase in myocyte cross-sectional area and reexpression of the fetal gene program. Four weeks of TACE inhibition abrogated the LV dilation in the MHCsTNF mice and resulted in an increase in LV wall thickness and increased myocyte cross-sectional area, thus mimicking the effects observed in the mice with noncleavable, transmembrane TNF. CONCLUSIONS: These studies show that transmembrane TNF is biologically active and provokes a concentric hypertrophic cardiac phenotype, thus suggesting that posttranslational processing (ie, secretion) of TNF is responsible for the dilated cardiomyopathic phenotype in mice with targeted, cardiac-restricted overexpression of TNF.

ADAM Proteins↗
PubMed2003

Activation and functional significance of the renin-angiotensin system in mice with cardiac restricted overexpression of tumor necrosis factor.

BACKGROUND: The functional significance of cross-regulation between the renin-angiotensin system (RAS) and tumor necrosis factor (TNF) has been established in nonmyocyte cell types; however, the degree and functional significance of the interaction between RAS and TNF has not been characterized in the heart. METHODS AND RESULTS: We examined the expression of components of the RAS in a line of transgenic mice (MHCsTNF) with cardiac restricted overexpression of TNF. When examined at 4, 8, and 12 weeks of age, the MHCsTNF mice had increased activation of myocardial RAS, as shown by an increase in ACE mRNA level and ACE activity and increased angiotensin II peptide levels. Furthermore, myocardial angiotensin receptor mRNA and protein levels were reduced in the MHCsTNF mice, consistent with homologous desensitization of the receptors. However, expression of renin and angiotensinogen was not increased in MHCsTNF mice compared with littermate controls. To determine the functional significance of RAS activation in the MHCsTNF mice, we treated the mice with an angiotensin type I receptor antagonist, losartan (30 mg/kg), or diluent from 4 to 8 weeks of age. Analysis of cardiac structure with MRI showed that treatment with losartan normalized left ventricular mass and wall thickness. Furthermore, treatment with losartan reduced myocardial collagen content and reduced the incidence of myocyte apoptosis. CONCLUSIONS: Taken together, these results show that there are functionally significant interactions between RAS and TNF in the heart and that these interactions play an important role in the development and progression of left ventricular remodeling.

Age Factors↗
PubMed2003

Region- and type-specific induction of matrix metalloproteinases in post-myocardial infarction remodeling.

BACKGROUND: Induction of matrix metalloproteinases (MMPs) contributes to adverse remodeling after myocardial infarction (MI). Whether a region- and type-specific distribution of MMPs occurs within the post-MI myocardium remained unknown. METHODS AND RESULTS: Ten sheep were instrumented with a sonomicrometry array to measure dimensions in 7 distinct regions corresponding to the remote, transition, and MI regions. Eight sheep served as reference controls. The relative abundance of representative MMP types and the tissue inhibitors of the MMPs (TIMPs) was quantified by immunoblotting. Segment length increased from baseline in the remote (24.9+/-5.4%), transition (18.0+/-2.9%), and MI (53.8+/-11.0%) regions at 8 weeks after MI (P<0.05) and was greatest in the MI region (P<0.05). Region- and type-specific changes in MMPs occurred after MI. For example, MMP-1 and MMP-9 abundance was unchanged in the remote, fell to 3+/-2% in the transition, and was undetectable in the MI region (P<0.05). MMP-13, MMP-8, and MT1-MMP increased by >300% in the transition and MI regions (P<0.05). TIMP abundance decreased significantly in the transition region after MI and fell to undetectable levels within the MI region. CONCLUSIONS: The unique findings of this study were 2-fold. First, changes in regional geometry after MI were associated with changes in MMP levels. Second, a region-specific portfolio of MMPs was induced after MI and was accompanied by a decline in TIMP levels, indicative of a loss of MMP inhibitory control. Targeting the regional imbalance between specific MMPs and TIMPs within the post-MI myocardium holds therapeutic potential.

Animals↗
PubMed2003

Selective matrix metalloproteinase inhibition with developing heart failure: effects on left ventricular function and structure.

The matrix metalloproteinases (MMPs) are an endogenous family of proteolytic enzymes implicated to contribute to LV remodeling. However, broad-spectrum MMP inhibition (MMPi), particularly inhibition of interstitial collagenase (MMP-1), may not be clinically applicable. This study examined the effects of selective MMPi (sparing MMP-1) in a model of developing congestive heart failure. Pigs were randomly assigned to 3 groups: (1) rapid pacing for 3 weeks (240 bpm, n=10); (2) selective MMPi (20 mg/kg per day-PO;PGE7113313) and rapid pacing (n=12); and (3) controls (n=10). LV peak wall stress increased from controls with rapid pacing (140+/-6 versus 319+/-18 g/cm2; P<0.05) and was reduced with selective MMPi (208+/-9 g/cm2; P<0.05. Preload recruitable stroke work was reduced with rapid pacing (4.3+/-0.4 versus 1.2+/-0.2 dyne. cm/mm Hg; P<0.05) and was increased with selective MMPi (2.6+/-0.3 dyne. cm/mm Hg; P<0.05). Plasma norepinephrine increased by 6-fold in the rapid pacing group (P<0.05) and was reduced from untreated values with selective MMPi (P<0.05). At the myocardial level, myocyte cross-sectional area was increased with selective MMPi but fibrillar collagen volume fraction remained unchanged relative to control values. These results suggest that targeting a selective portfolio of myocardial MMP species for inhibition may provide a more rational therapeutic strategy in the setting of congestive heart failure.

Animals↗
PubMed2003

Myocardial infarct expansion and matrix metalloproteinase inhibition.

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.

Animals↗
PubMed2003

Pharmacologic inhibition of intracellular caspases after myocardial infarction attenuates left ventricular remodeling: a potentially novel pathway.

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.

Animals↗
PubMed2003

Modulation of calcium transport improves myocardial contractility and enzyme profiles after prolonged ischemia-reperfusion.

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.

Animals↗
PubMed2003

Matrix metalloproteinase abundance in human myocardial fibroblasts: effects of sustained pharmacologic matrix metalloproteinase inhibition.

BACKGROUND: A cause-effect relationship has been established between matrix metalloproteinases (MMPs) and left ventricular (LV) myocardial remodeling through the use of pharmacologic MMP inhibitors. However, the direct effects of MMP inhibition on MMPs and endogenous tissue inhibitors of metalloproteinases (TIMPs) in LV human myocardial fibroblasts (LVHMFs) remain unknown. This study measured MMP-2, MMP-9, MMP-13, MT1-MMP, and TIMP-1 release in LVHMFs. METHODS AND RESULTS: LVHMF cultures were established from six individual patients (passages 2-5) and incubated with and without the broad-spectrum MMP inhibitor PD166793 (100 microM) for 12-36 h. While PD166793 did not influence MMP-2 release, MMP-9 levels based on substrate zymography increased at 36 h by over 30% (P < 0.05). TIMP-1 levels increased in a time-dependent manner with no effect from PD166793 incubation. However, the MMP-9/TIMP-1 ratio was increased by over 20% from time-matched values following 12-36 h of exposure to PD166793 (P < 0.05). Similar results obtained after incubation of LVHMF cultures with the broad-spectrum MMP inhibitor Batimastat (BB-94) suggest that these observations are due to a general class effect of broad-spectrum MMP inhibitors. CONCLUSIONS: This study is the first to demonstrate that a selective induction and release of an MMP species occurs with sustained exposure to pharmacologic MMP inhibition in LVHMFs. These observations may have particular importance with respect to controlling this proteolytic system in the context of LV myocardial remodeling.

Enzyme-Linked Immunosorbent Assay↗
PubMed2003

A murine model of thoracic aortic aneurysms.

BACKGROUND: The mechanisms of thoracic aortic aneurysm (TAA) formation are poorly understood, mainly due to the lack of a useful and reproducible model. Accordingly, the goal of this study was to test the hypothesis that abluminal calcium chloride (CaCl(2)) application could create TAAs in the mouse. MATERIALS AND METHODS: Adult 129/SvE mice (n = 8) were anesthetized and their thoracic aortas exposed via left thoracotomy. CaCl(2) (0.5M) was applied to the distal descending thoracic aorta for 15 min followed by chest closure. At 4 weeks, the perfusion-fixed aorta was harvested from the root to the renal arteries. Diameter measurements were made using confocal microscopy, and wall thickness was measured from hematoxylin and eosin-stained sections. RESULTS: The control (n = 15) distal descending thoracic aortic diameter was 0.60 +/- 0.04 mm and increased by 25% (0.76 +/- 0.06 mm, P < 0.05) following CaCl(2) treatment. Control aortic wall thickness was 48 +/- 9 mum and decreased by 47% in corresponding CaCl(2)-exposed segments (25 +/- 8 mum, P < 0.05). The diameter and wall thickness of the ascending aorta (used as an internal control) were not significantly different between groups. Picrosirius red staining of the TAA showed adventitial collagen breakdown and disruption of lamellar organization. CONCLUSIONS: We conclude that abluminal application of CaCl(2) to the thoracic aorta reliably produces dilation, wall-thinning, and disruption of mural architecture, the hallmark signs of aneurysm formation. To our knowledge, these findings describe for the first time the generation of a reproducible model of isolated TAA formation in a murine system.

Animals↗
PubMed2003

Direct inhibition of the sodium/hydrogen exchanger after prolonged regional ischemia improves contractility on reperfusion independent of myocardial viability.

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.

Animals↗
PubMed2003

Matrix metalloproteinase inhibition modifies left ventricular remodeling after myocardial infarction in pigs.

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.

Analysis of Variance↗
PubMed2003

Extracellular matrix remodeling following myocardial injury.

While current therapeutic strategies restore blood flow to the ischemic myocardium and limit infarct size, adverse left ventricular (LV) remodeling that progresses to dysfunction remains a significant complication following myocardial infarction (MI). The extracellular matrix (ECM) is a key component in the remodeling process, and increases in collagen occur in the infarct area to replace necrotic myocytes and form a scar. The ECM is coupled to the cell through cell surface receptors, primary of which are the integrins. In addition, the matrix metalloproteinases coordinate ECM turnover through degradation of ECM components. Several laboratories have demonstrated matrix metalloproteinase (MMP) participation in remodeling events that lead to LV dilation, and inhibition or targeted deletion of specific MMPs has beneficial effects post-MI. MMP inhibition is a particular focus of recent studies designed to understand the underlying mechanisms of LV remodeling and to evaluate pharmacologic strategies that target the ECM to affect adverse LV remodeling following MI.

Coronary Vessels↗