Ignite Creation Date:
2024-05-05 @ 4:50 PM
Last Modification Date:
2024-10-26 @ 9:25 AM
Study NCT ID:
NCT00328185
Status:
TERMINATED
Last Update Posted:
2012-03-16
First Post:
2006-05-18
Brief Title:
Allograft Fibrosis Following Pediatric Cardiac Transplantation
Sponsor:
Childrens Healthcare of Atlanta
Organization:
Childrens Healthcare of Atlanta
Study Overview
Official Title:
Allograft Fibrosis Its Regulation and Significance Following Pediatric Cardiac Transplantation
Status:
TERMINATED
Status Verified Date:
2006-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
unable to gather sufficient data
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Transplantation is the preferred method of treating many forms of end-stage organ failure While short-term results have improved long-term outcomes remain inadequate Myocardial fibrosis could potentially have an adverse effect on long-term cardiac function We wish to study the degree of fibrosis to see if we can predict survival following pediatric heart transplantation
Detailed Description:
There has been recent evidence that demonstrates a significant racial disparity in outcomes following pediatric heart transplantationDifferences in fibrosis or its regulation may offer an explanation to these differencesJust as the pathologic alterations of cardiac connective tissue in the ischemic heart and in cardiomyopathies support the view that the matrix plays a fundamental role in ventricular functionit is likely that other forms of cardiac dysfunctionsuch as that following heart transplantationmay also be related to changes in the extracellular matrixFibrosis has been identified in allografts following transplantalthough the degree and significance relative to cardiac function remains unclearMany of the regulatory substances have also been identified in the microenvironment of the allograft following transplantbut their role in collagen deposition and proteaseanti-protease balance is unclear as wellIt has been speculated that individualracialand regional disparities in outcome following pediatric heart transplantation may be the result of an underlying difference in fibrosisThis in turn influences the tolerance of the recipient to the graftand ultimatelythe time for graft failure to ensueOf the 4227 pediatric heart transplants performed in the US 1987-2004717 were African-AmericanThe 1-year graft survival did not differ among groups5-year graft survival was significantly lower among African-Americans compared to other racial groupsThe median graft survival for African-American recipients was 53 years compared to 110 years for other recipientsAfrican-American recipients had an increased likelihood of more HLA mismatcheslower median household incomeAfter adjusting for disparities in a multivariate analysis African-American race remained significantly associated with graft failureWhile the cellular component of the myocardium has been extensively studied the extracellular matrix is less well examined or understoodProcesses of synthesisdegradationand turnover are important for the understanding of the physiology of development and remodeling of tissues and the pathology of hypertrophy and fibrosisCollagen Fibroblasts are responsible for the biosynthesisassemblyand maintenance of the extracellular matrix Collagen is one of the components of the extracellular matrixWhile collagen proteins serve primarily as an inert structural support of connective tissuethey also control multiple cellular parameters such as adhesionmigrationcell shapecytoskeletal architectureand gene expressionFibronectin is a protein of the extracellular matrixFibronectin primarily serves as an adhesive proteinfacilitating cell adhesion to fibrincollagensheparinand proteoglycansFibronectin is important in contact inhibitioncell movementcell-substrate adhesioninflammationand wound healingAnother function of fibronectin may be in the homing of lymphocytic cellsAllograft rejection has been associated with infiltration of inflammatory cells and local deposition of fibronectinPerforming immunohistochemical analysis for collagen and fibronectin will determine the degree of fibrosis in serial endomyocardial biopsies over the duration of graft survivalThis data will determine the correlation between allograft fibrosis and clinical parameters of cardiac functionand will uncover differences in the degree of fibrosis that may exist between racial groupsThe interactions between cellsimmune mediatorsgrowth factorsand proteins that regulate fibrosis have been well documented in some clinical areasThroughout the transplant literatureseveral points in the fibrosis cascade have been identified as potential important regulatory components These include transforming growth factor-βtumor necrosis factor-αplasminogen activator inhibitor matrix metalloproteinase-2and matrix metalloproteinase-9All have the possibility of affecting the production of collagen and fibronectinand the degree of allograft fibrosisTransforming growth factor-β has many propertiesTGF-β has potential value as an immunosuppressant in tissueIt can serve as an anti-inflammatory agent based on its ability to inhibit the growth of both T and B cellsTGF-β has the ability to regulate growth depending on the surrounding cell type and whether or not other growth factors are presentTGF-β stimulates fibroblast chemotaxis and proliferationAs the most potent stimulator of collagen synthesisit regulates deposition of extracellular matrix and cell attachment to itIt induces fibronectinchondroitindermatin sulfate proteoglycanscollagenand glycoaminoglycansTGF-β promotes the formation and secretion of protease inhibitorsfurther contributing to collagen accumulationTGF-β decreases collagenaseincreases tissue inhibitors of metalloproteinasesand increases PAI-1 productionStudies have been done implicating TGF-β in the pathogenesis of small-airway fibrosis characteristic of obliterative bronchiolitis following lung transplantTGF-β expression was higher in OB patients in comparison to patients without OBand positive TGF-β staining preceded the histologic confirmation of OB by 6 monthsTGF-β has been implicated as a contributing factor to the overproduction of collagen characteristic of dilated cardiomyopathyAdministration of neutralizing antibodies to TGF-β has been shown to limit collagen accumulation in woundsTumor necrosis factor-α is a cytotoxic monokine produced by macrophages TNF-α is associated with the inflammatory response present following exposure to bacterial endotoxinTNF-α is produced within the first three days of wound healingIt facilitates leukocyte recruitmentinduces angiogenesisand promotes fibroblast proliferationIn animal modelsa prominent feature of acute allograft rejection is the dense deposition of fibronectin at the graft siteAdministration of anti-TNF-α serum into the hosts abrogated acute rejection and prolonged allograft survivalIt was accompanied by a decrease in intragraft TNF-α levels and down-regulated fibronectin mRNA expressionCertain serine proteases are thought to be key regulators of connective tissue turnoverPlasminogen activators generate plasmina serine proteasewhich has activity against a number of connective tissue macromoleculesincluding fibronectinproteoglycan core proteinsother glycoproteinscollagenas well as fibrinPlasmin has been shown to initiate the autoactivation of other proteinasesThe activity of plasminogen activators is closely regulated by specific inhibitorsThe plasminogen activator inhibitors are potentially one of the most important regulators of connective tissue degradation because of their control of the rate of plasmin generation in local environmentsPAI-1 is deposited pericellularly where its function is to regulate pericellular proteolysisThe connective tissue matrix metalloproteinase family consists of enzymes derived from mesenchymal cells and hematopoietic cellsThey are metal-binding proteinases secreted in proenzyme forms requiring extracellular activationThe MMPs can be divided into subgroupsone of which is the interstitial collagenasesThis group is responsible for regulating the extracellular collagenTheir activity is further regulated by a secreted inhibitortissue inhibitor of metalloproteinaseswhich forms a high-affinity irreversible complex with the active form of the MMPWhether or not matrix production and degradation occur depends on the relative amounts of the metalloproteinases and inhibitors and also on the complex interplay with serum inhibitorsIn disease states where the control mechanisms become uncoordinatedthe uaction and nature of MMP activities may be one of the factors leading to an imbalance of the extracellular matrixStudies have shown an increased expression of several MMPs during cardiacrenaland pulmonary allograft rejectionIn animalsallografts in the presence of MMP-9 showed lower cellular infiltration and fibrosis than allografts harvested from MMP-9 deficient recipientsThe reverse was true with MMP-2suggesting that MMP-2 and MMP-9 may play different roles in the process of allograft fibrosis and rejectionBy performing immunohistochemical analysiswe will determine the various amounts of these potential regulatory substances in serial endomyocardial biopsies over the duration of graft survivalThis data will allow us to compare the changes in regulatory factors with the degree of fibrosis over timeIt will enable us to uncover differences in regulation that may exist between racial groupsDuring the isovolumetric contraction phase of systoleventricular wall pressure develops rapidlyDuring the ejection phasepressure is transmitted to the ventricular cavityAssociated with ejectiongeometric changes occur in the ventricleTransmission of force to the ventricle must involve the myocardial matrixOf the structural proteins in the heartcollagen has the physical properties necessary for force transmission to the ventricleOne can conclude that a complex system composed primarily of collagen is necessary for at least systolic stress distribution and tethering of myocytes one to another during the spatial translocations that accompany systoleFor proper ventricular functioncontiguous myocytes must be stretched to near the same amountThis implies a mechanism for distribution of stress throughout the entire ventricular wallIt appears that not only the total amount or collagen presentbut also the distribution may be importantIncreases and decreases in collagen have been noted in various disease states and affect cardiac functionThe pathologic alterations of the intrinsic cardiac connective tissue in the ischemic heart and in cardiomyopathies support the view that the extracellular matrix plays a fundamental role in ventricular functionIschemic damage of the myocardium is a blood flow-mediatedtime-dependent processEven in the absence of tissue necrosisthere is reversible loss of contractile functionAlthough myocytes are not morphologically damaged when stunnedthey may lose their interconnections through damage to collagen and the extracellular matrixThe individual cells then move relative to each other without generating coordinatedforceful contractionsIn animalsstudies have shown systolic bulgingmural thinningand regions of absent connective tissueWith congestive cardiomyopathythere is ventricular dilationglobal wall thinning and diffuse contractile dysfunctionAlthough a significant component of ventricular dysfunction may relate to loss of contractile massthere are regions of connective tissue absence within the normal myocardium in animal modelsThe untethering of myocytes again leads to defectiveuncoordinated contractile activitySimilarlythe loss or damage of intrinsic connective tissue may account for the characteristic global wall thinningThis may lead to a spiral of progressive damageas the ventricular cavity enlargesend-diastolic pressure increasesthereby causing further injury to the connective tissueIn contrast to congestive cardiomyopathysome forms of heart disease are associated with decreased compliance and diminished diastolic fillingIncreased collagen has been demonstrated in hypertrophied heartsRather than a thin-walled dilated heartanimal models demonstrate mural hypertrophy with a small ventricular cavityIn patients with hypertrophicobstructive cardiomyopathybiopsies of the septum revealed severe myocellular hypertrophymyocyte disorganizationand pronounced interstitial collagen depositionThere is an increase in all components and disorganization in the arrangementAfter quantifying the degree of fibrosis and the various amounts of regulatory substanceswe will correlate this data to clinical parametersWe will compare changes in fibrosis over time with measurements of cardiac functionand with graft survival
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None