Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT00328185 |
| Other study ID # |
05-217 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
N/A
|
| First received |
May 18, 2006 |
| Last updated |
March 14, 2012 |
| Start date |
January 2006 |
| Est. completion date |
December 2006 |
Study information
| Verified date |
January 2006 |
| Source |
Children's Healthcare of Atlanta |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Food and Drug Administration |
| Study type |
Observational
|
Clinical Trial 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.
Description:
There has been recent evidence that demonstrates a significant racial disparity in outcomes
following pediatric heart transplantation.Differences in fibrosis or its regulation may
offer an explanation to these differences.Just 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 function,it is likely that other forms of
cardiac dysfunction,such as that following heart transplantation,may also be related to
changes in the extracellular matrix.Fibrosis has been identified in allografts following
transplant,although the degree and significance relative to cardiac function remains
unclear.Many of the regulatory substances have also been identified in the microenvironment
of the allograft following transplant,but their role in collagen deposition and
protease:anti-protease balance is unclear as well.It has been speculated that
individual,racial,and regional disparities in outcome following pediatric heart
transplantation may be the result of an underlying difference in fibrosis.This in turn
influences the tolerance of the recipient to the graft,and ultimately,the time for graft
failure to ensue.Of the 4227 pediatric heart transplants performed in the US 1987-2004,717
were African-American.The 1-year graft survival did not differ among groups;5-year graft
survival was significantly lower among African-Americans compared to other racial groups.The
median graft survival for African-American recipients was 5.3 years compared to 11.0 years
for other recipients.African-American recipients had an increased likelihood of more HLA
mismatches,lower median household income.After adjusting for disparities in a multivariate
analysis, African-American race remained significantly associated with graft failure.While
the cellular component of the myocardium has been extensively studied, the extracellular
matrix is less well examined or understood.Processes of synthesis,degradation,and turnover
are important for the understanding of the physiology of development and remodeling of
tissues and the pathology of hypertrophy and fibrosis.Collagen Fibroblasts are responsible
for the biosynthesis,assembly,and maintenance of the extracellular matrix. Collagen is one
of the components of the extracellular matrix.While collagen proteins serve primarily as an
inert structural support of connective tissue,they also control multiple cellular parameters
such as adhesion,migration,cell shape,cytoskeletal architecture,and gene
expression.Fibronectin is a protein of the extracellular matrix.Fibronectin primarily serves
as an adhesive protein,facilitating cell adhesion to fibrin,collagens,heparin,and
proteoglycans.Fibronectin is important in contact inhibition,cell movement,cell-substrate
adhesion,inflammation,and wound healing.Another function of fibronectin may be in the homing
of lymphocytic cells.Allograft rejection has been associated with infiltration of
inflammatory cells and local deposition of fibronectin.Performing immunohistochemical
analysis for collagen and fibronectin will determine the degree of fibrosis in serial
endomyocardial biopsies over the duration of graft survival.This data will determine the
correlation between allograft fibrosis and clinical parameters of cardiac function,and will
uncover differences in the degree of fibrosis that may exist between racial groups.The
interactions between cells,immune mediators,growth factors,and proteins that regulate
fibrosis have been well documented in some clinical areas.Throughout the transplant
literature,several points in the fibrosis cascade have been identified as potential
important regulatory components. These include transforming growth factor-β,tumor necrosis
factor-α,plasminogen activator inhibitor, matrix metalloproteinase-2,and matrix
metalloproteinase-9.All have the possibility of affecting the production of collagen and
fibronectin,and the degree of allograft fibrosis.Transforming growth factor-β has many
properties.TGF-β has potential value as an immunosuppressant in tissue.It can serve as an
anti-inflammatory agent based on its ability to inhibit the growth of both T and B
cells.TGF-β has the ability to regulate growth depending on the surrounding cell type and
whether or not other growth factors are present.TGF-β stimulates fibroblast chemotaxis and
proliferation.As the most potent stimulator of collagen synthesis,it regulates deposition of
extracellular matrix and cell attachment to it.It induces fibronectin,chondroitin/dermatin
sulfate proteoglycans,collagen,and glycoaminoglycans.TGF-β promotes the formation and
secretion of protease inhibitors,further contributing to collagen accumulation.TGF-β
decreases collagenase,increases tissue inhibitors of metalloproteinases,and increases PAI-1
production.Studies have been done implicating TGF-β in the pathogenesis of small-airway
fibrosis characteristic of obliterative bronchiolitis following lung transplant.TGF-β
expression was higher in OB patients in comparison to patients without OB,and positive TGF-β
staining preceded the histologic confirmation of OB by 6 months.TGF-β has been implicated as
a contributing factor to the overproduction of collagen characteristic of dilated
cardiomyopathy.Administration of neutralizing antibodies to TGF-β has been shown to limit
collagen accumulation in wounds.Tumor necrosis factor-α is a cytotoxic monokine produced by
macrophages. TNF-α is associated with the inflammatory response present following exposure
to bacterial endotoxin.TNF-α is produced within the first three days of wound healing.It
facilitates leukocyte recruitment,induces angiogenesis,and promotes fibroblast
proliferation.In animal models,a prominent feature of acute allograft rejection is the dense
deposition of fibronectin at the graft site.Administration of anti-TNF-α serum into the
hosts abrogated acute rejection and prolonged allograft survival.It was accompanied by a
decrease in intragraft TNF-α levels and down-regulated fibronectin mRNA expression.Certain
serine proteases are thought to be key regulators of connective tissue turnover.Plasminogen
activators generate plasmin,a serine protease,which has activity against a number of
connective tissue macromolecules,including fibronectin,proteoglycan core proteins,other
glycoproteins,collagen,as well as fibrin.Plasmin has been shown to initiate the
autoactivation of other proteinases.The activity of plasminogen activators is closely
regulated by specific inhibitors.The 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 environments.PAI-1 is deposited pericellularly where
its function is to regulate pericellular proteolysis.The connective tissue matrix
metalloproteinase family consists of enzymes derived from mesenchymal cells and
hematopoietic cells.They are metal-binding proteinases secreted in proenzyme forms requiring
extracellular activation.The MMPs can be divided into subgroups,one of which is the
interstitial collagenases.This group is responsible for regulating the extracellular
collagen.Their activity is further regulated by a secreted inhibitor,tissue inhibitor of
metalloproteinases,which forms a high-affinity irreversible complex with the active form of
the MMP.Whether 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 inhibitors.In disease states where the control mechanisms become uncoordinated,the
uaction and nature of MMP activities may be one of the factors leading to an imbalance of
the extracellular matrix.Studies have shown an increased expression of several MMPs during
cardiac,renal,and pulmonary allograft rejection.In animals,allografts in the presence of
MMP-9 showed lower cellular infiltration and fibrosis than allografts harvested from MMP-9
deficient recipients.The reverse was true with MMP-2,suggesting that MMP-2 and MMP-9 may
play different roles in the process of allograft fibrosis and rejection.By performing
immunohistochemical analysis,we will determine the various amounts of these potential
regulatory substances in serial endomyocardial biopsies over the duration of graft
survival.This data will allow us to compare the changes in regulatory factors with the
degree of fibrosis over time.It will enable us to uncover differences in regulation that may
exist between racial groups.During the isovolumetric contraction phase of
systole,ventricular wall pressure develops rapidly.During the ejection phase,pressure is
transmitted to the ventricular cavity.Associated with ejection,geometric changes occur in
the ventricle.Transmission of force to the ventricle must involve the myocardial matrix.Of
the structural proteins in the heart,collagen has the physical properties necessary for
force transmission to the ventricle.One 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 systole.For
proper ventricular function,contiguous myocytes must be stretched to near the same
amount.This implies a mechanism for distribution of stress throughout the entire ventricular
wall.It appears that not only the total amount or collagen present,but also the distribution
may be important.Increases and decreases in collagen have been noted in various disease
states and affect cardiac function.The 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 function.Ischemic damage of the
myocardium is a blood flow-mediated,time-dependent process.Even in the absence of tissue
necrosis,there is reversible loss of contractile function.Although myocytes are not
morphologically damaged when stunned,they may lose their interconnections through damage to
collagen and the extracellular matrix.The individual cells then move relative to each other
without generating coordinated,forceful contractions.In animals,studies have shown systolic
bulging,mural thinning,and regions of absent connective tissue.With congestive
cardiomyopathy,there is ventricular dilation,global wall thinning and diffuse contractile
dysfunction.Although a significant component of ventricular dysfunction may relate to loss
of contractile mass,there are regions of connective tissue absence within the normal
myocardium in animal models.The untethering of myocytes again leads to
defective,uncoordinated contractile activity.Similarly,the loss or damage of intrinsic
connective tissue may account for the characteristic global wall thinning.This may lead to a
spiral of progressive damage;as the ventricular cavity enlarges,end-diastolic pressure
increases,thereby causing further injury to the connective tissue.In contrast to congestive
cardiomyopathy,some forms of heart disease are associated with decreased compliance and
diminished diastolic filling.Increased collagen has been demonstrated in hypertrophied
hearts.Rather than a thin-walled dilated heart,animal models demonstrate mural hypertrophy
with a small ventricular cavity.In patients with hypertrophic,obstructive
cardiomyopathy,biopsies of the septum revealed severe myocellular hypertrophy,myocyte
disorganization,and pronounced interstitial collagen deposition.There is an increase in all
components and disorganization in the arrangement.After quantifying the degree of fibrosis
and the various amounts of regulatory substances,we will correlate this data to clinical
parameters.We will compare changes in fibrosis over time with measurements of cardiac
function,and with graft survival.
