Assessment of Translesional Markers and Metabolomics
| Status: | Completed |
|---|---|
| Conditions: | Peripheral Vascular Disease, Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 21 - Any |
| Updated: | 2/7/2015 |
| Start Date: | April 2006 |
| End Date: | May 2006 |
| Contact: | Abdul M Sheikh, MD |
| Email: | asheikh@learnlink.emory.edu |
| Phone: | 404-686-5500 |
An Assessment of Translesional Markers and Metabolomics
Blockages in the blood vessels of the heart are the main cause of chest pain, heart attacks,
and sudden death. A cardiac catheterization, or injecting x-ray dye into the blood vessels
of the heart and taking pictures, is currently the best way of assessing these blockages.
This procedure, however, does not allow us to know what is happening inside the blockages.
Some blockages have a higher risk of “rupturing” and completely blocking of the blood vessel
while others are at low risk for doing this.
Blood levels of different substances produced by the body have been shown to be associated
with a higher risk of having chest pain, a heart attack, or sudden death. There is also
evidence from studies in animals and tissues taken from humans during surgery that some of
these substances are made in the blockages themselves.
We would like to investigate whether a number of these substances are made in the blockages
and released into the bloodstream. We will do this by taking one tablespoon samples of blood
upstream and downstream of the blockages in the blood vessels of the heart. The samples will
be obtained by using a very thin catheter, or plastic tubing, that is about 1/3 the size of
the blood vessels of the heart. We will take samples from the tightest blockage found as
well as another, less tight, blockage and compare the two. We will also sample blood from
the tightest blockage after it is opened by doing an angioplasty. Finally, we will also take
pictures of the blockages studied using a very small ultrasound camera inserted into the
blood vessel. We will compare the levels of the substances measured with the features we see
on the pictures.
We hope to learn if some or all of the substances measured can identify which blockages are
more at risk for rupturing and causing heart attacks and sudden death.
All patients who are entered into this study will already be having an angioplasty done. The
procedures needed for the study (sampling of blood and taking pictures with an ultrasound)
are already often, though not always, used in patients undergoing an angioplasty.
and sudden death. A cardiac catheterization, or injecting x-ray dye into the blood vessels
of the heart and taking pictures, is currently the best way of assessing these blockages.
This procedure, however, does not allow us to know what is happening inside the blockages.
Some blockages have a higher risk of “rupturing” and completely blocking of the blood vessel
while others are at low risk for doing this.
Blood levels of different substances produced by the body have been shown to be associated
with a higher risk of having chest pain, a heart attack, or sudden death. There is also
evidence from studies in animals and tissues taken from humans during surgery that some of
these substances are made in the blockages themselves.
We would like to investigate whether a number of these substances are made in the blockages
and released into the bloodstream. We will do this by taking one tablespoon samples of blood
upstream and downstream of the blockages in the blood vessels of the heart. The samples will
be obtained by using a very thin catheter, or plastic tubing, that is about 1/3 the size of
the blood vessels of the heart. We will take samples from the tightest blockage found as
well as another, less tight, blockage and compare the two. We will also sample blood from
the tightest blockage after it is opened by doing an angioplasty. Finally, we will also take
pictures of the blockages studied using a very small ultrasound camera inserted into the
blood vessel. We will compare the levels of the substances measured with the features we see
on the pictures.
We hope to learn if some or all of the substances measured can identify which blockages are
more at risk for rupturing and causing heart attacks and sudden death.
All patients who are entered into this study will already be having an angioplasty done. The
procedures needed for the study (sampling of blood and taking pictures with an ultrasound)
are already often, though not always, used in patients undergoing an angioplasty.
Introduction
Hypothesis
Coronary heart disease is the leading cause of death in the United States, accounting for >
500,000 lives each year. Atherosclerosis is the underlying mechanism for unstable angina,
myocardial infarction, and sudden cardiac death. Luminal narrowing of the arteries caused by
atherosclerotic plaque encroachment causes the chronic ischemic manifestations of coronary
heart disease, whereas superimposition of thrombi over the plaques leads to acute coronary
syndromes. To date, angiography has been the method of choice of detecting arterial lesions.
However, this diagnostic technique, which approximately compares the degree of luminal
stenosis of arteries relative to its’ segments, does not provide insight into the disease
state within the artery, and often fails to detect those lesions prone to thrombosis, often
referred to as ‘vulnerable plaque’. Multiple invasive and non-invasive methods have been
employed in order to identify vulnerable plaque, usually by trying to image the plaque and
its morphology, however none has gained widespread use.
Elevation of several biochemical markers in the bloodstream has been associated with adverse
cardiovascular events. Inflammation has been identified as a significant component of the
unstable atherosclerotic plaque. The inflammatory response seems to participate early in the
development of atherosclerosis and involves multiple pathways3. Indeed, many markers of
inflammation have now been shown to predict cardiovascular risk4-7 and recent studies have
shown that key inflammatory markers are synthesized within atherosclerotic lesions8-10.
Another process that appears to precede inflammation is oxidative stress. Increased
cellular oxidative stress may be the process that initiates much of the subsequent
inflammation and ultimately to development of the atherosclerotic process. Our preliminary
data demonstrates that oxidative stress is increased in patients with acute coronary
syndromes and after coronary stenting. The immune system is also activated in those with
unstable atherosclerotic plaque with well documented changes in the T cells11-12.
An exciting new field of medicine is the application of systems approaches. One of these
systems approaches is metabolomics. Metabolomics is based on the use of NMR (and other
spectroscopic methods) and multivariate statistics for data analysis and interpretation.
NMR spectroscopy is based on the behavior of atoms placed in a static external magnetic
field. 1H-NMR spectroscopy allows the simultaneous detection and quantification of thousands
of low-molecular-weight metabolites within a biologic fluid, resulting in the generation of
an endogenous profile that may be altered in disease to provide a characteristic
“fingerprint” of the disease process. It has been used clinically in the detection of
ovarian cancer and coronary artery disease13, 14.
With this in mind, the difference in levels of oxidation and inflammatory markers, activated
leucocytes, and the metabolomic profile across an atherosclerotic lesion, that is the
translesional gradient, may be of clinical utility. An elevated translesional gradient of
inflammatory and oxidative markers, leucocyte activation, as well as a change in the
metabolomic profile, could be used to identify plaques prone to rupture. By implication,
the ability to simply and reliably identify such plaques would have profound clinical
consequences by either allowing placement of intracoronary stents in high-risk, but not yet
flow-limiting lesions that if left untreated would rupture and lead to an acute coronary
syndrome.
We hypothesize that:
1. the translesional gradients of (a) markers of oxidative stress, and (b) inflammation,
and (c) activated leucocytes will be elevated across culprit lesions as opposed to
non-culprit lesions in the same individuals; and
2. the translesional gradients of markers of oxidation, inflammation and leucocyte
activation will differ in plaques with high-risk morphologic appearance compared to
plaques with low-risk morphologic appearance, as assessed by intravascular ultrasound
(IVUS); and
3. The metabolomic profile assessed by 1H-NMR spectroscopy will differentiate culprit and
non-culprit lesions as well as plaques that have high-risk and low-risk morphologies.
Objectives
Aim 1: To determine and compare the translesional gradients of established markers of
oxidative stress, inflammation, and leucocyte activation across culprit lesions vs
non-culprit lesions in the same individuals.
Aim 2: To compare the translesion gradients of markers of oxidation, inflammation and
leucocyte activation with plaque morphology as assessed by intravascular ultrasound (IVUS).
Aim 3: To determine if a systems approach using 1H-NMR-based metabolomics can be used to
distinguish ruptured culprit and non-culprit lesions as well as plaques that have high-risk
and low-risk morphologies.
Endpoints
1. A comparison of the markers of oxidation, inflammation, and leucocyte activation in the
following:
1. A comparison will be made between the translesional marker gradients (distal level
– proximal level) of samples from the culprit lesion and non-culprit lesion.
2. A comparison will be made between levels (distal level – proximal level) to the
culprit lesion before and after angioplasty/stenting.
2. A comparison of the markers of oxidation, inflammation, and leucocyte activation with
plaque morphologic indices as assessed by intravascular ultrasound.
3. A comparison of 1H-NMR metabolomic spectra from culprit and non-culprit lesions as well
as plaques that have high-risk and low-risk plaque morphologies.
Hypothesis
Coronary heart disease is the leading cause of death in the United States, accounting for >
500,000 lives each year. Atherosclerosis is the underlying mechanism for unstable angina,
myocardial infarction, and sudden cardiac death. Luminal narrowing of the arteries caused by
atherosclerotic plaque encroachment causes the chronic ischemic manifestations of coronary
heart disease, whereas superimposition of thrombi over the plaques leads to acute coronary
syndromes. To date, angiography has been the method of choice of detecting arterial lesions.
However, this diagnostic technique, which approximately compares the degree of luminal
stenosis of arteries relative to its’ segments, does not provide insight into the disease
state within the artery, and often fails to detect those lesions prone to thrombosis, often
referred to as ‘vulnerable plaque’. Multiple invasive and non-invasive methods have been
employed in order to identify vulnerable plaque, usually by trying to image the plaque and
its morphology, however none has gained widespread use.
Elevation of several biochemical markers in the bloodstream has been associated with adverse
cardiovascular events. Inflammation has been identified as a significant component of the
unstable atherosclerotic plaque. The inflammatory response seems to participate early in the
development of atherosclerosis and involves multiple pathways3. Indeed, many markers of
inflammation have now been shown to predict cardiovascular risk4-7 and recent studies have
shown that key inflammatory markers are synthesized within atherosclerotic lesions8-10.
Another process that appears to precede inflammation is oxidative stress. Increased
cellular oxidative stress may be the process that initiates much of the subsequent
inflammation and ultimately to development of the atherosclerotic process. Our preliminary
data demonstrates that oxidative stress is increased in patients with acute coronary
syndromes and after coronary stenting. The immune system is also activated in those with
unstable atherosclerotic plaque with well documented changes in the T cells11-12.
An exciting new field of medicine is the application of systems approaches. One of these
systems approaches is metabolomics. Metabolomics is based on the use of NMR (and other
spectroscopic methods) and multivariate statistics for data analysis and interpretation.
NMR spectroscopy is based on the behavior of atoms placed in a static external magnetic
field. 1H-NMR spectroscopy allows the simultaneous detection and quantification of thousands
of low-molecular-weight metabolites within a biologic fluid, resulting in the generation of
an endogenous profile that may be altered in disease to provide a characteristic
“fingerprint” of the disease process. It has been used clinically in the detection of
ovarian cancer and coronary artery disease13, 14.
With this in mind, the difference in levels of oxidation and inflammatory markers, activated
leucocytes, and the metabolomic profile across an atherosclerotic lesion, that is the
translesional gradient, may be of clinical utility. An elevated translesional gradient of
inflammatory and oxidative markers, leucocyte activation, as well as a change in the
metabolomic profile, could be used to identify plaques prone to rupture. By implication,
the ability to simply and reliably identify such plaques would have profound clinical
consequences by either allowing placement of intracoronary stents in high-risk, but not yet
flow-limiting lesions that if left untreated would rupture and lead to an acute coronary
syndrome.
We hypothesize that:
1. the translesional gradients of (a) markers of oxidative stress, and (b) inflammation,
and (c) activated leucocytes will be elevated across culprit lesions as opposed to
non-culprit lesions in the same individuals; and
2. the translesional gradients of markers of oxidation, inflammation and leucocyte
activation will differ in plaques with high-risk morphologic appearance compared to
plaques with low-risk morphologic appearance, as assessed by intravascular ultrasound
(IVUS); and
3. The metabolomic profile assessed by 1H-NMR spectroscopy will differentiate culprit and
non-culprit lesions as well as plaques that have high-risk and low-risk morphologies.
Objectives
Aim 1: To determine and compare the translesional gradients of established markers of
oxidative stress, inflammation, and leucocyte activation across culprit lesions vs
non-culprit lesions in the same individuals.
Aim 2: To compare the translesion gradients of markers of oxidation, inflammation and
leucocyte activation with plaque morphology as assessed by intravascular ultrasound (IVUS).
Aim 3: To determine if a systems approach using 1H-NMR-based metabolomics can be used to
distinguish ruptured culprit and non-culprit lesions as well as plaques that have high-risk
and low-risk morphologies.
Endpoints
1. A comparison of the markers of oxidation, inflammation, and leucocyte activation in the
following:
1. A comparison will be made between the translesional marker gradients (distal level
– proximal level) of samples from the culprit lesion and non-culprit lesion.
2. A comparison will be made between levels (distal level – proximal level) to the
culprit lesion before and after angioplasty/stenting.
2. A comparison of the markers of oxidation, inflammation, and leucocyte activation with
plaque morphologic indices as assessed by intravascular ultrasound.
3. A comparison of 1H-NMR metabolomic spectra from culprit and non-culprit lesions as well
as plaques that have high-risk and low-risk plaque morphologies.
Inclusion Criteria:
- Men and women from the ages of 21 and older
- Able to give informed consent
- Already scheduled to undergo diagnostic catheterization or percutaneous coronary
intervention
- A culprit lesion (>60% diameter stenosis) in an artery that is at least 2.5 mm in
diameter immediately proximal to the lesion.
- Presence of a second, non-culprit lesion, that is between 20 and 60% diameter
stenosis in an artery that is at least 2.5 mm in diameter immediately proximal to the
lesion.
Exclusion Criteria:
- ST-segment elevation myocardial infarction
- Thrombolysis in Myocardial Infarction (TIMI) grade 0 flow in the vessel containing
the culprit lesion
- Autoimmune diseases, malignancy, or with active infections
- Taking immune-modulating therapies, eg prednisone
- Culprit lesion is in-stent restenosis
- Culprit lesion cannot be crossed with a wire and/or balloon
- Those enrolled in another research study
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