CAD AND PLAQUE STABILIZATION & REVERSAL.
Most likely same pathways stabilize and reverse the plaques.
"IN THE PAST, IT WAS BELIEVED THAT PLAQUE BUILT UP IN ARTERIES OVER A PERIOD OF DECADES UNTIL
THEY BECAME SO CLOGGED THAT A HEART ATTACK ENSUED. WE NOW KNOW THAT THESE MECHANISMS ARE MUCH MORE DYNAMIC, WITH MINUTE-TO-MINUTE
CHANGES IN HOW DILATED OR CONSTRICTED ARTERIES ARE."
"THIS HELPS TO EXPLAIN WHY THE STUDIES I MENTIONED IN CHAPTER 1 FAILED TO SHOW THAT ANGIOPLASTY
OR BYPASS SURGERY PROLONGS LIFE OR PREVENT HEART ATTACKS IN MOST PATIENTS. MOST DOCTORS ARE NOT GOING TO PUT A STENT OR OR
A BYPASS GRAFT IN AN ARTERY THAT'S ONLY 30% BLOCKED, YET THESE ARE THE ONES THAT ARE MOST LIKELY TO CAUSE A HEART ATTACK."
"SURPRISINGLY, ARTERIES THAT ARE ONLY 30 TO 40% CLOGGED MAY ACTUALLY BE MORE LIKELY TO CAUSE
HEART ATTACK THAN THOSE THAT ARE 90 TO 95% BLOCKED.
BECAUSE WHEN THERE IS A SIGNIFICANT AMOUNT OF PLAQUE IN YOUR ARTERIES,
IT 'S MORE LIKELY TO BE CALCIFIED AND STABLE.
ALSO, OVER TIME, NEW BLOOD VESSELS CALLED COLLATERAL GROW AROUND BLOCKED ARTERIES--A TYPE OF
"BUILT-IN-BYPASS." SO IF AN ARTERY BECOMES COMPLETELY OBSTRUCTED, A HEART ATTACK MAY NOT NECESSARILY ENSUE SINCE THERE IS
ANOTHER PATHWAY BLOOD TO FLOW AROUND THE BLOCKAGE.
IN CONTRAST, AN ARTERY THAT IS ONLY 30 TO 40% CLOGGED HAS NOT HAD TIME TO GROW NEW COLLATERAL
VESSELS. ALSO. IT'S NOT LIKELY TO BE CALCIFIED AND STABLE, SO THERE IS A GREATER RISK OF IT CONSTRICTING DURING TIMES OF EMOTIONAL
STRESS. WHEN ARTERY IN YOU HEART CONSTRICTS, IT MAY CAUSE RUPTURE IN PLAQUES THAT ARE WEAKENED, CALLED VULNERABLE PLAQUES.
WHEN A PLAQUE RUPTURES, THE ARTERY MAY GO FROM 30 TO 40 % TO 100% BLOCKED WITHIN SECONDS TO MINUTES. THIS IS CALLED
CATASTROPHIC PROGRESSION (IT'S AS BAD AS SOUNDS) AND MAY LEAD TO HEART ATTACK, STROKE OR SUDDEN CARDIAC DEATH. PLAQUE RUPTURE
CAN OCCUR DUE TO SUDDEN PHYSICAL OR EMOTIONAL STRESS."
PLAQUE DISRUPTION AND THROMBOSIS: Potential Role of
Inflammation and Infection. Cardiology ClinicsVolume 17, Issue 2
, 1 May 1999, Pages 271-281
Ischemic heart disease, a consequence of coronary atherosclerosis, is the leading
cause of death in the United States and developing countries. The clinical manifestations of coronary atherosclerosis range
from asymptomatic state and stable angina, to acute coronary syndromes, such as unstable angina, acute myocardial infarction
(MI), and many cases of sudden cardiac death. Acute coronary events are the first clinical expression of coronary atherosclerosis
in 30% to 40% of cases. A better understanding of the pathophysiology of acute coronary syndromes could provide improved preventive
and therapeutic strategies against coronary artery disease.
"Recent studies have challenged the old paradigm, which was based on the notion that coronary syndromes resulted
from gradual and progressively luminal obstruction (stenosis) caused by growth of the atherosclerotic plaque. In the new paradigm,
plaque disruption and thrombosis, the vulnerability to which is determined by intrinsic characteristics of the plaque (plaque
vulnerability) and extrinsic triggers rather than the stenosis severity, are the most important determinants of the more lethal
clinical manifestations of coronary atherosclerosis.* Coronary artery disease progresses in a nonlinear and often unpredictable fashion leading to a rapid worsening of coronary
luminal obstruction, including the sudden development of total or near total occlusion. This rapid change is largely related
to superimposition of a thrombus on top of a disrupted plaque.25 Several studies have demonstrated a high prevalence of coronary thrombosis in acute coronary syndromes with an underlying
substrate of plaque-cap fissure or rupture in 60% to 80% or superficial plaque-endothelial erosion in 20% to 40%.* Serial angiography has revealed an interesting angiographic-clinical paradox whereby 60% to 70% of acute coronary syndromes
(and by inference plaque disruptions with thrombosis leading to total or subtotal occlusion) evolve from lesions that are
non–flow-limiting with only a mild to moderate luminal stenosis even though severely stenotic lesions are more likely
to progress to total occlusion over time.  ,  ,  and  Stress testing in patients with known chronic coronary artery disease has also shown that MI often occurs in coronary
territories that did not produce stress-induced ischemia months prior to development of MI.77 The apparent paradox may be largely explained by the fact that mildly stenotic lesions outnumber the severely stenotic lesions
by a factor of 5 to 10 and that angiography often underestimates the extent of the plaque as well as the severity of anatomic
cross-sectional narrowing that is observed in autopsy studies.82 Furthermore, a rapid transition of a mildly stenotic lesion to total occlusion is more likely to result in a clinical event,
because of a low likelihood of protective collateral, compared with when a severely stenotic lesion becomes totally occluded.
Finally, mildly obstructive plaques are often large and may be subject to a greater degree of wall stress because of a larger
luminal diameter.  ,  and  ."
References for the above paragraphs.
Most patients with angina don't need angioplasty to reduce angina. Frequency of angina can be
reduced by 90% + in few weeks if they adhere to Dr. Ornish's programs.
Why aggressive diet therapies such as of Drs. Ornish's and Esselstyn's programs are so highly
successful, specially within just few weeks reducing cardiac events and those who with lasting effect one adhere to the diet!
and non cellular elements
in the plaque and stress from heart's dynamic activity make plaque to rupture.
Discussed more later.
The smaller, lipid-rich plaques that are prone to rupture are also the ones most likely
to stabilize and reverse (13).
It has been shown that the presence of a space-occupying plaque is commonly associated with the
expansion of the arterial wall or ‘vessel remodeling’.1
The coronary artery
atheromatous plaques are usually eccentric and grow towards the adventitia, and later towards the lumen of the artery.
and ‘negative’ types of vascular remodeling have been identified. Positive or outward plaque bulging remodeling
are associated with the thinning of the arterial media. Negative remodeling is described as a ‘paradoxical wall shrinkage’
at the site of atheromatous plaques.
A sizable proportion
of atherosclerotic coronary arteries do not undergo remodeling and is lesion-specific.7
Remodeling is influenced
by dynamic changes in vessel diameter such as blood flow, shear stress forces and the substances affecting vasomotor tone.8 And also implicated are Inflammation and endothelial cell activation that cause plaque fissuring.9
macrophages within atheromatous plaques releases metalloproteinases, a family of enzymes. These enzymes can weaken the plaque
fibrous capsule and rupture by degrading both the connective tissue plaque matrix and the muscular media.10
interferon gamma can thin the fibrous capsule of the plaque by inhibiting collagen synthesis by vascular smooth muscle cell.
It is thought that
inflammation may represent a link between plaque fissuring and positive vessel remodeling.
34-60% of patients with acute coronary syndromes
exhibit positive remodeling at the culprit lesion site.11,12
This could be the rationale of treat inflammation
to stop macrophage collection and activities and vitamin C for connective tissue formation.
Ref: J.C. Kaski * Atheromatous plaque location and arterial remodeling. Eur
Heart J (2003) 24 (4): 291-293.
Plaques, associated with positive remodeling are tend to rupture, and those are negative
remodeling, tend not to rupture. Positive remodeling associated plaques contain "soft" non calcified plaque with
large lipid cores and an active inflammatory process (17) and strongly associated with ACS and plaque rupture.
Constrictive or negative remodeling is more common in patients with stable
Diminished lipid core, negative remodeling, and small changes in plaque size are observed
in response to intensive lipid lowering (19).
Treatment with statins is associated with constrictive remodeling (21) and increased (22) hyperechogenicity index (composed of dense fibrous or elastic tissue) in atorvastatin-treated patients, whereas
calcification and hypoechogenic plaque (loose fibrous, lipoid, and necrotic tissue) remained constant.
(23), Patients with ACS treated with statin resulted in regression of atherosclerotic lesions 6 months
later and 13 reduction of plaque volume from baseline but increased 9% in the control group (p < 0.03).
Stable atheromas would be more resistant to regression by statin therapy.
Obstructive stenoses have been shown to have the potential for the greatest
degree of regression (24,25). Plaque (26), regression of types I to III (early and preatheroma) to normal is possible, whereas decreasing lipid
content in lesion types IV to VI (atheromas, fibroatheromas, and complicated lesions) transformed to types VII
to VIII (calcific and fibrotic lesions).
Pathways for plaque reversal.
a) Cholesterol esters can be mobilized if macrophage reverse
is activated (9,10
b) By increasing cholesterol
efflux, either via the reverse cholesterol transport
c) by conversion to high-density lipoprotein esters via the cholesterol
ester transfer protein pathway (11,12), an imbalance between the deposition and removal of vascular cholesterol
after endothelial injury may be corrected.
d) Inflammatory reactions (cellular migration, humeral substance release, and edema) are preventable
and reversible by therapy.
Composition of the plaque may not be removable!
a) Fibrous tissue and ground substances.
b) calcified areas
a)Fibrous tissue and ground substance would seem to be irreversible. However, statins have been
shown to diminish smooth muscle cell accumulation and collagen deposition (13). b) Calcification also seems to be a non reversible change. (14–16). Bur recent studies of calcium score studies show that calcium score could get less after therapy. This indicates that calcification
can also be removed.
Lloyd W. Klein. Atherosclerosis Regression, Vascular Remodeling, and Plaque Stabilization.J Am
Coll Cardiol, 2007; 49:271-273.
Event rates were related to baseline calcium score (per-specified analysis) and may
have been reduced in a subgroup of participants with baseline calcium score >400 (8.7% vs. 15.0%,
p = 0.046 [not a per-specified analysis]).
Yadon Arad et al.
Treatment of Asymptomatic Adults With Elevated Coronary Calcium Scores With Atorvastatin, Vitamin C, and Vitamin E
The St. Francis Heart Study Randomized Clinical Trial
J Am Coll Cardiol, 2005; 46:166-172, doi:10.1016/j.jacc.2005.02.089
An immunomodulator, reducing the expression of matrix metalloproteinases, cellular
adhesion molecules, and macrophage content within atherosclerotic plaques.[24-26]
Milita Crisby, et al.Clinical Investigation and ReportsPravastatin Treatment Increases
Collagen Content and Decreases Lipid Content, Inflammation, Metalloproteinases, and Cell Death in Human Carotid Plaques. Implications
for Plaque Stabilization. Circulation. 2001;103:926-933
Despite statin therapy, cardiovascular events continue to occur.
Statins may or may not seem to have effect against either plaques
already destabilized or non-lipid-rich plaques or plaque with overlying thrombus. These groups form one third of major coronary
Percutaneous intervention or long-term antithrombotic and/or anticoagulant therapy, or possibly aggressive
lipid lowering will stabilize these lesions.
However, short-term antithrombotic approaches alone with GP platelet IIb/IIIa inhibitors have not been effective
to stabilize plaques.
ACE inhibitors, β-blockers, and antithrombotic agents in addition statins, reduce cardiac events.This
could be in part due to plaque-stabilizing.
John A. Ambrose, and Eulogio E. Martinez
A New Paradigm for Plaque Stabilization.
Circulation. 2002; 105: 2000-2004
The Medicines Company's MDCO-216 (ApoA-I Milano Complex)
4:31p ET November 14, 2011 (Market Wire)
MDCO-216 is a naturally occurring variant of a protein called ApoA-I found in human high-density lipoprotein,
or HDL, which enable lipids cholesterol and triglycerides to be transported from inside cells outward to the bloodstream,
to the liver and eventually out of the body in a process called reverse cholesterol transport.
The variant has been found in approximately 45 individuals from Limone sul Garda, a small village in northern
Italy. Carriers of this variant appear to have reduced risk of cardiovascular disease.
ApoA-I Milano rapidly removed excess cholesterol from artery walls, thereby stabilizing and regressing atherosclerotic
plaque. A phase I/II study in 36 patients demonstrated statistically significant reductions of coronary plaque volume by 4.2%
in six weeks.
MDCO-216 induced cholesterol efflux via ABCA1 and SR-BI, which are cellular transporters involved with
clearing cholesterol out of cells. It was also reported that the treatment was well tolerated up to the highest dose tested.
MDCO-216 has the potential to reverse plaque buildup in arteries in patients with acute coronary syndromes.
The Medicines Company's MDCO-216 (ApoA-I Milano Complex) Demonstrates Capacity to Clear
Cholesterol From Cells in Preclinical Model
4:31p ET November 14, 2011 (Market Wirehttp://research.tdameritrade.com/public/markets/news/story.asp?docKey=100-318u1307-1&clauses=)
HDL based therapy, such as direct infusion of HDL or HDL like molecules seems to stabilize or regress atherosclerosis
Shah, P. K. Apolipoprotein A-I/HDL Infusion Therapy for Plaque Stabilization-Regression: A Novel Therapeutic
Multiple doses of recombinant apolipoprotein A-IMilano phospholipid complex (apoA-Im)
reduce atherosclerosis and favorably change plaque in rabbits and mice.
A single high dose of recombinant apoA-Im rapidly mobilized tissue cholesterol and reduced plaque
lipid and macrophage content in apoE-deficient mice.
Prediman K. Shah, et al. High-Dose Recombinant Apolipoprotein A-IMilano
Mobilizes Tissue Cholesterol and Rapidly Reduces Plaque Lipid and Macrophage Content in Apolipoprotein E–Deficient Mice.
Potential Implications for Acute Plaque Stabilization. Circulation. 2001;103:3047-3050
Monocyte recruitment into the arterial wall is one of the stages in atherogenesis. Monocyte chemoattractant
protein-1 (MCP-1) chemokine does monocyte recruitment, and its receptor (CCR2) mediates.
Transfection is a process of deliberately introducing nucleic
acids into cells.
A strategy for anti–MCP-1 gene therapy to treat atherosclerosis was devised. This is devised by transfecting
an N-terminal deletion mutant of the human MCP-1 gene into a remote organ (skeletal muscle) in apolipoprotein E–knockout
mice. The anti–MCP-1 gene therapy effectively blocked MCP-1 activity, inhibited and reduced atherosclerotic lesions
and also stabilize vulnerable atheromatous plaques.
Weihua Ni,etal. New Anti–Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates
Atherosclerosis in Apolipoprotein E–Knockout Mice. Circulation. 2001; 103: 2096-2101.
Coronary artery disease could be caused by infection.
148 patients with acute non–Q-wave infarction or unstable
angina were studied. They were randomly assigned to receive double-blind treatment with either clarithromycin or placebo for
3 months. 16 patients in the clarithromycin group and 27 in the placebo group had experienced a cardiovascular event (risk
ratio 0.49, 95% CI 0.26 to 0.92; P=0.03).
The primary end point was either death, myocardial infarction, or unstable angina during treatment. The
secondary end point was any cardiovascular event. The entire follow-up period was average 555 days, and the range was 138
to 924 days.
Effect of 3 Months of Antimicrobial Treatment With Clarithromycin
in Acute Non–Q-Wave Coronary Syndrome. Circulation. 2002;105:1555-1560, published
online before print March 11 2002.
P947, a magnetic resonance (MR) imaging contrast agent. It molecularly targets
matrix metalloproteinases (MMPs), detected and improved images signal intensity of MMPs in atherosclerotic lesions.
Atherosclerosis and Matrix Metalloproteinases: Experimental Molecular MR Imaging in Vivo. May
2009 Radiology, 251, 429-438.
Labeled oxidation-specific antibodies (Ox-AB) can detect, quantify, and image
Intravenous injection of Ox-AB showed its focally diminished uptake in plaques, and usual features of plaque
Reduced In Vivo Aortic Uptake of Radio labeled Oxidation-Specific Antibodies Reflects
Changes in Plaque Composition Consistent With Plaque Stabilization Arteriosclerosis, Thrombosis, and Vascular
Biology. 2004; 24: 2307-2312
Inflammation and oxidative processes are key components of atherosclerosis,
from fatty streak formation to plaque rupture and thrombosis. Recent basic and clinical studies have identified a number of
inflammatory and oxidative processes that appear to play a direct role in atherothrombosis and identify potentially clinically
useful markers of inflammation and oxidative stress. In this review, we highlight recent results on several of the more promising
markers of inflammation for cardiovascular disease risk assessments, such as C-reactive protein, myeloperoxidase, and soluble
CD40 ligand and nitrotyrosine, as well as other potential markers.
Inflammatory and oxidative markers in atherosclerosis: Relationship to outcome
Current Pharmaceutical Design, Volume 13, Number 10, April 2007 , pp. 1031-1038(8)
4. Improve endothelial function and have been shown to have direct effects on vascular
wall up-regulation of endothelial cell nitric oxide synthase.
Statin drugs have been seen to lower LDL levels from 18% - 55% and to raise HDL levels 5% - 15%.
can help the body reabsorb cholesterol that has accumulated on the artery walls.
large dosages of statin drugs may prevent heart attacks.
According to the Mayo Clinic, raising your HDL cholesterol level 1 milligram per deciliter (mg/dL) of blood
can reduce your heart attack risk by 3 percent.
Peiotropic effects (effects for which they were not originally intended) - relates to cardiovascular system.
They reduce oxidative stress of body tissue,
they reduce inflammation (like aspirin), and
they stabilize plaque on the blood vessel walls. Above ffects operate independently of LDL-cholesterol reduction
People on statins are less likely to die from influenza and pneumonia
The antioxidative, anti inflammatory and improve endothelial function properties may led to improvement
of prognosis in patients with CAD.
www.ajronline.org/content/191/1/50.full.pdfby JL Kelly - 2008 - Cited by 20 - Related articleswith a normal calcium score had at least moderate stenosis, five
(1.5%) of whom had severe stenosis. ... be helpful to identify noncalcified plaque and guide therapy. Kelly
et al. ..... a normal calcium score was diminished be- cause of the high ...
Regression and stabilization
of advanced murine atherosclerotic lesions: a comparison of LDL lowering and HDL raising gene transfer strategies.
Both reductions in atherogenic lipoproteins and increases in high-density lipoprotein (HDL) levels may affect
Here, the relative potential of low-density lipoprotein (LDL) lowering and HDL raising gene transfer strategies
to induce regression of complex murine atherosclerotic lesions was directly compared.
Male C57BL/6 LDL receptor (LDLr)(-/-) mice were fed
diet (1.25% cholesterol and 10% coconut oil) to induce advanced atherosclerotic lesions.
A baseline group was killed after 6 months and
remaining mice were randomized into
a control progression (Adnull or saline), an apolipoprotein (apo) A-I (AdA-I), an LDLr (AdLDLr),
or a combined apo A-I/LDLr
(AdA-I/AdLDLr) adenoviral gene transfer group and
followed-up for another 12 weeks with continuation of the atherogenic diet.
Gene transfer with AdLDLr
decreased non-HDL cholesterol levels persistently by 95% (p < 0.001) compared with baseline.
This drastic reduction of non-HDL cholesterol
levels induced lesion regression by 28% (p < 0.001) in the aortic root and by 25% (p < 0.05) in the brachiocephalic
artery at 12 weeks after transfer.
Change in lesion size was accompanied by enhanced plaque stability, as evidenced by increased collagen content,
reduced lesional macrophage content, a drastic reduction of necrotic core area, and decreased expression of inflammatory genes.
Elevated HDL cholesterol
following AdA-I transfer increased collagen content in lesions, but did not induce regression. Apo A-I gene transfer on top
of AdLDLr transfer resulted in additive effects, particularly on inflammatory gene expression.
In conclusion, drastic lipid lowering
induced by a powerful gene transfer strategy leads to pronounced regression and stabilization of advanced murine atherosclerosis.
Samir Damani etal. Characterization
of Circulating Endothelial Cells in Acute Myocardial Infarction. Sci Transl Med 21 March 2012: Vol. 4, Issue 126, p. 126ra33
Circulating endothelial cells (CECs counts may be a clinical test for predicting plaque rupture .
endothelial cells (CECs) assay was done"..... in 50 consecutive patients with ST-segment
MI and 44 consecutive healthy controls. CEC
counts were significantly elevated in MI cases versus controls, with
of 19 and 4 cells/ml, respectively (P = 1.1 × 10−10)".
A receiver-operating characteristic (ROC) curve analysis demonstrated a near-dichotomization
of MI cases versus controls.
correlation between CECs and typical markers of myocardial necrosis (ρ =
creatine kinase–myocardial band; ρ = −0.03,
".....morphological analysis of the microscopy
images of CECs
2.5-fold increase (P < 0.0001) in cellular area and a twofold increase (P
< 0.0001) in nuclear area of MI CECs versus healthy controls,
age-matched CECs, as well as CECs obtained from patients with
preexisting peripheral vascular disease.... MI patients were the only subject group to
contain more than 3 nuclei per image, indicating that multicellular and
clusters are specific for acute MI."
Progenitor Cells Predict Heart Disease Severity
Kunz presented the results of the Duke analysis March 9, 2004, at the annual scientific sessions of the American College of
Cardiology in New Orleans.
It is noted that a strong
relationship between the severity of heart disease
and the level of endothelial progenitor cells (EPCs) from bone marrow circulating in the
progenitor cells (EPCs) are produced in the bone
of the roles of EPCs is to repair damage to the lining of
Patient with multi-vessel disease had fewer EPCs
EPCs are inable to
keep up with repairing the ongoing damage to the endothelium.
There may not be enough EPCs to do repair the damaging endothelium..
EPCs level and the severity of coronary artery disease were determined in
122 patients undergoing diagnostic cardiac catheterization procedures
Specifically, they determined how many of the coronary
arteries showed signs of atherosclerosis.
Their average age
was 58, 37 percent had multi-vessel disease, 29 percent had diabetes and 20 percent had a recent heart attack.
The EPCs from the
blood samples were submitted to cell culture to determine how many of the cells would grow to form colony-forming units (CFU).
The patients with
multi-vessel disease had
significantly lower EPC counts than those without -- 13 CFU vs. 41.7
every 10 CFU increase in EPC level, multi-vessel disease declined by 20 percent.
The EPC levels
did not vary significantly by age, gender or
other risk factors.
The levels were lower for
diabetics (19 CFU vs. 36 CFU) and recent heart attack patients (23 CFU vs. 34 CFU).
a strong inverse relationship between
circulating EPCs and coronary artery disease, independent of traditional
disease risk factors.
Prevention or halt of atherosclerosis:
It seems that it may
be possible to halt or even prevent development of atherosclerosis by injecting EPCs into patients or by retraining
the patient's own stem cells
to differentiate into EPCs.
from a young person, and depending on measurements of the EPC levels, one may take actions early that prevent the depletion
The EPCs may halt development of
congestive heart failure in patients who have suffered a heart attack.
an article published last year in Circulation (July 29, 2003), Duke researchers reported discovering in
Mouse genetically induced risk of development of high blood pressure and lipid levels showed that aging caused their bone marrow to produce EPCs and demonstrated that these cells are critical to determining
the onset and progression of atherosclerosis.
Lifestyle modifications and/or medications
may preserve EPCs for a longer period of time and delay or prevent atherosclerosis onset.
Duke cardiologists offer new view of link between aging, atherosclerosis
Aging, Progenitor Cell Exhaustion, and Atherosclerosis
- Frederick M. Rauscher, MD;
- Pascal J. Goldschmidt-Clermont, MD;
- Bryce H. Davis, BSE*;
- Tao Wang, MD, PhD*;
- David Gregg, MD;
- Priya Ramaswami, BE;
- Anne M. Pippen, BS;
- Brian H. Annex, MD;
- Chunming Dong, MD;
- Doris A. Taylor, PhD
Atherosclerosis is largely attributed to chronic vascular injury, as
occurs with excess cholesterol; however, the effect
of concomitant vascular aging remains
unexplained. We hypothesize that the effect of time in atherosclerosis
related to obsolescence of endogenous progenitor
cells that normally repair and rejuvenate the arteries.
Methods and Results— Here we show that chronic treatment
with bone marrow–derived progenitor cells from young nonatherosclerotic ApoE−/− mice prevents
atherosclerosis progression in ApoE−/− recipients despite persistent hypercholesterolemia. In contrast,
treatment with bone marrow cells from older ApoE−/− mice with atherosclerosis is much less effective.
Cells with vascular progenitor potential are decreased in the bone marrow
of aging ApoE−/− mice, but cells injected from donor mice engraft on recipient
arteries in areas at risk for atherosclerotic injury.
Conclusions— Our data indicate that progressive progenitor
cell deficits may contribute to the development of atherosclerosis.
progenitor cells (EPCs) may be defined as adherent cells derived from
peripheral blood- or bone marrow-derived mononuclear cells demonstrating
acLDL uptake and isolectin-binding capacity. The number of circulating
EPCs inversely correlates with the number of cardiovascular risk factors
and is reduced in cardiovascular disease. This measurement may
therefore serves as a surrogate marker for cardiovascular disease risk.
EPC numbers can be modified by various means. However, the effectiveness
of risk-factor modification on EPC number and function is currently
unknown. Furthermore, EPCs may be used as a potential therapy for a
variety of vascular disease states including ischaemia, restenosis and
pulmonary hypertension. This review provides an update on multiple
factors that affect EPC number as well as highlighting the potential use
of EPCs as a novel marker of vascular dysfunction. Furthermore,
potential gene- and/or EPC-based approaches to a number of vascular
disease states are explored. BioEssays 28: 261–270, 2006. © 2006 Wiley
progenitor cells: diagnostic and therapeutic considerations
- Frank Barry1,*,
- Timothy O'Brien1,2
Cardiac Positron EmissionTomography
Frank M. Bengel, MD*,
Takahiro Higuchi, MD,
Mehrbod S. Javadi, MD and
Riikka Lautamäki, MD, PhD
Division of Nuclear Medicine/PET, Russell H. Morgan Department of
Radiology and Radiological Science, Johns Hopkins University, Baltimore,
J Am Coll Cardiol, 2009; 54:1-15,
117. Nahrendorf M, Zhang
H, Hembrador S, et al. Nanoparticle PET-CT
imaging of macrophages in inflammatory atherosclerosis Circulation
2008;117:379-387.[Abstract/Free Full Text]
Macrophages participate centrally in atherosclerosis, and macrophage
markers (eg, CD68, MAC-3) correlate well with lesion
severity and therapeutic modulation. On the
basis of the avidity of lesional macrophages for
structures such as nanoparticles, we have
developed a new positron emission tomography (PET) agent with optimized
to allow in vivo imaging at tracer
Methods and Results— A dextranated and DTPA-modified
magnetofluorescent 20-nm nanoparticle was labeled with the PET tracer 64Cu
(1 mCi/0.1 mg nanoparticles) to yield a PET, magnetic resonance, and
optically detectable imaging agent. Peak PET activity
24 hours after intravenous injection into mice
deficient in apolipoprotein E with experimental atherosclerosis mapped
of high plaque load identified by computed
tomography such as the aortic root and arch and correlated with magnetic
and optical imaging. Accumulated dose in
apolipoprotein E–deficient aortas determined by gamma counting was 260%
and in carotids
392% of respective wild-type organs (P<0.05
both). Autoradiography of aortas demonstrated uptake of the agent into
macrophage-rich atheromata identified by Oil
Red O staining of lipid deposits. The novel
nanoagent accumulated predominantly in macrophages as determined by
microscopy and flow cytometry of cells
dissociated from aortas.
This report establishes the capability of a novel trimodality
nanoparticle to directly detect macrophages in atherosclerotic
plaques. Advantages include improved
sensitivity; direct correlation of PET signal with an established
biomarker (CD68); ability
to readily quantify the PET signal, perform
whole-body vascular surveys, and spatially localize and follow the
by microscopy; and clinical translatability of
the agent given similarities to magnetic resonance imaging probes in
Received August 3, 2007; accepted October 19, 2007.
Rudd JH, Warburton EA, Fryer TD, et al. Imaging atherosclerotic
plaque inflammation with [18F]-fluorodeoxyglucose positron emission
tomography Circulation 2002;105:2708-2711.[Abstract/Free Full Text]
plaque rupture is usually a consequence of inflammatory cell activity within the plaque. Current imaging
techniques provide anatomic data but no indication of plaque inflammation. The glucose analogue [18F]-fluorodeoxyglucose
(18FDG) can be used to image inflammatory cell activity non-invasively by PET. In this study we tested whether
18FDG-PET imaging can identify inflammation within carotid artery atherosclerotic plaques.
Methods and Results—
Eight patients with symptomatic carotid atherosclerosis were imaged using 18FDG-PET and co-registered CT. Symptomatic
carotid plaques were visible in 18FDG-PET images acquired 3 hours post-18FDG injection. The estimated
net 18FDG accumulation rate (plaque/integral plasma) in symptomatic lesions was 27% higher than in contralateral
There was no measurable 18FDG uptake
into normal carotid arteries. Autoradiography of excised plaques
confirmed accumulation of deoxyglucose in macrophage-rich
areas of the plaque.
study demonstrates that atherosclerotic plaque inflammation can be imaged with 18FDG-PET, and that symptomatic,
unstable plaques accumulate more 18FDG than asymptomatic lesions.
Received March 5, 2002; revision received April 19, 2002;
accepted April 22, 2002.