Amy l. Doneen: Imaging & Inflammation: Applying the Evidence to Clinical Practice

Imaging & Inflammation: Applying the
Evidence to Clinical Practice
9/12/2014
Amy L. Doneen DNP, ARNP
Adjunct Professor at TTUHS School of Nursing
Director of the Heart Health & Stroke Prevention Center
Spokane, Washington
Copyright Bale/Doneen Paradigm

Outline for Tonight
1. The Magnitude of Vascular Disease.
2. Atherosclerosis: A silent threat
3. Inflammation: The catalyst for an event
4. Biomarkers: Clinical application.
5. Case Application: Using inflammation to guide
therapy and assess effectiveness of treatment.

Current AHA statistics
Every 34 seconds, an American
will have a heart attack.
Every 40 seconds, an American has a stroke.
Average number of years of life lost
because of a heart attack is 16.6.
64% of women and 50% who die suddenly from a heart attack
have no idea that they have vascular disease!

Annual number of adults per 1000 having diagnosed
heart attack or fatal coronary heart disease
(2005–2010 ARIC Study).
55-64 highest risk group
Go A et al. Circulation 2014;129:e28-e292

Proportion of patients with recurrent stroke within 5
years after first stroke.

Projected total costs of CVD 2015 to 2030
(2012 $ in billions) in the United States.
= $1.2 trillion

How do we change this?
Copyright: Bale/Doneen Method
Death, Disability
& Cost of CVD

We could use a calculator 
It is called the Framingham Risk
Calculator

Framingham Risk Score and
Reynolds Risk Score Frequently Fail to
Indentify Who Will Have an Event
Percent who had events
Cook N R et al. Circulation 4/2012;125:1748-1756

Bale/Doneen Method is Effective in Generating a
Positive Effect on the Atherosclerotic Disease
Process
Mean cIMT score decreased by 0.01mm/yr –
p<0.001
cIMT plaque burden score decreased by 0.17mm/yr-p<
0.001
Feng, D., Esperat, M. C., Doneen, A. L., Bale, B., Song, H., & Green, A. E. (2014).
8-Year Outcomes of a Program for Early Prevention of Cardiovascular Events: A
Growth-Curve Analysis. J Cardiovasc Nurs. doi: 10.1097/jcn.0000000000000141

Bale/Doneen Method is Effective in Generating a
Positive Effect on the Atherosclerotic Disease
Process
Feng, D., Esperat, M. C., Doneen, A. L., Bale, B., Song, H., & Green, A. E. (2014).
8-Year Outcomes of a Program for Early Prevention of Cardiovascular Events: A
Growth-Curve Analysis. J Cardiovasc Nurs. doi: 10.1097/jcn.0000000000000141

86% of Heart Attacks
Caused by Non-obstructing Plaques!!
86% are from plaque <70% obstructing
68% are from plaque <50% obstructing
E Falk, PK Shah, V Fuster. Circulation 1995;92:657

Silent potentially deadly plaque!
*
*
Nature Clinical Practice 3/06, Vol 3, NO 3:155

It’s a Thrombus!
Clot
Plaque
Lumen

How do we define an event?
 Heart Attack
 Ischemic Stroke
 Microvascular Dementia?
 Macular Degeneration?
 Erectile Dysfunction?
 Peripheral Arterial Disease?
 Chronic Kidney Disease?
 Liver disease?
 Etc…..

IMT of Carotid
American Heart Association
“Carotid Artery B-mode Ultrasound imaging is a safe,
non-invasive and relatively inexpensive means of
assessing subclinical atherosclerosis. The technique
is valid and reliable.”
AHA Expert Panel Statement of Prevention V Conference – Circulation. 2000.

Carotid Intima Media Thickness
Polak J F et al. Stroke 2011;42:3017-3021

Predictive value of plaque
The presence of Internal carotid artery plaque > 1.5 mm
was a significant independent predictor of stroke.
Polak JF et al. N Engl J Med July 21, 2011;365:213-221

Carotid Atherosclerosis and Risk of
Subsequent Heart Attacks
Plaques seem to appear later in the carotids than in
the aorta and coronary arteries
Presence of carotid atherosclerosis independently
increases the risk of coronary events and is a marker
of disease severity
Sirimarco, G, Amarenco, P, et al. Stroke. Published online Jan 10, 2013. Stroke
2013;44:00-00.

Carotid ASVD Strong Predictor of Adverse CAD
Events
 1,391 post angiogram pts; 79% + for CAD; same
day carotid US; followed ~ 4 ½ yrs.
 Objective: is carotid ASVD & or stenosis associated
with CV risk in pts with or without CAD?
 Primary end point: MACE- all-cause mortality, MI,
stroke, and any coronary revascularization.
Steinvil, A., et. al. (6.25,2014). Impact of Carotid Atherosclerosis on the Risk of
Adverse Cardiac Events in Patients With and Without Coronary Disease. Stroke.
doi: 10.1161/STROKEAHA.114.005663

Carotid ASVD Strong Predictor of Adverse CAD
Events
The presence of carotid ASVD of any degree
portends a risk of future MACE similar to that seen in
pts with established CAD.
Substantiates the concept that carotid stenosis
should be considered a CAD equivalent.
Steinvil, A., et. al. (June 25,2014). Stroke. doi: 10.1161/STROKEAHA.114.005663

The carotid arteries serve as a window to
systemic atherosclerosis
Willeit, K., et. al. (Sept 12, 2013). Carotid Atherosclerosis and Incident Atrial Fibrillation.
Arteriosclerosis, Thrombosis, and Vascular Biology. doi: 10.1161/atvbaha.113.302272

Dr. Virchow 158 Years Ago Proposed
Inflammation as Cause of
Atherosclerosis
Virchow R: Phlogose und Thrombose im Gefasssystem, Gesammelte Abhandlungen zur
Wissenschaftlichen Medicin, Frankfurt-am-Main, Meidinger Sohn and Company, 1856,
p458

Inflammation is Causal
The interleukin-6 receptor as a target for prevention of coronary heart
disease: a mendelian randomisation analysis. The Lancet, 379(9822), 1214-
1224.
IL6R Genetics Consortium and Emerging Risk Factors Collaboration, Dr
Nadeem Sarwar, Dr Adam S Butterworth, et. al. Lancet 3/31/2012; 379:
1205–13

Arterial Inflammation Precedes Calcification
137 pts; age-61±13 yrs; 48.1% men; serial PET/CT
scans 1–5 yrs apart; thoracic aorta focal arterial
inflammation was prospectively (baseline) determined by
PET/FDG
A blinded investigator evaluated calcium deposition on
the baseline and follow-up computed tomographic scans
along the same standardized sections of the aorta.
A vascular segment was classified as either with or
without subsequent calcification.
Abdelbaky, A., et. al. (2013). Focal Arterial Inflammation Precedes Subsequent Calcification in the Same
Location: A Longitudinal FDG-PET/CT Study. Circulation: Cardiovascular Imaging, 6(5), 747-754.

Across all patients, subsequent Ca deposition was
associated with the underlying inflammatory signal,
OR of 2.94 (95%CI- 1.27-6.89) p values of 0.01–
adjusted for CV risk factors.
First-in-human evidence that arterial inflammation
precedes subsequent Ca deposition.
Abdelbaky, A., et. al. (2013). Focal Arterial Inflammation Precedes Subsequent
Calcification in the Same Location: A Longitudinal FDG-PET/CT Study.
Circulation: Cardiovascular Imaging, 6(5), 747-754.

Local FDG uptake was the strongest predictor of
subsequent local calcification compared to traditional
risk factors.
Arterial segments that manifest any subsequent
calcium deposition had higher inflammatory signals
at baseline.
Abdelbaky, A., et. al. (2013). Focal Arterial Inflammation Precedes Subsequent
Calcification in the Same Location: A Longitudinal FDG-PET/CT Study.
Circulation: Cardiovascular Imaging, 6(5), 747-754.

Inflammation is an important driver of plaque
progression.
It is reasonable to assume that inflammation and
calcification represent different phases of
atherosclerosis.
Human studies have shown that high aortic and
carotid FDG uptake is related to subsequent risk of
plaque rupture and clinical events.
Abdelbaky, A., et. al. (2013). Focal Arterial Inflammation Precedes Subsequent Calcification in
the Same Location: A Longitudinal FDG-PET/CT Study. Circulation: Cardiovascular Imaging,
6(5), 747-754.

Baseline (PET) and sequential (CT) images of incident calcium deposition.
Abdelbaky A et al. Circ Cardiovasc Imaging 2013;6:747-754

Best way to keep our hearts safe?
Keep our arteries cool!

How do we measure
Inflammation?

Tools to measure vascular
inflammation?
Endothelium
F2-Isoprostane
Fibrinogen
hsCRP
MACR
MPO
Intima
LpPLA2

Is This Happening to You?
Rusting

38
Oxidative Stress
 Oxidative stress: imbalance between the
formation of free radicals and antioxidant
protective mechanism
 Oxidation is pro-inflammatory
Griffiths HR et. al. Mol Aspects Med 2002; 23:101-208
Montuschi P et. al. FASEB J 2004; 18:1791-800
Basu S. Free Radic Res 2004; 38:105-22

Atherosclerosis and Senescence
 Cell senescence = irreversible loss of the ability of
cells to divide. Two types.
 1)- replicative senescence; occurs with exhaustion
of proliferative lifespan over time; ‘aging’; shortened
telomeres induce DNA damage
 2) stress-induced premature senescence (SIPS);
triggered by external stimuli, including oxidizing
agents and radiation; not usually characterized by
telomere shortening
Wang J C , Bennett M Circulation Research 7/2012;111:245-259

Atherosclerosis and Senescence
 Endothelial senescence is associated with loss of
function and a shift toward a proinflammatory and
proapoptotic state.
 VSMCs senescence generate a proinflammatory
environment and have diminished ability to repair
plaque.
 Monocyte senescence generates a greater
proinflammatory environment
Wang J C , Bennett M Circulation Research 7/2012;111:245-259

Oxidative Stress Increases Risk of
Thrombosis
 Oxidant stress is associated with platelet activation
 Isoprostanes significantly increase platelet
aggregation via activation of the glycoprotein IIb/IIIa.
Pignatelli P et al. Circulation 7/2012;126:92-103

42
Oxidative Stress:
How can we measure it?
Isoprostane is “gold standard” to
measure oxidative stress
Morrow, J. D. (2005). Quantification of Isoprostanes as Indices of Oxidant Stress
and the Risk of Atherosclerosis in Humans.
Arteriosclerosis, Thrombosis, and Vascular Biology, 25(2), 279-286.

Bio-markers for Endothelial
(‘Tennis Court’) Inflammation

C-Reactive Protein & Fibrinogen Are as
Predictive for First Cardiovascular Events as
Total Cholesterol and HDL
 Pooled analysis of data from ~250,000 people
without CVD
 Adding CRP and or fibrinogen significantly
improved risk assessment for a first event.
The Emerging Risk Factors Collaboration. N Engl J Med. October 4, 2012 Volume
367(14):1310-1320

Microalbumin/Creatinine Ratio (MACR)
Independently Predicts Risk of CV Events
Biomarker Adjusted hazard ratio per 1 SD
increment in the log value
MACR 1.20
Framingham data; 3209 pts.; followed 7.4 yrs.; 207 deaths
Eight markers not predictive: CRP, N-terminal proatrial NP,
aldosterone, fibrinogen, D-dimer, PAI-1, renin, homocysteine
Bottom line: MACR trumps hsCRP and fibrinogen
Wang TJ et al. N Engl J Med 12/21/2006; 355:2631-2639.

46
MACR Cut Points for Marking
Increased CV Risk
Risk when MACR > 7.5 in women and > 4.0 in men
End point Hazard ratio p
CV event 2.92 <0.001
1568 Fram. Offspring healthy pts. ; mean age 55; 58% women
Followed 6 yrs.
Ärnlöv J et al. Circulation 8/16/2005; 112:969-975.

How hot is it under your tennis
court ??!!
Lipoprotein associated phospholipase A2
(Lp-PLA2 or PLAC2 test)
FDA Approval:
2003: CHD Risk
2005: CVA Risk

Endothelial Dysfunction in Coronary Arteries
Worsens as Lp-PLA2 Rises
This is why we use 180 ng/ml as our goal
100 Unadjusted
*P<0.001
% Rebound in Coronary Blood Flow after
Acetylcholine Induced Vasoconstriction
Tertile 1
(110-181 ng/ml)
Tertile 2
(181-240 ng/ml)
Tertile 3
(240-443 ng/ml)
Lp-PLA2 Levels
80
60
40
20
0
Adjusted
Yang EH, et al. Arterioscler Thromb Vasc Biol.
2006;26.

Lp-PLA2 is not an Acute Phase Reactant as
Opposed to CRP and TNF-alpha
 32 healthy subjects; 50% female; mean age 26 + 4
yrs.; infused with 3 ng/kg endotoxin
 Endotoxin produced an acute febrile illness
 Resulted in an immediate transient rise in TNF-alpha
and a 100 fold increase in CRP at 24 hours
 No significant change in Lp-PLA2
Ferguson, J. F. et al. J Am Coll Cardiol 2/2012;59:764-772

Myeloperoxidase (MPO)
 Member of the heme peroxidase family
 Stored in crystalline form within azurophilic
granules in leukocytes
 Secreted during leukocyte activation
 Important in innate infectious disease host
defenses
Nicholls, S.J.; Hazen, S.L., Arterioscler. Thromb. Vasc. Biol.
3/2005;25;1102-1111

MPO Impairs Endothelial Function via
Effects on NO
 Consumes NO as a co-substrate
 Reduces production of NO by crippling NOS
a) reactive nitrogen species uncouple NOS
b) oxidized HDL inhibits NOS activity
c) HOCl chlorinates arginine which reduces the
activity of NOS
3/2005;25;1102-1111

MPO activity
 MPO co-substrate is hydrogen peroxide
 MPO generates numerous reactive oxidants
– Chlorinates hydrogen peroxide into hypochlorous
acid (HOCl) – active ingredient in bleach
– Halogenating oxidants – create chlorotyrosine
– Creates nitrogen species = nitrotyrosine
3/2005;25;1102-1111

MPO is Detrimental to the Lipids
 HOCl oxidizes apo B-100
 Reactive nitrogen species oxidize LDL (NO2LDL)
 Oxidizes HDL
 Nitrotyrosine and chlorotyrosine bind to apo A-1
and HDL
interferes with ABCA-1 reverse cholesterol transport
chloronated-HDL competes as a ligand for SR-B1
3/2005;25;1102-1111

MPO can create vulnerable plaques
 HOCl promotes activation of MMP-7 - promotes
fibrous cap rupture
 HOCl promotes endothelial apoptosis and
detachment:
apoptotic endothelial cells are prothrombotic
superficial erosions can trigger events
3/2005;25;1102-1111

MPO Generates Dysfunctional HDL in CAD Pts
 Isolated HDL; 20 control subjects and 20 pts with
stable CAD & 20 ACS pts.
 Used spectrometry to explore the relationship btw
oxidation of apoA-I and it’s ability to promote
cholesterol efflux by the ABCA1 pathway.
Shao, B., et. al. (2014). Humans with Atherosclerosis have Impaired ABCA1
Cholesterol Efflux and Enhanced HDL Oxidation by Myeloperoxidase. Circ Res.
doi: 10.1161/circresaha.114.303454

MPO Generates Dysfunctional HDL in CAD Pts
 Levels of chlorinated and oxidized apoA-I by MPO
were elevated in CAD and ACS pts.
 This correlated inversely with HDL’s cholesterol
efflux capacity.
 MPO may help generate dysfunctional HDL in
humans.
Shao, B., et. al. (2014). Humans with Atherosclerosis have Impaired ABCA1
Cholesterol Efflux and Enhanced HDL Oxidation by Myeloperoxidase. Circ Res.
doi: 10.1161/circresaha.114.303454

Myeloperoxidase (MPO), predicts
future risk of coronary
artery disease in healthy people
Regardless of other known risk factors !
Meuwese MC et al. J Am Coll Cardiol 7/2/2007; available at:
http://content.onlinejacc.org.

Clinical Application
Bale/Doneen Method
E education
D disease
F ‘fire’ arterial inflammation
R root causes
O optimal goals
G genetics
I individual management
R reassess regularly
A annual disease assessment
ED

Clinical application of our
disease/inflammatory paradigm
Case Application

Amy l. Doneen: Imaging & Inflammation: Applying the Evidence to Clinical Practice

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