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Inflammation and Cardiovascular
Disease: the Missing Link?
Vijay U. Rao, MD, PhD, FACC, FASE
Director Inpatient Heart Failure and Cardiac Research
Franciscan Physician Network, Indiana Heart Physicians
Franciscan St. Francis Health
Indianapolis, IN
Presenter Disclosure Information
Inflammation and Cardiovascular Disease: the
Missing Link?
Vijay Rao, MD, PhD, FACC, FASE
• Speaker’s Bureau for Pfizer, Bristol Myers
Squibb, Daichi Sankyo, Novartis
• I will not discuss off label or investigational
use in my presentation.
Beyond Cholesterol: Predicting Cardiovascular Risk In
the 21st Century
Cardiovascular Risk
Lipids
HTN
Diabetes
Behavioral
Hemostatic
Thrombotic
Inflammatory
•On the basis of 2008 mortality rate data, more than 2200
Americans die of CVD each day, an average of 1 death every
39 seconds.
•Coronary heart disease caused ≈1 of every 6 deaths in the
United States in 2008.
Circulation. 2012; 125: e2-e220
Genetic
Inflammation: A Historical Perspective
• Roman Celsus in 1st century AD: 4 signs of inflammation (rubor et tumor
cum calore et dolore “redness and swelling with heat and pain”)
• 2 centuries later, Galen developed the humoral view of inflammation as a
beneficial response to injury (pus generation)
• In 1871, Virchow: function laesa, loss of function as the 5th cardinal sign
Inflammatory Cascade
Outline
Inflammation and CV risk
– Inflammatory conditions (RA, gout, PD)
– Atherosclerosis
– Inflammatory biomarker: hs-CRP
– Statins and the JUPITER trial
– Exercise and inflammation
– Anti-inflammatory medicines (NSAIDs)
Rheumatoid Arthritis
 Rheumatoid arthritis (RA) is a chronic systemic inflammatory
disease characterized by persistent symmetric polyarthritis
(synovitis) that affects the hands and feet, although any joint
lined by a synovial membrane may be involved.
 Cardiovascular (CV) disease is the leading cause of mortality (up
to 50%) in patients with rheumatoid arthritis (RA)
 Traditional CV risk factors do not fully explain the higher
incidence of CV disease in patients with RA.
 RA specific risk factors (rheumatoid factor or anti-CCP antibody
positivity, HLA-DR shared epitope, inflammatory markers such as
CRP, joint erosions, extra-articular disease characteristics, and
duration of disease) appear to have a stronger association with CV
events
Morbidity and mortality studies show that the incidence of CV
disease is about 1.5 – 3 fold greater in RA patients than in the general
population.
Event rate per
1000 person-years
Cardiovascular event rates among subjects with and without RA in a cohort study in British
Columbia
Myocardial infarction (MI), stroke, or cardiovascular (CV) death
Solomon DH, et al. Ann Rheum Dis. 2006;65:1608-1612.
The increased incidence of CV events in patients with RA is not
explained by traditional CV risk factors alone
Male Gender
Current smoker
Personal Hx of IHD
Family Hx of IHD
Hypertension
Dyslipidemia
RA
Non-RA
BMI 30 kg/m2
Diabetes mellitus
BMI <20 kg/m2
Hazard Ratios and 95% CI at baseline
Gonzalez. Ann Rheum Dis 2008;67:64-69.
Inflammatory conditions associated with
enhanced CV risk and/or premature CAD







Systemic lupus erythematosis
HIV
Gout
Periodontitis
Inflammatory bowel disease
Severe psoriasis
Treatments (anti-TNF-alpha, IL-6 inhibitors) raise
cholesterol levels; jury is still out on whether these
agents will reduce CV risk, though TNF-alpha blockers
were shown to be detrimental in CHF patients
Inflammation and Atherogenesis
Libby P. Circ J 2010; 74: 213 – 220
CRP vs hs-CRP
• CRP is an acute-phase protein produced by the liver in
response to cytokine production (IL-6, IL-1, tumor
necrosis factor) during tissue injury, inflammation, or
infection.
• Standard CRP tests determine levels which are
increased up to 1,000-fold in response to infection or
tissue destruction, but cannot adequately assess the
normal range
• High-sensitivity CRP (hs-CRP) assays (i.e. Dade Behring)
detect levels of CRP within the normal range, levels
proven to predict future cardiovascular events.
hs-CRP and Risk of Future MI in Apparently
Healthy Men (Physician’s Health Study)
P Trend <0.001
P<0.001
Relative Risk of MI
3
P<0.001
2
P=0.03
1
0
1
2
Quartile of hs-CRP
Ridker et al, N Engl J Med. 1997;336:973–979.
3
4
hs-CRP and Risk of Future Stroke in
Apparently Healthy Men
P Trend <0.03
Relative Risk of
Ischemic Stroke
2
P=0.02
P<0.02
3
4
1
0
1
2
Quartile of hs-CRP
Ridker et al, N Engl J Med. 1997;336:973–979.
hs-CRP Adds Prognostic Information at all Levels of
LDL-C and at all Levels of the Framingham Risk Score
<1.0
1.0-3.0
>3.0
<1.0
C-Reactive Protein (mg/L)
25
3
1.0-3.0
>3.0
C-Reactive Protein (mg/L)
15
Relative risk
10
5
0
0-1
2-4
5-9
10-20
Framingham estimate of 10-year risk (%)
Ridker et al, N Engl J Med. 2002;347:1557.
Multivariable relative risk
20
2
1
0
<130
130-160
>160
LDL cholesterol (mg/dL)
Is there clinical evidence that inflammation can be
modified by preventive therapies?
Long-Term Effect of Statin Therapy on
hs-CRP: Placebo and Pravastatin Groups (CARE trial)
Placebo
0.25
Median hs-CRP
Concentration
(mg/dL)
0.24
0.23
-21.6%
(P=0.004)
0.22
0.21
0.20
Pravastatin
0.19
0.18
Baseline
Ridker et al, Circulation. 1999;100:230-235.
5 Years
Effect of Statin Therapy on hs-CRP Levels
at 6 Weeks
hs-CRP (mg/L)
6
*p<0.025 vs. Baseline
5
*
4
*
*
3
2
1
0
Baseline
Prava
Simva
Atorva
(40 mg/d) (20 mg/d) (10 mg/d)
Jialal I et al. Circulation 2001;103:1933-1935Circulation
2001;103:1933-1935.
JUPITER: Justification for the Use of statins In
Primary prevention: An Intervention Trial
Evaluating Rosuvastatin
• Inflammation plays a crucial role in atherogenesis/plaque
rupture
• Inflammatory biomarker hs-CRP independently predicts
vascular events and improves global classification of risk
regardless of LDL-c levels
• Statin therapy largely reduces hs-CRP in a manner independent
of LDL-c reduction
• Subgroup of AFCAPS/TexCAPS trial: no benefit of statin therapy
with LDL-c < 150mg/dl and hs-CRP < 2mg/dl, whereas large
clinical benefit seen when LDL-c < 150mg/dl and hs-CRP >
2mg/dl
JUPITER: Primary Endpoint
Ridker PM. N Engl J Med. 2008;359:2195–2207
Limitations of JUPITER
• Of the approximately 90,000 individuals screened to
participate in the JUPITER trial, approximately 26,000,
or 28%, were excluded because their hsCRP was < 2
mg/L.
• The JUPITER trial did not allow for comparison
between individuals with an hsCRP < 2 mg/L to those
with an hsCRP > 2 mg/L.
• The JUPITER trial did not establish a particular goal of
therapy for CRESTOR with respect to hsCRP levels.
• Was the reduction in events driven by lowering of LDL
or hsCRP?
Exercise and Inflammation
• Exercise induced muscle injury is thought to be
responsible stimulus for IL-6 increases
•IL-6 is thought to act like a hormone assisting
glucose homeostasis and lipolysis
From: The Effects of Physical Activity on Serum CReactive Protein and Inflammatory Markers: A
Systematic Review
J Am Coll Cardiol. 2005;45(10):1563-1569.
doi:10.1016/j.jacc.2004.12.077
Exercise and Inflammation
• Relationship between increased physical activity and lower
CRP persists even after adjusting for BMI, waist-to-hip ratio,
and fasting insulin concentration suggesting that other factors
contribute to the exercise-related anti-inflammatory effect
• Exercise training reduces CRP both directly by reducing
cytokine production in fat, muscle, and mononuclear cells and
indirectly by increasing insulin sensitivity, improving
endothelial function, and reducing body weight.
• High-intensity interval training (HIIT) vs continuous moderateintensity training (MICT), need more data about safety and
outcomes
J Am Coll Cardiol. 2005;45(10):15631569. doi:10.1016/j.jacc.2004.12.077
Elevated CRP Levels in Obesity:
NHANES 1988-1994
Percent with CRP 0.22
mg/dL
25
20
15
10
5
0
Normal
Overweight
Visser M et al. JAMA 1999;282:2131-2135.
Obese
Effects of Weight Loss on CRP
Concentrations in Obese Healthy Women
 83 women (mean BMI 33.8, range 28.2-43.8 kg/m2) placed
on very low fat, energy-restricted diet (6.0 MJ, 15% fat) for
12 weeks
 Baseline CRP positively associated with BMI (r=0.281,
p=0.01)
 CRP reduced by 26% (p<0.001)
 Average weight loss 7.9 kg, associated with change in CRP
 Change in CRP correlated with change in TC (r=0.240,
p=0.03) but not changes in LDL-C, HDL-C, or glucose
 At 12 weeks, CRP concentration highly correlated with TG
(r=0.287, p=0.009), but not with other lipids or glucose
Heilbronn LK et alArterioscler Thromb Vasc Biol 2001;21:968-970sc
Biol 2001;21:968-970.
NSAIDS and CV risk
(estimated 30 million people
worldwide use every day)
AHA 2007 statement: celecoxib should be used
"as a last resort on patients who have heart
disease or a risk of developing it”
Elevated risks occur because COX-2
inhibitors suppress prostacyclin—a
vasodilator and platelet inhibitor
with heart-protecting properties—in
vascular cells (Yu Y et al. Sci Transl
Med. 2012;4[132]:132ra54)
How big a CV risk does NSAID use pose?
Are certain NSAIDs safer than others?
From: Cardiovascular Risk and Inhibition of Cyclooxygenase: A Systematic Review of the Observational
Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2
JAMA. 2006;296(13):1633-1644. doi:10.1001/jama.296.13.jrv60011
Putting it all together
• Inflammatory conditions (eg RA) have increased CV risk
not fully explained by traditional CV risk factors
• 50% of CHD occurs in people with below average total
cholesterol
• Inflammation (as measured by hs-CRP) is a powerful
marker of enhanced CV risk
• JUPITER study (inflammation and/or lipid reduction)
makes a strong argument for increased statin usage to
prevent CV events
• Exercise and weight loss lower inflammation
• NSAIDs are not innocuous; consider naproxen and
ibuprofen as first line NSAIDs
Future Directions
• IL-1 beta mAb, p38MAPK inhibitor in phase III trials for
ACS (reduce infarct size and prevent re-infarction)
• Vaccination with anti-inflammatory peptides (target
innate immune response, ? Which target)
• Low-dose methotrexate in DM2 or metabolic syndrome
with hx of vascular disease (CIRT trial)
• Rationale, design, and governance of Prospective
Randomized Evaluation of Celecoxib Integrated Safety
versus Ibuprofen Or Naproxen (PRECISION), a
cardiovascular end point trial of nonsteroidal
antiinflammatory agents in patients with arthritis.
Any
questions?
Back-Up slides
How do JUPITER results affect my
practice?
• CLASS IIa (ACC/AHA 2010 guidelines), Evidence B
– In men ≥ 50 yo or women ≥ 60 yo with LDL cholesterol
< 130 mg/dL
– not on lipid-lowering, hormone replacement, or
immunosuppressant therapy;
– without clinical CHD, diabetes, chronic kidney disease,
severe inflammatory conditions, or contraindications
to statins,
measurement of hs-CRP can be useful in the
selection of patients for statin therapy
When should I check a hs-CRP?
• Class IIb (ACC/AHA 2010 guidelines), Evidence B
• In asymptomatic intermediate-risk men ≤50 yo
or women ≤ 60 yo
measurement of hs-CRP may be reasonable for
cardiovascular risk assessment
Class III: No benefit to hs-CRP
measurement for CV risk assessment
• Asymptomatic high risk individuals
• Low-risk men<50yo or women<60yo
Clinical Application of hs-CRP for
Cardiovascular Risk Prediction
1 mg/L
Low
Risk
3 mg/L
Moderate
Risk
10 mg/L
High
Risk
>100 mg/L
Acute Phase Response
Ignore Value, Repeat Test in 3 weeks
Measurements of hs-CRP:
• Should be performed twice (2 weeks apart)
• Results averaged, expressed as mg/L
• Fasting or nonfasting in metabolically stable patients
(any time of day)
• Cost: $60-150 depending upon lab
Ridker PM. Circulation 2003;107:363-9; AHA/CDC panel recommendations for hs-CRP testing