&

2015

. MD,
Phds, FESC, FEAS
.

Prevalence of Risk Factors in CHD

4
3

Cholesterol distribution in CHD

and non-CHD populations
In spite of major advances
made in the screening,
detection, and management
of heart disease, a major
need exists for more
accurate ways to predict CV
risk

Framingham Heart Study 26-year follow-up

35% of CHD occurs
in people with
TC considered optimal
(<200mg/dL)

No CHD

Approximately 50% of
individuals diagnosed
with coronary artery
disease do not have high
blood cholesterol levels
(<240 mg/dl)
Therefore, other
factors must be involved

CHD

150

200

250

300

Total cholesterol (mg/dL)

Adapted from Castelli W. Atherosclerosis 1996

Rudolf Virchow
Inflammation-based
arterial changes as
a mechanism of
primary importance
in atherogenesis

mid 19th century

Lamond, B. The American Journal of Pathology. 2008

Inflammation and Atherosclerosis

Inflammation may determine plaque stability
- Unstable plaques have increased leukocytic infiltrates
- T cells, macrophages predominate rupture sites
- Cytokines & MMPs influence both stability and degradation
of the fibrous cap
Lipid lowering may reduce plaque inflammation
- nr of macrophage
- expression of collagenolytic enzymes (MMP-1)
- interstitial collagen
- expression of E-selectin
- calcium deposition

Is there clinical evidence that inflammatory

markers predict future coronary events
and provide additional predictive
information beyond traditional risk
factors?

Emerging Cardiac Risk Factors

Lp(a)

homocysteine

Lp-PLA2
fibrinogen

CRP

Lipoprotein(a)
KIV-2 copy
number
variant:
2 to >40
repeats

apolipoprotein(a)

Koschinsky et al. Cur Opin Lipidol 2004

LDL-like
particle

Nordestgaard B G et al. Eur Heart J 2010

Typical distributions of lipoprotein(a) levels in the

general population from 3000 & 3000 from the
Copenhagen General Population Study (from 2003 2004)

Nordestgaard B G et al. Eur Heart J 2010

36 prospective studies
Mean age 578y - 48%
47% Europeans & 50% N. Americans

JAMA 2009

Risk ratio for CHD, Ischemic Stroke, Nonvascular Death by

quantile of usual Lp(a) level

European Heart Journal 2010

Emerging Risk Factor Collaboration. JAMA 2009; 302: 412-23

Emerging Risk Factor Collaboration. JAMA 2009; 302: 412-23

Lp(a) should be measured once in all subjects at

intermediate or risk of CVD/CHD who present
with:
Premature CVD
Familial hypercholesterolaemia
A family history of premature CVD
&/orLp(a)
Recurrent CVD despite statin treatment
3% 10-y risk of fatal CVD according to the
European guidelines
10% 10-y risk of fatal and/or non-fatal CHD
according to the US guidelines
European Heart Journal 2010

C-reactive protein CRP)

C-reactive protein
(CRP)
Is the response to inflammation ( acute-phase protein)
Is synthesized by the liver in response to factors

released by fat cells (adipocytes)

Discovered by Tillett and Francis in 1930
The CRP gene is located on the 1st chromosome (1q21q23).
CRP rises up to 50,000-fold in acute inflammation

Potential Mechanisms Linking CRP to

Atherothrombosis
Confounding by cigarette

Marker for subclinical

consumption
Innocent bystander

- Acute phase response

Cytokine surrogate

- IL-6, TNF- , IL-1

Direct effects of CRP
- Innate immunity

- Complement activation
- CAM induction

Prior infection
- Chlamydia, H pylori, CMV

atherosclerosis
- EBCT / IMT / ABI
Marker for insulin resistance/
obesity
Marker for endothelial
dysfunction
Marker for dysmetabolic
syndrome
Marker for plaque
vulnerability

CRP vs hs-CRP
CRP is an acute-phase protein produced by the liver
in response to cytokine production (IL-6, IL-1, TNF)
during tissue injury, inflammation, or infection

Standard CRP tests determine levels which are >

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 CVD events

hs-CRP as a Risk Factor for Future CVD

MRFIT (Kuller 1996) CHD Death
PHS (Ridker 1997)

MI

PHS (Ridker 1997)

Stroke

CHS/RHPP (Tracy 1997)

CHD

PHS (Ridker 1998)

PVD

WHS (Ridker 1998, 2000)

CVD

MONICA (Koenig 1999)

CHD

Helsinki (Roivainen 2000)

CHD

Caerphilly(Mendall 2000)

CHD

Britain (Danesh 2000)

CHD
0

1.0

2.0

3.0

4.0

5.0

6.0

Relative Risk (upper vs lower quartile)

Circulation. Eur Heart J, BMJ 2000

Fully Adjusted Relative Risk

hsCRP Adds Prognostic Information Beyond Traditional

Risk Factors in All Major Cohorts Evaluated

PHS 1997

HPFUS 2004

WHS 2000

UK 2000

EPIC-N 2005 Strong 2005

< 1 mg/L

MONICA 2004

Kuopio 2005

ARIC 2004

Iceland 2004

NHS 2004

CHS 2005

PIMA 2005

FHS 2008

1 to 3 mg/L

> 3 mg/L
Ridker P. JACC 2007

CRP concentration and risk of CVD events : 2010

Coronary Heart Disease
3.0
2.5
2.0
1.5

Risk ratio (95% CI)

1.0

Ischaemic Stroke

3.0
2.5
2.0
1.5
1.0

All Vascular Deaths

3.0
2.5
2.0
1.5
1.0

0.5

1.0

2.0

4.0

8.0

0.5

1.0

2.0

4.0

8.0

hsCRP concentration (mg/L)

Age, gender adjusted

Fully adjusted

Lancet Jan 2010

hs-CRP, Lipids, and Risk of Future Coronary

Events: Women's Health Study (WHS)
9
8
7
6
5
4
3
2
1
0

Quartile of TC:
HDL-C

Quartile
of hs-CRP

Ridker PM et al. N Engl J Med 2000

hs-CRP: Potential Clinical Applications

Adjunct to lipid screening in the detection of
individuals at high risk for CAD
Method to better target statin therapy in the setting
of primary prevention (AFCAPS/TexCAPS)
Potential prognostic value in ACS

Inflammation is likely to represent a new

target for both the treatment and prevention of
acute myocardial infarction

Fibrinogen

Promotes atherosclerosis
Essential component of platelet aggregation
Relates to fibrin deposited and the size of the clot
Increases plasma viscosity
May also have a proinflammatory role
Measurement of fibrinogen, incl. Test variability,
remains difficult
No known therapies to selectively lower fibrinogen
levels in order to test efficacy in CHD risk reduction
via clinical trials

Fibrinogen & CHD Risk: Epidemiologic Studies

Recent meta-analysis of 18 studies involving 4018
CHD cases showed a relative risk of CHD of 1.8 (95%
CI 1.6-2.0) comparing the highest vs lowest tertile of
fibrinogen levels (mean .35 vs. .25 g/dL)

ARIC study in 14,477 adults aged 45-64 showed

relative risks of 1.8 in & 1.5 in

Scottish Heart Health Study of 5095 & 4860

showed fibrinogen to be an independent risk factor for
new events--RRs 2.2-3.4 for coronary death and allcause mortality.

Homocystein
Homocysteine is a non-protein amino acid
It is a homologue of the amino acid cysteine, differing
by an additional methylene (-CH2-) group

It is biosynthesized from methionine (dietary protein)

Homocysteine can be recycled into methionine or
converted into cysteine with the aid of B-vitamins.

EAMA VIth Course: Nutrition in the Elderly

Hyperhomocysteinaemia: Clinical Impact

Elevated homocysteine is an idependent risk-factor for
artherosclerotic diseases
thromb-embolic events
cognitive disorders
CHD-Risk

15

20

25

30
35
Serum Homocystin(mol/L)
JAMA 1995

Albertinen-Haus, Forschung

Dr. J. Anders2004

Homocysteine and cardiovascular disease

tHcy in blood is emerging as a prevalent and
strong rf for atherosclerotic vascular disease
in the coronary, cerebral, and peripheral
vessels, for arterial & venous thromboembolism
These conclusions are based on data from about
80 clinical and epidemiological studies including
more than 10,000 pts
tHcy confers a graded risk and may enhance
the effect of the conventional rfs, and seems
to be a particularly strong predictor of CVD
mortality

Annu Rev Med. 1998

SEARCH: FOLATE/B12 on MAJOR

VASCULAR EVENTS
Event

Folate allocation
Risk ratio & 95% CI
Active
Placebo Active better Placebo better
(n=6033)
(n=6031)

Non-fatal MI
Coronary revascularisation
CHD death

431
590
463

Major coronary events

(7.1%)
(9.8%)
(7.7%)

429
591
422

(7.1%)
(9.8%)
(7.0%)

1229 (20.4%) 1185 (19.6%)

4.7% SE 4.2
increase

Fatal stroke
Non-fatal stroke

59
218

(1.0%)
(3.6%)

65
222

(1.1%)
(3.7%)

Total stroke

269

(4.5%)

265

(4.4%)

1.8% SE 8.7
increase

Non-coronary revascularisation 178

(3.0%)

153

(2.5%)

16.9% SE 11.9
increase

MAJOR VASCULAR EVENTS

1537 (25.5%) 1493 (24.8%)

4.0% SE 3.7
increase
0.6

Circulation 118: 2310, 2008

0.8

1.0

1.2

1.4

SEARCH: Effects of Folate/B12 on

Mortality
Cause of death

Folate allocation
Active
Placebo
(n=6033)
(n=6031)

CHD

463

(7.7%) 422

(7.0%)

59
51

(1.0%)
(0.8%)

65
58

(1.1%)
(1.0%)

All vascular

573

(9.5%)

545

(9.0%)

Neoplastic
Respiratory
Other medical
Non-medical

260
67
67
16

(4.3%) 251
(1.1%) 65
(1.1%) 78
(0.3%) 11

(4.2%)
(1.1%)
(1.3%)
(0.2%)

All non-vascular

410

(6.8%)

(6.7%)

All causes

983 (16.3%)

Stroke
Other vascular

Circulation 118: 2310, 2008

405

Risk ratio & 95% CI

Active better Placebo better

5.5% SE 6.1
increase

1.6% SE 7.0
increase
3.8% SE 4.6
increase

950 (15.8%)

0.6

0.8

1.0

1.2

1.4

BVTT meta-analysis: Effects of FOLATE

on MAJOR VASCULAR EVENTS by trial
Events (%)
Treatment
Control
(n=11,658)
(n=11,707)
(n=17,691)
(n=17,691)

Risk ratio (CI)

Trial
CHAOS-2

111 (11.8)

95 (10.1)

1.21 (0.84- 1.73)

WENBIT

327 (21.2)

313 (20.2)

1.06 (0.86- 1.30)

VISP

300 (16.4)

300 (16.2)

1.01 (0.82- 1.25)

NORVIT

978 (52.2)

1011 (53.9)

0.96 (0.86- 1.08)

WAFACS

376 (13.8)

366 (13.5)

1.02 (0.84- 1.23)

HOPE-2

790 (28.7)

796 (28.8)

1.01 (0.89- 1.15)

SEARCH

1537 (25.5)

1493 (24.8)

1.04 (0.95- 1.14)

Total

4419 (25.0)

4374 (24.7)

1.02 (0.98- 1.06)

99% CI
95% CI

0.5

Treatment

better

1.0

Control
better

2.0

Effects of BVTT of B-vitamins on

Figure 1: Effects BVTT of B-vitamins on coronary events,
coronary events,
in published
trials
in published
trials
Events (%)
Treatment
Control
(n=17,783) (n=17,820)
HOST

129 (12.5)

WENBIT

135

(8.8)

VISP

114

(6.2)

NORVIT

RR (CI)

150 (14.6)

0.92 (0.78- 1.07)

113

(7.3)

1.22 (0.87- 1.72)

123

(6.6)

0.91 (0.54- 1.52)

329 (17.6)

314 (16.7)

1.05 (0.86- 1.29)

WAFACS

283 (10.4)

280 (10.3)

1.01 (0.80- 1.27)

HOPE-2

341 (12.4)

349 (12.6)

0.97 (0.73- 1.29)

SEARCH

1229 (20.4) 1185 (19.6)

1.05 (0.93- 1.18)

ALL

2560 (14.4) 2514 (14.1)

1.01 (0.96- 1.07)

Heterogeneity: 6 5.91; p=0.4

99% CI
95% CI

0.5

Treatment
better

1.0

Control
better

2.0

Effects
of
BVTT
of
B-vitamins
on
Figure 2: Effects BVTT of B-vitamins on stroke events,
in published
trials
stroke events,
in published
trials
Events (%)
Treatment Control
(n=17,783) (n=17,820)
HOST

37 (3.6)

41 (4.0)

0.95 (0.71- 1.26)

WENBIT

28 (1.8)

39 (2.5)

0.72 (0.38- 1.36)

152 (8.3)

148 (8.0)

1.07 (0.67- 1.70)

NORVIT

49 (2.6)

49 (2.6)

1.00 (0.62- 1.61)

WAFACS

79 (2.9)

69 (2.5)

1.15 (0.75- 1.77)

HOPE-2

111 (4.0)

147 (5.3)

0.67 (0.43- 1.05)

SEARCH

269 (4.5)

265 (4.4)

1.01 (0.81- 1.28)

ALL

725 (4.1)

758 (4.3)

0.96 (0.87- 1.07)

VISP

25%

RR (CI)

Heterogeneity: 6 7.52; p=0.3

99% CI
95% CI

0.5

Treatment
better

1.0

Control
better

2.0

Effects of BVTT of B-vitamins on

Figure 4: Effects BVTT of B-vitamins on mortality,
mortality,
in published
in published
trials trials
Events (%)
Treatment
Control
(n=18,723) (n=18,762)
CHAOS-2
HOST

74

(7.9)

448 (43.4)

RR (CI)

(7.9)

1.00 (0.41- 2.49)

436 (42.6)

1.02 (0.91- 1.13)

74

WENBIT

73

(4.7)

58

(3.7)

1.28 (0.81- 2.03)

VISP

99

(5.4)

117

(6.3)

0.78 (0.46- 1.35)

NORVIT

184

(9.8)

181

(9.6)

1.02 (0.79- 1.31)

WAFACS

250

(9.2)

256

(9.4)

0.97 (0.77- 1.24)

HOPE-2

470 (17.0)

475 (17.2)

0.99 (0.77- 1.27)

SEARCH

983 (16.3)

950 (15.8)

1.04 (0.92- 1.18)

2581 (13.8) 2547 (13.6)

1.02 (0.97- 1.07)

ALL

Heterogeneity: 7 3.7; p=0.8

99% CI
95% CI

0.5

Treatment
better

1.0

Control
better

2.0

B vitamins in pts with recent TIA/stroke in the VITAmins TO

Prevent Stroke (VITATOPS) trial: a randomised, double-blind,
parallel, placebo-controlled trial
METHODS: In this randomised, double-blind, parallel, placebo-controlled trial, we
assigned patients with recent stroke or TIA (within the past 7 months) to receive
one tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B6, and
0.5 mg vitamin B12).
B12 The primary endpoint was the composite of stroke,
myocardial infarction, or vascular death. 8164 pts were randomly assigned to
receive B vitamins (n=4089) or placebo (n=4075). Pts were followed up for a
median duration of 3.4 years.
years 616 (15%) patients assigned to B vitamins and 678
(17%) assigned to placebo reached the primary endpoint (risk ratio [RR] 0.91,
p=0.05; absolute risk reduction 1.56%. There were no unexpected serious adverse
reactions and no significant differences in common adverse effects between the
treatment groups.

INTERPRETATION: Daily administration of folic acid, vitamin

B6, and vitamin B12 to patients with recent stroke or TIA did not
seem to be more effective than placebo in reducing the incidence
of major vascular events
Lancet Neurol. 2010 Sep. Epub 2010 Aug

Lp-PLA2
(lipoprotein-associated phospholipase A2)
Commonly called the PLAC Test
Measures Lp-PLA2 , a vascular specific inflammatory enzyme
implicated in the formation of rupture-prone plaque.
Produced by macrophages, T cells, and mast cell
Prominantly bound to atherogenic lipoproteins
Localized to the vulnerable shoulder region of rupture prone
plaques.
Over 65 studies support Lp-PLA2 as a CV risk marker for MI
and ischemicLp(a)
CVA (LDL does not predict stroke risk)
Not affected by systemic inflammation
Arterioscler Thromb Vasc Biol 2006

Contrasting histopathologic characteristics of a

stable versus ruptured plaque.

Stable plaque
Low Lp-PLA2 content

Ruptured plaque
High Lp-PLA2 content
Corson MA, et al. Am J Cardiol 2008;101[suppl]:41F

2000

Circulation, 2004

Circulation, 2004

Circulation, 2006

JACC, 2008

Elevated Lp-PLA2 as a Predictor of Coronary and CV Events

in Primary Prevention

Elevated Lp-PLA2 as a Predictor of Coronary and CV Events

in Secondary Prevention

Elevated Lp-PLA2 is consistently associated

with a doubling of risk for CVD

ARIC Study: Lp-PLA2 Increases Risk of

Ischemic Stroke at All Levels of Blood Pressure

High Lp-PLA2 Activity Adds to CV Risk

Associated with the Metabolic Syndrome in the
Malm Study

Recommendation for use of Lp-PLA2

testing

Davidson , et al. Am J Cardiol 2008;

Conclusion
Although LDL remains the
principal predictive risk factor
for the CVDs, all the above
markers could be helpful as
predictive risk factors in
patients that are in grey zone