CV Biomarkers Today Inflammation and ProliferationCRP

Lp-PLA2MCSFPDGFFDFFGF

Interleukins (1,6,8,10,12,15)MMPs (1,2,3,9)

MIP1 (alpha and beta)TNF alpha

Proliferating cell nuclear antigenHyaluronan receptors

SR-A, SR-B1TGF

SM myacin heavy chainsCD 11, 18, 36, 40, 68

MCP-1CCR2

Pentraxin-3C4b binding protein

I kappa B-alphaTotal sialic acid

Osteopontin

Adhesion moleculess-ICAMs-VCAM

P-selectinE-selectin

Serum glycoproteinsAlpha 1-antitrypsinAlpha 1 acid glycoproteinAlpha 2-macroglobulinCeruloplasminhaptoglobin

CoagulationVWFtPA

PAI-1PF4

D-dimerTissue factorFibrinogen

Beta thromboglobulinErythrocyte sed. Rate

RBC adhesiveness/aggreg

GeneticsACE polymorphism

methylenetetrahydrofolate reductase [MTHFR] apolipoprotein E [apo E]

paraoxonase [PON] Immunology

Anti-oxLDL IgG

ImagingAngiography

IVUS

3D reconstruction IVUS Ultrafast CT (coronary)

Carotid ultrasound – IMTMRI (carotid, PAD, aortic)

PETAortic CT

Scintigraphy (thallium, sestimibe)Intracoronary endo fct (Ach)

Brachial ultrasoundPlethysmography

TEE (aortic)Skin cholesterol

Monoclonal antibody imagingPulsatile flow visualization (aorta)

Regional aortic distensibilityAortic stiffness (Doppler)Coronary thermographyCoronary elastography

Coronary NIR spectroscopy

Lipidslipoproteins

lipoprotein subfractions(L1-3, V1-6, H1-5) Apolipoproteins

(CIII, AII:E, LpB…)Lp(a)

Lipid ratios

Endothelial Dysfunction and CAD

Adapted from Dzau and Braunwald, Adapted from Dzau and Braunwald, Am Heart J,Am Heart J, 1991. 1991.

Risk factorsRisk factors Chol, Chol, BP, DM, BP, DM,

insulin resistance),insulin resistance),platelets, fibrinogen, etcplatelets, fibrinogen, etc

End-stageEnd-stageheart diseaseheart disease

Endothelialdysfunction

CoronaryCoronarythrombosisthrombosis

MIMI

Arrhythmia andArrhythmia andloss of muscleloss of muscle

Sudden Sudden deathdeath

MyocardialMyocardialischemiaischemia RemodellingRemodelling

CADCAD VentricularVentriculardilationdilation

AtherosclerosisAtherosclerosisCHFCHF

Smoothmuscle

- PGI

- NO

- EDHF

Relaxation

Inhibition ofProliferation

Tone

Structure

-

-

Endothelium-derivedRelaxing Factors

2

Proliferation

Contraction

Endothelium-derivedContracting Factors

+

+

- TXA2

- Freeradical

- Ang II

- Endothelin

BASELINE(3.65 mm)

REACTIVE HYPEREMIA (4.02 mm)

Flow-Mediated Vasodilation

FMD = 10 %

Microvasculature

Philpott et al. ATVB 2007;27:2065

Shear stress, hyperemic velocity and Risk Factors

FATE – n=1477 , Overall R2 for hyperemic velocity = 0.171

*Unadjusted (univariate)Coefficient

p value **Adjusted Coefficient

Age -1.633 <0.001 -1.004

Systolic BP -0.894 <0.001 -0.489

Fasting Glucose -10.774 <0.001 -3.889

LDL -8.211 <0.001 -6.201

HDL 21.187 <0.001 13.667

Current Smoking -2.869 0.514 ----

CRP -1.712 <0.001 -0.915

BMI -3.898 <0.001 -1.930

Methods

QCA distal to Doppler site for Flow calculation

QCA in distal site for vasomotion

LAD-D5W LAD- Ach 10-6

Mild Coronary Dilation

Endothelial Function and Atherosclerosis

Methods

Coronary flow response to Atrial Pacing

Increase in Coronary velocity in normal subject

FATE

Prognostic Significance of Markers of Vascular Health: Long-term Results from the Firefighters and their

Endothelium (FATE) Study

Todd J Anderson, Francois Charbonneau, Lawrence Title, Jean Buithieu, M. Sarah Rose, Heather Conradson, Kathy Hildebrand, Marinda Fung, Subodh Verma, Eva M. Lonn

University of Calgary and Libin Cardiovascular InstituteMcMaster UniversityMcGill UniversityUniversity of TorontoDalhousie University

Methods – Vascular End-points

FMD Hyperemic VTI

IntimaMediaAdventitia

Lumen

CIMT

Results – Cox proportional hazardsn HR 95% CI Wald p

FRS/unit SD 1569 2.28 1.82 – 2.87 <0.001

FRS/unit SD 1536 1.97 1.53 – 2.54 <0.001

VTI/unit SD 0.70 0.54 – 0.90 0.006

FRS/ unit SD 1548 1.97 1.53 – 2.54 <0.001

Log IMT/unit SD

1.45 1.15 – 1.82 0.002

FRS/unit SD 1564 2.18 1.70 – 2.78 <0.001

Log CRP/unit SD

1.12 0.88 – 1.44 0.349

FRS/unit SD 1511 1.65 1.23 – 2.20 0.001

VTI/unit SD 0.69 0.53 – 0.90 0.005

Log IMT/unit SD 1.44 1.14 – 1.83 0.002

Log CRP/unit SD 1.09 0.85 – 1.42 0.494

Results – Net Clinical Reclassification Index

Clinical Reclassification Improvement

I1 I2 NCRI Z p

VTI/unit SD 16.67 12.02 28.7 3.3755 <0.001

(N = 1500)

Log IMT/unit SD 8.33 9.67 18.0 2.115 0.034

(N = 1512)

Log CRP/unit SD 4.17 2,82 6.99 0.959 0.338

(N = 1528)

VTI/unit SD 25.0 12.81 37.81 3.2907 0.002

Log IMT/unit SD

(N = 1480)

• Endothelial dysfunction thought to play an important role in systolic CHF

• Role in diastolic CHF has not been as well defined• Ventricular-vascular coupling likely important

AB-HEART – Vascular physiology studies

• Compare peripheral endothelial function in subjects with systolic, diastolic HF with healthy controls– Flow-mediated dilation- conduit vessel function

– Hyperemic VTI and PAT – microvascular function

– Pulse wave velocity with applanation tonometry

• Assess the prognostic implication of these measurements in patients with HF

AB-HEART – Peripheral arterial studies

• Compare coronary endothelial function in subjects with systolic, diastolic HF with healthy controls– Intracoronary Ach, and adenosine

– Measures of Pressure and Flow to calculate microvascular resistance

– 25 patients per group

• Have not begun these studies as yet

AB-HEART – Coronary studies