Phenotyping hypertensive patients Phenotyping hypertensive patients with blood and urine - with blood and urine -

inflammation, oxidative stress, fibrosis, angiogenesisinflammation, oxidative stress, fibrosis, angiogenesis

Jan Menne, Hermann Haller Department of Nephrology, Medical School Hannover

haller.hermann@mh-hannover.de

The first problem: The first problem: how translate risk factors into vascular disase ?how translate risk factors into vascular disase ?

Risk factors Clinical diseaseClinical disease

years and decadesyears and decades

Organ damage Organ damage „subclinical“„subclinical“

glucoseglucoselipidslipids

smokingsmokinghypertensionhypertension

Mechanisms of cardiovascular morbidity and mortalityMechanisms of cardiovascular morbidity and mortality

Progressive deterioration of organ function

years and decades

Sympatheticactivity

RAAS

Hypertension

DiabetesSmoking

Cholesterol

Risk factors

Clinical diseaseClinical disease

Mechanisms of cardiovascular morbidity and mortalityMechanisms of cardiovascular morbidity and mortality

Progressive deterioration of organ function

years and decades

Sympatheticactivity

RAAS

Hypertension

DiabetesSmoking

Cholesterol

Risk factors

Clinical diseaseClinical disease

Oxidative stress

Mechanisms of cardiovascular morbidity and mortalityMechanisms of cardiovascular morbidity and mortality

Progressive deterioration of organ function

years and decades

Sympatheticactivity

RAAS

Hypertension

DiabetesSmoking

Cholesterol

Risk factors

Clinical diseaseClinical disease

Oxidative stress

EC dysfunction

Mechanisms of cardiovascular morbidity and mortalityMechanisms of cardiovascular morbidity and mortality

Progressive deterioration of organ function

years and decades

Sympatheticactivity

RAAS

Hypertension

DiabetesSmoking

Cholesterol

Risk factors

Clinical diseaseClinical disease

Oxidative stress

EC dysfunction

Microinflammation

Mechanisms of cardiovascular morbidity and mortalityMechanisms of cardiovascular morbidity and mortality

Progressive deterioration of organ function

years and decades

Sympatheticactivity

RAAS

Hypertension

DiabetesSmoking

Cholesterol

Risk factors

Clinical diseaseClinical disease

Oxidative stress

EC dysfunction

Microinflammation

Hypertrophy/Fibrosis

Risk Factors for Future Cardiovascular Events

Relative Risk of Future Cardiovascular Events0

Ridker PM et al. N Engl J Med 2000;342:836-843.

Lipoprotein(a)

Homocysteine

IL-6

TC

LDL-C

sICAM-1

SAA

Apo B

TC:HDL-C

hs-CRP

hs-CRP + TC:HDL-C1.0 2.0 4.0 6.0

PREVEND Study (n = 8,592)

Blood pressure, hsCRP and microalbuminuria

Stuveling EM et al. Hypertension 2004; 43: 791

phenotyping - we are looking for patterns phenotyping - we are looking for patterns

hypertensionhypertension

OxidativeOxidativestressstress

Micro-Micro-inflammationinflammation

Hypertrophy Hypertrophy fibrosisfibrosisEC function/EC function/

AngiogensisAngiogensis

Ingenious Hypercare phenotyping platformsIngenious Hypercare phenotyping platforms

Oxidative stressOxidative stress

Micro-Micro-inflammationinflammation

Hypertrophy Hypertrophy FibrosisFibrosis

EC function/EC function/AngiogenesisAngiogenesis

Structure of the phenotyping program

patient information

Clinical assessment

clinical data

data processing and management

vascular function

blood samples

ELISAMS

UltrasoundNMRFMDSphygmocor

urine analysis

proteomics

storage

Ingenious Hypercare phenotyping platformsIngenious Hypercare phenotyping platforms

Oxidative stressOxidative stress

Micro-Micro-inflammationinflammation

Hypertrophy Hypertrophy FibrosisFibrosis

EC function/EC function/AngiogenesisAngiogenesis

Ingenious Hypercare phenotyping platformsIngenious Hypercare phenotyping platforms

Oxidative Oxidative stressstress

ADMAADMAAOPPAOPPOx-LDLOx-LDL

GlutathionperoxidaseGlutathionperoxidaseCarbonylated proteinsCarbonylated proteinsMPOMPOMalondialdehydMalondialdehyds-RAGEs-RAGE

Others others others ?Others others others ?

Zoccali et al. Lancet 358:2113-7, 2001

Fatal and non fatal Fatal and non fatal cardiovascular eventscardiovascular events

1.01.0

.9.9

.8.8

.7.7

.6.6

.5.5

46.746.740.040.033.333.326.726.720.020.013.313.36.76.700

TimeTime(months)(months)

All cause mortalityAll cause mortality

46.746.740.040.033.333.326.726.720.020.013.313.36.76.700

1.01.0

.9.9

.8.8

.7.7

.6.6

.5.5

TimeTime(months)(months)

Cumulative Cumulative survivalsurvival

<50<50thth percentile percentile

5050thth –75th percentile –75th percentile

>75th percentile>75th percentile

<50<50thth percentile percentile

5050thth –75th percentile –75th percentile

>75th percentile>75th percentile

* * Fully adjusted for traditional and non Fully adjusted for traditional and non traditional risk factorstraditional risk factors

* * Fully adjusted for traditional and non Fully adjusted for traditional and non traditional risk factorstraditional risk factors

ADMA and cardiovascular mortality

Ingenious Hypercare phenotyping platformsIngenious Hypercare phenotyping platforms

Micro-Micro-inflammationinflammation

C-reactive proteinC-reactive proteinSerum amyloid ASerum amyloid AFibrinogenFibrinogenIL-6IL-6IL-6 STIL-6 STIL-12IL-12TNF-aTNF-aMCP-1MCP-1s-ICAMs-ICAMCD 40CD 40s-VCAMs-VCAM

gluPAI ?gluPAI ?Others others others ?Others others others ?

LeukocytesLeukocytesAlbuminAlbumin

Ingenious Hypercare phenotyping platformsIngenious Hypercare phenotyping platforms

EC function/EC function/AngiogenesisAngiogenesis vWFvWF

circulating damaged ECcirculating damaged ECMicroparticlesMicroparticlesEPCsEPCs

VEGFVEGFs-flt-1s-flt-1angiopoietin-1, -2angiopoietin-1, -2

uPA/s-uPA-R ?uPA/s-uPA-R ?

Endothelial cell

Basement membrane

Tie2 controls endothelial activation

Ang-1Ang-1

Ang-2Ang-2(Weibel-Palade-(Weibel-Palade-

bodies)bodies)

Disassembley of

adherence junctions

E-selectin, ICAM-1, VCAM-1

Survival

Tie2Tie2RezeptorRezeptor

Stimulation (e.g. Immune complex)

Maintenance

(A) CKD Patienten (HD, PD, und NTx zusammen, n=117) (B) HD Patienten (n=61) (C) PD Patienten (n=24) und (D) NTx Patienten (n=32)

Coronary angiography

Doppler ultrasound

PAOD [Fontaine]

CHD (1 VD)

CHD (2 VD)

CHD (3 VD)

Stadium I

Stadium IIa

Stadium IIb

Stadium III

Stadium IV

mild

moderate

severe

+1

+2

+3

+2

+3

+4

+5

+1

+3

+1

+2

min points 00

max points 1111

Circulating Ang-2 correlates with atherosclerotic burden

Kümpers P, David S, Hellpap J, Horn R, Leitolf H, Haller H, Kielstein JT.Angiopoietin 2 and Cardiovascular Disease in Dialysis and Kidney Transplantation.Am J Kidney Dis. 2009 Mar 4. [Epub ahead of print]

Circulating Ang-2 levels are higher in hypertensive patients

Kümpers P, David S, Hellpap J, Horn R, Leitolf H, Haller H, Kielstein JT.Angiopoietin 2 and Cardiovascular Disease in Dialysis and Kidney Transplantation.Am J Kidney Dis. 2009 Mar 4. [Epub ahead of print]

Ingenious Hypercare phenotyping platformsIngenious Hypercare phenotyping platforms

TGF-bTGF-bOsteopontinOsteopontinCTGFCTGFMMPMMPAdiponectinAdiponectinFGFsFGFs

gluPAI ?gluPAI ?Others others others ?Others others others ?

Hypertrophy Hypertrophy FibrosisFibrosis

Effects of treatment is important to knowEffects of treatment is important to know

30

40

Baseline 6 weeks 12 weeks

p < 0.05

p < 0.001

A

plas

ma

OP

N (

ng

/ml)

Angiopoetin -2 Osteopontin

no phenotyping without well characterized no phenotyping without well characterized patients and families !patients and families !

hypertensionhypertension

OxidativeOxidativestressstress

Micro-Micro-inflammationinflammation

Hypertrophy Hypertrophy fibrosisfibrosisEC function/EC function/

AngiogensisAngiogensis