European Society of Cardiology

ESC Congress 2012

Munich

M.Poulakis, C.Tsioufis, K.Dimitriadis, M.Giakoumis, L.Lioni, V.Tzamou, A.Kordalis, C.Stefanadis

First Cardiology Clinic, University of Athens, Hippokration

Hospital, Athens, Greece

LEVELS OF SOLUBLE RECEPTOR FOR

ADVANCED GLYCATION END-PRODUCTS ARE

RELATED WITH ARTERIAL STIFFENING,

ALBUMINURIA AND GLOMERULAR FILTRATION

RATE IN ESSENTIAL HYPERTENSIVE SUBJECTS

Presenter Disclosure Information

No relationships to disclose

AGEs, their receptor and the CV

system

result from non-enzymatic

reaction sugars-free amino of

intra-extra cellular proteins

accumulate through aging

depend on glucose levels

AGEs cental role in hypertension

pathogenesis and stiffening

Truncated isoform sRAGE detoxificates AGEs /microvascular protection and

remove inflammatory ligands (HMBG-1)

sRAGE administration prevent AGE-RAGE mediated injury

(Aronson D. J Hypertens 2003;21:3-12) (Zeiman J, et al. Drugs 2004;64:459-470)

(Paul RG, et al. Int J Biochem Cell Biol 1996; 28: 1297-1310) (Basta G, et al. Circulation 2002;105:816-822)

Enhance oxidative

stress / endothelial

dysfunction/ loss of

arterial elasticity by

collagen crosslinks its deposition occurs

also in euglycemia …and

(Yan SF, et al. Circ Res 2003;93:1159-1169)

(Yonekura H, et al. Biochem J 2003; 370:1097-1099)

non-diabetics with CHD

hypertensives

ESRD

CV mortality in ESRD

associations with

sRAGE and CV system: An emerging key receptor

Diverse mechanisms of oxidative stress-inflammation-stiffening

(Koyama, et al. ATVB 2007;27:147)

(Humpert , et al. Cardiovascular Diabetology 2007;6:9)

(Geroldi D, et al. J Hypertens 2005;23:1725)

sRAGE

“integrative

molecule of

vascular

health”

insulin sensitivity/abdominal obesity

CRP/PLT activation/ADMA

ACR in DM2/Pathogenesis of hypertension...

Lack of data on sRAGE correlates in hypertension

Urinary albumin excretion - Microalbuminuria:

New perspectives

Altered clinical positioning of UAE

Independent predictor of CVD:

non-diabetics Lancet 1988; 2: 530-533

elderly Hypertens Res 2003; 26 (8): 603-608

general population ArtThr Vasc Biol 1999; 19:

hypertensives JHH 2002; 16: 79-89

JNC VII Microalbuminuria: major risk

factor in EH

ESH 2007 Recommended lab test for

subclinical TOD assessment

Microalbuminuria, TOD and CVD risk

x2 predictive effect than conventional risk factors for IHD in

hypertensives (Hypertension 2000;35:898-903)

HOPE, Framingham Offspring study any degree of albuminuria CVD risk factor

without thresholds or plateaus (JAMA 2001; 286: 421-426)

(Arnlov J et a;. Circulation 2005;112:969)

MA is associated with indices of TOD in EH:

prevalence LVH AJH 1998; 11: 430-438

LV diastolic dysfunction AJH 2001; 14: 644-648

IMT Atherosclerosis 2002; 16: 161-166

Microalbuminuria and TOD in EH

our contribution

Unfavorable alterations of LV geometry

(concentric remodelling)(Tsioufis et al.J HH 2002; 16: 249-254)

Arterial stiffness (Tsioufis, et al. Nephron Clin Pract 2003; 93: 106-111)

(Tsioufis et al. Am J Cardiol 2000; 86: 797-801)

Low-grade inflammation and adiponectin (Tsioufis, Dimitriadis, et al. Am J Hypertens 2006; 19:462)

(Tsioufis, Dimitriadis, et al. Am J Cardiol 2005; 96:946)

“The interrelationships of microalbuminuria with the other surrogates of the atherosclerotic cardiovascular disease in hypertensive subjects”

Tsioufis C, Dimitriadis K, et al. Am J Hypertens 2004;17:470-476

GFR and CVD risk: Established knowledge and the effect of albuminuria

Recent K/DOQI and AHA statements: Estimating renal function in

CVD stratification and Tx (Am J Kindey Dis 2002;39:S1-266)

(Sarnak, et al. Circulation 3;108:2154-2169)

GFR predicts risk

(Astor B, et al. Am J Epidemiol 2008;167:1226)

Most studies

with MDRD

Correlates with

albuminuria

CVD pts, hypertensives and general population

NHANES III, 14586 US

adults/13 years follow-up

Albuminuria and Renal function interact

on CVD risk in hypertension

(Hypertension 2008; 115-122)

GFR and Artery Stiffness: The data so far

GFR inversely relates to aortic PWV in nondialysis-dependent renal insufficiency

(Wang MC, et al. Am J Kidney Dis 2005;45:494)

Hypertensives with mild renal dysfunction:

weak association GFR-stiffness of CA/not radial

(Mourad JJ, et al. Kidney Int 2001;59:18)

Most studies

with MDRD

Correlates with

albuminuria

305 hypertensives, free of CVD, renal

disease (Schillaci G, et al. Hypertension 2006;:48:616-621)

Carotid distensibility and

brachial artery in HOORN (Hermans

M, et al. J Am Soc Nephrol 2007;18:1942)

PWV in hypertension: Clinical status

and correlations with ACR

ACR in general population, hypertensives, DM, renal disease pts

(Smith A, et al. J Am Soc Nephrol 2005; 16: 1069) (Kohara K et al, Hypertens Res 2004; 27: 471)

Scarce data in untreated essential hypertension regarding ACR – GFR-PWV interrelationships (

PWV

Essential hypertensives Diabetics End-stage renal disease

Predicts outcome

(Blacher, et al. Kidney Int 2003;66)

(Laurent S, et al. Hypertension 2001;37: 12360)

Arterial stiffening

impairs buffering function of vascular system

systolic BP

LV mass

PURPOSE

To investigate the possible relationships

between sRAGE, arterial stiffness,

urinary albumin excretion, expressed as

the ACR and estimated GFR in essential

hypertensive subjects

Exclusion criteria

Secondary hypertension

Heart failure, atherosclerotic or valvular heart disease

Augmented serum creatinine concentration or overt proteinuria at

the dipstick test or renal failure (GFR<30 ml/min/1.73m2)

Atrial fibrillation, impulse conduction abnormalities

IFG, DM, familial dyslipidemia, and any other clinically significant

concurrent systemic disease

Tissue injury, chronic infection and inflammation or any medical

(such as antibiotics, antiplatelet, antinflammatory or hypolipidaemic

agents) or dental treatment over a period of 1 month before entry to

the study

Study participants

320 newly diagnosed untreated non-

diabetic patients with stage I to II essential

hypertension [192 men, mean age=52

years, office blood pressure (BP)=145/93

mmHg]

A/C estimation (quantitative assay-coefficient of variation of 2.8%)

2 non-

consecutive

morning

spot urine

samples

Procedures-

c-f PWV estimation

c-f PWV computerized method, by a

validated device (Complior SP®) online recording

and calculation of c-f PWV

Procedures-

c-f PWV estimation

…Transducers placed on the

common carotid and right

femoral artery –

2 different PWV tracings

recorded simultaneously

Time delay between rapid

upstroke of c-f artery pulse

waves

5 consecutive measurements

obtained and averaged

Procedures: Metabolic profile, SRAGE and GFR estimation

Venous blood sampling was performed from

the anticubital fossa between 8:00 AM and 9:00

AM.

sRAGE was assessed using a commercially

available solid-phase sandwich ELISA kit (R&D

Systems) with intra-assay and inter-assay

coefficients of variation of 4.8% and 8.2%

Estimated GFR (by the MDRD formula) - (ml/min/1.73m2) = 186 x (Creatinine)-1.154 x(age) -0.203 x (0.742 if female)x(1.210 in blacks)

Methods-Study participants

According sRAGE values hypertensives

were classified

Hypertensives

with high sRAGE

(n=156) (sRAGE1060.1 pg/ml)

Hypertensives

With low sRAGE

(n=164) (sRAGE<1060.1 pg/ml)

Statistical analysis

Mean values ± SD

Log transformation of skewed variables

Student independent-samples t-test or chi square

Stepwise multiple regression analysis

Analysis of variance for differences between study subgroups

Pearson correlations

All tests significant at the level of p<0.05 SPSS statistical package, release 12.0 (SPSS inc. Chicago.

Illinois, USA)

Demographic and clinical data

Parameters

Low sRAGE

(n=164)

High sRAGE

(n=156)

p

Age (yrs) 536 518 0.185

Males (%) 621 59 0.134

BMI (kg/m2) 29.72.9

27.12.5

<0.05

WHR

Smokers (%)

0.940.07

41

0.870.05

38

0.001

0.231

Off SBP (mmHg) 15115 14319 0.024

Off DBP (mmHg) 957 916 0.035

Off HR (bpm) 817 798 0.452

24h SBP (mmHg) 1398 1316 0.001

24h DBP (mmHg) 8210 797 0.045

24-h HR (bpm) 747 716 0.605

Echocardiographic and stiffness

data for study groups

Parameters

Low sRAGE

(n=164)

High sRAGE

(n=156)

p

LVMI (g/m2) 102.216.8 99.411.2 0.156

RWT 0.420.05 0.400.08 0.232

PWV (m/sec) 9.11.7 7.51.2 <0.0001

Laboratory data for the subgroups

Parameters

Low sRAGE

(n=164)

High sRAGE

(n=156) P

Hct (%) 42.43 42.44 0.863

Glucose (mg/dl) 883 875 0.763

Total chol (mg/dl) 21837 21839 0.897

TGL (mg/dl) 12668 12665 0.959

HDL(mg/dl) 5313 5313 0.717

LDL (mg/dl) 1432 14035 0.926

Renal function data for the

subgroups

Parameters

Low sRAGE (n=164)

High sRAGE (n=156)

p

Cr (mg/dl) 10.15 0.920.13 0.041

eGFR (ml/min/1.73m2) 65.97.2 92.69.1 0.03

ACR (mg/g) 50.5614.3

20.7515.5

<0.0001

Correlations in the entire

population

sRAGE was associated with:

Age (r=-0.312, p=0.001)

24-h SBP (r=-0.388, p<0.0001)

24-h pulse pressure (r=-0.371, p=0.001)

ACR (r=-0.274, p=0.019)

eGFR (r=0.236, p=0.03)

PWV (r=-0.401, p<0.0001)

Correlation of sRAGE

with log ACR

log

sRAGE

(pmol/l)

log ACR (mg/g)

r=0.075, p=0.02

0,00 0,50 1,00 1,50 2,00 2,50LOGACR

2,70

2,80

2,90

3,00

3,10

3,20

3,30

3,40

3,50

LOGRAG

E

R Sq Linear = 0,016

r=-0.274, p=0.019

Correlations in the entire

population

PWV was associated with:

Age (r=0.525, p<0.0001)

Waist (r=0.105, p=0.002)

Off SBP (r=0.242, p<0.0001)

LVMI (r=0.188, p<0.0001)

logACR (r=0.275, p=0.02)

Correlation of sRAGE

with PWV

log

sRAGE

(pmol/l)

PWV (m/sec)

r=0.075, p=0.02

r=-0.274, p=0.019

6,0 8,0 10,0 12,0PWV

2,70

2,80

2,90

3,00

3,10

3,20

3,30

3,40

3,50

LOGRAG

E

R Sq Linear = 0,042

r=-0.401, p<0.0001

Correlations in the entire

population

log ACR was associated with:

Age (r=0.097, p=0.004)

WHR (r=0.071, p=0.045)

Off SBP (r=0.137, p<0.0001)

eGFR (r=-0.074, p=0.03)

eGFR was associated with: Off PP (r=-0.118, p=0.001)

RWT (r=-0.092, p=0.007)

Total Chol (r=-0.121, p<0.0001)

Correlations in the entire

population

log ACR was associated with:

Age (r=0.097, p=0.004)

WHR (r=0.071, p=0.045)

Off SBP (r=0.137, p<0.0001)

eGFR (r=-0.074, p=0.03)

eGFR was associated with: Off PP (r=-0.118, p=0.001)

RWT (r=-0.092, p=0.007)

Total Chol (r=-0.121, p<0.0001)

Multiple linear regression analysis for

sRAGE values in the study population

Explanatory variables Unstandardized

beta coefficient

Standardized

beta coefficient

SE p

Age (years) 0.055 0.322 0.010 <0.0001

ACR (mg/g) 0.072 0.231 0.005 <0.0001

BMI (kg/m2) 0.451 0.144 0.102 <0.0001

24-h SBP (mmHg) 0.016 0.190 0.008 <0.0001

PWV (m/sec) 0.007 0.095 0.003 0.032

Intercept 1.340 0.685 0.005

Overall p-value<0.0001

R2=0.57

Adjusted R2=0.51

Variables excluded from the model were waist/hip, 24-h

DBP, glucose, lipids and eGFR

Limitations

Cross-sectional nature of the study

Exclusion of CVD and diabetic pts

Single measurement of sRAGE/ detection system cannot discriminate between different splice variants esRAGE

Single measurement of eGFR (not use of Cockroft-Gault formula)

Variations in creatinine production (muscle mass etc)

Augmentation index not estimated for a more integrated approach to stiffness

Unrecognized factors associated with arterial stiffening

No estimation of RAGE ligands: circulating AGEs, HMBG-1

Untreated, middle-aged patients referred to outpatient unit

Strength: ABPM determination of hemodynamic load

Pathophysiological and clinical

perspectives

Estimation of sRAGE adds clinical information in hypertensives-elucidates the albuminuria/PWV/eGFR-related CVD risk

sRAGE ACR/PWV bi-directional pathophysiology?

Progression and maintenance of hypertension by AGE?

ACR and PWV along with hemodynamic load were independent prognosticators of sRAGE (accounting age, sex, body size, and metabolic profile) underscores its potential clinical correlation with TOD

Evaluate the exact role of agents that prevent AGE formation and break crosslinks

sRAGE reflects pronounced vascular and renal

dysfunction in the early stages of hypertension

Conclusions

In essential hypertension, decreased sRAGE levels are

associated with increased PWV, pronounced

albuminuria and impairment of renal function

Moreover, the close relation of sRAGE with arterial

stiffening, ACR and eGFR, supports the potent role of

sRAGE in renal and vascular atherosclerotic disease

progression

Thank you