1. Dementia IGHC Tatiana Kuznetsova, Jan A. Staessen University of Leuven, Belgium Diagnostic criteria for subclinical systolic and diastolic LV function Diagnostic criteria for subclinical systolic and diastolic LV function JRP A3

2. Stages of heart failure Stage A: asymptomatic subjects with normal LV structure and function at high risk for HF, because of hypertension, obesity and/or diabetes; Stage B: asymptomatic patients with structural and/or functional LV abnormalities; Stage C: symptomatic patients with structural and/or functional LV abnormalities; Stage D: patients with refractory symptoms of heart failure. ACC/AHA Guidelines, Circulation 2005; 112: 1825-52 Heart failure

3. Background and objectives Above age 65, the incidence of overt HF is currently ~10/1000 person-years. Because of the ageing of populations, the prevalence of HF will rise by 50% over the next 10-15 years, increasing health care costs. 50% of HF patients die within 4 years. The diagnosis of asymptomatic LV dysfunction (imaging + biomarkers) is key in the prevention and treatment of HF. Objectives:  To explore (using TDI) the prevalence of asymptomatic systolic and diastolic LV dysfunction in a general population;  To identify (cross-sectionally and prospectively) risk factors and biomarkers for LV dysfunction. Heart failure

4. Methods:  Epidemiological approach;  Echocardiography for cardiac phenotyping; Results:  Systolic LV dysfunction;  Diastolic LV dysfunction; Conclusions. Outline of presentation IGHC

5. Methods Methods Epidemiological approach – echocardiography Dementia IGHC JRP A3

6. Epidemiological methods Randomly recruited nuclear and complex (Belgium) families; Standardised and validated questionnaires in 8 languages; BP at baseline: 2 x 5 conventional BP readings at home, 5 BP readings at examination centre, and 24-h ABPM; Large number of intermediate phenotypes: blood and 24-h urine samples (biobank); Technical examinations: ECG, vascular and cardiac phenotypes; Longitudinal FU (median 15 y in Belgium and 5 years in other centres). EPOGH

7. Standardised echocardiographic protocol Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO); A single observer is performing all echocardiographic examinations by means of Vivid 7 ultrasound scanner (GE Vingmed, Horten, Norway) according to a standardised protocol; All echocardiographic examinations are stored in digital format on a local network for off-line reading (EchoPac, GE and SPEQLE, University of Leuven); Leuven is the core centre for cardiac and arterial phenotyping, management of samples, database construction, and statistical analysis. EPOGH

8. Subclinical LV dysfunction Subclinical LV dysfunction Systolic Dementia IGHC

9. Background Conventional echocardiography enables the assessment of global LV systolic function: FS or EF; Colour tissue Doppler imaging makes it possible to specifically evaluate the longitudinal and radial components of regional LV systolic function. SysLVF

10. Basal segments of inferior and infero- lateral walls AVCMVO Time integration Peak systolic SR End-systolic S Strain Strain rate AVCMVO Longitudinal and radial strain: off-line analysis of TDI SPEQLE: Software Package for Echocardiographic Quantification, Leuven; version 4.06 ECHO

11. Echocardiographic characteristics Women (n=243)Men (n=237) Conventional LV mass index (g/m 2 ) 83 (17) 98 (20)† RWT 0.37 (0.071) 0.37 (0.072) EF (%) 69.6 (7.3) 67.8 (7.2)** TDI Strain longitudinal (%) 23.0 (3.7) 22.7 (3.6) SR longitudinal (1/s) 1.31 (0.26) 1.31 (0.23) Strain radial (%) 60.7 (12.5) 57.6 (12.9)* SR radial (1/s)3.44 (0.86) 3.34 (0.82) * p  0.05; ** p  0.01; † p  0.001 Strain Kuznetsova T et al, Eur Heart J 2008; 29: 2014-23

12. Longitudinal and radial S and SR by age Strain p-values for trends  0.001 Kuznetsova T et al, Eur Heart J 2008; 29: 2014-23 70 65 60 55 50 25 24 23 22 21 20 <30 30-39 40-49 50-59 60-69 ≥70 4.0 3.5 3.0 2.5 1.5 1.4 1.3 1.2 1.1 <30 30-39 40-49 50-59 60-69 ≥70 n=48 43 113 104 60 32 N=52 48 123 86 48 Strain (%) Strain rate (1/s) Age group (years)

13. Longitudinal strain vs WT, WHR and BW Strain p-values  0.00 1 Kuznetsova T et al, Eur Heart J 2008; 29: 2014-23

14. Summary of stepwise selection* * p<0.10 – significance level for entry into the model Variable Par Est (SE) R 2 (%)p-value Strain longitudinal (%) Age (+10 years)- 0.35 (0.14)8.4.007 RWT (+0.1)- 0.74 (0.26)8.4.001 WHR (+0.1)- 0.59 (0.28)1.5.010 Strain radial (%) Age (+10 years)- 1.08 (0.48)8.4.027 RWT (+0.1)- 2.57 (1.02)2.0.010 BW (+1 kg)- 0.15 (0.05)5.7.0004 Ejection fraction (%) Age (+10 years)+ 1.59 (0.26)16.1<.0001 RWT (+0.1)+ 1.67 (0.49)2.2.001 Strain Kuznetsova T et al, Eur Heart J 2008; 29: 2014-23

15. Proposal for reference values* for S and SR Healthy reference group (n=239) Strain (%) Longitudinal > 18.5 Radial > 44.5 SR (1/s) Longitudinal > 1.00 Radial> 2.45 *Upwards rounded the 5 th percentiles Strain

16. Annexins are Ca 2+ and phospholipid binding proteins; Annexin A5 participates in the regulation of ion (Ca 2+ ) currents across the cardiomyocyte membrane; Ravassa et al. showed that the upregulation of myocardial Annexin A5 is associated with impairment of LV systolic function (EF) in patients with HF (Eur Heart J 2007; 28: 2785-91). Annexin A5 Strain

17. Radial strain vs annexin A5 Strain

18. Conclusions of this section LV strain and strain rate, as measured by 1-dimensional colour Doppler imaging in a general population, decreased with age, body weight, central obesity, and RWT. LV strain and strain rate are sensitive tools for the detection of subclinical systolic dysfunction associated with abdominal obesity and LV remodelling. The clinical applicability of strain and strain rate in the stratification and/or in the administration of treatment remains to be established. This cross-sectional study shows that LV radial strain decreased with plasma Annexin A5. Strain

19. Subclinical LV dysfunction Subclinical LV dysfunction Diastolic Dementia IGHC

20. Transmitral and pulmonary vein blood flows, and pulsed TDI A DiaHF

21. Age-specific percentiles of E/A and E/Ea in 392 “healthy” subjects 2.75 2.50 2.25 2.00 1.75 1.50 1.25 1.00 0.75 0.50 <3030-39 40-49 50-59 ≥60 97.5% 75% 50% 25% 2.5% <3030-39 40-49 50-59 ≥60 10 9 8 7 6 5 4 3 97.5% 75% 50% 25% 2.5% Age group (years) E/A ratio E/Ea ratio DiaHF Kuznetsova T et al, Circulation Heart Failure 2009; 2:105-112

22. Classification of LV diastolic dysfunction Kuznetsova T et al, Circulation Heart Failure 2009; 2:105-112 DiaHF * p ≤0.05 vs normal: 214 pmol/l 1 group - impaired relaxation (n=53; 9.8%; NT-proBNP 269 pmol/l*):  E/A: abnormally low age-specific values  E/Ea: normal range (< 8.5) 2 group – elevated E/Ea (end-diastolic LV filling pressure?) (n=76; 14.1%; NT-proBNP 302 pmol/l*):  E/A: normal age-specific range;  E/Ea: > 8.5  (Adur < ARdur) + 10  3 group – elevated E/Ea ratio and an abnormally low age-specific E/A (n=18; 3.4%; NT-proBNP 245 pmol/l*)

23. Diastolic dysfunction stages* Zile MR et al, Circulation 2002; 105:1387-93 DiaHF Normal DIASTOLIC HEART FAILURE Pseudonormal Restrictive Impaired Relaxation LV Press LA Press Mitral Doppler Velocity Pulmonary Vein Velocity Doppler Tissue Imaging E E E E A A A PV s PV d PV a A SmSm SmSm SmSm SmSm EmEm EmEm EmEm EmEm AmAm AmAm AmAm AmAm

24. Correlates of LV diastolic dysfunction 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 2.712.02-3.61<0.0001 Women 1.630.86-3.090.13 2.071.42-3.040.0002 1.551.16-2.100.0035 SBP (+10 mm Hg) 1.271.07-1.690.0052 1.940.98-3.840.056 Insulin (  2 µU/ml) 1.431.03-1.930.032 1.331.05-1.690.018 2.201.47-3.310.0001 OR 95% CIp-value Age (+10 years) BMI (+5 kg/m 2 ) Heart rate (+10 bpm) Use of β-blockers Serum creatinine (+10 µmol/l) NT-pro BNP (  2 pmol/ml) Odds ratio DiaHF Kuznetsova T et al, Circulation Heart Failure 2009; 2:105-112

25. Conclusions LV diastolic dysfunction in a random population sample, as estimated from echocardiographic measurements, is common (27.3%). Our findings are clinically relevant, because patients with subclinical diastolic dysfunction often progress to overt HF. TDI is a sensitive method for the detection of early diastolic (and systolic) LV dysfunction in a general population, particularly in subjects with LV remodelling and normal EF. DiaHF

26. Katholieke Universiteit Leuven, BJA Staessen, T Kuznetsova, Y Jin, L Thijs, T Richart Jagiellonian University Cracow, PL K Kawecka-Jaszcz, K Stolarz Universitá degli Studi di Padova, I E Casiglia, V Tikhonof Institute of Internal Medicine, RU Y Nikitin, S Malyutina, G Simonova University of Gdánsk, PL K Narkiewicz, W Sakiewicz, A Rojch Team work EPOGH

27. Charles University Pilzen, CZ J Filipovsky, J Kucerová Universidad de Navarra, EJ Diez, S Ravassa, A González B López Universitá di Milano, IG Bianchi, P Manunta, C Lanzani, L Tizzoni Universität Münster, DE Brand, SM Herrmann, Hasenkamp S Universiteit Maastricht, NLH Struijker-Boudier, S Heymans University of Lausanne, CH M Burnier, M Bochud, M Maillard University of Leicester, UKN Samani, V Codd Team work (2) EPOGH