Dementia

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

2. Heart failure 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 patientswith structural and/or functional LV abnormalities; • Stage C:symptomatic patientswith structural and/or functional LV abnormalities; • Stage D: patients with refractory symptoms of heart failure. ACC/AHA Guidelines, Circulation2005; 112: 1825-52

3. Heart failure 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.

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

5. IGHC JRP A3 Dementia MethodsEpidemiological approach – echocardiography

6. EPOGH 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).

7. EPOGH Standardisedechocardiographic 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.

8. IGHC Dementia Subclinical LV dysfunctionSystolic

9. SysLVF 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.

10. Strain Echocardiographic characteristics Kuznetsova T et al, Eur Heart J2008; 29: 2014-23 * p0.05; ** p0.01; † p0.001

11. Strain Longitudinal and radial S and SR by age 70 4.0 65 3.5 43 60 113 Strain (%) Strainrate (1/s) n=48 3.0 104 55 60 50 32 2.5 25 1.5 24 48 1.4 N=52 23 123 1.3 123 22 86 1.2 21 48 20 1.1 <30 40-49 60-69 50-59 30-39 ≥70 <30 40-49 60-69 50-59 30-39 ≥70 Age group (years) Kuznetsova T et al, Eur Heart J2008; 29: 2014-23 p-values for trends  0.001

12. Strain Longitudinal strain vs WT, WHR and BW Kuznetsova T et al, Eur Heart J2008; 29: 2014-23 p-values 0.001

13. Strain Summary of stepwise selection* Kuznetsova T et al, Eur Heart J2008; 29: 2014-23 * p<0.10 – significance level for entry into the model

14. Strain Proposal for reference values* for S and SR *Upwards rounded the 5th percentiles

15. Strain Annexin A5 • Annexins are Ca2+ and phospholipid binding proteins; • Annexin A5 participates in the regulation of ion (Ca2+) currents across the cardiomyocyte membrane; • Ravassaet 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).

16. Strain Radial strain vs annexin A5

17. Strain 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.

18. IGHC Dementia Subclinical LV dysfunctionDiastolic

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

20. Age-specific percentiles of E/A and E/Ea in 392 “healthy” subjects DiaHF 2.75 10 2.50 9 E/A ratio E/Ea ratio 2.25 97.5% 8 2.00 75% 50% 7 1.75 25% 1.50 6 97.5% 1.25 2.5% 75% 5 1.00 50% 4 25% 0.75 2.5% 0.50 3 <30 30-39 40-49 ≥60 50-59 <30 30-39 40-49 ≥60 50-59 Age group (years) Kuznetsova T et al, Circulation Heart Failure2009;2:105-112

21. DiaHF Classification of LV diastolic dysfunction • 1 group - impaired relaxation (n=53; 9.8%; NT-proBNP269 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-proBNP302 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-proBNP245 pmol/l*) Kuznetsova T et al, Circulation Heart Failure2009;2:105-112 * p ≤0.05 vs normal: 214 pmol/l

22. DiaHF Diastolic dysfunction stages* DIASTOLIC HEART FAILURE Pseudonormal Impaired Relaxation Normal Restrictive LV Press LA Press E E A E E A A Mitral DopplerVelocity A Pulmonary VeinVelocity PVd PVd PVs PVs PVs PVd PVd PVs PVa PVa PVa PVa Sm Sm Sm Sm Doppler Tissue Imaging Am Em Am Am Em Em Am Em Zile MR et al, Circulation2002; 105:1387-93

23. OR 95% CI p-value 2.71 2.02-3.61 <0.0001 Women 1.63 0.86-3.09 0.13 2.07 1.42-3.04 0.0002 1.55 1.16-2.10 0.0035 SBP (+10 mm Hg) 1.27 1.07-1.69 0.0052 1.94 0.98-3.84 0.056 Insulin(2 µU/ml) 1.43 1.03-1.93 0.032 1.33 1.05-1.69 0.018 2.20 1.47-3.31 0.0001 0.5 4.0 3.5 3.0 2.0 1.0 2.5 1.5 DiaHF Correlates of LV diastolic dysfunction Age (+10 years) BMI (+5 kg/m2) Heart rate (+10 bpm) Use of β-blockers Serum creatinine (+10 µmol/l) NT-pro BNP (2 pmol/ml) Odds ratio Kuznetsova T et al, Circulation Heart Failure2009;2:105-112

24. DiaHF 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.

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

26. EPOGH Team work (2) Charles University Pilzen, CZ J Filipovsky, J Kucerová Universidad de Navarra, EJ Diez, S Ravassa, A González B López UniversitádiMilano, 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, CHM Burnier, M Bochud, M Maillard University of Leicester, UK N Samani, V Codd