Was passiert im Gehirn bei Vorhofflimmern

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1 Herzzentrum Was passiert im Gehirn bei Vorhofflimmern Stefan Osswald Kardiologie, Universitätsspital Basel

2 AF & Brain Epidemiologie Mechamismen Swiss-AF - hotline news Therapeutische Ansätze Summary

3 Epidemiologie von VHF Lifetime Risiko 25% *ATRIA Study. JAMA 2001;285(18):

4 Feinberg WM. Arch Intern Med 1995;155: Prävalenz U.S. population x ,000 20,000 U.S. population Population with atrial fibrillation Population with AF x % , < >95 0 Age, yr

5 Atrial fibrillation: arrhythmia only? Women Atrial fibrillation (AF) Men Causes of death in CH Women Dementia Men Age CVD Dementia Cancer Other Krijthe et al. Eur Heart J 2013 Kraft et al. Swiss Med Wkly 2010 Federal Statistical Office (FSO) 2010

6 Cognitive function (DSST score) Vorhofflimmern & Kognition Cognitive function over time AF DSST: Digit Symbol Substitution Test MMSE: Mini-Mental State Examination Individuals with (N = 552) and without AF (N = 4598) from the Cardiovascular Health Study (follow-up of >25 yrs) Thaker EL, et al. Neurology 2013;81: Nishtala A et al. Heart Rhythm 2017

Incidental dementia associated with AF Meta-analysis of 9 observational cohort studies (N =77 668 pts)

7 Incidental dementia associated with AF Meta-analysis of 9 observational cohort studies (N = pts) Santangeli P, et al. Heart Rhythm 2012 Kalantarian Heart S, Rhythm et al. Ann 2012;9: Intern Med 2013

8 SUMMARY AF & Brain Epidemiologie - VHF: Prävalenz (65-90 J.): 2% -> 20-25% - Demenz: Prävalenz (65-90 J.): 1% -> 30-35% - Demenz Inzidenz mit VHF: 1.4x häufiger

9 Gründe für Demenz? Schlaganfälle? Infarktareal Embolus Halsschlagader 3 h 6 h 24 h Stroke Rate 0.5%-12% pro Jahr! Stroke durch OAK 60% reduzierbar! Demenz auch beeinflussbar???

10 Mechanisms of Cognitive Impairment through AF EHRA Position Paper arrhythmia & cognitive function, Europace 2018;0:1-23.

11 Bludruck: beat-to-beat Variabilität Variabilität: BD syst Amplitude mmhg mmhg

12 Reduzierter zerebraler Blutfluss bei VHF Gardarsdottir M, et al. Europace 2017

13 SUMMARY AF & Brain Epidemiologie - VHF: Prävalenz (65-90 J.): 2% -> 20-25% - Demenz: Prävalenz (65-90 J.): 1-2% -> 30-35% - Demenz Inzidenz mit VHF: 1.4x häufiger Meachnismen - Main Drivers für VHF & Demenz = cvrf: Alter, HTN, Chol, Diabetes, OSA - VHF spezifisch: Mico- und Makroembolie, Entzüdung (?) - verminderter cardiac output, beat-to-beat BD-Variabilität (?)

14 Stroke Brain damage in AF patients 6% / year Microbleeds Microangiopathy Silent infarcts Asymptomatic Cognitive impairment? Dementia?

15 SWISS-AF Study Centers Kardiologie

16 SWISS-AF Overview Design: SNSF sponsored prospective, observational, multicenter cohort study in Switzerland Recruitment: April August 2017 Sample size: Follow-up: patients with AF enrolled yearly Kardiologie

17 SWISS-AF Study Procedures Baseline FU 1 FU 2 FU 3 FU 4+ Study questionnaires X X X X X 16-lead electrocardiogram X X X X X Cognitive assessment X X X X X Brain MRI X X Blood sampling X X Outcome assessments X X X X Kardiologie

18 SWISS-AF Cognitive Assessment by MoCA 30/30...no issue!

19 SWISS-AF Baseline Characteristics n=2415 Age 73 years Female sex 655 (27%) AF type Paroxysmal 1081 (45%) Persistent 708 (29%) Permanent 626 (26%) History of Hypertension 1679 (70%) History of Heart Failure 625 (26%) History of Stroke 318 (13%) Oral Anticoagulation 2173 (90%) unpublished data Kardiologie

20 SWISS-AF OAC by CHA 2 DS 2 -VASc Score unpublished data Kardiologie

21 SWISS-AF Burden Infarctions Microbleeds Lacunes Paroxysmal 161 (20.6%) 157 (20.1%) 156 (20.0%) Persistent 101 (20.1%) 96 (19.1%) 83 (16.5%) Permanent 126 (30.7%) 111 (27.1%) 89 (21.7%) All 388 (22.9%) 364 (21.5%) 328 (19.4%) Wieviel Vorhofflimmern ist nötig, um einen Stroke zu verursachen? The Swiss-AF-Burden study mit Langzeit-EKG und Loop recorder unpublished data Kardiologie

SWISS-AF NfL as bioamarkers of brain damage Neurofilament Heavy (NfH): 200 kda Neurofilament Medium (NfM): 150 kda Neurofilament Light (NfL): 68 kda Teunissen et al.

22 SWISS-AF NfL as bioamarkers of brain damage Neurofilament Heavy (NfH): 200 kda Neurofilament Medium (NfM): 150 kda Neurofilament Light (NfL): 68 kda Teunissen et al., 2012 highly specific neuronal proteins, very stable in vitro 1,2 NfL in CSF reflects neuronal damage (MS 6, AD 7, ALS 8, PD 9 and trauma 10 ) NfL in blood below assay detection limits for a long time (50-100x lower than in CSF) 1. Kuhle, J. et al (2013) MSJ; 2. Gaiottino, J. et al (2013) plos One; 3. Morris, JR. et al, (1982) J Cell Biol; Morris, JR. et al (1998) 4. Fuchs, E. et al, (1998) Science; 5. Yuan, A et al, (2015) Mol Psychiatry; 6. Kuhle J. et al,(2016) Mult Scler.; 7. Zetterberg H. et al, (2016) JAMA Neurol.; 8. Weydt et al, (2016) Ann Neurol.; 9. Bacioglu M. et al, (2016) Neuron; 10. Bergman J. et al, (2016) Neurol Neuroimmunol Neuroinflamm.

23 SWISS-AF NfL - new marker of brain damage N=278 patients with AF included in the SWISS-AF cohort study Mean age 73y, 75% male, 90% under oral anticoagulation Serum light-chain neurofilament (snfl) at baseline LH Bonati, J Kuhle, SWISS-AF Investigators: unpublished data

24 SWISS-AF NfL predicts brain atrophy at 2 yrs N=278 patients with AF included in the SWISS-AF cohort study Mean age 73y, 75% male, 90% under oral anticoagulation Serum light-chain neurofilament (snfl) at baseline Sinnecker, J Würfel, LH Bonati, J Kuhle, SWISS-AF Investigators: unpublished data

25 SUMMARY AF & Brain Swiss-AF hotline news - Klinische bekannter Stroke 13% (OAC 90%) - grosse Mehrheit der cerebralen Ereignisse verlaufen klinisch stumm! - Stumme Läsionen: Infarkte 15%, Lakunen 16%, Microbleeds 20% - small vessel disease: 99% (by volume: vs mm 3 infarcts) - NfL möglicher neuer Prädiktor für silent brain damage (?) - Verlust der cognitiven Funktion durch strokes, teils durch SVD (?) - overt vs. silent strokes sind gleichbedeutend für Kognitions-Verlust

26 Genes - Predispostions - Habits - Inactivity The Heart-Rhythm-Brain Syndrome Hypertension - LA enlargement - HFpEF - AF Metabolic Syndrome - Overweight - Diabetes - OSA - Lipids Congestive Heart Failure - Hypoxemia - Renal dysfunction - Hyperaldosteronism Athersoclerosis - Brain - Aorta - Heart & AMI Microangiopathy - Brain - Kidney - Nerves SMVD - Microbleed - Infarcts - Lacunes - Atrophy - Hemorrhage The Silent Brain Shower

27 Time outside therapeutic range & dementia Study settings N= pts with AF, yrs no Hx of stroke/dementia managed by Anticoagulation Service Center endpoint: new incident dementia (CDC 9) Heart Rhythm2014;11:

28 Meta-analysis of randomised NOAC trials (RE-LY ROCKET-AF, ARISTOLE, ENGAGE AF-TIMI 48) Outcome stroke or systemic emboli N = pts Lancet 2014; 383:

29 Meta-analysis of randomised NOAC trials (RE-LY ROCKET-AF, ARISTOLE, ENGAGE AF-TIMI 48) Major bleeding Lancet 2014; 383:

30 Statin Use and Incidental Dementia in Taiwan Nation Health Insurance Database (follow-up data ) Chen CY, J Int Cardiol 2014;173:

31 Statin Use and Incidental Dementia in Taiwan Statins prevent Dementia Chen CY, J Int Cardiol 2014;173:

32 Gender Effects on Incident Dementia Class effect, but female respond better Potentency matters The longer the better Chen CY, J Int Cardiol 2014;173:

33 Incident AF and antihypertensive drug therapy Schaer B et al, Ann Intern Med. 2010;152:78-84.

34 DIAMOND-CHF Trial Dofetilide for rhythm control versus rate control N Engl J Med 1999; 341:

35 CASTLE-AF Trial Catheter ablation for rhytm control versus rate control P = Symptomatic AF Failure or intolerance to take AAD LVEF 35% NYHA class II N Engl J Med 2018; 378:

36 CASTLE-AF Trial catheter ablation for rhytm control versus rate control N Engl J Med 2018; 378:

Incidence of Dementia over 3 Decades in the Framingham Heart Study 1970-1980 1980-1990 1990-2000

37 Incidence of Dementia over 3 Decades in the Framingham Heart Study N = persons >60 years at study entry Demenz Inzidenz nimmt ab! N Engl J Med 2016;374:

Incidence of Dementia over 3 Decades in the Framingham Heart Study N = 5 205 persons >60 years at study entry Trends

38 Incidence of Dementia over 3 Decades in the Framingham Heart Study N = persons >60 years at study entry Trends über 30 Jahre Bildung besser BD, Nicotin, Chol besser BMI & DM nehmen zu Stroke unverändert N Engl J Med 2016;374:

39 SUMMARY AF & Brain Epidemiologie - VHF: Prävalenz (65-90 J.): 2% -> 20-25% - Demenz: Prävalenz (65-90 J.): 1-2% -> 30-35% - Demenz Inzidenz mit VHF: 1.4x häufiger Meachnismen - Main Drivers für VHF & Demenz = cvrf: Alter, HTN, Chol, Diabetes, OSA - VHF spezifisch: Mico- und Makroembolie, Entzüdung (?) - verminderter cardiac output, beat-to-beat BD-Variabilität (?)

40 SUMMARY AF & Brain Swiss-AF hotline news - Klinische bekannter Stroke 13% (OAC 90%) - Stumme Läsionen: Infarkte 10%, Lakunen 19%, Microbleeds 22% - NfL möglicher neuer Prädiktor für silent brain damage (?) - overt vs. silent strokes sind gleichbedeutend für Kognitions-Verlust Therapeutische Ansätze - aggressives Management aller cardiovaskulärer Risikofaktoren - OAC: Demenz wenn TTR >75%, NOAC sind VKA überlegen (ausser GI Blutung) - Statine: Demenz in Abhängigkeit von Wirkgrad, Dauer, Geschlecht - Rhythm control: Mortalität durch Ablation (stroke?), nicht durch Med. - BD-Einstellung: ACEI/ARB überlegen bei VHF (pleiotrope Effekte?)

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