Attualità in tema di fibrillazione atriale

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1 Attualità in tema di fibrillazione atriale Barbara Casadei MD DPhil FRCP Professor of Cardiovascular Medicine John Radcliffe Hospital University of Oxford

2 Are you crazy? Ma sei matta? Bene...ma son sicuro che non torni! Ma sei matta? Ma sei matta?

3 AF: epidemiology & treatment Most common sustained clinical arrhythmia (1:4 lifetime risk)

4 AF: epidemiology & treatment Most common sustained clinical arrhythmia (1:4 lifetime risk) AF is associated with a significantly increased morbidity and with high medical costs (ca. 3% of the UK NHS budget)

5 AF: epidemiology & treatment Most common sustained clinical arrhythmia (1:4 lifetime risk) AF is associated with a significantly increased morbidity and with high medical costs (ca. 3% of the NHS budget) Available treatment is suboptimal: rhythm control drugs pro-arrhythmic risk ablation expensive, complex and only suitable to a small proportion of AF patients rate control need for anticoagulation, loss of physiological HR adaptation

6 AF begets AF Wijffels et al, 1995 l 0.5Hz 1Hz 2Hz 4Hz Short APD without rate adaptation Shorter AERP Re-entry entry l 200 ms

7 Oxidative stress and atrial remodelling in AF + ATRIAL FIBRILLATION RAPID ATRIAL ACTIVATION OXIDATIVE STRESS AF begets AF ELECTRICAL REMODELLING

8 Atrial oxidative stress and AF There is evidence of oxidative injury in atrial samples from patients with AF (Mihm et al. Circ 2001) There is a correlation between oxidative stress and atrial ERP shortening in animal models (Carnes et al. Circ Res 2004) Treatment with anti-oxidant/anti-inflammatory agents prevents atrial electrical remodelling and AF induction in a dog model of atrial tachypacing (Carnes et al. Circ Res 2001, Shiroshita-Takeshita et al. Circ Res 2004)

9 The Antioxidants Paradox Why have the trials of antioxidant vitamins been so disappointing? Would targeted inhibition of the relevant source of reactive oxygen species be a more successful approach? What are the sources of reactive oxygen species in the human atrial myocardium?

10 1cm Lucigenin-enhanced chemiluminescence 2OH-ethidium by HPLC Biopterins Immunoblotting & immunolocalisation NOS & arginase activity Real time RT-PCR

11 O 2. O 2 - H + A NOX2 oxidase in human atrial cells Kim et al, Circ Res 2005 NOX2. NAD(P)H p22 phox rac p67 phox p47 phox NAD(P)+ Anti-p22 phox Anti-p47 phox Anti-p67 phox Immunoblotting + RAA atrial myocytes 22kD 47kD 67kD Immunolocalization in human atrial myocytes Test Stain NC p47 phox p67 phox Phase Contrast

12 Atrial NOX2 activity and AF: Koch s s postulates NOX2 oxidases are present in the human atrial myocardium AF is associated with increased atrial NOX2 activity Does an increase in atrial NOX2 activity precede AF??

13 Post-operative operative atrial fibrillation Atrial fibrillation is a frequent complication of most types of cardiac surgery, occurring in ca. 35% of patients within the first 2-5 postoperative days The inflammatory reaction associated with cardiac surgery and cardiopulmonary bypass has been implicated in the genesis of this arrhythmia NOX2 activity is stimulated by cytokines

14 Hypotheses: Atrial NOX2 oxidases may sense systemic inflammation and translate it into a local increase in oxidative stress leading to arrhythmogenesis Atrial NOX2 activity may predict the occurrence of postoperative AF

15 Atrial NOX2 activity is an independent predictor of new-onset AF after cardiac surgery (n=305) Tertiles of atrial NOX2 activity Highest Mid Lowest AF-free survival Kim et al JACC 2008 Antoniades et al. JACC 2011 (in press) 0 Cox-regression (HR[95%CI], P): Lowest tertile: Ref Mid tertile: 3.15[ ], P=0.039 Highest tertile: 6.43[ ], P= Post-operative days

16 Atrial NOX2 activity is a predictor of in-hospital outcome after cardiac surgery Atrial NOX2 activity (RLU/sec/mg protein) 12x x10 4 8x10 4 6x10 4 4x10 4 2x P= Inotropic support (days) Hospital discharge Tertiles of atrial NOX2 activity Post-operative days Highest Mid Lowest Cox-regression (HR[95%CI], P): Lowest: Ref Mid: 0.78[ ], P=0.234 Highest: 0.61[ ], P=0.02 Antoniades et al. JACC 2011 (in press)

17 Summary (I) The main source of superoxide production in the human atrial myocardium is a membrane-bound NOX2 oxidase Atrial NOX2 activity is an independent predictor of post-operative complications and in-hospital stay Can atrial NOX2 oxidases be a therapeutic target in patients undergoing cardiac surgery?

18 NOX2 activation O 2 NOX2 p22 phox NADPH rac p67 phox O 2 - p47 phox NADP + H +

19 Statin-mediated inhibition of NOX2 O 2 NOX2 p22 phox rac p67 phox p47 phox STATINS

20 Effect 3-day preoperative treatment with atorvastatin (20 mg od vs. placebo) on atrial and vascular redox state in 42 CABG patients Atrial NOX2 Activity (RLU/sec/mg protein) 10x10 4 8x10 4 6x10 4 4x10 4 2x Placebo P<0.01 Statin IMA NOX2 Activity * Antoniades et al. JACC 2011 (In press) Antoniades et al; Circulation 2011 Antoniades et al. Circulation. 2010

21 Statins and short-term term AF in dogs Treatment with simvastatin (SIM) prevents atrial ERP shortening and AF after 1 week of Atrial TachyPacing (ATP) (Shiroshita-Takeshita et al. Circ Res 2004)

22 Effect of peri-operative statin treatment on post-operative operative AF Chen et al. J Thorac Cardiovasc Surg. 2010

23 Atorvastatin and persistent AF following cardioversion: a randomized placebo-controlled controlled multicentre study Almoroth et al. Eur Heart J 2009

24 Does atrial ROS production or its enzymatic sources vary with the duration and substrate of AF? and might this affect the efficacy of statins in the prevention of AF?

25 Study Design We investigated the expression and activity of atrial oxidase systems: stems: (i) in the right and left atrial myocardium of 48 goats after 14 days (n=15 ) and 6 months (n=10) of pacing-induced induced AF and in their controls in SR (n=23) with or without atrial structural remodeling secondary to a surgically-induced induced AV block (n=9). (ii) in samples of the right atrial appendage from 130 patients (26 with permanent AF, 32 who developed AF post-operatively operatively and 72 who were in normal sinus rhythm before and after cardiac surgery) - the effect of ex vivo atorvastatin on NADPH oxidase- derived atrial ROS production, biopterin levels and NOS activity. Reilly et al. Circulation 2011

26 AF and AVB are associated with increased superoxide production in goats 10 2-O H E (m M/m g/m in) RA LA RA LA RA LA RA LA SR * 2W-AF * * * * 6M-AF AVB (RLU/s/µg protein) O NOX2 activity is increased in the LA of goats after 2 weeks of AF Control Apo Rot L-NAME Oxy Right Atrium * Control Apo Rot L-NAME Oxy Left Atrium Atrial NOX2 activity is increased in patients who develop post-op AF Basal O2 - (RLU/s/µg) Pre SR-post SR Pre SR post AF * * Control Apo Rot L-Name Oxy Control Apo Rot L-Name Oxy

27 Atrial sources of oxidative stress change with the duration of AF and the presence of atrial structural remodelling (RLU/s/µg protein) O 2 - O 2 - (RLU/s/µg protein) * 6M AF (n=10) Control Apo Rot L-NAME Oxy Right Atrium * Control Apo Rot L-NAME Oxy Left Atrium Chronic AF (n=26) vs. SR in humans (n=72) Control Apo Rot Sinus Rhythm * L-Name Oxy Control Apo * Rot L-Name Oxy Chronic Atrial Fibrillation (Right Atrium) (RLU/s/µg protein) O p22 phox GAPDH NOX2 GAPDH * Control Apo Rot L-NAME Oxy Right Atrium AV block (n=9) SR * P-op AF Control Apo Rot L-NAME Oxy Left Atrium CAF Reilly et al. Circulation 2011

28 Statin-mediated inhibition of NOX2 O 2 NOX2 p22 phox rac p67 phox p47 phox STATINS

29 Ex-vivo atorvastatin inhibits Rac1 and NOX2 activity in post-operative operative AF patients but not in those with chronic AF O 2 NOX2 p22 phox GTP-Rac1 Total Rac1 Postop AF CAF - + STATINS rac p67 phox p47 phox p47 phox p67 phox GAPDH Atorvastatin + + Mevalonate NADPH-stimulated O 2 RLU/s/mg # Atorvastatin Mevalonate GTP-Rac1/total Rac # Postop AF Atorvastatin Mevalonate CAF * * * + +

30 Summary Increased atrial NOX2 activity is an early (but transient) event in the natural history of AF. By contrast, in the presence of longstanding AF and atrial structural remodelling, increased mitochondrial ROS production and dysfunctional nitric oxide synthase activity account for the increased atrial oxidative stress. These findings may have important implications for atrial remodelling, thrombogenesis, and the anti-arrhythmic arrhythmic efficacy of statins.

31 Atrial NOX2 activity and AF: Koch s s postulates NOX2 oxidases are present in the human atrial myocardium AF is associated with increased atrial NOX2 activity An increase in atrial NOX2 activity precedes AF Increasing atrial NOX2 activity creates a substrate for AF Pharmacological interventions that inhibit NOX2 activity prevent AF..??

32 Evaluation of AF inducibility in mnox2 Tg mice and in models of local inflammation by programmed electrical stimulation Does Does increasing increasing atrial atrial NOX2 NOX2 activity activity creates creates a substrate substrate for for AF? AF?

33 Do pharmacological interventions that inhibit NOX2 activity prevent AF?

34 STICS (Statin Therapy In Cardiac Surgery) Prevention of myocardial damage and postoperative atrial fibrillation in patients undergoing cardiac surgery. A double-blind, randomised, placebo-controlled trial of perioperative Rosuvastatin (20 mg od) Treatment is started 3-7 days before surgery and continued until the 5 th post-operative day 1000 patients undergoing cardiac surgery Duration 18 months

35 STICS (Statin Therapy In Cardiac Surgery) Primary Objectives To establish whether perioperative administration of Rosuvastatin leads to a reduction in: the incidence of post-operative AF (as assessed by continuous ECG monitoring) perioperative myocardial injury (as assessed by serial Troponin measurements).

36 What will we learn? Is aggressive statin treatment in the perioperative period beneficial? Are statins cardioprotective and anti- arrhythmic in these patients? Are pleiotropic effects of statins (e.g.( e.g., NOX2 inhibition) clinically relevant?

37 Young Min Kim Svetlana Reilly Raja Jayaram Keshav Nahar Yin Hua Zhang Mei Hua Zhang Keith Channon Nick Alp Paul Leeson Charis Antoniades Stefan Neubauer Theo Karamitsos (Cardiovascular Medicine) Chandana Ratnatunga Rana Sayed David Taggart (Cardiothoracic Unit) Ajay Shah Phil Eaton (King s College) Emilio Hirsch (University of Turin) Uli Schotten Sander Verheule (Maastricht University) Zhengming Chen Rory Collins Jonathan Emberson Zhengshou Hu Zhe Zheng Lixin Jiang (CTSU & Fuwai Hospital)

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41 NOX2 activity and NOS inhibition are associated with APD shortening Superoxide Production (RLU/s/um) y = x R² = 0.25 ms 2 1 ADP20 3 ** AERP (pacing interval 300 ms) 0 WT NOS1 KO WT-SMTC

42 STICS (Statin Therapy In Cardiac Surgery) Secondary Objectives In-hospital clinical outcomes: Hospital and intensive care unit stay Major in-hospital cardiac or cerebrovascular events Biomarkers: Myocardial oxidase activity and serum CD40L, NT-proBNP, lipids, and renal function. LV function by echocardiography