History report Spain's Moro Policy Spanish-Moro Wars Phase 1 and Phase 2
Prof. C. Moro, Madrid
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Transcript of Prof. C. Moro, Madrid
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Prof. C. Moro, Madrid
Non antiarrhythmic drugs for AF
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AF Treatment
Substrate Modifyers
Drugs
Antiagregation
Anticoagulation
Rate Control ?
Substrate Ablation AVN
Ablation
Rhythm Control ?
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Therapy Objectives for AF•Symptomatic Improvement•Quality of life Improvement•Thromboembolism
Prevention•Remodelling Prevention•Heart Failure Prevention •Mortality Reduction
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Therapy Options in AF – Type and Duration of AF– Type y Severity of Symptoms– Associated Cardiac Diseases– Age– Systemic Associated Diseases– Long or Short Term Follow up– Pharmacologic or Non
Pharmacologic
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Upstream Therapy in AF – Renin Angiotensin Inhibitors Drugs
•ACE`s•ARB`s
– Statins– Steroids– PUFA
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• Blockade of Ang II prevents electrical remodeling induced by rapid atrial pacing. Nakashima, 2000.
• ACE–dependent Ekr1/Ekr2 responsible of atrial fibrosis. Goette, 2000
• Candesartan prevents development of structural remodeling in the atria. Kumagai, 2003
Experimental DataExperimental Data
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Nakashima et al . 2000
Effect of Candesartan/ Captopril preventing electrical remodeling with rapid atrial pacing in the animal model
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Genetic Determinants of AF Genetic Determinants of AF Potasium and Sodium ChannelsPotasium and Sodium Channels
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Candesartan
Kumagai K et al. JACC 2003
Experimental AF. Electro/Anatomic Changes with Candesartan
Control
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ACEI´s and ARB´s Hemodynamic Effects
• Decrease Peripheral Vascular Resistance
• Improve Cardiac Distensibility• Reduce Arterial Pressure in
Hypertension• In HF patients
– Venous and Arterial Dilatation– Reduce Preload and Afterload– Reduce PWP and Pulmonary Congestion– Increase Cardiac Output
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ACEI´s and ARB´s Neurohormonal Effects
•Decrease Angiotensin II.•Decrease Aldosterone. •Increase in Renin and Angiotensin I.
•Reduce Epinephrine and Norepinephrine.
•ACEI´s increase Bradikinin.
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ACEI`s or ARB`s for IHD Prevention
•Plaque Stabilization• Improvement of Endothelial Dysfunction• Improvement of Fibrinolysis• Modulation of Arterial Vasoconstriction • Blood Pressure Reduction
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ACEI´s and ARB´s Antiproliferative Effects
•Reduction of Vascular Hypertrophy.
•Reduction of Ventricular Hypertrophy.
•Reduce Extracellular Proliferation. –Reduction of Fibrosis.
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Atrial Remodeling: Mechanisms of Efficacy for ARB´s• Hemodynamic effect:
– Decreased atrial stretch– Lowering end-diastolic left ventricular pressure
• Prevention of electrical remodeling:– Direct action on ionic currents at the atrial level– Modifying the sympathetic tone
• Preventing structural remodeling– Reduction of atrial fibrosis
• Reduction of atrial dilatation and apoptosisMadrid A , Moro C. Circulation 2002;106:331–6
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Electrophysiological Effect of Irbesartan
1. Irbesartán does not modify IKr or IKs:Should not alter APD at VENTRICULAR level
2. Irbesartán blocks moderately IKur and Ito currents: it should prolong APD at ATRIAL level
200 ms
0.5
nA
Control
Irbesartan0.1 M
50 ms
1 nA
Control
Irbesartan0.1M
IKur: hKv1.5 ITo: Kv4.3
Moreno et al., J Pharmacol Exp Ther 2003;304:862
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Maintenance of Sinus Rhythm after Conversion from Persistent AF
Amiodarone + Irbesartan
Amiodarone
1.00.90.80.70.60.50.40.30.20.10.0
0 30 60 90 120 150 180 210 240 270 300 330 360 390
Follow-up (days)
2-month lower recurrence rate of atrial fibrillation
Longer time to first arrhythmia recurrence
Log Rank = 0.007
Madrid AH, Moro C et al. Circulation 2002;106:331-6.
% E
vent
-free
pat
ient
s
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Madrid AH, Moro C. PACE 2004
Prevention of Atrial Fibrillation Metaanalysis with ACEI’s ARB’s
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Irbesartan in Lone AFDose Response : 150-300 mg
Madrid AH, Moro C. JRAAS 2004; 5 :114-120
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RAS Inhibitors in Lone AF
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RAS Inhibitors in Lone AF
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RAS Inhibitors in Lone AF
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Ramipril in Lone AF• Preventing histological remodeling
such as Inflammation, myocarditis-like changes,Fibrosis and atrial dilatation.
• Preventing electrical remodeling induced by Angiotensin II.
• Reducing atrial stretch and intraatrial pressure.
• Reduction of sympathetic tone. • Reduction of blood pressure.
Belluzi et al JACC 2009;53:24
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Randomized clinical trials of RAS I in AF Primary Prevention
Trial Pat N Drug Results
CAPP2 10985 Captopril/St No Diff
STOP-2 6628 Enal-Lisi/St No Diff
LIFE 8851 Losart/Ateno 3,5 vs 5,3%
HOPE 8335 Ramip/Plac No Diff
VALUE 13760 Vals/Amlod 3,7 vs 4,3%
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Randomized clinical trials of RAS I in AF Secondary Prevention
Author/year Pat N Drug Results
Van den Bergh
18 Lisinopril/Plac Sig reduction
Madrid 154 Irb+Amio/Amio Sig Reduction
Ueng 145 Ena+Amio/Amio Sig Reduction
Tveit 137 Cande/Plac Sig reduction
Fogari 222 Losar+Amio/Amlo+Amio
Sig Reduction
Yin 177 Losar+Amio/ Peri+Amio/Amio
Sig Reduction
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APD
EEF
SR
AF
SR
AF
ACTION POTENTIAL
ANATOMICAL
Fybrosis
Hypertrophy
Inflammation
Reduced AERP
Loss of AERP adaptation to rate
Inflammation and AF
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Statins for AF
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Statins for AF
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Statins for AF
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Review of randomized clinical trials of Statins to prevent Post Thoracic Surgery AF
Author/year Design n Findings
Auer/04 Prospective 253 Sig reduction
Amar/05 Prospective 131 Sig Reduction
Marin/06 Prospective 234 Sig Reduction
Patty/06 Double blind 200 Sig Reduction
Chello/06 Doble blind 40 Sig reduction
Ozaydin/07 Prospective 362 Sig ReductionVirani/08 Retrospective 4044 No Diff
Letsburapa/08 Prospective 555 Sig Reduction
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Steroids for AF Prevention• Double blind study with 104 patients• Persistent AF. After Cardioversion. High
PCR levels. • Profafenone + 16mg-4 mg
Methylprednisolone vs Placebo. Follow-up mean 23 months.
• Recurrent AF was reduced from 50-9,6%• Permanent AF was reduced from 29-2%.• Significant reduction also of PCR levels.
•Dernellis et al Eur H J 2004; 25:1100-07
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Steroids for AF Prevention
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Clinical Trials with PUFA
• Mozaffarian/04 4815 12 years ++• Calo/05 160 days ++• Frost/05 47949 5,7 years --• Brouwer/06 5284 6,4 years --
Author/Year Publication Patients Follow up Results
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Conclusions
• ACE`s and ARB´s are equipotent tools to fight against AF in primary and secondary prevention .
• Lone AF may also be treated with them. (Not recognized yet in Guidelines).
• The RR for AF prevention with those drugs is higher in patients with high arryhthmogenic risk.
• Steroids should not be used in AF prevention due to its plural and potent adverse effects.
• Statins are useful to prevent post surgical AF.• PUFA effects for AF prevention show controversial
results.