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<ul><ul><li>報告 : R1 林軒名醫師 </li></ul></ul><ul><ul><li>指導 : VS 林聰明醫師 VS 陳業鵬醫師 </li></ul></ul>Renin-Angiotensin system “Progress in the future”

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Renin Angiotensin System (RAS) overview Renin-angiotensin system and cardiovascular risk Lancet 2007; 369: 1208–19

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Cell surface receptors of RAS <ul><li>AT1: Angiotensin II type 1 receptor </li></ul><ul><ul><li>Angiotensin II, Angiotensin III </li></ul></ul><ul><ul><li>Vasoconstriction, stimulation of aldosterone release and sympathetic nerve activity, promotion of cell growth, matrix deposition, inflammation </li></ul></ul><ul><li>AT2: Angiotensin II type 2 receptor </li></ul><ul><ul><li>Angiotensin II </li></ul></ul><ul><ul><li>Antagonism of the effects of AT1, promotion of apoptosis, protection of neural tissue, possible synergism with AT1 in promoting inflammation </li></ul></ul>Renin-angiotensin system and cardiovascular risk Lancet 2007; 369: 1208–19

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Cell surface receptors of RAS <ul><li>AT4 Angiotensin IV receptor </li></ul><ul><ul><li>Angiotensin IV,LVV-haemorphin 7 </li></ul></ul><ul><ul><li>Vasodilatation, decreased tubular sodium transport, improved memory, possibly promoting inflammation. </li></ul></ul><ul><li>R/P-R Renin/prorenin receptor </li></ul><ul><ul><li>Renin and prorenin </li></ul></ul><ul><ul><li>Increase of angiotensin generation, further independent promotion of matrix deposition </li></ul></ul>Renin-angiotensin system and cardiovascular risk Lancet 2007; 369: 1208–19

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Cell surface receptors of RAS <ul><li>mas : mas oncogene </li></ul><ul><ul><li>Angiotensin(1-7) </li></ul></ul><ul><ul><li>Antagonism of the effects of AT1, antidiuretic, inhibits cell growth. </li></ul></ul><ul><ul><li>Not yet clear whether ornot all actions of angiotensin(1-7) are mediated by mas oncogene </li></ul></ul>Renin-angiotensin system and cardiovascular risk Lancet 2007; 369: 1208–19

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Angiotensin Receptor 1 (AT1) http://www.mpi-magdeburg.mpg.de/research/projects/1010/1014/neuron_modeling

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Nature Reviews Drug Discovery 1 ; 621-636 (2002); doi:10.1038/nrd873

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RAS and NOS Angiotensin II-nitric oxide interaction in the kidney Current Opi Nephrol Hypertens 16:61-51,2007

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RAS and sympathetic regulation

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What’s the relationship ? <ul><li>RAS and Left Ventricular Hypertrophy </li></ul><ul><li>RAS and Atrial fibrillation </li></ul><ul><li>RAS and Stroke </li></ul><ul><li>RAS and Atherosclerosis </li></ul><ul><li>RAS and type II DM </li></ul><ul><li>RAS and sympathetic regulation </li></ul><ul><li>RAS and Congestive heart failure </li></ul>

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RAS and Left Ventricular Hypertrophy

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Left ventricular hypertrophy <ul><li>High angiotensin II concentrations were closely associated with high left ventricular mass </li></ul><ul><li>Growth stimulating effects of angiotensin II via the AT1 receptor </li></ul><ul><li>left ventricular mass & Angiotensin II concentrations </li></ul>

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Reduction of left ventricular mass <ul><li>Calcium antagonists, ACE inhibitors, and ARBs reduce left ventricular mass to a greater extent than do β blockers (including vasodilatory β blockers) and diuretics. </li></ul>

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Reduction of left ventricular mass <ul><li>Losartan Intervention For Endpoint reduction in hypertension [LIFE] study: </li></ul><ul><ul><li>Reduction of left ventricular hypertrophy was greater with the ARB losartan than with the β blocker atenolol </li></ul></ul><ul><li>Reduction of left ventricular hypertrophy translates into a reduced rate of cardiovascular complications and improved prognosis . </li></ul>

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RAS and Atrial fibrillation

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Risk of Atrial fibrillation Prevention of new-onset atrial fibrillation and its predictors with angiotensin II-receptor blockers in the treatment of hypertension and heart failure Journal of Hypertension 2007, 25:15–23

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Large hypertension (HT) and heart failure (CHF) trials reporting new-onset atrial fibrillation Prevention of new-onset atrial fibrillation and its predictors with angiotensin II-receptor blockers in the treatment of hypertension and heart failure Journal of Hypertension 2007, 25:15–23

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Preventive effects of angiotensin II-receptor blockers Prevention of new-onset atrial fibrillation and its predictors with angiotensin II-receptor blockers in the treatment of hypertension and heart failure Journal of Hypertension 2007, 25:15–23

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Meta-analysis: Inhibition of renin-angiotensin system prevents new-onset atrial fibrillation Meta-analysis: Inhibition of renin-angiotensin system prevents new-onset atrial fibrillation (Am Heart J 2006;152:217222.)

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Forest plot and RR of individual trial and summary pooled estimate. Meta-analysis: Inhibition of renin-angiotensin system prevents new-onset atrial fibrillation (Am Heart J 2006;152:217222.)

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Conclusion <ul><li>The use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers had an overall effect of 18% risk reduction in new-onset AF across the trials and 43% risk reduction in patients with heart failure. </li></ul>Meta-analysis: Inhibition of renin-angiotensin system prevents new-onset atrial fibrillation (Am Heart J 2006;152:217222.)

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Possible preventive mechanisms Prevention of new-onset atrial fibrillation and its predictors with angiotensin II-receptor blockers in the treatment of hypertension and heart failure Journal of Hypertension 2007, 25:15–23

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RAS and Stroke

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Angiotensin and stoke Hypertension, Angiotensin, and Stroke: Beyond Blood Pressure ( Stroke February 2004)

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AT1 and AT2 <ul><li>AT2 receptor </li></ul><ul><ul><li>Activate nitric oxide and prostacyclin </li></ul></ul><ul><ul><li>Induced vasodilatation </li></ul></ul><ul><ul><li>Improve cerebral blood flow by collateral circulation. </li></ul></ul><ul><li>In stoke pt, AT1 receptor density remained unaltered, AT2 receptors were upregulated in neurons </li></ul><ul><li>Selective blockade of central AT2 receptors abolished the neuroprotective effect of ARBs </li></ul>

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AT4 <ul><li>Pharmacological doses of Angiotnesin IV are protective against acute cerebral ischemia by triggering an AT(4)-mediated, NO-dependent intracerebral hemodynamic mechanism. </li></ul>(Cerebroprotective effect of angiotensin IV in experimental ischemic stroke in the rat mediated by AT(4) receptors. Journal of Physiology & Pharmacology. 57(3):329-42, 2006 Sep. )

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ACEI,ARB , diuretics, Beta-Blocker in Stroke <ul><li>Perindopril Protection Against Recurrent Stroke Study: showed that the ACE inhibitor, perindopril, resulted in only a 5% stroke reduction , compared with a 43% stroke reduction if the diuretic indapamid was added to the ACE inhibitor. </li></ul><ul><li>ALLHAT study: Treatment of hypertensive patients with lisinopril resulted in a 15% higher frequency of strokes in the whole study population and a 40% higher frequency of strokes in black patients , than treatment with the diuretic chlorthalidone. </li></ul><ul><li>LIFE study : 25% reduction in strokes with ARB based regimen than the β blocker based regimen . </li></ul>

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Cumulative incidence of cerebrovascular events (secondary endpoint) in patients in the MOSES study

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Summary for stroke <ul><li>The most important factor in stroke prevention is good blood pressure control , and the control of aortic systolic blood pressure might be of particular importance. </li></ul><ul><li>The cerebroprotective effects of the AT2 receptor stimulation by ARBs need more clinical trial to determine. </li></ul>

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RAS and Atherosclerosis

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Renin-angiotensin system and atherosclerosis

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Mechanism of Atherosclerosis <ul><li>Vascular inflammation , generation of reactive oxygen species , and alterations of endothelial function </li></ul><ul><li>Renin-angiotensin system: AT1 receptors is major effecter </li></ul><ul><li>Production of pro-inflammatory cytokines: interleukin 1, tumor necrosis factor α, and interleukin 6 . </li></ul><ul><li>The concentration of circulating cytokines is associated with an adverse outcome in patients with coronary atherosclerosis. </li></ul>

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Angiotensin II and Interleukin-18 ( Circ Res . 2005;96:1064-1071.)

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<ul><li>Plaque rupture has been connected with activation of matrix metalloproteinases (MMP) in the fibrous cap of the atherosclerotic lesion and there is evidence that angiotensin II is implicated in matrix metalloproteinases activation, both through direct actions and through induction of interleukin 6. </li></ul>

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<ul><li>Angiotensin II stimulates the redox sensitive transcription factor nuclear factor kappa B (NF-κB), which could serve as a unifying signaling system for inflammatory stimuli in atherogenesis , through enhanced expression of adhesion molecules (intercellular and vascular adhesion molecules [ICAM-1 and VCAM-1], and E-selectin), monocyte chemo attractant proteins (MCP-1), and interleukin 8. </li></ul>

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Angiotensin and atheroslcerosis Hypertension, Angiotensin, and Stroke: Beyond Blood Pressure ( Stroke February 2004)

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Comparison of three large scale clinical trials examining the effect of ACE inhibition on cardiovascular events

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Renin Angiotensin system and type 2 diabetes

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<ul><li>Reduces insulin resistance </li></ul><ul><ul><li>increase skeletal muscle perfusion, improvement of microvascular changes, and increased perfusion of the pancreatic islet cell. </li></ul></ul><ul><ul><li>Direct effects of angiotensin II on the pancreatic β cells from a local renin-angiotensin system in the islet might contribute to a loss of β cell function. </li></ul></ul><ul><ul><li>fibrosis of pancreatic islets in animals with type 2 diabetes. </li></ul></ul>

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New-onset diabetes in comparative outcome trials involving the use of RAS blockade versus non-RAS blockade Why blockade of the renin–angiotensin system reduces the incidence of new-onset diabetes (Journal of Hypertension 2005, Vol 23 No 3 )

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The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication trial <ul><li>5269 patients without cardiovascular disease but with impaired fasting glucose. Ramipril did not reduce the development of diabetes (primary endpoint) compared with placebo within the first 3 years. </li></ul>

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Risk of developing type 2 diabetes with ACE inhibitors or ARBs compared with other antihypertensive treatment

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Change of albuminuria predicts occurrence of cardiovascular events and heart failure in patients with overt diabetic nephropathy Reproduced with permission from de Zeeuw D et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 2004; 110: 921–27.143

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Ｔ hanks for your attention

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Exocytose by Angiotensin II Involves Multiple G-Protein-Regulated Transduction Pathways in Chromaffin Cells The Journal of Neuroscience, July 1, 2000, 20 (13):4776–4785