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ACE inhibitor ajuda a reverter a degeneração da aorta
ACE inhibitor thelps reverse aortic degeneration in Marfan syndrome
Oct 2, 2007
O losartan é um dos muitos BRAs (antagonistas dos receptores de angiotensina) enquanto o perindopril é um dos muitos IECAs (inibidores da enzima conversora da angiotensina), que inibe a transformação da angiotensina 1 em angiotensina 2. Como você pode imaginar os dois agem uma mesma via, mas em pontos diferentes dela, causando efeitos discretamente diferentes, mas eventualmente importantes. Entre outras coisas eles interferem no remodelamento cardiovascular e no depósito de colágeno.
Melbourne, Australia - Patients with Marfan syndrome who took perindopril on top of standard beta blocker therapy showed significant improvements in aortic stiffness and aortic-root diameter over six months, compared with a control group that didn't receive the ACE inhibitor, in a small randomized study [ 1 ].
The drug appears to work in Marfan's by attenuating the arterial pathology behind the genetic disorder's major life-threatening complications, aortic-root dilatation and aortic dissection and rupture, according to the authors, Dr Anna A Ahimastos (Baker Heart Research Institute, Melbourne, Australia) and colleagues. In contrast, beta blockers help indirectly by reducing aortic-root pressures and other hemodynamic effects.
"These are very remarkable findings," coauthor Dr Bronwyn A Kingwell (Baker Heart Research Institute) told heart wire. "There were substantial changes in aortic diameter, over a relatively short intervention period, that were highly significant." The study, although it randomized only 17 patients, was "carefully placebo-controlled, and treatment was double-blinded," she said. "So I'm confident about the results but would like to see them substantiated in a larger trial."
As reported in the October 3, 2007 issue of the Journal of the American Medical Association, 10 patients received perindopril, escalated from 2 mg/day to 8 mg/day over the first three weeks of the 24-week study; the remaining seven patients received placebo. All patients were adults without a history of aortic surgery. The two groups didn't differ significantly at baseline with respect to body dimensions, CV risk factors, prevalence and type of cardiac valve dysfunction, or type and dosage of background beta-blocker therapy.
Arterial stiffness as assessed by carotid tonometry, Doppler velocimetry, and pulse-wave velocity readings was significantly reduced in the perindopril group as compared with controls, with p values ranging from < 0.001 to <0.01.
The active-therapy group also benefited with reductions in aortic-root diameter at both end-systole and end-diastole, also with p values ranging from < 0.001 to <<0.01.
Arterial blood pressure dropped slightly but significantly in the perindopril group; improvements in arterial stiffness and aortic diameter were independent of arterial pressure.
Effects on underlying biochemistry
Perindopril's effects likely derive from attenuation of angiotensin-2-receptor signaling, the authors write, as well as reductions in matrix metalloproteinase (MMP) levels and declines in transforming growth factor beta (TGF- ), a cytokine.
Patients who received the ACE inhibitor showed significantly reduced levels of TGF- (p<0.02) and of MMP-2 and MMP-3 (p< 0.001 for both) compared with placebo at 24 weeks.
Marfan syndrome is caused by a mutation in FBN1, the gene encoded for fibrillin 1, a component of extracellular matrix elastic fibers that controls TGF- and MMP activity, the authors note.
Other potential treatment options
In April 2006, heartwire reported that the angiotensin-receptor blocker (ARB) losartan, on its own, was being compared with atenolol in an ongoing randomized trial of "up to 1000" Marfan's patients. Led by coprincipal investigators Dr Harry C Dietz (Johns Hopkins University School of Medicine) and Dr Ron Lacro (Boston Children's Hospital, MA), the projected three-year study follows evidence from mice suggesting that the ARB improves aortic wall thickness, aortic-root size, and elastic-fiber architecture.
But there are theoretical reasons why ACE inhibitors might work better in Marfan's than ARBs alone, according to Kingwell. The key defects in arterial structure are mediated through both angiotensin-2 type-1 (AT 1) and angiotensin-2 type-2 receptor pathways, both of which are downregulated by ACE inhibition; ARBs directly inhibit only the AT1 receptor.
Kingwell said perindopril's benefits observed in the study probably represent a class effect. "I don't think there's any reason to believe that perindopril is extra special. Perindopril is known to reduce arterial stiffness, but then a lot of other ACE inhibitors are, too."
Servier Laboratories supplied perindopril and matching placebo for this study, which was otherwise funded by the National Health and Medical Research Council of Australia.
1. Ahimastos AA, Anuradha Aggarwal A, D'Orsa KM, et al. Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: A randomized controlled trial. JAMA 2007; 298:1539-1547.