Does Treatment with Olmesartan Improve Arterial Stenoses Due to ﬁbromuscular Dysplasia?

CORRESPONDENCE

Does treatment with olmesartan improve arterial stenoses due to ﬁbromuscular dysplasia?

Hypertension Research (2009) 32, 927–929; doi:10.1038/hr.2009.126; published online 28 August 2009

Fibromuscular dysplasia (FMD) represents a follow-up, blood pressure was normalized follow-up; this finding led to a repeat neck group of non-atherosclerotic, non-inflamma- (124/78 mm Hg), heart rate decreased from 88 ultrasound of extracranial vessels and to sub- tory arterial diseases that most commonly to 64 b.p.m. and the patient stopped smoking; sequent angiographic imaging. The patient involve renal and carotid arteries. Histological no neurological symptoms or angina abdomi- underwent carotid ultrasonography, showing classification discriminates three main sub- nis were reported. An ultrasonography of the that the stenoses observed 14 months later types (intimal, medial and perimedial), which right internal carotid artery performed before were no longer present (Figure 1b). may be associated in the same patient. treatment with olmesartan shows alternating Computed angiotomography of the Although the etiology of FMD is not well regions of lumen narrowing (stenoses) and arteries involved by FMD also showed that understood, several mechanisms have been vessel dilation several centimetres distal to the the string-of-beads pattern, the severe steno- proposed, such as genetic predisposition, carotid bifurcation (Figure 1a). sis of the celiac tripod and the moderate hormonal factors, paucity of vasa vasorum, The bilateral carotid bruits found at the stenosis of the mesenteric superior artery repeated microtrauma, inadequate hormonal initial physical examination disappeared at previously observed were no longer evident, background, a-antitrypsin deficiency and arterial wall ischemia.1 The molecular biology of FMD is unclear. Pathology seems to be characterized by smooth muscle hyperplasia, elastic fiber destruction, fibrous tissue proliferation and arterial wall disorganization. Angiographic classification includes a multi- focal type (with multiple stenoses) and the string-of-beads pattern (related to medial FMD), and tubular and focal types (which are not clearly related to specific histological lesions). No data are available in literature about the remission of arterial stenoses during treatment of FMD. As suggested by the Fibromus- cular Dysplasia Society of America, there are no treatment protocols for FMD, and management depends on which arteries are affected and on symptoms. When FMD pro- duces minimal stenotic lesions, it may be managed conservatively by antiplatelet or anticoagulant therapy as prophylaxis against complications. As described in a recent paper by our group,2 a case of FMD diagnosed in a 52-year-old hypertensive woman involving internal caro- tidarteries,celiactripodandthemesenteric superior artery was treated with acetylsalicylic acid (100 mg daily), and for arterial hypertension with olmesartan (20 mg daily) and Figure 1 Ultrasonography of right internal carotid artery (RICA) before (a) and after (b) treatment with hydrochlorothiazide 12.5 mg daily. At 14-month olmesartan. Stenoses of RICA (arrows) improved after treatment (dashed square). Correspondence 928

and the arterial wall became almost a multifactorial disease, the pathogenesis of rectilinear, particularly in the right internal which is often difficult to explain. Our patient carotid artery (Figures 2 and 3). Laboratory probably had a common case of essential tests confirmed slight normocitic anemia hypertension that arise in a young subject (hemoglobin 11.8 g per 100 ml) and hyper- with a family history and sustained-to- cholesterolemia (218 mg per 100 ml), whereas moderate sympathetic overactivity due in the antinuclear antibodies title decreased part to a smoking habit. In agreement with (from 1:140 to 1:40) and extractable this hypothesis, a slight increase in the plasma antinuclear antibodies, antineutrophil cyto- renin activity showing sympathetic overactiv- plasmic antibodies, antiphospholipid anti- ity was found at baseline (2.1 ng mlÀ1 hÀ1). bodies, rheumatoid factor, C3 and C4 com- Moreover, the 27% decrease in heart rate plement fraction and cryoglobulins remained observed after treatment with olmesartan normal. No change in coagulation status was indirectly confirms the modulation of the observed before and after the beginning of sympathetic activity through AT1-blockade. medication. Another question is that if FMD was present C-reactive protein was in the normal range at the first check, why did arterial stenoses both before (0.15 mg per 100 ml) and after improve? The pathophysiology and molecular treatment (0.11 mg per 100 ml, n.v.o0.50), biology of FMD are unknown, and this dis- supporting the opinion that FMD is a non- ease was listed by the National Organization inflammatory disease. After treatment with of Rare Diseases only last year. If FMD causes olmesartan, a slight increase in plasma renin abnormal cell development in the arterial activity (2.9 vs. 2.1 ng mlÀ1 hÀ1, n.v. 0.3–1.9) wall, it is only natural to assume that and a decrease in plasma aldosterone (212 vs. endothelium has a role in its genesis. It is 124 pg mlÀ1) were found, secondary to the well established that endothelium contributes physiological effect of angiotensin-II type I to maintain cardiovascular homeostasis, receptor (AT1) blockers on the renin–angio- mainly through the activity of endothelium- tensin–aldosterone system (RAS). derived nitric oxide (NO). However, in the These results raise important questions. presence of proatherogenic risk factors, Did our patient really have FMD? The including hypertension, diabetes mellitus, female gender and the young age of the hypercholesterolemia and tobacco smoking, patient, together with the radiological pattern the bioavailability of NO is reduced. This of lesions and their presence in other vascular condition, labeled as endothelial dysfunction, beds, hardly deny FMD. Furthermore, is characterized by vasoconstriction, platelet biochemical examinations excluded other ill- aggregation, leukocyte adhesion and smooth nesses producing non-atherosclerotic FMD- muscle cell proliferation. like stenoses, such as Ehlers–Danlos and Reduced availability of NO is mainly due Williams syndromes, or type 1 neurofibro- to an increase in reactive oxygen species matosis.1 Dyslipidemia and smoking are two production, which in turn is responsible for strong risk factors for atherosclerosis. Our NO breakdown. A large body of evidence patient was a moderate smoker (5–7 cigar- indicates that, especially under pathological ettes daily) and had mild hypercholesterole- conditions, the activity of RAS is associated mia (245 mg per 100 ml) with high high- with angiotensin II-mediated reactive oxygen Figure 2 Three-dimensional cerebral computed density lipoprotein-cholesterol values (69 mg species production, thus unbalancing angiotomography of right internal carotid artery per 100 ml), this latter a well-established pre- endothelial function and leading to progres- (RICA) before (a) and after (b) treatment with olmesartan. Dashed lines show the string-of- ventive factor for atherosclerosis. The diag- sive vascular disease.3 The action of the beads pattern that is typical of fibromuscular nostic process differentiating FMD from renin–angiotensin system is mostly linked to dysplasia. atherosclerosis comes not from risk factors the downstream effects of binding with but from imaging techniques. It is usually not AT1-receptors, and its selective blockade too difficult to differentiate between athero- restores endothelial function in patients sclerosis and FMD, as the former generally with cardiovascular risk factors. Olmesartan, that modifies the natural history of FMD, it is occurs at the origin or proximal portion of beyond its blood pressure-lowering effects, difficult as well to not attribute the modifica- the carotid artery in older subjects with has been reported to affect the redox state tions of arteries observed on imaging to classic cardiovascular risk factors, the latter of the vessel wall by restoring NO availability medical treatment. Our results are not a in the middle or distal carotid artery in young under different pathological conditions to completely new notation, as it has recently subjects with moderate cardiovascular risk exert anti-inflammatory effects and to been shown that AT1-blockers are effective factors, such as in our patient. The hyperten- increase the production of endothelial both in remodeling and in delaying the sion observed in our patient when FMD progenitor cells in diabetic subjects,4 in re-stenosis of renal arteries after angioplasty was diagnosed could be related to the high whom endothelial function is more injured in subjects with FMD.5 doses of nimesulide taken for headache, and than in hypertensives. The Fibromuscular Dysplasia Society of to the sudden cessation of smoking 4 days Although it is arduous to accept that America is working together with the Univer- before observation. Essential hypertension is AT1-blockers may have a pleyotropic effect sity of Michigan on an International Patient

Hypertension Research Correspondence 929

Alberto Mazza1, Stefano Cuppini1, Sergio Zamboni1, Laura Schiavon1, Luca Zattoni2, Andrea Viale2, Francesco Corbetti3, Roberta Ravenni4, Alberto Sacco5 and Edoardo Casiglia6 1Department of Internal Medicine, General Hospital of Rovigo, Rovigo, Italy; 2Department of Imaging, General Hospital of Rovigo, Rovigo, Italy; 3Division of Radiology, Padova, Italy; 4Department of Neuroscience, General Hospital of Rovigo, Rovigo, Italy; 5Department of Vascular Surgery, General Hospital of Rovigo, Rovigo, Italy and 6Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy E-mail: [email protected]

Figure 3 Three-dimensional computed angiotomography of abdominal vessels before (a) and after 1 Slovut DP, Olin JW. Fibromuscular dysplasia. NEnglJ (b) treatment with olmsertan. Dashed lines show severe stenosis of the celiac tripod (CLT) and Med 2004; 350: 1862–1871. moderate stenosis of the mesenteric superior artery (MSA). 2 Mazza A, Zamboni S, Cuppini S, Zattoni L, Ravenni R, Sacco A, Casiglia E. Internal carotid artery fibromuscular dysplasia in arterial hypertension: management in clinical practice. Blood Press 2008; 17: 274–277. Registry, and the National Institute of two conditions, AT1-blocker effect is not only 3 Ohtani K, Egashira K, Ihara Y, Nakano K, Funakoshi K, Zhao G, Sata M, Sunagawa K. Angiotensin II type 1 Health is conducting a research on FMD to exerted on AT1 receptors but also on the receptor blockade attenuates in-stent restenosis by inhi- individualize its biological and molecular transforming growth factor-b pathway. This biting inflammation and progenitor cells. Hypertension mechanisms. Some researchers of this society finding, first observed in an animal model, was 2006; 48: 664–670. (http://www.fmdsa.org) suggest that FMD is recently confirmed in humans. In this respect, 4 Bahlmann FH, de Groot K, Mueller O, Hertel B, Haller H, Fliser D. Stimulation of endothelial progenitor cells: a 7 probably due to an overactivity of the trans- Brooke et al. reported that AT1-blockers sig- new putative therapeutic effect of angiotensin II receptor forming growth factor-b pathway, as shown in nificantly slowed the rate of progressive aortic- antagonists. Hypertension 2005; 45: 526–529. 5 Tanemoto M, Takase K, Yamada T, Satoh A, Abe T, Ito S. other non-atherosclerotic and non-inflamma- root dilation in a small cohort of pediatric Dilation of renal artery stenosis after administration of tory arterial diseases, for example, the Marfan’s patients with Marfan’s syndrome. This effect is losartan. Hypertens Res 2007; 30: 999–1002. syndrome, a disorder caused by mutations in independent of blood pressure lowering, as no 6 Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu G, Calvi C, Podowski the gene that encodes fibrillin-1, determining difference in blood pressure values was found M, Neptune ER, Halushka MK, Bedja D, Gabrielson K, aortic aneurysm and dissection. Habashi after treatment. This suggests a potential effi- Rifkin DB, Carta L, Ramirez F, Huso DL, Dietz HC. et al.6 report that in a mouse model of cacy of AT -blockers in modifying the natural Losartan, an AT1 antagonist, prevents aortic aneurysm 1 in a mouse model of Marfan sindrome. Science 2006; Marfan’s syndrome, aortic aneurysm can be history of non-atherosclerotic arterial diseases 312: 117–121. prevented by transforming growth factor-b such as FMD. 7 Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz III HC. Angiotensin II blockade and aortic-root antagonists such as transforming growth fac- We hope that this case can help to dilation in Marfan’s syndrome. NEnglJMed2008; tor-b-neutralizing antibody or AT1-blockers stimulate further investigations with regard 358: 2787–2795. administration. Particularly, losartan-based to FMD, a disease that has been reported to 8 Brodsky SV, Ramaswamy G, Chander P, Braun A. Rup- tured cerebral aneurysm and acute coronary artery dis- treatment prevented aortic aneurysms and be the cause of sudden death in young section in the setting of multivascular fibromuscular marfanoid lesions, suggesting that in these people.8 dysplasia: a case report. Angiology 2007; 58: 764–767.

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