MD PhD FESC Angela H E M Maas
email: angela.maas@radboudumc.nl

MSc Nabila Bouatia-Naji

MD PhD Alexandre Persu

MD David Adlam

Spontaneous coronary artery dissections and fibromuscular dysplasia: current insights on pathophysiology, sex and gender

Keywords: arteriopathy, fibromuscular dysplasia, gender, spontaneous coronary artery dissections, women

come

Introduction

An acute coronary syndrome (ACS) caused by a spontaneous coronary artery dissection (SCAD) is less rare than previously considered and occurs 9 times more often in women than in men [START_REF] Adlam | European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection[END_REF]. A SCAD is defined as an acute development of a false lumen within the arterial wall, either caused by an intimal tear or an acute bleeding within the tunica media of the coronary artery wall. This leads to a compression of the true lumen, resulting in the clinical features of an ACS. In most cases women between 35-65 years are affected, with a peak around 53 years of age [START_REF] Tweet | Spontaneous coronary artery dissection: revascularization versus conservative therapy[END_REF][START_REF] Saw | Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes[END_REF][START_REF] Alfonso | Spontaneous coronary artery dissection: long-term follow-up of a large series of patients prospectively managed with a "conservative" therapeutic strategy[END_REF]. It is estimated that up to 25% of all ACS within this age-group are caused by SCAD. Fewer than 10% of all SCADs appear in (late) pregnancy or after delivery (P-SCAD). In clinical practice, a SCAD is diagnosed by acute chest pain, (N)STEMI changes on the ECG, elevation of Troponins and characteristics at coronary angiography. The number of SCADs is still underestimated, as the angiographic features may be mistakenly for atherosclerosis [START_REF] Saw | Coronary angiogram classification of spontaneous coronary artery dissection[END_REF]. Three major types of angiographic characteristics can be identified: type I with a double lumen, type II with a long and smooth stenosis and type III with an atherogeneous-like aspect. In addition, increased coronary tortuosity is often present. In case of uncertainty intracoronary imaging with OCT/IVUS can be done to establish the correct diagnosis. In almost 60% of cases the LAD is affected, followed by the RCA (26%) and RCX (19%) [START_REF] Giacoppo | Spontaneous coronary artery dissection[END_REF]. Although hypertension is present in one third of SCAD patients, other traditional cardiovascular disease (CVD) risk factors are less often reported than in traditional ACS [START_REF] Adlam | European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection[END_REF]. Predisposing factors for the heterogeneous population of SCAD patients are female sex, pregnancy-related factors and hereditary mixed connective tissue disorders, whereas there are possibly associations with hormonal therapy, fibromuscular dysplasia (FMD) and inflammatory disorders. Emotional or physical triggers may act as precipitating stressors [START_REF] Saw | Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes[END_REF]. Gender differences in the pathophysiological impact of stress may be one of the reasons why an ACS caused by SCAD is so disproportionately predominant in women [START_REF] Saw | Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes[END_REF][START_REF] Nakashima | Prognostic impact of spontaneous coronary artery dissection in young female patients with acute myocardial infarction: A report from the Angina Pectoris-Myocardial Infarction Multicenter Investigators in Japan[END_REF][START_REF] Fahmy | Pre-Disposing and Precipitating Factors in Men With Spontaneous Coronary Artery Dissection[END_REF]. Fibromuscular dysplasia is the most commonly observed arteriopathy associated with SCAD.

Patient series report a wide range in prevalence of FMD, varying between 17-86% [START_REF] Hayes | Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association[END_REF]. As many SCAD patients are not routinely examined for FMD, more precise estimates are lacking. Like SCAD, FMD also has a strong female predominance (>80%) and it affects the renal and carotid arteries in about 75% of patients [START_REF] Persu | European consensus on the diagnosis and management of fibromuscular dysplasia[END_REF][START_REF] Olin | The United States Registry for Fibromuscular Dysplasia: results in the first 447 patients[END_REF]. Fibromuscular dysplasia can manifest as vascular stenosis, aneurysm, dissection, occlusion or arterial tortuosity. Preliminary data from the US registry suggest that women may have more frequently carotid FMD lesions than men (74.9 vs. 44.1%, p=0.0004). On the contrary, renal FMD might be even more frequent in men than in women (89.7 vs. 74.1%, p=0.032) [START_REF] Kim | Clinical manifestations of fibromuscular dysplasia vary by patient sex: a report of the United States registry for fibromuscular dysplasia[END_REF]. Up to now the strong female predominance in SCAD and FMD patients suggest that sex-and gender related factors are important in both entities and possibly also in their mutual relationship. In this paper we aim to focus on common aspects of SCAD and FMD.

Role of sex steroids and TGF-beta in arterial malformations

Both estrogens and androgens are involved in the development of CVD and hypertension. Estrogens have complex but important regulating effects on vascular reactivity, blood pressure, endothelial relaxation and cardiac/vascular remodeling through genomic and non-genomic effects [START_REF] Mendelsohn | Molecular and cellular basis of cardiovascular gender differences[END_REF][START_REF] Miller | Vascular actions of estrogens: functional implications[END_REF][START_REF] Menazza | The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System[END_REF]. Rapid actions of estrogens include the ability to stimulate endothelial NO synthase (eNOS) in vascular endothelial cells and the inhibition of proliferation of smooth muscle cells (SMC). Estrogens also modulate angiogenic factors, such as matrix metallo-proteinases (MMPs) and tissue growth factor-β (TGF-β). Elevated levels of TGF-β have been found in patients with the Marfan syndrome and in patients with FMD [START_REF] Chung | Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in the thoracic aortic aneurysm in Marfan syndrome[END_REF][START_REF] Ganesh | Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-beta expression and connective tissue features[END_REF]. Estrogen decreases deposition of collagen and increases deposition of elastin, whereas testosterone has an opposite effect [START_REF] Natoli | Sex steroids modulate human aortic smooth muscle cell matrix protein deposition and matrix metalloproteinase expression[END_REF]. This is mediated by the expression of important MMPs including collagen, elastin, and fibrillin-1 and their regulators. In contrast, progesterone attenuates the increase in elastin deposition observed with 17 β-estradiol alone. A possibly consequence is that high cyclic progesterone levels in premenopausal women may attenuate the beneficial effects of 17 β estradiol on the elastin/collagen ratio of the vascular wall.

Cyclic symptoms in women before/after SCAD have been reported [START_REF] Al-Hussaini | Spontaneous coronary artery dissection[END_REF]. After menopause low 17 β estradiol levels enhance vascular stiffness and lower arterial compliance, resulting in more stiffened arteries and higher pulse pressure in elderly women than in age-matched males [START_REF] Regnault | Sex difference in cardiovascular risk: role of pulse pressure amplification[END_REF][START_REF] Ogola | New Insights into Arterial Stiffening: Does Sex Matter?[END_REF]. Modulation of sex steroid levels with ageing are therefore likely to interact with important sex differences in arterial stiffness across the lifespan. While a small study performed in a limited number of samples suggests that progesterone receptors are expressed in the nuclei of vascular smooth muscle cells of renal arteries from patients with FMD (n=6) but not from controls (n=3) [START_REF] Silhol | Intranuclear expression of progesterone receptors in smooth muscle cells of renovascular fibromuscular dysplasia: a pilot study[END_REF] , the role of sex hormones including progesterone in the pathophysiology of arterial changes in FMD needs to be further explored. TGF-β enhances the production of collagen and the remodeling of the extracellular matrix [START_REF] Dietz | Curt Stern Award Address. Marfan syndrome: from molecules to medicines[END_REF]. Overproduction of TGF-β in Marfan patients reduces connective tissue elasticity and leads to weakness of the vascular wall. Aortic manifestations of the disease occur predominantly in male patients [START_REF] Villard | Abdominal aortic aneurysm: Sex differences[END_REF]. Arterial tortuosity in the coronary arteries is often present in SCAD patients (figure 1) and is a major though insufficiently studied vascular phenotype of FMD [START_REF] Eleid | Coronary artery tortuosity in spontaneous coronary artery dissection: angiographic characteristics and clinical implications[END_REF]. Increased TGF-β activity has been postulated to affect the degree of arterial tortuosity [START_REF] Franken | Increased aortic tortuosity indicates a more severe aortic phenotype in adults with Marfan syndrome[END_REF] . Accordingly, genetic syndromes in which arterial tortuosity is at the forefront, such as the Loeys Dietz syndrome and the rare Aneurysms Osteoarthritis Syndrome, are due to mutations in genes involved in the TGF-beta pathway (TGFBR1/TGFBR2 and SMAD3, respectively) [START_REF] Loeys | A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2[END_REF][START_REF] Van De Laar | Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis[END_REF]. Hypertension is in part regulated by steroid sex hormones and probably plays an important role in the pathophysiology of arterial tortuosity [START_REF] Li | Impact of coronary tortuosity on coronary pressure: numerical simulation study[END_REF].

SCAD in pregnancy

Although SCAD was once considered primarily a peripartum condition, it is now clear from large multinational registry studies that pregnancy-associated SCAD (P-SCAD) accounts for a minority (≤10%) of women with SCAD [START_REF] Tweet | Spontaneous coronary artery dissection: revascularization versus conservative therapy[END_REF][START_REF] Saw | Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes[END_REF][START_REF] Nakashima | Prognostic impact of spontaneous coronary artery dissection in young female patients with acute myocardial infarction: A report from the Angina Pectoris-Myocardial Infarction Multicenter Investigators in Japan[END_REF][START_REF] Tweet | Clinical features, management, and prognosis of spontaneous coronary artery dissection[END_REF][START_REF] Lettieri | Management and Long-Term Prognosis of Spontaneous Coronary Artery Dissection[END_REF][START_REF] Rogowski | Spontaneous Coronary Artery Dissection: Angiographic Follow-Up and Long-Term Clinical Outcome in a Predominantly Medically Treated Population[END_REF]. However SCAD accounts for around a quarter of ACS occurring during pregnancy and half of ACS in post partum patients [START_REF] Elkayam | Pregnancy-associated acute myocardial infarction: a review of contemporary experience in 150 cases between 2006 and 2011[END_REF][START_REF] Bush | Myocardial infarction in pregnancy and postpartum in the UK[END_REF]. Most P-SCAD events occur in a period from the third trimester of pregnancy peaking in the early (up to 6-months) post partum period but cases have been reported throughout gestation and late (up to 2-years) post partum, including in association with breast feeding (or the recent cessation of breast feeding) [START_REF] Adlam | European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection[END_REF][START_REF] Hayes | Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association[END_REF][START_REF] Havakuk | Pregnancy and the Risk of Spontaneous Coronary Artery Dissection: An Analysis of 120 Contemporary Cases[END_REF]. At present it is unclear if these very early or very late events represent true P-SCAD or are due to sporadic SCAD recurrence occurring by coincidence at these times. The true at-risk period for P-SCAD therefore remains ill-defined. Despite a hypothetical mechanistic association with increased coronary sheer stress, delivery per se does not appear to be a prime driver of P-SCAD events [START_REF] Havakuk | Pregnancy and the Risk of Spontaneous Coronary Artery Dissection: An Analysis of 120 Contemporary Cases[END_REF]. The very high progesterone-levels during pregnancy and the rapid hormonal changes thereafter may be an important reason why SCADs occur more often during or shortly after pregnancy.

Acute management of P-SCAD presents a unique series of challenges and requires a careful multidisciplinary approach with close monitoring of mother and fetus. [START_REF] Codsi | Spontaneous Coronary Artery Dissection in Pregnancy: What Every Obstetrician Should Know[END_REF] There is growing evidence that P-SCAD patients present with a more extreme SCAD phenotype characterized by more proximal coronary involvement and a higher proportion of ST-elevation myocardial infarction (STEMI), cardiogenic shock, arrhythmia (including as a cause of maternal death) and a reduction in post infarct ejection fraction [START_REF] Havakuk | Pregnancy and the Risk of Spontaneous Coronary Artery Dissection: An Analysis of 120 Contemporary Cases[END_REF][START_REF] Cade | Pregnancy-associated spontaneous coronary artery dissection: insights from a case series of 13 patients[END_REF][START_REF] Tweet | Spontaneous Coronary Artery Dissection Associated With Pregnancy[END_REF]. The suggested approach to coronary management in P-SCAD is based on expert consensus. [START_REF] Adlam | European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection[END_REF][START_REF] Hayes | Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association[END_REF][START_REF] Codsi | Spontaneous Coronary Artery Dissection in Pregnancy: What Every Obstetrician Should Know[END_REF] The benefits of an accurate angiographic diagnosis and risk stratification outweigh the fetal X-ray exposure , which is manageable with contemporary techniques. [START_REF] Codsi | Spontaneous Coronary Artery Dissection in Pregnancy: What Every Obstetrician Should Know[END_REF] In line with general recommendations in patients with SCAD, a conservative approach to revascularization is favored, reserving percutaneous coronary intervention (PCI) for cases with poor or absent coronary flow, ongoing evidence of significant ischaemia or infarction and a large myocardial area in jeopardy. [START_REF] Adlam | European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection[END_REF][START_REF] Hayes | Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association[END_REF][START_REF] Codsi | Spontaneous Coronary Artery Dissection in Pregnancy: What Every Obstetrician Should Know[END_REF][START_REF] Regitz-Zagrosek | ESC Guidelines for the management of cardiovascular diseases during pregnancy[END_REF] Coronary bypass surgery may be a useful bail-out in extremely high risk scenarios such as unstable proximal dissections or a failure of PCI to restore flow to a large myocardial territory but increased late graft failure following healing of the native coronary circulation has been reported. [START_REF] Tweet | Spontaneous coronary artery dissection: revascularization versus conservative therapy[END_REF] Timing and mode of delivery should be an individualized multi-disciplinary decision [START_REF] Regitz-Zagrosek | ESC Guidelines for the management of cardiovascular diseases during pregnancy[END_REF]. Time interval since SCAD, left ventricular function, use of antiplatelet therapy and presence of a known connective tissue disorders or aortopathy will impact on this decision. Operative delivery is not mandatory in all cases and consideration of supported vaginal delivery with measures to minimize cardiac demand has been advocated. [START_REF] Codsi | Spontaneous Coronary Artery Dissection in Pregnancy: What Every Obstetrician Should Know[END_REF] There is currently very limited data on the risk of pregnancy in survivors of SCAD. Recurrence is well recognized in SCAD and is a potential additional concern over and above the issues of teratogenicity, the impact of left ventricular impairment and the risk of stent thrombosis on pregnancy risk. [START_REF] Hayes | Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association[END_REF][START_REF] Codsi | Spontaneous Coronary Artery Dissection in Pregnancy: What Every Obstetrician Should Know[END_REF][START_REF] Adlam | Management of spontaneous coronary artery dissection in the primary percutaneous coronary intervention era[END_REF] A single series of nine pregnancies in survivors of SCAD reported a single recurrent SCAD occurring 9 weeks post partum. [START_REF] Tweet | Pregnancy after spontaneous coronary artery dissection: a case series[END_REF] It is not currently clear to what extent pregnancy per se constitutes an additional risk over and above the background recurrence risk in SCAD. However, patients should avoid unplanned pregnancy and those contemplating planned pregnancy should be carefully counseled [START_REF] Regitz-Zagrosek | ESC Guidelines for the management of cardiovascular diseases during pregnancy[END_REF].

The risks of pregnancy in patients with FMD are less well studied. However, several elements should be kept in mind. First, patients with FMD may harbour aneurysms of renal or visceral arteries, with a potentially increased risk of rupture during pregnancy [START_REF] La Chapelle | Maternal mortality attributable to vascular dissection and rupture in the Netherlands: a nationwide confidential enquiry[END_REF][START_REF] Hellmund | Rupture of renal artery aneurysm during late pregnancy: clinical features and diagnosis[END_REF]. Second, a retrospective study by Vance et al. suggests a substantially increased risk of preeclampsia in women with FMD [START_REF] Vance | Increased prevalence of preeclampsia among women undergoing procedural intervention for renal artery fibromuscular dysplasia[END_REF].

Finally, in some instances, hypertension due to renal artery FMD may become refractory during pregnancy [START_REF] Berra | Management of a Pregnant Woman With Fibromuscular Dysplasia[END_REF]. Accordingly, screening for renal artery FMD using sensitive methods such as CT-or MR-angiography is worth considering in all hypertensive women planning a pregnancy. In case of FMD lesions of renal arteries requiring revascularization, percutaneous angioplasty should be performed before pregnancy, and a comprehensive vascular screening (from brain to iliac arteries) should be foreseen, in order to rule out the existence of aneurysms or dissections of other arterial beds. Finally, patients with known FMD who decide to become pregnant should be followed in a high volume obstetrical centre with expertise in at-risk pregnancies [START_REF] Regitz-Zagrosek | ESC Guidelines for the management of cardiovascular diseases during pregnancy[END_REF], in tight collaboration with a specialist in vascular medicine or FMD expert.

Risk factors and precipitators for SCAD

A large number of conditions have been described in case reports or small case series in patients with SCAD. [START_REF] Adlam | European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection[END_REF][START_REF] Hayes | Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association[END_REF] However, many of these are probably simply co-incident conditions rather than true risk factors. It is now well-recognized that SCAD is not confined to women of child-bearing potential but that its incidence extends well into the post-menopausal years. [START_REF] Adlam | European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection[END_REF][START_REF] Hayes | Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association[END_REF] Furthermore, although exogenous sex hormones (i.e. hormonal contraception and hormone replacement therapy) are frequently considered a risk, [START_REF] Saw | Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes[END_REF][START_REF] Tweet | Clinical features, management, and prognosis of spontaneous coronary artery dissection[END_REF][START_REF] Azam | Spontaneous coronary artery dissection associated with oral contraceptive use[END_REF][START_REF] Pan | Spontaneous Coronary Artery Dissection following Topical Hormone Replacement Therapy[END_REF][START_REF] Zehir | Myocardial infarction and spontaneous dissection of coronary artery due to oral contraceptive[END_REF] given the highly prevalent population use of these drugs, an association with either SCAD or SCAD recurrence has yet to be clearly established and the relative risk or benefit of specific hormone treatment strategies is unknown.

The precise relationship between exercise and SCAD is also complex. It is clear that extreme (and particularly isometric) exercise can rarely trigger SCAD, [START_REF] Balakrishnan | A confluence of circumstances: A case of IVF, extreme exercise and spontaneous coronary artery dissection[END_REF][START_REF] El-Sherief | Spontaneous coronary artery dissection after intense weightlifting UCSF Fresno Department of Cardiology[END_REF][START_REF] Ellis | Spontaneous coronary artery dissection in a young woman resulting from an intense gymnasium "work-out[END_REF][START_REF] Choi | Spontaneous multivessel coronary artery dissection in a longdistance runner successfully treated with oral antiplatelet therapy[END_REF][START_REF] Aghasadeghi | Spontaneous coronary artery dissection in a professional body builder[END_REF] with an association reportedly more frequent in men. [START_REF] Fahmy | Pre-Disposing and Precipitating Factors in Men With Spontaneous Coronary Artery Dissection[END_REF] There also seem to be a subset of SCAD patients who exercise to a high (if not elite) level. In these patients the temporal association between specific exercise episodes and the onset of SCAD-related symptoms does not suggest that exercise is acting as a trigger. [START_REF] Adlam | Management of spontaneous coronary artery dissection in the primary percutaneous coronary intervention era[END_REF] There is no evidence that exercise is a precipitating factor for SCAD recurrence and whilst avoidance of extreme exercise seems sensible, cardiac rehabilitation is reportedly beneficial. [START_REF] Chou | The First Dedicated Cardiac Rehabilitation Program for Patients With Spontaneous Coronary Artery Dissection: Description and Initial Results[END_REF][START_REF] Krittanawong | Usefulness of Cardiac Rehabilitation After Spontaneous Coronary Artery Dissection[END_REF] It is increasingly recognized that SCAD is one of a series of partially overlapping disorders. These include hereditary connective tissue disorders (CTD), FMD, cervical and intracerebral dissection, migraine and pre-eclampsia (Figure 2). [START_REF] Adlam | European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection[END_REF][START_REF] Hayes | Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association[END_REF] These associations maybe partly genetic (see below) but the precise mechanisms explaining the interrelationship between these conditions remain to be elucidated. In some series the occurrence of SCAD has been associated with (systemic) inflammatory disorders and autoimmune diseases, but this has not been reported by others [START_REF] Saw | Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes[END_REF][START_REF] Alfonso | Spontaneous coronary artery dissection: long-term follow-up of a large series of patients prospectively managed with a "conservative" therapeutic strategy[END_REF].

Thus far, inflammation has not been found to be associated with FMD [START_REF] Persu | European consensus on the diagnosis and management of fibromuscular dysplasia[END_REF].

Psychosocial stress-related factors and SCAD

Severe emotional distress is a potential trigger for an ACS in both women and men, but coping with stress is importantly different among both genders [START_REF] Saw | Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes[END_REF][START_REF] Edmondson | Emotional triggers in myocardial infarction: do they matter?[END_REF][START_REF] Faravelli | Gender differences in depression and anxiety: the role of age[END_REF]]. Psychosocial stress is often reported by SCAD patients in the months/weeks before the acute event. This may act as a 'trigger' for SCAD.

One working hypothesis in SCAD patients is that (prolonged) emotional distress leads to endothelial dysfunction and low-thresholds for vascular spasm. These pathophysiological processes may create a substrate that increases the vulnerability for a sudden intimal tear in the vessel wall that is triggered by physical and emotional stressors, resulting in a SCAD. As a SCAD usually occurs in previously 'healthy' young women, the impact of such an event is huge. The use of antidepressants/anxiolytic agents has been reported in more than 30% of patients after SCAD [START_REF] Liang | Prevalence and predictors of depression and anxiety among survivors of myocardial infarction due to spontaneous coronary artery dissection[END_REF]. Mental stress-induced ischemia occurs twice as often in women after ACS than in men [START_REF] Vaccarino | Mental Stress-Induced-Myocardial Ischemia in Young Patients With Recent Myocardial Infarction: Sex Differences and Mechanisms[END_REF]. This may account for the relative high percentage (>50%) of reported residual symptoms in predominant women after SCAD [START_REF] Tweet | Insights Into Spontaneous Coronary Artery Dissection: Can Recurrence Be Prevented?[END_REF]. Patients with FMD also report an array of psychological symptoms and concerns [START_REF] Bumpus | Diagnosed and living with fibromuscular dysplasia: A qualitative inquiry[END_REF]. Whether the latter are secondary to the announcement of the disease, severity of complications and related anxiety or, at least in some patients, may be part of the disease spectrum is the object of current investigations.

Genetic aspects of SCAD and FMD

There is evidence for a genetic component for SCAD and FMD but the identification of the genetic causes has been a challenging task. Familial recurrence was investigated in a series of ~100 FMD patients and their hypertensive relatives and concluded to the presence of familial FMD in ~11% of cases, with no evidence for a more severe presentation among familial versus sporadic cases [START_REF] Perdu | Inheritance of arterial lesions in renal fibromuscular dysplasia[END_REF].

However, such familial cases may be overrepresented in a highly specialized FMD center. By contrast, in registries, familial FMD was reported in only 2.8-2.9% of symptomatic cases, though admittedly systematic screening of asymptomatic family members may have led to a higher prevalence [START_REF] Plouin | High Prevalence of Multiple Arterial Bed Lesions in Patients With Fibromuscular Dysplasia: The ARCADIA Registry (Assessment of Renal and Cervical Artery Dysplasia)[END_REF][START_REF] Monaco | Genomics of Fibromuscular Dysplasia[END_REF].

Familial cases of SCAD were reported to be rare (<2%) in series of over 400 patients and were limited to siblings or mother-daughter pairs [START_REF] Goel | Familial spontaneous coronary artery dissection: evidence for genetic susceptibility[END_REF]. SCAD and FMD were considered for long time rare vascular diseases and their clinical overlap with some rare CTD suggested that a similar genetic model might apply to their mode of inheritance. Features of CTD appear to be more frequent in patients with FMD, though data on the prevalence of such systemic manifestations are conflicting [START_REF] Ganesh | Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-beta expression and connective tissue features[END_REF]. Notably however, such patients generally do not harbour mutations in genes causative for vascular and connective tissue Mendelian disorders (e.g Marfan, Loeyz-Dietz, vascular Ehlers Danlos syndromes among others) [START_REF] Chung | Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in the thoracic aortic aneurysm in Marfan syndrome[END_REF]. This finding further supports a previous investigation that showed low yield of genetic testing in patients with FMD for most of known vascular and connective tissue genes [START_REF] Poloskey | Low yield of genetic testing for known vascular connective tissue disorders in patients with fibromuscular dysplasia[END_REF].

More recently, among 44 SCAD patients who underwent cardiovascular genetics testing in a prospective setting, 6 patients (~8%) had an identifiable genetic cause, with 3 patients carrying mutation in COL3A1, the causative gene for vEDS [START_REF] Kaadan | Prospective Cardiovascular Genetics Evaluation in Spontaneous Coronary Artery Dissection[END_REF]. Overall, SCAD and FMD patients only exceptionally carry mutations for known genes of inherited vascular diseases and CTD. This motivates and encourages specific genetic investigation to understand the etiology of FMD and SCAD. The investigation of the exomes of 16 FMD related patients showed genetic heterogeneity and made unlikely the existence of a major gene for FMD, although this study was underpowered and largescale exome studies are still missing [START_REF] Kiando | Exome sequencing in seven families and gene-based association studies indicate genetic heterogeneity and suggest possible candidates for fibromuscular dysplasia[END_REF]. A recent study identified the genetic cause of the Grange Syndrome, a rare autosomal-recessive disorder characterized by severe and early onset vascular abnormalities, comparable to focal FMD [START_REF] Guo | Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease[END_REF]. In this study, the author reported mutations in YY1P1 encoding a protein involved in transcription regulation, DNA repair and replication and provided evidence for this gene to be important for the proliferation and TGF-beta mediated differentiation of vascular smooth muscle cells [START_REF] Guo | Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease[END_REF]. Given the rarity of this syndrome, only 1 frameshift mutation was found in YY1P1 in non syndromic FMD and this gene is thus unlikely to be at the origin of common forms of FMD [START_REF] Guo | Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease[END_REF]. On the other hand, increasing epidemiological evidence supports FMD and SCAD to be neglected rather than rare and alternative strategies to genetic testing or exome studies to decipher their genetic causes proved to be informative. The study of 26,000 common genetic variants in ~250 FMD patients and followed up in >900 patients and ~2,500 controls supported the association with FMD of PHACTR1/EDN1 [START_REF] Kiando | PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance[END_REF], a genetic locus on chromosome 6q24 reported to confer risk for Coronary Artery Disease and Acute Myocardial Infarction, but in an opposite directional effect of the risk allele compared to FMD [START_REF] Genetics | Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants[END_REF][START_REF] Nikpay | A comprehensive 1,000 Genomes-based genome-wide association metaanalysis of coronary artery disease[END_REF]. PHACTR1/EDN1 risk allele for FMD is also associated with migraine [START_REF] Anttila | Genome-wide meta-analysis identifies new susceptibility loci for migraine[END_REF] and cervical artery dissection [START_REF] Debette | Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection[END_REF], supporting shared genetic control between these cardiovascular and neurovascular diseases (figure 2). The putative causal genetic variant at the PHACTR1 locus has recently reported to lie in a putative enhancer for EDN1, the endothelin-1 gene [START_REF] Gupta | A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression[END_REF]. However, this locus only contributes to a ~40% increased risk for FMD and the mechanism that may link a decrease in endothelin-1 circulating levels with an increased risk for FMD is still to be determined. These genetic findings suggest that FMD and likely SCAD, are under the control of numerous genetic variants, with weak to moderate individual effects. We expect that genetic studies, including well-powered full exome and genome-wide association studies will shed light on the full picture of the genetic makeup of FMD and SCAD patients, and potentially enhance our scarce knowledge about the underlying biology of these atypical and women-specific vascular diseases.

Connective tissue diseases (CTD) in FMD and SCAD : similarities and differences

Several arguments suggest the existence of an overlap between FMD and CTDs: (i) FMD is associated with a wide spectrum of vascular abnormalities, including aneurysms, dissections and arterial tortuosity [START_REF] Persu | European consensus on the diagnosis and management of fibromuscular dysplasia[END_REF][START_REF] Olin | Expanding Clinical Phenotype of Fibromuscular Dysplasia[END_REF], which are also part of the phenotype of inherited CTDs such as vascular Ehlers-Danlos [START_REF] Byers | Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome[END_REF] and Loeys-Dietz syndrome [START_REF] Loeys | A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2[END_REF]; (ii) both FMD and less often CTD can be associated with SCAD [START_REF] Adlam | European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection[END_REF][START_REF] Fahmy | Pre-Disposing and Precipitating Factors in Men With Spontaneous Coronary Artery Dissection[END_REF]; (iii) FMD is a systemic vascular disease, with two or more vascular beds involved in over 50% of cases [START_REF] Plouin | High Prevalence of Multiple Arterial Bed Lesions in Patients With Fibromuscular Dysplasia: The ARCADIA Registry (Assessment of Renal and Cervical Artery Dysplasia)[END_REF] and (iv) cases of patients with Ehlers-Danlos type IV or Marfan syndrome coexisting with FMD-like abnormalities [START_REF] Poloskey | Low yield of genetic testing for known vascular connective tissue disorders in patients with fibromuscular dysplasia[END_REF], or FMD patients with features suggestive of CTD have been occasionally reported [START_REF] O'connor | Systemic connective tissue features in women with fibromuscular dysplasia[END_REF][START_REF] Dejardin | Severe hypoplasia of the abdominal aorta and its branches in a patient and his daughter[END_REF].

Screening for systemic features suggestive of CTD in patients with FMD (mostly females with multifocal FMD) was performed in two cohorts, both from the United States. In 47 FMD patients explored at the National Institute on Ageing (NIA, Baltimore) 4 or more features suggestive of mild CTD were documented in 95.7% of patients, including hyperlaxity (Beighton score ≥ 5 in 57.4% of patients), early onset degenerative spine disease (95.7%), pectus deformity (40.4%) and various craniofacial abnormalities [START_REF] Ganesh | Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-beta expression and connective tissue features[END_REF][START_REF] Beighton | Articular mobility in an African population[END_REF]. In contrast, in a cohort of 139 patients followed at the Cleveland Clinic [START_REF] O'connor | Systemic connective tissue features in women with fibromuscular dysplasia[END_REF], only 18.7% of patients harboured ≥ 4 features suggestive of CTD, hyperlaxity (Beighton score ≥ 5) was rare (2.9%), pectus deformities were present in only 7.2% of patients, and other classical CTD features such as hypertelorism or cleft palate were not or seldom observed. Still, compared to historical control populations, several characteristics were more often encountered.

Besides pectus deformities, the latter include palatal abnormalities (56.1%), dental crowding (29.7%), moderately severe myopia (29.1%), and early onset arthritis (15.6%). Furthermore, in the same cohort [START_REF] O'connor | Systemic connective tissue features in women with fibromuscular dysplasia[END_REF], several CTD features such as high palate, pneumothorax and atrophic scarring tended to be more frequent in patients harbouring at least one arterial dissection or two aneurysms ("high risk vascular group"). Discrepancies between both studies [START_REF] Ganesh | Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-beta expression and connective tissue features[END_REF][START_REF] O'connor | Systemic connective tissue features in women with fibromuscular dysplasia[END_REF] may reflect differences in patient characteristics and disease severity: in the NIA cohort [START_REF] Chung | Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in the thoracic aortic aneurysm in Marfan syndrome[END_REF], 21.3% of patients underwent open surgery and 48.9% had a cerebrovascular event, while patients from the Cleveland cohort [START_REF] Poloskey | Low yield of genetic testing for known vascular connective tissue disorders in patients with fibromuscular dysplasia[END_REF] appeared more representative of patients included in the US registry. Interestingly, compared to age and gender-matched controls, patients with FMD included in the NIA study (n=38) had evidence of increased inflammatory markers, including TGF-beta 1 and 2 [START_REF] Ganesh | Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-beta expression and connective tissue features[END_REF]. In particular, plasma levels of TGF-beta1 were similar to those observed in patients with Marfan syndrome [START_REF] Matt | Circulating transforming growth factor-beta in Marfan syndrome[END_REF], while, in multivariable regression, plasma TGF-beta2 levels were predictive of the number of arterial beds affected by FMD (string-of-beads, aneurysms, stenosis or tortuosity). As mentioned above, TGF-beta 1 and TGF-beta 2 secretion in dermal fibroblast cell lines of patients with FMD (n=16) was higher than in age and gender-matched controls. Finally, in a series of 35 patients with FMD, two variants in the transforming growth factor beta receptor 1 (TGFβR1) gene were identified in two unrelated patients, both with medial fibroplasia and a history of multivessel dissection [START_REF] Poloskey | Low yield of genetic testing for known vascular connective tissue disorders in patients with fibromuscular dysplasia[END_REF]. Both variants induced an amino acid substitution in a highly conserved region of TGFβR1, however their role is unknown.

These findings are of interest, since both Loeys-Dietz syndrome, due to mutations in genes encoding TGF-beta receptors 1 and 2, and the very rare Aneurysms Osteoarthritis Syndrome, due to mutations in SMAD3, are associated with aneurysms, arterial tortuosity and for the latter early-onset osteoarthritis [START_REF] Loeys | A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2[END_REF][START_REF] Van De Laar | Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis[END_REF] . Still, as mentioned above, the yield of genetic screening oriented by clinical indications (including genes such as TGFβR2, COL3A1, FBN1, ACTA2, or SMAD3) was low [START_REF] Ganesh | Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-beta expression and connective tissue features[END_REF][START_REF] Poloskey | Low yield of genetic testing for known vascular connective tissue disorders in patients with fibromuscular dysplasia[END_REF].

As a whole, while arterial aneurysms, dissections and arterial tortuosity may occur both in FMD and several inherited CTDs, the typical string-of-beads (figure 1) is almost pathognomonic of multifocal FMD [START_REF] Persu | European consensus on the diagnosis and management of fibromuscular dysplasia[END_REF][START_REF] Olin | Expanding Clinical Phenotype of Fibromuscular Dysplasia[END_REF]. Even in FMD patients with extra-vascular features suggestive of CTD, mutations in genes at the origin of inherited CTDs are seldom identified. Still, CTD clinical features are probably more frequent in patients with FMD than in healthy controls, but their exact prevalence remains to be determined in larger and more diverse cohorts, compared with matched controls from the same populations. Whatever their prevalence, CTD-like extravascular abnormalities identified in patients with FMD appear to be milder than those observed in CTDs. Thus, major complications suggestive of CTD such as hollow organ rupture associated with a history of arterial aneurysms or dissection should prompt genetic screening for CTDs, even in presence of vascular images compatible with FMD [START_REF] Poloskey | Low yield of genetic testing for known vascular connective tissue disorders in patients with fibromuscular dysplasia[END_REF].

SCAD has also been associated with CTD, especially Marfan syndrome and vascular Ehlers-Danlos syndrome [START_REF] Sato | Natural course of isolated spontaneous coronary artery dissection in Marfan syndrome[END_REF][START_REF] Nakamura | Vascular Ehlers-Danlos syndrome--all three coronary artery spontaneous dissections[END_REF]. In clinical practice genetic screening is not routinely performed in SCAD patients and often randomly done in those who have signs of hypermobility or Marfan-like physical characteristics. Data from a single center patient series showed that 3 out of 59 patients had a clear CTD mutation (FBN1 and COL3A1), 20.3% had genetic variants of unknown significance, but a distinct vascular phenotype was not identified [START_REF] Henkin | Spontaneous coronary artery dissection and its association with heritable connective tissue disorders[END_REF]. Further genetic studies are warranted in SCAD patients to unravel potential CTD abnormalities.

Conclusion

The vast majority of patients diagnosed with SCAD and FMD are women below 60 years of age.

Although the mutual relationship of both entities is complex and only partly understood, there seems to be some overlap in genetic background and interaction with endogenous sex-steroids. A variety of external factors and co-morbidities interfere with their occurrence. A diversity of phenotypes of FMD are expressed in individuals, leading to a heterogeneous group of patients. Identification of susceptibility genes and associated biomarkers, as well as careful study of hormonal profile, in correlation with various clinical presentations will help unraveling the pathophysiology and improving the classification of this intriguing group of diseases. The final aim would be to individualize management and follow-up according to each patient's specificities, with particular attention to sex and gender-related issues such as pregnancy, breastfeeding or exogenous hormonal intake.


Patrice Pajusco

Pascal Pagani

COMPARISON OF TWO TIME REVERSAL SCHEMES USING CIRCULAR UWB MEASUREMENTS

Time Reversal is a promising technique for the improvement of future telecommunication systems. It may increase throughput while reducing receiver complexity. A better understanding of this capability requires more investigation on measured channels. This study used circular array propagation measurements. These measurements are efficient to estimate space-time focusing characteristics simultaneously. Because the delay spread parameter is inappropriate, a new parameter is introduced to study time focusing. Focusing parameters of two time reversal schemes are investigated. Time Reversal improves the data rate by a factor of three and increases the received power using the entire FCC bandwidth. The one-bit time reversal scheme improves space focusing but provides smaller gain on other focusing parameters. The trend is the same with smaller bandwidth, but the benefits are reduced. The optimal bandwidth should be close to 3 GHz.

I. INTRODUCTION

Time Reversal [START_REF] Derode | Acoustic time-reversal through high-order multiple scaterring[END_REF] has been studied for many years. It was initially investigated in the field of acoustics and more recently in the field of electromagnetics. Basically, Time Reversal (TR) consists in using channel state information at the transmitter. The channel impulse response is time reversed and complex conjugated. This calculation is equivalent to a matched filter applied at the transmitter. The perceived transmission channel becomes the autocorrelation of the propagation channel, which induces a channel hardening effect. The second and unexpected property is the spatial focusing. If the antenna is placed at some distance from the intended receiver, the peak of the perceived channel disappears. These two focusing properties are very promising for communication systems. TR may increase throughput while reducing the receiver complexity. Spatial focusing may enable space division multiple access, simultaneous streams towards a single user using antenna array or more confidential communications. TR requires a propagation channel with a large delay spread value. Such channels appear in rich scattering environments. Reciprocal and stationary channels are also needed. TR was successfully used in underwater acoustic communication [START_REF] Edelmann | An initial demonstration of underwater acoustic communication using time reversal[END_REF]. MIMO transmission schemes were also achieved [START_REF] Song | Coherent MIMO time reversal communications in shallow water[END_REF]. Capabilities of TR with electromagnetic waves were investigated recently in [START_REF] Emami | Predicted time reversal performance in wireless communication using channel measurements[END_REF]. UWB channel measurements were used to demonstrate the strength of TR using channel reciprocity. Other investigations were done in the same way for outdoor mobile wireless access at 2 GHz [START_REF] Nguyen | The potential use of time reversal techniques in multiple element antenna systems[END_REF], fixed wireless access at 5 GHz [START_REF] Kyritsi | MISO time reversal and delay-spread compression for FWA channels at 5 GHz[END_REF] and short range applications [START_REF] Emami | Predicted time reversal performance in wireless communication using channel measurements[END_REF][START_REF] Akogun | Demonstrating Time Reversal in Ultra-wideband Communications using Time Domain Measurements[END_REF][START_REF] Qiu | Time reversal with MISO for ultrawideband communications: experimental results[END_REF]. TR of wideband microwaves were experimentally demonstrated in reverberant rooms [START_REF] Lerosey | Time Reversal of electromagnetic waves[END_REF][START_REF] Lerosey | Time reversal of wideband microwaves[END_REF]. UWB and acoustic waves have many similarities. UWB appears to be the most appropriate technology to combine with TR because of the success of TR in the field of acoustics. This paper presents the capability of two Time Reversal schemes using propagation measurement data. TR is introduced in section II and the two schemes are presented. Thereafter, the parameters used in the analysis are discussed in section III. A UWB propagation experiment is detailed in section IV. Statistical results are analyzed in section V. Finally, conclusions are drawn in section VI.

II. TIME REVERSAL

A. Principle

A radio link between an access point and a portable device is considered. The access point is stationary and defines the origin of the space. We assume a reciprocal channel which is true in linear medium. Thus, the channel impulse response is the same regardless of the direction of the radio link. Hence, the channel impulse response of the propagation channel between the access point and a terminal will be simply expressed by   , hr where denotes the excess delay and r the location of the terminal. The intended receiver is located at the location 0 r . TR consists in estimating the channel impulse response at the transmitter. For example, the intended receiver can transmit a pulse which is sampled by the transmitter. Basically, the channel estimate is time reversed and complex conjugated, but other schemes are possible. Each of them has its own space-time focusing properties. The signal derived from the channel estimate   0 , TR gr  is used as a coding waveform and transmitted back to the receiver. The transmitted power is normalized to the unitary power to enable comparison between different schemes. At any location r , the perceived channel impulse response will be:

        0 2 0 , , , , TR per TR gr h r h r g r d        (1)
where   0 , TR gr  denotes the reversed signal of a time reversal scheme and  the convolution with respect to the delay  .

B. Basic Time Reversal scheme

The channel estimate is time reversed and complex conjugated. This operation is similar to a phase conjugation in the frequency domain. The time reversed signal can be expressed by :

    * 0 0 , , TR Simple g r h r      (2)
Where 0 r denotes the location of the receiver and   , hr  the channel impulse response at location r .

C. One-bit Time Reversal scheme

One-bit time reversal scheme was introduced in [START_REF] Derode | Ultrasonic pulse compression with one-bit time reversal through multiple scattering[END_REF]. The signal transmitted back is expressed by

              1 0 0 0 , sgn , sgn , TR bit g r h r j h r           (3)
Where sgn denotes the sign function and

  h  and   h 
denote the real and imaginary part of h respectively.

The use of one-bit digital converter may reduce costs and enable higher sampling rates. The definition of the start and the end of the channel impulse response is very important for the noise removal. In fact, each reversed tap has the same weight. The boundaries of the channel impulse response were obtained with a 20 dB threshold below the peak of the channel impulse response.

III. ANALYSIS PARAMETERS

A. Temporal focusing parameters 1) Delay spread

Delay Spread (DS) parameter is widely used to study wideband channels. It is often related to the achievable data rates. It is computed with the second moment of the average power delay profile. This parameter characterizes the spreading of the channel impulse response. A typical indoor channel was simulated using the Saleh & Valenzuela (SV) model [START_REF] Saleh | A Statistical Model for Indoor Multipath Propagation[END_REF]. It is represented on the left of Fig. 1. The perceived channel is plotted on the right. A Hanning window was used to reduce sidelobes and compute DS value. Table 1 shows the results for different threshold values.

B. Signal to interference ratio

When the level of the received signal is sufficiently high, the bitrate is only limited by the Inter Symbol Interference (ISI). In this noise-free configuration, if the bitrate and the channel impulse response are known, the average ISI can be evaluated. An Equivalent Signal to Interference Ratio parameter denoted by ESIR is introduced to characterize the improvement of TR accurately. It corresponds to the average SIR for a given symbol rate R. The intended signal is assumed to be at the peak of the channel impulse response. Transmitted symbols are supposed independent. Multi-path interference are supposed equivalent to a gaussian noise. Considering this hypothesis, the average level of interference is the sum of the power of each interferer. The parameter is defined by:

      2 max 10 2 max 0 10 log / h k h k k h ESIR R h k R                       (4)
This parameter provides the average SIR of the received signal at the sampling instant. An estimate of the maximal symbol rate in noise-free configuration is:

  k dB k dB R with ESIR R k  (5)
Considering a static channel and a simple uncoded BPSK modulation scheme, a SIR of 10.5 dB is required to achieve 10 -6 bit error rate [START_REF] Proakis | Digital Communications[END_REF]. Hereunder, the parameter 10.5

R will be computed to evaluate the upper bitrate of a basic receiver structure.

C. Spatial focusing parameters 1) Peak to Peak Gain

A simple receiver structure estimates data by sampling the peak of the received signal. In order to study the improvement of TR, the Peak to Peak gain parameter is used. This parameter corresponds to the ratio between the strongest path

               (6)
where 0 r denotes the target location 2) Total received power gain Advanced receiver structures are able to capture all the power carried by the channel impulse response. In order to evaluate potential gain of TR, the total received power gain is defined by:

    2 0 10 2 0 , 10 log , per h r d h r d                (7)
3) Spatial focusing gain Spatial focusing may transmit streams simultaneously towards nearby users. To evaluate interference between users, the spatial focusing gain parameter is defined by:

          2 10 2 0 max , 10 log max , per per h r r h r                 (4)

IV. UWB PROPAGATION CHANNEL MEASUREMENTS

A. Circular array measurements

A better understanding of TR capability requires more investigation on measured channels. An efficient way to characterize space-time characteristic simultaneously was presented in [START_REF] Pajusco | Characterization of UWB Time Reversal using circular array measurements[END_REF],. The principle consists in using a virtual circular array. This particular configuration provides many combinations of angles and distances from each possible target along the circle. It enables reliable computation of the average focusing gain. The 2D focusing area can be also obtained. The experiment is briefly discussed hereafter for the purpose of this study. A sounding technique in the frequency domain was used. The entire FCC frequency band for indoor UWB applications was probed. CMA 118 antennas were used at each side of the radio link. The schematic diagram of the experiment is depicted in Fig. 2. The transmitting antenna was mounted on a trolley to simplify the displacement to the different location points. A step motor, controlled using a RS232 link, enabled the rotation of the transmitter antenna. For measurement, 90 complex channel impulse responses were sampled along a circle of 40 centimeters in diameter.

The receiving antenna was placed on a wall at a height of about 2 meters above the floor. Due to the asymmetry of the antenna pattern, the antenna was mounted upside down. This antenna was placed next to the VNA to minimize the loss of the received signal. A LNA was used to improve the link budget and the signal to noise ratio. The other input of the VNA was connected to the TX antenna with a long, low-loss cable. The maximum distance was limited to 20 m. The UWB propagation channel was measured using the VNA HP8510C. The channel impulse responses were obtained using standard S21 parameter measurements. The propagation channel was sampled over 4005 equally spaced frequency tones between 3.1 and 11.1 GHz. This setup allowed a maximum excess delay of ~500 ns and a time resolution of ~125 ps. The entire measurement process was automated using the GPIB and RS232 links with Matlab TM software.

B. Measurement experiment setup

Two indoor office configurations were investigated. In the first scenario, the fixed antenna was located in a meeting room (h = 2.19m). In the second scenario, the fixed antenna was located in a corridor (h = 2.45m). In both cases, Line-Of-Sight (LOS) and Non Line-Of-Sight (NLOS) measurements were performed. The distance between transmitter and receiver ranges from 1 meter to 18 meters. More than 120 location points were measured corresponding to just under to 11 000 UWB channel impulse responses.

A. Statistical analysis on the entire bandwidth 1) Basic time reversal scheme

The wider the bandwidth, the greater the benefit of TR. As an upper limit, the entire UWB frequency band between 3.1 and 10.6 GHz is considered to study focusing parameters. The statistical results of the basic TR scheme are presented on the left of Table 2. The LOS and NLOS configurations are reported. Considering the same transmitted power, TR increases the received power. In NLOS, the peak power of the perceived channel impulse is about 12 dB higher than the peak of the channel impulse response. In the same configuration, the total received power is also 7 dB higher. Such a gain can improve the link budget and the coverage of an UWB system. A path loss model was defined in [START_REF] Pagani | Experimental Analysis of the Ultra Wideband Propagation Channel over the 3.1 GHz -10[END_REF] using the same measurements. Using this path loss model in NLOS configuration, the 7 dB gain on the received power increases the cell radius by 65% and the coverage area by 172%. TR also reduces the Inter Symbol Interference. According to the parameter 10.5 R , the data rate can be triple in NLOS using a basic receiver structure. At a distance of 9 from the intended receiver, a loss of 10 dB is observed at the peak of the perceived channel impulse response. This highlights a good spatial focusing capability. TR reduces interference level between close users and enables simultaneous transmissions. In LOS, the trend is the same but the gains are much smaller. To illustrate the behaviour of a simple TR scheme, a typical file was selected. The measurement file was chosen so that their focusing parameters were close to the average values. The results of this typical file are depicted in Fig. 4. On the left, the power delay profile of the 90 measured and perceived channel impulse responses are represented. The gain on the strongest path is about 12 dB and the total power gain is 7 dB. On the right, the focusing area is depicted. It is elongated and is directed inline with the transmitter location. The average focusing gain far from the intended centre is -10 dB.

2) One-bit time reversal scheme

The statistical results of the one-bit TR scheme are reported on the right of the Table 2. One-bit scheme reduces the interference between users from -10.3 to -11.9 dB. The focusing area is two times smaller and may facilitate the transmission of simultaneous streams to the same user. Unfortunately, all the other gains are reduced. In NLOS, the average achievable bitrate is only multiplied by 1.4 instead of 3.1 with basic TR scheme. In LOS configuration, the achievable bitrate is worse with one-bit TR than without TR. One-bit TR scheme was applied on the previous typical example. The results are depicted in Fig. 5. On the left of the figure, the peak is not as high and the side lobe levels are higher than those depicted in Fig. 4. As a result, the ISI is bigger and explains the decrease in the bitrate. On the right of Fig. 5, the focusing area is depicted. The area is two times smaller than the basic TR scheme.

B. Statistical analysis versus bandwidth

In a real communication system, the use of the entire bandwidth is not possible. Technology constraints limit the transmitted bandwidth to a few GHz. In order to obtain more relevant results, the statistical analysis was repeated using smaller bandwidth values. These values range from 0.5 to 7.5 GHz. The behavior of the received power is depicted in Fig. 6. On the left, the total power gain is depicted. The wider the bandwidth, the greater the gain in received power. One-bit TR scheme is not efficient enough to improve received power level. The gain is about 1.5 dB lower. On the right, the peak to peak gain is depicted. The bandwidth is represented on a log scale. An acceptable linear dependence is found on both schemes. The gain with one-bit scheme is about 3 dB lower. In a basic TR scheme, the transfer function of the transmitted signal is the complex conjugate of the channel impulse response. Thus, more power is allocated on frequencies which are less attenuated. Considering the same transmitted power, the received power is increased. With a flat transfer function with Rayleigh fading, the gain is 3dB. When the bandwidth increases, the upper band is much more attenuated than the lower band. This explains that the gain increases with bandwidth. However, this scheme may need to reduce the transmitted power to fulfill transmit UWB requirements. In the previous section, the improvement of spatial focusing of the one-bit TR scheme was presented. However, this gain is reduced when the bandwidth is smaller. The value tends to be the same as basic TR schemes. The last parameter is the R 10.5 . This parameter estimates the achievable bitrate. The R 10.5 ratio between the perceived channel and the measured channel provides an estimate of the improvement of bitrate on a basic receiver. Results are depicted on the right of Fig. 7. Basic TR scheme increases bitrate whatever the bandwidth. The wider the bandwidth, the greater the improvement. However, above 3 GHz the gain remains stable. The optimal bandwidth should be close to 3 GHz.

VI. CONCLUSION

This study investigated TR capability using extensive circular array propagation measurements. A new parameter was introduced to study time focusing because of the weakness of the delay spread parameter. The advantages and drawbacks of two TR schemes were presented. Over the entire FCC bandwidth, TR improves the data rate by three and increases the received power. The one-bit TR scheme improves spatial focusing but provides less gain on the other focusing parameters.

Figure 1 :

 1 Figure 1: Simulation of TR with SV model

Figure 2

 2 Figure 2 Schematic diagram of the measurement device

Figure 3

 3 Figure 3 Floor plan of the two measurement areas

Figure 4 :Figure 5 :Figure 6 :

 456 Figure 4 : Typical NLOS measurement (basic TR scheme)

Figure 7 :

 7 Figure 7 : Spatial focusing and bitrate gain function of bandwidth in the NLOS configuration

Table 1 :

 1 Influence of threshold on delay spread values DS parameter is very sensitive to the cut-off threshold, especially with the perceived channel impulse response. Depending on the cut-off level, TR can reduce or increase the DS value. Moreover, this parameter does not show improvement of TR. Such a parameter is not appropriate to qualify time focusing of TR. To avoid biased results, a new parameter is introduced in the next section.

Table 2 :

 2 Statistical of focusing parameters