Correspondence Diagnosis and management of fibromuscular dysplasia Antonio Bozzani and Vittorio Arici
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES
P
ersua et al. [1] reported, in their recent article, an interesting expert consensus on the recommendations for daily practice in the definition, classification, diagnosis, and management of fibromuscular dysplasia (FMD) in adult patients with symptomatic involvement of the renal arteries, supra-aortic trunks, and digestive and peripheral arteries. We agree with their definition of FMD: ‘FMD is an idiopathic, segmental, nonatherosclerotic and noninflammatory disease of the musculature of arterial walls, leading to stenosis of small and mediumsized arteries. The diagnosis of FMD requires exclusion of renal artery spasm, arterial diseases of monogenic origin, and inflammatory arterial diseases’. The renal arteries and cervicocephalic trunks are most frequently involved. However, we reported the first case, to our knowledge, of an elderly patient with infrarenal aortic FMD associated with aortic hypoplasia and downstream aneurysm [2,3]. In rare cases, FMD has been described in the distal aorta and primarily associated with coarctation, which is a focal narrowing of the aorta. FMD has been exceptionally described to cause aortic aneurysms [4]. Both FMD and aortic hypoplasia are usually diagnosed in the first stage of life, with different latency periods. The clinical onset of aortic hypoplasia is usually characterized by severe hypertension and different pulses between the arms and legs. FMD is diagnosed between the second and the fourth decade, and particularly in childbearing-aged women, with milder symptoms. The coassociation of aortic hypoplasia with infrarenal aortic aneurysm has been described exceptionally and in patients older than those with aortic hypoplasia only. In our patient, we observed fibrous dysplasia of the media and intima, and atherosclerotic plaques were absent. Our findings suggest the combined effects of age (fibrous intimal thickening) and disease-related aortic wall degeneration and fibrosis. In fact, the severe loss of elastic fibers and thinning of the tunica media, the prominent muscle cells, and the segmental nonatherosclerotic narrowing of the aortic lumen provided the pathologic criteria for the diagnosis of FMD. The core matter that makes this case extremely rare is the finding, assessed by an expert team of pathologists, of a histologic pattern consistent with FMD in the site of aortic hypoplasia. Although the definition of FMD is strictly related to muscle arteries and to histopathologic changes and has typical angiographic features, the definition of aortic hypoplasia is based on the macroscopic appearance of an elastic vessel. The histopathologic finding consistent with FMD occurring in aortic hypoplasia indicates that the association between aortic hypoplasia and FMD does exist. What do you think about this case? How do you classify in your Consensus Document? 2098
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1. Persua A, Giavarinic A, Touze´ E, Januszewiczf A, Sapovalg M, Azizic M, et al., on behalf of the ESH Working Group ‘Hypertension and the Kidney’. European consensus on the diagnosis and management of fibromuscular dysplasia. J Hypertens 2014; 32:1367–1378. 2. Odero A, Bozzani A, Arici V, Agozzino M. Hypoplasia and fibromuscular dysplasia of infrarenal abdominal aorta with downstream aneurysm: case report and review of the literature. J Vasc Surg 2008; 48:1589–1592. 3. Bozzani A, Moia A, Carlino M, Caldana M, Ragni F. Response to ‘Fibromuscular dysplasia affecting a two-branched renal artery in a patient with a solitary kidney: case presentation’. Clin Cardiol 2013; 36:E50. 4. Matsushita M, Yano T, Ikezawa T, Sakurai T, Nimura Y, Shionoya S. Fibromuscular dysplasia as a cause of abdominal aortic aneurysm. Cardiovasc Surg 1994; 2:615–618.
Journal of Hypertension 2014, 32:2098–2105 Division of Vascular Surgery, Foundation I.R.C.C.S. Policlinico San Matteo, Pavia, Italy Correspondence to Antonio Bozzani, MD, Division of Vascular Surgery, Foundation I.R.C.C.S. Policlinico San Matteo, Viale Camillo Golgi, 19, 27100 Pavia, Italy. Tel: +39 382 502068; fax: +39 382 502007; e-mail: [email protected] J Hypertens 32:2098–2105 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000314
Reply Alexandre Persu a,b, Andrzej Januszewicz c, Alberto Morganti d, Pierre-Franc¸ois Plouin e,f, and Peter de Leeuw g
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e thank Bozzani and Arici [1] for drawing our attention on a case of aortic hypoplasia associated with fibromuscular dysplasia (FMD)-like lesions [2]. As indicated in our consensus document [3], ‘mid-aortic syndrome (also called hypoplasia or coarctation of the abdominal aorta), [. . .] may also be associated with renal artery stenosis, – particularly in children – and in some cases, histological lesions similar to those of medial fibromuscular dysplasia (FMD) may be observed on examination of the aorta or renal artery’. Though rare, the finding of this association in a 77-year-old patient [2] is not unexpected, as both entities were occasionally described in older patients [4,5]. However, in this consensus, we chose to restrict the term ‘FMD’ to patients with involvement of small and middle-sized arteries, and to consider FMD-like lesions of large vessels such as the aorta as a separate entity [3]. Admittedly, as long as the genetic and molecular aetiopathology of FMD remains obscure, any classification is to some extent arbitrary. Volume 32 Number 10 October 2014
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ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES 1. Bozzani A, Arici V. Diagnosis and management of fibromuscular dysplasia. J Hypertens 2014; 32:2098. 2. Odero A, Bozzani A, Arici V, Agozzino M. Hypoplasia and fibromuscular dysplasia of infrarenal abdominal aorta with downstream aneurysm: case report and review of the literature. J Vasc Surg 2008; 48:1589– 1592. 3. Persu A, Giavarini A, Touze´ E, Januszewicz A, Sapoval M, Azizi M, et al. European consensus on the diagnosis and management of fibromuscular dysplasia. J Hypertens 2014; 32:1367–1378. 4. Prieto LN, Dyer CB, Thompson PM, Whigham C Jr. The oldest reported patient with fibromuscular dysplasia of the renal artery. South Med J 1996; 89:405–408. 5. Sung SA, Hwang YH, Lee SY, Cho YK, Kwon TW. An infrarenal aortic hypoplasia presented with claudication. J Korean Med Sci 2010; 25:950– 952.
Journal of Hypertension 2014, 32:2098–2105 a Pole of Cardiovascular Research, Institut de Recherche Expe´rimentale et Clinique, Universite´ Catholique de Louvain, bDivision of Cardiology, Cliniques Universitaires Saint-Luc, Universite´ Catholique de Louvain, Brussels, Belgium, cDepartment of Hypertension, Institute of Cardiology, Warsaw, Poland, dDepartment of Internal Medicine and Hypertension Center, San Giuseppe Hospital, University of Milan, Milan, Italy, eHypertension Unit, Assistance Publique – Hoˆpitaux de Paris, European Georges Pompidou Hospital, fUniversite´ Paris-Descartes, Paris Sorbonne Cite´, Paris, France and gDepartment of Medicine, University Hospital Maastricht, Maastricht, the Netherlands
Correspondence to Professor Alexandre Persu, MD, PhD, Division of Cardiology, Cliniques Universitaires Saint-Luc (UCL), 10 Avenue Hippocrate 1200, Brussels, Belgium. Tel secretary: þ32 2 764 63 06, Tel: +32 2 764 25 33; fax: +32 2 764 89 80; e-mail: [email protected] J Hypertens 32:2098–2105 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000315
Contribution of the ABP-International study to the definition of night-time tachycardia Paolo Palatini a, Gianpaolo Reboldi b, Lawrence J. Beilin c, Kazuo Eguchi d, Yutaka Imai e, Kazuomi Kario d, Takayoshi Ohkubo e,f, Sante D. Pierdomenico g, Joseph E. Schwartz h,i, Lindon Wing j, and Paolo Verdecchia k
A
large number of studies have shown that high heart rate (HR) is associated with adverse cardiovascular outcome in patients with hypertension or cardiovascular diseases and that it should be considered an important component of the cardiovascular risk profile [1]. However, controversy still exists on the normal limits for this clinical variable. In most studies, participants were considered to have tachycardia if they were in the highest
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quartile or quintile of the HR distribution because a clinically relevant increase in the risk of cardiovascular events (CVEs) or mortality was found in the participants of the top HR quantile. According to this approach, the upper normal limit for resting HR was set at 80–85 bpm, which corresponds to the lower limit of the top quantile in most population studies. More recently, some investigators have focused their attention on HR measured with 24-h ambulatory recording and found that among the ambulatory HRs, average night-time HR but not daytime HR was an independent predictor of cardiovascular or noncardiovascular mortality [2–6]. In some studies, its association with outcome also appeared to be stronger than that of office HR [3,4]. This finding again raises the issue of how to identify the upper normal limit for HR recorded during the nighttime. Clearly, HR during sleep is much lower than HR measured in the office by healthcare personnel [2–10] with differences ranging from 6.5 (in the International Database of Ambulatory blood pressure in relation to Cardiovascular Outcome (IDACO) study [6]) to 12.1 bpm (in the Hypertension and Ambulatory Recording VEnetia STudy (HARVEST) [10]). In a recent article published in this Journal, Vinyoles et al. [11] used data from a large cross-sectional study to identify the night-time threshold associated with ‘cardiovascular risk office tachycardia,’ which was defined as an office HR of at least 85 bpm. Different night-time thresholds were estimated by receiver-operating characteristic (ROC) curve analysis and the authors selected the optimal threshold that maximized the sum of sensitivity and specificity. According to this approach, the night-time HR value that best predicted cardiovascular risk office tachycardia in their sample was higher than 66 bpm for the whole group with different thresholds for the two sexes (>65 bpm in men and >68 bpm in women). However, this threshold is close to the median value of the night-time HR distribution in most studies [2–10] and thus can hardly be proposed as the upper limit of normal for this variable. As Vinyoles et al. themselves admitted, an important limitation of their approach was the cross-sectional design of their study, which did not allow the investigators to establish a night-time HR threshold prospectively associated to hard endpoints [11]. This issue could be appropriately addressed in the ABPInternational database [3], the largest ever study of hypertensive patients assessed with ambulatory HR monitoring (n ¼ 7600). In that study, we found an independent association of ambulatory HR with the combination of fatal and nonfatal CVE [3]. Among the ambulatory HRs, night-time HR showed the strongest predictive value for cardiovascular outcomes. This relationship was linear and similar in the two sexes. In a new unpublished analysis of the ABPInternational data, using the lower limit of the top (fifth) quintile to identify the upper limit of normal, the threshold for resting office tachycardia was 85.0 bpm (Fig. 1). The corresponding value for average night-time HR was 73.1 bpm. The lower limits of the top quartile and top tertile for night-time HR in the ABP-International study were 71.0 and 69.0 bpm, respectively, well above the threshold proposed by Vinyoles et al. and the median value was 65 bpm. Interestingly, in the ABP-International study, the lower limit of the top night-time HR quintile was exactly the same in the www.jhypertension.com
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Correspondence Office heart rate 14
Night-time heart rate 14
85
12
12
10
10
8
8
6
6
4
4
2
2
0
73
0 40 46 52 58 64 70 76 82 88 94 100 106 112
31 37 43 49 55 61 67 73 79 85 91 97 103
Beats per minute
Beats per minute
FIGURE 1 Distribution of office heart rate and average night-time heart rate in 7600 hypertensive participants (4165 men) from the ABP-International Study. The dotted line corresponds to the lower limit of the top heart rate quintile. Office heart rate: median (interquartile range) ¼ 76 (68–83) bpm. Coefficient of skewness ¼ 0.43, coefficient of Kurtosis ¼ 0.48 (both P < 0.0001). Kolmogorov–Smirnov test for normal distribution, P < 0.0001. Night-time heart rate: median (interquartile range) ¼ 65 (59–71) bpm. Coefficient of skewness ¼ 0.41, coefficient of Kurtosis ¼ 0.40 (both P < 0.0001). Kolmogorov–Smirnov test for normal distribution, P < 0.0001.
two sexes (73.1 bpm), thereby avoiding the problem of using different sex-specific reference values. Using a timedependent ROC curve analysis, the optimal night-time HR cutoff value for prediction of CVEs at 10 years in the ABP-International participants was 73.6 bpm, with 84% specificity, 22% sensitivity, 89% negative predictive value and 16% positive predictive value. As the clinical significance of HR in hypertension is still debated, we believe that a high specificity better suits the application of this variable in clinical practice. In a multivariable fully adjusted Cox model, compared with the bottom quintile (HR 66 bpm) with resting office tachycardia of cardiovascular risk (>84 bpm)
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described in the Framingham cohort of hypertensive patients [6].
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES 1. Palatini P, Reboldi G, Beilin LJ, Eguchi K, Imai Y, Kario K, et al. Contribution of the ABP-International study to the definition of nighttime tachycardia. J Hypertens 2014; 32:2099–2100. 2. Vinyoles E, de la Sierra A, Roso A, de la Cruz JJ, Gorostidi M, Segura J, et al. Night-time heart rate threshold definition by resting office tachycardia in untreated hypertensive patients: data of the Spanish ABPM registry. J Hypertens 2014; 32:1016–1024. 3. Prineas RJ, Le A, Soliman EZ, Zhang ZM, Howard VJ, Ostchega Y, et al. US national prevalence of electrocardiographic abnormalities in black and white middle aged (45–64 years) and older (65 years) adults (from the reasons for geographic and racial differences in Stroke study). Am J Cardiol 2012; 109:1223–1228. 4. Hall MH, Middleton K, Thayer JF, Lewis TT, Kline CE, Matthews KA, et al. Racial differences in heart rate variability during sleep in women: the study of women across the nation sleep study. Psychosom Med 2013; 75:783–790. 5. Palatini P, Casiglia E, Pauletto P, Staessen J, Kaciroti N, Julius S. Relationship of tachycardia with high blood pressure and metabolic abnormalities: a study with mixture analysis in three populations. Hypertension 1997; 30:1267–1273. 6. Gillmann MW, Kannel WB, Belanger A, D’Agostino RB. Influence of heart rate on mortality among persons with hypertension: the Framingham study. Am Heart J 1993; 125:1148–1154.
Journal of Hypertension 2014, 32:2098–2105 a La Mina Primary Care Center, University of Barcelona, bHypertension Unit, Hospital Mu´tua de Terrassa, University of Barcelona, cJordi Gol Institute for Research in Primary Care, Barcelona, dDepartment of Preventive Medicine and Public Health, Universidad Auto´noma de Madrid, CIBER en Epidemiologı´a y Salud Pu´blica, Madrid, eNephrology Service, Hospital Universitario Central de Asturias, Oviedo, fHypertension Unit, Doce de Octubre Hospital, Madrid and gHypertension Unit, Instituto de Investigacio´n Sanitaria. Hospital Clı´nico San Carlos, Madrid, Spain
Correspondence to Ernest Vinyoles, CAP La Mina. Carrer Mar s/n, 08930 - Sant Adria` de Beso`s, Spain. Tel: +34 933811593; fax: +34 933812141; e-mail: 23561evb@ comb.cat J Hypertens 32:2098–2105 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000335
Renal artery stenosis following renal denervation: a matter of concern Alexandre Persu a,b, Marc Sapoval c,d, Michel Azizi c,e, Matthieu Monge e, Etienne Danse f, Frank Hammer f, and Jean Renkin a,b
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n the recent Symplicity HTN-3 trial [1] – the singleblinded randomized controlled trial in the field so far – renal sympathetic denervation (RDN) by radiofrequency using the Ardian–Medtronic system failed to show superiority over medical treatment alone in patients with www.jhypertension.com
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drug treatment-resistant hypertension. Nevertheless, the global SYMPLICITY registry [2] continues to recruit, and RDN is still proposed as treatment of resistant hypertension all over Europe (http://www.tctmd.com/show.aspx?id= 123265), partly based on apparent efficacy in previous observational [3–5] and unblinded studies [6], partly on overall safety in previous Symplicity studies [1–4,6]. In particular, in Symplicity HTN-3 [1], only one de novo renal artery stenosis was detected after RDN (0.3%), versus 0 in the sham group. However, it should be pointed out that screening was based on renal duplex rather than on computed tomography (CT) scan, which is state of the art [7–9], assessment was performed only 6 months after RDN, and stenosis 70% or less were not taken into consideration [1]. In other Symplicity studies and registries [2–4,6], assessment of renal arteries after RDN was neither systematic nor state of the art [7]. Furthermore, whether safety data obtained with the Ardian–Medtronic system can be extrapolated to other RDN systems remains to be demonstrated. In theory, the vascular thermal lesions provoked by radiofrequency may induce renal artery stenoses, as reported for pulmonary veins after radiofrequency ablation for atrial fibrillation [10]. Optical coherence tomography (OCT) performed in a prospective series of 16 patients with resistant hypertension disclosed renal artery constriction and local tissue damage with oedema and thrombus formation at the ablation site after RDN using the Symplicity or the EnligHTN multielectrode RDN catheters [11]. While the clinical relevance and prognostic value of such lesions are still unclear, long-term safety of renal artery ablation remains thus a legitimate concern.
We report here a case of multiple bilateral stenoses (Fig. 1) associated with severe hypertension (SBP 240– 260 mmHg), fluid retention, dyspnoea and tachycardia, occurring 6 months after RDN, using the Vessix–Boston radiofrequency balloon catheter in a patient with previously normal renal arteries (patient no. 1). Cardiac echography showed minor mitral insufficiency and left atrial dilatation, with preserved ejection fraction. Renal function was normal. The renal angiogram showed a 50–60% stenosis of the superior main left renal artery and three stenosis of the right renal artery (most severe 75–80%). Three consecutives angioplasties (1.5–2 min inflations) of the right renal artery were performed with a 4 20 mm monorail balloon (Sterling, Boston Medical). The result was acceptable, but not perfect (30% residual stenosis). On the basis of the initial quantitative measurements during index ablation procedure (5 mm Vessix balloon), a second dilatation was done with a 5 20 mm balloon (Rx Viatrac, Abbott), inducing a major dissection. In the absence of improvement after prolonged low-pressure dilatation, a 6 40 mm nitinol self-expandable stent (Astron Pulsar, Biotronik) was implanted in the right renal artery. The procedure was followed by polyuria, rapid resolution of symptoms, body weight loss and improvement of blood pressure after discharge (205/127 mmHg). Six months later, control arteriography showed progression of the left renal artery stenosis to 70–80%. Angioplasty of the left renal artery was performed, without further improvement of blood pressure. Furthermore, we document unexpected progression of mild baseline stenosis (28–31%; exclusion limit in the
FIGURE 1 Arteriography of the left (panels a and b) and right (panels c and d) renal arteries of case 1 immediately after renal sympathetic denervation (RDN) (panels a and c) and 6 months later (panels b and d). Although baseline RDN angiogram showed no renal artery plaques, stenosis or lesions whatsoever, arteriography performed in emergency 6 months after RDN for malignant hypertension and fluid overload disclosed a 50–60% stenosis of the superior main left renal artery and three stenosis of the right renal artery (most severe stenosis 75–80%).
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Treatment of Resistant Hypertension Using a Radiofrequency Percutaneous Transluminal Angioplasty Catheter (REDUCE-HTN) protocol: 30%) in three other patients (patient nos. 2–4) treated using the same RDN system. Renal duplex performed per protocol at 6 months was in favour of haemodynamically significant stenosis in cases 1, 2 and 4, while flow velocities were normal at baseline. In case nos. 2 and 3, RDN was complicated by a mild dissection, without need for stenting. Patients 1–3 were recruited at the Cliniques Universitaires Saint-Luc (Brussels, Belgium) and patient 4 at the Hoˆpital Europe´en Georges Pompidou (Paris, France). All patients were included in the REDUCE-HTN study (NCT01541865). The main characteristics of patients at baseline and evolution at 6 months are summarized in Table 1. Taking into account the total number of RDN procedures performed with this system in our two centres (n ¼ 13), this gives an incidence of renal artery stenosis of 30.7%. While the latter needs reassessment in the whole REDUCE-HTN cohort, our results are worth notice, because computed tomography angiography (CTA) or magnetic resonance angiography (MRA) was performed in all our 13 patients, both at baseline and follow-up, which may not be the case in other centres. These findings support the need for CTA/MRA follow-up in all clinical studies evaluating new RDN catheters. Our observations should be discussed within the context of previous reports. Screening of the literature disclosed 25 other cases of de-novo renal artery stenosis or stenosis progression occurring after RDN performed using four
different renal ablation systems [1,4,6,12–27] (Table 2). Most cases were detected between 3 and 6 months after RDN, following blood pressure increase after an initial decrease and/or compared to baseline [12–21,24]. In two cases, the diagnosis was made in the context of recurrent episodes of flash pulmonary oedema and renal function degradation [21,24]. Notably, systematic CTA after RDN was performed in only three small cohorts [18,23,25,26], with an apparent prevalence of renal artery stenosis of 2/11 (18%), 3/46 (6.6%) and 2/15 (13.3%), respectively. In the absence of an independent and mandatory registry like those established for trans-catheter aortic valve implantation (TAVI) [28,29] and of systematic, state-of-the art axial imaging by a dedicated radiologist, it is unlikely that cases of renal artery stenosis occurring after RDN are systematically reported, or even detected. Many renal artery stenoses may be overlooked, or discovered only following blood pressure or renal function degradation, or even more threatening complications such as flash pulmonary oedema [21,24]. Furthermore, the prevalence, natural history and predictive factors of de-novo renal artery stenosis or stenosis progression after RDN are unknown. Whether some renal denervation systems are more prone to promote renal artery stenosis or vascular remodelling also remains to be established. The design of the catheter, the use of a balloon, the presence or absence of a cooling/irrigation system, the depth profile of the temperature increase during ablation may all play a role. It may be speculated that balloon catheters using radiofrequency ablation are more prone to
TABLE 1. Characteristics of patients with stenosis after renal denervation
Baseline characteristics Age (years) Sex BMI (kg/m2) Office BP Daytime ambulatory BP No. of antihypertensive drugs eGFR Right renal artery Length (mm) Mean diameter (mm) Baseline stenosis Left renal artery Length (mm) Mean diameter (mm) Baseline stenosis Per-procedural complications Stenosis Topography Time after renal denervation (months) Degree of stenosis (CT-angiography) Degree of stenosis (arteriography) Action taken Evolution at diagnosis of stenosis Office BP Daytime ambulatory BP No. of antihypertensive drugs eGFR
1
2
3
4
49 Female 26.8 190/98 167/92 4 84
55 Female 33.2 230/128 221/131 5 55
68 Female 34.1 210/90 189/84 2 68
65 Female 30.5 158/92 140/84 6 69
38 4.43 11%
66 4.66 18%
24 4.49 28%
76 5.0 29%
36 4.59 13% –
34 4.44 29% Minor dissection of the left ostial plaque
40 4.69 15% Minor dissection of the right ostial plaque
52 4.7 31% –
Bilateral multiple 6 – 50–80% Bilateral PTA
Left ostial 3 80% 44% Follow-up
Right ostial 3 40% 33% Follow-up
Left ostial 6 – 60% Follow-up
205/127 204/111 6 90
214/114 189/117 6 45
196/83 184/79 2 79
125/77 137/82 6 51
BP, blood pressure (mmHg); CT, computed tomography; eGFR, estimated glomerular filtration rate according to the Modification of Diet in Renal Disease (MDRD) formula (ml/min/ 1.73 m2); PTA, percutaneous angioplasty. Bilateral percutaneous angioplasty; stenting of the right renal artery due to a major dissection.
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Correspondence TABLE 2. Previous reports of renal artery stenosis following renal denervation RDN system
Studies [reference]
No. of cases
Pre-existing stenosis (N)
Time after RDN (months)
Bilateral/multiple stenosis (N)
Stenting (N)
Symplicity (Ardian–Medtronic) EnligHTN (Saint–Jude) Paradise (Recor, 1st generation) One Shot (Maya Covidien)
[1,3,4,6,12–27] EnligHTN I [23,24] REDUCE; Mabin et al. [25,26] RAPID; S. Verheye [27]
19 3 /46a 2/15a 1
5 2 No NR
6 (median) 5.5; 9 6 6
3 1 NR NR
14 1 1 –
CT, computed tomography; NR, not reported; RDN, renal denervation. a Systematic CT assessment 6 months after RDN.
induce arterial lesions and subsequent stenosis. Arguments in favour of this hypothesis include: theoretical concerns about extensive endothelial damage/plaque inflammation induced by balloon inflation, even at low pressure, because of stretching and metallic microelectrodes impaction; high proportion of renal artery stenosis using balloon ablation systems (7/33) despite the fact that most RDN procedures worldwide are still performed using the Symplicity system, a non-balloon catheter; occurrence of mild dissection in two of our 13 patients treated using the Vessix system. Finally, in upcoming randomized controlled studies, serial assessment of renal arteries by CTA or MRA should be considered both in the RDN and control groups, in order to estimate the contribution of lesions induced by RDN per se versus natural or accelerated progression of atherosclerotic disease. Notably, in a large US series [30], spontaneous progression of renal artery atherosclerotic stenosis assessed by arteriography was observed in only 11.1% of patients (133/1189) after a mean follow-up of 2.6 1.6 years. Independent predictors of disease progression were female sex, age, coronary artery disease at baseline, and time between baseline and follow-up [30]. Several studies aiming to address these important issues are currently planned or ongoing within the European Network COordinating research on Renal Denervation (ENCOReD) [31]. For the time being, we suggest that RDN should remain the last resort in patients with truly resistant hypertension, preferably in a research context (6); RDN should be considered as contra-indicated in the presence of renal artery stenosis of 50% or more; RDN systems using balloons should be avoided in patients with renal artery stenosis of 30% or more (an exclusion criteria of the REDUCE-HTN study) and/or plaques; a systematic follow-up by CTA or, if contra-indicated, MRA should be proposed 6–12 months after RDN, or earlier in case of dissection or other significant vascular damage during the procedure, blood pressure or renal function degradation or unexplained fluid overload/ flash pulmonary oedema; all cases of stenosis or stenosis progression should be collected in an independent registry; patients developing renal artery stenosis after RDN should be proposed for an indefinite follow-up.
ACKNOWLEDGEMENTS Conflicts of interest All four patients treated by the Vessix renal denervation system were included in the REDUCE-HTN study (NCT01541865). A.P., E.D., M.S., M.A. and J.R. are investigators in the REDUCE-HTN study (NCT01541865). A.P., M.S., M.A. and J.R. have been investigators of the SYMPLICITY HTN-2 trial. M.S. and M.A. are co-PI of the French 2104
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health ministry-funded DENER-HTN (NCT01570777) and DERENEDIAB (NCT01588795) studies. M.S. is member of Advisory Board of Cordis and ReCor medical and stock holder for ReCor.
REFERENCES 1. Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, et al. the SYMPLICITY HTN-3 Investigators. Controlled Trial of Renal Denervation for Resistant Hyper-tension. N Engl J Med 2014; 370:1393–1401. 2. Bo¨hm M, Mahfoud F, Ukena C, Bauer A, Fleck E, Hoppe UC, et al. Rationale and design of a large registry on renal denervation: the Global SYMPLICITY registry. EuroIntervention 2013; 9:484–492. 3. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009; 373:1275–1281. 4. Symplicity HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant hypertension. Durability of blood pressure reduction out to 24 months. Hypertension 2011; 57:911–917. 5. Davis MI, Filion KB, Zhang D, Eisenberg MJ, Afilalo J, Schiffrin EL, Joyal D. Effectiveness of renal denervation therapy for resistant hypertension: a systematic review and meta-analysis. J Am Coll Cardiol 2013; 62:231–241. 6. Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN2 Trial): a randomised controlled trial. Lancet 2010; 376:1903–1909. 7. Persu A, Renkin J, Thijs L, Staessen JA. Renal denervation: ultima ratio or standard in treatment-resistant hypertension. Hypertension 2012; 60:596–606. 8. Pellerin O, Sapoval M, Trinquart L, Redheuil A, Azarine A, Chatellier G, Mousseaux E. Accuracy of multidetector computed tomographic angiography assisted by postprocessing software for diagnosis atheromatous renal artery stenosis. Diagn Interv Imaging 2013; 94:1123– 1131. 9. Hutchinson BD, Keane D, Dodd JD. Renal sympathetic denervation: MDCT evaluation of the renal arteries. AJR Am J Roentgenol 2013; 201:W342–346. 10. Holmes DR Jr, Monahan KH, Packer D. Pulmonary vein stenosis complicating ablation for atrial fibrillation: clinical spectrum and interventional considerations. JACC Cardiovasc Interv 2009; 2:267– 276. 11. Templin C, Jaguszewski M, Ghadri JR, Sudano I, Gaehwiler R, Hellermann JP, et al. Vascular lesions induced by renal nerve ablation as assessed by optical coherence tomography: preand postprocedural comparison with the Simplicity( catheter system and the EnligHTN ( multielectrode renal denervation catheter. Eur Heart J 2013; 34:2141– 2148. 12. Krum H, Schlaich MP, Sobotka PA, Bo¨hm M, Mahfoud F, Rocha-Singh K, et al. Percutaneous renal denervation in patients with treatmentresistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet 2014; 383:622–629. 13. Kaiser L, Beister T, Wiese A, von Wedel J, Meincke F, Kreidel F, et al. Results of the ALSTER BP real-world registry on renal denervation employing the Symplicity system. EuroIntervention 2014; 10:157–165. 14. Vonend O, Antoch G, Rump LC, Blondin D. Secondary rise in blood pressure after renal denervation. Lancet 2012; 380:778. 15. Kaltenbach B, Id D, Franke JC, Sievert H, Hennersdorf M, Maier J, Bertog SC. Renal artery stenosis after renal sympathetic denervation. J Am Coll Cardiol 2012; 60:2694–2695.
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Correspondence 16. Bacaksiz A, Uyarel H, Jafarov P, Kucukbuzcu S. Iatrogenic renal artery stenosis after renal sympathetic denervation. Int J Cardiol 2014; 172:e389–e390. 17. Pucci G, Battista F, Lazzari L, Dominici M, Boschetti E, Schillaci G. Progression of renal artery stenosis after renal denervation. Circ J 2014; 78:767–768. 18. Versaci F, Trivisonno A, Olivieri C, Caranci F, Brunese L, Prati F. Late renal artery stenosis after renal denervation: Is it the tip of the iceberg? Int J Cardiol 2014; 172:e507–e508. 19. Jae´n A´guila FJ, Mediavilla Garcı´a JD, Navarro EM, Vargas Hitos JA, Ferna´ndez-Torres C. Bilateral renal artery stenosis after renal denervation. Hypertension 2014; 63:e126–e127. 20. Versaci F, Trivisonno A, Olivieri C, Magri G, Caranci F, Prati F. Is an abnormal vascular response after renal sympathetic denervation predictive of permanent damage? An unusual case of late renal artery stenosis after energy delivery. J Endovasc Ther 2014; 21:191–196. 21. Raman B, Pathik B, Bridgman C. Recurrent pulmonary oedema after percutaneous radiofrequency renal denervation. Int J Cardiol 2014; 174:e42–e43. 22. http://www.tctmd.com/show.aspx?id¼113832. [Accessed 26 February 2014]. 23. Worthley SG, Tsioufis CP, Worthley MI, Sinhal A, Chew DP, Meredith IT, et al. Safety and efficacy of a multielectrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial. Eur Heart J 2013; 34:2132–2140. 24. Chandra AP, Marron CD, Puckridge P, Spark JI. Severe bilateral renal artery stenosis after transluminal radiofrequency ablation of renal sympathetic nerve plexus. J Vasc Surg 2014; [Epub ahead of print]. 25. Mabin T, Sapoval M, Cabane V, Stemmett J, Iyer M. First experience with endovascular ultrasound renal denervation for the treatment of resistant hypertension. EuroIntervention 2012; 8:57–61. 26. http://www.tctmd.com/show.aspx?id¼120456. [Accessed 26 February 2014].
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27. http://www.tctmd.com/txshow.aspx?tid¼208&id¼121514&trid¼198. [Accessed 26 February 2014]. 28. Gilard M, Eltchaninoff H, Iung B, Donzeau-Gouge P, Chevreul K, Fajadet J, et al. FRANCE 2 Investigators. Registry of transcatheter aortic-valve implantation in high-risk patients. N Engl J Med 2012; 366:1705–1715. 29. Grube E, Sinning JM, Vahanian A. The Year in Cardiology 2013: valvular heart disease (focus on catheter-based interventions). Eur Heart J 2014; 35:490–495. 30. Crowley JJ1, Santos RM, Peter RH, Puma JA, Schwab SJ, Phillips HR, et al. Progression of renal artery stenosis in patients undergoing cardiac catheterization. Am Heart J 1998; 136:913–918. 31. Persu A, Jin Y, Azizi M, Baelen M, Vo¨lz S, Elvan A, et al. Blood pressure changes after renal denervation at 10 European expert centers. J Hum Hypertens 2014; 28:150–156.
Journal of Hypertension 2014, 32:2098–2105 a
Pole of Cardiovascular Research, Institut de Recherche Expe´rimentale et Clinique, Division of Cardiology, Cliniques Universitaires Saint-Luc, Universite´ Catholique de Louvain, Brussels, Belgium, cUniversite´ Paris-Descartes, Paris Sorbonne Cite´, dAssistance Publique – Hoˆpitaux de Paris, European Georges Pompidou Hospital, Interventional Radiology Unit, eAssistance Publique – Hoˆpitaux de Paris, European Georges Pompidou Hospital, Hypertension Unit, Paris, France and fDepartment of Radiology Cliniques Universitaires Saint-Luc, Universite´ Catholique de Louvain, Brussels, Belgium b
Correspondence to Alexandre Persu, MD, Ph.D, Cardiology Department, Cliniques Universitaires Saint Luc (UCL), 10 avenue Hippocrate, 1200 Brussels, Belgium. Tel: +32 2 764 63 06; fax: +32 2 764 89 80; e-mail: [email protected] J Hypertens 32:2098–2105 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000323
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ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES
P
ersua et al. [1] reported, in their recent article, an interesting expert consensus on the recommendations for daily practice in the definition, classification, diagnosis, and management of fibromuscular dysplasia (FMD) in adult patients with symptomatic involvement of the renal arteries, supra-aortic trunks, and digestive and peripheral arteries. We agree with their definition of FMD: ‘FMD is an idiopathic, segmental, nonatherosclerotic and noninflammatory disease of the musculature of arterial walls, leading to stenosis of small and mediumsized arteries. The diagnosis of FMD requires exclusion of renal artery spasm, arterial diseases of monogenic origin, and inflammatory arterial diseases’. The renal arteries and cervicocephalic trunks are most frequently involved. However, we reported the first case, to our knowledge, of an elderly patient with infrarenal aortic FMD associated with aortic hypoplasia and downstream aneurysm [2,3]. In rare cases, FMD has been described in the distal aorta and primarily associated with coarctation, which is a focal narrowing of the aorta. FMD has been exceptionally described to cause aortic aneurysms [4]. Both FMD and aortic hypoplasia are usually diagnosed in the first stage of life, with different latency periods. The clinical onset of aortic hypoplasia is usually characterized by severe hypertension and different pulses between the arms and legs. FMD is diagnosed between the second and the fourth decade, and particularly in childbearing-aged women, with milder symptoms. The coassociation of aortic hypoplasia with infrarenal aortic aneurysm has been described exceptionally and in patients older than those with aortic hypoplasia only. In our patient, we observed fibrous dysplasia of the media and intima, and atherosclerotic plaques were absent. Our findings suggest the combined effects of age (fibrous intimal thickening) and disease-related aortic wall degeneration and fibrosis. In fact, the severe loss of elastic fibers and thinning of the tunica media, the prominent muscle cells, and the segmental nonatherosclerotic narrowing of the aortic lumen provided the pathologic criteria for the diagnosis of FMD. The core matter that makes this case extremely rare is the finding, assessed by an expert team of pathologists, of a histologic pattern consistent with FMD in the site of aortic hypoplasia. Although the definition of FMD is strictly related to muscle arteries and to histopathologic changes and has typical angiographic features, the definition of aortic hypoplasia is based on the macroscopic appearance of an elastic vessel. The histopathologic finding consistent with FMD occurring in aortic hypoplasia indicates that the association between aortic hypoplasia and FMD does exist. What do you think about this case? How do you classify in your Consensus Document? 2098
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1. Persua A, Giavarinic A, Touze´ E, Januszewiczf A, Sapovalg M, Azizic M, et al., on behalf of the ESH Working Group ‘Hypertension and the Kidney’. European consensus on the diagnosis and management of fibromuscular dysplasia. J Hypertens 2014; 32:1367–1378. 2. Odero A, Bozzani A, Arici V, Agozzino M. Hypoplasia and fibromuscular dysplasia of infrarenal abdominal aorta with downstream aneurysm: case report and review of the literature. J Vasc Surg 2008; 48:1589–1592. 3. Bozzani A, Moia A, Carlino M, Caldana M, Ragni F. Response to ‘Fibromuscular dysplasia affecting a two-branched renal artery in a patient with a solitary kidney: case presentation’. Clin Cardiol 2013; 36:E50. 4. Matsushita M, Yano T, Ikezawa T, Sakurai T, Nimura Y, Shionoya S. Fibromuscular dysplasia as a cause of abdominal aortic aneurysm. Cardiovasc Surg 1994; 2:615–618.
Journal of Hypertension 2014, 32:2098–2105 Division of Vascular Surgery, Foundation I.R.C.C.S. Policlinico San Matteo, Pavia, Italy Correspondence to Antonio Bozzani, MD, Division of Vascular Surgery, Foundation I.R.C.C.S. Policlinico San Matteo, Viale Camillo Golgi, 19, 27100 Pavia, Italy. Tel: +39 382 502068; fax: +39 382 502007; e-mail: [email protected] J Hypertens 32:2098–2105 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000314
Reply Alexandre Persu a,b, Andrzej Januszewicz c, Alberto Morganti d, Pierre-Franc¸ois Plouin e,f, and Peter de Leeuw g
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e thank Bozzani and Arici [1] for drawing our attention on a case of aortic hypoplasia associated with fibromuscular dysplasia (FMD)-like lesions [2]. As indicated in our consensus document [3], ‘mid-aortic syndrome (also called hypoplasia or coarctation of the abdominal aorta), [. . .] may also be associated with renal artery stenosis, – particularly in children – and in some cases, histological lesions similar to those of medial fibromuscular dysplasia (FMD) may be observed on examination of the aorta or renal artery’. Though rare, the finding of this association in a 77-year-old patient [2] is not unexpected, as both entities were occasionally described in older patients [4,5]. However, in this consensus, we chose to restrict the term ‘FMD’ to patients with involvement of small and middle-sized arteries, and to consider FMD-like lesions of large vessels such as the aorta as a separate entity [3]. Admittedly, as long as the genetic and molecular aetiopathology of FMD remains obscure, any classification is to some extent arbitrary. Volume 32 Number 10 October 2014
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ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES 1. Bozzani A, Arici V. Diagnosis and management of fibromuscular dysplasia. J Hypertens 2014; 32:2098. 2. Odero A, Bozzani A, Arici V, Agozzino M. Hypoplasia and fibromuscular dysplasia of infrarenal abdominal aorta with downstream aneurysm: case report and review of the literature. J Vasc Surg 2008; 48:1589– 1592. 3. Persu A, Giavarini A, Touze´ E, Januszewicz A, Sapoval M, Azizi M, et al. European consensus on the diagnosis and management of fibromuscular dysplasia. J Hypertens 2014; 32:1367–1378. 4. Prieto LN, Dyer CB, Thompson PM, Whigham C Jr. The oldest reported patient with fibromuscular dysplasia of the renal artery. South Med J 1996; 89:405–408. 5. Sung SA, Hwang YH, Lee SY, Cho YK, Kwon TW. An infrarenal aortic hypoplasia presented with claudication. J Korean Med Sci 2010; 25:950– 952.
Journal of Hypertension 2014, 32:2098–2105 a Pole of Cardiovascular Research, Institut de Recherche Expe´rimentale et Clinique, Universite´ Catholique de Louvain, bDivision of Cardiology, Cliniques Universitaires Saint-Luc, Universite´ Catholique de Louvain, Brussels, Belgium, cDepartment of Hypertension, Institute of Cardiology, Warsaw, Poland, dDepartment of Internal Medicine and Hypertension Center, San Giuseppe Hospital, University of Milan, Milan, Italy, eHypertension Unit, Assistance Publique – Hoˆpitaux de Paris, European Georges Pompidou Hospital, fUniversite´ Paris-Descartes, Paris Sorbonne Cite´, Paris, France and gDepartment of Medicine, University Hospital Maastricht, Maastricht, the Netherlands
Correspondence to Professor Alexandre Persu, MD, PhD, Division of Cardiology, Cliniques Universitaires Saint-Luc (UCL), 10 Avenue Hippocrate 1200, Brussels, Belgium. Tel secretary: þ32 2 764 63 06, Tel: +32 2 764 25 33; fax: +32 2 764 89 80; e-mail: [email protected] J Hypertens 32:2098–2105 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000315
Contribution of the ABP-International study to the definition of night-time tachycardia Paolo Palatini a, Gianpaolo Reboldi b, Lawrence J. Beilin c, Kazuo Eguchi d, Yutaka Imai e, Kazuomi Kario d, Takayoshi Ohkubo e,f, Sante D. Pierdomenico g, Joseph E. Schwartz h,i, Lindon Wing j, and Paolo Verdecchia k
A
large number of studies have shown that high heart rate (HR) is associated with adverse cardiovascular outcome in patients with hypertension or cardiovascular diseases and that it should be considered an important component of the cardiovascular risk profile [1]. However, controversy still exists on the normal limits for this clinical variable. In most studies, participants were considered to have tachycardia if they were in the highest
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quartile or quintile of the HR distribution because a clinically relevant increase in the risk of cardiovascular events (CVEs) or mortality was found in the participants of the top HR quantile. According to this approach, the upper normal limit for resting HR was set at 80–85 bpm, which corresponds to the lower limit of the top quantile in most population studies. More recently, some investigators have focused their attention on HR measured with 24-h ambulatory recording and found that among the ambulatory HRs, average night-time HR but not daytime HR was an independent predictor of cardiovascular or noncardiovascular mortality [2–6]. In some studies, its association with outcome also appeared to be stronger than that of office HR [3,4]. This finding again raises the issue of how to identify the upper normal limit for HR recorded during the nighttime. Clearly, HR during sleep is much lower than HR measured in the office by healthcare personnel [2–10] with differences ranging from 6.5 (in the International Database of Ambulatory blood pressure in relation to Cardiovascular Outcome (IDACO) study [6]) to 12.1 bpm (in the Hypertension and Ambulatory Recording VEnetia STudy (HARVEST) [10]). In a recent article published in this Journal, Vinyoles et al. [11] used data from a large cross-sectional study to identify the night-time threshold associated with ‘cardiovascular risk office tachycardia,’ which was defined as an office HR of at least 85 bpm. Different night-time thresholds were estimated by receiver-operating characteristic (ROC) curve analysis and the authors selected the optimal threshold that maximized the sum of sensitivity and specificity. According to this approach, the night-time HR value that best predicted cardiovascular risk office tachycardia in their sample was higher than 66 bpm for the whole group with different thresholds for the two sexes (>65 bpm in men and >68 bpm in women). However, this threshold is close to the median value of the night-time HR distribution in most studies [2–10] and thus can hardly be proposed as the upper limit of normal for this variable. As Vinyoles et al. themselves admitted, an important limitation of their approach was the cross-sectional design of their study, which did not allow the investigators to establish a night-time HR threshold prospectively associated to hard endpoints [11]. This issue could be appropriately addressed in the ABPInternational database [3], the largest ever study of hypertensive patients assessed with ambulatory HR monitoring (n ¼ 7600). In that study, we found an independent association of ambulatory HR with the combination of fatal and nonfatal CVE [3]. Among the ambulatory HRs, night-time HR showed the strongest predictive value for cardiovascular outcomes. This relationship was linear and similar in the two sexes. In a new unpublished analysis of the ABPInternational data, using the lower limit of the top (fifth) quintile to identify the upper limit of normal, the threshold for resting office tachycardia was 85.0 bpm (Fig. 1). The corresponding value for average night-time HR was 73.1 bpm. The lower limits of the top quartile and top tertile for night-time HR in the ABP-International study were 71.0 and 69.0 bpm, respectively, well above the threshold proposed by Vinyoles et al. and the median value was 65 bpm. Interestingly, in the ABP-International study, the lower limit of the top night-time HR quintile was exactly the same in the www.jhypertension.com
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Correspondence Office heart rate 14
Night-time heart rate 14
85
12
12
10
10
8
8
6
6
4
4
2
2
0
73
0 40 46 52 58 64 70 76 82 88 94 100 106 112
31 37 43 49 55 61 67 73 79 85 91 97 103
Beats per minute
Beats per minute
FIGURE 1 Distribution of office heart rate and average night-time heart rate in 7600 hypertensive participants (4165 men) from the ABP-International Study. The dotted line corresponds to the lower limit of the top heart rate quintile. Office heart rate: median (interquartile range) ¼ 76 (68–83) bpm. Coefficient of skewness ¼ 0.43, coefficient of Kurtosis ¼ 0.48 (both P < 0.0001). Kolmogorov–Smirnov test for normal distribution, P < 0.0001. Night-time heart rate: median (interquartile range) ¼ 65 (59–71) bpm. Coefficient of skewness ¼ 0.41, coefficient of Kurtosis ¼ 0.40 (both P < 0.0001). Kolmogorov–Smirnov test for normal distribution, P < 0.0001.
two sexes (73.1 bpm), thereby avoiding the problem of using different sex-specific reference values. Using a timedependent ROC curve analysis, the optimal night-time HR cutoff value for prediction of CVEs at 10 years in the ABP-International participants was 73.6 bpm, with 84% specificity, 22% sensitivity, 89% negative predictive value and 16% positive predictive value. As the clinical significance of HR in hypertension is still debated, we believe that a high specificity better suits the application of this variable in clinical practice. In a multivariable fully adjusted Cox model, compared with the bottom quintile (HR 66 bpm) with resting office tachycardia of cardiovascular risk (>84 bpm)
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described in the Framingham cohort of hypertensive patients [6].
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES 1. Palatini P, Reboldi G, Beilin LJ, Eguchi K, Imai Y, Kario K, et al. Contribution of the ABP-International study to the definition of nighttime tachycardia. J Hypertens 2014; 32:2099–2100. 2. Vinyoles E, de la Sierra A, Roso A, de la Cruz JJ, Gorostidi M, Segura J, et al. Night-time heart rate threshold definition by resting office tachycardia in untreated hypertensive patients: data of the Spanish ABPM registry. J Hypertens 2014; 32:1016–1024. 3. Prineas RJ, Le A, Soliman EZ, Zhang ZM, Howard VJ, Ostchega Y, et al. US national prevalence of electrocardiographic abnormalities in black and white middle aged (45–64 years) and older (65 years) adults (from the reasons for geographic and racial differences in Stroke study). Am J Cardiol 2012; 109:1223–1228. 4. Hall MH, Middleton K, Thayer JF, Lewis TT, Kline CE, Matthews KA, et al. Racial differences in heart rate variability during sleep in women: the study of women across the nation sleep study. Psychosom Med 2013; 75:783–790. 5. Palatini P, Casiglia E, Pauletto P, Staessen J, Kaciroti N, Julius S. Relationship of tachycardia with high blood pressure and metabolic abnormalities: a study with mixture analysis in three populations. Hypertension 1997; 30:1267–1273. 6. Gillmann MW, Kannel WB, Belanger A, D’Agostino RB. Influence of heart rate on mortality among persons with hypertension: the Framingham study. Am Heart J 1993; 125:1148–1154.
Journal of Hypertension 2014, 32:2098–2105 a La Mina Primary Care Center, University of Barcelona, bHypertension Unit, Hospital Mu´tua de Terrassa, University of Barcelona, cJordi Gol Institute for Research in Primary Care, Barcelona, dDepartment of Preventive Medicine and Public Health, Universidad Auto´noma de Madrid, CIBER en Epidemiologı´a y Salud Pu´blica, Madrid, eNephrology Service, Hospital Universitario Central de Asturias, Oviedo, fHypertension Unit, Doce de Octubre Hospital, Madrid and gHypertension Unit, Instituto de Investigacio´n Sanitaria. Hospital Clı´nico San Carlos, Madrid, Spain
Correspondence to Ernest Vinyoles, CAP La Mina. Carrer Mar s/n, 08930 - Sant Adria` de Beso`s, Spain. Tel: +34 933811593; fax: +34 933812141; e-mail: 23561evb@ comb.cat J Hypertens 32:2098–2105 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000335
Renal artery stenosis following renal denervation: a matter of concern Alexandre Persu a,b, Marc Sapoval c,d, Michel Azizi c,e, Matthieu Monge e, Etienne Danse f, Frank Hammer f, and Jean Renkin a,b
I
n the recent Symplicity HTN-3 trial [1] – the singleblinded randomized controlled trial in the field so far – renal sympathetic denervation (RDN) by radiofrequency using the Ardian–Medtronic system failed to show superiority over medical treatment alone in patients with www.jhypertension.com
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drug treatment-resistant hypertension. Nevertheless, the global SYMPLICITY registry [2] continues to recruit, and RDN is still proposed as treatment of resistant hypertension all over Europe (http://www.tctmd.com/show.aspx?id= 123265), partly based on apparent efficacy in previous observational [3–5] and unblinded studies [6], partly on overall safety in previous Symplicity studies [1–4,6]. In particular, in Symplicity HTN-3 [1], only one de novo renal artery stenosis was detected after RDN (0.3%), versus 0 in the sham group. However, it should be pointed out that screening was based on renal duplex rather than on computed tomography (CT) scan, which is state of the art [7–9], assessment was performed only 6 months after RDN, and stenosis 70% or less were not taken into consideration [1]. In other Symplicity studies and registries [2–4,6], assessment of renal arteries after RDN was neither systematic nor state of the art [7]. Furthermore, whether safety data obtained with the Ardian–Medtronic system can be extrapolated to other RDN systems remains to be demonstrated. In theory, the vascular thermal lesions provoked by radiofrequency may induce renal artery stenoses, as reported for pulmonary veins after radiofrequency ablation for atrial fibrillation [10]. Optical coherence tomography (OCT) performed in a prospective series of 16 patients with resistant hypertension disclosed renal artery constriction and local tissue damage with oedema and thrombus formation at the ablation site after RDN using the Symplicity or the EnligHTN multielectrode RDN catheters [11]. While the clinical relevance and prognostic value of such lesions are still unclear, long-term safety of renal artery ablation remains thus a legitimate concern.
We report here a case of multiple bilateral stenoses (Fig. 1) associated with severe hypertension (SBP 240– 260 mmHg), fluid retention, dyspnoea and tachycardia, occurring 6 months after RDN, using the Vessix–Boston radiofrequency balloon catheter in a patient with previously normal renal arteries (patient no. 1). Cardiac echography showed minor mitral insufficiency and left atrial dilatation, with preserved ejection fraction. Renal function was normal. The renal angiogram showed a 50–60% stenosis of the superior main left renal artery and three stenosis of the right renal artery (most severe 75–80%). Three consecutives angioplasties (1.5–2 min inflations) of the right renal artery were performed with a 4 20 mm monorail balloon (Sterling, Boston Medical). The result was acceptable, but not perfect (30% residual stenosis). On the basis of the initial quantitative measurements during index ablation procedure (5 mm Vessix balloon), a second dilatation was done with a 5 20 mm balloon (Rx Viatrac, Abbott), inducing a major dissection. In the absence of improvement after prolonged low-pressure dilatation, a 6 40 mm nitinol self-expandable stent (Astron Pulsar, Biotronik) was implanted in the right renal artery. The procedure was followed by polyuria, rapid resolution of symptoms, body weight loss and improvement of blood pressure after discharge (205/127 mmHg). Six months later, control arteriography showed progression of the left renal artery stenosis to 70–80%. Angioplasty of the left renal artery was performed, without further improvement of blood pressure. Furthermore, we document unexpected progression of mild baseline stenosis (28–31%; exclusion limit in the
FIGURE 1 Arteriography of the left (panels a and b) and right (panels c and d) renal arteries of case 1 immediately after renal sympathetic denervation (RDN) (panels a and c) and 6 months later (panels b and d). Although baseline RDN angiogram showed no renal artery plaques, stenosis or lesions whatsoever, arteriography performed in emergency 6 months after RDN for malignant hypertension and fluid overload disclosed a 50–60% stenosis of the superior main left renal artery and three stenosis of the right renal artery (most severe stenosis 75–80%).
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Treatment of Resistant Hypertension Using a Radiofrequency Percutaneous Transluminal Angioplasty Catheter (REDUCE-HTN) protocol: 30%) in three other patients (patient nos. 2–4) treated using the same RDN system. Renal duplex performed per protocol at 6 months was in favour of haemodynamically significant stenosis in cases 1, 2 and 4, while flow velocities were normal at baseline. In case nos. 2 and 3, RDN was complicated by a mild dissection, without need for stenting. Patients 1–3 were recruited at the Cliniques Universitaires Saint-Luc (Brussels, Belgium) and patient 4 at the Hoˆpital Europe´en Georges Pompidou (Paris, France). All patients were included in the REDUCE-HTN study (NCT01541865). The main characteristics of patients at baseline and evolution at 6 months are summarized in Table 1. Taking into account the total number of RDN procedures performed with this system in our two centres (n ¼ 13), this gives an incidence of renal artery stenosis of 30.7%. While the latter needs reassessment in the whole REDUCE-HTN cohort, our results are worth notice, because computed tomography angiography (CTA) or magnetic resonance angiography (MRA) was performed in all our 13 patients, both at baseline and follow-up, which may not be the case in other centres. These findings support the need for CTA/MRA follow-up in all clinical studies evaluating new RDN catheters. Our observations should be discussed within the context of previous reports. Screening of the literature disclosed 25 other cases of de-novo renal artery stenosis or stenosis progression occurring after RDN performed using four
different renal ablation systems [1,4,6,12–27] (Table 2). Most cases were detected between 3 and 6 months after RDN, following blood pressure increase after an initial decrease and/or compared to baseline [12–21,24]. In two cases, the diagnosis was made in the context of recurrent episodes of flash pulmonary oedema and renal function degradation [21,24]. Notably, systematic CTA after RDN was performed in only three small cohorts [18,23,25,26], with an apparent prevalence of renal artery stenosis of 2/11 (18%), 3/46 (6.6%) and 2/15 (13.3%), respectively. In the absence of an independent and mandatory registry like those established for trans-catheter aortic valve implantation (TAVI) [28,29] and of systematic, state-of-the art axial imaging by a dedicated radiologist, it is unlikely that cases of renal artery stenosis occurring after RDN are systematically reported, or even detected. Many renal artery stenoses may be overlooked, or discovered only following blood pressure or renal function degradation, or even more threatening complications such as flash pulmonary oedema [21,24]. Furthermore, the prevalence, natural history and predictive factors of de-novo renal artery stenosis or stenosis progression after RDN are unknown. Whether some renal denervation systems are more prone to promote renal artery stenosis or vascular remodelling also remains to be established. The design of the catheter, the use of a balloon, the presence or absence of a cooling/irrigation system, the depth profile of the temperature increase during ablation may all play a role. It may be speculated that balloon catheters using radiofrequency ablation are more prone to
TABLE 1. Characteristics of patients with stenosis after renal denervation
Baseline characteristics Age (years) Sex BMI (kg/m2) Office BP Daytime ambulatory BP No. of antihypertensive drugs eGFR Right renal artery Length (mm) Mean diameter (mm) Baseline stenosis Left renal artery Length (mm) Mean diameter (mm) Baseline stenosis Per-procedural complications Stenosis Topography Time after renal denervation (months) Degree of stenosis (CT-angiography) Degree of stenosis (arteriography) Action taken Evolution at diagnosis of stenosis Office BP Daytime ambulatory BP No. of antihypertensive drugs eGFR
1
2
3
4
49 Female 26.8 190/98 167/92 4 84
55 Female 33.2 230/128 221/131 5 55
68 Female 34.1 210/90 189/84 2 68
65 Female 30.5 158/92 140/84 6 69
38 4.43 11%
66 4.66 18%
24 4.49 28%
76 5.0 29%
36 4.59 13% –
34 4.44 29% Minor dissection of the left ostial plaque
40 4.69 15% Minor dissection of the right ostial plaque
52 4.7 31% –
Bilateral multiple 6 – 50–80% Bilateral PTA
Left ostial 3 80% 44% Follow-up
Right ostial 3 40% 33% Follow-up
Left ostial 6 – 60% Follow-up
205/127 204/111 6 90
214/114 189/117 6 45
196/83 184/79 2 79
125/77 137/82 6 51
BP, blood pressure (mmHg); CT, computed tomography; eGFR, estimated glomerular filtration rate according to the Modification of Diet in Renal Disease (MDRD) formula (ml/min/ 1.73 m2); PTA, percutaneous angioplasty. Bilateral percutaneous angioplasty; stenting of the right renal artery due to a major dissection.
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Correspondence TABLE 2. Previous reports of renal artery stenosis following renal denervation RDN system
Studies [reference]
No. of cases
Pre-existing stenosis (N)
Time after RDN (months)
Bilateral/multiple stenosis (N)
Stenting (N)
Symplicity (Ardian–Medtronic) EnligHTN (Saint–Jude) Paradise (Recor, 1st generation) One Shot (Maya Covidien)
[1,3,4,6,12–27] EnligHTN I [23,24] REDUCE; Mabin et al. [25,26] RAPID; S. Verheye [27]
19 3 /46a 2/15a 1
5 2 No NR
6 (median) 5.5; 9 6 6
3 1 NR NR
14 1 1 –
CT, computed tomography; NR, not reported; RDN, renal denervation. a Systematic CT assessment 6 months after RDN.
induce arterial lesions and subsequent stenosis. Arguments in favour of this hypothesis include: theoretical concerns about extensive endothelial damage/plaque inflammation induced by balloon inflation, even at low pressure, because of stretching and metallic microelectrodes impaction; high proportion of renal artery stenosis using balloon ablation systems (7/33) despite the fact that most RDN procedures worldwide are still performed using the Symplicity system, a non-balloon catheter; occurrence of mild dissection in two of our 13 patients treated using the Vessix system. Finally, in upcoming randomized controlled studies, serial assessment of renal arteries by CTA or MRA should be considered both in the RDN and control groups, in order to estimate the contribution of lesions induced by RDN per se versus natural or accelerated progression of atherosclerotic disease. Notably, in a large US series [30], spontaneous progression of renal artery atherosclerotic stenosis assessed by arteriography was observed in only 11.1% of patients (133/1189) after a mean follow-up of 2.6 1.6 years. Independent predictors of disease progression were female sex, age, coronary artery disease at baseline, and time between baseline and follow-up [30]. Several studies aiming to address these important issues are currently planned or ongoing within the European Network COordinating research on Renal Denervation (ENCOReD) [31]. For the time being, we suggest that RDN should remain the last resort in patients with truly resistant hypertension, preferably in a research context (6); RDN should be considered as contra-indicated in the presence of renal artery stenosis of 50% or more; RDN systems using balloons should be avoided in patients with renal artery stenosis of 30% or more (an exclusion criteria of the REDUCE-HTN study) and/or plaques; a systematic follow-up by CTA or, if contra-indicated, MRA should be proposed 6–12 months after RDN, or earlier in case of dissection or other significant vascular damage during the procedure, blood pressure or renal function degradation or unexplained fluid overload/ flash pulmonary oedema; all cases of stenosis or stenosis progression should be collected in an independent registry; patients developing renal artery stenosis after RDN should be proposed for an indefinite follow-up.
ACKNOWLEDGEMENTS Conflicts of interest All four patients treated by the Vessix renal denervation system were included in the REDUCE-HTN study (NCT01541865). A.P., E.D., M.S., M.A. and J.R. are investigators in the REDUCE-HTN study (NCT01541865). A.P., M.S., M.A. and J.R. have been investigators of the SYMPLICITY HTN-2 trial. M.S. and M.A. are co-PI of the French 2104
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health ministry-funded DENER-HTN (NCT01570777) and DERENEDIAB (NCT01588795) studies. M.S. is member of Advisory Board of Cordis and ReCor medical and stock holder for ReCor.
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Journal of Hypertension 2014, 32:2098–2105 a
Pole of Cardiovascular Research, Institut de Recherche Expe´rimentale et Clinique, Division of Cardiology, Cliniques Universitaires Saint-Luc, Universite´ Catholique de Louvain, Brussels, Belgium, cUniversite´ Paris-Descartes, Paris Sorbonne Cite´, dAssistance Publique – Hoˆpitaux de Paris, European Georges Pompidou Hospital, Interventional Radiology Unit, eAssistance Publique – Hoˆpitaux de Paris, European Georges Pompidou Hospital, Hypertension Unit, Paris, France and fDepartment of Radiology Cliniques Universitaires Saint-Luc, Universite´ Catholique de Louvain, Brussels, Belgium b
Correspondence to Alexandre Persu, MD, Ph.D, Cardiology Department, Cliniques Universitaires Saint Luc (UCL), 10 avenue Hippocrate, 1200 Brussels, Belgium. Tel: +32 2 764 63 06; fax: +32 2 764 89 80; e-mail: [email protected] J Hypertens 32:2098–2105 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000323
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