Atenolol versus Losartan in Marfan s Syndrome

estimated GFR slopes to evaluate the benefit of therapy. In our study, patients in the low-bloodpressure group, as compared with patients in the standard-blood-pressure group, had a slower increase in total kidney volume (P = 0.006), a greater reduction in the left-ventricular-mass index (P<0.001), and reduced urinary albumin excretion (P<0.001). We also agree that the on-treatment slope of the estimated GFR shows a benefit for the low blood-pressure group (P = 0.05). In patients with chronic kidney disease such as ADPKD, the degree of proteinuria is a risk factor for cardiovascular complications and a decrease in kidney function. Thus, Wetzels s point is valid in that dual renin angiotensin blockade may be indicated if it is shown to lower urinary protein excretion significantly more than monotherapy and is safe. Such may be the case in younger patients with ADPKD. We agree with Benck et al. that aiming for blood pressure of less than 120/80 mm Hg may not be advisable in patients with chronic kidney disease, particularly in elderly patients. However, among patients with chronic kidney disease who have type 2 diabetes, those with blood pressure lower than 130/80 mm Hg have fewer complications and longer survival than those with blood pressure lower than 140/90 mm Hg. 1 Robert W. Schrier, M.D. University of Colorado School of Medicine Aurora, CO robert.schrier@ucdenver.edu Since publication of his article, the author reports no further potential conflict of interest. 1. Schrier RW, Savage S. Appropriate Blood Pressure Control in type II diabetes (ABCD Trial): implications for complications. Am J Kidney Dis 1992;20:653-7. DOI: 10.1056/NEJMc1500332 Atenolol versus Losartan in Marfan s Syndrome To the Editor: Lacro et al. (Nov. 27 issue) 1 report no benefit of losartan, an angiotensinreceptor blocker (ARB), over the beta-blocker atenolol in respect to the rate of aortic-root dilatation in Marfan s syndrome. A possible interpretation of this study might be that ARBs are as effective as beta-blockers in the treatment of patients with Marfan s syndrome. 2 However, such an interpretation assumes that beta-blockers are an effective treatment option. Beta-blockers are presently considered to be first-line therapy in patients with Marfan s syndrome. However, their benefit is debatable and not supported by robust evidence. Several observational studies and only one clinical trial 3 have evaluated the effectiveness of beta-blockers in patients with Marfan s syndrome, and the results have been conflicting. Two meta-analyses also reached opposing conclusions 4,5 (Table 1). Remarkably, no study showed a benefit of betablockers in preventing clinical end points (e.g., death or dissection). As a reflection of these uncertainties, the 2010 guidelines of the American College of Cardiology Foundation and the American Heart Association recommend the use of beta-blockers, whereas the 2014 guidelines of the European Society of Cardiology do not. If beta-blockers are not truly effective, then the study by Lacro et al. has really shown that ARBs are as effective as a placebo. Bulat A. Ziganshin, M.D. Sandip K. Mukherjee, M.D. John. A. Elefteriades, M.D. Aortic Institute at Yale New Haven Hospital New Haven, CT john.elefteriades@yale.edu 1. Lacro RV, Dietz HC, Sleeper LA, et al. Atenolol versus losartan in children and young adults with Marfan s syndrome. N Engl J Med 2014;371:2061-71. 2. Bowen JM, Connolly HM. Of Marfan s syndrome, mice, and medications. N Engl J Med 2014;371:2127-8. 3. Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan s syndrome. N Engl J Med 1994;330:1335-41. 4. Gersony DR, McClaughlin MA, Jin Z, Gersony WM. The effect of beta-blocker therapy on clinical outcome in patients with Marfan s syndrome: a meta-analysis. Int J Cardiol 2007;114: 303-8. 5. Gao L, Mao Q, Wen D, Zhang L, Zhou X, Hui R. The effect of beta-blocker therapy on progressive aortic dilatation in children and adolescents with Marfan s syndrome: a meta-analysis. Acta Paediatr 2011;100(9):e101-e105. n engl j med 372;10 nejm.org march 5, 2015 977

The new england journal of medicine Table 1. Studies on the Effectiveness of Beta-Blockers in Patients with Marfan s Syndrome.* Type of Trial and Author Year of Publication Designed to Evaluate Beta- Blocker Effect? Beta-Blocker Group Control Group Study Results No. of Patients Age Patients with Clinical End Points No. of Patients Age Patients with Clinical End Points Do Beta-Blockers Slow Aortic Dilatation? Do Beta-Blockers Prevent Clinical End Points? Randomized clinical trial: Shores et al. Observational study yr no./total no. (%) yr no./total no. (%) 1994 Yes 32 15.4 5/32 (16) 38 14.5 9/38 (24) Yes No (P = 0.40) Tahernia 1993 Yes 3 10.0±1.0 0/3 3 8.3±4.9 0/3 Yes No (P = 1.0) Roman et al. 1993 No 79 28±15 18/79 (23) 34 28±15 3/34 (9) NA No (P = 0.08) Salim et al. 1994 Yes 100 11.1±3.4 5/100 (5) 13 10.2±4.6 0/13 Yes No (P = 1.00) Silverman et al. 1995 No 191 33±14 58/191 (30) 226 31±17 54/226 (24) NA No (P = 0.14) Legget et al. 1996 No 28 21 9/28 (32) 55 21 8/55 (15) NA No (P = 0.06) Rossi-Foulkes et al. 1999 Yes 15 11.2±5.3 4/15 (27) 27 8.0±5.2 0/16 Yes No (P = 0.04) Tierney et al. 2007 Yes 29 9.2±4.0 1/29 (3) 34 8.8±4.8 3/34 (9) No No (P = 0.62) Ladouceur et al. 2007 Yes 77 6.1±3.2 3/77 (4) 78 7.4±5.2 8/78 (10) Yes No (P = 0.12) Meta-analysis Gersony et al. 2007 NA NA NA NA NA NA NA NA No Gao et al. 2011 NA NA NA NA NA NA NA Yes** No * Plus minus values are means ±SD. NA denotes not available in the study. Clinical end points included death or related cardiovascular events. Of the eight listed observational studies, four involved fewer than 30 patients. The listed value is a median. The meta-analysis by Gersony et al. 4 includes studies by Tahernia, Roman et al., Shores et al., Salim et al., Silverman et al., and Legget et al. In this meta-analysis, there was no evidence that beta-blocker therapy had a clinical benefit in patients with Marfan s syndrome. The meta-analysis by Gao et al. 5 includes studies by Tahernia, Salim et al., Rossi-Foulkes et al., Tierney et al., and Ladouceur et al. In this meta-analysis, there was evidence that betablocker therapy could slow down the rate of dilatation of the aorta and had clinical benefits in children and adolescents with Marfan s syndrome. ** Although this meta-analysis included the study by Tierney et al., the calculations on aortic growth rates did not include findings from that study. 978 n engl j med 372;10 nejm.org march 5, 2015

To the Editor: The evidence is accruing for pharmacologic protection against aortic dilatation in patients with Marfan s syndrome. Meanwhile, families still face the anxiety of monitoring with echocardiography until a size threshold is reached when root replacement is advised. 1 Some patients will have aortic dissection before surgery is advocated. Personalized external aortic-root support (PEARS) is an alternative to replacement for patients with genetically determined root aneurysms before the aortic valve fails or the size of the root aneurysm mandates root replacement. 2 During the past 10 years, more than 40 patients whose somatic growth was complete have undergone a procedure in which a computer-modeled, macroporous, pliant mesh sleeve was placed around the aorta from the aortoventricular junction to beyond the brachiocephalic artery. This intimately fitting support becomes incorporated into the aortic adventitia to form a composite nonexpansile aortic wall. 3 This does not preclude any future surgical options. The aortic root retains the same shape and size, thereby conserving aortic-valve anatomy and function (Fig. 1). The physiologic blood endothelial interface is preserved, so no anticoagulation is required. Outcomes have been published for the first 30 patients who underwent surgery 1 to 10 years ago. 4 Twenty patients have a stable aortic root and valve at more than 5 years of follow-up. Tom Treasure, M.D. University College London tom.treasure@gmail.com John Pepper, F.R.C.S. Royal Brompton Hospital Raad Mohiaddin, M.D. Imperial College London A 2004 B 2014 Figure 1. Patient with Marfan s Syndrome before and after Undergoing Personalized External Aortic-Root Support. Shown are long-axis magnetic resonance images of the ascending aorta obtained in 2004 and in 2014. The aortic root, which had been increasing in size before 2004, was held stable at a largest sinus of Valsalva diameter of 49 mm, without aortic regurgitation (Panels A and B, green arrows). The incorporated mesh support cannot be seen, but some thickening is visible, owing to incorporation with collagen fibers where there is a mesh aorta composite wall (Panel B, yellow arrows). The inset images show the aortic cross section at the level of coaptation of the aortic-valve leaflets (green arrows). n engl j med 372;10 nejm.org march 5, 2015 979

The new england journal of medicine 1. Bowen JM, Connolly HM. Of Marfan s syndrome, mice, and medications. N Engl J Med 2014;371:2127-8. 2. Treasure T, Crowe S, Chan KM, et al. A method for early evaluation of a recently introduced technology by deriving a comparative group from existing clinical data: a case study in external support of the Marfan aortic root. BMJ Open 2012; 2(2):e000725. 3. Pepper J, Goddard M, Mohiaddin R, Treasure T. Histology of a Marfan aorta 4.5 years after personalized external aortic root support. Eur J Cardiothorac Surg 2014 November 18 (Epub ahead of print). 4. Treasure T, Takkenberg JJ, Golesworthy T, et al. Personalised external aortic root support (PEARS) in Marfan syndrome: analysis of 1-9 year outcomes by intention-to-treat in a cohort of the first 30 consecutive patients to receive a novel tissue and valve-conserving procedure, compared with the published results of aortic root replacement. Heart 2014;100:969-75. To the Editor: Losartan was shown to be superior to propranolol in mice with Marfan s syndrome. 1 However, hemodynamic data were not provided in that study to show equal effectiveness in reducing blood pressure. Losartan is not an antagonist of transforming growth factor β (TGF-β) but, rather, an ARB. It did not reduce circulating TGF-β levels in patients with Marfan s syndrome. 2 A reduction in TGF-β is not a prerequisite for the beneficial effect of losartan. Patients with a reduction in TGF-β after losartan therapy showed accelerated aortic-root dilatation, as compared with patients who had increased TGF-β levels after treatment. 2 The evidence that activation of TGF-β is the driver of Marfan s syndrome is weak. The use of a rabbit polyclonal anti TGF-β antibody to block in vivo signaling in mice 1 was not state-of-the-art. These results do not fit with the acceleration of aortic disease after genetic abrogation of TGF-β signaling in vascular smooth-muscle cells, 3 nor do they fit with the very high susceptibility of mice treated with angiotensin II to fatal aortic dissection after blockade of TGF-β signaling with the use of a mouse monoclonal antibody. 4 Ziad Mallat, M.D., Ph.D. University of Cambridge Cambridge, United Kingdom zm255@medschl.cam.ac.uk Alain Tedgui, Ph.D. INSERM Unité 970 Paris, France 1. Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006;312:117-21. 2. Franken R, Radonic T, den Hartog AW, et al. The revised role of TGF-β in aortic aneurysms in Marfan syndrome. Neth Heart J 2014 October 24 (Epub ahead of print). 3. Li W, Li Q, Jiao Y, et al. Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis. J Clin Invest 2014;124:755-67. 4. Wang Y, Ait-Oufella H, Herbin O, et al. TGF-beta activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice. J Clin Invest 2010; 120:422-32. The authors reply: Ziganshin and colleagues raise the question of whether beta-blockers are efficacious in patients with Marfan s syndrome. The dose of atenolol in our trial was adjusted to heart-rate response and was higher than that used in most trials, which may explain the mixed results in the literature. We could not include a placebo group because prospective participants and their families were opposed; beta-blockers are considered by most observers to be the standard of care. Instead, we designed a comparative effectiveness trial in which we evaluated a new therapy with the current standard. Comparing losartan with placebo might have resulted in a positive trial, but it would not have answered a key clinical question. Furthermore, we found a robust relationship between age and response of the aorta to treatment with beta-blockers and believe that this fact alone supports a treatment effect. Treasure et al. describe their experience with external support of the dilated ascending aorta instead of more traditional interventions. Their procedure does not address patients with aortic regurgitation or dissection. Longer-term followup and experience at multiple centers would be helpful to evaluate the role of this procedure in the care of these patients. The cumulative output of many laboratories over many years has made an extremely strong mechanistic link between altered TGF-β signaling and aortic disease associated with Marfan s syndrome, with the bulk of experimental observations specifically reconciled by pathologically high activity during postnatal aneurysm progression a time with particular therapeutic relevance. There is absolute agreement among all groups that aortic-root tissue from patients with Marfan s syndrome and mouse models of the disease show a clear tissue signature for increased TGF-β signaling and that provocations 980 n engl j med 372;10 nejm.org march 5, 2015

that attenuate or accentuate aneurysm progression are associated with a decrease or increase in TGF-β activity, respectively. 1 Although some studies have shown that potent TGF-β antagonism can result in vascular disease in normal mice in a highly context-specific manner, the relevance of these findings to human aneurysm conditions remains speculative. Mallat and Tedgui found aneurysm formation after TGF-β blockade only in C57BL/6 inbred mice treated with angiotensin II, 2 whereas Li et al. 3 found that induced complete loss of TGF-β receptor function caused vessel-wall hemorrhage if it was initiated in the early postnatal period but not thereafter, at which time mice and patients with Marfan s syndrome typically show the onset or progression of aneurysm. In both circumstances, catastrophic vessel-wall disease evolves within days after provocation and is characterized by intense transmural inflammation that is not characteristic of the human conditions. 2-4 Ronald V. Lacro, M.D. Boston Children s Hospital Boston, MA ron.lacro@cardio.chboston.org Harry C. Dietz, M.D. Johns Hopkins University School of Medicine Baltimore, MD Lynn Mahony, M.D. University of Texas Southwestern Medical Center Dallas, TX Since publication of their article, the authors report no further potential conflict of interest. 1. Lindsay ME, Dietz HC. The genetic basis of aortic aneurysm. Cold Spring Harb Perspect Med 2014;4:a015909. 2. Wang Y, Ait-Oufella H, Herbin O, et al. TGF-beta activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice. J Clin Invest 2010; 120:422-32. 3. Li W, Li Q, Jiao Y, et al. Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis. J Clin Invest 2014;124:755-67. 4. Dietz HC. TGF-beta in the pathogenesis and prevention of disease: a matter of aneurysmic proportions. J Clin Invest 2010; 120:403-7. Case 38-2014: A Man with Sore Throat, Hoarseness, Fatigue, and Dyspnea To the Editor: Iyasere et al. (Dec. 11 issue) 1 present the case of an 87-year-old man in whom severe hypothyroidism developed after he stopped taking his prescribed levothyroxine. Although nonadherence to medications is common across all age groups, in older adults, difficulty in managing medications or other daily activities is often an early sign of cognitive impairment. 2 In addition to ensuring that the patient receives assistance in managing his medications, it would be valuable to probe closely for difficulty in performing other daily activities such as managing finances, shopping, and arranging transportation and to screen the patient for cognitive impairment. Difficulty in performing such activities often reflects problems with executive function (i.e., the ability to plan and organize information). 3 Therefore, an initial screening tool that includes an assessment of executive function, such as the Mini-Cog, 4 may be most helpful. If the results of the Mini-Cog are abnormal, additional history taking and screening with an instrument such as the Montreal Cognitive Assessment 5 may be warranted. Formally screening for cognitive impairment and discussing the findings with the patient and his or her family would help in planning ahead for needed social supports and services. Rebecca T. Brown, M.D., M.P.H. Michael A. Steinman, M.D. University of California, San Francisco San Francisco, CA rebecca.brown@ucsf.edu 1. Case Records of the Massachusetts General Hospital (Case 38-2014). N Engl J Med 2014;371:2321-7. 2. Pérès K, Helmer C, Amieva H, et al. Natural history of decline in instrumental activities of daily living performance over the 10 years preceding the clinical diagnosis of dementia: a prospective population-based study. J Am Geriatr Soc 2008;56: 37-44. 3. Cahn-Weiner DA, Malloy PF, Boyle PA, Marran M, Salloway S. Prediction of functional status from neuropsychological tests in community-dwelling elderly individuals. Clin Neuropsychol 2000;14:187-95. 4. Borson S, Scanlan JM, Chen P, Ganguli M. The Mini-Cog as a screen for dementia: validation in a population-based sample. J Am Geriatr Soc 2003;51:1451-4. 5. Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal n engl j med 372;10 nejm.org march 5, 2015 981