European Heart Journal Advance Access published February 22, 2016 European Heart Journal EHJ BRIEF COMMUNICATION doi:10.1093/eurheartj/ehw033 Valvular heart disease Aortic stenosis and transthyretin cardiac amyloidosis: the chicken or the egg? Arnault Galat1,2,3,4,5, Aziz Guellich1,2,3,4,5, Diane Bodez1,2,3,4,5, Michel Slama6, Marina Dijos7, David Messika Zeitoun8, Olivier Milleron8, David Attias9, Jean-Luc Dubois-Rande´ 1,2,3,4,5, Dania Mohty10, Etienne Audureau1,2,4,5,11,12, Emmanuel Teiger1,2,3,4,5, Jean Rosso1,2,13, Jean-Luc Monin1,2,3,4,5, and Thibaud Damy1,2,3,4,5* 1UPEC, Cre´teil F-94000, France; 2MondorAmyloidosis Network, Cre´teil F-94000, France; 3Department of Cardiology, AP-HP, Henri-Mondor Teaching Hospital, Cre´teil F-94000, Downloaded from France; 4INSERM U955, Cre´teil F-94000, France; 5DHU A-TVB, Cre´teil F-94000, France; 6Department of Cardiology, AP-HP, Antoine Be´cle`re Teaching Hospital, Clamart F-92140, France; 7Department of Cardiology, Bordeaux Teaching Hospital, Pessac F-33604, France; 8Department of Cardiology, AP-HP, Bichat Teaching Hospital, Paris F-75018, France; 9Department of Cardiology, Centre Cardiologique du Nord, Saint-Denis F-93200, France; 10Department of Cardiology, Dupuytren Teaching Hospital, Limoges F-87042, France; 11Department of Public Health, Henri-Mondor Teaching Hospital, Cre´teil F-94000, France; 12CEpiA (Clinical Epidemiology and Ageing), EA4393, Universite´ Paris Est (UPE), UPEC, F-94000, Cre´teil, France; and 13Department of Nuclear Medicine, AP-HP, Henri-Mondor Teaching Hospital, Cre´teil F-94000, France Received 8 July 2015; revised 18 November 2015; accepted 21 January 2016 http://eurheartj.oxfordjournals.org/ Background Aortic stenosis (AS) and transthyretin cardiac amyloidosis (TTR-CA) are both frequent in elderly. The combination of these two diseases has never been investigated. ..................................................................................................................................................................................... Aims To describe patients with concomitant AS and TTR-CA. ..................................................................................................................................................................................... Methods Six cardiologic French centres identified retrospectively cases of patients with severe or moderate AS associated with TTR-CA hospitalized during the last 6 years. ..................................................................................................................................................................................... Results Sixteen patients were included. Mean + SD age was 79 + 6 years, 81% were men. Sixty per cent were NYHA III–IV, by guest on March 2, 2016 31% had carpal tunnel syndrome, and 56% had atrial fibrillation. Median (Q1;Q4) NT-proBNP was 4382 (2425;4730) pg/mL and 91% had elevated cardiac troponin level. Eighty-eight per cent had severe AS (n ¼ 14/16), of whom 86% (n ¼ 12) had low-gradient AS. Mean + SD interventricular septum thickness was 18 + 4 mm. Mean left ventricular ejection fraction and global LS were 50 + 13% and 27 + 4%, respectively. Diagnosis of TTR-CA was histologically pro- ven in 38%, and was based on strong cardiac uptake of the tracer at biphosphonate scintigraphy in the rest. Eighty-one per cent had wild-type TTR-CA (n ¼ 13), one had mutated Val122I and 19% did not had genetic test (n ¼ 3). Valve replacement was surgical in 63% and via transcatheter in 13%. Median follow-up in survivors was 33 (16;65) months. Mortality was of 44% (n ¼ 7) during the whole follow-up period. ..................................................................................................................................................................................... Conclusions Combination of AS and TTR-CA may occur in elderly patients particularly those with a low-flow low-gradient AS pat- tern and carries bad prognosis. Diagnosis of TTR-CA in AS is relevant to discuss specific treatment and management. ----------------------------------------------------------------------------------------------------------------------------------------------------------- Keywords Aortic stenosis † Transthyretin † Cardiac amyloidosis † Low-flow low-gradient Introduction fraction (LVEF). Low-flow low-gradient AS is a severe form character- ized by low cardiac output (CO), or as was defined recently by a Degenerative aortic stenosis (AS) is currently the most common stroke volume index (SVi),35 mL/m2, and low trans-valvular gradient valvular heart disease in Western developed countries. Severe AS is (TG). Reduced CO could be due to decreased LVEF or to an exces- defined as aortic valve area (AVA) ,1.0 cm2, generally with a mean sive cardiac remodelling and/or restrictive physiology with preserved gradient . 40 mmHg. Several AS patterns have been described de- LVEF also called ‘paradoxical low-flow low-gradient AS’.1 Patients with pending on AS area, flow, gradient, and left ventricular ejection this last pattern are often older and have poor prognosis.1 * Corresponding author. Tel: +33 149 812 253, Fax: +33 149 812 805, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2016. For permissions please email: [email protected]. Page 2 of 7 A. Galat et al. Interestingly, excessive cardiac remodelling and/or a restrictive The mean age was 79 + 6 years, 81% were men (n ¼ 13), 60% physiology are both features of another frequent disease en- (n ¼ 9/14) were in NYHA-class III or IV. Carpal tunnel syndrome countered in elderly known as transthyretin (TTR) cardiac amyloid- was observed in 31% of the patients (n ¼ 5/16), atrial fibrillation osis (TTR-CA). This disorder is characterized by extracellular in 56% (n ¼ 9/16). The patients had also elevated levels of biomar- deposits of fibrillar TTR proteins in different organs including kers of HF with a median of NT-proBNP of 4382(2425;4730) pg/mL. the heart, resulting in LV dysfunction.2 The two common types Troponin was elevated in 10 of the 11 patients with available data. are wild-type transthyretin (WT-TTR) and hereditary-transthyretin Before AS management, 88% (n ¼ 14) had severe AS of whom 86% (h-TTR) amyloidosis.2 Wild-type transthyretin is also known as (n ¼ 12/14) had low transaortic gradient and 87% had low-flow AS de- ‘senile systemic amyloidosis’ with a prevalence of 25% in the gen- fined by SVi , 35 ml/m2 (n ¼ 13/15). They all had increased interven- eral population .80 years according to post-mortem studies.3 tricular septum thickness (18 + 4 mm). Left ventricular dysfunction Hereditary-transthyretin is inherited in an autosomal dominant was moderate when estimated by LVEF (50 +13%). However, when mode with .120 identified mutations.4 The penetrance and sever- it was available, global LS was dramatically decreased (27+4%). ity of the disease are variable and depend on the mutation with some associated almost exclusively with cardiac involvement (e.g. Diagnosis of transthyretin cardiac Val122Ile). Transthyretin cardiac amyloidosis (TTR-CA) patients amyloidosis usually have biventricular increased wall thicknesses, diffuse late Eighty-one per cent (n ¼ 13) had WT-TTR and one h-TTR with gadolinium enhancement (LGE) on cardiac magnetic resonance im- Val122I mutation. Three did not have genetic sequencing of TTR. aging (MRI) and cardiac uptake at biphosphonate scintigraphy (BS).5 The diagnosis of TTR-CA was histologically proved in 6 (38%) and Downloaded from Transthyretin cardiac amyloidosis carries poor prognosis and is on scintigraphy for the other patients. Seventy-five per cent of the often complicated by HF. patients (n ¼ 12) had cardiac MRI with all showing diffuse LGE. Although aging associated factors may influence the development or progression of AS, the combination AS and TTR-CA remains Management of aortic stenosis/ poorly described. transthyretin cardiac amyloidosis http://eurheartj.oxfordjournals.org/ Theaimsofthisstudyweretoreportcasesofpatientswith patients and outcomes both TTR-CA and AS in order to describe their specific phenotype, Based on Heart-Team decision, 10 patients (63%) were referred management, and outcomes. for aortic valve replacement (AVR), of whom one refused surgery; transcatheter aortic valve implantation (TAVI) was scheduled in two Methods cases (12%), of whom one died before the procedure. Conservative treatment was indicated in four patients (25%). The follow-up for Six centres had to identify in their records patients with AS and TTR-CA the survivors was 33 (16;65) months. Forty-four (n ¼ 7) died during for the last 6 years. Inclusion criteria were diagnosis of CA associated with follow-up, four from HF, one from pneumopathy, one of cardiogenic a moderate or severe aortic valve stenosis (aortic valve area ,1.5 cm2). shock (before undergoing TAVI), and one at home from unknown by guest on March 2, 2016 Diagnosis of TTR-CA had to be confirmed on endomyocardial biopsy or cause. There were no significant differences in baseline characteris- by strong cardiac retention (visual score ≥ 2) at BS (99mTc-HMDP or 99m tics between the alive and the dead groups (Table 2). Figure 1 shows Tc-DPD). Patients were managed according to contemporary guide- lines.6 The investigation was in line with the Declaration of Helsinki. an example of a patient with the combination of AS and TTR-CA Clinical, biological, trans-thoracic echocardiography (TTE), cardiac treated by TAVI. MRI, BS, histology, and treatment data