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DOI: 10.1161/CIRCULATIONAHA.113.006242 Left Ventricular Structure and Function in TTR-Related versus AL Cardiac Amyloidosis Running title: Quarta et al.; Echocardiography in Cardiac Amyloidosis Candida Cristina Quarta, MD1,2; Scott D. Solomon, MD1; Imran Uraizee, BS1; Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 Jenna Kruger, BS3; Simone Longhi, MD2; Marinella Ferlito, MD2; Christian Gagliardi, MD2; Agnese Milandri, MD2; Claudio Rapezzi, MD2; Rodney H. Falk, MD4 1 Cardiovascular Card Ca rd dio iova vasc s ullar D sc Division, ivision, Brigham and Women's Women en n'ss Hospital, Harvard d Me M Medical dical School, Boston, MA;; 2In MA IInstitute sttittute of C Cardiology, ardi ar diol olog ogy, y, U University nive ni vers rsitty of Bologna Bol oloogna and and S.Orsola-Malpighi S Orrso S. solla-M Mal alpi p gh hi Ho Hosp Hospital, spit ital al,, Bo Bolo Bologna, logn g a, gn IItaly; taly; 3Deptt ooff Ca Card Cardiology, rdiiolo iology gy, Ha gy Harvard arv rvarrd V Vanguard anngu nguardd M Medical ed dical ical A Associates, ssoociiates,, Boston, Bossto ton, n MA; MA; A; 4De Dept pt ooff Cardiology, Card Ca rdio rd i lo logy gy,, H gy Harvard arvar rvardd Vang V Vanguard a guaard M Medical ed diccal a A Associates, sssoc ociiattes e , Brig B Brigham rig ighaam an and nd W Women's om men's Ho men Hosp Hospital spiitaal C sp Cardiac arddiaac ar ac Amyl Am yloi yl oido oi dosi do siss Program, si Prog Pr ogra og ram ra m, Harvard m, Har arva varrd Medical va Medi Me dica di call School, ca Scho Sc hool ho ol,, Boston, ol Bost Bo ston st on,, MA on Amyloidosis Address for Correspondence: Rodney H. Falk, MD Department of Cardiology, Harvard Vanguard Medical Associates 133 Brookline Avenue Boston, MA 02215 Tel: 617-421-6094 Fax: 617-421-6083, E-mail: [email protected] Journal Subject Codes: Diagnostic testing:[31] Echocardiography, Hypertension:[16] Myocardial cardiomyopathy disease 1 DOI: 10.1161/CIRCULATIONAHA.113.006242 Abstract Background—Immunoglobulin light chain (AL)-related cardiac amyloidosis (CA) has a worse prognosis than either wild type (ATTRwt) or mutant (ATTRm) transthyretin (TTR) CA. Detailed echocardiographic studies have been performed in AL, but not in TTR amyloidosis, and might give insight into this difference. We assessed cardiac structure and function and outcome in a large population of patients with CA and compared findings in TTR and AL-related disease. Methods and Results—We analyzed 172 patients with CA (AL, n=80; ATTRm, n=36; ATTRwt, n=56) by standard echocardiography and two-dimensional speckle tracking imaging (STI)derived left ventricular (LV) longitudinal (LS), radial (RS) and circumferential strain (CS). Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 Despite a preserved LV ejection fraction (55±12%), LS was severely impaired in CA. Standard measures of LV function as well as STI worsened as wall thickness increased, wh hille ap pic ical al L S while apical LS was preserved irrespective of the etiology of CA and the degree of wall thickeni ing ng. Co Comp mpar mp ared ar ed tto o thickening. Compared ATTRm and AL, ATTRwt was characterized by greater LV wall thickness and lower ejection frac cti tion on. LS was on wass more mor o e depressed in both ATTRwt wt and and AL (respectively (respectiveely --11±3% 11±3% and -12±4%, fraction. p= =0..54 54), tha hann in nA TTRm TT Rm ((-15±4%, -15± -1 5±4% 4%,, p< 4% pp<0.01 0.01 0. 01 vvs. s. A L aand nd AT ATTR T wt TR wt)). T TR-r TR -rrel e at ated ed d etiologies eti t ol olog oggiees were were p=0.54), than ATTRm AL ATTRwt). TTR-related faa orable predictors favo predicttor tors of of survival, surviiva ival, al whereas whher ereeas eas LS S and and advanced advan nce cedd NYHA NYHA HA class classs were weeree nega gaatiivee favorable negative pred pr edic ed icto ic t rs to rs.. predictors. Conc Co nclu nc lusi lu sion si onss—In ppatients on atie at ient ie ntss wi nt with th C A, w orse or seni se ning ni ng L V ffunction unct un ctio ct ionn co io corr rrel rr elat el ated at ed w ithh in it incr crea cr easi ea sing si ng w alll al Conclusions—In CA, worsening LV correlated with increasing wall hic ickn knes esss regardless rega re gard rdle less ss of of etiology. etio et iolo logy gy Patients Pati Pa tien ents ts w ithh AT it ATTR TRwt wt hhad ad a sstatistically tati ta tist stic ical ally ly ggreater reat re ater er w alll th al thic ickn knes esss thickness with ATTRwt wall thickness but lesser mortality than those with AL, despite very similar degrees of longitudinal strain impairment. This paradox suggests an additional mechanism for LV dysfunction in AL amyloidosis, such as previously demonstrated light-chain toxicity. Key words: amyloid, cardiomyopathy, deformation, echocardiography, speckle tracking, 2dimensional, Transthyretin 2 DOI: 10.1161/CIRCULATIONAHA.113.006242 Introduction The systemic amyloidoses are a group of uncommon diseases characterized by extracellular deposition of fibrillar proteins that lead to loss of normal tissue architecture and function.1 Cardiac amyloidosis (CA) is due to intramyocardial amyloid infiltration, which leads to a progressive increase of ventricular wall thickness and stiffness.1,2 The most frequent types of systemic amyloidosis associated with clinically relevant cardiac involvement are: light-chain amyloidosis (AL) due to a clonal plasma cell dyscrasia, which produces the immunoglobulin light chains of the fibrillary deposits; hereditary, transthyretin-related form (ATTRm), which can Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 be caused by over 100 mutations of transthyretin (TTR), a transport protein mainly synthesized by the liver; wild-type (non-mutant) transthyretin-related amyloidosis (ATTRwt) t)), wh w ichh ma ic main inly ly (ATTRwt), which mainly affects the hearts of elderly men.2,3 Cardiac involvement is common and carries a negative pr rog ogno nosi sis is in all all etiological eti tioological subtypes.2,3 However However, r, ddespite espite apparently apparent nttly l ssimilar im milar il degrees of prognosis m myocardial yoocardial oc infiltration inf nfil ilttratio il on as as aassessed ssses esse sedd by by w wall all thickness, thicknnes ess, these the hese se etiologies eti t ol ti olog ogie og ies are aree characterized ch harrac acte teeriize z d by 3 different clinical di diff ffer ff eren er entt cl en lin iniical ical ccourses. o rsess.3,4 ou The Thee severity sev ever eriity ity of heart hea eart rt failure failu ure and and nd survival sur u viva viva vall are aree much mu uch h worse wor orsse in in AL L 34 th han in in TTR-related TT TRR re rela laate tedd amyloidoses, amyl am yloi oido oi dose do sess, se s,3,4 w with itth a median medi me dian di an survival surrvi v va vall of approximately apppro roxi xima xi m tely 6 ma amyloidosis than months in untreated AL amyloidosis with heart failure compared to 6 years in ATTRwt.4 This finding has been partly attributed to a direct cardio-toxic effect of circulating immunoglobulin lights chains.5 Although standard echocardiography remains the mainstay for the non-invasive diagnosis of CA, contemporary echocardiographic techniques, such as myocardial deformation imaging, have proven to play an adjunctive role in the diagnosis and prognostic stratification of CA.6 Specifically, strain and strain rate imaging parameters obtained by tissue Doppler (TDI) techniques and 2-dimensional (2D) speckle-tracking imaging (STI) have been shown to be 3 DOI: 10.1161/CIRCULATIONAHA.113.006242 significantly reduced in AL-related CA (both in advanced and in asymptomatic heart involvement) when compared to unaffected controls and to other causes of wall thickening (such as hypertensive heart disease and hypertrophic cardiomyopathy).7,8 Recently, reduced longitudinal strain (LS) in CA has been shown to have an unusual and typical pattern, with severe impairment of strain at the base and an ‘apical sparing’ pattern that differentiates CA from other causes of true LV hypertrophy.9 Finally, LV longitudinal function has proven to be an independent predictor of survival in AL amyloidosis.10,11 Given the markedly different prognoses in AL and TTR amyloidosis with cardiac Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 involvement, there may be differences in the echocardiographic profiles of the diseases. However, as all of the previous larger studies of strain imaging have been perfor performed rme medd in A AL L amyloidosis, it is not clear whether similar findings are seen in the TTR-related forms of CA. Th her eref efoore, ef ore, we we compared co ompared mp (booth conventional (b conventionnal a and ndd 2D-STI) 2DD STI) and outcome Therefore, the echocardiographic (both profiles prof fil i es of fami familial miili liall aand n w nd wild-type ildil d-ty dtype ty pe T TTR TR aamyloidosis mylloidossiss wi with ith a grou ith ggroup roupp of of ppatients attieent ntss wi w with ith th A AL L am amyloidosis myl yloi oido oi doosis to o ddefine effin inee th the he fe feat features atturres ooff TT TTR R am amyloidosis, myl yloi o doosiis, oi s, aand ndd th thr through roug roug ughh co comp comparative mpar mp a ativ ar at ve an analysis, nallys y is is,, to t ddetermine eterm et mine mine n whether anyy ob obse observed s rv se rved ed ddifferences i feere if renc nces nc es m might i ht aaccount ig ccou cc ount ou n ffor nt or th thee ve very ry ddifferent iffe if f re rent nt pprognoses rogn ro gnos gn osses between bet etwe w en AL and TTR CA. Methods Setting and study design We conducted a multicenter longitudinal study of patients with etiologically defined CA, based on data pooled from two large international centers providing facilities for the diagnosis and treatment of systemic amyloidosis. All consecutive patients diagnosed with CA who underwent echocardiographic evaluation at the Brigham and Women’s Hospital (Boston) from 2006 to 4 DOI: 10.1161/CIRCULATIONAHA.113.006242 2012, or at the S.Orsola-Malpighi Hospital (Bologna) from 2009 to 2012 were included in the analysis. We compared ATTRwt, ATTRm and AL-related CA in terms of clinical/instrumental profiles at the time of their first evaluation, and determinedoutcome. Analysis of echocardiograms was done by 2 investigators blinded to the etiology of amyloidosis. After analysis, patients were divided into 3 groups, based on the etiology of amyloidosis (AL, ATTRm or ATTRwt). At the Bologna center, all patients provided informed consent for anonymous publication of scientific data. At the Boston center, the collection of medical records was Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 approved by the Institutional review board (IRB). Diagnostic definitions For the diagnosis of systemic amyloidosis and of the specific amyloid subtypes (AL, ATTRm, ATTRwt), well involvement, kidney ATTR AT TRwt TR wt)), wt ), aass we ell aass for the definition of cardiac acc in nvolvement, ki idn d ey y iinvolvement, nv nvolvement, peripheral nervous nerv vou o s system m involvement, invvollveme ment me nt, autonomic nt auto auto onoomicc impairment, im mpa pairm ment, and and disease disseas ase duration, dura du rati t on, on, we w referred refferrre r d to o tthe he 2,3,12-18 2 , 12 12-18 -18 standard criteria. tan nda dard r ddiagnostic rd iaggnos ia gnosstiic cr riteeria eria.2,3,12 A de detailed etaail iled ed llist istt of ddiagnostic is iagn gnoosti os ic de definitions, efiini niti tioons, ons, aalong l ng w lo with it tthe ith hee card ca r io rd iova v sc va scul u ar comorbidities, com mor o bi bidi diti ties ti ess, is i reported rep epor orte or teed as Supplemental Sup uppl plem pl emen em enta en tall data. ta data da ta.. ta definition off cardiovascular Cardiac evaluation All patients had had an initial diagnostic assessment that included clinical evaluation, ECG, echocardiogram, and biochemical evaluation. Twelve-lead electrocardiograms, performed at the time of t echocardiography, were reviewed for rhythm disturbances and presence of low-voltage pattern (QRS amplitude 0.5 mV in all limb leads or 1 mV in all precordial leads). Voltage-tomass ratio was calculated as Sokolow index divided by the cross-sectional area of the LV wall with the formula defined by Carroll et al.19 Echocardiograms were performed at both centers using commercially available ultrasound systems (iE33, Philips Medical Systems and Vivid 5 DOI: 10.1161/CIRCULATIONAHA.113.006242 7, GE Medical Systems, Milwaukee, WI). Analysis of the echocardiographic images (both conventional and STI measurements) was conducted at the cardiac imaging core laboratory of the Brigham and Women’s Hospital. Views of the heart were obtained from the parasternal, apical and subcostal positions. A summary of conventional echocardiographic variables analyzed in the study and their definitions is reported as Supplemental data.20-24 2-D speckle tracking imaging For offline 2D-STI, digitally-acquired echocardiographic images in DICOM format with acceptable image quality were uploaded to the vendor-independent offline 2D Cardiac Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 Performance Analysis software (TomTec Imaging System, Munich, Germany). These methods 25,26 25, 26 have been validated with MRI and sonomicrometry and have proven highly repr reproducible. roduc odu ib ible le.25 le Non-acceptable image quality was defined as lack of a full cardiac cycle, more than 1 segment dropout, dr rop opou outt, ou t, digital dig igit ital format it for orma m t other than DICOM, missing missi sing si ng view, or significant signnif i ican an nt foreshortening for o eshortening of the left vventricle. enntri ntr cle. Thee endocardial end n oc ocar arrdiial border bor ordder der was wa traced traaced tr d at at ann eend-diastolic ndd-d -dia iassto stolic olic fframe rame inn ap apical pic ical al vviews i ws ie ws aand nd aatt aan n end-systolic en ndd sy syst stol olic ic frames fra rame mess inn short me short hor axis axis vviews. iews ie wss. En End End-diastole d-di dias di a tolle as le w was as ddefined effine n d by tthe he Q QRS RS ccomplex RS om mplex pl x oorr byy tthe h he frame just bef before effor oree mi mitr mitral tral al val valve alve al ve oopening. peni pe niing n . Th Thee so software oft f wa ware ree ttracked raack cked ed sspeckles peck pe ck kle less al aalong ongg th on the he en endo endocardial doca do c rdial andd epicardial borders throughout the cardiac cycle. Peak longitudinal (LS), radial (RS) and circumferential strain (CS) values were computed automatically generating regional data from 6 segments and an average value for each view. Peak average LS and RS values were measured in the apical 4 and apical 2 chamber views and averaged, while peak CS was measured in the mid-papillary level short axis view. Abnormality of LS, RS and CS values was defined based on published data in healthy subjects.27 Inter- and intraobserver variability was assessed for LS in a sample of 20 randomly selected patients. The coefficient of variation for interobserver variability was 4.9%, with an 6 DOI: 10.1161/CIRCULATIONAHA.113.006242 intraclass correlation coefficient of 0.99 (95% CI 0.98-1.00). The coefficient of variation for intraobserver variability was 6.3%, with an intraclass correlation coefficient of 0.97 (95% CI 0.94-1.00). Follow-Up In both centers, follow-up visits were planned for every 6 months (or more frequently if clinically appropriate). Follow-up was closed in May 2013,; for patients who had not attended a visit in the last 6 months, vital status was ascertained by telephone and/or by contacting referring physicians. Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 Statistical Analysis numbers Summary statistics are expressed as mean±SD/median (interquartile range) or nu umbe umbe b rss (percentages). percentages). In contingency tables, independence of categorical variables was tested using Fisher's Fi ishherr's exact exa xact ct test tes esst or or Pearson's chi-square testt (according (ac acco ac co ording to Cochran’s Cochr hrran a ’ss rule). rule). ul Independence of continuous variables co ontin nti uous var aria iabl ia blless was was tested tes este tedd using te ussin ng one-way onne-w way analysis way an nalysiis is of of variance vari va riaance or or Kruskal-Wallis Krusska kall-W Wall Wall llis i test is tes esst in case normally not respectively. For multiple ca ase of of no norm rmal rm ally ly y oorr no ot no nnormally rm mal ally ly distributed dis istr triibut ibut uted ed variables, var aria iaablles es,, re esp spec eccti tive veely y. Fo or mu mult l ip lt ple ccomparisons ompar omp pariso risons ns Bonferroni-corrected we calculated calculateed Bo B nfer nf e ro er roni n -ccor orre r ct re cted ed p vvalues. a ue al ues. s Comparisons s. C mp Co mpar a isson ar onss of eechocardiographic choc ch occar ardi diog di ogra og raph ra phhic pparameters aram ar a eters were also adjusted for a priori selected demographic, clinical and laboratory covariates, using analysis of variance, logistic or ordered logistic regression models. Spearman’s rank correlation coefficient (rho) was used to study the association between LS and LV ejection fraction, LV mean wall thickness and E wave deceleration time, both in the overall population and among the different etiologies. We tested a priori selected variables chosen for their potential clinical relevance in a series of multivariable models constructed to assess their association with parameters of systolic and diastolic function. Skewed variables were log-transformed. Multivariable regression models were reported as ȕ coefficient and 95% CI. 7 DOI: 10.1161/CIRCULATIONAHA.113.006242 To assess whether clinical parameters or echocardiographic indices of cardiac function were associated with LV wall thickness, we categorized the overall population of patients with CA by tertiles of LV wall thickness and applied non-parametric tests for trend across ordered groups . Overall survival and survival free from incident heart failure were analyzed with KaplanMeier curves. Survival was censored at the time of liver or combined liver transplantation for ATTRm. To explore risk factors that could be associated with all-cause mortality and incident heart failure, univariate Cox regression analysis was initially performed using clinical and Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 instrumental variables. Multivariable analysis was then performed by entering into the model a set et of variables that were considered significant on univariate analysis (p<0.1) oorr onn the he bbasis asis as is ooff their heir potential clinical or pathophysiological relevance. We considered incident HF only if the event required medications. ev ven entt re requ quuir ired e hhospitalization ed ospi os pitalization for intravenous vasoactive vaaso s active medicat tio i nss. Analyses An were conducted SE Corporation, College Station, TX). tests were uusing sin ng STATA A 12 S E (S ((Stata tata ta ta C orpoora orpo rati t on, on, Co olleege St tatio io on, n, T X) All X). All te test stts we wer re ttwo-sided re woo-s -sid ided id e aand ed nd a pp-value statistically presence valu va luee < 0. lu 0.05 05 was wass cconsidered onssiddere on deredd st stat atis at isti is tica ti callly lly significant. siggnif si ific if fic i an antt. t. IIn n th thee pr res e ence ence ooff high hhighly ighhly ccorrelated orrre rellate teed Harrell’s coefficient included parameters, only onnly y one one variable var a iaabl b e – selected sele se leect c ed based bassed on on Ha Harr r el ell’ l s C co coef e fi ef fici cien ci entt – wa en wass in incl clud cl u ed in the ud final model. Results Study Population A total of 172 patients (62 patients first evaluated in Bologna, 110 seen in Boston) entered the analysis: 36 affected by ATTRm, 56 affected by ATTRwt, and 80 affected by AL amyloidosis. AL mainly derived from the Boston center (55/80, 69%), as did ATTRwt patients (43/56, 77%), while ATTRm patients mainly derived from the Bologna center (24/36, 67%). Endomyocardial 8 DOI: 10.1161/CIRCULATIONAHA.113.006242 biopsy was performed in all the ATTRwt patients to confirm the diagnosis. Among patients with AL amyloidosis, endomyocardial biopsy was performed in 57 cases (71%). In the remaining cases extra-cardiac biopsies were performed to confirm the diagnosis, including liver (3 cases), kidney (5), and bone marrow (15). Among patients with ATTRm, endomyocardial biopsy was performed in 26 cases (72%). In all patients from the Bologna center, immunohistochemistry along with genotyping and serum/urine immunofixation was used to confirm the amyloid subtype. In only 2 cases where immunohistochemistry was inconclusive, was proteomics performed. Proteomics was performed in 6 cases from Boston. The TTR mutations were: Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 Ile68Leu (n=10), Glu89Gln (n=6), Val122Ile (n=5), Val30Met (n=4), Thr60Ala (n=4), Thr49Ala (n=2), Ala81Thr (n=1). n=2), Arg34Thr (n=1), Glu54Gln (n=1), Gly47Ala (n=1), Thr59Lys (n=1), Ala a81Th T r (n Th (n=1 =1). =1 ). Table 1 summarizes the main clinical findings in the overall population and according to the specific As anticipated, patients with were more peccif ific ic amyloid amy mylloid d subtype. subtype. ub patien nts w ith ATTRwt w eree mo m ore likely to be elderly men disease duration. m enn with a higher hig ghe her prevalence prreval alen ence en ce of of atrial atri at rial ri al fibrillation, fibrilllattionn, as as well well as as longer lonngeer di lo dis seaase ase du dura rati tion ti on n. NT NT-proBNP ATTRm patients proB pr oBNP oB N values NP val alue uess were were lower low wer in in ATTRm ATTR AT TRm TR m than th han AL or or ATTRwt. ATTR AT TR Rwt. wt Unsurprisingly, Unsu Un suurp rpri rissinngly ngly y, AT A TRm TR m pa ati tien en ntss displayed neurological whereas involvement wass frequent most frequently frequen ntl tlyy di isp spla laaye yed ne neur u ol ur olog ogic og i all iinvolvement, ic nvol nv o vem ol emen en nt, w here he reas re a kkidney as idne id neey in invo volv vo lvem lv em men entt wa w only in AL. Median values of kappa and lambda light chains were 14 [7-96] mg/L and 56 [21170] mg/L, respectively, with a kappa/lambda ratio of 0.2 [0.06-1.7]. Echocardiographic findings Table 2 summarizes the main conventional echocardiographic findings in the overall population and in the different etiological subgroups. Overall, CA was characterized by a symmetric increase of LV wall thickness with non-dilated ventricles, enlarged LA, preserved LV ejection fraction, and increased pulmonary pressures. Pericardial effusion coexisted in ~50% of cases. Despite preserved LV ejection fraction, the longitudinal systolic function evaluated by TDI was 9 DOI: 10.1161/CIRCULATIONAHA.113.006242 considerably depressed when compared with normal reference values.24 Diastolic function was abnormal in over 80% of cases.28 Two-dimensional STI variables in the overall population and in the different etiological subgroups are listed in table 3. Both global LS and RS were significantly depressed in CA patients compared to normal reference values,27 while CS was preserved. No major differences emerged in STI-derived parameters when comparing patients from the two centers (data not shown). There was an inverse correlation between global LS and LV ejection fraction (r=-0.55, Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 p<0.001), a weak positive correlation between global LS and LV mean wall thickness (r=0.34, p<0.001), and a weak inverse correlation between global LS and E wave deceleration decelerratio io on time tiime (r=(r= r 0.39, p<0.001). ATTRm showed the highest correlation between global LS and both LV ejection fr raccti tion on (r=-0.61, (r= r=-0 -0.61, -0 1, p<0.001) p<0 < .001) and mean LV wall thickness thhic i kness (r=0.56, p<0.001), p<0 0.0001), 01 while ATTRwt was fraction asso oci c ated with witth a higher high gher gh err correlation cor orrrel relati lation on between betw ween n LS LS and and E wave wav ve deceleration deccellera de rati tion ti n ttime im me (r (r= =-0. 0 43 0. 43, associated (r=-0.43, p=0. p= 0 00 0. 009) 9).. Am 9) Amon onng pa ppatients tiien nts w i h AL aamyloidosis, it mylo mylo loid idossis id is,, we ffound ound ou nd a w eaak di ddirect reectt correlation corrreela l tiion between betw ween ween n p=0.009). Among with weak ambda lightt cchains hain ha in ns va alu uess aand n E nd /A rratio attio ((Spearman’s Spe pear arma ar man’ ma n s rh ho= o 0. 0 44 44,, p= =0. 0.00 002) 00 2).. No rrelations 2) elat el atio at io ons n between n lambda values E/A rho=0.44, p=0.002). light chains (kappa or lambda) values and LV wall thickness, LV ejection fraction or LV LS were observed. Figure 1 shows the frequency of abnormal indices of systolic and diastolic function in the overall population:2D STI-derived parameters (global RS and LS) were more frequently impaired than conventional echocardiographic indices of systolic and diastolic function. Patients with ATTRwt were more likely to display a higher degree of both morphological and functional impairment, as expressed by higher values of LV wall thickness and mass, LA size, and more depressed indices of systolic function including LV ejection fraction, S’, stroke 10 DOI: 10.1161/CIRCULATIONAHA.113.006242 work, stroke volume and cardiac output (Table 2), even when adjusting for pre-existing demographic/clinical differences. No major differences were apparent between etiologies in terms of E, E/A ratio and E/E’ ratio, as well as of the prevalence of the different grades of diastolic dysfunction. LS values were least impaired in patients with ATTRm (Table 3). Despite a lower LV mass and slightly higher LV ejection fraction when compared to patients with ATTRwt (table 2), AL patients displayed similar degrees of depressed longitudinal and radial function (table 3). As previously documented,9 a pattern of “apical sparing” of longitudinal strain was common, Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 with preservation of apical strain in 2/3 of cases. Apicalstrain was preserved irrespective of the etiology of CA (table 3). Supplemental figure 1 (Supplemental data) graphical graphically lly y hhighlights ig ghl hlig ight ig htss ht selected elected data from table 3, showing regional LS and RS function at basal, mid-ventricular, and ap apical piccal llevels evel ev elss iin el n tthe he tthree hree etiologies of CA. Interes Interestingly, stiinglly, ly wh whil while ilee al il alm almost mostt aall most ll iindices ndicees ooff sys systolic ystoli ys liic and and diastolic diaasto di oli lic function funnct ctio ionn including io incl in c ud cl udin ingg ST in STII derived strain worsened tertiles wall thickness the de deri rive ri veed st stra raain w orsene ors seneed wi with h iincreasing ncre nc reas re asin in ng te tert rtiiles rt es ooff LV w alll th al hic ickknes knes esss ((Table Tabl Ta ablee 44), ), LS LS in th he aapex he pexx remained emained unc unchanged ncha hang ha nged ng ed aand n w nd within itthi h n no nnormal rmal rm al llimits. imit im its. it s 290 At multivariable s. mul ulti tiva ti vari va riab ri able ab le aanalysis naly na lysi ly siss ((table si ta abl blee 5) 5) LV wall thickening and ATTRm etiology were independently associated with global LS. Outcome Median follow-up was 24 [17-33] months (21 [11-30] months in AL, 29 [21-47] months in ATTRm, 24 [19-33] months in ATTRwt). All patients with AL amyloidosis received chemotherapeutic agents, and 19 (24%) had high-dose chemotherapy with stem cell replacement, 2 of whom also received heart transplantation. Among patients with ATTRm, 4 (11%) underwent liver transplantation and 3 (8%) underwent combined heart/liver transplantation. One patient affected by ATTRwt underwent heart transplantation. 11 DOI: 10.1161/CIRCULATIONAHA.113.006242 During the study period there were 57 (33%) deaths (35 among AL patients, 7 among ATTRm patients, and 15 among ATTRwt patients), for a death rate of 6.9/100 person years among AL patients, 2.04/100 person years among ATTRm patients, and 3.4/100 person years among ATTRwt patients. Hospitalizations for HF (occurring either at the time of the first evaluation or subsequently during the follow-up period) were recorded in 81 (47%) patients (39 AL, 18 ATTRm, and 24 ATTRwt), with an incidence rate of 10.3/100 person years among AL patients, 4.9/100 person years among ATTRm patients, and 4.8/100 person years among ATTRwt patients. Figure 2 reports the overall unadjusted survival (a) and survival free from HF Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 (b) according to the specific etiology of cardiac amyloidosis. As expected, AL patients fared statistical worse than ATTRwt and ATTRm (log-rank p value=0.002), while there were noo st tat a issti tica call ca differences between the three etlogies when considering freedom from HF (log-rank p value=0.11) difference va alu ue= =0. 0.11 11)) ((Figure 11 Figu gurre gu re 2). We did not observe anyy sstatistical tatistical differen ence iin en n ooverall verall survival or survival incident AL patients with and without multiorgan involvement urv viv i al free fr from om m inc ncid iden entt HF bbetween en ettwee ween A L pa atien nts w ithh an it nd wi ith thouut mu mult ltio io organ rgan inv nvol nv olveemeentt ol (log-rank log g-rran a k p va vvalue=0.56 alu lue= e=0. e= 0.556 and and 00.97, .977, rrespectively). .9 espe es peecttiv iveely) ely)). Table multivariable ATTRm ATTRwt Tablle 6 rreports epor ep o ts the or thee results res esul ullts of of mu mult lttiv ivar aria ar iabl ia blle analysis. anal an alys ysis ys is. AT is ATTR TRm TR m an andd AT A TRwt TR wt eetiologies t ologies andd ti eGFR were favorable predictors of overall survival, whereas severe heart failure (NYHA class III to IV), and global LV LS were unfavorable. When analyzing separately AL and TTR etiologies, eGFR was the only still significant predictor of survival (HR 0.98, 95%CI=0.97-0.99, p=0.029 in AL; HR 0.96, 95%CI=0.93-0.99, p=0.06 in TTR amyloidoses). With regard to freedom from incident HF, none of the variables that were statistically related to the outcome at univariate analysis (including etiology and LS) reached statistical significance at multivariable analysis. 12 DOI: 10.1161/CIRCULATIONAHA.113.006242 Discussion Our study, which includes the largest series so far of patients with TTR-related CA comprehensively studied by both conventional echocardiography and 2D STI, supports the role of myocardial deformation imaging as a sensitive tool for characterizing LV dysfunction in CA over more traditional echocardiographic parameters. Our findings provide insights into the pathophysiological mechanisms underlining LV dysfunction in amyloid heart disease, suggesting a role for specific etiology and LV wall thickness in determining LV dysfunction in CA. Along with etiology, LV longitudinal strain turned out to be an independent predictor of overall Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 survival, confirming the previously observed prognostic significance of strain in patients with AL amyloidosis. Cardiac amyloidosis is commonly considered a form of restrictive cardiomyopathy and the attributed he pathophysiology path pa thop th opphy hyssiollog ogyy of heart failure has traditionally traditiona nallly been attribut na utted e tto o diastolic di dysfunction. Only O nlly ly a few studies stu udi diess have hav avee assessed assse sess sssed the the individual individdual du contributions con onntrib butio utio onss of of systolic syyst stol olic ol ic and and diastolic dia iast stol st olic ol ic dysfunction LV CA. Most the published data dysf dy sfun sf unct un ctio ionn to to the the pathophysiology pat atho ho oph p yssio i log ogyy of L V dysf ddysfunction ysf sfun unct un ctiionn in nC A M A. ost ooff th he pu publ blis bl ishe hedd da he ataa aare ree techniques and mainly address AL amyloidosis based on conventional con nve vent n io nt iona n l echocardiographic na e ho ec oca card dio iogr grrap a hi h c te ech hni n qu ques ess an nd ma main in nly add ddre dd ress re ss A L am amyl y oi yl oido d sis and to o a much lesser extent the echocardiographic profiles of TTRCA.3,4,30 Our study shows that, despite different pathophysiological backgrounds, AL and ATTRwt were characterized by similar degrees of impairment in longitudinal and radial strain, while ATTRm had better functional parameters and, as expected, a better outcome. Apical LV segments were preserved independent of the specific etiology of amyloidosis and the degree of LV wall thickening. Myocardial deformation imaging is a sensitive method for the assessment of cardiac performance and there is a growing interest in the use of strain imaging for the evaluation of patients with CA.6 Previously published data has shown severe impairment of longitudinal 13 DOI: 10.1161/CIRCULATIONAHA.113.006242 function with apical preservation of myocardial strain.7,9 However, most of these studies were done with Doppler-derived TDI strain, which is subject to considerable inter- and intra-observer variability and artefacts.7,10 Our study, using the more accurate speckle tracking imaging, confirmed these earlier findings, supporting the role of myocardial deformation imaging as a sensitive tool for characterizing LV dysfunction in CA over more traditional echocardiographic parameters. Furthermore, as longitudinal strain using either Doppler-derived indices or STI has been shown to be a marker of prognosis in AL CA,7,11 it is likely that STI will also be a robust technique for predicting prognosis in TTR-amyloidosis. Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 Although it is recognized that TTR-related cardiac amyloidosis patients have similar conventional echocardiographic appearances to AL amyloidosis, they have a ma arked rked e ly y bbetter ette et terr te markedly prognosis.30 We therefore anticipated that indices of myocardial deformation might be less mpa pair ired ir ed. Although ed Alth Al thouugh ATTRm patients showed better bet ettterr average valus et valu us of L V strain than AL patients, impaired. LV this hiss difference differencee was wass also allso present pre rese seent nt in in comparison compa com mparison onn to ATTRwt ATTR AT TR Rwt ppatients atient atie ntss an andd may may refl rreflect eflec ectt le ec les less ss myocardial my yoc ocar ardi ar dial all iinvolvement, nvolveemeentt, aass ssuggested nvo ugge ug gest ge sted st ed bby y th the lo low lower wer LV wer Vm mass. ass. M ass. More orre su surprising urp rpri risi siing w was as tthe as hee ffinding inding indi ng iin n ATTRwt patients: pattieent n s:: these the h se patients pat atie ieent ntss showed s ow sh o ed a similar sim mil i ar degree degr de g ee of gr of myocardial myoc my o ar ardi dial di al dysfunction dys ysfu fu unc ncti tion ti on to to the AL patients as well as a similar pattern of regional variability characterized by “apical sparing” of longitudinal strain. Thus the vastly different clinical course of these patient groups is unlikely to be explained by differences in myocardial function, either systolic or diastolic. The explanation for this is unclear. Perhaps a longer history of myocardial amyloid deposition in ATTRwt might allow the development of local mechanisms, including some degree of LV hypertrophy, which might compensate for the effect of amyloid deposition. Alternatively, non-myocardial cardiovascular factors, such as involvement of the autonomic nervous system control of the vasculature (known to be much more prevalent in AL amyloidosis) might play a role in the poor 14 DOI: 10.1161/CIRCULATIONAHA.113.006242 prognosis of cardiac AL amyloidosis.31 Another possibility for the worse outcome in AL amyloidosis is the effect of cardiotoxic light chains, present in the active stage of AL amyloidosis.5 The majority of the AL patients in this study had active disease at the time of the echocardiogram and showed elevated lambda or kappa circulating light chains. The better outcome of ATTRwt amyloidosis and the absence of differences in strain values between AL and ATTRwt patients do not preclude an effect of light-chain toxicity on cardiac function, as patients with ATTRwt tended to have a higher LV mass than patients with AL and more depressed indices of contractility (including stroke volume and work indexed, LV ejection fraction, cardiac Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 output). Since increasing LV mass was associated with worsening indices of strain, it is possible hat in patients with AL amyloidosis (a rapidly progressive disease) LV longitudi diinaal fu func ncti cti tion on that longitudinal function gets impaired before other measures of LV contractility. This suggests that a toxic effect exerted by y ccirculating ircu ir cula cu lati la ting ti ng lig ght cchains hains on longitudinal fiberss ((which which are distri ibu b teed in the subendocardial light distributed ayeers r ) occurss bbefore eforee th tthee ma m ss eeffect fffec ectt eexerted xertedd bby y cchronic hrroniic ic aamyloid myloi oidd depo ddeposition. eposi s tionn. The The la latt t err tt layers) mass latter me mechanism ech chan anis an ism m is m more ore ev ore evident vid den ent in A ATTRwt. TTRw TT Rwt. Rw Limitations Although this study represents the largest series of patients with CA of the three main etiologies comprehensively characterized by means of both conventional and speckle tracking echocardiography thus far, the absolute number of patients within each etiology is relatively small. However, the findings in the 80 patients with AL amyloidosis are similar to those in somewhat larger series confined to AL amyloidosis, suggesting that the data from the ATTR group is also likely to be sound. The cross sectional design of the study does not allow speculation on the natural history of amyloid infiltration in the heart. However, this was not the aim of the study, and our findings provide new insights into the functional abnormalities in TTR- 15 DOI: 10.1161/CIRCULATIONAHA.113.006242 related CA and suggest hypotheses concerning the nature of these abnormalities. Finally, the cases included in the present study generally had an advanced stage of the disease and therefore preclude insights into the earlier stages of CA disease. Conclusions This study of a large series of patients with CA highlights the role of speckle tracking echocardiography in characterizing LV dysfunction in CA. Our analysis shows that, despite different pathophysiological backgrounds, TTR-related CA (particularly that due to wild-type Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 TTR deposition) has a very similar pattern of myocardial deformation to AL amyloidosis, including ncluding the typical “apical sparing pattern” of regional strain. Although the de degree egr gree eee ooff LV w wall all thickening hickening seems to be an important determinant of LV longitudinal strain, this relationship is less esss evident evi vide dent de nt in in AL amyloidosis, amyloidosis, underscoring the hee possible possible import importance tan a cee of oother ther contributors to the pathophysiology path hop o hysiolog ogyy of of LV LV dysfunction dysf dy sfun sf unct un ctio io on such suuchh as the th he toxicity to oxicity ty of of circulating circ ci rcuulatin ingg light l ght li ght ch chai chains. ains nss. 0,11 0,11 As previously pre revi viou ousl ou slyy documented doocu cume meent nted ed ffor or A AL L am amyl amyloidosis, yloi yl oido dosi do s s, s 110,11 strain str trai tr a n im ai imaging mag gin ng was was co confirmed onf nfiirm medd to bee related elated to prognosis pro ogn gnos ossis in in CA C due due u to to different diiff f erren entt etiologies. e io et iolo l gi lo gies ess. Yet Yet we showed sho howe wedd that we th hat sstrain trai tr ainn wa ai wass eq eequally ually impaired in both AL and ATTRwt amyloidosis. Since patients with ATTRwt amyloidosis have a much better prognosis than those with AL amyloidosis,3,4 our findings underscore the need to recognize the etiology of amyloidosis when evaluating regional strain, and highlight the importance of designing future large studies to determine the real contribution of regional strain impairment to prognosis in TTR amyloidosis (mutant or wild-type). Funding Sources: CCQ received research funding from the Italian Society of Cardiology, “Borse di Studio per la Ricerca Scientifica SIC – Fondazione SIC Sanofi-Aventis”. RHF was partly supported by the Harold Grinspoon Charitable Foundation and the Demarest Lloyd, Jr. Foundation. 16 DOI: 10.1161/CIRCULATIONAHA.113.006242 Conflict of Interest Disclosures: None. References: 1. Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. 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Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, Merlini G, Moreau P, Ronco P, Sanchorawala V, Sezer O, Solomon A, Grateau G. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th international symposium on amyloid and amyloidosis. Am J Hematol. 2005;79:319-328. Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 14. Ferlini A, Fini S, Salvi F, Patrosso MC, Vezzoni P, Forabosco A. Molecular strategies in genetic diagnosis of transthyretin-related hereditary amyloidosis. FASEB J. 1992;6:2864-2866. Pepys 15. Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD, P ep pys y MB, MB, amyloidosis. Hawkins PN. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidos ossiss. N En Engl gl J Med. 2002;6;346:1786-1791. 16. Palladini G, Perfetti V, Merlini G. Therapy a and management of systemic sys ystemic AL (primary) amyloidosis. 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Widespread cardiovascular autonomic dysfunction in primary amyloidosis: does spontaneous hyperventilation have a compensatory role against postural hypotension? Heart. 2002;88:615-621. 19 DOI: 10.1161/CIRCULATIONAHA.113.006242 Table 1. Main clinical characteristics in the overall population and according to the etiological subtype of cardiac amyloidosis. Age (years) Male, n (%) Previous NYHA class II, n (%) NYHA III-IV at first evaluation, n (%) Disease duration (months) Sensorimotor peripheral neuropathy, n/N (%) Renal involvement, n (%) Autonomic impairment, n (%) NT-proBNP (pg/ml) Overall (n=172) 66±12 129 (75) 114 (66) 53 (31) 12 [5-29] 33/165 (20) AL (n=80) 62±10‡ 53 (66)‡ 53 (66) 23 (29) 9 [3-17]†‡ 15/75 (20)†‡ ATTRm (n=36) 62±13$ 27 (75) 17 (47) 12 (33) 15 [6-40] 16 (44)$ ATTRwt (n=56) 76±6 49 (88) 44 (79) 18 (32) 21 [5-37] 2/54 (4) p* <0.001 0.019 0.89 0.86 0.03 <0.001 Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 37/163 (23) 35/73 (48)†‡ 0 (0) 2/54 (4) <0.001 34/165 (21) 18/75 (24)‡ 15 (42)$ 1/54 (2) <0.001 2885 3085 1636 3708 0.05 [1289-6094] [1314-11260] [770-3396] [1807-6068] Troponin T (ng/ml) 0.04 0.04 0.04 0.04 0.96 [0.01-0.09] [0.01-0.12] [0.01-0.08] [0.01-0.07] Creatinine (mg/dl) 1.1 [0.9-1.5] 1.1 [0.8-1.5] 1.1 [1-1.4] 1.3 [1-1.6] 0.12 eGFR (ml/min/m2) 62±25 64±27 69±28 56±18 0.07 (n=45) (n=139) (n=68) (n=25) (n=4 (n =4 45)) 0.999 Obstructive Coronary artery disease, n (%) 14 (8) 7 (9) 3 (8) 4 ((7) 7) 0.9 Diabetes, n (%) 10 (6) 5 (6) 1 (3) 4 ((7) 7) 00.84 . 0.86 History of hypertension, n/N (%) 53/164 (32) 24 (30) 13 (36) 16 (29) 0. 0.02 Systolic blood pressure (mmHg) 120 110 120 120 0. [108-130] [109-140] [108-1 -130 30] 30 [100-125] [109 [1 0 -140] [110-130] Diastolic blood [60-80] [60-78] 0.04 Dias Di assto toli licc bl li bloo oo od ppressure resssu surre re (mmHg) 70 [60 60-8 60 -800] 70 [60-78 8] 75 [[70-80] 70-80] 70 [65-77] 0. pressure [83-97] 0.03 Mean Me an n arteriall pr ressuuree ((mmHg) mmHg mm Hgg) 87 [[80-94] 80-9 80 -944] 884 4 [7 [[76-92]† 6-92 92 2]† 993 3 [833-97 97]] 87 [[80-93] 80-9 80 -93] 3]] 0. 25± 25±4 ±4 25± 25±4 5 4 5± 226±4 6±4 ±4 226±4 6±44 6± 00.6 (kg/m Bodyy mass indexx (k Body kg/ g m2) Sinus Siinuus rhythm, n/N (% S (%) %) 1124/168 244/1688 (7 (74) 74) 68/7 68 68/78 78 (8 (87) 87) 299 (8 (81)$ 81))$ 227/54 7/5 54 ((50) 50) <0. <0.001 Atrial fibrillation, (17) 6/78 (11) (37) 0.001 Attri r al fibrillatio io on, n n/N n//N (%) %) 228/168 28/ 8/168 /1 (1 17) 6/ /78 8 ((8)‡ 8)‡ 8) 4 (1 11)) 188 (3 37) 0.0 Heart 76±14 70±14 <0.001 Hearrt ra He rate te ((bpm) bpm) bp m m) 76± 76 ±1 ±14 779±14‡ 79 ±14‡ ±1 4‡ 777±14$ 7 144$ 7± 70±1 70 ±1 14 < <0 . Low 34/76 8/35 w QRS QR voltage, volt vo ltag ge, n/N N ((%) %) 58/162 58 62 ((35) 35)) 34/7 34 /766 (4 ((45) 5) 8/3 35 (2 (23) 3) 116/51 6/51 ((31) 6/ 31)) 31 00.86 0. Sokolow-Lyon iindex (%) 78/162 45/76 13/35 20/51 ndex nd e 1155 mm, ex mm n/N n/N (% %) 78/1 78 /162 /1 62 ((48) 48)) 48 45/7 45 /7 76 (59) (59 13/ 3/35 35 ((37) 377) 20 0/5 / 1 (39) 00.03 . Voltage-to-mass ratio [0.7-1.4] [0.7-1.3]‡ [0.8-1.8] [1.2-1.6] <0.001 Volt Vo ltag agee to to-m mas asss ra rati tioo 11.2 1. 2 [0 [0.7 7-1 -1.44] 1. 11.1 1 [0 [0.7 7-1.3]‡ 3]‡ 1. 11.2 2 [0 [0.8 8-1.8] 8] 11.3 .33 [1 .2-1 2 1.6] 6] <0 0. (n=146) (n=72) (n=35) (n=39) Treatment with beta-blockers, n/N (%) 60/167 (36) 24/76 (32) 13/35 (37) 23 (41) 0.53 Treatment with diuretics, n/N (%) 112 (65) 48/76 (63) 24 (67) 40 (71) 0.61 Treatment with calcium channel blockers, n/N (%) 8/162 (5) 4/76 (5) 3/35 (9) 1/51 (2) 0.46 Treatment with Amiodarone drugs, n/N (%) 15/163 (9) 5/77 (6) 2/35 (6) 8/51 (16) 0.16 Treatment with ARBs/ACE inhibitors, n/N (%) 37/163 (23) 15/77 (19) 8/35 (23) 14/51 (27) 0.57 Data are shown as mean ± SD, median [IQR] or n (percentage). *p-values were corrected according to the Bonferroni method. †p< 0.05 at post hoc analysis: AL vs. ATTRm; ‡p< 0.05 at post hoc analysis: AL vs. ATTRwt; $p< 0.05 at post hoc analysis: ATTRm vs. ATTRwt. Abbreviations: NYHA=New York Heart Association; eGFR=glomerular filtration rate. 20 DOI: 10.1161/CIRCULATIONAHA.113.006242 Table 2. Conventional echocardiographic findings in the overall population and according to the etiological subtype of cardiac amyloidosis. IVS thickness (mm) PW thickness (mm) Mean wall thickness (mm) LV mass/BSA (g/m2) Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 LV diastolic diameter (mm) LV systolic diameter (mm) LV ejection fraction (%) LA diameter (mm) LV diastolic volume (ml) LV diastolic volume index (ml/m2) LV systolic volume (ml/m2) LV systolic volume index (ml/m2) LA volume index (ml/m2) RV diastolic area (cm2) RV fractional change area (%) E wave w ve (cm/s) wa (cm cm/s)) A wave wave wa ve (cm/s) (cm m/s /s)) E wave wav Dec time tim im me (ms) (ms) E/A E/ Lateral Late La tera te raal E’ E (cm/s) (cm m/s /s)) Lateral Lateera rall A’ ((cm/s) cm/s)) cm Lateral Latterall S’ ((cm/s) cm//s) / s) E/lateral E’ Tricuspid regurgitation velocity (m/s) Systolic Pulmonary Pressure (mmHg) Stroke volume (mL/beat) Stroke volume index (mL/beat/m2) Cardiac output (L/min) LV stroke work (ml*mmHg/min) LV stroke work index to LV mass (ml*mmHg*g/min) Diastolic pattern, n/N (%) -normal -grade I -grade II -grade III RV free wall thickness (mm) Overall AL ATTRm ATTRwt (n=172) (n=80) (n=36) (n=56) 16±2 15±2‡ 16±3$ 17±2 15±2 14±2‡ 14±3$ 16±2 16±2 15±2‡ 15±2$ 17±2 146 134 150 154 [122-168] [110-156]‡ [124-174] [134-174] 42±6 43±5 44±6 42±5 28 [25-33] 28 [25-31]‡ 30 [25-35] 31 [26-35] 55±12 56±14‡ 57±13 51±11 45±6 43±5‡ 43±6 47±5 80 [64-101] 77 [61-100] 92 [70-102] 79 [66-104] 44 [35-52] 44 [35-52] 48 [38-58] 41 [35-52] 36 [25-50] 33 [23-44] 37 [25-53] 39 [29-53] 19 [14-26] 19 [13-23] 18 [15-29] 19 [14-26] 38 [30-47] 36 [27-45]‡ 36 [29-47] 41 [35-51] 18±5 17±5‡ 17±3$ 19±4 (n=154) (n=73) (n=31) 42±11 43±11 40±9 42±10 (n=154) (n=73) (n=31) 81 [67-94] 84 [69-94] 78 [65-100] 77 [69[6 9 94] 97 [65-93] 55 [34-74] 56 [33-80]†‡ 38 [333-80]†‡ 66 [47-78]$ [3 [47-78 78]$ 78 38 [29-55] 168 166 188 156 16 68 1666 18 88 15 56 [130-216] [130-201] [142-231] [127-201] [1330-2 [1 30 2166] [130 0-2 201] [1 142 42-2 -2 2311] [127 27 7-2 -201 01]] [0.9-1.8] [1.2-2.8] 1.66 [[1-2.5] 1--2.5 5] 1.6 [[1-2.5] 1--2.5]] 11.3 1. 3 [0.9 9-1 1.8] 2 [1 [1.2-2.8] [5-7] [5-7] 6 [5 [5-7]] 6 [5[[5-8] 5-8] 6 [5 [[5-8] -8]] 6 [5 [5-7 7] [4-7] [4-8]†‡ 6 [4-9] [3-5]A’) 5 [4-7 7] 5 [4 -8]† 8]† ]†‡‡ [ -9 [4 9] 4 [3 [3-5 -5]A ]A A’) [4-6] [5-8] [4-5] 5 [4 [4-6 -6]] 6 [4-7]†‡ [4-7]† 7]† ]†‡‡ 6 [5 -8] 8] 5 [4 -5] 5] [11-18] [10-16] 13 [[10-17] 13 10-1 10 -1 17] 114 4 [1 [111-18 18] 8] 122 [[10-17] 10-17] 10 7] 112 2 [1 [100-16 16]] 2.7±0.4 2.7±0.5 2.7±0.4 2.7±1.0 (n=137) (n=66) (n=22) (n=49) 40±10 41±10 39±11 40±8 (n=138) (n=66) (n=22) 52 [41-66] 51 [39-67] 57 [50-72] 50 [42-58] 28 [22-34] 28 [21-36] 31 [27-41]$ 25 [20-29] 3.8 [2.9-4.8] 4 [2.9-5]†‡ 4.3 [3.6-5.6] 3.2 [2.7-3.8] 4383 4321 5281 4192 [3464-5829] [3135-6080] [4328-6761]$ [3486-4966] 16.4 17.9 20.6 14.1 [12.6-22.5] [11.1-23.2] [15.4-29.6]$ [12.6-19.6 16/162 (22) 20/162 (12) 70/162 (43) 56/162 (35) 6/77 (8) 11/77 (14) 34/77 (44) 26/77 (34) 7/35 (20) 3/35 (9) 15/35 (42) 10/35 (29) 3/50 (6) 6/50 (12) 21/50 (42) 20/50 (40) 8±2 (n=156) 7±2 (n=70) 8±2 (n=33) 8±2 (n=53) 21 p* p** <0.001 <0.001 <0.001 0.005 0.005 0.02 0.006 0.06 0.16 0.008 0.02 <0.001 0.38 0.21 0.18 0.35 0.02 0 02 0. 00.002 .0002 .002 0.69 0.21 0.02 0.46 0.91 0.78 0.39 0.29 0.45 0.4 .45 00.31 .31 .3 0.38 0.54 0.4 0.004 0.18 0..18 0.71 0.002 0.11 0.1 .11 00.06 .006 0.38 0. .38 00.003 .0 .003 003 00.003 .00 0033 0.38 0. 0.79 0.04 0.0 04 0.69 0.6 69 00.28 .28 .2 28 00.03 .03 03 0.68 0.42 0.86 0.58 0.05 0.001 0.008 <0.001 <0.001 0.001 0.01 0.001 0.007 0.007 0.49 0.38 0.03 0.02 DOI: 10.1161/CIRCULATIONAHA.113.006242 Interatrial septum (mm) 9±2 8±2 9±2 9±2 0.08 0.007 (n=168) (n=78) Pericardial effusion, n (%) 89 (52) 48 (60) 15 (42) 26 (46) 0.12 0.53 Data are shown as mean ± SD, median [IQR] or n (percentage). *Unadjusted comparisons, p-values were corrected according to the Bonferroni method. **Multiple comparisons adjusted for age, gender, systolic blood pressure, diastolic blood pressure, disease duration, glomerular filtration rate, body mass index, heart rate and presence of atrial fibrillation. †p< 0.05 at post hoc analysis: AL vs. ATTRm; ‡p< 0.05 at post hoc analysis: AL vs. ATTRwt; $p< 0.05 at post hoc analysis: ATTRm vs. ATTRwt. Abbreviations: IVS=interventricular septum, PW=posterior wall, LV=left ventricle, LA=left atrium, RV=right ventricle, E/A=early to late mitral inflow velocity ratio, E’=lateral mitral early relaxation velocity, A’=lateral mitral late relaxation velocity, S’=lateral mitral systolic velocity, E/E’=mitral inflow to mitral relaxation velocity ratio. Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 22 DOI: 10.1161/CIRCULATIONAHA.113.006242 Table 3. Speckle tracking echocardiography findings in the overall population and according to the etiological subtype of cardiac amyloidosis. Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 4-chamber global LS (%) 2-chamber global LS (%) Global LS (%) Basal LS (%) Mid Ventricular LS (%) Apical LS (%) 4-chamber global RS (%) 2-chamber global RS (%) Global RS (%) Basal RS (%) Mid Ventricular RS (%) Apical RS (%) Global CS (%) -Septal -Lateral -Inferior -An Ante teri rior or -Anterior --Posterior Post Po ster st eriorr --Anterior-septal Annte t rior-sep eptaal Overall AL (n=172) (n=80) -13±4 -12±4† -12±4 -12±4† -12±4 -12±4† -8 [-12, -4] -8 [-12, -5]† -8 [-11, -6] -8 [-11, -6]† -19 [-23, -15] -19 [-22, -15] 20±8 20±9 20±8 21±8‡ 20±7 21±7 16±9 17±9 20±8 21±8‡ 24±9 25±9 -24±8 -23±7 -23±11 -25±11‡ -22±9 -22±9 -21±9 -22±9 -26±10 0 -25±9 9 -23±9 -23±9 -26± -2 6±11 6± 11 --26±11 26±1 26 ± 1 ±1 -26±11 ATTRm ATTRwt p* p** (n=36) (n=56) -15±4$ -12±4 0.002 0.03 -14±4$ -11±3 0.006 0.006 -15±4$ -11±3 <0.001 0.02 -10 [-16, -7]$ -7 [-9, -4] <0.001 0.05 -11 [-15, -7]$ -7 [-9, -5] 0.001 0.06 -19 [-23, -18] -19 [-24, -15] 0.66 0.03 22±8 19±7 0.34 0.19 22±8$ 17±7 0.01 0.09 21±7 18±6 0.05 0.12 18±9 15±7 0.15 0.85 22±8 18±7 0.02 0.09 24±7 22±8 0.28 0.11 -24±7 -21±6 0.09 0. 09 00.04 .04 -25±9$ -19±9 00.005 .005 .0 05 00.003 .00 .0 0 -22±10 -21±7 0.7 71 00.6 .6 6 0.71 -23±8 -18±8 0.04 0.07 -26±8 -24±9 0.77 0.39 -23±9 --22±8 -2 2±8 0.82 0.33 -28± -2 8 11 8± 1 --23±10 2 ±1 23 10 0.11 0.11 00.009 . 0 .0 -28±11 Data D ataa are are shown as mean mean ± SD, mea SD D, median D, mediian [IQR] [IQ IQR R] oorr n (p (percentage). per erccentaage age). *Unadjusted comparisons, p-values method. Unaadj d usted co com mparissons, p-vallue ues we were r ccorrected o rected according or acccordinng ng tto o th thee Bonferroni Bonfferro Bo onii meth hodd. **Multiple pressure, duration, *Mu Mult ltip lt iple ip le comparisons com ompa pari risoons adjusted adjuuste usted for f r age, fo age, gender, gen ende d r, systolic de sys ysto oli licc bblood loood pressure, p es pr essu suree, di su ddiastolic asto to oli licc bblood loood pr pres esssu sure ree, ddisease iseeasee du dur rattion o , glomerular glom merul ular lar filtration fil iltr t attio ion rate, raate te,, body body bod dy mass mas asss index, index, ind dex heart heaart rate rate and and presence preseenc ncee of atrial atr triial ia fibrillation. fibr b illa br illati tion io . post AL ATTRm; †p< 0.05 †p< 0.05 05 at at po stt hhoc oc aanalysis: nally na lysi sis: is: A L vs vs. AT ATTR TRm; TR m; ‡‡p< p< < 00.05 .05 05 att ppost ostt hoc os hoc analysis: anal alys lysiis: is: AL vvs. s. ATTRwt; ATT TTR Rwt; Rwt t; $$p< p< < 00.05 .05 05 att ppost ostt hoc os hoc analysis: ATTRm ATTRwt. nalysis: ATTR TR Rm vs vs. AT ATTR TRw TR wt. Abbreviations: LS=longitudinal CS=circumferential RS=radial Abb i i LS l i di l strain, i CS i f i l strain, i RS di l strain i 23 DOI: 10.1161/CIRCULATIONAHA.113.006242 Table 4. Distribution of systolic and diastolic indices values across tertiles of mean LV wall thickness in the overall population of patients with CA. Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 LA volume index (ml/m2) LV ejection fraction (%) E wave (ms) A wave (ms) S’ (cm/s) E’ (cm/s) A’ (cm/s) E/E’ E/E Global LS (%) Basal LS (%) Mid ventricular LS (%) Apic ical al LS LS (%) (% Apical III tertile of mean p trend I tertile of mean LV II tertile of mean LV wall thickness LV wall thickness wall thickness (13.5 [11.5-15] mm) (16 [15.1-16.8] mm) (17.5 [16.9-2.1] mm) (n=57) (n=52) (n=63) 33 [27-45] 38 [33-45] 41 [32-53] 0.001 57±12 54±11 52±11 0.01 84 [72-94] 64 [40-91] 6 [4-8] 6 [6-8] 7 [4-10] 12 [9-17] -14±5 -12 [-16, -5] -10 [-15, -7] -19 [-25, -15] 81 [68-94] 48 [29-70] 5 [4-6] 6 [5-7] 5 [4-6] 13 [11-17] -12±3 -8 [-10, -5] -8 [-10, -6] -20 [-23, -16] 76 [63-91] 41 [31-61] 5 [4-5] 5 [5-6] 4 [3-6] 13 [11-1 [11-16] 16] -10± -10±3 0± ±3 -7 [-9 9, -4] 4] [-9, -6 [-9, -4] -18 [-22, -14] 0.04 0.004 0.001 0.002 0.002 00.19 .19 < <0.00 <0.001 0 <0 .000 <0.001 <0.00 <0.001 0.22 Data are Data are re shown sho own wn as mean mean ± SD, median [IQR] or n (percent (percentage). ntaage age). Abbreviations: LV=left LS=longitudinal mitral velocity; Abbr Ab rev e iations:: LA=left LA= A=le left le ft atrium, atrriu ium, m, L V=le V= left le ft ve vventricle, ntri nt ricl cle, cl e, L S lo S= long ngituudinal all strain; str trai ain; ai n S’=lateral S’= ’=laate tera rall mi m trall ssystolic ysto ys toli to l c ve li velo loci city ci ty y; E’=lateral late E/E’=mitral mitral E ’=llateral mitrall early earl ea r y relaxation reela laxa xaati tion on velocity; vel eloc ocit ity; y A’=lateral y; A’= =laateraal mitral mitrall la ate rrelaxation ellaxa xattioon on vvelocity; elo oci city ty;; E/ E/E E’=m =miitra =m itrall in iinflow flow fl ow too mi mitr t all tr relaxation velocity elax xa xation veloccity rat rratio. atio. Tablee 5. A Table Tabl Association ssoc ss ocia i tiion of ia of clinical clin cl i ic in i al characteristics char arac actteri terist stic icss an andd LV L w wall alll thickness al th thi hickn icknes esss with wiith h systolic sys ysto toli licc fu li func function ncti tion on parameters (multivariable linear regression). Age (per 1 year) Male gender ATTRm ATTRwt Mean LV wall thickness (per 1 mm) Disease duration (per 1 month) LV ejection fraction (%) TDI derived S’ (cm/s) Global LS (%) ȕ 95% CI p ȕ 95% CI p ȕ 95% CI 0.09 -0.11 to 0.30 0.36 -0.001 -.007 to 0.006 0.81 -0.0007 -0.006 to 0.005 -3.85 -8.77 to 1.06 0.12 0.15 -.007 to 0.31 0.06 -0.01 -0.14 to 0.12 0.08 -5.18 to 5.35 0.98 -0.012 -0.18 to 0.15 0.88 0.19 0.06 to 0.34 -4.96 -10.5 to 0.59 0.08 -0.158 -0.33 to 0.01 0.07 0.02 -0.13 to 0.16 -5.18 -14.9 to 4.54 0.29 -0.48 -.79 to -0.17 0.003 -0.37 -0.63 to -0.12 P 0.78 0.86 0.005 0.84 0.005 0.36 0.74 -1.31 to 2.02 0.67 -0.005 -0.06 to 0.05 0.86 Abbreviations: LV=left ventricle, TDI=tissue Doppler imaging, LS=longitudinal strain. 24 0.007 -0.04 to 0.05 DOI: 10.1161/CIRCULATIONAHA.113.006242 Table 6. Multivariable analysis of risk of death resulting from any cause and incident heart failure. Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 Death resulting from any cause Etiology ATTRm vs. AL Etiology ATTRwt vs. AL NYHA class III-IV eGFR (each incremental 1 ml/min) Global LV longitudinal strain (each incremental 1 %) Incident heart failure Etiology ATTRm vs. AL Etiology ATTRwt vs. AL Heart rate (each incremental 1 bpm) Restrictive filling pattern NT-proBNP (each incremental pg/mL) Global LV longitudinal strain (each incremental 1 %) HR 95% CI p 0.39 0.36 1.92 0.98 1.1 1.66-0.92 0.18-0.71 1.00-3.65 0.97-0.99 1.01-1.19 0.032 0.003 0.047 0.001 0.026 0.61 0.71 1.02 2.03 1.00 1.01 0.23-1.56 0.31-1.60 0.99-1.04 0.80-5.13 0.99-1.00 0.91-1.122 0.29 0.41 0.10 0.13 0.39 0.88 0.88 Abbreviations: HR=hazard ratio; CI=confidence intervals; NYHA=New York Heart Association; n; eeGFR=glomerular G R= GF R=gl glom gl omer om erul er ular a filtration iltration rate. Figure Fi igu ure Legends: Leg gen nds ds:: Figure Figu gure re 11.. Pr P Prevalence ev val a en nce of fr freq frequency eque uenc ncyy of abn abnormal bnor orm mall in indice indices cess of ssystolic ysto ys toliic an andd dias diastolic asto oli lic fu func function cti tionn iin n patients pati pa tien ents ts w with ithh cardiac it card ca rdia iacc am amyl amyloidosis. yloi oido dosi siss Speckle Spe peck ckle le tracking-derived tra rack ckin ingg de deri rive vedd st stra strain rain in pparameters aram ar amet eter erss we were re m more oree or sensitive than the conventional echocardiographic parameters of systolic and diastolic function in characterizing left ventricular dysfunction. S’= lateral mitral systolic velocity; LV=left ventricular. Figure 2. Overall survival (a) and freedom from incident heart failure (b) in patients with AL, ATTRm and ATTRwt. HF=heart failure; AL=light chain amyloidosis; ATTRm=hereditary transthyretin-related amyloidosis; ATTRwt=wild-type transthyretin-related amyloidosis. 25 Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 Figure 1 Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 Figure 2A Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 Figure 2B Left Ventricular Structure and Function in TTR-Related versus AL Cardiac Amyloidosis Candida Cristina Quarta, Scott D. Solomon, Imran Uraizee, Jenna Kruger, Simone Longhi, Marinella Ferlito, Christian Gagliardi, Agnese Milandri, Claudio Rapezzi and Rodney H. Falk Circulation. published online February 21, 2014; Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/early/2014/02/21/CIRCULATIONAHA.113.006242 Data Supplement (unedited) at: http://circ.ahajournals.org/content/suppl/2014/02/21/CIRCULATIONAHA.113.006242.DC1 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/ SUPPLEMENTAL MATERIAL Diagnostic definitions Diagnosis of systemic amyloidosis was defined by histological documentation of Congored staining and apple-green birifrangence under cross-polarized light in at least one involved organ.12 Cardiac involvement was defined as echocardiographic end-diastolic LV wall thickness >1.2 cm (in the absence of any other plausible causes of LV hypertrophy).2,3,13 Other echocardiographic signs suggesting CA (in addition to increased LV wall thickness) were systematically checked and included granular sparkling appearance of ventricular myocardium, increased thickness of atrioventricular valves, or right ventricular free wall, or interatrial septum, and pericardial effusion. Distinction between TTR-related and AL amyloidosis was based on genotyping and/or immunohistochemistry or mass spectrometry.2,12 ATTRm was defined by a documented TTR mutation with DNA analysis.14 AL was defined by the presence of monoclonal plasma-cell dyscrasia with serum electrophoresis, serum or urine immunofixation, and abnormal serum free light chain assay, in the absence of any TTR mutation at DNA analysis.15,16 ATTRwt was defined by positive immunohistochemistry for TTR in the absence of any TTR mutation at DNA analysis.17 In equivocal cases, biopsy specimens underwent proteomics evaluation.18 Disease duration was calculated as the time interval between the onset of symptoms and the final diagnosis of the amyloid disease. The onset of symptoms was derived by patients’ selfreport of striking changes in their clinical condition in the past weeks/months/years that were judged to be compatible with manifestations of the disease. Kidney involvement was defined as the presence of 24-hour urine protein excretion ≥0.5 g/d,13 and renal insufficiency was defined as glomerular filtration rate <60 mL/min. The definition of peripheral nervous system involvement was based on characteristic neurological signs and symptoms (typical symmetric ascending sensorimotor peripheral neuropathy).13 Autonomic impairment was defined by the presence of orthostatic hypotension, gastric-emptying disorder, pseudo-obstruction, and voiding dysfunction not related to direct organ infiltration.13 History of coronary artery disease was defined as a previous coronary artery bypass surgery or percutaneous coronary intervention, a self-reported history of angina, myocardial infarction or unstable angina, or stable angina with a positive stress test or more than 50% stenosis of at least one major coronary artery on angiography. History of hypertension was defined as systolic pressure repeatedly >140 mm Hg or diastolic pressure >90 mm Hg, or as the use of antihypertensive medication. History of diabetes was defined as use of antidiabetic medication or self-report of clinically diagnosed diabetes. Cardiac evaluation, echocardiographic variables LV wall thickening, LV ejection fraction, right ventricular fractional area change, and left atrial (LA) size were measured using criteria defined by the American Society of Echocardiography.20 LV mass was calculated according to the Devereux method.21 E-wave deceleration time accompanied by early to late mitral inflow velocity ratio (E/A ratio) on pulsed Doppler echocardiography as well as TDI-derived longitudinal function parameters (lateral mitral early relaxation velocity (E’), lateral mitral late relaxation velocity (A’), and mitral inflow to mitral relaxation velocity ratio (E/E’)) were used to characterize diastolic function.22 LV restrictive filling pattern was defined as E-wave deceleration time <150 ms accompanied by E/A wave ratio >2.5 on pulsed Doppler at the level of the mitral valve.23Error! Reference source not found. LV volumes were traced manually at end-diastole and -systole at apical 4- and 2-chamber views and derived from modified biplane Simpson’s method. Abnormality of E’, A’, lateral mitral systolic velocity (S’), E/A and E/E’ ratio values was defined based on data published on healthy subjects.24 Figure legends Supplemental Figure 1. Overview of averaged regional function, including longitudinal (LS) and radial (RS) at basal, mid ventricular (mid), and apical levels of LV among patients with different etiological subtypes of cardiac amyloidosis. While AL and ATTRwt showed a similar impairment of LS and RS at the basal and mid level of LV, with better values in ATTRm, apical LS was preserved independently of the specific etiological subtype. AL=light chain amyloidosis; ATTRm=hereditary transthyretin-related amyloidosis; ATTRwt=wild-type transthyretin-related amyloidosis; LS= longitudinal strain; RS=radial strain; MID=mid ventricular. Supplemental Figure 1. Overview of averaged regional function in the three etiologies of CA.
