C. Quarta, L. Obici, S. Longhi, S. Perlini, A. Milandri, F. Del Corso, F. Perfetto, F. Cappelli, G. Merlini, C. Rapezzi

Transcription

1 Hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: disease profile and differential diagnosis with hypertrophic cardiomyopathy and senile systemic amyloidosis C. Quarta, L. Obici, S. Longhi, S. Perlini, A. Milandri, F. Del Corso, F. Perfetto, F. Cappelli, G. Merlini, C. Rapezzi University of Bologna and S.Orsola-Malpighi Hospital, Bologna, Italy Center for Amyloidosis, "Fondazione IRCCS San Matteo, University of Pavia, Italy Careggi University Hospital, Florence, Italy

2 Disclosure of interest None

3 BACKGROUND Transthyretin-related amyloidosis ATTR (FAP) SSA

4 BACKGROUND Genotypic-Phenotypic Correlation in ATTR V30M early onset C10R F33L S50R Neurologic T49A G47A A36P F64L E89Q R34T Phenotype V30M late onset W41L H88R S23N T60A L111M I68L V122I Cardiac EHJ 2012, in press

5 ATTR SSA CMPI

6 Research Questions What s the prevalence of an exclusively cardiac phenotype among Caucasian patients with ATTR from a non-endemic area? What s the clinical, electrocardiographic, echocardiographic and genotypic profile of these patients? What s the outcome? Does the phenotype remain exclusively cardiac along time? Are there any useful hints for the differential diagnosis with HCM and SSA?

7 METHODS Setting of the Study Three main Italian referral Centers for the diagnosis and treatment of hereditary amyloidosis (Bologna, Florence and Pavia), providing coordinated amyloidosis networks and liver/heart transplantation programs Study period

8 METHODS Methods Cross-sectional study Retrospective analysis of ATTR patients data at presentation by means of dedicated databases Systematic evaluation of follow-up

9 METHODS Phenotypic Classification 1) Exclusively cardiac involvement (echocardiographic and/or ECG evidence of cardiac amyloidosis in the absence of any sign or symptom of neurologic involvement)* 2) Exclusively neurologic involvement 3) Mixed cardiac/neurologic involvement *Of note, carpal tunnel syndrome was not considered as evidence of neurologic involvement in this context

10 METHODS Definition of Amyloidotic CMP ED-IVS SIV > Td 12 >12 mm in mm the in absence assenza of other i altre causes cause of LV di ventricular ipertrofia hypertrophy ventricolare Granular granular sparkling sparkling appearance de of setto ventricular interventricolare myocardium Increased thickness of RV free wall Pericardial effusion Increased thickness of ispessimento atrioventricular valvole valves A-V Increased thickness of interatrial septum ispessimento setto interatriale

11 RESULTS Results Study population Patients, n 186 Families, n 89 Men, n (%) 130 (70%) Age at diagnosis, years Age at onset of symptoms, yr 54 ± ± 15

12 RESULTS Frequency of the Different Phenotypes MIXED CARDIAC 17% (n=31) 58% (n=109) 25% (n=46) NEUROLOGIC

13 Patients characteristics according to Phenotypes EHJ 2012, in press Cardiac Mixed Neurologic p Patients, n (%) 31 (17%) 109 (58%) 46 (25%) na Male gender, n (%) 29 (94%) 73 (67) 28 (61) Age at onset of symptoms, yrs 67 [60-73] 50 [40-59] 41 [33-58] <0.001 Age at diagnosis, yrs 70 [41-66] 53 [43-62] 42 [37-61] <0.001 NYHA III-IV, n(%) 13(41.9) 11(10) 0(0) n.a. Carpal tunnel sd, n (%) 14 (45%) 45 (41%) 6 (13%) <0.001 TTR mutations, n (%) Ile68Leu Val30Met Val122Ile Val14Leu Hys88Arg Glu89Gln Ser23Asn Tyr78Phe Gly89Lys Other mutations 23 (74.3%) 2 (6.5%) 1 (3.2%) 1 (3.2%) 1 (3.2%) 1 (3.2%) 1 (3.2%) 1 (3.2%) 1 (1%) 30 (27.5%) 31 (30.6%) 1 (1%) 43 (42.7%) 3 (6.5%) 16 (34.8%) 1 (2.2%) 8 (17.4%) 22 (40.7%) <0.001 < n.a.

14 RESULTS Electrocardiographic Characteristics CARDIAC (N=31) MIXED (N=109) Atrial fibrillation, n (%) 9(29) 3(3) <0.001 Pace-maker, n (%) 4 (13) 1 (1) Total QRS score (mv) 123 [99 144] 102 [89 120] QTc interval, msec 486 [ ] 431 [ ] <0.001 Low QRS voltage, n (%) 11 (35) 25(23) LBBB, n (%) 3 (10) 5 (5) RBBB, n (%) 6 (19) 12 (11) Ischemic pattern (negative T waves), n (%) 17 (55) 29 (27) Pseudoinfarct pattern, n(%) 17 (55) 50 (46) P EHJ 2012, in press

15 RESULTS Echocardiographic Characteristics CARDIAC (N=31) MIXED (N=109) ED-IVS thickness, mm 18 [16 20] 16 [13 18] ED-LVPW thickness, mm 16 [15 18] 14 [13 16] LA diameter, mm 47 [44 51] 42 [38 45] <0.001 LVEDD, mm 49 [48 51] 42 [40 46] <0.001 LVESS, mm 38 [37 40] 26 [25 30] <0.001 LV-EF, % 45 [36 51] 58 [52 66] <0.001 Restrictive filling pattern, n (%) 12 (39) 27 (25) LV mass of men (g/m2) 225 [ ] 185 [ ] <0.001 Atrioventricular valve thickening, n (%) 19 (61) 43 (39) P EHJ 2012, in press

16 Exclusively Cardiac Phenotype: F-UP Average duration: 36 [14 50] months Cardiac related death: 3 patients Heart / liver transplantation: 4 patients Development of abnormalities at neurologic examination in 5 patients, not associated with spontaneously reported symptoms

17 General Profile of ATTR patients with Exclusively Cardiac Phenotype Male gender Average age > 65 yrs Symmetric LV hypertrophy Slightly increased LV diameters Mild LV systolic dysfunction Normal or near normal QRS voltages No neurologic impairment during follow-up

18 RESULTS Exclusively cardiac phenotype: diagnostic pathways Intermediate (wrong) diagnosis hypertrophic CMP: 7 cases (23%) dilated CMP: 2 cases hypertensive heart disease: 3 cases ischemic heart disease: 2 cases Family history family history of ATTR in 1 case sudden death among relatives in 2 cases

19 RESULTS Differential diagnoses ATTR with Cardiac Phenotype vs SSA vs HCM ECHOCARDIOGRAPHY ATTR (n=31) SSA (n=30) HCM (n=30) End-diastolic IVS thickness, mm End-diastolic LV posterior wall thickness, mm 18[16 20] 18[16 22] 19[17 22] 16[15 18] 17[14 19] 14[13 15]* Symmetric LVH, n (%) 30(97) 29(97) 15(50)* LV mass of men (g/m2) 225[ ] 247[ ] 186[ ]* LV end-diastolic diameter, mm 49[48 51] 47[43 50] 44[40 47]* LV ejection fraction, % 45[36 51] 50[35 58] 68[67 76]* Restrictive filling pattern, n (%) 12(39) 9(30) 4(13) Pericardial effusion, n (%) 17(55) 13(43) 1(3)* Atrioventricular valve thickening, n (%) 19(61) 15(50) 1(3)* * P<0.05 EHJ 2012, in press

20 RESULTS Differential diagnoses ATTR with Cardiac Phenotype vs SSA vs HCM ECG ATTR (n=31) SSA (n=30) HCM (n=30) Atrial fibrillation, n (%) 9(29) 11(37) 2(7)* Total QRS score (mv) 123[99 144] 122[ ] 155[ ] Low QRS voltage, n (%) 11(35) 10(33) 2(7)* LBBB, n (%) 3(10) 9(30) 2(7)* LVH, n (%) 2(7) 3(10) 17(57)* Ischemic pattern (negative T waves), n (%) 17(55) 15(50) 24(80)* QTc interval, msec 486[ ] 472[ ] 450[ ]* * P<0.05 EHJ 2012, in press

21 Conclusions Over 15% of Caucasian ATTR patients from a non-endemic area have an exclusively cardiac phenotype at presentation, characterized by symmetric LV hypertrophy and systolic dysfunction. These patients who are generally elderly men do not develop relevant neurologic symptoms at a mid-term follow up. Although various mutations are associated with this phenotype, Ile68Leu occurs very frequently

22 Conclusions While an accurate study of the echocardiographic and ECG findings can direct towards the right diagnosis between ATTR and HCM, the differential diagnosis between ATTR and SSA is based solely on molecular genetics. In patients with an exclusively cardiac phenotype the role of liver transplantation should be reconsidered, since the absence of neurologic manifestations may be the rationale to perform isolated heart transplantation.