http://informahealthcare.com/amy ISSN: 1350-6129 (print), 1744-2818 (electronic) Amyloid, 2014; 21(4): 246–255 ! 2014 Informa UK Ltd. DOI: 10.3109/13506129.2014.956924

ORIGINAL ARTICLE

Noninvasive detection of cardiac involvement in patients with hereditary transthyretin associated amyloidosis using cardiac magnetic resonance imaging: a prospective study Jean-Franc¸ois Deux1,2,3, Thibaud Damy3,4, Alain Rahmouni1, Julie Mayer1,3, and Violaine Plante´-Bordeneuve3,5

Amyloid Downloaded from informahealthcare.com by Universitat de Girona on 12/03/14 For personal use only.

1

Radiology Department, Henri Mondor Hospital, University Paris Est Cre´teil, Assistance Publique-Hoˆpitaux de Paris, Cre´teil, France, 2CNRS EAC 4396, Centre de Recherches Chirurgicales, Henri Mondor Hospital, University Paris Est Cre´teil, Assistance Publique-Hoˆpitaux de Paris, Cre´teil, France, 3 Amyloid Network, Henri Mondor Hospital, Cre´teil, France, 4Cardiology Department, Henri Mondor Hospital, University Paris Est Cre´teil, Assistance Publique-Hoˆpitaux de Paris, Cre´teil, France, and 5Neurology Department, Henri Mondor Hospital, University Paris Est Cre´teil, Assistance PubliqueHoˆpitaux de Paris, Cre´teil, France Abstract

Keywords

Background: Most of the studies that described cardiac amyloidosis using cardiac magnetic resonance (CMR) imaging refer to patients with primary light chain (AL) amyloidosis. The goal of this study was to evaluate cardiac involvement in patients with hereditary transthyretin associated (ATTR) amyloidosis and asymptomatic carriers and its relationships with clinical symptoms and genotype, using CMR imaging. Methods and results: Fifty-three patients with hereditary ATTR amyloidosis and 14 asymptomatic carriers were included in this study. Morphological, functional and late gadolinium enhancement (LGE) findings were noted on CMR images. A positive LGE suggesting cardiac amyloidosis was detected in 60% of patients. The pattern of LGE was diffuse, focal and circumferential in 32, 26 and 2% of patients, respectively. The inferior basal segment was the most frequently involved (93%) in case of focal involvement. Diffuse pattern was exclusively encountered in patients with cardiac symptoms. Nineteen percent of patients with isolated neurological symptoms and 20% of subjects without left ventricular wall thickening exhibited cardiac abnormalities on CMR. Conclusion: Cardiac involvement can be detected in patients with hereditary ATTR amyloidosis with isolated neurological symptoms and without left ventricular wall thickening, suggesting that CMR could be useful in detecting preclinical cardiac amyloidosis.

Amyloid, cardiac, magnetic resonance imaging, transthyretin History Received 15 February 2014 Revised 28 July 2014 Accepted 18 August 2014 Published online 11 September 2014

Abbreviations: AL: light-chain amyloidosis; ATTR: transthyretin associated; CMR: cardiac magnetic resonance; EKG: electrocardiogram; LGE: late gadolinium enhancement; NT-proBNP: N-terminal pro-brain natriuretic peptide; NYHA: New York Heart Association; PSIR: phase sensitive inversion recovery; SSFP: steady state free precession

Introduction Cardiac amyloidosis is induced by deposition of misfolded amyloid proteins within the myocardial tissue. This deposit leads to thickening of the cardiac walls, restrictive cardiomyopathy, right- and/or left-sided heart failure and conduction abnormalities [1,2], and has major clinical implications [1,3,4]. The diagnostic of cardiac amyloidosis is frequently delayed because of various clinical presentations that may cloud the cardiac symptoms. Non invasive imaging techniques such as echocardiography [5–7], radionuclide imaging [8] and cardiac magnetic resonance imaging (CMR) [9–12] Address for correspondence: Pr Jean-Franc¸ois Deux, Amyloidosis Network, Radiology Department; Henri Mondor Hospital, 51 av Mal de Lattre de Tassigny, Cre´teil 94000, France. Tel: + 33 1 49 81 26 34. Fax: +33 1 49 81 46 23. E-mail: [email protected]

are of interest to help the clinician to suspect cardiac involvement. CMR is a powerful noninvasive tool in the diagnosis of cardiac amyloidosis and late gadolinium enhancement (LGE) imaging has been reported to be the most accurate predictor of endomyocardial biopsy positive amyloidosis [13]. A diffuse or global subendocardial enhancement of myocardial tissue is highly characteristic of cardiac amyloidosis on late gadolinium enhanced (LGE) images. More recently a suboptimal myocardial nulling or a patchy focal LGE pattern have been reported [12]. Most reports have described abnormal LGE in series mainly including patients with amyloid light-chain (AL) amyloidosis [9,10,12], but relatively few studies have studied the pattern of cardiac involvement in patients with hereditary ATTR amyloidosis [10,14–16]. In addition, relationships between neurological and cardiac symptoms and MR findings have not been

DOI: 10.3109/13506129.2014.956924

precisely reported in patients with hereditary ATTR amyloidosis. In this work, we prospectively investigated patients with hereditary ATTR amyloidosis and asymptomatic carriers of the TTR mutation using CMR. Our primary aim was to assess the cardiac MR spectrum of abnormalities to refine the diagnostic process of ATTR cardiac amyloidosis and to identify early markers of cardiac involvement on CMR.

CMR in patients with hereditary ATTR amyloidosis

247

600E apparatus (Roche Diagnostics, Basel, Switzerland) using a commercially available kit as per routine clinical procedure. NT-proBNP had a limit of detection of 1 pg/mL. All subjects that exhibited a BNP level beyond 82 pg/mL were noted. This threshold best identified patients with echocardiographic abnormalities as we recently reported [17]. CMR protocol

Methods

Amyloid Downloaded from informahealthcare.com by Universitat de Girona on 12/03/14 For personal use only.

Study patients From January 2009 to January 2012, 70 consecutive subjects referred to our institution were included in this prospective study and explored by cardiac MRI. Three subjects were excluded because pace maker implantation (1) or severe claustrophobia (n ¼ 2). The remaining 67 subjects (53 patients with hereditary ATTR amyloidosis and 14 asymptomatic carriers) were included in this prospective study. The study was approved by our local Research Ethics Committee and each included subject provided written informed consent. Genetic testing for hereditary ATTR amyloidosis was obtained for all individuals: overall, 37 subjects (55%) had the Val30Met TTR mutation and the remaining 30 (46%) carried other mutations: Val122Ile (n ¼ 10), Ser77Tyr (n ¼ 5), Ile107Val (n ¼ 3), Tyr116Ser (n ¼ 2), Val71Ala (n ¼ 2), Ala91Ser (n ¼ 2) and one for each of the following variants: Ser77Phe, Thr57Ile, Val28Met, Ala19Asp, Thr69Ile, Thr95Ile. Forty-eight of the 53 (90%) patients with hereditary ATTR amyloidosis had histopathological confirmation of amyloidosis by tissue biopsies of the labial salivary gland (n ¼ 34); nerve (n ¼ 5); heart (n ¼ 5) or gastrointestinal (n ¼ 4). Histopathological analysis was considered positive for amyloidosis in case of characteristic yellow-green birefringence under crossed polarizers on Congo red staining. According to clinical evaluation, the 53 patients were divided into two groups according to symptoms. The first group (the ‘‘Neuro group’’) was composed of patients with hereditary ATTR amyloidosis who had neurological symptoms and signs related to amyloidosis, i.e. peripheral polyneuropathy and/or autonomic nervous system involvement, in the absence of any clinical evidence of cardiomyopathy. The second group (the ‘‘Cardiac group’’) was composed of patients who had clinical evidence of cardiac involvement i.e. a cardiac New York Heart Association (NYHA) functional class of at least 2, with or without neurological symptoms. We also considered the overall population of patients in terms of genotype and disease onset and identified three groups of patients. The first group (the ‘‘Early Val30Met patients’’) was composed of patients carrying the Val30Met mutation and with a disease onset before 50 years. The second group (the ‘‘Late Val30Met patients’’) was composed of patients with a disease onset after 50 years. The last group (the ‘‘Other mutation patients’’) was composed of patients carrying other pathogenic ATTR mutations. An electrocardiogram (EKG) was obtained for all patients and asymptomatic carriers. Signs of cardiac amyloidosis were defined as case of microvoltage (55 mm on standard leads) or presence of Q waves. For all patients and asymptomatic carriers, the blood level of amino-terminal pro-brain natriuretic peptide (NT-proBNP) was assessed on Roche Cobas

CMR was performed on a 1.5-Tesla system (Magnetom Avanto; Siemens Healthcare, Erlangen, Germany) equipped with a high-performance gradient subsystem (maximum amplitude: 40 mT/m, minimum rise: 200 ms) using an 8-channel phased-array cardiac coil. Consecutive breath-hold balanced steady state free precession (SSFP) slices (with no gap) were acquired in the short axis on the left ventricle from base to apex. The following parameters were used: repetition time of 2.8 ms, echo time of 1.4 ms, flip angle of 82 , matrix size of 192  192, field of view of 300  270 mm, and 8 mm slice thickness. Retrospective ECG gating was used with 25 phases per section. Parallel imaging was performed (GRAPPA algorithm) with a 2-fold acceleration factor. Late gadolinium enhanced images covering the left ventricle in short-axis and long-axis views were obtained 10 minutes after injection of 0.2 mmol/kg of gadolinium (Dotarem; Guerbet, Aulnay-sousBois, France) in all the patients. A segmented 3D IR gradientecho T1-weighted sequence was used with the following parameters: repetition time of 3.9 ms, echo time of 1.4 ms, flip angle of 10 , matrix size of 192  192, field of view of 300  270 mm, 12 sections, and 6 mm slice thickness. Image acquisition lasted between 12 and 20 seconds depending on the heart rate. A dedicated TI scouting sequence was used before acquisition of LGE images to adjust the optimal inversion recovery time (TI). Parameters of the TI scouting sequence were as follows: 26 cardiac phases were acquired by using a segmented true FISP readout resulting in a temporal resolution of 15 ms, repetition time of 23 ms, echo time of 1.1 ms, flip angle of 30 , matrix size of 192  192, field of view of 300  270 mm and 8 mm slice thickness. Image acquisition lasted between 12 and 18 seconds depending on the heart rate. From the images obtained with TI values of 87–700 ms, the optimum TI value was determined with visual assessment performed by one operator (J.F.D.). The optimum TI was chosen in order to obtain the image in which the signal intensity of normal myocardium was near null. Because suboptimal nulling of the myocardial signal may be encountered in amyloidosis [18,19], phase sensitive inversion recovery (PSIR) images were systematically acquired after acquisition of LGE images. Sequence parameters of the PSIR sequence were as follows: repetition time of 835 ms, echo time of 3.3 ms, flip angle of 10 , matrix size of 256  156, field of view of 300  270 mm, and 8 mm slice thickness. Image acquisition lasted between 8 and 12 s, depending on the heart rate. Five PSIR images were acquired in the short-axis plane encompassing the left ventricle. One slice was also acquired in the 4-chamber and in the 2-chamber view. CMR analysis Image analysis was performed on an offline workstation (Leonardo; Siemens Medical Solution, Erlangen, Germany).

248

J.-F. Deux et al.

Amyloid Downloaded from informahealthcare.com by Universitat de Girona on 12/03/14 For personal use only.

Quantitative analysis Thickness of the anterior, inferior, septal and lateral left ventricular wall was measured on a short-axis SSFP section acquired at the middle part of the LV in end-diastolic phase for all subjects. The measurement was performed from the endocardial to the epicardial borders. Trabeculations and papillary muscles were not taken account in the measurement. In case of difficulty to determine the exact limit of the left ventricular wall, measurements were performed on the next contiguous short-axis section. Patients with at least one measurement over 12 mm were considered to have LV wall thickening and suspected of having cardiac involvement. Left ventricular end-diastolic volume, left ventricular end-systolic volume, left ventricular ejection fraction and mass were calculated using a dedicated software (Argus; Siemens Medical Solution, Erlangen, Germany). The endocardial and epicardial borders of the LV were automatically delimitated by the software on end-diastolic and on end-systolic frames of the SSFP sequences acquired in the short-axis plane from base to apex. Trabeculations and papillary muscles were included in the volume of the left ventricular cavity on diastolic and systolic cine images. A visual inspection was systematically performed at this stage by one operator (J.F.D.) and a manual correction was effected in case of false borders. Qualitative analysis LGE and PSIR images were analyzed by consensus of two radiologists (J.F.D.; J.M.) who have 8 and 3 years of experience in cardiac imaging, respectively. Three patterns of enhancement were defined as previously reported [14]: diffuse, circumferential or patchy focal. The ‘‘diffuse’’ pattern was defined as contrast enhancement being observed in all segments of the left ventricle but without systematic involvement of the subendocardial region. The ‘‘circumferential’’ pattern corresponded to enhancement of the entire subendocardial circumference extending to various degrees into the neighboring myocardium. The ‘‘patchy focal’’ pattern was attributed to patients with contrast enhancement of several, but not all, myocardial segments. In cases of patchy focal enhancement, the number and location of involved segments was noted according to the American Heart Association classification [20]. Involvement of the right ventricle was defined as a wall thickness 44 mm associated with positive LGE. Right ventricle wall thickness was measured on a middle ventricular end-diastolic short-axis section. As for the left ventricle, trabeculations were not taken account in the measurement. Involvement of right and/or left atria was defined as diffuse LGE of the atrial wall. Interatrial septum was considered as involved if there was thickening (45 mm) and positive LGE. Presence of pericardial effusion or valve thickening was also specified. Statistical analysis The population was divided into three groups depending on clinical signs and mutations. Quantitative data are expressed as means ± standard deviation except for NT-proBNP level where medians and interquartiles (IQR) were used. Numbers and percentages are given for categorical data. The null

Amyloid, 2014; 21(4): 246–255

hypothesis (H0) was defined as the absence of significant differences between clinical and genetic groups. The null hypothesis was rejected if p50.05. Differences between continuous data were tested using analysis of variance (ANOVA) and post-hoc analysis using Bonferonni correction at 95% confidence interval. Proportions were compared using the chi-square test. Spearman’s correlation coefficient was calculated to assess correlation between variables. Analyses were performed using SPSS 16.0 software (SPSS Inc., Chicago, IL).

Results Clinical and biological characteristics of the 14 asymptomatic carriers and 53 patients with hereditary ATTR amyloidosis Among patients, 16 belong to the Neuro group and 37 belong to the Cardiac group. Patients of the Cardiac group were significantly (p ¼ 0.01) older than other subjects. Most of them (34/37 ¼ 92%) had a mixed phenotype with cardiac and neurological symptoms. No significant differences were detected in term of gender, and in term of mutations between groups except for Early Val30Met patients that were statistically (p ¼ 0.007) more frequently encountered in the Neuro group (Table 1). None asymptomatic carrier exhibit EKG signs of cardiac amyloidosis that were statistically (p ¼ 0.04) more frequently detected in the patients of the Neuro and Cardiac groups (25 and 19% of the patients, respectively). As expected, patients in the Cardiac group exhibited a significantly (p50.0001) higher level of NT-proBNP (749 pg/mL (270–3825)) in comparison to asymptomatic carriers (28 pg/mL (17–50)) and the Neuro group (40 pg/mL (32–112)). Level of NT-proBNP was in the same range between Neuro group and asymptomatic carriers (p ¼ NS). One (7%), 4 (25%) and 33 (89%) subjects had a BNP level superior to 82 pg/mL, in the asymptomatic carriers group, in the Neuro group and in the Cardiac group, respectively. CMR findings in asymptomatic carriers and in patients with hereditary ATTR amyloidosis Two (14%) asymptomatic carriers, 2 patients of the Neuro group (12%) and 26 (70%) of patients of the Cardiac group exhibited LV wall thickening on MRI. Patients of the Cardiac group exhibited significantly (p50.0001) higher left ventricular wall thickness compared to rest of the study population, and significantly (p50.04) higher LV mass compared to asymptomatic carriers. Asymptomatic carriers and patients of the Neuro group showed similar morphological and functional variables (Table 2). LGE was detected in 60% (32/53) of the patients and only in one asymptomatic carrier (who had cardiac hypertrophy). It was statistically (p50.0001) more frequently encountered in the patients of the Cardiac group (78%) than in those of the Neuro group (19%). Figure 1 illustrates the percentages of positivity for EKG, BNP level, LV wall thickening and LGE in each group of patients. Among the 4 patients with a BNP level beyond 82 pg/mL, only one exhibited positive LGE. The diffuse pattern of LGE was the most frequent (32% of all patients) and exclusively encountered in the Cardiac group

CMR in patients with hereditary ATTR amyloidosis

DOI: 10.3109/13506129.2014.956924

249

Table 1. Characteristics of asymptomatic carriers, patients with neurological symptoms and no clinical cardiomyopathy (Neuro group) and patients with clinical cardiomyopathy (Cardiac group).

Variables Clinical Age, (years) Men (%) Val30Met (%) Early (%) Late (%) Other mutations (%) Signs of amyloidosis on EKG**

Asymptomatic carriers

Neuro group (n ¼ 16)

Cardiac group (n ¼ 37)

p

48 ± 7 12 (86) 10 (71) NA NA 4 (29) 0(0)

47 ± 10 6 (37) 11 (69) 9 (56) 2 (12) 5 (31) 4 (25)

62 ± 15 23 (62) 16 (43) 7 (19) 9 (24) 21 (57) 7 (19)

0.01* NS NS 0.007 NS NS 0.04$

Amyloid Downloaded from informahealthcare.com by Universitat de Girona on 12/03/14 For personal use only.

Data are mean ± SD or number (%) except for NT-proBNP level where medians and interquartiles (IQR) were used. EKG ¼ electrocardiogram; NA ¼ not applicable; NS ¼ non significant (p40.05). **Microvoltage (55 mm on all leads) or Q waves. *Cardiac group versus Asymptomatic carriers and Cardiac group versus Neuro group. $Asymptomatic carriers versus Neuro group and Asymptomatic carriers versus Cardiac group.

Table 2. Morphologic, functional and LGE CMR findings in asymptomatic carriers, in patients with neurological symptoms and no clinical cardiomyopathy (Neuro group) and in patients with clinical cardiomyopathy (Cardiac group). Variables Diastolic anterior wall thickness (mm) Diastolic inferior wall thickness (mm) Diastolic interventricular wall thickness (mm) Diastolic lateral wall thickness (mm) LV wall thickening** (%) LV mass (g/m2) LV EDV (mL) LV ESV (mL) LVEF (%) Cardiac Positive LGE (%) LV positive LGE (%) LV diffuse pattern (%) LV circumferential pattern (%) LV focal pattern (%) Positive LGE detected in others chambers (%) Right ventricle (%) Left atria (%) Right atria (%) Interatrial septum (%)

Asymptomatic carriers

Neuro group

Cardiac group

p

7.0 ± 1.9 6.8 ± 1.8 9.8 ± 2.7 7.1 ± 1.4 2 (14) 65 ± 12 70 ± 8 28 ± 4 62 ± 10 1 (7) 1 (7) 0 (0) 0 (0) 1 (7) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

7.2 ± 2.0 7.5 ± 1.8 10.0 ± 2.7 8.2 ± 1.9 2 (12) 71 ± 13 64 ± 13 24 ± 9 61 ± 9 3 (19) 3 (19) 0 (0) 0 (0) 3 (19) 2 (12) 2 (12) 2 (12) 2 (12) 2 (12)

9.9 ± 3.4 11.0 ± 4.2 15.0 ± 5.3 10.3 ± 4.5 26 (70) 77 ± 24 80 ± 35 37 ± 23 53 ± 15 29 (78) 29 (78) 17 (53) 1 (3) 11 (30) 23 (62) 15 (40) 20 (54) 20 (54) 21 (57)

50.007* 50.005* 50.001* 50.05* 50.0001* 50.04$ NS NS NS 50.0001* 50.0001* 50.0001* NS NS 50.0001* 50.005* 50.005* 50.005* 50.003*

Data are mean ± SD or number (%); EDV ¼ end diastolic volume, EF ¼ ejection fraction, ESV ¼ end systolic volume, LGE ¼ late gadolinium enhancement, LV ¼ left ventricular, NS ¼ non significant (p value40.05). **Defined as wall thickness 412 mm. *Cardiac group versus asymptomatic carriers and cardiac group versus neuro group. $Cardiac group versus Asymptomatic carriers.

(p50.0001), followed by the patchy focal pattern (26% of all patients and 7% of asymptomatic carriers) and the circumferential pattern (2% of all patients). Patients of the Neuro group and asymptomatic carrier with positive LGE (3 and 1 subjects respectively) showed exclusively a patchy focal pattern of LGE. Suboptimal myocardial nulling, detected in 15% (5/32) of patients with positive LGE on IR gradientecho T1-weighted images, disappeared on PSIR images. Figures 2–4 illustrate the three patterns of LGE. In case of focal pattern of LGE, the mean number of involved segments was 1.9 ± 1 (1–4). The inferior basal segment was the most frequently involved (93 %) followed by the basal inferolateral segment (43%), the basal anterolateral and inferoapical segments (21% each) and the basal inferoseptal and medial inferior segment (7%). Figure 5 shows a Bull’s-eye representation of the percentage of

involvement of cardiac segments in patients on the LGE sequence according to the AHA classification. Subjects presenting a focal pattern of LGE (14 patients and 1 asymptomatic carrier) had a significantly lower men wall thickness (8.4 ± 2 and 11.6 ± 3 mm respectively; p ¼ 0.009), a lower left ventricular mass (79 ± 13 versus 104 ± 22 g/m2; p ¼ 0.05) and a higher LVEF (62 ± 9 versus 44 ± 15%; p ¼ 0.02) than patients exhibiting diffuse or circumferential patterns of LGE. EKG, NT-proBNP level and CMR findings in patients with and without LV wall thickening Among the 53 patients, 28 (53%) exhibited LV wall thickening. Signs of amyloidosis on EKG were in the same range between patients with and without LV wall thickening

Amyloid Downloaded from informahealthcare.com by Universitat de Girona on 12/03/14 For personal use only.

250

J.-F. Deux et al.

Amyloid, 2014; 21(4): 246–255

Figure 1. Percentage of positivity for EKG abnormalities, BNP level (threshold: 482 pg/mL), LV wall thickening (412 mm) and LGE in each group.

and, as expected, NT-proBNP level was statistically (p50.0001) higher in patients with LV wall thickening. LGE was statistically (p50.0001) more frequently detected in patients with LV wall thickening (96% of cases) but 20% (5/25) of patients without LV wall hypertrophy showed also a positive LGE, exclusively in a patchy focal pattern (Table 3). Other chambers were rarely affected on LGE in patients without LV wall hypertrophy (8% of cases). The 5 patients without LV wall thickening but with positive LGE on MRI had no signs of cardiac amyloidosis on EKG, a normal LV mass (71 ± 10 g/m2) and a normal level of NT-proBNP (68 pg/mL (55-95)). CMR findings in patients according to ATTR mutations The number of EarlyVal30Met, LateVal30Met and Other mutation patients was 16, 11 and 26, respectively. Early Val30Met patients rarely exhibited statistically less frequently LV wall thickening (19% of cases; p ¼ 0.002) and positive LGE (25%; p ¼ 0.002) in contrast to Late Val30Met (64 and 82%, respectively for wall thickening and LGE) and Other mutation patients (69 and 73%, respectively for wall thickening and LGE). LV mass of LateVal30Met and Other mutation patients was statistically (p ¼ 0.03) higher than EarlyVal30Met patients. Patients belonging to the Other mutation group had a significantly higher end systolic volume (p ¼ 0.04), a significantly reduced LVEF (p ¼ 0.009), and a significantly higher frequency of diffuse pattern of LGE and

other chambers involvement (54 and 65% of cases, respectively) than other groups (p ¼ 0.008 and p ¼ 0.01, respectively). In contrast, focal pattern was statistically (p ¼ 0.001) more frequently encountered in Late Val30Met patients (64% of cases). Extensive data are reported in Table 4.

Discussion We report here the largest prospective MRI study of cardiac amyloidosis in patients with hereditary ATTR amyloidosis to date. We found that (1) 60% of patients with hereditary ATTR amyloidosis showed positive LGE on CMR suggesting cardiac amyloidosis involvement, (2) 20% of patients without LV wall thickening and 19% of patients with isolated symptoms exhibited positive LGE on cardiac MRI suggesting cardiac involvement and (3) a focal pattern of enhancement in the inferior basal and inferolateral segments was common and associated with an early stage of cardiac involvement. Frequency of cardiac involvement on MRI LGE is common in cardiac amyloidosis, being reported in approximately three quarters of patients in series mainly including patients with AL amyloidosis [10,11,13,21]. A few MR studies have specifically evaluated cardiac involvement of patients with hereditary ATTR amyloidosis. Most of them have reported a lower rate of cardiac involvement on MRI compared to AL amyloidosis, with between 37 [14] and 55% of patients [15] exhibiting positive LGE. These results on

DOI: 10.3109/13506129.2014.956924

Amyloid Downloaded from informahealthcare.com by Universitat de Girona on 12/03/14 For personal use only.

Figure 2. A 77-year-old man with signs of heart failure, autonomic nervous system involvement and positive results of genetic testing for hereditary ATTR amyloidosis Val30Met. End-diastolic SSFP MR images acquired in the four-chamber-view (A) and in the short-axis (B) section evidenced thickening of the left ventricular wall. A pericardial effusion was associated (arrowhead). LGE images acquired in the horizontal long-axis (C) and in the short-axis (D) sections evidenced diffuse enhancement of the left ventricle (C and D, arrow). Additional involvement of the right ventricle (C and D, double arrow) and of the interatrial septum (C, double arrowhead) was also detected.

Figure 3. A 72-year-old man with signs of heart failure, autonomic nervous system involvement and positive results of genetic testing for hereditary ATTR amyloidosis Val122Ile. End-diastolic SSFP MR images acquired in the four-chamber-view (A) and in the short-axis (B) section evidenced thickening of the interventricular septum (arrow). A small pericardial (arrowhead) and pleural (A, star) effusions were associated. LGE images acquired in the horizontal long-axis (C) and in the short-axis (D) sections evidenced circumferential enhancement of the left ventricle (C, arrowheads) associated with various degrees of myocardial enhancement (C and D, arrowheads). Additional involvement of the right ventricle was also evidenced (D, arrow).

CMR in patients with hereditary ATTR amyloidosis

251

252

J.-F. Deux et al.

Amyloid, 2014; 21(4): 246–255

Amyloid Downloaded from informahealthcare.com by Universitat de Girona on 12/03/14 For personal use only.

Figure 4. An 80-year-old woman with signs of heart failure, peripheral neuropathy and positive results of genetic testing for hereditary ATTR amyloidosis Tyr116Ser. End-diastolic SSFP MR images acquired in the four-chamber-view (A) and in the shortaxis (B) section did not detect thickening of the left ventricular wall. LGE images evidenced focal enhancement in the inferior and lateral wall of the basal part of the left ventricle on the horizontal long-axis (C, arrowhead) and on the short-axis (D, arrows) sections.

small series of patients are in the same range as the 60% of positive LGE that we found. Positive LGE and cardiac hypertrophy

Figure 5. Bull’s-eye representation of the of cardiac segments in patients on LGE the AHA classification. Data are number age of involvement). Segments 4 and 5 involved.

percentage of involvement sequence with respect to of each segment (percentwere the most frequently

Positive LGE was frequently associated with LV wall thickening in our study but the presence of 20% of patients without wall thickening and positive LGE must be pointed out and enhance the potential role of cardiac MRI for detecting preclinical involvement of cardiac amyloidosis. In the same way nineteen percent of patients with isolated neurological symptoms (the Neuro group) exhibited positive LGE in our study, suggesting that CMR examination could be useful in patients with hereditary ATTR amyloidosis with neurological symptoms to detect preclinical cardiac involvement of amyloidosis. In a large study including mainly patients with AL amyloidosis, Syed et al. reported that LGE was present in 47% of patients without evidence of cardiac amyloidosis by echocardiography, suggesting that CMR may detect early cardiac abnormalities in patients with normal left ventricular thickness [12]. Not surprisingly, the frequency of positive LGE increased (78%) in our study when cardiac symptoms were present in patients with hereditary ATTR amyloidosis. Positive LGE was associated with a thickening of the left ventricular wall and an increase in the left ventricular mass, in line with previous studies [12,16]. In contrast, only one

CMR in patients with hereditary ATTR amyloidosis

DOI: 10.3109/13506129.2014.956924

253

Table 3. EKG, NT-proBNP level and MRI characteristics in the 53 patients depending on the presence of LV wall thickening or not.

Variables Signs of amyloidosis on EKG$ NT-proBNP level (pg/mL) Cardiac Positive LGE (%) LV positive LGE (%) LV diffuse pattern (%) LV circumferential pattern (%) LV focal pattern (%) Positive LGE detected in others chambers (%) Right ventricle (%) Left atria (%) Right atria (%) Interatrial septum (%)

Absence of LV wall thickening (n ¼ 25) 7 81 5 5 0 0 5 2 0 2 2 2

Presence of LV wall thickening* (n ¼ 28)

(28) (33-255) (20) (20) (0) (0) (20) (8) (0) (8) (8) (8)

4 1269 27 27 18 1 8 23 20 20 20 21

(16) (404-5211) (96) (96) (64) (4) (29) (82) (71) (71) (71) (75)

p NS 50.0001 50.0001 50.0001 50.0001 NS NS 50.0001 50.0001 50.0001 50.0001 50.0001

Amyloid Downloaded from informahealthcare.com by Universitat de Girona on 12/03/14 For personal use only.

Data are mean ± SD or number (%); LGE ¼ late gadolinium enhancement, LV ¼ left ventricular, NS ¼ non significant (p40.05). *Defined as LV wall thickness412 mm. $Defined as microvoltage (55 mm on all leads) or presence of Q waves

Table 4. Morphologic, functional and LGE CMR findings in patients in terms of type of pathogenic ATTR mutation.

Variables Diastolic anterior wall thickness (mm) Diastolic inferior wall thickness (mm) Diastolic interventricular wall thickness (mm) Diastolic lateral wall thickness (mm) LV wall thickening** (%) LV mass (g/m2) LV EDV (mL) LV ESV (mL) LVEF (%) Cardiac Positive LGE (%) LV positive LGE (%) LV diffuse pattern (%) LV circumferential pattern (%) LV focal pattern (%) Positive LGE in other chambers (%) Right ventricle (%) Left atria (%) Right atria (%) Interatrial septum (%)

Early Val30Met patients

Late Val30Met patients

Patients carrying Other mutation

p

7.6 ± 2.1 7.8 ± 2.3 9.7 ± 3.0 7.8 ± 1.5 3 (19) 67 ± 12 66 ± 12 24 ± 8 63 ± 9 4 (25) 4 (25) 2 (12) 0 (0) 2 (12) 3 (19) 1 (6) 3 (19) 3 (19) 3 (19)

10.2 ± 3.2 11.0 ± 3.1 15.5 ± 5.2 10.8 ± 4.6 7 (64) 80 ± 9 91 ± 49 25 ± 10 61 ± 12 9 (82) 9 (82) 2 (18) 0 (0) 7 (64) 5 (45) 3 (27) 5 (45) 4 (36) 4 (36)

9.5 ± 3.8 10.8 ± 4.6 14.9 ± 5.3 9.7 ± 4.0 18 (69) 79 ± 31 74 ± 27 40 ± 24 50 ± 14 19 (73) 19 (73) 14 (54) 1 (4) 4 (15) 17 (65) 13 (50) 14 (57) 15 (57) 16 (61)

0.1* 0.05* 0.008* 0.1* 0.002* 0.03* NS 0.04£ 0.009£ 0.002* 0.002* 0.008£ NS 0.001$ 0.01x 0.01x NS 0.04x 0.02x

Data are mean ± SD or number (%); EDV ¼ end diastolic volume, EF ¼ ejection fraction, ESV ¼ end systolic volume, LGE ¼ late gadolinium enhancement, LV ¼ left ventricular, NS ¼ non significant (p40.05) **Defined as wall thickness412 mm; *Early V30Met versus Late V30Met and Early V30Met versus Other mutation; £Other mutation versus Late V30Met and Other mutation versus Early V30Met; $Late V30Met versus Early V30Met and Late V30Met versus Other mutation xEarly V30Met versus Other mutation.

asymptomatic carrier exhibited cardiac abnormalities on CMR in our study. The usefulness of CMR in this population is thus questionable and remains to be confirmed by studies of larger series. Patterns of involvement The most common LGE pattern encountered in cardiac amyloidosis is a characteristic global subendocardial or diffuse transmural LGE [9,10,12], and less frequently (520% of cases) a suboptimal myocardial nulling or a patchy focal LGE pattern [12]. In the present large study of patients with hereditary ATTR amyloidosis, we found a high rate of focal pattern of LGE: in 26% of the patients (19% in the Neuro group and 30% of the Cardiac group), frequently

located in the basal inferior and basal inferolateral segments, in line with previous reports on small series [14,16]. This basal involvement appears similar to the functional changes of strain and strain rate observed on echocardiography. In fact, it has been reported that patients with cardiac amyloidosis exhibited a much greater restriction of basal compared to apical strain and had an inverse pattern of the physiological gradient of basoapically decreasing radial strain [5,6,22]. Thus, the strain-pattern appears to be helpful to distinguish between amyloidosis and other causes that lead to left ventricular hypertrophy. Recently, Baccouche et al. [22] reported in 12 patients with cardiac amyloidosis a high negative correlation between LGE and radial strain, underlining the relationships between morphological (LGE) and functional (strain) abnormalities. A focal pattern of LGE may

Amyloid Downloaded from informahealthcare.com by Universitat de Girona on 12/03/14 For personal use only.

254

J.-F. Deux et al.

be surprising in a disease with diffuse cardiac involvement. However, a recent report based on histological analysis of explanted or autopsied hearts from amyloidosis patients [23] revealed that amyloid infiltration was more frequently localized in the inferolateral walls and in the septum in the case of segmental involvement, suggesting that the basal part of the left ventricle (and especially inferolateral walls) may be preferentially involved, confirming our MR findings. Moreover, in our study patchy focal pattern on LGE was associated with a lower left ventricular wall thickness and mass than diffuse or circumferential patterns, possibly reflecting an earlier stage of cardiac involvement. We therefore believe that in patients with hereditary ATTR amyloidosis with suspected cardiac amyloidosis, focal enhancement of the left ventricle, especially of the inferior and inferolateral segments, should suggest early disease stage to the radiologist. In our study, the diffuse pattern of LGE was only seen in patients of the Cardiac group, revealing an advanced stage of cardiac amyloidosis, as already reported by Syed et al. in a study including mainly patients with AL cardiac amyloidosis [12]. The low rate of circumferential classical pattern observed in our study (1%) may seem surprising when compared with other studies including mainly patients with AL amyloidosis where this pattern was very common [12,24]. In line with our results, Di Bella et al. [14] and Syed et al. [12] also described relatively low rates of circumferential pattern in patients with hereditary ATTR amyloidosis with cardiac amyloidosis (6 and 9%, respectively). These results along with ours imply that a characteristic circumferential enhancement of cardiac amyloidosis does not suggest familial amyloidotic cardiomyopathy in first line analysis. Furthermore, the suboptimal nulling pattern was not encountered in our study. This may be due to the use of phase sensitive sequences in our imaging protocol, sequences that did not require fine settings of the inversion time to provide a correct nullification of remote myocardial signal and thus that probably eliminated the suboptimal nulling pattern. Others chambers Involvement of others chambers and right ventricle were statistically more frequently encountered in patients of the Cardiac group (62 and 40%, respectively). Higher rate of right ventricle involvement (100%) has been recently reported on LGE, but in a group of patients including both senile and patients with hereditary ATTR cardiac amyloidosis [25]. ATTR mutations and cardiac MRI phenotype Our population displays a panel of different ATTR pathogenic mutations including Val30Met patients with early and late onset symptoms. Three patients (8%) exhibited an exclusively cardiac phenotype in the same range as Rapezzi et al., who reported that a clinically relevant subset of Caucasian patients with hereditary ATTR amyloidosis (15%) present an exclusively cardiac phenotype [26]. In our study, cardiac involvement in patients with Early ATTR-Val30Met was detected in a clinically relevant subset of patients (25%) on LGE, in line with the clinical history of these patients in whom cardiac amyloidosis is unusual [27]. Interestingly, we observed that

Amyloid, 2014; 21(4): 246–255

Late Val30Met patients exhibited statistically more frequently a focal pattern of enhancement (64% of cases) than nonVal30Met patients who exhibited a diffuse pattern in 47% of cases. This suggests a more advanced stage of cardiac involvement in the latter group and/or different mechanisms of deposit of the amyloid protein between mutations. To the best of our knowledge, these results have never been reported before. Larger studies are required to confirm these differences in LGE pattern. Limitations of the study This descriptive study has several limits. The first and main limit is the lack of endomyocardial biopsy for most of the patients, barring the possibility of assessing whether all LGE abnormalities detected on CMR (especially focal ones) corresponded to areas of ATTR deposit. Indeed, unlike diffuse or subendocardial patterns that are relatively specific to cardiac amyloidosis, focal myocardium enhancement may be encountered in many cardiac diseases such as lysosomal storage diseases. Nevertheless, it is important to note that in our study the focal pattern of LGE was frequently associated with an involvement of other cardiac chambers (78% of cases), increasing the specificity of diagnosing cardiac amyloidosis. Second the cardiac group was defined solely on NYHA classification leading difficult to distinguish finely the real cause of functional impairment. Third, we did not perform analysis of T1 blood-pool gadolinium kinetics [9] or measurement of T1 using mapping sequence that have been reported to be modified in cardiac amyloidosis [28]. Lastly, despite this work being the largest reporting MR aspects of patients with cardiac hereditary ATTR amyloidosis, the number of patients remains relatively small due to the rarity of this disease.

Conclusion This study refines MR aspects of cardiac involvement in a wide spectrum of patients with hereditary ATTR amyloidosis. A positive LGE suggesting cardiac amyloidosis, usually associated with LV wall thickening, was detected in 60% of subjects with hereditary ATTR amyloidosis. Nineteen percent of patients with hereditary ATTR amyloidosis with isolated neurological symptoms and 20% of subjects without LV wall thickening exhibited MR abnormalities, indicating that CMR is useful in detecting preclinical cardiac amyloidosis. A focal pattern of enhancement in the inferior basal and inferolateral segment was quite common, especially in patients with neurological symptoms and Late Val30Met patients, and seems to be associated with an early stage of cardiac involvement. A diffuse pattern was exclusively encountered in patients with cardiac symptoms and was the most present abnormality in patients carrying non-Val30Met mutations.

Declaration of interest The authors report no conflicts of interest.

References 1. Dungu JN, Anderson LJ, Whelan CJ, Hawkins PN. Cardiac transthyretin amyloidosis. Heart 2012;98:1546–54.

Amyloid Downloaded from informahealthcare.com by Universitat de Girona on 12/03/14 For personal use only.

DOI: 10.3109/13506129.2014.956924

2. Rapezzi C, Merlini G, Quarta CC, Riva L, Longhi S, Leone O, Salvi F, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation 2009;120:1203–12. 3. Falk RH. Cardiac amyloidosis: a treatable disease, often overlooked. Circulation 2011;124:1079–85. 4. Rapezzi C, Quarta CC, Riva L, Longhi S, Gallelli I, Lorenzini M, Ciliberti P, et al. Transthyretin-related amyloidoses and the heart: a clinical overview. Nat Rev Cardiol 2010;7:398–408. 5. Koyama J, Ray-Sequin PA, Falk RH. Longitudinal myocardial function assessed by tissue velocity, strain, and strain rate tissue Doppler echocardiography in patients with AL (primary) cardiac amyloidosis. Circulation 2003;107:2446–52. 6. Quarta CC, Solomon SD, Uraizee I, Kruger J, Longhi S, Ferlito M, Gagliardi C, et al. Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation 2014;129:1840–9. 7. Sun JP, Stewart WJ, Yang XS, Donnell RO, Leon AR, Felner JM, Thomas JD, et al. Differentiation of hypertrophic cardiomyopathy and cardiac amyloidosis from other causes of ventricular wall thickening by two-dimensional strain imaging echocardiography. Am J Cardiol 2009;103:411–15. 8. Aljaroudi WA, Desai MY, Tang WH, Phelan D, Cerqueira MD, Jaber WA. Role of imaging in the diagnosis and management of patients with cardiac amyloidosis: state of the art review and focus on emerging nuclear techniques. J Nucl Cardiol 2014;21:271–83. 9. Maceira AM, Joshi J, Prasad SK, Moon JC, Perugini E, Harding I, Sheppard MN, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005;111:186–93. 10. Ruberg FL, Appelbaum E, Davidoff R, Ozonoff A, Kissinger KV, Harrigan C, Skinner M, et al. Diagnostic and prognostic utility of cardiovascular magnetic resonance imaging in light-chain cardiac amyloidosis. Am J Cardiol 2009;103:544–9. 11. Sparrow P, Amirabadi A, Sussman MS, Paul N, Merchant N. Quantitative assessment of myocardial T2 relaxation times in cardiac amyloidosis. J Magn Reson Imaging 2009;30:942–6. 12. Syed IS, Glockner JF, Feng D, Araoz PA, Martinez MW, Edwards WD, Gertz MA, et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imaging 2010;3:155–64. 13. Austin BA, Tang WH, Rodriguez ER, Tan C, Flamm SD, Taylor DO, Starling RC, et al. Delayed hyper-enhancement magnetic resonance imaging provides incremental diagnostic and prognostic utility in suspected cardiac amyloidosis. JACC Cardiovasc Imaging 2009;2:1369–77. 14. Di Bella G, Minutoli F, Mazzeo A, Vita G, Oreto G, Carerj S, Anfuso C, et al. MRI of cardiac involvement in transthyretin familial amyloid polyneuropathy. AJR Am J Roentgenol 2010;195: W394–9. 15. Minutoli F, Di Bella G, Mazzeo A, Donato R, Russo M, Scribano E, Baldari S. Comparison between 99mTc-diphosphonate imaging and mri with late gadolinium enhancement in evaluating cardiac involvement in patients with transthyretin familial amyloid polyneuropathy. AJR Am J Roentgenol 2013;200:W256–65.

CMR in patients with hereditary ATTR amyloidosis

255

16. Perugini E, Rapezzi C, Piva T, Leone O, Bacchi-Reggiani L, Riva L, Salvi F, et al. Non-invasive evaluation of the myocardial substrate of cardiac amyloidosis by gadolinium cardiac magnetic resonance. Heart 2006;92:343–9. 17. Damy T, Deux JF, Moutereau S, Guendouz S, Mohty D, Rappeneau S, Guellich A, et al. Role of natriuretic peptide to predict cardiac abnormalities in patients with hereditary transthyretin amyloidosis. Amyloid 2013;20:212–20. 18. Benson L, Hemmingsson A, Ericsson A, Jung B, Sperber G, Thuomas KA, Westermark P. Magnetic resonance imaging in primary amyloidosis. Acta Radiol 1987;28:13–15. 19. Fattori R, Rocchi G, Celletti F, Bertaccini P, Rapezzi C, Gavelli G. Contribution of magnetic resonance imaging in the differential diagnosis of cardiac amyloidosis and symmetric hypertrophic cardiomyopathy. Am Heart J 1998;136:824–30. 20. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, Pennell DJ, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002;105:539–42. 21. Maceira AM, Prasad SK, Hawkins PN, Roughton M, Pennell DJ. Cardiovascular magnetic resonance and prognosis in cardiac amyloidosis. J Cardiovasc Magn Reson 2008;10:54. 22. Baccouche H, Maunz M, Beck T, Gaa E, Banzhaf M, Knayer U, Fogarassy P, et al. Differentiating cardiac amyloidosis and hypertrophic cardiomyopathy by use of three-dimensional speckle tracking echocardiography. Echocardiography 2012;29:668–77. 23. Leone O, Longhi S, Quarta CC, Ragazzini T, De Giorgi LB, Pasquale F, Potena L, et al. New pathological insights into cardiac amyloidosis: implications for non-invasive diagnosis. Amyloid 2012;19:99–105. 24. Vogelsberg H, Mahrholdt H, Deluigi CC, Yilmaz A, Kispert EM, Greulich S, Klingel K, et al. Cardiovascular magnetic resonance in clinically suspected cardiac amyloidosis: noninvasive imaging compared to endomyocardial biopsy. J Am Coll Cardiol 2008;51: 1022–30. 25. Dungu JN, Valencia O, Pinney JH, Gibbs SD, Rowczenio D, Janet AG, Lachmann HJ, et al. CMR-based differentiation of AL and ATTR cardiac amyloidosis. JACC Cardiovasc Imaging 2014;7: 133–42. 26. Rapezzi C, Quarta CC, Obici L, Perfetto F, Longhi S, Salvi F, Biagini E, et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J 2013;34:520–8. 27. Koike H, Tanaka F, Hashimoto R, Tomita M, Kawagashira Y, Iijima M, Fujitake J, et al. Natural history of transthyretin Val30Met familial amyloid polyneuropathy: analysis of late-onset cases from non-endemic areas. J Neurol Neurosurg Psychiatry 2012;83:152–8. 28. Fontana M, Banypersad MC, Treibel TA, Maestrini V, Sado DM, White SK, Pica S, et al. Native T1 mapping in Transthyretin Amyloidosis. JACC Cardiovasc Imaging 2014;7:157–65.

Noninvasive detection of cardiac involvement in patients with hereditary transthyretin associated amyloidosis using cardiac magnetic resonance imaging: a prospective study.

Most of the studies that described cardiac amyloidosis using cardiac magnetic resonance (CMR) imaging refer to patients with primary light chain (AL) ...
883KB Sizes 0 Downloads 5 Views