- Email: [email protected]
The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience
HLC 2287 1–8
ORIGINAL ARTICLE
Heart, Lung and Circulation (2017) xx, 1–8 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2016.12.017
The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience
1 2 3 4
5 6 7 8 9 10 11 12
13 14 15 16 17
Q1
Peter T. Moore, MBBS, FRACP a,b*, Matthew K. Burrage, MBBS a,b, Emily Mackenzie, MBBS, FRACP a,b, W. Philip Law, FRANZCR, FAANMS a,b, Dariusz Korczyk, MDipl, FRACP a,b, Peter Mollee, MBBS, MMedSc a,b a
Amyloidosis Centre, Princess Alexandra Hospital, Brisbane, Qld, Australia School of Medicine, University of Queensland, Brisbane, Qld, Australia
b
Received 6 November 2016; accepted 19 December 2016; online published-ahead-of-print xxx
Background
The uptake of bone-seeking radiotracers in the amyloid heart is well recognised. 99mTc-DPD has been shown to be highly sensitive for cardiac transthyretin (ATTR) amyloid in an overseas population, but is not registered for use in Australia. We explored its utility as a diagnostic tool within our population.
Methods
Patients diagnosed with AL and ATTR (wild-type and inherited) cardiac amyloidosis were prospectively recruited from the Princess Alexandra Hospital Amyloidosis Centre. Patients underwent injection with 99m Tc-DPD then planar whole body imaging was performed at five minutes post-injection (soft tissue phase) and three hours (bone phase). A myocardial SPECT and low amperage CT were acquired after the late whole-body scan. Scans were analysed by two nuclear imaging specialists. Intensity of cardiac 99m Tc-DPD uptake was graded as 0 to 3 in accordance with previous criteria, and semiquantitative analysis was performed using a heart to whole body ratio (H:WB) on the three-hour scan. Patients also underwent electrocardiography and transthoracic echocardiography, and blood samples were taken for troponin I and brain natriuretic peptide levels, to assess for any correlation with DPD uptake.
Results
Twenty-one patients (8 AL and 13 ATTR) completed the study. Median age was 58 and 70 years for AL and ATTR patients respectively, and 19 (90.5%) were male. 99mTc-DPD scintigraphy was positive in 2 (25%) of AL, and 13 (100%) of ATTR patients. Grade of cardiac uptake, and mean H:WB (0.1249 v. 0.0794) was greater in the ATTR cohort (p-value < 0.001 and 0.001 respectively). No statistically significant correlation was identified between H:WB and echocardiographic parameters. There was a significant positive correlation between H:WB and the PR interval on ECG (p = 0.026).
Conclusions
99m[6_TD$IF]Tc-DPD scintigraphy is highly sensitive for the diagnosis of cardiac ATTR amyloid, but less so for AL amyloid.
Keywords
99mTc-DPD scintigraphy Bone scan Cardiac amyloidosis Nuclear imaging
Introduction Amyloidosis is a disease characterised by the extracellular deposition of misfolded proteins leading to organ
dysfunction. Cardiac amyloidosis is characterised by myocardial infiltration [1] with the vast majority of clinically significant cases being caused by immunoglobulin light chain (AL), or transthyretin (ATTR) deposition [2].
*Corresponding author. Email: [email protected] © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
18 19 20 21
HLC 2287 1–8
2
22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76
Q2
P.T. Moore et al.
Transthyretin may be due to deposition of wild-type (formerly senile systemic amyloidosis) or mutant protein (inherited). The correct diagnosis of cardiac amyloidosis, and its subtype, is paramount to provide accurate prognosis and treatment. Immunoglobulin light chain cardiac amyloidosis carries a poorer prognosis [3], but may respond to chemotherapy [2]. The gold standard for diagnosis remains tissue biopsy of the affected organ revealing deposits that, when stained with Congo red, demonstrate apple-green birefringence under polarised light. The gold standard for amyloid subtyping is proteomic analysis of the amyloid deposits from such biopsy specimens, but in centres of excellence, immunohistochemistry or immunogold electron microscopy are diagnostic [4]. Although endomyocardial biopsy carries a risk of serious morbidity [5], confirmation of ATTR subtype should be pursued in light of emerging evidence for novel therapies [6]. Biochemistry [7] and imaging provide diagnostic support of cardiac amyloidosis, but are not conclusive. Classic echocardiographic findings [8,9] are non-specific, and strain techniques are laboratory (user and equipment)-dependent [10]. Whilst magnetic resonance imaging (MRI) is more specific [11], its use is limited to patients without serious kidney disease (often present in this population) due to the need for intravenous gadolinium administration. Newer modalities such as positron emission tomography (PET) imaging with amyloid-specific radiotracers appear promising, but remain in the research phase [12]. Radiolabelled phosphate derivatives are commonly used bone-scanning agents and in 1977, Kula et al. were the first to identify the uptake of 99mTc-diphosphonate in cardiac amyloid deposits [13]. Phosphate derivatives are believed to localise to calcium content in amyloid deposits however the mechanism remains unclear. In the 1980s, small studies with 99mTc-pyrophosphate (99mTc-PYP) and 99m Tc-methylene diphosphonate (99mTc-MDP) yielded varying sensitivities for detection of cardiac amyloidosis [14–16]. However, in the last decade several series have shown 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) to be highly sensitive in the diagnosis of ATTR cardiac amyloidosis [17–21], and potentially prognostic [21]. Contemporary evidence for 99mTc-PYP has shown similar results [22]. Although the specificity of these agents is reduced by cardiac uptake in a proportion of AL patients [17,18,20], the use of this widely available imaging modality as a part of the diagnostic work-up of suspected cardiac amyloidosis shows great promise in reducing the need for tissue diagnosis. The aim of this study was to assess the sensitivity and specificity of 99mTc-DPD in an Australian population of patients with cardiac amyloidosis, to clarify its role in the diagnostic work-up of suspected cases. Secondly, we aimed to define any association between the quantity of 99mTc-DPD uptake and classic echocardiographic, electrocardiographic and biochemical features of this disease.
Methods
77
Patients with cardiac amyloidosis of AL or ATTR (wild-type or inherited) origin were prospectively recruited from the Princess Alexandra Hospital Amyloidosis Centre between 2013 and 2015. Cardiac involvement of AL amyloidosis was defined in accordance with international consensus criteria [23]: either an endomyocardial biopsy demonstrated amyloidosis in the presence of clinical or laboratory evidence of AL amyloid; or echocardiographic evidence of amyloidosis was identified in a patient with a positive result of noncardiac biopsy (in the absence of hypertension or other potential causes of left ventricular thickening). Transthyretin cardiac amyloidosis was diagnosed by endomyocardial biopsy and patients were planned to undergo genetic testing for transthyretin mutations. Patients were required to be over the age of 50 years. Patients lacking the capacity to provide consent were excluded. The Metro South Human Research Ethics Committee approved the study and all subjects provided informed consent. Scintigraphic imaging was performed at the PAH using a SPECT/CT scanner (Symbia TruePoint SPECT CT, Siemens, Munich, Germany). 99mTc-DPD, not available for use on the Australian Register of Therapeutic Goods, was accessed through the Therapeutic Goods Administration of Australia Clinical Trial Notification Scheme. After intravenous cannulation and injection with 99mTc-DPD, planar whole body imaging was performed at five minutes (soft tissue phase) and three hours (bone phase) post-injection. A myocardial SPECT and low amperage CT were acquired after the late whole-body scan. Each subject received between 700–800 MBq of 99m[7_TD$IF]Tc-DPD. Image analysis was performed by two experienced nuclear imaging specialists blinded to all patient data. Visual scoring of cardiac retention was performed in accordance with the criteria from Perugini et al. [19]:
78
0, absent cardiac uptake and normal bone uptake; 1, mild cardiac uptake inferior to bone uptake; 2, moderate cardiac uptake associated with attenuated
112
bone uptake; or 3, cardiac uptake with mild or absent bone uptake ([1_TD$IF]Figure 1).
115
Cardiac uptake visualised on SPECT-CT ([1_TD$IF]Figure 2) but not on planar imaging was also classified as grade 1 [18]. Semiquantitative analysis of heart retention, whole body retention, and heart retention to whole body retention ratio (H: WB) were evaluated from radiotracer activity within regionsof-interest drawn to include the heart and whole body on three-hour post-radiotracer injection images ([1_TD$IF]Figure 3). Participants underwent an electrocardiogram (ECG) to assess for the presence of low voltage criteria, defined as a QRS height <5 mm in all limb leads [2]. Transthoracic echocardiography was performed using commercially available ultrasound systems (Vivid 7 and E9, GE-Vingmed, Horten, Norway; IE33 and CX50, Philips, Royal Philips, Amsterdam, The Netherlands) and stored digitally on hard disks for
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 113 114 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132
HLC 2287 1–8 99m
3
Tc-DPD Scintigraphy in Cardiac Amyloidosis
[1_TD$IF]Figure 1 Visual scoring of cardiac 99mTc-DPD retention: 0, absent cardiac uptake and normal bone uptake (A); 1, mild cardiac uptake inferior to bone uptake (B); 2, moderate cardiac uptake associated with attenuated bone uptake (C); or 3, cardiac uptake with mild or absent bone uptake (D). Arrows indicate cardiac 99m Tc-DPD uptake.
133 134 135 136
offline analysis (EchoPAC version 108.1.5). Measurements of interventricular septum (IVS) and posterior wall (PW) thickness, left ventricular mass index (LVMI), and septal early diastolic mitral annular tissue velocity (E’) were performed
together with assessment for a restrictive diastolic LV filling pattern. Left ventricular mass index was calculated according to the American Society of Echocardiography guidelines [24]. A restrictive filling pattern was defined as a mitral
Figure 2 SPECT-CT images in a patient with no cardiac uptake of 99m[2_TD$IF] Tc-DPD (left); and in a patient with a planar scan indicating grade 2 99m Tc-DPD uptake (right). Arrow indicates cardiac 99m Tc-DPD uptake.
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
137 138 139 140
HLC 2287 1–8
4
P.T. Moore et al.
Table 1 Baseline characteristics of participants.
N Male sex Median age (years) 2
BMI (kg/m ) *
Figure 3 Heart retention to whole body retention ratio (H:WB) were evaluated from radiotracer activity within regions-of-interest on 3-hour post-radiotracer injection images.
147
inflow E/A ratio >2 and E-wave deceleration time <160 ms [25]. Venous blood samples were taken and analysed for cardiac troponin I (cTnI; Beckman-Coulter immunoassay; normal range <0.04 ug/L), and brain natriuetic peptide (BNP; Beckman-Coulter Alere immunoassay; normal range <100 ng/L) levels.
148
Statistical Analysis
149
Summary statistics were expressed as a median, a mean standard deviation or numbers (percentages). In contingency tables, independence of categorical variables was tested using Fisher’s exact test. A Mann-Whitney U test was used for comparison between groups in cases of nonnormally distributed variables. A linear regression t-test was used to study the association between H:WB and other variables. Regression models were reported as a b coefficient. P-values < [8_TD$IF]0.05 were considered significant.
141 142 143 144 145 146
150 151 152 153 154
ATTR
8 7 (87.5%)
13 12 (92.3%)
58
70
0.016*[3_TD$IF]
26.7
26.7
0.7
denotes statistical significance.
1 died prior to genetic testing performed (likely wild-type) and 1 whose genetic testing is still pending (likely wildtype)). No complications or adverse effects from radiotracer injection or scanning were encountered. Baseline characteristics of participants are shown in Table 1.
162
99m
167
Tc-DPD Scintigraphy
179 180
Table 2 Results of
99m
Tc-DPD scintigraphy.
AL
ATTR 13 13 (100%)
DPD grade 0
6 (75%)
0 (0%)
1
1 (12.5%)
0 (0%)
Results
2
0 (0%)
8 (61.5%)
3
1 (12.5%)
5 (38.5%)
159
Patient Population
H:WB
0.0794
0.1249
160
Twenty-one patients were included in the study: 8 with AL amyloidosis, and 13 with ATTR (8 wild-type, 3 ATTR T60A,
161
166
Results of ECG and echocardiography are summarised in Table 3. There were no statistically significant differences in ECG parameters between AL and ATTR participants. On echocardiography, IVS and PW thickness, and LVMI, were statistically significantly greater in patients with ATTR amyloidosis, but there was no statistically significant difference in the diastolic parameters of E’ or the presence of a restrictive filling pattern.
8
158
165
ECG and Echocardiography
2 (25%)
157
164
168 169
Positive DPD scan
156
163
All 13 (100%) ATTR patients exhibited cardiac uptake on 99m Tc-DPD scintigraphy, compared with 2 (25%) of 8 AL patients (p = 0.001). Grade of 99mTc-DPD uptake was significantly greater in ATTR patients; a grade of 2 or greater was 100% sensitive and 88% specific for the diagnosis of ATTR cardiac amyloidosis. H:WB at three-hours was similarly increased in ATTR patients. Using a receiver-operating characteristic curve, a cut-off of >0.091 was 92% sensitive and 88% specific for the diagnosis of ATTR amyloidosis (area under the curve 0.91; p-value < 0.0001). 99m[9_TD$IF]Tc-DPD scintigraphy results are shown in Table 2.
N
155
p-value
AL
*
P-value
0.001*
<0.001*
0.001*
denotes statistical significance.
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
170 171 172 173 174 175 176 177 178
181 182 183 184 185 186 187
HLC 2287 1–8 99m
5
Tc-DPD Scintigraphy in Cardiac Amyloidosis
Table 3 ECG, echocardiographic and biochemical parameters of participants. AL
ATTR
p-value
ECG Low voltage
1/8 (12.5%) 2/13 (15.4%) NS
PR interval (ms)
189 37
226 43
NS
QRS duration (ms)
110 17
132 30
NS
QTc (ms)
450 26
459 41
NS
IVS thickness (mm) PW thickness (mm)
15 3 15 3
18 3 18 3
0.037* 0.045*
LVMI (g/m2)
126 35
171 38
0.013*
E’ (m/s)
4.1 0.8
3.3 1.1
NS
1/13 (7.7%)
NS
Echocardiography
Restrictive filling pattern 2/8 (25%) Biochemistry
*
TnI (ug/L)
0.06 0.04
0.17 0.23
NS
BNP (ng/L
491 294
456 443
NS
denotes statistical significance; NS = non-significant.
188
Biochemical Parameters
189
Whilst mean TnI and BNP were lower in AL participants than in their ATTR counterparts, these differences were not statistically significant (Table 3).
190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205
Relationship Between 99mTc-DPD Scintigraphy and Other Parameters Whilst there was a weak association between increasing H: WB and PW thickness (p = 0.099), no statistically significant correlation was identified between H:WB and echocardiographic parameters. There was a significant correlation between H:WB and the PR interval on ECG (p = 0.026 using a linear regression t-test). For each ms increase in the PR interval, H:WB increased by 0.0004. No other statistically significant association was identified between H:WB ECG parameters. When participants were divided into AL and ATTR cohorts, no statistically significant correlation between H:WB and ECG or echocardiographic parameters was identified.
206
Discussion
207
This study confirms the high sensitivity of cardiac 99mTcDPD uptake in ATTR cardiac amyloidosis in an Australian population, consistent with previous European and North American series. By using H:WB we were able to quantify the differences in uptake between ATTR and AL patients, and for the first time identified a relationship between amount of uptake and the lengthening of PR interval on ECG. All ATTR patients showed 99mTc-DPD myocardial uptake on scintigraphy. Perugini et al. first established a convincing relationship between cardiac 99mTc-DPD uptake and ATTR cardiac amyloidosis in all of 15 (wild-type and hereditary)
208 209 210 211 212 213 214 215 216 217
ATTR patients [19]. The 100% sensitivity of 99mTc-DPD was replicated in other series [18,20,21] and most recently Gillmore et al., in a collaboration of European and American amyloidosis centres, published by far the largest series of bone scans in endomyocardial biopsy-confirmed ATTR patients [17]. In 374 subjects, the sensitivity for ATTR diagnosis was >99% with radiolabelled phosphate derivatives (predominantly 99mTc-DPD and 99mTc-PYP, but also 99m Tc-hydroxymethylene diphosphonate). DPD uptake was present in only 25% of AL amyloidosis patients within our study. Despite initial excitement regarding the utility of DPD scintigraphy in differentiating ATTR and AL cardiac amyloidosis [19], our findings are consistent with the aforementioned series that identified a 32% to 51% uptake of DPD in AL patients [17,18,20]. Uptake in non-ATTR amyloidosis (predominantly AL but also in hereditary apolipoprotein variants) reduces the specificity for 99mTc-DPD in ATTR amyloidosis; reported as 68% in Gillmore et al. [17]. The presence of positive 99mTc-DPD scans in AL amyloidosis has quelled excitement over the ability of this scan alone to differentiate amyloidosis subtype. Even when combined with haematological results, diagnosis can be difficult, given there is a 19–31% prevalence of a monoclonal gammopathy amongst ATTR patients [17,26,27]. The diagnostic accuracy of 99mTc-DPD scintigraphy can be increased by quantifying the degree of cardiac uptake, which is greater in ATTR patients. In this study mean 99mTc-DPD uptake was statistically significantly greater in ATTR patients. A grade of uptake of two or greater was associated with 100% sensitivity and 88% specificity for the diagnosis of ATTR cardiac amyloidosis. Analysis of the amount of 99mTc-DPD uptake at three hours by calculating H:WB further quantified this increase in 99mTc-DPD uptake in ATTR patients. Using a ROC curve we identified a cut-off H:WB of 0.091 as 92% sensitive and 88% specific for the differentiation of ATTR and AL cardiac amyloidosis patients within this population. The diagnostic certainty can be further increased when the above means of 99mTc-DPD quantification are combined with the presence or absence of a monoclonal protein [17]. The combination of these investigations lends itself to incorporation within a diagnostic framework for suspected cardiac amyloidosis (Figure 4). We feel this scan is of greatest utility in assessing elderly patients with left ventricular thickening of unclear aetiology, in the absence of other organ involvement suggesting AL aetiology. In this setting, correct diagnosis of ATTR amyloidosis provides the patient and clinician with prognostic information, and in the future may guide treatment with emerging therapies [6]. Cardiac amyloidosis is most commonly characterised on echocardiography by concentric left ventricular thickening and diastolic dysfunction [8,9]. Tissue Doppler imaging elicits the first sign of longitudinal systolic impairment, a reduction in septal E’ [28,29]. As the disease advances, a restrictive transmitral flow pattern (a short E-wave deceleration time and E/A ratio >2) becomes apparent [8]. In this study, mean septal and posterior wall thickness, and LVMI, were
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
218 219 220 221 222 223 224 225 226 Q3 227
228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274
HLC 2287 1–8
6
P.T. Moore et al.
Figure 4 Diagnostic framework for suspected cardiac amyloidosis.
275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290
abnormally increased in both AL and ATTR patients, but moreso in the ATTR cohort. Rapezzi et al. demonstrated a positive correlation between H:WB and LVMI in ATTR patients [21], however this was not replicated in this study, perhaps due to the smaller number of patients. E’ was reduced similarly in both groups, and there was no difference in the presence of a restrictive mitral inflow pattern. The proportion of low-voltage ECGs (14.2%) in our population was lower than previously characterised in amyloid patients [21,30], and not statistically different between AL and ATTR patients. Comparison of PR, QRS and QTc intervals between amyloid subtypes did not demonstrate a statistically significant difference. Assessing all patients, a positive correlation between increasing H:WB and lengthening of the PR interval (0.0004 for every millisecond) was identified. Whilst unsurprising given the known association
of cardiac amyloid infiltration of the atria and conduction disease, to our knowledge such a correlation with DPD uptake has not been described previously. There are limitations of this study, the first being the small sample size. Secondly, no control subjects underwent 99m[1_TD$IF]TcDPD scintigraphy, and as such we are unable to exclude the potential for 99mTc-DPD uptake in people without cardiac amyloidosis. However Perugini et al. did not identify any uptake in 10 control subjects, and Gillmore et al. recorded ‘‘false positive scans” in <1% of 1217 patients (attributed to subclinical amyloidosis after assessment for other causes of cardiomyopathy). Thirdly, it is possible differences in 99mTcDPD uptake between ATTR and AL patients is confounded by the stage of disease at time of scanning. Despite documented biochemical and clinical progression, serial imaging of ATTR patients with 99mTc-PYP over 18 months did not
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306
HLC 2287 1–8 99m
7
Tc-DPD Scintigraphy in Cardiac Amyloidosis
307
329
show a significant increase in tracer uptake [31]. Therefore it seems likely that differences in tracer uptake between ATTR and AL amyloid represent the disease process rather than disease stage. Lastly, all series, including ours, have represented highly select populations of patients with known or suspected cardiac amyloidosis. This has two implications: firstly, the prevalence of 99mTc-DPD uptake in patients without amyloidosis or left ventricular thickening is not known (although real-world experience would suggest this as rare); and secondly, the sensitivity for detection of early, or subclinical, ATTR amyloidosis is unclear. Given the prevalence of some degree of cardiac amyloidosis in 25% of people in autopsy studies [32], the utility of early detection may be less relevant, although this may change should experimental therapies for ATTR amyloidosis show efficacy. This study demonstrates the utility of 99mTc-DPD scintigraphy in the diagnosis of ATTR cardiac amyloidosis. Whilst promising, the use of 99mTc-DPD scintigraphy still requires concomitant assessment of haematological and genetic abnormalities to ensure diagnostic and treatment errors are not made. Given emerging trials in novel ATTR therapies, the utility of 99mTc-DPD scintigraphy in monitoring response to therapy may also be of interest in the future.
330
Funding
331 332
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
333
Disclosures
334
Nil.
335
Acknowledgements
336
We thank QFAB Bioinformatics for their assistance with statistical analysis.
308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328
337 338
339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360
References [1] Smith TJ, Kyle RA, Lie JT. Clinical significance of histopathologic patterns of cardiac amyloidosis. Mayo Clin Proc 1984;59(8):547–55. [2] Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112(13):2047–60. [3] Ng B, Connors LH, Davidoff R, Skinner M, Falk RH. Senile systemic amyloidosis presenting with heart failure: a comparison with light chainassociated amyloidosis. Arch Intern Med 2005;165(12):1425–9. [4] Mollee P, Renaut P, Gottlieb D, Goodman H. How to diagnose amyloidosis. Intern Med J 2014;44(1):7–17. [5] Yilmaz A, Kindermann I, Kindermann M, Mahfoud F, Ukena C, Athanasiadis A, et al. Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance. Circulation 2010;122(9):900–9. [6] Vranian MN, Sperry BW, Valent J, Hanna M. Emerging Advances in the Management of Cardiac Amyloidosis. Curr Cardiol Rep 2015;17(11):100. [7] Comenzo RL, Reece D, Palladini G, Seldin D, Sanchorawala V, Landau H, et al. Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis. Leukemia 2012;26(11):2317–25. [8] Klein AL, Hatle LK, Taliercio CP, Taylor CL, Kyle RA, Bailey KR, et al. Serial Doppler echocardiographic follow-up of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1990;16(5):1135–41.
[9] Siqueira-Filho AG, Cunha CL, Tajik AJ, Seward JB, Schattenberg TT, Giuliani ER. M-mode and two-dimensional echocardiographic features in cardiac amyloidosis. Circulation 1981;63(1):188–96. [10] Quarta CC, Falk RH. Longitudinal strain imaging in light-chain cardiac amyloidosis: can it help to refine the approach to treatment? J Am Coll Cardiol 2012;60(12):1077–8. [11] Perugini E, Rapezzi C, Piva T, Leone O, Bacchi-Reggiani L, Riva L, et al. Non-invasive evaluation of the myocardial substrate of cardiac amyloidosis by gadolinium cardiac magnetic resonance. Heart 2006;92(3):343–9. [12] Law WP, Wang WY, Moore PT, Mollee PN, Ng AC. Cardiac amyloid imaging with 18F-florbetaben positron emission tomography: a pilot study. J Nucl Med )2016;(June). [13] Kula RW, Engel WK, Line BR. Scanning for soft-tissue amyloid. Lancet 1977;1(8002):92–3. [14] Eriksson P, Backman C, Bjerle P, Eriksson A, Holm S, Olofsson BO. Noninvasive assessment of the presence and severity of cardiac amyloidosis: A study in familial amyloidosis with polyneuropathy by cross sectional echocardiography and technetium-99 m pyrophosphate scintigraphy. Br Heart J 1984;52(3):321–6. [15] Falk RH, Lee VW, Rubinow A, Hood Jr WB, Cohen AS. Sensitivity of technetium-99m-pyrophosphate scintigraphy in diagnosing cardiac amyloidosis. Am J Cardiol 1983;51(5):826–30. [16] Lee VW, Caldarone AG, Falk RH, Rubinow A, Cohen AS. Amyloidosis of heart and liver: comparison of Tc-99 m pyrophosphate and Tc-99 m methylene diphosphonate for detection. Radiology 1983;148(1):239–42. [17] Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation 2016;133(24):2404–12. [18] Hutt DF, Quigley AM, Page J, Hall ML, Burniston M, Gopaul D, et al. Utility and limitations of 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy in systemic amyloidosis. Eur Heart J Cardiovasc Imaging 2014;15(11):1289–98. [19] Perugini E, Guidalotti PL, Salvi F, Cooke RM, Pettinato C, Riva L, et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3, 3diphosphono-1, 2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol 2005;46(6):1076–84. PubMed PMID: 16168294. Epub 2005/09/ 20.eng. [20] Rapezzi C, Quarta CC, Guidalotti PL, Longhi S, Pettinato C, Leone O, et al. Usefulness and limitations of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy in the aetiological diagnosis of amyloidotic cardiomyopathy. Eur J Nucl Med Mol Imaging 2011;38(3):470–8. [21] Rapezzi C, Quarta CC, Guidalotti PL, Pettinato C, Fanti S, Leone O, et al. Role of (99m)Tc-DPD scintigraphy in diagnosis and prognosis of hereditary transthyretin-related cardiac amyloidosis. JACC Cardiovasc Imaging 2011;4(6):659–70. [22] Bokhari S, Castano A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. (99m) Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging 2013;6(2):195–201. [23] Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, et al. 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, Tours, France, 18-22 April 2004. Am J Hematol 2005;79(4):319–28. [24] Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28(1). 1–39 e14. [25] Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr 2009;10(2):165–93. [26] Maleszewski JJ, Murray DL, Dispenzieri A, Grogan M, Pereira NL, Jenkins SM, et al. Relationship between monoclonal gammopathy and cardiac amyloid type. Cardiovasc Pathol 2013;22(3):189–94. [27] Pinney JH, Whelan CJ, Petrie A, Dungu J, Banypersad SM, Sattianayagam P, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc 2013;2(2):e000098. [28] Koyama J, Davidoff R, Falk RH. Longitudinal myocardial velocity gradient derived from pulsed Doppler tissue imaging in AL amyloidosis: a sensitive indicator of systolic and diastolic dysfunction. J Am Soc Echocardiogr 2004;17(1):36–44. [29] Koyama J, Ray-Sequin PA, Davidoff R, Falk RH. Usefulness of pulsed tissue Doppler imaging for evaluating systolic and diastolic left ventricular function in patients with AL (primary) amyloidosis. Am J Cardiol 2002;89(9):1067–71.
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436
HLC 2287 1–8
8
437 438 439 440 441 442
P.T. Moore et al.
[30] Murtagh B, Hammill SC, Gertz MA, Kyle RA, Tajik AJ, Grogan M. Electrocardiographic findings in primary systemic amyloidosis and biopsy-proven cardiac involvement. Am J Cardiol 2005;95(4):535–7. [31] Castano A, DeLuca A, Weinberg R, Pozniakoff T, Blaner WS, Pirmohamed A, et al. Serial scanning with technetium pyrophosphate (99m Tc-PYP) in advanced ATTR cardiac amyloidosis. J Nucl Cardiol 2015;9.
[32] Tanskanen M, Peuralinna T, Polvikoski T, Notkola IL, Sulkava R, Hardy J, et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med 2008;40(3): 232–9.
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
443 444 445 446 447
ORIGINAL ARTICLE
Heart, Lung and Circulation (2017) xx, 1–8 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2016.12.017
The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience
1 2 3 4
5 6 7 8 9 10 11 12
13 14 15 16 17
Q1
Peter T. Moore, MBBS, FRACP a,b*, Matthew K. Burrage, MBBS a,b, Emily Mackenzie, MBBS, FRACP a,b, W. Philip Law, FRANZCR, FAANMS a,b, Dariusz Korczyk, MDipl, FRACP a,b, Peter Mollee, MBBS, MMedSc a,b a
Amyloidosis Centre, Princess Alexandra Hospital, Brisbane, Qld, Australia School of Medicine, University of Queensland, Brisbane, Qld, Australia
b
Received 6 November 2016; accepted 19 December 2016; online published-ahead-of-print xxx
Background
The uptake of bone-seeking radiotracers in the amyloid heart is well recognised. 99mTc-DPD has been shown to be highly sensitive for cardiac transthyretin (ATTR) amyloid in an overseas population, but is not registered for use in Australia. We explored its utility as a diagnostic tool within our population.
Methods
Patients diagnosed with AL and ATTR (wild-type and inherited) cardiac amyloidosis were prospectively recruited from the Princess Alexandra Hospital Amyloidosis Centre. Patients underwent injection with 99m Tc-DPD then planar whole body imaging was performed at five minutes post-injection (soft tissue phase) and three hours (bone phase). A myocardial SPECT and low amperage CT were acquired after the late whole-body scan. Scans were analysed by two nuclear imaging specialists. Intensity of cardiac 99m Tc-DPD uptake was graded as 0 to 3 in accordance with previous criteria, and semiquantitative analysis was performed using a heart to whole body ratio (H:WB) on the three-hour scan. Patients also underwent electrocardiography and transthoracic echocardiography, and blood samples were taken for troponin I and brain natriuretic peptide levels, to assess for any correlation with DPD uptake.
Results
Twenty-one patients (8 AL and 13 ATTR) completed the study. Median age was 58 and 70 years for AL and ATTR patients respectively, and 19 (90.5%) were male. 99mTc-DPD scintigraphy was positive in 2 (25%) of AL, and 13 (100%) of ATTR patients. Grade of cardiac uptake, and mean H:WB (0.1249 v. 0.0794) was greater in the ATTR cohort (p-value < 0.001 and 0.001 respectively). No statistically significant correlation was identified between H:WB and echocardiographic parameters. There was a significant positive correlation between H:WB and the PR interval on ECG (p = 0.026).
Conclusions
99m[6_TD$IF]Tc-DPD scintigraphy is highly sensitive for the diagnosis of cardiac ATTR amyloid, but less so for AL amyloid.
Keywords
99mTc-DPD scintigraphy Bone scan Cardiac amyloidosis Nuclear imaging
Introduction Amyloidosis is a disease characterised by the extracellular deposition of misfolded proteins leading to organ
dysfunction. Cardiac amyloidosis is characterised by myocardial infiltration [1] with the vast majority of clinically significant cases being caused by immunoglobulin light chain (AL), or transthyretin (ATTR) deposition [2].
*Corresponding author. Email: [email protected] © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
18 19 20 21
HLC 2287 1–8
2
22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76
Q2
P.T. Moore et al.
Transthyretin may be due to deposition of wild-type (formerly senile systemic amyloidosis) or mutant protein (inherited). The correct diagnosis of cardiac amyloidosis, and its subtype, is paramount to provide accurate prognosis and treatment. Immunoglobulin light chain cardiac amyloidosis carries a poorer prognosis [3], but may respond to chemotherapy [2]. The gold standard for diagnosis remains tissue biopsy of the affected organ revealing deposits that, when stained with Congo red, demonstrate apple-green birefringence under polarised light. The gold standard for amyloid subtyping is proteomic analysis of the amyloid deposits from such biopsy specimens, but in centres of excellence, immunohistochemistry or immunogold electron microscopy are diagnostic [4]. Although endomyocardial biopsy carries a risk of serious morbidity [5], confirmation of ATTR subtype should be pursued in light of emerging evidence for novel therapies [6]. Biochemistry [7] and imaging provide diagnostic support of cardiac amyloidosis, but are not conclusive. Classic echocardiographic findings [8,9] are non-specific, and strain techniques are laboratory (user and equipment)-dependent [10]. Whilst magnetic resonance imaging (MRI) is more specific [11], its use is limited to patients without serious kidney disease (often present in this population) due to the need for intravenous gadolinium administration. Newer modalities such as positron emission tomography (PET) imaging with amyloid-specific radiotracers appear promising, but remain in the research phase [12]. Radiolabelled phosphate derivatives are commonly used bone-scanning agents and in 1977, Kula et al. were the first to identify the uptake of 99mTc-diphosphonate in cardiac amyloid deposits [13]. Phosphate derivatives are believed to localise to calcium content in amyloid deposits however the mechanism remains unclear. In the 1980s, small studies with 99mTc-pyrophosphate (99mTc-PYP) and 99m Tc-methylene diphosphonate (99mTc-MDP) yielded varying sensitivities for detection of cardiac amyloidosis [14–16]. However, in the last decade several series have shown 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) to be highly sensitive in the diagnosis of ATTR cardiac amyloidosis [17–21], and potentially prognostic [21]. Contemporary evidence for 99mTc-PYP has shown similar results [22]. Although the specificity of these agents is reduced by cardiac uptake in a proportion of AL patients [17,18,20], the use of this widely available imaging modality as a part of the diagnostic work-up of suspected cardiac amyloidosis shows great promise in reducing the need for tissue diagnosis. The aim of this study was to assess the sensitivity and specificity of 99mTc-DPD in an Australian population of patients with cardiac amyloidosis, to clarify its role in the diagnostic work-up of suspected cases. Secondly, we aimed to define any association between the quantity of 99mTc-DPD uptake and classic echocardiographic, electrocardiographic and biochemical features of this disease.
Methods
77
Patients with cardiac amyloidosis of AL or ATTR (wild-type or inherited) origin were prospectively recruited from the Princess Alexandra Hospital Amyloidosis Centre between 2013 and 2015. Cardiac involvement of AL amyloidosis was defined in accordance with international consensus criteria [23]: either an endomyocardial biopsy demonstrated amyloidosis in the presence of clinical or laboratory evidence of AL amyloid; or echocardiographic evidence of amyloidosis was identified in a patient with a positive result of noncardiac biopsy (in the absence of hypertension or other potential causes of left ventricular thickening). Transthyretin cardiac amyloidosis was diagnosed by endomyocardial biopsy and patients were planned to undergo genetic testing for transthyretin mutations. Patients were required to be over the age of 50 years. Patients lacking the capacity to provide consent were excluded. The Metro South Human Research Ethics Committee approved the study and all subjects provided informed consent. Scintigraphic imaging was performed at the PAH using a SPECT/CT scanner (Symbia TruePoint SPECT CT, Siemens, Munich, Germany). 99mTc-DPD, not available for use on the Australian Register of Therapeutic Goods, was accessed through the Therapeutic Goods Administration of Australia Clinical Trial Notification Scheme. After intravenous cannulation and injection with 99mTc-DPD, planar whole body imaging was performed at five minutes (soft tissue phase) and three hours (bone phase) post-injection. A myocardial SPECT and low amperage CT were acquired after the late whole-body scan. Each subject received between 700–800 MBq of 99m[7_TD$IF]Tc-DPD. Image analysis was performed by two experienced nuclear imaging specialists blinded to all patient data. Visual scoring of cardiac retention was performed in accordance with the criteria from Perugini et al. [19]:
78
0, absent cardiac uptake and normal bone uptake; 1, mild cardiac uptake inferior to bone uptake; 2, moderate cardiac uptake associated with attenuated
112
bone uptake; or 3, cardiac uptake with mild or absent bone uptake ([1_TD$IF]Figure 1).
115
Cardiac uptake visualised on SPECT-CT ([1_TD$IF]Figure 2) but not on planar imaging was also classified as grade 1 [18]. Semiquantitative analysis of heart retention, whole body retention, and heart retention to whole body retention ratio (H: WB) were evaluated from radiotracer activity within regionsof-interest drawn to include the heart and whole body on three-hour post-radiotracer injection images ([1_TD$IF]Figure 3). Participants underwent an electrocardiogram (ECG) to assess for the presence of low voltage criteria, defined as a QRS height <5 mm in all limb leads [2]. Transthoracic echocardiography was performed using commercially available ultrasound systems (Vivid 7 and E9, GE-Vingmed, Horten, Norway; IE33 and CX50, Philips, Royal Philips, Amsterdam, The Netherlands) and stored digitally on hard disks for
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 113 114 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132
HLC 2287 1–8 99m
3
Tc-DPD Scintigraphy in Cardiac Amyloidosis
[1_TD$IF]Figure 1 Visual scoring of cardiac 99mTc-DPD retention: 0, absent cardiac uptake and normal bone uptake (A); 1, mild cardiac uptake inferior to bone uptake (B); 2, moderate cardiac uptake associated with attenuated bone uptake (C); or 3, cardiac uptake with mild or absent bone uptake (D). Arrows indicate cardiac 99m Tc-DPD uptake.
133 134 135 136
offline analysis (EchoPAC version 108.1.5). Measurements of interventricular septum (IVS) and posterior wall (PW) thickness, left ventricular mass index (LVMI), and septal early diastolic mitral annular tissue velocity (E’) were performed
together with assessment for a restrictive diastolic LV filling pattern. Left ventricular mass index was calculated according to the American Society of Echocardiography guidelines [24]. A restrictive filling pattern was defined as a mitral
Figure 2 SPECT-CT images in a patient with no cardiac uptake of 99m[2_TD$IF] Tc-DPD (left); and in a patient with a planar scan indicating grade 2 99m Tc-DPD uptake (right). Arrow indicates cardiac 99m Tc-DPD uptake.
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
137 138 139 140
HLC 2287 1–8
4
P.T. Moore et al.
Table 1 Baseline characteristics of participants.
N Male sex Median age (years) 2
BMI (kg/m ) *
Figure 3 Heart retention to whole body retention ratio (H:WB) were evaluated from radiotracer activity within regions-of-interest on 3-hour post-radiotracer injection images.
147
inflow E/A ratio >2 and E-wave deceleration time <160 ms [25]. Venous blood samples were taken and analysed for cardiac troponin I (cTnI; Beckman-Coulter immunoassay; normal range <0.04 ug/L), and brain natriuetic peptide (BNP; Beckman-Coulter Alere immunoassay; normal range <100 ng/L) levels.
148
Statistical Analysis
149
Summary statistics were expressed as a median, a mean standard deviation or numbers (percentages). In contingency tables, independence of categorical variables was tested using Fisher’s exact test. A Mann-Whitney U test was used for comparison between groups in cases of nonnormally distributed variables. A linear regression t-test was used to study the association between H:WB and other variables. Regression models were reported as a b coefficient. P-values < [8_TD$IF]0.05 were considered significant.
141 142 143 144 145 146
150 151 152 153 154
ATTR
8 7 (87.5%)
13 12 (92.3%)
58
70
0.016*[3_TD$IF]
26.7
26.7
0.7
denotes statistical significance.
1 died prior to genetic testing performed (likely wild-type) and 1 whose genetic testing is still pending (likely wildtype)). No complications or adverse effects from radiotracer injection or scanning were encountered. Baseline characteristics of participants are shown in Table 1.
162
99m
167
Tc-DPD Scintigraphy
179 180
Table 2 Results of
99m
Tc-DPD scintigraphy.
AL
ATTR 13 13 (100%)
DPD grade 0
6 (75%)
0 (0%)
1
1 (12.5%)
0 (0%)
Results
2
0 (0%)
8 (61.5%)
3
1 (12.5%)
5 (38.5%)
159
Patient Population
H:WB
0.0794
0.1249
160
Twenty-one patients were included in the study: 8 with AL amyloidosis, and 13 with ATTR (8 wild-type, 3 ATTR T60A,
161
166
Results of ECG and echocardiography are summarised in Table 3. There were no statistically significant differences in ECG parameters between AL and ATTR participants. On echocardiography, IVS and PW thickness, and LVMI, were statistically significantly greater in patients with ATTR amyloidosis, but there was no statistically significant difference in the diastolic parameters of E’ or the presence of a restrictive filling pattern.
8
158
165
ECG and Echocardiography
2 (25%)
157
164
168 169
Positive DPD scan
156
163
All 13 (100%) ATTR patients exhibited cardiac uptake on 99m Tc-DPD scintigraphy, compared with 2 (25%) of 8 AL patients (p = 0.001). Grade of 99mTc-DPD uptake was significantly greater in ATTR patients; a grade of 2 or greater was 100% sensitive and 88% specific for the diagnosis of ATTR cardiac amyloidosis. H:WB at three-hours was similarly increased in ATTR patients. Using a receiver-operating characteristic curve, a cut-off of >0.091 was 92% sensitive and 88% specific for the diagnosis of ATTR amyloidosis (area under the curve 0.91; p-value < 0.0001). 99m[9_TD$IF]Tc-DPD scintigraphy results are shown in Table 2.
N
155
p-value
AL
*
P-value
0.001*
<0.001*
0.001*
denotes statistical significance.
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
170 171 172 173 174 175 176 177 178
181 182 183 184 185 186 187
HLC 2287 1–8 99m
5
Tc-DPD Scintigraphy in Cardiac Amyloidosis
Table 3 ECG, echocardiographic and biochemical parameters of participants. AL
ATTR
p-value
ECG Low voltage
1/8 (12.5%) 2/13 (15.4%) NS
PR interval (ms)
189 37
226 43
NS
QRS duration (ms)
110 17
132 30
NS
QTc (ms)
450 26
459 41
NS
IVS thickness (mm) PW thickness (mm)
15 3 15 3
18 3 18 3
0.037* 0.045*
LVMI (g/m2)
126 35
171 38
0.013*
E’ (m/s)
4.1 0.8
3.3 1.1
NS
1/13 (7.7%)
NS
Echocardiography
Restrictive filling pattern 2/8 (25%) Biochemistry
*
TnI (ug/L)
0.06 0.04
0.17 0.23
NS
BNP (ng/L
491 294
456 443
NS
denotes statistical significance; NS = non-significant.
188
Biochemical Parameters
189
Whilst mean TnI and BNP were lower in AL participants than in their ATTR counterparts, these differences were not statistically significant (Table 3).
190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205
Relationship Between 99mTc-DPD Scintigraphy and Other Parameters Whilst there was a weak association between increasing H: WB and PW thickness (p = 0.099), no statistically significant correlation was identified between H:WB and echocardiographic parameters. There was a significant correlation between H:WB and the PR interval on ECG (p = 0.026 using a linear regression t-test). For each ms increase in the PR interval, H:WB increased by 0.0004. No other statistically significant association was identified between H:WB ECG parameters. When participants were divided into AL and ATTR cohorts, no statistically significant correlation between H:WB and ECG or echocardiographic parameters was identified.
206
Discussion
207
This study confirms the high sensitivity of cardiac 99mTcDPD uptake in ATTR cardiac amyloidosis in an Australian population, consistent with previous European and North American series. By using H:WB we were able to quantify the differences in uptake between ATTR and AL patients, and for the first time identified a relationship between amount of uptake and the lengthening of PR interval on ECG. All ATTR patients showed 99mTc-DPD myocardial uptake on scintigraphy. Perugini et al. first established a convincing relationship between cardiac 99mTc-DPD uptake and ATTR cardiac amyloidosis in all of 15 (wild-type and hereditary)
208 209 210 211 212 213 214 215 216 217
ATTR patients [19]. The 100% sensitivity of 99mTc-DPD was replicated in other series [18,20,21] and most recently Gillmore et al., in a collaboration of European and American amyloidosis centres, published by far the largest series of bone scans in endomyocardial biopsy-confirmed ATTR patients [17]. In 374 subjects, the sensitivity for ATTR diagnosis was >99% with radiolabelled phosphate derivatives (predominantly 99mTc-DPD and 99mTc-PYP, but also 99m Tc-hydroxymethylene diphosphonate). DPD uptake was present in only 25% of AL amyloidosis patients within our study. Despite initial excitement regarding the utility of DPD scintigraphy in differentiating ATTR and AL cardiac amyloidosis [19], our findings are consistent with the aforementioned series that identified a 32% to 51% uptake of DPD in AL patients [17,18,20]. Uptake in non-ATTR amyloidosis (predominantly AL but also in hereditary apolipoprotein variants) reduces the specificity for 99mTc-DPD in ATTR amyloidosis; reported as 68% in Gillmore et al. [17]. The presence of positive 99mTc-DPD scans in AL amyloidosis has quelled excitement over the ability of this scan alone to differentiate amyloidosis subtype. Even when combined with haematological results, diagnosis can be difficult, given there is a 19–31% prevalence of a monoclonal gammopathy amongst ATTR patients [17,26,27]. The diagnostic accuracy of 99mTc-DPD scintigraphy can be increased by quantifying the degree of cardiac uptake, which is greater in ATTR patients. In this study mean 99mTc-DPD uptake was statistically significantly greater in ATTR patients. A grade of uptake of two or greater was associated with 100% sensitivity and 88% specificity for the diagnosis of ATTR cardiac amyloidosis. Analysis of the amount of 99mTc-DPD uptake at three hours by calculating H:WB further quantified this increase in 99mTc-DPD uptake in ATTR patients. Using a ROC curve we identified a cut-off H:WB of 0.091 as 92% sensitive and 88% specific for the differentiation of ATTR and AL cardiac amyloidosis patients within this population. The diagnostic certainty can be further increased when the above means of 99mTc-DPD quantification are combined with the presence or absence of a monoclonal protein [17]. The combination of these investigations lends itself to incorporation within a diagnostic framework for suspected cardiac amyloidosis (Figure 4). We feel this scan is of greatest utility in assessing elderly patients with left ventricular thickening of unclear aetiology, in the absence of other organ involvement suggesting AL aetiology. In this setting, correct diagnosis of ATTR amyloidosis provides the patient and clinician with prognostic information, and in the future may guide treatment with emerging therapies [6]. Cardiac amyloidosis is most commonly characterised on echocardiography by concentric left ventricular thickening and diastolic dysfunction [8,9]. Tissue Doppler imaging elicits the first sign of longitudinal systolic impairment, a reduction in septal E’ [28,29]. As the disease advances, a restrictive transmitral flow pattern (a short E-wave deceleration time and E/A ratio >2) becomes apparent [8]. In this study, mean septal and posterior wall thickness, and LVMI, were
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
218 219 220 221 222 223 224 225 226 Q3 227
228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274
HLC 2287 1–8
6
P.T. Moore et al.
Figure 4 Diagnostic framework for suspected cardiac amyloidosis.
275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290
abnormally increased in both AL and ATTR patients, but moreso in the ATTR cohort. Rapezzi et al. demonstrated a positive correlation between H:WB and LVMI in ATTR patients [21], however this was not replicated in this study, perhaps due to the smaller number of patients. E’ was reduced similarly in both groups, and there was no difference in the presence of a restrictive mitral inflow pattern. The proportion of low-voltage ECGs (14.2%) in our population was lower than previously characterised in amyloid patients [21,30], and not statistically different between AL and ATTR patients. Comparison of PR, QRS and QTc intervals between amyloid subtypes did not demonstrate a statistically significant difference. Assessing all patients, a positive correlation between increasing H:WB and lengthening of the PR interval (0.0004 for every millisecond) was identified. Whilst unsurprising given the known association
of cardiac amyloid infiltration of the atria and conduction disease, to our knowledge such a correlation with DPD uptake has not been described previously. There are limitations of this study, the first being the small sample size. Secondly, no control subjects underwent 99m[1_TD$IF]TcDPD scintigraphy, and as such we are unable to exclude the potential for 99mTc-DPD uptake in people without cardiac amyloidosis. However Perugini et al. did not identify any uptake in 10 control subjects, and Gillmore et al. recorded ‘‘false positive scans” in <1% of 1217 patients (attributed to subclinical amyloidosis after assessment for other causes of cardiomyopathy). Thirdly, it is possible differences in 99mTcDPD uptake between ATTR and AL patients is confounded by the stage of disease at time of scanning. Despite documented biochemical and clinical progression, serial imaging of ATTR patients with 99mTc-PYP over 18 months did not
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306
HLC 2287 1–8 99m
7
Tc-DPD Scintigraphy in Cardiac Amyloidosis
307
329
show a significant increase in tracer uptake [31]. Therefore it seems likely that differences in tracer uptake between ATTR and AL amyloid represent the disease process rather than disease stage. Lastly, all series, including ours, have represented highly select populations of patients with known or suspected cardiac amyloidosis. This has two implications: firstly, the prevalence of 99mTc-DPD uptake in patients without amyloidosis or left ventricular thickening is not known (although real-world experience would suggest this as rare); and secondly, the sensitivity for detection of early, or subclinical, ATTR amyloidosis is unclear. Given the prevalence of some degree of cardiac amyloidosis in 25% of people in autopsy studies [32], the utility of early detection may be less relevant, although this may change should experimental therapies for ATTR amyloidosis show efficacy. This study demonstrates the utility of 99mTc-DPD scintigraphy in the diagnosis of ATTR cardiac amyloidosis. Whilst promising, the use of 99mTc-DPD scintigraphy still requires concomitant assessment of haematological and genetic abnormalities to ensure diagnostic and treatment errors are not made. Given emerging trials in novel ATTR therapies, the utility of 99mTc-DPD scintigraphy in monitoring response to therapy may also be of interest in the future.
330
Funding
331 332
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
333
Disclosures
334
Nil.
335
Acknowledgements
336
We thank QFAB Bioinformatics for their assistance with statistical analysis.
308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328
337 338
339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360
References [1] Smith TJ, Kyle RA, Lie JT. Clinical significance of histopathologic patterns of cardiac amyloidosis. Mayo Clin Proc 1984;59(8):547–55. [2] Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112(13):2047–60. [3] Ng B, Connors LH, Davidoff R, Skinner M, Falk RH. Senile systemic amyloidosis presenting with heart failure: a comparison with light chainassociated amyloidosis. Arch Intern Med 2005;165(12):1425–9. [4] Mollee P, Renaut P, Gottlieb D, Goodman H. How to diagnose amyloidosis. Intern Med J 2014;44(1):7–17. [5] Yilmaz A, Kindermann I, Kindermann M, Mahfoud F, Ukena C, Athanasiadis A, et al. Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance. Circulation 2010;122(9):900–9. [6] Vranian MN, Sperry BW, Valent J, Hanna M. Emerging Advances in the Management of Cardiac Amyloidosis. Curr Cardiol Rep 2015;17(11):100. [7] Comenzo RL, Reece D, Palladini G, Seldin D, Sanchorawala V, Landau H, et al. Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis. Leukemia 2012;26(11):2317–25. [8] Klein AL, Hatle LK, Taliercio CP, Taylor CL, Kyle RA, Bailey KR, et al. Serial Doppler echocardiographic follow-up of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1990;16(5):1135–41.
[9] Siqueira-Filho AG, Cunha CL, Tajik AJ, Seward JB, Schattenberg TT, Giuliani ER. M-mode and two-dimensional echocardiographic features in cardiac amyloidosis. Circulation 1981;63(1):188–96. [10] Quarta CC, Falk RH. Longitudinal strain imaging in light-chain cardiac amyloidosis: can it help to refine the approach to treatment? J Am Coll Cardiol 2012;60(12):1077–8. [11] Perugini E, Rapezzi C, Piva T, Leone O, Bacchi-Reggiani L, Riva L, et al. Non-invasive evaluation of the myocardial substrate of cardiac amyloidosis by gadolinium cardiac magnetic resonance. Heart 2006;92(3):343–9. [12] Law WP, Wang WY, Moore PT, Mollee PN, Ng AC. Cardiac amyloid imaging with 18F-florbetaben positron emission tomography: a pilot study. J Nucl Med )2016;(June). [13] Kula RW, Engel WK, Line BR. Scanning for soft-tissue amyloid. Lancet 1977;1(8002):92–3. [14] Eriksson P, Backman C, Bjerle P, Eriksson A, Holm S, Olofsson BO. Noninvasive assessment of the presence and severity of cardiac amyloidosis: A study in familial amyloidosis with polyneuropathy by cross sectional echocardiography and technetium-99 m pyrophosphate scintigraphy. Br Heart J 1984;52(3):321–6. [15] Falk RH, Lee VW, Rubinow A, Hood Jr WB, Cohen AS. Sensitivity of technetium-99m-pyrophosphate scintigraphy in diagnosing cardiac amyloidosis. Am J Cardiol 1983;51(5):826–30. [16] Lee VW, Caldarone AG, Falk RH, Rubinow A, Cohen AS. Amyloidosis of heart and liver: comparison of Tc-99 m pyrophosphate and Tc-99 m methylene diphosphonate for detection. Radiology 1983;148(1):239–42. [17] Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation 2016;133(24):2404–12. [18] Hutt DF, Quigley AM, Page J, Hall ML, Burniston M, Gopaul D, et al. Utility and limitations of 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy in systemic amyloidosis. Eur Heart J Cardiovasc Imaging 2014;15(11):1289–98. [19] Perugini E, Guidalotti PL, Salvi F, Cooke RM, Pettinato C, Riva L, et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3, 3diphosphono-1, 2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol 2005;46(6):1076–84. PubMed PMID: 16168294. Epub 2005/09/ 20.eng. [20] Rapezzi C, Quarta CC, Guidalotti PL, Longhi S, Pettinato C, Leone O, et al. Usefulness and limitations of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy in the aetiological diagnosis of amyloidotic cardiomyopathy. Eur J Nucl Med Mol Imaging 2011;38(3):470–8. [21] Rapezzi C, Quarta CC, Guidalotti PL, Pettinato C, Fanti S, Leone O, et al. Role of (99m)Tc-DPD scintigraphy in diagnosis and prognosis of hereditary transthyretin-related cardiac amyloidosis. JACC Cardiovasc Imaging 2011;4(6):659–70. [22] Bokhari S, Castano A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. (99m) Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging 2013;6(2):195–201. [23] Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, et al. 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, Tours, France, 18-22 April 2004. Am J Hematol 2005;79(4):319–28. [24] Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28(1). 1–39 e14. [25] Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr 2009;10(2):165–93. [26] Maleszewski JJ, Murray DL, Dispenzieri A, Grogan M, Pereira NL, Jenkins SM, et al. Relationship between monoclonal gammopathy and cardiac amyloid type. Cardiovasc Pathol 2013;22(3):189–94. [27] Pinney JH, Whelan CJ, Petrie A, Dungu J, Banypersad SM, Sattianayagam P, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc 2013;2(2):e000098. [28] Koyama J, Davidoff R, Falk RH. Longitudinal myocardial velocity gradient derived from pulsed Doppler tissue imaging in AL amyloidosis: a sensitive indicator of systolic and diastolic dysfunction. J Am Soc Echocardiogr 2004;17(1):36–44. [29] Koyama J, Ray-Sequin PA, Davidoff R, Falk RH. Usefulness of pulsed tissue Doppler imaging for evaluating systolic and diastolic left ventricular function in patients with AL (primary) amyloidosis. Am J Cardiol 2002;89(9):1067–71.
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436
HLC 2287 1–8
8
437 438 439 440 441 442
P.T. Moore et al.
[30] Murtagh B, Hammill SC, Gertz MA, Kyle RA, Tajik AJ, Grogan M. Electrocardiographic findings in primary systemic amyloidosis and biopsy-proven cardiac involvement. Am J Cardiol 2005;95(4):535–7. [31] Castano A, DeLuca A, Weinberg R, Pozniakoff T, Blaner WS, Pirmohamed A, et al. Serial scanning with technetium pyrophosphate (99m Tc-PYP) in advanced ATTR cardiac amyloidosis. J Nucl Cardiol 2015;9.
[32] Tanskanen M, Peuralinna T, Polvikoski T, Notkola IL, Sulkava R, Hardy J, et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med 2008;40(3): 232–9.
Please cite this article in press as: Moore PT, et al. The Utility of 99mTc-DPD Scintigraphy in the Diagnosis of Cardiac Amyloidosis: An Australian Experience. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2016.12.017
443 444 445 446 447