Author + information
- Candida Cristina Quarta, MD,
- Pier Luigi Guidalotti, MD,
- Simone Longhi, MD,
- Cinzia Pettinato, MD,
- Ornella Leone, MD,
- Alessandra Ferlini, MD,
- Elena Biagini, MD,
- Francesco Grigioni, MD,
- Maria Letizia Bacchi-Reggiani, MSc, MStat,
- Massimiliano Lorenzini, MD,
- Agnese Milandri, MD,
- Angelo Branzi, MD and
- Claudio Rapezzi, MD⁎ ()
- ↵⁎Istituto di Cardiologia, Policlinico S. Orsola-Malpighi, via Massarenti 9, 40138 Bologna, Italy
Senile systemic amyloidosis (SSA) is a cardiomyopathy mainly affecting elderly men due to intramyocardial deposition of wild-type (nonmutant) transthyretin (TTR) (1). Since the heart is the only involved organ, SSA—which requires endomyocardial biopsy (EMB) for a definite diagnosis—is often misdiagnosed as other, more common, causes of left ventricular “hypertrophy” (LVH), including hypertensive heart disease and hypertrophic cardiomyopathy (HCM) (1). We (2,3) and other groups (4,5) have previously documented that 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) has a high affinity for TTR-infiltrated myocardium (allowing a differential diagnosis with light-chain [AL] cardiac amyloidosis, in which the tracer uptake is low/absent) (2,3). However, the scintigraphic profiles of the non–amyloidotic cardiomyopathies potentially mimicking SSA are not known, and the specificity of 99mTc-DPD for the diagnosis of SSA in this context remains to be ascertained. To clarify this aspect, we retrospectively analyzed a group of consecutive patients with suspected SSA studied at our center, according to a pre-defined echocardiographic-scintigraphic-genetic and EMB protocol.
We considered all patients who underwent 99mTc-DPD scintigraphy from 2004 to 2011 for suspected SSA, that is, patients older than 65 years-of-age with unexplained concentric LVH (end-diastolic mean wall thickness >13 mm) and a nondilated left ventricle (LV), also presenting 1 or more of the following: male sex; thickened interatrial septum; thickened atrioventricular valves; mild pericardial effusion; granular sparkling appearance; and absent/mild LVH on the electrocardiogram (ECG). We excluded patients with a known definite diagnosis that explained LVH, including AL amyloidosis, hereditary TTR-related amyloidosis (ATTR), and sarcomeric HCM.
Patients received 740 MBq of 99mTc-DPD intravenously. Whole-body scans were obtained at 5 min (early) and 3 h (late) after injection. Visual score of cardiac retention was: 0, absent cardiac uptake, normal bone uptake; 1, mild cardiac uptake, inferior to bone uptake; 2, moderate cardiac uptake, attenuated bone uptake; and 3, strong cardiac uptake, mild/absent bone uptake (2,3). Heart retention (HR), whole-body retention, and heart/whole-body retention ratio (H/WB) were semiquantitatively assessed using a standard region-of-interest technique (2–4). Total counts in the scans were taken as whole-body counts. Early whole-body counts were assumed to represent total injected activity. Whole-body retention was evaluated by comparing counts in late images (after subtraction of counts in the bladder and urinary tract, and correction for decay and scan speed) with those in early whole-body images. HR was evaluated by comparing decay-corrected counts of the heart in late images with counts in early whole-body images. H/WB ratios were calculated by dividing counts in the heart by whole-body counts in late images.
Sixty-seven patients were included. Data are expressed as numbers and percentages or median value and [interquartile range]. Visual 99mTc-DPD myocardial uptake was present (positive) in 51 patients (all with a visual score ≥2) and absent (negative) in 16 (visual score = 0). EMB (including histological and immunohistochemical evaluation) was performed in 46 of 51 patients with positive scintigraphy (5 patients refused EMB) and documented TTR-related amyloid infiltration in all cases. At deoxyribonucleic acid analysis, TTR mutations were present in 14 patients (leading to a diagnosis of ATTR) and absent in 32 (leading to a diagnosis of SSA). No TTR mutations were found in the 16 patients with negative scintigraphy: 9 were found to carry sarcomeric gene mutations (MYBPC3 in 5 cases, MYH7 in 4 cases), leading to a diagnosis of HCM; a single patient was found to carry an alpha-galactosidase A gene mutation, leading to a diagnosis of Anderson-Fabry disease. The remaining 6 patients (without genetic abnormalities) underwent EMB, which documented only a mild nonspecific hypertrophy without myocardial disarray, supporting a diagnosis of hypertensive heart disease. In this way, 3 groups of patients with different diagnoses were identified: SSA, ATTR, and non–amyloidotic cardiomyopathies. Figures 1 and 2,⇓ respectively, show examples of individual scintigraphic profiles and median values of HR and H/WB in the 3 groups.
Clinically, 17 (53%) SSA and 7 (50%) ATTR patients were initially referred for heart failure, the other patients for atrial fibrillation or occasional finding of ECG/echocardiographic abnormalities. The 16 cases with non–amyloidotic LVH were initially referred for “diastolic heart failure” (n = 3, 19%), atrial fibrillation (n = 4, 25%), or occasional finding of ECG/echocardiographic abnormalities (n = 9, 56%). SSA patients were older (78 [74 to 81] years) than ATTR patients (69 [67 to 71] years) and patients with non–amyloidotic LVH (67 [66 to 70] years, p < 0.001). Male sex was predominant in all groups (91% in SSA, 100% in ATTR, 75% in non–amyloidotic LVH; p = 0.10). A concomitant carpal tunnel syndrome was present in 6 (46%) ATTR patients, 7 (22%) SSA patients, and 1 patient with non–amyloidotic LVH (p = 0.06). Low QRS voltage was present in 11 (34%) SSA patients, 6 (43%) ATTR patients, and 2 (13%) patients with non–amyloidotic LVH (p = 0.15).
Echocardiographically, despite a similar interventricular septal thickness (18 [16 to 20] mm in all groups), LV posterior wall thickness was higher among SSA (18 [15 to 19] mm) and ATTR (17 [15 to 19] mm) patients compared with those with non–amyloidotic LVH (14 [13 to 15] mm, p = 0.004). Interatrial septum thickening was more frequent in SSA (63%) and ATTR patients (57%) than in those with non–amyloidotic LVH (25%, p = 0.04). Atrioventricular valve thickening was more prevalent in ATTR patients (64%) than SSA patients (50%) and patients with non–amyloidotic LVH (19%, p = 0.03). Pericardial effusion was present in 14 (44%) SSA patients, 4 (28%) ATTR patients, and 3 (19%) patients with non–amyloidotic LVH (p = 0.2). LV ejection fraction was normal in non–amyloidotic LVH (68% [64% to 70%]), and within the lower normal limits or mildly reduced in patients with SSA (50% [35% to 59%]) and ATTR (50% [38% to 52%]).
Using genotyping/immunohistochemistry as the reference technique, the sensitivity and specificity of a myocardial 99mTc-DPD visual score ≥2 for the diagnosis of TTR-related cardiomyopathy were both 100%. All other clinical, echocardiographic, and electrocardiographic findings showed lower sensitivity and specificity values: respectively, 94% and 25% for male sex, 28% and 94% for carpal tunnel syndrome, 61% and 75% for interatrial septum thickening, 37% and 81% for atrioventricular valve thickening, 39% and 81% for pericardial effusion, and 37% and 88% for ECG low QRS voltage. When interpreting these values, one must consider the high “pre-test” probability of SSA in the study population—due to the accurate patient pre-selection—and the fact that in all positive cases, tracer uptake was intense (visual score ≥2). Indeed, as our previous studies showed, a visual score ≤2 is possible in AL amyloidotic cardiomyopathy.
Our study, which considered an accurately selected population with a high prevalence of non–AL amyloidotic cardiomyopathy, shows that in elderly patients with unexplained concentric LVH and a nondilated LV,99mTc-DPD scintigraphy can provide a valuable, accurate (and inexpensive) technique, able to increase the possibility of noninvasive identification of TTR-related amyloidotic cardiomyopathies on top of echocardiographic evaluation. This can be particularly useful for the noninvasive identification of SSA (for which, differing from ATTR, there is no genetic diagnostic standard) (Fig. 3).
- American College of Cardiology Foundation
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