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Etiology of Amyloidosis Determines Myocardial 99mTc-DPD Uptake in Amyloidotic Cardiomyopathy
Abstract
Tc-DPD (Tc-3,3-diphosphono-1,2-propanodicarboxylic acid) has a high affinity for transthyretin (TTR)-infiltrated myocardium, allowing a differential diagnosis with light chain cardiac amyloidosis and other nonamyloidotic cardiomyopathies with a hypertrophic phenotype, in which myocardial tracer uptake is low or absent. Myocardial bone tracer uptake in the rarer forms of amyloidosis (eg, apolipoprotein-related) has been rarely studied. We present 4 cases of cardiac amyloidosis that underwent Tc-DPD scintigraphy; myocardial DPD uptake was present in patients with ATTR, wtTTR and apolipoprotein AI and negative in cases with AL and apolipoprotein AII-related disease.
... Since the report by Puille et al. on 99m technetium-3,3-diphosphono-1,2-propanodicarboxylic acid ( 99m Tc-DPD) scintigraphy for visualization of amyloid deposition in ATTR amyloidosis, several additional studies have reported 99m Tc-DPD to have a high affinity and sensitivity for ATTR myocardial infiltration (22)(23)(24), but lack of uptake or only low-grade uptake (grade 1) has been observed in patients with immunoglobulin light chain amyloid protein (AL) cardiac amyloidosis which signifies that the precursor protein has an impact on the outcome of the investigation. Similarly, Longhi et al. recently described positive 99m Tc-DPD scans in apolipoprotein AI-related disease, and negative in disease related to apolipoprotein AII (25). In a study by Rapezzi et al. (26), positive 99m Tc-DPD scintigraphy was found in patients without echocardiographic findings consistent with heart hypertrophy, and endomyocardial biopsies confirmed the presence of ATTR amyloid. ...
... There were no statistically significant differences between numbers of males and females with type A amyloid fibrils (54% versus 68% respectively [p ¼ 0.30]) or regarding IVSD thickness between the genders (14 [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] versus 13 [9-23] mm respectively; p ¼ 0.5). When analysing differences between transplanted and non-transplanted patients, transplanted patients were younger (59 versus 69 [40-83] years; p ¼ 0.03) and had a longer disease duration (7 [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] versus 2 [0-11] years; p50.01), but the IVSD thickness was not different (12 [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] versus 14 [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] ...
... There were no statistically significant differences between numbers of males and females with type A amyloid fibrils (54% versus 68% respectively [p ¼ 0.30]) or regarding IVSD thickness between the genders (14 [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] versus 13 [9-23] mm respectively; p ¼ 0.5). When analysing differences between transplanted and non-transplanted patients, transplanted patients were younger (59 versus 69 [40-83] years; p ¼ 0.03) and had a longer disease duration (7 [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] versus 2 [0-11] years; p50.01), but the IVSD thickness was not different (12 [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] versus 14 [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] ...
Aims
In transthyretin amyloid (ATTR) amyloidosis various principal phenotypes have been described: cardiac, neuropathic, or a mixed cardiac and neuropathic. In addition, two different types of amyloid fibrils have been identified (type A and type B). Type B fibrils have thus far only been found in predominantly early-onset V30M and in patients carrying the Y114C mutation, whereas type A is noted in all other mutations currently examined as well as in wild-type ATTR amyloidosis. The fibril type is a determinant of the ATTR V30M disease phenotype. 99mTc-DPD scintigraphy is a highly sensitive method for diagnosing heart involvement in ATTR amyloidosis. The objective of this study was to determine the relationship between ATTR fibril composition and 99mTc-DPD scintigraphy outcome in patients with biopsy-proven ATTR amyloidosis.
Methods
Altogether 55 patients with biopsy-proven diagnosis of ATTR amyloidosis and amyloid fibril composition determined were examined by 99mTc-DPD scintigraphy. The patients were grouped and compared according to their type of amyloid fibrils. Cardiovascular evaluation included ECG, echocardiography, and cardiac biomarkers. The medical records were scrutinized to identify subjects with hypertension or other diseases that have an impact on cardiac dimensions.
Results
A total of 97% with type A and none of the patients with type B fibrils displayed 99mTc-DPD uptake at scintigraphy (p < 0.001). Findings from analyses of cardiac biomarkers, ECG, and echocardiography, though significantly different, could not differentiate between type A and B fibrils in individual patients.
Conclusion
In ATTR amyloidosis, the outcome of 99mTc-DPD scintigraphy is strongly related to the patients’ transthyretin amyloid fibril composition.
... Perugini score 3 in patient with ATTR-CM non-amyloidotic forms of cardiomyopathies with a hypertrophic phenotype where the uptake of myocardial tracer is minimal or nonexistent25,26 . ...
Two main types of cardiac amyloidosis (CA) exist, as a result of either aberrant plasma cell production of misfolded monoclonal light chains, known as immunoglobulin light chain amyloidosis (AL), or production of disintegrated and misfolded transthyretin (TTR) proteins by the liver, also called transthyretin amyloidosis (ATTR). Non-invasive (cardiac uptake on disphosphonate scintigraphy (Perugini score 2 or 3) has gained primacy in modern cardiology in relation with negative serum free light chain and negative serum and urinary immunofixation with echocardiographic or cardiac magnetic resonance criteria) is related to diagnostic modality of ATTR-cardiomyopathy (CM). A total of 3063 99mTc-MDP bone scintigrams were analyzed between August 2018 and March 2023, of which Perugini score 1 was validated in 13 patients, Perugini score 2 in 10 patients and Perugini score 3 in 1 patient. From our experience, we could observe that cardiac uptake can be verified in daily clinical practice and that is meaningful for monitoring patients with ATTR-CM. Although the sample is not large, the importance relies on the fact that these are patients whose findings were incidentally verified, and if the diagnosis is narrowed down, the number will potentially be increased. The goal of the healthcare system is to raise awareness regarding the diagnostic algorithm of infiltrative cardiomyopathies, with the aim of early recognition and earlier treatment through a multidisciplinary approach, because treatment is of utmost relevance at that stage. A meticulous diagnostic and therapeutic approach is therefore fundamental for improving clinical outcomes in patients with ATTR-CM, including careful attention to specific TTR genetic variants and longterm follow-up.
Keywords. Amyloidosis, Cardiomyopathies, Transthyretin amyloid cardiomyopathy, Radionuclide Imaging
... In our patient, we cannot exclude the possibility that the presence of LV segmental wall-motion abnormalities on the first echocardiogram could be secondary to obstructive microvascular amyloidosis, although this involvement was not apparent in the analysed tissue fragment. Myocardial uptake was negative in 99mTc-DPD scintigraphy, a result similar to that found in ApoAII-related disease but dissimilar to the ApoAI amyloidosis reported case [7,8] . As far as we know, this is the first report of the use of 99mTc-DPD scintigraphy in a patient with amyloidotic cardiomyopathy due to AApoAIV amyloidosis. ...
Amyloidosis is a group of disorders characterised by the accumulation of extracellular deposits of insoluble protein aggregates. Clinical management depends on the accurate identification of the amyloid precursor and underlying cause. We describe a rare case of apolipoprotein A-IV cardiac amyloidosis, the diagnosis of which required mass spectrometry-based proteomic analysis.
Learning points:
To be able to perform the differential diagnosis of cardiac amyloidosis subtypes using imaging methods, analytical results and tissue analysis.To recognise the added value of mass spectrometry (MS)-based proteomic analysis.
... however, neither clinical nor genetic information was provided. 28 Although no clinical evidence of extrarenal involvement was demonstrated in our or other reports of AApoAII amyloidosis, 14,15,26,27 extrarenal amyloid deposits were found either accidentally or at postmortem evaluation (Table 2). Autopsy results from the 78Glyext21 series revealed modest deposits in multiple organs from 2 individuals. ...
Here, we report a family with renal amyloidosis associated with a novel stop codon mutation in APOA2 and the apoA-II variant, 78Leuext21.
... Interestingly, authors reported that when only patients with suspected TTR-related amyloidosis were considered, accuracy reached 100%. Longhi et al. showed cardiac DPD accumulation in cases with mutated TTR, wild-type TTR, and apolipoprotein A-I amyloidosis, and no uptake in patients affected by AL and apolipoprotein A-II amyloidosis [43]. Furthermore, in a study enrolling 21 Australian patients, Moore et al. found 25% of AL patients and 100% of TTR patients showing radiotracer uptake; both grade of myocardial DPD accumulation and H/WB ratio were higher in TTR amyloidosis patients [44]. ...
Purpose
Cardiac amyloidosis is a rare and still underdiagnosed disease leading a poor prognosis. We reviewed the literature regarding non-invasive imaging of cardiac amyloidosis (i.e., echocardiography, magnetic resonance, and nuclear medicine imaging) with special attention to the clinical contribution of bone-seeking radiotracers.
Methods
We performed a PubMed and Scopus literature search using keywords related to imaging of cardiac involvement in systemic amyloidosis. In particular, a review of studies published in the English literature between 2002 and 2017 dealing with clinical contribution of in vivo nuclear medicine imaging using bone-seeking radiotracers has been performed; studies that do not clearly report final diagnoses have been excluded.
Results
Interest for cardiac amyloidosis imaging has raised in the last years; in particular, about 20 recent studies evaluating imaging with bone-seeking radiotracers have been considered for the review. Echocardiography represents the first imaging approach, although its sensitivity (in the early stage) and specificity are limited. Magnetic resonance imaging can show highly suggestive signs for cardiac amyloidosis. Imaging with bone-seeking radiotracers has high accuracy in revealing cardiac amyloidosis etiology—both sensitivity and specificity reach 100% in selected groups of patients—and performs better than other imaging modalities in revealing the early cardiac amyloidosis. PET radiotracers’ contribution is still under investigation.
Conclusions
Imaging can aid in differentiating cardiac amyloidosis from other diseases providing prognostic information. Bone-seeking radiotracers can establish the type of amyloidosis, even without performing biopsy, in a large part of patients, and are able to early detect cardiac involvement in subjects with transthyretin gene mutations.
... however, neither clinical nor genetic information was provided. 28 Although no clinical evidence of extrarenal involvement was demonstrated in our or other reports of AApoAII amyloidosis, 14,15,26,27 extrarenal amyloid deposits were found either accidentally or at postmortem evaluation (Table 2). Autopsy results from the 78Glyext21 series revealed modest deposits in multiple organs from 2 individuals. ...
... All these Various form of amyloidosis exists and in each one the myocardial involvement is variable. When the suspicion of cardiac amyloidosis is present other diagnostic techniques can be used: cardiac MRI [86][87][88] and 99mTc-DPD scan [89][90][91] are sensitive test for the detection, characterization and differentiation of forms of cardiac amyloidosis. The 99mTc-DPD scan is an exquisite test for the transthyretin-related amyloidosis (ATTR) diagnosis, far less sensitive in AL amyloidosis. ...
Cardiomyopathies are little known to internists and general practitioners (GPs), and not always able to arouse the interest of cardiologists. Probably, this happens because cardiomyopathies are perceived as rare and complex disorders, a prerogative of a few dedicated centers. This may partly explain why the diagnosis of cardiomyopathy is often missed and, consequently, why cardiomyopathies are largely underdiagnosed. Internists and general practitioners should have an interest in these conditions, because cardiomyopathies are not as rare as generally perceived, and because their complexity can be unravelled with knowledge and methodology. Cardiomyopathies are defined as myocardial disorders in which the heart is structurally and functionally abnormal in the absence of coronary artery disease or abnormal loading conditions. Irrespective of the cardiac imaging technique used, a limited number of phenotypes are defined based on ventricular morphology and function. These basic phenotypes include hypertrophic, dilated, restrictive and right ventricular arrhythmogenic cardiomyopathies. Aim of this review is to describe a simplified approach to the detection of the underlying causes of specific phenotypes. We will focus our attention on the basic phenotypes, presenting a diagnostic work-up and a suggestive clinical case for each phenotype.
Heart failure is a progressive disease, representing a growing cause of morbidity, hospitalization and mortality. An increasingly common type of heart failure with preserved ejection fraction (HFpEF) is the immunoglobulin light chain and transthyretin cardiac amyloidosis, in the pathophysiology of which oxidative damage appears to exert a strong impact. Reactive oxygen and nitrogen species have physiological signaling functions, but their overaccumulation, as in cardiac amyloidosis, leads to cardiomyocyte damage and apoptosis, and to cardiac hypertrophy and fibrosis. Moreover, such pathological processes worsen the redox damage with the perpetuation of an inflammatory state, in a vicious cycle. Here reviewed are the role of oxidative damage in the transthyretin and immunoglobulin light chain cardiac amyloidosis, the underlying pathogenic mechanisms, the therapeutic implications and possible future strategies.
Light chain amyloidosis needs to be considered in the differential diagnosis of patients with nondiabetic nephrotic range proteinuria, unexplained fatigue or heart failure with preserved ejection fraction, a progressive peripheral neuropathy associated with a monoclonal protein, or atypical multiple myeloma. Screening involves serum and urine immunofixation and an immunoglobulin free light chain assay. Most patients can have the diagnosis established via biopsy of the bone marrow and subcutaneous fat. Visceral organ biopsy is rarely needed. The prognosis is determined by the DFLC, the levels of cardiac biomarkers, troponin and BNP. Therapy includes high-dose chemotherapy; and for patients ineligible for high-dose chemotherapy, bortezomib appears to be the single most active agent. Combinations of bortezomib and the inclusion of monoclonal antibodies are the subject of further studies.
Systemic amyloidoses are rare, complex diseases caused by misfolding of autologous protein. The presence of heart involvement is the most important prognostic determinant. The diagnosis of amyloid cardiac involvement relies on echocardiography and magnetic resonance imaging, while scintigraphy with bone tracers is helpful in differentiating light chain amyloidosis from other types of amyloidosis involving the heart. Although these diseases are fatal, effective treatments exist that can alter their natural history, provided that they are started before irreversible cardiac damage has occurred. Refined diagnostic techniques, accurate patients' stratification based on biomarkers of cardiac dysfunction, the availability of novel, more powerful drugs, and ultimately, the unveiling of the cellular mechanisms of cardiac damage created a favorable environment for a dramatic improvement in the treatment of this disease that we expect in the next few years.
We investigated the diagnostic accuracy of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy for differentiation of monoclonal immunoglobulin light-chain (AL) and transthyretin (TTR)-related cardiac amyloidosis.
Differential diagnosis between TTR-related and AL amyloidosis is often complex and time-consuming.
Patients under routine observation with TTR-related/AL systemic amyloidosis and echocardiographic evidence of cardiac involvement were studied with 99mTc-DPD scintigraphy.
Patients with cardiac involvement of TTR-related (group A; n = 15) and AL (group B; n = 10) etiology were comparable for left ventricular mass and renal function. Heart and heart/whole-body tracer retention were significantly higher (p < 0.05) in group A as compared with group B and with 10 unaffected controls. At visual scoring, cardiac 99mTc-DPD uptake was present in all group A patients and absent in all group B patients; thus, using genotyping/immunohistochemistry as the reference technique, the accuracy of 99mTc-DPD scintigraphy for distinction of TTR-related and AL etiology was 100%. Cardiac 99mTc-DPD uptake was also absent among unaffected controls. Using echocardiography as the reference standard for recognition of cardiac involvement, sensitivity and specificity of scintigraphy were both 100% for group A patients; in group B, sensitivity was 0% and specificity was 100% (accuracy, 50%). Eleven patients with myocardial 99mTc-DPD uptake underwent 99mTc-methylene diphosphonate (99mTc-MDP) scintigraphy; all patients showed a 99mTc-MDP myocardial visual score of 0.
Etiology is a third major cause--in addition to type of organ-involved (soft-tissue/heart) and tracer type--of scintigraphic variability in cardiac amyloidosis. This is a highly relevant consideration for future studies. We conclude that 99mTc-DPD scintigraphy is a useful step in the workup of the differential diagnosis of TTR versus AL etiology in patients with documented cardiac amyloidosis.
Abstract Amyloidotic cardiomyopathy is still a widely underdiagnosed condition that usually requires endomyocardial biopsy (EMB) for a definite diagnosis. (99m)Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ((99m)Tc-DPD) has proven highly sensitive for detecting amyloidotic cardiomyopathy due to transthyretin-related amyloid deposition. Herein we report the first description of the (99m)Tc-DPD scintigraphy profile in a patient with suspected amyloidotic cardiomyopathy and a final EMB- and genetically-proven diagnosis of familial apolipoprotein AI amyloidosis due to Leu174Ser variant. Abbreviations: AL: light-chain associated amyloidosis; ApoAI: apolipoprotein AI; ATTR: hereditary transthyretin-related amyloidosis; EMB: endomyocardial biopsy; HCM: hypertrophic cardiomyopathy; HR: heart retention; H/WB: heart/whole-body retention ratio; LV: left ventricular; SPECT: single-photon emission computed tomography; SSA: senile systemic amyloidosis; (99m)Tc-DPD: (99m)Tc-3,3-diphosphono-1,2-propanodicarboxylic acid; TDI: tissue Doppler imaging; TTR: transthyretin.
Senile systemic amyloidosis (SSA) is a cardiomyopathy mainly affecting elderly men due to intramyocardial deposition of wild-type (nonmutant) transthyretin (TTR) ([1][1]). Since the heart is the only involved organ, SSA—which requires endomyocardial biopsy (EMB) for a definite diagnosis—is often
The phenotype of hereditary apolipoprotein A-I amyloidosis is heterogeneous with some patients developing extensive visceral amyloid deposits and end-stage renal failure as young adults and others having only laryngeal and/or skin amyloid, which may be of little clinical consequence. Clinical management and prognosis of patients with systemic amyloidosis depend entirely on correct identification of the fibril protein, such that light chain amyloidosis (AL, previously referred to as "primary"), the most frequently diagnosed type, is treated with chemotherapy, which has absolutely no role in hereditary apolipoprotein A-I amyloidosis. We report five novel apolipoprotein A-I variants, four of which were amyloidogenic and one of which was incidental in a patient with systemic AL amyloidosis. Interestingly, only one of four patients with apolipoprotein A-I amyloidosis had a family history of similar disease. Laser microdissection and tandem mass spectrometry-based proteomics were used to confirm the amyloid fibril protein and, for the first time in apolipoprotein A-I amyloidosis, demonstrated that only mutated protein as opposed to wild-type apolipoprotein A-I was deposited as amyloid. The clinical spectrum and outcome of hereditary apolipoprotein A-I amyloidosis are reviewed in detail and support the need for sequencing of the apolipoprotein A-I gene among patients with apparent localized amyloidosis in whom IHC is nondiagnostic of the fibril protein, even in the absence of a family history of disease.
We previously reported in a small series of patients that (99m)Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ((99m)Tc-DPD) scintigraphy tested positive in transthyretin-related (TTR) (both mutant and wild-type) but not in primary (AL) amyloidotic cardiomyopathy (AC). We extended our study to a larger cohort of patients with AC.
We evaluated (1) 45 patients with TTR-related AC (28 mutant and 17 wild-type), (2) 34 with AL-related AC and (3) 15 non-affected controls. Myocardial uptake of (99m)Tc-DPD (740 MBq i.v.) was semiquantitatively and visually assessed at 5 min and at 3 h.
Heart retention (HR) and heart to whole-body retention ratio (H/WB) of late (99m)Tc-DPD uptake were higher among TTR-related AC (HR 7.8%; H/WB 10.4) compared with both unaffected controls (HR 3.5%; H/WB 5.7; p < 0.0001) and AL-related AC (HR 4.0%; H/WB 6.1; p < 0.0001). For the diagnosis of TTR-related AC, positive and negative predictive accuracy of visual scoring of cardiac retention were: 80 and 100% (visual score ≥1); 88 and 100% (visual score ≥2); and 100 and 68% (visual score = 3). At adjusted linear regression analysis, TTR aetiology turned out to be the only positive predictor of increasing (99m)Tc-DPD uptake in terms of both HR [β 2.5, 95% confidence interval (CI) 1.5-3.5; p < 0.0001] and H/WB (β 3.5, 95% CI 2.1-4.9; p < 0.0001).
While (99m)Tc-DPD scintigraphy was confirmed to be useful for differentiating TTR from AL-related AC, diagnostic accuracy was lower than previously reported due to a mild degree of tracer uptake in about one third of AL patients. (99m)Tc-DPD scintigraphy can provide an accurate differential diagnosis in cases of absent or intense uptake evaluated by visual score.
Familial amyloidotic polyneuropathy (FAP) caused by amyloidogenic transthyretin (ATTR) mutations is the most common form of hereditary amyloidosis. We investigated the diagnostic value of the bone scanning agent technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) in this disease. Eight patients (four males, four females; age 54.4+/-8.3 years, range 43-67 years) with ATTR-FAP proven by immunohistochemistry and molecular analysis and a control group comprising ten oncological out-patients (five males, five females; age 53.4+/-8.5 years, range 34-66 years) without evidence of bony metastases were studied using 99mTc-DPD. Whole body tracer retention was 80.1%+/-10.3% (range 65.1%-94.8%) in FAP patients and 55.7%+/-8.1% (range 40.2%-66.7%) in controls at 3 h p.i. (P<0.001), and cardiac uptake was 7.3%+/-2.2% (range 4.2%-10.1%) in FAP patients and 3.1%+/-0.5% (range 2.3%-4.0%) in controls (P<0.001). The heart/whole body uptake ratio was 8.9%+/-1.7% (range 6.5%-11.0%) in FAP patients and 5.6%+/-0.5% (range 5.1%-6.8%) in controls (P<0.001). The three FAP patients with the highest cardiac tracer uptake had cardiomyopathy or arrhythmia. 99mTc-DPD scintigraphy is proposed as a simple and valuable diagnostic aid to evaluate the severity of the disease and the risk of concomitant heart problems.
Mutations in a number of plasma proteins, including transthyretin, apolipoprotein AI, fibrinogen Aalpha-chain, lysozyme, and apolipoprotein AII, are associated with hereditary systemic amyloidosis. Transthyretin amyloidosis is the most common and is usually associated with peripheral neuropathy. Mutations in the other proteins usually have no neuropathic consequences and, instead, cause principally renal and cardiac amyloidosis. Only the apolipoprotein AI glycine 26 arginine mutation may cause peripheral neuropathy and then in only some of the kindreds with this disease. This review is concerned with the non-neuropathic hereditary systemic amyloidoses. It strives to present a synopsis of the present day knowledge of these diseases including each feature of each precursor protein and its mutations; the clinical phenotype of the disease; and suggestions for treatment when feasible. The main objective is to increase awareness of these autosomal dominant diseases, enhance the chances of early diagnosis, enhance the physician's and subsequently the patient's knowledge of each disease, and finally emphasize the need for more research to find ways to treat or prevent these diseases.
Apolipoprotein A-I, the major structural apolipoprotein of high-density lipoproteins, efficiently protects humans from cholesterol accumulation in tissues; however, it can cause systemic amyloidosis in the presence of peculiar amino acid replacements. The wild-type molecule also has an intrinsic tendency to generate amyloid fibrils that localise within the atherosclerotic plaques. The structure, folding and metabolism of normal apolipoprotein A-I are extremely complex and as yet not completely clarified, but their understanding appears essential for the elucidation of the amyloid transition. We reviewed present knowledge on the structure, function and amyloidogenic propensity of apolipoprotein A-I with the aim of highlighting the possible molecular mechanisms that might contribute to the pathogenesis of this disease. Important clues on apolipoprotein A-I amyloidogenesis may be obtained from classical comparative studies of the properties of the wild-type versus the amyloidogenic counterpart. Additionally, in the case of apoA-I, further insights on the molecular mechanisms underlying its amyloidogenic propensity may derive from comparative studies between amyloidogenic variants and other mutations associated with hypoalphalipoproteinemia without amyloidosis.
From the *Cardiology Unit, and †Nuclear Medicine Unit, Department of Experimental , Diagnostic and Specialty Medicine–DIMES
Received for publication July 9, 2014; revision accepted January 8, 2015.
From the *Cardiology Unit, and †Nuclear Medicine Unit, Department of Experimental, Diagnostic and Specialty Medicine–DIMES, Alma Mater Studiorum, University of Bologna, Bologna; and ‡Amyloidosis Research and Treatment Center,
Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
Conflicts of interest and sources of funding: none declared.
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ISSN: 0363-9762/15/0000–0000