Author + information
- Received May 10, 2018
- Revision received July 23, 2018
- Accepted July 26, 2018
- Published online October 15, 2018.
- Brett W. Sperry, MDa,b@BrettSperryMD,
- Bryan A. Reyes, MDc,
- Asad Ikram, MBBSa,
- Joseph P. Donnelly, MDa,
- Dermot Phelan, MD, PhDa,
- Wael A. Jaber, MDa,
- David Shapiro, MDc,
- Peter J. Evans, MD, PhDc,
- Steven Maschke, MDc,
- Scott E. Kilpatrick, MDd,
- Carmela D. Tan, MDd,
- E. Rene Rodriguez, MDd,
- Cecilia Monteiro, MDe,
- W.H. Wilson Tang, MDa,
- Jeffery W. Kelly, PhDe,
- William H. Seitz Jr., MDc and
- Mazen Hanna, MDa,∗ (, )@maz_hanna@ClevelandClinic
- aDepartment of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
- bMid America Heart Institute, Saint Luke’s Hospital, Kansas City, Missouri
- cDepartment of Orthopaedic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio
- dDepartment of Pathology, Cleveland Clinic Foundation, Cleveland, Ohio
- eDepartments of Chemistry and Molecular Medicine, The Scripps Research Institute, La Jolla, California
- ↵∗Address for correspondence:
Dr. Mazen Hanna, Cleveland Clinic, 9500 Euclid Avenue, J3-4, Cleveland, Ohio 44195.
Background Patients with cardiac amyloidosis often have carpal tunnel syndrome that precedes cardiac manifestations by several years. However, the prevalence of cardiac involvement at the time of carpal tunnel surgery has not been established.
Objectives The authors sought to identify the prevalence and type of amyloid deposits in patients undergoing carpal tunnel surgery and evaluate for cardiac involvement. The authors also sought to determine if patients with soft tissue transthyretin (TTR) amyloid had abnormal TTR tetramer kinetic stability.
Methods This was a prospective, cross-sectional, multidisciplinary study of consecutive men age ≥50 years and women ≥60 years undergoing carpal tunnel release surgery. Biopsy specimens of tenosynovial tissue were obtained and stained with Congo red; those with confirmed amyloid deposits were typed with mass spectrometry and further evaluated for cardiac involvement with biomarkers, electrocardiography, echocardiography with longitudinal strain, and technetium pyrophosphate scintigraphy. Additionally, serum TTR concentration and tetramer kinetic stability were examined.
Results Of 98 patients enrolled (median age 68 years, 51% male), 10 (10.2%) had a positive biopsy for amyloid (7 ATTR, 2 light chain [AL], 1 untyped). Two patients were diagnosed with hereditary ATTR (Leu58His and Ala81Thr), 2 were found to have cardiac involvement (1 AL, 1 ATTR wild-type), and 3 were initiated on therapy. In those patients who had biopsy-diagnosed ATTR, there was no difference in plasma TTR concentration or tetramer kinetic stability.
Conclusions In a cohort of patients undergoing carpal tunnel release surgery, Congo red staining of tenosynovial tissue detected amyloid deposits in 10.2% of patients. Concomitant cardiac evaluation identified patients with involvement of the myocardium, allowing for implementation of disease-modifying therapy. (Carpal Tunnel Syndrome and Amyloid Cardiomyopathy; NCT02792790)
Amyloidoses are a group of protein misfolding disorders in which 1 of 35 distinct proteins pathologically misfolds and aggregates extracellularly as insoluble amyloid fibrils, ultimately leading to organ dysfunction. Each precursor protein defines the amyloid subtype, which determines the organs involved. Immunoglobulin light chain (AL) and transthyretin (ATTR) are the 2 primary protein types which deposit in the myocardium, ultimately leading to symptomatic heart failure and death (1).
Transthyretin (TTR), also called prealbumin, is predominantly a liver-secreted protein that circulates as a tetramer and is a known carrier for thyroxine and holo-retinol binding protein. In both the wild-type sporadic form (formerly called senile systemic amyloidosis) and in the mutant hereditary form (termed familial amyloid cardiomyopathy), the disease is thought to be linked to tetramer dissociation into folded monomers. This is considered the rate limiting step of the ATTR amyloidogenesis cascade. TTR monomers then partially misfold, leading to the formation of non-native oligomers and amyloid fibrils (2). A subunit exchange assay has been developed to assess the kinetic stability of the TTR tetramer in human plasma (3).
In addition to deposition in the myocardium, a significant proportion of patients with ATTR have deposition in soft tissue structures leading to spinal stenosis, biceps tendon rupture, and carpal tunnel syndrome. Carpal tunnel syndrome is frequently bilateral and typically manifests 5 to 10 years prior to cardiac diagnosis, often requiring carpal tunnel release surgery. Carpal tunnel syndrome in AL is less common (4), but similarly tends to precede overt cardiac disease. Amyloid deposits have been found in the flexor tenosynovium and transverse carpal ligament of the hand (5–9), raising the potential for early diagnosis prior to the development of cardiac symptoms (Central Illustration). However, the prevalence of cardiac involvement at the time of carpal tunnel surgery has not been established.
We sought to determine the prevalence and type of amyloid deposits in the tenosynovium of patients undergoing carpal tunnel release surgery and to investigate whether simultaneous cardiac involvement could be identified using biomarkers and advanced cardiac imaging. Additionally, we examined measured native TTR plasma concentration and tetramer kinetic stability using a subunit exchange assay with the hypothesis that those diagnosed with ATTR amyloidosis would have less stable tetramers.
This was a prospective, cross-sectional study in which consecutive patients undergoing carpal tunnel release by participating surgeons were screened for inclusion between May 2016 and May 2017. Four orthopedic hand surgeons participated in the study operating out of 6 surgical facilities in the Cleveland Clinic health system. Men age ≥50 years and women ≥60 years were included. Patients were excluded if they had a known diagnosis of amyloidosis or had carpal tunnel syndrome thought to be secondary to trauma or rheumatoid arthritis. The Institutional Review Board of the Cleveland Clinic approved this study. The research protocol was discussed with patients in person by the surgical team or via telephone by the study staff prior to the surgical date. Patients who agreed to participate were enrolled, and all patients provided written informed consent prior to surgery.
Sample collection, surgical procedure, and cardiac evaluation
Enrolled patients had a blood sample collected on the day of surgery. Open carpal tunnel release was performed in all patients. After transection of the transverse carpal ligament, the median nerve and flexor tendons were protected, and a small sample of tenosynovium was excised. The tenosynovium was then formalin fixed, processed routinely, and subsequently evaluated by hematoxylin and eosin and Congo red staining by Cleveland Clinic pathologists. Biopsy specimens with confirmed amyloid deposits via Congo red staining were further analyzed using mass spectrometry for subtyping. If there was insufficient tissue for mass spectrometry, immunohistochemistry was attempted for subtyping. Biopsy was not performed in cases with minimal visible tenosynovium or when disruption of adjacent neural or vascular architecture posed an increased risk to the patient.
Patients with evidence of amyloid deposition in tenosynovial tissue were further evaluated for cardiac involvement with a comprehensive physical examination, electrocardiography (ECG), N-terminal pro–B-type natriuretic peptide (NT-proBNP), troponin T, echocardiography with longitudinal strain imaging, and technetium pyrophosphate (TcPYP) nuclear scintigraphy. ECGs were reviewed for each patient to identify characteristics suggestive of cardiac amyloidosis including different degrees of heart block, low limb voltage (<5 mm in all limb leads), low Sokolow voltage, and presence of a pseudoinfarct pattern (10).
Echocardiography was performed using Vivid 7 or 9 ultrasound systems (GE Medical, Milwaukee, Wisconsin), and parameters including longitudinal strain were analyzed as previously described using EchoPAC software version 113 (Advanced Analysis Technologies, GE Medical Systems) (11,12). 99m-TcPYP scintigraphy was performed after patients received 20 mCi ± 10% of TcPYP intravenously, and images were obtained after a 1-h and 3-h uptake delay as previously described (13,14). Single-photon emission computer tomography and planar images were acquired with Siemens Symbia T6 cameras (Siemens Medical Solutions, Flanders, New Jersey), and images were analyzed using 4DM software (INVIA, Ann Arbor, Michigan) by 2 experienced readers (B.W.S. and W.A.J.) blinded to clinical and echocardiographic data. A semi-quantitative score as well as heart-to-contralateral lung ratio were calculated based upon planar images (13).
Measurement of native TTR in plasma
Native TTR tetramer levels in plasma were quantified using a Waters Acquity H-Class Bio-UPLC (Ultra-Performance Liquid Chromatography) instrument using a Waters Protein-Pak Hi Res Q ion exchange column (strong anion exchanger, 5-μm particle size, 4.6 × 100-mm column). A standard curve was prepared using recombinant wild-type TTR (15) at concentrations of 10 μmol/l, 5 μmol/l, 2.5 μmol/l, and 1 μmol/l in standard phosphate buffer. The freshly prepared standard curve samples and patient samples (9 μl) were incubated with 1 μl of the fluorogenic small molecule A2 (500 μmol/l) (16) for 3 h at room temperature. After incubation, the samples were injected into the ion exchange column and separated using a linear 24% to 29% buffer B gradient over 10 min (flow 0.5 ml/min, buffer A: 25 mmol/l Tris pH 8; buffer B: same as buffer A, but with 1 mol/l NaCl added). The TTR–(A2)2 fluorescent conjugate peak (excitation 328 nm emission 430 nm; elution time = 6 min) was integrated, and the concentration of TTR in patient samples was quantified using the standard curve.
Plasma-TTR subunit exchange assay to assess kinetic stability
Subunit exchange rates were determined as described previously (3) with the following minor modifications. FT2-WT-TTR (2 μl of a 40-μmol/l solution) was added to the plasma samples (38 μl) to afford a final FT2-WT-TTR concentration of 2 μmol/l. The samples were incubated at 25°C for 48 h to allow subunit exchange to occur. At 48 h, the reaction was stopped by the addition of the fluorogenic small molecule A2 at a final concentration of 500 μmol/l. The samples were incubated with A2 for at least 3 h to allow complete covalent labeling of TTR, before being injected into the ion exchange column and separated using the same gradient as described previously (3,17). The rate of exchange for all subunit exchange experiments was calculated using peak 1, as previously described (3).
Continuous variables are expressed as median (interquartile range [IQR]) and analyzed by the Wilcoxon rank-sum test. Categorical variables are expressed as n (%) and compared by the Fisher exact test. All analyses used double-sided p values, and <0.05 was considered statistically significant. Statistical analyses were performed using Stata 13.1 software (StataCorp LP, College Station, Texas) and GraphPad Prism 7 (GraphPad Software, La Jolla, California).
A total of 319 consecutive patients underwent carpal tunnel release between May 2016 and May 2017 by participating orthopedic surgeons. An overview of study enrollment is seen in Figure 1. Of 200 eligible patients, 98 were enrolled and biopsied. There were no procedural complications. Demographics, medical history, and results of laboratory testing are seen in Table 1 for the enrolled cohort. The mean age was 68 years, and 85% of patients had bilateral symptoms. Ten patients (10.2%; 95% confidence interval: 5% to 18%) were found to have amyloid in the tenosynovial biopsy after Congo red staining. Mass spectrometry was used to diagnose 7 patients with ATTR and 2 patients with AL.
Patients with amyloid-positive biopsies were more likely to have prior carpal tunnel release surgery. All 10 patients with amyloid-positive biopsies had either symptoms of bilateral carpal tunnel syndrome or a previous contralateral carpal tunnel release. A total of 6 of 10 patients had a history of intervention for trigger finger, and 6 had a history of lumbar spinal stenosis (4 ATTR, 2 AL), 3 of whom required surgery. A history of biceps tendon rupture was seen in 2 patients (both ATTR: 1 wild-type and 1 hereditary). A monoclonal protein was detected on serum immunofixation in 4 patients with biopsy-confirmed ATTR.
Tables 2 and 3⇓⇓ detail the cases of amyloid found in the carpal tunnel and the subsequent cardiac evaluation. Of the 10 patients with amyloid, 2 were diagnosed with cardiac involvement. Of note, no patients met criteria for an apical sparing pattern on echocardiography (18).
Patient #4 had AL amyloidosis of the lambda subtype with evidence of cardiac involvement based on echocardiography showing increased septal wall thickness to 1.3 cm, an elevated NT-proBNP and troponin T, and a physical examination consistent with heart failure. She was treated with dexamethasone, cyclophosphamide, and bortezomib. After 5 months of treatment, she had achieved a complete hematologic response with normalized lambda light chains. NT-proBNP decreased from 1,615 to 161 pg/ml, and the patient went from New York Heart Association functional class III to I symptoms. Patient #3 had no M protein and only a mildly elevated kappa level, but had kappa light chain deposits in the carpal tunnel. Patient #5 had ATTR amyloidosis with no mutation on TTR genetic testing consistent with the diagnosis of wild-type disease. Although he did not have signs or symptoms of heart failure and the ECG was normal, echocardiography did reveal increased septal wall thickness (1.3 cm) with borderline abnormal global longitudinal strain. Evidence of ATTR cardiac amyloidosis was confirmed by TcPYP nuclear scintigraphy showing grade 3 diffuse myocardial uptake (Figure 2). He was placed on diflunisal, a TTR stabilizer that slows ATTR polyneuropathy progression based on a randomized placebo-controlled trial (19). Patient #9 had TTR amyloid deposits in the tenosynovium and evidence of heart failure on examination, but TcPYP scintigraphy was not consistent with cardiac amyloidosis of the ATTR type. It was felt that he most likely had diastolic heart failure from hypertension and obesity and was treated with a loop diuretic. Patient #8 was not able to be subtyped due to an insufficient tissue sample to complete mass spectrometry or immunohistochemistry. The patient had no M protein on immunofixation of the serum and urine nor on serum protein electrophoresis. Despite initially having a mildly abnormal free light chain ratio, subsequent assays showed a normal ratio. A hematology consult was obtained and it was agreed the overall findings were not consistent with AL amyloidosis, and she was presumed to have ATTR.
Two patients were found to harbor known mutations in the TTR gene. Patient #1 was diagnosed with hereditary ATTR based on TTR genetic testing, which revealed a heterozygous Ala81Thr mutation that is known to cause late-onset cardiac amyloid. She had no evidence of heart involvement based on normal biomarkers, ECG, echocardiogram (septum 0.9 cm), and no cardiac uptake on TcPYP scan. Patient #6 was diagnosed with hereditary ATTR due to a Leu58His mutation, which has been described as familial amyloid polyneuropathy type 2 of Maryland/German type (20). Upon further questioning, his family originated in Maryland (of German descent), and several relatives had a history of progressive neuropathy. Although he had no cardiac involvement, the patient did complain of mild neuropathic symptoms in his lower extremities. He was referred to a neurologist who confirmed the diagnosis of a small fiber axonal sensory neuropathy. Based upon these findings as well as his known pathogenic TTR mutation, he was placed on diflunisal to slow neuropathy progression. Both hereditary ATTR patients and their families were offered genetic counseling.
Native TTR plasma concentrations and kinetic stability were evaluated, with results depicted in Figure 3. Median TTR concentration was 20.33 mg/dl (IQR: 15.84 to 26.68 mg/dl) in patients with ATTR and 20.46 mg/dl (IQR: 16.26 to 24.52 mg/dl) in patients without ATTR (p = 0.757), both within normal range (Figure 3A). Of the 7 patients with TTR-derived amyloid, 6 had a less stable TTR relative to the median stability of the whole group, although no statistical differences were found between patients with or without ATTR (−4.768 per h [IQR: −4.828 to −4.566 per h] vs. −4.934 per h [IQR: −5.203 to −4.711 per h]; p = 0.117) (Figure 3B).
In this study, we found that 10.2% of men age ≥50 years and women ≥60 years undergoing carpal tunnel release surgery for idiopathic carpal tunnel syndrome had amyloid identified on tenosynovial tissue biopsy. Two patients (20% of those with amyloid) had concomitant but previously unknown cardiac amyloidosis diagnosed by a comprehensive examination and advanced cardiac imaging, leading to intervention with medical treatment. A third patient had a mutation in the TTR gene, which leads to a progressive polyneuropathy and was also treated with disease-modifying therapy. Plasma TTR concentration and TTR kinetic stability were not different between patients with amyloid-positive biopsies. Our findings are novel, as we describe the prevalence of amyloid deposition found prospectively in the tenosynovial tissue of patients undergoing carpal tunnel release in the modern era with the reference standard diagnostic modality (mass spectrometry). Additionally, concomitant cardiac evaluation at the time of soft tissue amyloid diagnosis has not previously been described. These findings point to the importance of recognizing idiopathic carpal tunnel syndrome as a possible predictor for amyloid heart disease, and the opportunity for incorporating tenosynovial tissue biopsy for early detection and diagnosis of amyloidosis in the perioperative workflow.
Amyloid cardiomyopathy is an under-recognized etiology of heart failure with preserved ejection fraction. According to an international survey, amyloidosis was initially misdiagnosed in 57% of patients with hereditary ATTR, 39% of patients with wild-type ATTR, and 43.8% of patients with AL. Time between onset of symptoms and diagnosis was >6 months in 72% of patients with AL. Notably, 44% of patients with ATTR and 81% of patients with AL visited 3 or more different physicians before receiving a correct diagnosis (21,22). Indeed, our patient #4 had known monoclonal gammopathy of undetermined significance and clinically appeared to have signs and symptoms of heart failure, which were previously unevaluated and undiagnosed. It is estimated that up to one-fourth of patients over 85 years of age have wild-type ATTR deposits (23), and 13% of those admitted with heart failure with preserved ejection fraction and LV wall thickness >1.2 cm on echocardiography have ATTR (24). In addition, ATTR is often found in patients with aortic stenosis (25), with a prevalence of 6% to 8% in all-comers (26,27) and 16% in those evaluated for transcatheter aortic valve replacement (28). As the population ages and detection mechanisms improve, cardiac amyloidosis can no longer be considered a rare entity.
In addition to deposition in the myocardium, a significant proportion of patients with amyloidosis develop fibril deposition in the flexor tenosynovium and transverse carpal ligament in the hand as well as in other areas, such as the rotator cuff, biceps tendon, and ligamentum flavum in the spine. Prior studies showed that soft tissue removed at the time of carpal tunnel surgery stained positively with Congo red in 12% to 35% of patients with idiopathic carpal tunnel syndrome (6,8,9). In these studies, only the ATTR type was noted, and genetic mutations in the TTR gene were exceedingly rare (7-9,29). These studies did not use mass spectrometry for confirmation and typing, raising the concern for false positive interpretation of Congo red staining in some cases. Two older studies described non-ATTR type amyloidosis in the carpal tunnel, with up to 16% of amyloid deposits being due to AL (5,30). The remainder were predominantly thought to have localized amyloidosis; however, these studies enrolled patients prior to the development of current diagnostic techniques for ATTR. In our cohort, 2 of the 10 patients with biopsy-diagnosed amyloidosis were found to have AL. This is not surprising, as carpal tunnel syndrome may be present in 30% of patients with AL as well (4), although not as common as in ATTR. As AL is a much more rapidly progressive disease with a poor prognosis after cardiac involvement is advanced, the early recognition of this entity is even more important to initiate appropriate disease-modifying therapy (31).
ATTR amyloid deposition in the ligamentum flavum is associated with lumbar spinal stenosis and is present in up to 45% of surgical biopsies (32). In our study, 6 of the 10 amyloid-positive patients had a history of lumbar spinal stenosis (4 ATTR, 2 AL). Three of those required surgical intervention, including the 2 patients with AL, both of whom were also afflicted by cervical spinal stenosis. Two (20%) of the amyloid-positive patients had a history of biceps tendon rupture (1 wild-type ATTR, 1 hereditary ATTR). While uncommon, biceps tendon rupture is found much more often in ATTR than in the general population, perhaps indicative that it is a more specific extracardiac finding (33).
The prevalence of cardiac involvement at the time of carpal tunnel release surgery has not previously been established. As several emerging pharmacological treatments are in development that may slow, halt, or reverse ATTR, earlier diagnosis is advantageous. Based upon several clinical trials meeting their primary endpoint, 3 new therapies have received breakthrough designation from the U.S. Food and Drug Administration, with more in the pipeline. Identification and implementation of therapy for prevention or early disease treatment may alter the natural history of this progressive systemic disease.
The native TTR concentration in our cohort was not different between patients with or without soft tissue ATTR deposition. A recent study in patients with wild-type ATTR evaluated the association between serum TTR concentration and outcomes (34), and described a median TTR concentration of 23 mg/dl (IQR: 20 to 26 mg/dl). They noted that lower TTR concentrations were associated with lower survival in a multivariable stepwise model, particularly if levels were below the lower limit of normal (18 mg/dl). As the median values for TTR concentration are similar in patients with normal biopsies, with soft tissue amyloid deposition, and with wild-type cardiac amyloidosis as noted in the previous text, it is unlikely that this marker will aid in the diagnosis of patients. Our study also quantified TTR tetramer kinetic stability with a subunit exchange assay, a biochemical assay that has been used to measure endogenous plasma and CSF TTR kinetic stability of patients treated with the kinetic stabilizer tafamidis (3,17). There was a trend toward less stable TTR tetramers in patients with ATTR; however, there was significant overlap between groups. Retinol binding protein 4 (RBP4) and potentially other proteins might play an important role in plasma TTR kinetic stability. Moreover, the absolute value of the TTR kinetic stability may be less important than the change in kinetic stability over time or with disease modifying therapies. Kinetic stability, native TTR concentration, and RBP4 levels should be tested longitudinally in a larger group of patients to determine their usefulness to noninvasively diagnose and follow ATTR.
This study along with other emerging data surrounding soft tissue amyloidosis has led to a change in practice at our institution. A screening algorithm has been implemented (Online Figure 1) to guide the hand surgeons regarding the appropriateness of tenosynovial biopsy at the time of carpal tunnel release surgery. If Congo red staining is positive, prompt typing with mass spectrometry and referral to an amyloidosis specialist is recommended. We believe that the low cost of screening patients for amyloidosis at the time of carpal tunnel release surgery may avert the expense of progressive heart failure care in patients diagnosed early.
This study was performed with an open carpal tunnel release, although some surgeons used a minimally invasive technique with a smaller incision. Obtaining a sample of tenosynovial tissue with a nonopen (endoscopic) release is more challenging and may limit application of this strategy for those surgeons who use this surgical approach. Inclusion criteria were limited to older adults given the high prevalence of both types of cardiac amyloidosis; this acknowledges a decrease in sensitivity of identifying younger patients who may be more likely to have AL. There was a limited number of African Americans in the study cohort. This was due to the demographics of patients undergoing carpal tunnel release at our institution and a higher percentage of African-American patients who declined to participate (10% African Americans in the screened cohort vs. 5% enrolled). It would be important to know the prevalence of biopsy-diagnosed carpal tunnel amyloidosis in this cohort, as it is estimated that 3% to 4% of African Americans in the United States carry the V122I TTR gene mutation, which is a known cause of hereditary cardiac amyloidosis (35). Additionally, low RBP4 levels have been shown to potentially help identify patients with V122I ATTR (36), and it has been hypothesized that TTR kinetic stability is related to the relative concentrations of RBP4 to tetrameric TTR (3); these hypotheses were not studied in this analysis. Last, the progression from soft tissue amyloidosis to the involvement of other organs over time is unknown. Long-term follow-up of this cohort may be able to shed light on the natural history of this disease and is already planned as the next phase of this study.
We demonstrate that 10.2% of a cohort of men age ≥50 years and women ≥60 years undergoing carpal tunnel release surgery for idiopathic carpal tunnel syndrome had amyloidosis diagnosed from tenosynovial tissue biopsy. Subsequent cardiac workup identified patients with both clinical and subclinical cardiac amyloid involvement of both the AL and ATTR subtypes. TTR concentration and tetramer kinetic stability were not able to classify patients with biopsy-diagnosed disease. We believe that hand surgeons should be aware of the association between carpal tunnel syndrome and amyloidosis and consider biopsy of tenosynovial tissue with subsequent Congo red staining, particularly in patients with bilateral symptoms. Tenosynovial biopsy is a low-risk procedure that may lead to early diagnosis of amyloidosis, thereby allowing for timely intervention to combat this life-threatening disease.
COMPETENCY IN MEDICAL KNOWLEDGE: One in 10 older patients undergoing carpal tunnel release surgery for idiopathic carpal tunnel syndrome have either TTR or AL amyloidosis in tenosynovial tissue, and this may be an early marker or precursor of amyloid heart disease.
TRANSLATIONAL OUTLOOK: Long-term follow-up of patients with tenosynovial amyloidosis is needed to understand the natural history, frequency of cardiac involvement, and implications for management.
This study was funded by Dr. Hanna’s Term Chair in Amyloid Heart Disease: Case Western Reserve University/Cleveland Clinic CTSA Grant Number UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCATS or NIH. Dr. Sperry has received consulting fees from GlaxoSmithKline. Dr. Monteiro has been supported by an American Heart Association Predoctoral Grant (16PRE31130009). Dr. Tang has been supported by grants from the NIH (R01HL103931) and Collins Family Fund; and has served as a consultant for the Advisory Board Company. Dr. Kelly has been supported by NIH NIDDK 046335; is a shareholder of FoldRx/Pfizer equity; and receives tafamidis royalties from Pfizer. Dr. Seitz Jr. has served as a consultant for Stryker, Zimmer/Biomet, and Kapp Surgical; and has served as an orthopedic surgery consultant. Dr. Hanna has received funding from the NCATS/NIH (UL1TR000439); and has received consulting fees from Pfizer, Ionis, and Eidos pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- immunoglobulin light chain amyloidosis
- transthyretin amyloidosis
- N-terminal pro–B-type natriuretic peptide
- technetium pyrophosphate
- Received May 10, 2018.
- Revision received July 23, 2018.
- Accepted July 26, 2018.
- 2018 American College of Cardiology Foundation
- Sperry B.W.,
- Tang W.H.W.
- Rappley I.,
- Monteiro C.,
- Novais M.,
- et al.
- Sperry B.W.,
- Vranian M.N.,
- Hachamovitch R.,
- et al.
- Senapati A.,
- Sperry B.W.,
- Grodin J.L.,
- et al.
- Vranian M.N.,
- Sperry B.W.,
- Hanna M.,
- et al.
- Sperry B.W.,
- Gonzalez M.H.,
- Brunken R.,
- Cerqueira M.D.,
- Hanna M.,
- Jaber W.A.
- Phelan D.,
- Collier P.,
- Thavendiranathan P.,
- et al.
- McCausland K.L.,
- White M.K.,
- Guthrie S.D.,
- et al.
- ↵Lousada I, Maurer MS, Warner M, Guthrie S, Hsu K, Grogan M. Amyloidosis Research Consortium cardiac amyloidosis survey: results from patients with ATTR amyloidosis and their caregivers. Poster presented at: European ATTR Amyloidosis Meeting for Patients and Doctors. Paris, France. November, 2017.
- Sperry B.W.,
- Jones B.M.,
- Vranian M.N.,
- Hanna M.,
- Jaber W.A.
- Treibel T.A.,
- Fontana M.,
- Gilbertson J.A.,
- et al.
- Cavalcante J.L.,
- Rijal S.,
- Abdelkarim I.,
- et al.
- Castaño A.,
- Narotsky D.L.,
- Hamid N.,
- et al.
- Sperry B.W.,
- Ikram A.,
- Hachamovitch R.,
- et al.
- Geller H.I.,
- Singh A.,
- Alexander K.M.,
- Mirto T.M.,
- Falk R.H.
- Hanson J.L.S.,
- Arvanitis M.,
- Koch C.M.,
- et al.
- Arvanitis M.,
- Koch C.M.,
- Chan G.G.,
- et al.