Association between spinal stenosis and wild-type ATTR amyloidosis

Godara, Amandeep; Riesenburger, Ron I.; Zhang, Diana X; Varga, Cindy; Fogaren, Teresa; Siddiqui, Nauman; Yu, Anthony; Wang, Andy; Mastroianni, Michael; Dowd, Richard S.; Nail, Tara Jayde; McPhail, Ellen D.; Kurtin, Paul J.; Theis, Jason D.; Toskic, Denis; Arkun, Knarik; Pilichowska, Monika; Kryzanski, James; Patel, Ayan R.; Comenzo, Raymond L.

doi:10.1080/13506129.2021.1950681

Cited by 27 publications

(19 citation statements)

References 32 publications

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“…Although surgical pathologic data has been mixed, 324 patients in one study underwent surgery for spinal stenosis, and 43 (13%) had ATTRwt in the ligamentum flavum, with 2 cases of confirmed cardiac involvement. 31 , 51 , 52 In a recent publication, 34% of patients undergoing spinal stenosis surgery had amyloid deposition. Unfortunately, of those with amyloid deposition, more than one-third could not be accurately typed.…”

Section: Part Iv: Opportunities For Earlier Identification Of Cardiac...mentioning

confidence: 99%

Opportunities for Earlier Diagnosis and Treatment of Cardiac Amyloidosis

Martyn

Rubio

Estep

et al. 2022

Methodist DeBakey Cardiovascular Journal

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Despite the rapid expansion of noninvasive (nonbiopsy) diagnosis, contemporary patients with cardiac amyloidosis too often present with advanced features of disease, such as diminished quality of life, elevated natriuretic peptides, and advanced heart failure. Therapeutics for transthyretin cardiomyopathy (ATTR-CM) are most effective when administered before significant symptoms of cardiac dysfunction manifest, making early identification of affected individuals of paramount importance. Community engagement and ensuring that a broad range of clinicians have working knowledge of how to screen for ATTR-CM in everyday practice will be an important step in moving disease identification further upstream. However, reliance on the appropriate and timely diagnosis by individual clinicians may continue to underperform. This review highlights how targeted screening of special populations may facilitate earlier diagnosis. Systems of care that operationalize screening of high-risk subpopulations and prospective validation of novel approaches to ATTR-CM identification are needed.

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Section: Part Iv: Opportunities For Earlier Identification Of Cardiac...mentioning

confidence: 99%

Opportunities for Earlier Diagnosis and Treatment of Cardiac Amyloidosis

Martyn

Rubio

Estep

et al. 2022

Methodist DeBakey Cardiovascular Journal

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“…4 Recent research has suggested that patients with ATTRwt amyloidosis may also present with an antecedent history of lumbar stenosis, with amyloid deposition in the LF hypothesized as possibly leading to its thickening. 3, 5-8 As ATTRwt is found in the LF of many older individuals who ultimately do not develop cardiac amyloidosis, it may be of interest outside of systemic amyloidosis as a factor in the pathophysiology of lumbar stenosis.…”

Section: Introductionmentioning

confidence: 99%

The relationship between wild-type transthyretin amyloid load and ligamentum flavum thickness in lumbar stenosis patients

Wang

Saini

Tingen

et al. 2022

Preprint

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Background: One key contributor to lumbar stenosis is thickening of the ligamentum flavum (LF), a process still poorly understood. Wild-type transthyretin amyloid (ATTRwt) has been found in the LF of patients undergoing decompression surgery, suggesting that amyloid may play a role. However, it is unclear whether within patients harboring ATTRwt, the amount of amyloid is associated with LF thickness. Methods: From an initial cohort of 324 consecutive lumbar stenosis patients whose LF specimens from decompression surgery were sent for analysis (2018-2019), 33 patients met the following criteria: (1) Congo red-positive amyloid in the LF; (2) ATTRwt by mass spectrometry-based proteomics; and (3) an available preoperative MRI. Histological specimens were digitized, and amyloid load quantified through Trainable Weka Segmentation (TWS) machine learning. LF thicknesses were manually measured on axial T2-weighted preoperative MRI scans at each lumbar level, L1-S1. The sum of thicknesses at every lumbar LF level (L1-S1) equals "lumbar LF burden." Results: Patients had a mean age of 72.7 years (range 59-87), were mostly male (61%) and white (82%); and predominantly had surgery at L4-L5 levels (73%). Amyloid load was positively correlated with LF thickness (R=0.345, p=0.0492) at the levels of surgical decompression. Furthermore, amyloid load was positively correlated with lumbar LF burden (R=0.383, p=0.0279). Conclusions: Amyloid load is positively correlated with LF thickness and lumbar LF burden across all lumbar levels, in a dose-dependent manner. Further studies are needed to validate these findings, uncover the underlying pathophysiology, and pave the way towards using therapies that slow LF thickening.

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“…1 The biological mechanism underlying degeneration in LSS has not been fully elucidated. Emerging data suggest that transthyretin (TTR) amyloidosis, characterized by deposition of the misfolded protein TTR, is age-dependent, unrecognized, and commonly present in surgical specimens (e.g., ligamentum flavum) in LSS [2][3][4][5] that may precede the development of cardiac involvement. 6,7 TTR cardiac amyloidosis (ATTR-CA) is caused by misfolded monomers of the protein TTR (also known as prealbumin) which deposit as amyloid fibrils in the myocardium causing a restrictive cardiomyopathy, atrial and ventricular arrhythmias, heart failure and premature death.…”

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Analysis of lumbar spine stenosis specimens for identification of amyloid

Maurer

Smiley

Simsolo

et al. 2022

J American Geriatrics Society

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Background Lumbar spinal stenosis (LSS) is a common reason for spine surgery in which ligamentum flavum is resected. Transthyretin (TTR) amyloid is an often unrecognized and potentially modifiable mechanism for LSS that can also cause TTR cardiac amyloidosis. Accordingly, older adult patients undergoing lumbar spine (LS) surgery were evaluated for amyloid and if present, the precursor protein, as well as comprehensive characterization of the clinical phenotype. Methods A prospective, cohort study in 2 academic medical centers enrolled 47 subjects (age 69 ± 7 years, 53% male) undergoing clinically indicated LS decompression. The presence of amyloid was evaluated by Congo Red staining and in those with amyloid, precursor protein was determined by laser capture microdissection coupled to mass spectrometry (LCM‐MS). The phenotype was assessed by disease‐specific questionnaires (Swiss Spinal Stenosis Questionnaire and Kansas City Cardiomyopathy Questionnaire) and the 36‐question short‐form health survey, as well as biochemical measures (TTR, retinol‐binding protein, and TTR stability). Cardiac testing included technetium‐99m‐pyrophosphate scintigraphy, electrocardiograms, echocardiograms, and cardiac biomarkers as well as measures of functional capacity. Results Amyloid was detected in 16 samples (34% of participants) and was more common in those aged ≥ 75 years of age (66.7%) compared with those <75 years (22.3%, p < 0.05). LCM‐MS demonstrated TTR as the precursor protein in 62.5% of participants with amyloid while 37.5% had an indeterminant type of amyloid. Demographic, clinical, quality‐of‐life measures, electrocardiographic, echocardiographic, and biochemical measures did not differ between those with and without amyloid. Among those with TTR amyloid (n = 10), one subject had cardiac involvement by scintigraphy. Conclusions Amyloid is detected in more than a third of older adults undergoing LSS. Amyloid is more common with advancing age and is particularly common in those >75 years old. No demographic, clinical, biochemical, or cardiac parameter distinguished those with and without amyloid. In more than half of subjects with LS amyloid, the precursor protein was TTR indicating the importance of pathological assessment.

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Association between spinal stenosis and wild-type ATTR amyloidosis

Cited by 27 publications

References 32 publications

Opportunities for Earlier Diagnosis and Treatment of Cardiac Amyloidosis

Opportunities for Earlier Diagnosis and Treatment of Cardiac Amyloidosis

The relationship between wild-type transthyretin amyloid load and ligamentum flavum thickness in lumbar stenosis patients

Analysis of lumbar spine stenosis specimens for identification of amyloid

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