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JACC. Cardiovascular Imaging Nov 2023The noninvasive detection of cardiac amyloid, as well as deposits in other vital organs, is critical for early diagnosis and quantitative disease monitoring. Positron...
BACKGROUND
The noninvasive detection of cardiac amyloid, as well as deposits in other vital organs, is critical for early diagnosis and quantitative disease monitoring. Positron emission tomography is an intrinsically quantitative imaging modality suitable for high-resolution amyloid detection.
OBJECTIVES
This study sought to evaluate the safety and efficacy of a novel amyloid-reactive peptide, designated p5+14, labeled with iodine-124 (I), in patients with diverse types of systemic amyloidosis.
METHODS
In a single-site, open label phase 1/2 study (NCT03678259), the safety, biodistribution, and sensitivity of a single intravenous infusion of I-evuzamitide was assessed in patients with systemic amyloidosis (n = 50), asymptomatic transthyretin sequence variant carriers (n = 2), and healthy volunteers (n = 5). Subjects were administered 1.4 ± 0.2 mg of I-evuzamitide (71.5 ± 12.4 MBq) and positron emission tomography/x-ray computed tomography images acquired at 5.2 hours (Q25-Q75: 4.9-5.4 hours) postinfusion. Images were assessed visually and semi-quantitatively for positive uptake of radiotracer in the heart and other major organs.
RESULTS
Uptake of I-evuzamitide in the heart and other abdominothoracic organs was consistent with the patient's clinical presentation and the type of amyloidosis. The patient- and cardiac-associated sensitivity for imaging and clinical observations was 93.6% (95% CI: 82.8%-97.8%) and 96.2% (95% CI: 81.8%-99.8%), respectively. Semi-quantitative uptake of the radiotracer correlated significantly with serum N-terminal pro-B-type natriuretic peptide measurements in patients with light chain-associated amyloidosis. Cardiac uptake was not observed in any healthy volunteers. The agent was well tolerated, with 1 drug-related adverse event and no deaths.
CONCLUSIONS
I-evuzamitide is an amyloid-binding radiotracer capable of detecting cardiac amyloid in patients with high sensitivity.
Topics: Humans; Positron Emission Tomography Computed Tomography; Tissue Distribution; Predictive Value of Tests; Amyloid; Iodine Radioisotopes; Amyloidosis; Immunoglobulin Light-chain Amyloidosis
PubMed: 37940323
DOI: 10.1016/j.jcmg.2023.08.009 -
Journal of Investigative Medicine : the... Jun 2024Cardiac amyloidosis (CA) is an infiltrative restrictive cardiomyopathy caused by the deposition of amyloid fibrils in the myocardium. It manifests in two primary... (Review)
Review
Cardiac amyloidosis (CA) is an infiltrative restrictive cardiomyopathy caused by the deposition of amyloid fibrils in the myocardium. It manifests in two primary subtypes: transthyretin cardiac amyloidosis (ATTR) and immunoglobulin light chain cardiac amyloidosis (AL). ATTR is further classified into wild-type (wtATTR) and hereditary (hATTR) based on transthyretin gene mutation. Advances in diagnostics and therapeutics have transformed CA from a rare and untreatable condition to a more prevalent and manageable disease. Non-invasive diagnostic tools such as electrocardiography, echocardiography, and cardiac magnetic resonance can raise suspicion for CA; bone scintigraphy can non-invasively confirm ATTR, while AL necessitates histological confirmation. The severity of ATTR and AL can be assessed through serum biomarker-based staging. Treatment approaches differ, ranging from silencing or stabilizing transthyretin and degrading amyloid fibrils in ATTR to employing anti-plasma cell therapies and autologous stem cell transplantation in AL.
PubMed: 38869161
DOI: 10.1177/10815589241261279 -
International Journal of Molecular... Mar 2024Peripheral and autonomic neuropathy are common disease manifestations in systemic amyloidosis. The neurofilament light chain (NfL), a neuron-specific biomarker, is... (Review)
Review
Peripheral and autonomic neuropathy are common disease manifestations in systemic amyloidosis. The neurofilament light chain (NfL), a neuron-specific biomarker, is released into the blood and cerebrospinal fluid after neuronal damage. There is a need for an early and sensitive blood biomarker for polyneuropathy, and this systematic review provides an overview on the value of NfL in the early detection of neuropathy, central nervous system involvement, the monitoring of neuropathy progression, and treatment effects in systemic amyloidosis. A literature search in PubMed, Embase, and Web of Science was performed on 14 February 2024 for studies investigating NfL levels in patients with systemic amyloidosis and transthyretin gene-variant (v) carriers. Only studies containing original data were included. Included were thirteen full-text articles and five abstracts describing 1604 participants: 298 controls and 1306 v carriers or patients with or without polyneuropathy. Patients with polyneuropathy demonstrated higher NfL levels compared to healthy controls and asymptomatic carriers. Disease onset was marked by rising NfL levels. Following the initiation of transthyretin gene-silencer treatment, NfL levels decreased and remained stable over an extended period. NfL is not an outcome biomarker, but an early and sensitive disease-process biomarker for neuropathy in systemic amyloidosis. Therefore, NfL has the potential to be used for the early detection of neuropathy, monitoring treatment effects, and monitoring disease progression in patients with systemic amyloidosis.
Topics: Humans; Prealbumin; Intermediate Filaments; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Polyneuropathies; Biomarkers
PubMed: 38612579
DOI: 10.3390/ijms25073770 -
International Journal of Cardiology May 2024This systematic review aimed to assess the tolerability of patients with cardiac amyloidosis (CA) to beta-blockers (BBs) and evaluate its association with adverse... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
This systematic review aimed to assess the tolerability of patients with cardiac amyloidosis (CA) to beta-blockers (BBs) and evaluate its association with adverse outcomes.
METHODS
We performed a comprehensive search from January 1, 2000 to October 20, 2023. Studies examining BB use and tolerance or the relationship between BB use and outcomes in patients with CA were included. Pooled adjusted hazard ratios (aHRs) for all-cause mortality were calculated using random- and fixed-effects models.
RESULTS
Eight observational studies involving 4002 patients with CA (87.5% with transthyretin CA [ATTR-CA] and 12.5% with immunoglobulin light chain CA [AL-CA]) were assessed. BBs were used by 52.5% of the patients. However, 26.3% of the patients discontinued BBs because of hypotension, bradycardia, or fatigue. Regarding the association between BB use and all-cause death, four studies were identified that included 2874 patients with ATTR-CA and 16 patients with AL-CA. The meta-analysis revealed no apparent relationship between BB use and all-cause mortality (pooled aHR = 0.78, 95% confidence interval (CI) = 0.40-1.51). Two studies on patients with ATTR-CA found no impact of BB use on all-cause mortality in the subgroup with left ventricular ejection fraction (LVEF) > 40%, but conflicting results exist for those with LVEF ≤40% (pooled aHR = 0.78, 95% CI = 0.40-1.54).
CONCLUSION
The limited number of observational studies that predominantly enrolled patients with ATTR-CA showed that BBs were used in almost half of the patients with CA, with varying tolerability. However, no significant association was observed between BB use and all-cause mortality.
Topics: Humans; Amyloid Neuropathies, Familial; Stroke Volume; Ventricular Function, Left; Immunoglobulin Light-chain Amyloidosis; Prealbumin; Cardiomyopathies
PubMed: 38278490
DOI: 10.1016/j.ijcard.2024.131813 -
International Journal of Cardiology Oct 2023Chest pain is experienced by patients with cardiac amyloidosis (CA), but a systematic investigation of its frequency, underlying etiologies and clinical significance is...
BACKGROUND
Chest pain is experienced by patients with cardiac amyloidosis (CA), but a systematic investigation of its frequency, underlying etiologies and clinical significance is lacking.
METHODS
Clinical, echocardiographic, laboratory characteristics, available coronary arteries imaging and endomyocardial biopsy (EMB) findings of 174 patients with CA (n = 104 with transthyretin, ATTR; n = 70 with light chains, AL) were analyzed.
RESULTS
Chest pain was reported in 66 (38%) CA patients. Compared to those without, patients with chest pain had more frequently a history of coronary artery disease (CAD) (27% vs 15%, p = 0.048) and heart failure (HF) symptoms (62% vs 43%, p = 0.015), higher high sensitivity troponin I (hs-cTnI, 101 vs 65 ng/L, p = 0.032) and higher brain natriuretic peptide (597 vs 407 ng/L, p = 0.024). Among CA patients with chest pain undergoing coronary arteries imaging (n = 37), obstructive CAD was detected in 14 (38%), 13 of whom with ATTR-CA. Of these 37 patients, EMB was available in 10 and vascular/perivascular amyloid deposition was detected in 4/5 (80%) of AL-CA patients and 1/5 ATTR-CA. Among patients with suspected acute coronary syndrome (n = 22), obstructive CAD was detected in 9/17 (53%) ATTR-CA and 0/5 AL-CA; hs-cTnI levels were similar between those with and without obstructive CAD. During a follow-up of 17 (8-34) months, chest pain was a significant predictor of HF hospitalization (HR1.86, 95% CI 1.02-3.39, p = 0.042), even after adjustment for CA subtype and CAD.
CONCLUSION
Chest pain is a common symptom in patients with CA, reflects a more advanced cardiac impairment and predicts future HF hospitalization. The etiology of chest pain seems to differ, with obstructive CAD more frequent in ATTR-CA whilst amyloid vascular/perivascular involvement more common in AL-CA.
Topics: Humans; Prognosis; Amyloidosis; Heart Diseases; Chest Pain; Coronary Artery Disease; Immunoglobulin Light-chain Amyloidosis
PubMed: 37481000
DOI: 10.1016/j.ijcard.2023.131204 -
Circulation Apr 2024The extent of myocardial bone tracer uptake with technetium pyrophosphate, hydroxymethylene diphosphonate, and 3,3-diphosphono-1,2-propanodicarboxylate in transthyretin...
BACKGROUND
The extent of myocardial bone tracer uptake with technetium pyrophosphate, hydroxymethylene diphosphonate, and 3,3-diphosphono-1,2-propanodicarboxylate in transthyretin amyloid cardiomyopathy (ATTR-CM) might reflect cardiac amyloid burden and be associated with outcome.
METHODS
Consecutive patients with ATTR-CM who underwent diagnostic bone tracer scintigraphy with acquisition of whole-body planar and cardiac single-photon emission computed tomography (SPECT) images from the National Amyloidosis Centre and 4 Italian centers were included. Cardiac uptake was defined according to the Perugini classification: 0=absent cardiac uptake; 1=mild uptake less than bone; 2=moderate uptake equal to bone; and 3=high uptake greater than bone. Extent of right ventricular (RV) uptake was defined as focal (basal segment of the RV free wall only) or diffuse (extending beyond basal segment) on the basis of SPECT imaging. The primary outcome was all-cause mortality.
RESULTS
Among 1422 patients with ATTR-CM, RV uptake accompanying left ventricular uptake was identified by SPECT imaging in 100% of cases at diagnosis. Median follow-up in the whole cohort was 34 months (interquartile range, 21 to 50 months), and 494 patients died. By Kaplan-Meier analysis, diffuse RV uptake on SPECT imaging (n=936) was associated with higher all-cause mortality compared with focal (n=486) RV uptake (77.9% versus 22.1%; <0.001), whereas Perugini grade was not associated with survival (=0.27 in grade 2 versus grade 3). On multivariable analysis, after adjustment for age at diagnosis (hazard ratio [HR], 1.03 [95% CI, 1.02-1.04]; <0.001), presence of the p.(V142I) variant (HR, 1.42 [95% CI, 1.20-1.81]; =0.004), National Amyloidosis Centre stage (each category, <0.001), stroke volume index (HR, 0.99 [95% CI, 0.97-0.99]; =0.043), E/e' (HR, 1.02 [95% CI, 1.007-1.03]; =0.004), right atrial area index (HR, 1.05 [95% CI, 1.02-1.08]; =0.001), and left ventricular global longitudinal strain (HR, 1.06 [95% CI, 1.03-1.09]; <0.001), diffuse RV uptake on SPECT imaging (HR, 1.60 [95% CI, 1.26-2.04]; <0.001) remained an independent predictor of all-cause mortality. The prognostic value of diffuse RV uptake was maintained across each National Amyloidosis Centre stage and in both wild-type and hereditary ATTR-CM (<0.001 and =0.02, respectively).
CONCLUSIONS
Diffuse RV uptake of bone tracer on SPECT imaging is associated with poor outcomes in patients with ATTR-CM and is an independent prognostic marker at diagnosis.
Topics: Humans; Cardiomyopathies; Prealbumin; Prognosis; Tomography, Emission-Computed, Single-Photon
PubMed: 38328945
DOI: 10.1161/CIRCULATIONAHA.123.066524 -
Frontiers in Cardiovascular Medicine 2023Both light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis are types of cardiac amyloidosis (CA) that require accurate prognostic stratification to plan...
BACKGROUND
Both light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis are types of cardiac amyloidosis (CA) that require accurate prognostic stratification to plan therapeutic strategies and follow-ups. Cardiac biomarkers, e.g., N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (Hs-cTnT), remain the cornerstone of the prognostic assessment. An increased level of soluble suppression of tumorigenesis-2 (sST2) is predictive of adverse events [all-cause death and heart failure (HF) hospitalizations] in patients with HF. This study aimed to evaluate the prognostic value of circulating sST2 levels in AL-CA and ATTR-CA.
METHODS
We carried out a multicenter study including 133 patients with AL-CA and 152 patients with ATTR-CA. During an elective outpatient visit for the diagnosis of CA, Mayo Clinic staging [NT-proBNP, Hs-cTnT, differential of free light chains (DFLCs)] and sST2 were assessed for all AL patients. Gillmore staging [including estimated glomerular filtration rate (eGFR), NT-proBNP] and Grogan staging (including NT-proBNP and Hs-cTnT) were assessed for TTR-CA patients.
RESULTS
The median age was 73 years [interquartile range (IQR) 61-81], and 53% were men. The endpoint was the composite of all-cause death or first HF-related hospitalization. The median follow-up was 20 months (IQR 3-34) in AL amyloidosis and 33 months (6-45) in TTR amyloidosis. The primary outcome occurred in 70 (53%) and 99 (65%) of AL and TTR patients, respectively. sST2 levels were higher in patients with AL-CA than in patients with ATTR-CA: 39 ng/L (26-80) vs. 32 ng/L (21-46), < 0.001. In AL-CA, sST2 levels predicted the outcome regardless of the Mayo Clinic score (HR: 2.16, 95% CI: 1.17-3.99, < 0.001). In TTR-CA, sST2 was not predictive of the outcome in multivariate models, including Gillmore staging and Grogan staging (HR: 1.17, CI: 95% 0.77-1.89, = 0.55).
CONCLUSION
sST2 level is a relevant predictor of death and HF hospitalization in AL cardiac amyloidosis and adds prognostic stratification on top of NT-proBNP, Hs cTnT, and DFLC.
PubMed: 37600055
DOI: 10.3389/fcvm.2023.1179968 -
Zhonghua Bing Li Xue Za Zhi = Chinese... Jul 2023To investigate the histological features and clinical manifestations in different types of cardiac amyloidosis to improve diagnostic accuracy. The histopathological... (Review)
Review
To investigate the histological features and clinical manifestations in different types of cardiac amyloidosis to improve diagnostic accuracy. The histopathological features and clinical manifestations of 48 patients diagnosed with cardiac amyloidosis by Congo red stain and electron microscopy through endomyocardial biopsy were collected in West China Hospital of Sichuan University from January 2018 to December 2021. Immunohistochemical stains for immunoglobulin light chains (κ and λ) and transthyretin protein were carried out, and a review of literature was made. The patients age ranged from 42 to 79 years (mean 56 years) and the male to female ratio was 1.1 to 1.0. The positive rate of endomyocardial biopsy was 97.9% (47/48), which was significantly higher than that of the abdominal wall fat (7/17). Congo red staining and electron microscopy were positive in 97.9% (47/48) and 93.5% (43/46), respectively. Immunohistochemical stains showed 32 cases (68.1%) were light chain type (AL-CA), including 31 cases of AL-λ type and 1 case of AL-κ type; 9 cases (19.1%) were transthyretin protein type (ATTR-CA); and 6 cases (12.8%) were not classified. There was no significant difference in the deposition pattern of amyloid between different types (>0.05). Clinical data showed that ATTR-CA patients had less involvement of 2 or more organs and lower N-terminal pro-B-type natriuretic peptide (NT-proBNP) than the other type patients (<0.05). The left ventricular stroke volume and right ventricular ejection fraction of ATTR-CA patients were better than the other patients (<0.05). Follow-up data of 45 patients was obtained, and the overall mean survival time was 15.6±2.0 months. Univariate survival analysis showed that ATTR-CA patients had a better prognosis, while cardiac amyloidosis patients with higher cardiac function grade, NT-proBNP >6 000 ng/L, and troponin T >70 ng/L had a worse prognosis (<0.05). Multivariate survival analysis showed that NT-proBNP and cardiac function grade were independent prognostic factors for cardiac amyloidosis patients. AL-λ is the most common type of cardiac amyloidosis in this group. Congo red staining combined with electron microscopy can significantly improve the diagnosis of cardiac amyloidosis. The clinical manifestations and prognosis of each type are different and can be classified based on immunostaining profile. However, there are still a few cases that cannot be typed; hence mass spectrometry is recommended if feasible.
Topics: Humans; Male; Female; Adult; Middle Aged; Aged; Prealbumin; Stroke Volume; Cardiomyopathies; Congo Red; Ventricular Function, Right; Amyloidosis; Prognosis
PubMed: 37408396
DOI: 10.3760/cma.j.cn112151-20221230-01082 -
Journal of Clinical Pathology Nov 2023Monoclonal gammopathy is a spectrum of disorders characterised by clonal proliferation of plasma cells or lymphocytes, which produce abnormal immunoglobulin or its...
Monoclonal gammopathy is a spectrum of disorders characterised by clonal proliferation of plasma cells or lymphocytes, which produce abnormal immunoglobulin or its components (monoclonal proteins). Monoclonal gammopathies are often categorised as low-tumour-burden diseases (eg, amyloid light chain (AL) amyloidosis), premalignant disorders (such as monoclonal gammopathy of undetermined significance and smouldering multiple myeloma), and malignancies (eg, multiple myeloma and Waldenström's macroglobulinaemia). Such diversity of concentration and structure makes monoclonal protein a challenging clonal marker. This article provides an overview on initial laboratory testing of monoclonal gammopathy to guide clinicians and laboratory professionals in the selection and interpretation of appropriate investigations.
Topics: Humans; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Paraproteinemias; Precancerous Conditions
PubMed: 37604683
DOI: 10.1136/jcp-2023-208774 -
Current Cardiology Reviews 2024Amyloidosis is a systemic disease initiated by deposition of misfolded proteins in the extracellular space, due to which multiple organs may be affected concomitantly.... (Review)
Review
Amyloidosis is a systemic disease initiated by deposition of misfolded proteins in the extracellular space, due to which multiple organs may be affected concomitantly. Cardiac amyloidosis, however, remains a major cause of morbidity and mortality in this population due to infiltrative /restrictive cardiomyopathy. This review attempts to focus on contemporary medical and surgical therapies for the different types of cardiac amyloidosis. Amyloidosis affecting the heart are predominantly of the transthyretin type (acquired in the older or genetic in the younger patients), and the monoclonal immunoglobulin light chain (AL) type which is solely acquired. A rare form of secondary amyloidosis AA type can also affect the heart due to excessive production and accumulation of the acute-phase protein called Serum Amyloid A" (SAA) in the setting of chronic inflammation, cancers or autoinflammatory disease. More commonly AA amyloidosis is seen in the liver and kidney. Other rare types are Apo A1 and Isolated Atrial Amyloidosis (AANF). Medical therapies have made important strides in the clinical management of the two common types of cardiac amyloidosis. Surgical therapies such as mechanical circulatory support and cardiac transplantation should be considered in appropriate patients. Future research using AI driven algorithms for early diagnosis and treatment as well as development of newer genetic engineering technologies will drive improvements in diagnosis, treatment and patient outcomes.
Topics: Humans; Amyloidosis; Cardiomyopathies; Heart Transplantation
PubMed: 38682372
DOI: 10.2174/011573403X240302230925043500