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International Journal of Cardiology May 2024Cardiac amyloidosis is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality. With the emergence of novel therapies, there is a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cardiac amyloidosis is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality. With the emergence of novel therapies, there is a growing interest in prognostication of patients with cardiac amyloidosis using cardiac magnetic resonance imaging (CMR). In this systematic review and meta-analysis, we aimed to examine the prognostic significance of myocardial native T1 and T2, and extracellular volume (ECV).
METHODS
Observational cohort studies or single arms of clinical trials were eligible. MEDLINE, EMBASE and CENTRAL were systematically searched from their respective dates of inception to January 2023. No exclusions were made based on date of publication, study outcomes, or study language. The study populations composed of adult patients (≥18 years old) with amyloid cardiomyopathy. All studies included the use of CMR with and without intravenous gadolinium contrast administration to assess myocardial native T1 mapping, T2 mapping, and ECV in association with the pre-specified primary outcome of all-cause mortality. Data were extracted from eligible primary studies by two independent reviewers and pooled via the inverse variance method using random effects models for meta-analysis.
RESULTS
A total of 3852 citations were reviewed. A final nine studies including a total of 955 patients (mean age 65 ± 10 years old, 32% female, mean left ventricular ejection fraction (LVEF) 59 ± 12% and 24% had NYHA class III or IV symptoms) with cardiac amyloidosis [light chain amyloidosis (AL) 50%, transthyretin amyloidosis (ATTR) 49%, other 1%] were eligible for inclusion and suitable for data extraction. All included studies were single centered (seven with 1.5 T MRI scanners, two with 3.0 T MRI scanners) and non-randomized in design, with follow-up spanning from 8 to 64 months (median follow-up = 25 months); 320 patients died during follow-up, rendering a weighted mortality rate of 33% across studies. Compared with patients with AL amyloid, patients with ATTR amyloid had significantly higher mean left ventricular mass index (LVMi) (102 ± 34 g/m vs 127 ± 37 g/m, p = 0.02). N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin T levels, mean native T1 values, ECV and T2 values did not differ between patients with ATTR amyloid and AL amyloid (all p > 0.25). Overall, the hazard ratios for mortality were 1.33 (95% CI = [1.10, 1.60]; p = 0.003; I = 29%) for every 60 ms higher T1 time, 1.16 (95% CI = [1.09, 1.23], p < 0.0001; I = 76%) for every 3% higher ECV, and 5.23 (95% CI = [2.27, 12.02]; p < 0.0001; I = 0%) for myocardial-to-skeletal T2 ratio below the mean (vs above the mean).
CONCLUSION
Higher native T1 time and ECV, and lower myocardial to skeletal T2 ratio, on CMR are associated with worse mortality in patients with cardiac amyloidosis. Therefore, tissue mapping using CMR may offer a useful non-invasive technique to monitor disease progression and determine prognosis in patients with cardiac amyloidosis.
Topics: Adult; Humans; Female; Middle Aged; Aged; Adolescent; Male; Cardiomyopathies; Stroke Volume; Ventricular Function, Left; Magnetic Resonance Imaging; Myocardium; Amyloid Neuropathies, Familial; Disease Progression; Magnetic Resonance Imaging, Cine; Predictive Value of Tests; Contrast Media; Observational Studies as Topic
PubMed: 38382853
DOI: 10.1016/j.ijcard.2024.131892 -
World Journal of Clinical Cases Jul 2023Gene mutations in ATP-binding cassette, subfamily B () lead to autosomal recessive disorders. Primary light amyloidosis is a rare and incurable disease. Here, we report...
BACKGROUND
Gene mutations in ATP-binding cassette, subfamily B () lead to autosomal recessive disorders. Primary light amyloidosis is a rare and incurable disease. Here, we report a rare case of liver cirrhosis caused by gene mutation combined with primary light amyloidosis.
CASE SUMMARY
We report a case of a 25-year-old female who was hospitalized due to recurrent abdominal pain caused by calculous cholecystitis and underwent cholecystectomy. Pathological examination of the liver tissue suggested liver cirrhosis with bile duct injury. Exon analyses of the whole genome from the patient's peripheral blood revealed the presence of a heterozygous mutation in the gene. Bone marrow biopsy tissues, renal puncture examination, and liver mass spectrometry confirmed the diagnosis of a rare progressive familial intrahepatic cholestasis type 3 with systemic light chain type κ amyloidosis, which resulted in cirrhosis. Ursodeoxycholic acid and the cluster of differentiation 38 monoclonal antibody daretozumab were administered for treatment. Following treatment, the patient demonstrated significant improvement. Urinary protein became negative, peripheral blood-free light chain and urine-free light chain levels returned to normal, and the electrocardiogram showed no abnormalities. Additionally, the patient's lower limb numbness resolved, and her condition remained stable.
CONCLUSION
This report presents the diagnosis and treatment of liver cirrhosis, a rare disease that is easily misdiagnosed or missed.
PubMed: 37584002
DOI: 10.12998/wjcc.v11.i20.4903 -
Coexistence of variant-type transthyretin and immunoglobulin light-chain amyloidosis: a case report.European Heart Journal. Case Reports Jun 2024Determining the type of amyloid deposits is clinically important for choosing the specific therapies for cardiac amyloidosis.
BACKGROUND
Determining the type of amyloid deposits is clinically important for choosing the specific therapies for cardiac amyloidosis.
CASE SUMMARY
A 78-year-old woman who had been experiencing fluid retention and dyspnoea on exertion for 6 months was referred to our hospital for the management of heart failure with left ventricular hypertrophy. Since Tc-hydroxymethylene diphosphonate scintigraphy showed mild cardiac uptake and significant elevation of serum free lambda chain (with a difference of 263 mg/L in free light chain), we suspected immunoglobulin light-chain amyloidosis (AL), and endomyocardial biopsy was performed. The deposit site within the myocardial tissue exhibited positive for Congo red staining and transthyretin immunostaining, however negative or non-specific for light-chain immunostaining including lambda and kappa staining. Genetic testing confirmed a mutation in V122I, variant-type transthyretin amyloidosis (ATTRv). Despite the administration of patisiran, her condition exhibited progressive deterioration. Additionally, she displayed macroglossia, an atypical manifestation in ATTRv amyloidosis. Further biopsies from tongue and abdominal wall fat culminated in a final diagnosis: the coexistence of ATTRv and AL (of the lambda type). Although treatment with melphalan and dexamethasone was started, she passed away 24 months after the initial visit. When the endomyocardial biopsy specimen underwent mass spectrometry as a analysis, both ATTR and AL amyloid were significantly detected.
DISCUSSION
Coexistence of ATTRv and AL within cardiac amyloidosis is extremely uncommon. In situations where incongruities arise between the amyloid type determined via immunohistochemistry findings and the amyloid type assumed based on other clinical findings, mass spectrometry should be considered.
PubMed: 38872953
DOI: 10.1093/ehjcr/ytae264 -
MedRxiv : the Preprint Server For... Sep 2023Myocardial immunoglobulin light-chain (AL) amyloid deposits trigger heart failure, cardiomyocyte stretch and myocardial injury, leading to adverse cardiac outcomes....
BACKGROUND
Myocardial immunoglobulin light-chain (AL) amyloid deposits trigger heart failure, cardiomyocyte stretch and myocardial injury, leading to adverse cardiac outcomes. Positron emission tomography/computed tomography (PET/CT) with F-florbetapir, a novel amyloid-targeting radiotracer, can quantify left ventricular (LV) amyloid burden, but its prognostic value is not known. Therefore, we aimed to evaluate the prognostic value of LV amyloid burden quantified by F-florbetapir PET/CT and to identify mechanistic pathways mediating its association with outcomes.
METHODS
Eighty-one participants with newly-diagnosed systemic AL amyloidosis were prospectively enrolled and underwent F-florbetapir PET/CT. LV amyloid burden was quantified using F-florbetapir LV percent injected dose (%ID). Mayo AL stage was determined using troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and difference between involved and uninvolved free light chain levels. Major adverse cardiac events (MACE) were defined as all-cause death, heart failure hospitalization, or cardiac transplantation within 12 months.
RESULTS
Among participants (median age 61 years, 57% males), 36% experienced MACE. Incidence of MACE increased across tertiles of LV amyloid burden from 7% to 63% (p<0.001). LV amyloid burden was significantly associated with MACE in univariable analysis (hazard ratio 1.45, 95% confidence interval 1.15-1.82, p=0.002). However, this association became non-significant in multivariable analyses adjusted for Mayo AL stage. Mediation analysis showed that the association between F-florbetapir LV %ID and MACE was primarily mediated by NT-proBNP (p<0.001), a marker of cardiomyocyte stretch and component of Mayo AL stage.
CONCLUSION
In this first study to link cardiac F-florbetapir uptake to subsequent outcomes, LV amyloid burden estimated by LV %ID predicted MACE in AL amyloidosis. But this effect was not independent of Mayo AL stage. LV amyloid burden was associated with MACE primarily via NT-pro-BNP, a marker of cardiomyocyte stretch and component of Mayo AL stage. These findings provide novel insights into the mechanism through which myocardial AL amyloid leads to MACE.
CLINICAL PERSPECTIVE
In systemic light-chain (AL) amyloidosis, cardiac involvement is the key determinant of adverse outcomes. Usually, prognosis is based on the Mayo AL stage, determined by troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the difference between involved and uninvolved immunoglobulin free light chain levels (dFLC). Cardiac amyloid burden is not considered in this staging. In the present study, we used the amyloid-specific radiotracer F-florbetapir to quantify left ventricular (LV) amyloid burden in 81 participants with newly-diagnosed AL amyloidosis and evaluated its prognostic value on major adverse outcomes (MACE: all-cause death, heart failure hospitalization, or cardiac transplantation within 12 months). We found that higher LV amyloid burden by F-florbetapir positron emission tomography/computed tomography (PET/CT) was strongly associated with MACE. However, this association became non-significant after adjustment for the Mayo AL stage. Mediation analysis offered novel pathophysiological insights, implying that LV amyloid burden leads to MACE predominantly through cardiomyocyte stretch and light chain toxicity (by NT-proBNP), rather than through myocardial injury (by troponin T), also considering the severity of plasma cell dyscrasia (by dFLC). This mediation by NT-proBNP may explain why the association with outcomes was non-significant with adjustment for Mayo AL stage. Together, these results establish quantitative F-florbetapir PET/CT as a valid method to predict adverse outcomes in AL amyloidosis. These results support the use of F-florbetapir PET/CT to measure the effects of novel fibril-depleting therapies, in addition to plasma cell therapy, to improve outcomes in systemic AL amyloidosis.
PubMed: 37745589
DOI: 10.1101/2023.09.13.23295520 -
International Medical Case Reports... 2023This is a case of localized primary tracheobronchial amyloidosis in a patient who presented with upper airway obstruction. Tracheobronchial amyloidosis is a type of...
This is a case of localized primary tracheobronchial amyloidosis in a patient who presented with upper airway obstruction. Tracheobronchial amyloidosis is a type of localized bronchopulmonary amyloidosis that is frequently overlooked. It involves the deposition of amyloid protein on the tracheal and bronchial tissue, leading to progressive tracheal stenosis and airway obstruction that can be seen on imaging as a tracheal mass. Because of its significant diagnostic difficulty and therapeutic conundrum, it ought to be considered in the differential diagnosis of upper airway symptoms with an unknown etiology.
PubMed: 38020579
DOI: 10.2147/IMCRJ.S438379 -
Frontiers in Cardiovascular Medicine 2023The humanistic burden of transthyretin amyloid cardiomyopathy (ATTR-CM) is poorly defined.
Burden of untreated transthyretin amyloid cardiomyopathy on patients and their caregivers by disease severity: results from a multicenter, non-interventional, real-world study.
BACKGROUND
The humanistic burden of transthyretin amyloid cardiomyopathy (ATTR-CM) is poorly defined.
METHODS
An international study to comprehensively characterize the burden of ATTR-CM on patients naïve to disease-modifying therapy and their unpaid primary caregivers using study-specific and established surveys (patients: Kansas City Cardiomyopathy Questionnaire Overall Summary [KCCQ-OS], 12-Item Short Form Health Survey [SF-12], Hospital Anxiety and Depression Scale [HADS], Patient-Reported Outcomes Measurement Information System [PROMIS] Fatigue and Dyspnea; caregivers: SF-12, HADS, PROMIS Fatigue, Zarit Burden Interview [ZBI]). All data were summarized descriptively.
RESULTS
208 patient and caregiver pairs were included. 86% of patients were male, median age was 81 years, and 91% (141/155 with genetic testing) had wild-type ATTR-CM. Patient responses characterized the mental and physical burden of ATTR-CM, which was numerically higher among those who were New York Heart Association (NYHA) class III ( = 43) vs. class I/II ( = 156). NYHA class III patients had particularly low KCCQ-OS (36) and SF-12 physical component (27) scores, and 67% had a HADS depression score ≥8. Caregivers (median age 68 years; 85% female; 59% spouse of the patient; median duration of caregiving 1.5 years) reported that NYHA III patients more frequently required help with a range of physical activities than NYHA class I/II patients. 51% of caregivers to NYHA class III patients reported at least a mild-to-moderate burden in the ZBI. A plain language summary of this paper can be found as a supplemental material.
CONCLUSIONS
Untreated ATTR-CM is a burden to both patients and their caregivers.
PubMed: 37711563
DOI: 10.3389/fcvm.2023.1238843 -
Kidney International Reports Jan 2024Although serum amyloid A (AA) amyloid may occasionally show nonspecific staining by immunofluorescence (IF), the correct diagnosis can usually be determined by...
INTRODUCTION
Although serum amyloid A (AA) amyloid may occasionally show nonspecific staining by immunofluorescence (IF), the correct diagnosis can usually be determined by integrating pathologic features and clinical scenario, and using AA amyloid immunohistochemistry (IHC) and/or mass spectrometry. A recent mass spectrometry-based study described false-positive Ig IF staining in a subset of AA amyloid cases.
METHODS
We sought to delineate clinicopathologic features of AA amyloid with Ig-dominant staining by using a retrospective review.
RESULTS
AA amyloid with Ig-dominant staining was identified in 10 patients from 5 institutions, representing 1.2% to 4% of AA amyloid kidney biopsies. Evidence of a monoclonal protein was documented in 0% to 2.7% of patients with AA amyloid screened for inclusion, but 30% of those with Ig-dominant staining. The patient population had equal sex distribution and presented at median age of 68.5 years with nephrotic proteinuria and kidney impairment. Etiologies of AA amyloid included injection drug use (30%), autoimmune disease (20%), and chronic infection (10%); 40% had no identified clinical association. On biopsy, heavy chain (co)dominant staining by IF (in 80%), discordant distribution in Ig staining (in 20%), tubulointerstitial nephritis (in 30%), and/or crescents (in 10%) were present. Two of 3 patients with paraproteinemia had concordant heavy and/or light chain dominant staining within the AA amyloid. Two cases were initially misdiagnosed as Ig-associated amyloidosis.
CONCLUSION
We describe the morphologic spectrum of AA amyloidosis with Ig-dominant staining which may have clinical, laboratory, and pathologic overlap with amyloid light chain (AL), amyloid heavy chain, and heavy and light chain (AHL) amyloidosis.
PubMed: 38312779
DOI: 10.1016/j.ekir.2023.10.005 -
Current Heart Failure Reports Jun 2024Cardiac amyloidosis (CA) constitutes an important etiology of heart failure with preserved ejection fraction (HFpEF) or heart failure with mildly reduced ejection... (Review)
Review
PURPOSE OF REVIEW
Cardiac amyloidosis (CA) constitutes an important etiology of heart failure with preserved ejection fraction (HFpEF) or heart failure with mildly reduced ejection fraction (HFmrEF). Since patients with CA show early exhaustion, we aimed to investigate whether non-exertional variables of cardiopulmonary exercise testing (CPET) provide additional information in comparison to traditional peak oxygen consumption (VO).
RECENT FINDINGS
We retrospectively investigated CPET variables of patients with HFpEF and HFmrEF with (n = 21) and without (n = 21, HF) CA at comparable age and ejection fraction. Exertional and non-exertional CPET variables as well as laboratory and echocardiographic markers were analyzed. The primary outcome was the difference in CPET variables between groups. The secondary outcome was rehospitalization in patients with CA during a follow-up of 24 months. Correlations between CPET, NTproBNP, and echocardiographic variables were calculated to detect patterns of discrimination between the groups. HF patients with CA were inferior to controls in most exertional and non-exertional CPET variables. Patients with CA were hospitalized more often (p = 0.002), and rehospitalization was associated with VE/VCO (p = 0.019), peak oxygen pulse (p = 0.042), the oxygen equivalent at the first ventilatory threshold (p = 0.003), circulatory (p = 0.024), and ventilatory power (p < .001), but not VO (p = 0.127). Higher performance was correlated with lower E/e' and NTproBNP as well as higher resting heart rate and stroke volume in CA. Patients with CA displayed worse non-exertional CPET performance compared to non-CA HF patients, which was associated with rehospitalization. Differences between correlations of resting echocardiography and CPET variables between groups emphasize different properties of exercise physiology despite comparable ejection fraction.
Topics: Humans; Heart Failure; Exercise Test; Stroke Volume; Amyloidosis; Retrospective Studies; Oxygen Consumption; Male; Female; Aged; Echocardiography; Exercise Tolerance; Middle Aged; Cardiomyopathies
PubMed: 38635117
DOI: 10.1007/s11897-024-00661-1 -
PloS One 2024Amyloidosis is a rare multi-system disorder associated with frequently delayed diagnosis, enormous disease burden and psychosocial distress.
BACKGROUND
Amyloidosis is a rare multi-system disorder associated with frequently delayed diagnosis, enormous disease burden and psychosocial distress.
METHODS
Systematic assessment of needs was performed by a subtype-spanning questionnaire-based survey within the AMY-NEEDS research and care program.
RESULTS
118 patients with proven amyloidosis (62.7% ATTR, 22.0% AL, 15.3% other forms) were included in August 2020 until February 2021 (mean age 71.2 ±11.3 years; 30% women). The median diagnostic delay between onset of symptoms and diagnosis was 9.0 (range: 2.5; 33.0) months. Local health care providers (HCPs) play a central role on the way to diagnosis. Diagnosis itself typically requires a clinical but not necessarily a university setting. In the treatment phase, the focus moves to the amyloidosis centre as primary contact and coordinator, with general practitioners (GPs) acting predominantly as a contact point in crisis and link to additional services. About half of patients reported impaired quality of life and one third suffering from anxiety and depressed mood, respectively. The majority of patients talk about their concerns with close caregivers and local HCPs. Advance care planning is a relevant, yet insufficiently met need.
CONCLUSION
The journey of patients with amyloidotic disease, their contact partners and needs at different stages were characterized in detail within the German health care system. An amyloidosis-specific care concept has to master the multitude of interfaces connecting the numerous treatment providers involved with the amyloidosis centre and GPs as key players. Telemedical approaches could be a promising and well-accepted option allowing optimal coordination and communication.
Topics: Humans; Female; Male; Aged; Germany; Amyloidosis; Middle Aged; Aged, 80 and over; Surveys and Questionnaires; Quality of Life; Caregivers; Delayed Diagnosis
PubMed: 38768126
DOI: 10.1371/journal.pone.0297182 -
JFMS Open Reports 2023A 3-year-old male neutered Sphynx cat was referred for history of chronically increased liver enzymes and lower urinary tract signs that were first reported when the cat...
CASE SUMMARY
A 3-year-old male neutered Sphynx cat was referred for history of chronically increased liver enzymes and lower urinary tract signs that were first reported when the cat was 5 months old. Urine metabolic profile revealed increased amino aciduria and glucosuria despite normoglycemia, suggesting Fanconi syndrome. Urine sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed a banding pattern suggestive of primary tubular damage. Serial blood work showed non-regenerative normocytic normochromic anemia, persistently elevated liver enzymes, worsening azotemia and progressive hyperchloremic metabolic acidosis. Ultrasound revealed irregular kidneys and bilaterally hyperechoic cortices and medullae with a loss of normal corticomedullary distinction. Laparoscopic kidney biopsy revealed a moderate-to-severe chronic interstitial fibrosis with chronic lymphoplasmacytic inflammation, tubular degeneration and atrophy, mild glomerulosclerosis and mild large vascular amyloidosis. Tubular epithelial cell karyomegaly was multifocally evident throughout the kidney. The liver had moderate diffuse zone 1 hepatocellular atrophy, periportal fibrosis, biliary hyperplasia, mild perisinusoidal amyloidosis and hepatocyte karyomegaly in zones 2 and 3. The patient continued to decline and developed polyuria, polydipsia, lethargy and hyporexia irrespective of rigorous management, which failed to curtail the progressive anemia and azotemia. The patient was euthanized 8 months from the onset of clinical signs.
RELEVANCE AND NOVEL INFORMATION
Fanconi syndrome in cats is a rare condition, with most reports occurring secondary to chlorambucil treatment. This is the first known case of Fanconi syndrome occurring with concurrent hepatorenal epithelial karyomegaly in a young Sphynx cat.
PubMed: 37810577
DOI: 10.1177/20551169231190611