Cardiac amyloidosis is not a single disease: a multiparametric comparison between the light chain and transthyretin forms.

AIMS: Systemic amyloidosis represents a heterogeneous group of diseases resulting from amyloid fibre deposition. The purpose of this study is to establish a differential diagnosis algorithm targeted towards the two most frequent subtypes of CA. METHODS AND RESULTS: We prospectively included all consecutive patients with ATTR and AL evaluated between 2018 and 2022 in two centres in a score derivation cohort and a different validation sample. All patients had a complete clinical, biomarker, electrocardiographic, and imaging evaluation. Confirmation of the final diagnosis with amyloid typing was performed according to the current international recommendations. The study population included 81 patients divided into two groups: ATTR (group 1, n = 32: 28 variant and 4 wild type) and AL (group 2, n = 49). ATTR patients were younger (50.7 ± 13.9 vs. 60.2 ± 7.3 years, P = 0.0001), and significantly different in terms of NT-proBNP [ATTR: 1472.5 ng/L (97-4218.5) vs. AL 8024 ng/L (3058-14 069) P = 0.001], hs-cTn I [ATTR: 10 ng/L (4-20) vs. AL 78 ng/L (32-240), P = 0.0002], GFR [ATTR 95.4 mL/min (73.8-105.3) vs. AL: 68.4 mL/min (47.8-87.4) P = 0.003]. At similar left ventricular (LV) wall thickness and ejection fraction, the ATTR group had less frequently pericardial effusion (ATTR: 15% vs. AL: 33% P = 0.0027), better LV global longitudinal strain (ATTR: -13.1% ± 3.5 vs. AL: -9.1% ± 4.3 P = 0.04), RV strain (ATTR: -21.9% ± 6.2 vs. AL: -16.8% ± 6 P = 0.03) and better reservoir function of the LA strain (ATTR: 22% ± 12 vs. AL: 13.6% ± 7.8 P = 0.02). Cut-off points were calculated based on the Youden method. We attributed to 2 points for parameters having an AUC > 0.75 (NT-proBNP AUC 0.799; hs-cTnI AUC 0.87) and 1 point for GFR (AUC 0.749) and TTE parameters (GLS AUC 0.666; RV FWS AUC 0.649, LASr AUC 0.643). A score of equal or more than 4 points has been able to differentiate between AL and ATTR (sensitivity 80%, specificity 62%, AUC = 0.798). The differential diagnosis score system was applied to the validation cohort of 52 CA patients showing a sensitivity of 81% with specificity of 77%. CONCLUSIONS: CA is a complex entity and requires extensive testing for a positive diagnosis. This study highlights a series of non-invasive checkpoints, which can be useful in guiding the decision-making process towards a more accurate and rapid differential diagnosis.

Muscle involvement with pseudohypertrophy in systemic light chain amyloidosis: Case report.

RATIONALE: Muscle pseudohypertrophy is a rare manifestation of light chain amyloidosis (AL) amyloidosis. PATIENT CONCERNS: A 63-year-old woman presented with a 2-year history of progressive asthenia, macroglossia, dysphonia, cachexia, hypotension, paresthesia, and lower limb muscle hypertrophy. DIAGNOSIS: Free serum lambda light chains were increased, and fat pad biopsy demonstrated Congo red-positive deposits. Additionally, electromyography showed a myopathic pattern, whereas muscle biopsy revealed amyloid deposits. A diagnosis of λAL with cardiac, renal, nervous system, and skeletal muscle involvement was established. INTERVENTIONS AND OUTCOMES: The patient received 3 subsequent lines of therapy over the following 23 months, with very slow hematological remission followed by resolution of organ dysfunction. LESSONS: Despite its rarity, muscle involvement should be considered in patients diagnosed with AL amyloidosis associated with unexplained muscle hypertrophy or weakness associated with macroglossia or elevated troponin T levels in the absence of clear cardiac involvement.

Progress and challenges in the treatment of cardiac amyloidosis: a review of the literature.

Cardiac amyloidosis is a restrictive cardiomyopathy determined by the accumulation of amyloid, which is represented by misfolded protein fragments in the cardiac extracellular space. The main classification of systemic amyloidosis is determined by the amyloid precursor proteins causing a very heterogeneous disease spectrum, but the main types of amyloidosis involving the heart are light chain (AL) and transthyretin amyloidosis (ATTR). AL, in which the amyloid precursor is represented by misfolded immunoglobulin light chains, can involve almost any system carrying the worst prognosis among amyloidosis patients. This has however dramatically improved in the last few years with the increased usage of the novel therapies such as proteasome inhibitors and haematopoietic cell transplantation, in the case of timely diagnosis and initiation of treatment. The treatment for AL is directed by the haematologist working closely with the cardiologist when there is a significant cardiac involvement. Transthyretin (TTR) is a protein that is produced by the liver and is involved in the transportation of thyroid hormones, especially thyroxine and retinol binding protein. ATTR results from the accumulation of transthyretin amyloid in the extracellular space of different organs and systems, especially the heart and the nervous system. Specific therapies for ATTR act at various levels of TTR, from synthesis to deposition: TTR tetramer stabilization, oligomer aggregation inhibition, genetic therapy, amyloid fibre degradation, antiserum amyloid P antibodies, and antiserum TTR antibodies. Treatment of systemic amyloidosis has dramatically evolved over the last few years in both AL and ATTR, improving disease prognosis. Moreover, recent studies revealed that timely treatment can lead to an improvement in clinical status and in a regression of amyloid myocardial infiltration showed by imaging, especially by cardiac magnetic resonance, in both AL and ATTR. However, treating cardiac amyloidosis is a complex task due to the frequent association between systemic congestion and low blood pressure, thrombo-embolic and haemorrhagic risk balance, patient frailty, and generally poor prognosis. The aim of this review is to describe the current state of knowledge regarding cardiac amyloidosis therapy in this constantly evolving field, classified as treatment of the cardiac complications of amyloidosis (heart failure, rhythm and conduction disturbances, and thrombo-embolic risk) and the disease-modifying therapy.

Clinical characteristics in patients with hereditary amyloidosis with Glu54Gln transthyretin identified in the Romanian population.

BACKGROUND: In Romania, 23 patients have been diagnosed with hereditary transthyretin amyloidosis (ATTRh), 18 of whom have the Glu54Gln mutation. This retrospective cohort included all patients with Glu54Gln-mutated ATTRh who were diagnosed in Romania from 2005 to 2018. RESULTS: Of 18 patients, 10 were symptomatic, five were asymptomatic carriers and three died during the study. All originated from North-East Romania. Median age at symptom onset was 45 years; median age at death was 51 years. All patients had cardiac involvement, including changes in biomarkers (mean N-terminal-pro B-type natriuretic peptide: 2815.6 pg/ml), electrocardiography (15% atrial fibrillation, 38% atrioventricular block, 31% right bundle block), and echocardiography (mean interventricular septum: 16 mm, mean left ventricular ejection fraction: 49%). Scintigraphy showed myocardial radiotracer uptake in all patients. In addition, 92% of patients had polyneuropathy at diagnosis and 53% had carpal tunnel syndrome; 69% exhibited orthostatic hypotension and 31% suffered from diarrhea. No renal or liver involvement was observed. CONCLUSIONS: This is the largest Glu54Gln-mutated ATTRh cohort diagnosed to date, and to our knowledge the first describing this variant worldwide. Clinical features of this variant are early onset, neurological and cardiac involvement, aggressive disease progression and short survival. Early diagnosis and therapeutic intervention have potential to improve prognosis in ATTRh.