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.

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 NorthEast 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.

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.

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Multiple myeloma is a malignant disease, which consists of the clonal proliferation of plasma cells that will lead to the accumulation of a monoclonal protein in the serum and/or urine, with organic damage. Extramedullary involvement is found in approximately 5% of cases of myeloma. Multiple myeloma with determination in the central nervous system is extremely rare and is associated with a bad prognosis. A targeted treatment scheme for this complication is not described, but the therapeutic approach should follow the same steps as in the case of other lymphoproliferative diseases with neurological involvement ( association of intrathecal chemotherapy applications cytarabine and methotrexate, with systemic treatment and depending on the response local radiotherapy should be performed). The occurrence of extramedullary disease in the evolution of multiple myeloma is a complication associated with a poor prognosis.

Hereditary spherocytosis is an inherited hemolytic anemia due to red cell membrane defects, characterised by chronic hemolysis with different severity degrees, splenomegaly and microspherocytosis on the peripheral blood film. Among the possible complications in these patients are aplastic crisis and extramedullary hematopoiesis. In this article we present the case of a 42 years old man with hereditary spherocytosis diagnosed during childhood (average haemoglobin (Hb) value of 11-12 g/dl), which presented with worsening anemia, fever, chills, bone and muscle pain. The evolution was with accentuation of anemia (Hb 4.2 g/dl), decease of reticulocyte number (Ret 0,8%) and bilirubin (indirect bilirubin 2.7 g/dl). ParvovirusB19 DNA was 100.000.000 copies/ml. A computer tomography (CT)scan was performed and showed extramedullary hematopoiesis areas situated paravertebraly in the inferior thorax and hepatosplenomegaly. The infectious episode was self-limited and improved with substitution treatment.

Funding Acknowledgements Type of funding sources: None. Background Cardiac amyloidosis (CA) is characterized by the extracellular deposition of amyloid fibrils in the heart, mostly light chain (AL) and transthyretin (ATTR) amyloidosis. Recent data have improved both the recognition and treatment of ATTR CA. The therapeutic advances in ATTR CA led to improvement in survival and quality of life, but less detailed evidence is available for the myocardial changes during treatment. Purpose The aim of this pilot study is to evaluate cardiac response under treatment with the genetic "silencer" patisiran in patients with mixed phenotype ATTR with an indication for neuropathy, using multimodal imaging techniques. Methods We prospectively evaluated consecutive patients with mixed phenotype v-ATTR amyloidosis who had received patisiran for aggravated polyneuropathy since 2021. All patients had a complete clinical, paraclinical and comprehensive echocardiography evaluation including myocardial deformation assessment, prior to receiving patisiran and at most recent follow-up. Five of our patient had complementary cardiac magnetic resonance (CMR) at baseline and 1 year follow-up. Results We included 13 patients (mean age 48.1±5.4 yo, 4 men) monitored for the therapeutic response based on the current ESC expert consensus on the monitoring of ATTR CA. They have all been diagnosed with variant ATTR with the same mutation - Glu54Gln - with severe mixed phenotype: both cardiac involvement and autonomous and peripheral polyneuropathy. Time since first diagnosis was 3.4 ±0.8 years, and they had all received Tafamidis 20 mg before being switched to patisiran. At 1 year of treatment, there was no significant change in NYHA functional class, but 6 MWT could not be performed due to impairment related to polyneuropathy. There was no significant change in NT-proBNP during treatment (median at baseline 543 pg/ml vs follow-up 255 pg/ml, p = 0.75). Echocardiography showed no significant change in LV maximal wall thickness (MWT), LV mass index (LVMi), LVEF, stroke volume and myocardial deformation (LV GLS) (Table). Based on these echocardiographic and biological parameters we considered our patients stationary. Meanwhile, CMR confirmed no significant difference between baseline and follow-up in LVMi, MWT and LVEF. Moreover, there was no difference in the visually assessed LGE distribution, native T1, T2 and ECV values (Table, Case vignette). Based on the tissue characterization all patients were considered stable regarding ATTR-CA evolution. We found strong correlations between echo and MRI for LVEF (r=0.71), LVEDV (r=0.67) and MWT (r=0.66). Conclusions Even if used after more than 3 years from first diagnosis in our cohort, structural and functional cardiac parameters remain stable under patisiran therapy. Our study highlights the utility of introducing CMR as an alternative to echocardiography in ATTR-CA disease monitoring protocols, based on its high accuracy, strong correlations and complexity of derived parameters.

Background Cardiac amyloidosis (CA) is described as one entity. However, several subtypes of amyloid can infiltrate the heart: light chain (AL) and tranthyretin (ATTR) are the most common. Purpose To characterize the specific findings of the CA subtypes as a tool to aid differential diagnosis between AL and ATTR CA. Material and methods: Consecutive patients with CA were evaluated by clinical examination, ECG, cardiac biomarkers and echocardiography with both conventional and myocardial deformation study of the left ventricle (LV), left atrium (LA) and right ventricle (RV). Amyloid subtype was described using light chain assessment for AL-CA and 99Tc-HMPD scintigraphy and TTR gene sequencing for ATTR-CA. Results 32 patients with CA were included, 13 with ATTR and 19 with AL. Patients in AL group were significantly older, with higher levels of cardiac biomarkers. At similar LV EF and wall thickness, they had lower GLS. LA function parameters were also lower in AL pts (table). Using ROC curves, the best predictors for AL diagnosis were NTproBNP (AUC 0.937) and Tn levels (AUC 0.958), as well as LV GLS and pericardial fluid presence (both AUC 0.750). Conclusions At similar LV wall thickness and ejection fraction, cardiac dysfunction appears to be more severe in AL pts, with lower global LV longitudinal strain, worse LA function, higher sPAP and NTproBNP. ATTR (13 pts) AL (19 pts) p Age (years) 50 ± 12 60 ± 8 0.01 NTproBNP (pg/mL) 3066 ± 3720 11755 ± 9114 0.02 hsTnI (ng/mL) 0.005 ± 0.008 0.147 ± 0.161 0.04 Pericardial fluid (%) 53% 100% 0.002 LVEDV (mL) 88 ± 25 75 ± 38 NS LVMi (g/m2) 166 ± 47 168 ± 41 NS LVEF (%) 50 ± 8 49 ± 16 NS LV GLS (%) -12.1 ± 3.8 -8.9 ± 4.5 0.04 Septal Basal/Apical LS 0.33 ± 0.17 0.25 ± 0.27 NS LAVi (mL/m2) 46 ± 21 45 ± 14 NS LAEF 4CV (%) 35 ± 21 24 ± 8 0.05 LA systolic strain (%) 17.4 ± 11.9 10.5 ± 5.0 0.02 RV free wall thickness (mm) 7.0 ± 1.5 7.6 ± 1.4 NS RV 6-segments strain (%) -15 ± 4 -10 ± 8 0.09 sPAP (mmHg) 36.6 ± 12.0 48.6 ± 17.2 0.04