Abstract Background Amyloidosis is a systemic disease caused by fibrillary misfolded protein deposition in several organs including the heart. Cardiac deposition is the leading cause of death in these patients. Echocardiography is the imaging technique mostly used to study cardiac amyloidosis. Many studies tried to identify earlier markers to stratify the mortality risk. Heart stiffness is the main issue leading the heart dysfunction. However, few data are available on the possible role of connection between heart and possible vessels alterations. Purpose: Aim of this study was to evaluate heart stiffness using Ventricular–arterial coupling (VAC) for relationship between heart and vessel tree. Methods We studied 58 patients (22 F and 36 M, aged 67.14± 12.49) with AL or ATTR amyloidosis and heart involvement. They were 42 AL and 16 ATTR patients. All patients were evaluated before treatment with a complete history, physical exam, serum markers of disease, and echocardiogram. The abdominal fat biopsy to confirm amyloid deposition was performed before treatment. Among all patients, 18 died with a mean OS of 12 months [IQR 1–24 months]. Results At baseline, VAC was increased in died patients (alive 1.53 ± 0.43 vs died 2.06 ± 1.73, p=0.09) but was ineffective to predict the risk of mortality (ROC analysis AUC 0.54, p=0.57). By analysing ejection and pre–ejection periods we found that they were both increased in alive patients (p=0.0016 and p=0.0072, respectively). Moreover, these periods were effective in prediction of the death risk (ejection time AUC 0.81, cut–off 239 msec, sensitivity 61.54% and specificity 88.24%; pre–ejection time AUC 0.75, cut–off 82 msec, sensitivity 84.62% and specificity 58.82%). No difference in VAC, ejection time or pre–ejection time were found comparing AL to ATTR, nor both parameters had a predictive role. Conclusion Amyloidosis induces an increase in heart stiffness and reduces heart contractility. This causes a reduction of peripheral blood flow and a worsening in heart failure. We demonstrated that this mechanism affects the capacity to pump blood in vessels due the reduction in time for loading during the systole. These results may predict the mortality with a significant sensitivity and specificity, regardless of the type of amyloidosis.

Abstract Amyloidosis is due to deposition of an excessive amount of protein in tissues. Cardiac Amyloidosis (CA) is an inauspicious prognostic factor and leading sudden death. We retrospectively analyzed 135 systemic amyloidosis, admitted between 1981 and 2019. 54 patients (46.30% F, aged 63.95±12.82) presented CA at baseline. In 53 patients, it was associated with a multiorgan involvement, while in one there was a primary myocardial deposition. We compared this group with the 81 patients (49.30% F, aged 58.33±15.65) who did not meet criteria for CA. CA presented a decreased SBP (p = 0.036), while nCA had an increased proteinuria (p = 0.02). TnI and NT–proBNP were significantly increased compared to nCA (p = 0.031 and p = 0.047, respectively). In CA patients we found an increased LDH compared to nCA (p = 0.0011). CA patients were also found to have an increased interventricular septum thickness compared to nCA (p = 0.002), a decreased Ejection Fraction (p = 0.0018) and Doppler velocity E/e’ ratio (p = 0.0095). Moreover, CA patients had an enhanced right atrium area (p = 0.0179), right ventricle basal diameter (p = 0.0112) and wall thickness (p = 0.0471) compared to nCA, and an increased inferior cava vein diameter (p = 0.0495) as well. TAPSE was the method chosen to evaluate systolic function of the right heart. In CA subjects very poor TAPSE levels were found compared to nCA patients (p = 0.0495). Additionally, we found a significant positive correlation between TAPSE and lymphocyte count (r = 0.47; p = 0.031) as well as Gamma globulins (r = 0.43, p = 0.033), Monoclonal components (r = 0.72; p = 0.047) and IgG values (r = 0.62, p = 0.018). CA patients had very poor survival rates compared to controls (30 vs. 66 months, p = 0.15). Mean survival of CA individuals was worse also when stratified according to NT–proBNP levels, using 2500 pg/mL as class boundary (174 vs. 5.5 months, respectively p = 0.013). In much the same way, a decreased right heart systolic function was correlated with a worse prognosis (18.0 months median survival, not reached in subjects with higher values than 18 mm, p = 0.0186). Finally, our data highlight the potential prognostic and predictive value of right heart alterations characterizing amyloidosis, as a novel clinical parameter correlated to increased LDH and immunoglobulins levels. Overall, we confirm the clinical relevance of cardiac involvement suggests that right heart evaluation may be considered as a new marker for clinical risk stratification in patients with amyloidosis.

Abstract Introduction Immunoglobulin (Ig) D (IgD) monoclonal gammopathy is a rare subtype of multiple myeloma (MM) associated with a worse prognosis. Ig light chains amyloidosis is a disorder characterized by extracellular deposition of Ig light chains in various tissues, leading to organ dysfunction. Case A 29–year–old woman was admitted for dyspnea and tachycardia for moderate efforts. Lab revealed hypogammaglobulinemia with a monoclonal IgD K paraprotein. There was an increase in K free chains, with a dramatic increase in K/λ free chains Ratio. Proteinuria was 1360 mg/24h with a free K chains Bence Jones Protein. An increase in values of Troponin–I (137,5 pg/mL) and NT–proBNP (12527 pg/mL) pointed towards heart involvement. Furthermore, the ECG showed low voltages in the peripheral leads. Echocardiogram showed a moderate concentric left ventricular hypertrophy with diffused myocardial speckled pattern, an ejection fraction (EF) of 53% and PAPs of 71 mmHg and pericardial effusion. Chest CT scan showed bilateral pleural effusion. Spine MRI and whole body PET/CT indicated areas of osteolytic lesions. Plasma cells infiltration (85% CD138, MUM1 and K chains positivity) was present at bone marrow biopsy. Amyloid deposition was detected in abdominal fat tissue sample. Total bone scintigraphy excluded a transthyretin heart deposition. Thus, amyloidosis associate to IgD MM was diagnosed. In few days heart failure worsened (hs–cTnI 156,6 pg/mL; NT–proBNP 26583 pg/mL, EF 48%,) and the patient began complaining non–productive cough, dyspnea, and columnar edema of the lower limbs. She was not eligible for bone marrow transplantation, so daratumumab, bortezomib, melphalan and prednisone were administered. Despite serological improvement after a short five days course of therapy, she worsened with a further reduction of EF (35%). Blood gas analysis showed hypoxemia and lactate increase quickly turned into a cardiogenic shock. She died by cardiac arrest, just three weeks after admission. Discussion The present case is remarkable for age and gender of the patient as well as the rapid onset and fast worsening of symptoms, which were related to secondary heart amyloid deposition. Symptoms associated to cardiac amyloidosis are expressions of right heart involvement. The early good results of the therapy did not turn the evolution of disease. The fatal and overwhelming progression of the myocardial involvement led to the patient’s death in less than one month.

Abstract Background Primary mediastinal B–cell lymphoma (PMBCL) is an aggressive B–cell lymphoma that represents 2–3% of non –Hodgkin lymphoma cases and typically affects young adult Caucasian women. Diagnosis can be difficult and often need a multidisciplinary approach. Case a 75 year old female, with history of hypertension, came to ER for severe dyspnea. She complains also neck and left arm oedema. Blue swelling of face and trunk were described. Heart PoCUS was inconclusive, describing only a hypoechoic dilation of right atrium while the other three heart chambers were reduced in dimensions. Chest TC revealed a huge mediastinal mass next to a thrombosis of superior cava vein and right atrium (7 cm diameter) and a diffuse subsegmental pulmonary embolism. Arm and neck Lymphnodes were also enlarged . Low molecular weight heparin was given twice a day. Due the respiratory failure a high–flow nasal cannula oxygen treatment was performed. PET revealed FDG uptake in antero–superior mediastinum, but there was the same uptake in heart right atrium without a connection with the previous described. Therefore, this was no more considered as thrombus but as mass. The micro–bubble test revealed right to left shunt. She refused heart MRI. The patient was not suitable for an open–surgery biopsy, thus she was scheduled for a TC guided one, in order to obtain a pathological diagnosis for a suspected right atrium sarcoma. Due to the high risk we choose to perform the less invasive as possible way to have a histological sample. Thus, and intravascular biopsy of atrial mass by femoral vein was performed. The patient did not present any sequelae after procedure and she continued anticoagulation. The subsequent histological analysis revealed a PMBCL with a primary localization in Right atrium. Unfortunately, a sepsis by multiple resistant pseudomonas Aeruginosa and Aspergillus spp. arose and the patient died three weeks after biopsy. Conclusion A PMBCL is a rare and aggressive disease. Like in our patient, mediastinal syndrome is often associated to the disease. However, intracardiac localization are even rarer events. In large case series, less than 1% of intracardiac masses were lymphomas. In our patient, open–surgery was not suitable for multiple comorbidities. However, intravascular approach was less aggressive but effective to obtain enough tissue for diagnosis. Unfortunately, the immune suppression related to PMBCL and opportunistic infections drive a mortal sepsis.

Abstract Funding Acknowledgements Type of funding sources: Private hospital(s). Main funding source(s): dedicated cardiovascular research foud Background Recent advances support the concept that pre-persistent Atrial Fibrillation (AF) does not explain the wholeness of embolic strokes, suggesting the recently postulated hypothesis of a broad Atrial Cardiomyopathy (AC). In contrast to its worldwide distribution and its very inclusive definition, pathogenic mechanisms underlying AC are still largely unknown. Folate cycle disorders (FCD) are a yet underrated dysmetabolism only partly explained by methylene tetrahydrofolate reductase (MTHFR)-inherited defects. On a translational basis, FCD could hinder both endothelial and circulating endothelial progenitor cell (EPCs) functioning, therefore providing one-shot explanation to both atrial stasis (increasing atrial fibrosis and generating atrial hypocontractility) and endothelial dysfunction (ED). If such cardiac-bone marrow networking would be verified, a fundamental pathogenic mechanism of AC and subsequent AF would be unraveled. Purpose This study aims to enquire for the hypothesis that: 1) atrial fibrosis (AFib) would relate to FCD (intended as both: a)MTHFR C677T inherited mutations and b)bone-marrow function disorders, here referring to erythropoiesis diversions) and 2) AF patients would show dysfunctional EPCs. Methods We studied 59 consecutive patients admitted to the Cardiology Unit of the General Hospital "F.Miulli", with preserved EF, subjected to AF ablation. AFib was quantified by relative % of low-voltage (<0,5 mV) bipolar peak-to-peak points, with respect to the wholeness of the endocavitary mapping. Blood count cell was evaluated. MTHFR C677T genotypes were elucidated by RT-PCR. Folate were measured by a commercial laboratory test. EPCs isolation and characterization were performed by Ficoll-Hypaque gradient and flow cytometry analysis for cell surface antigens: CD45, CD34, CD133, VEGFR2 and KDR. EPCs functional wound healing assay was performed. Results Baseline characteristics did not differ between Sample and Control groups (Fig. 1 – Left Table). % of Afib significantly differs between C677T MTHFR homozigosis patients (n=15) with respect to non-C677T MTHFR homozygosis patients (n=44) (Fig.1 – Right graph. - p < 0,02). Once univariate analysis was performed, subsequent multivariate analysis highlights highest fit once merged RBC, RDW-SD and folates values were inputed: Goodness of fit was proper, modelling good (Fig.2 – superior graph. - R2=0,39; p=0,0001). Either RBC, RDW-SD and folates coefficient reached significance (p < 0,0001; p < 0,01; p < 0,05 respectively). Number of EPCs significantly differs between AF patients and matched controls (Fig 2 – inferior graph. – p < 0,001). Conclusions Our findings support the hypothesis that genetically determined folates dysmetabolism (MTHFR dysfunction) promotes AFib via a complex cardiac-bone marrow networking involving circulating EPCs and unraveled by erythropoiesis diversions. Such results suggest a pathogenic role of folate cycle disorders in the AC development.

The somatotroph axis function shows a decline in the elderly (somatopause). In particular growth hormone (GH) response to GH-releasing hormone (GHRH) is reduced in aged man but less than that observed in GH-deficient adults (GHDAs). Plasma GH response to GHRH (1 mu g/kg BW) was significantly lower in four GHDAs than in seven healthy aged men 30, 60, and 90 min after acute GHRH administration. To verify whether a priming regimen might be able to increase the reduced GH response to GHRH, both healthy aged men and GHDA patients underwent repetitive administration of GHRH (100 mu g GHRH intravenously as a single morning dose, every 2 days for 12 days). After the GHRH-priming regimen, plasma GH values 30, 60, and 90 min after the acute GHRH test were significantly higher than values at the corresponding time points before priming regimen in healthy aged men but not in GHDA patients. These findings confirmed that somatotroph cells become less sensitive to GHRH with normal aging and demonstrate that repetitive administration of GHRH restores the attenuated response only in healthy aged men but not in GHDA patients. This could support the possible use of GHRH or its analogs instead of recombinant human GH in elderly patients with the advantage of preserving the endogenous pulses of GH with the secretion of the different isoforms of GH. However, concerns arise about the possible role of these molecules in tumorigenesis and tumor growth promotion.