[18F]-florbetaben PET/CT is sensitive for cardiac AL amyloidosis.

Often differential diagnosis between AL and ATTR amyloidosis is difficult. Concerning ATTR, sensitive diagnostic tool, as diphosphonate scintigraphy, was validated, instead of no imaging approach is as accurate in AL. Cardiac ultrasound and circulating biomarkers may raise the clinical suspicion but biopsy remains the only option for diagnosis. We aimed to explore the sensitivity of 18F-Florbetaben PET respect to blood tests or periumbilical fat (POF), cardiac, bone marrow (BM) or other tissues biopsies in a cohort of 33 patients.

Antithrombotic properties of Tafamidis: An additional protective effect for transthyretin amyloid cardiomyopathy patients.

INTRODUCTION: Tafamidis is a molecular chaperone that stabilizes the transthyretin (TTR) homo-tetramer, preventing its dissociation and consequent deposition as amyloid fibrils in organ tissues. Tafamidis reduces mortality and the incidence of hospitalization for cardiovascular causes in patients with TTR amyloid (ATTR) cardiomyopathy. As ATTR cardiomyopathy is associated with a high risk of thromboembolic complications, we hypothesized that tafamidis may have a direct ancillary anti-thrombotic effect. METHODS: Primary human aortic endothelial cells (HAECs) were treated with tafamidis at clinically relevant concentrations and with plasma of patients, before and after the initiation of treatment with tafamidis. The expression of TF was induced by incubation with Tumor Necrosis Factor α (TNFα). Intracellular expression of tissue factor (TF) was measured by western blot. TF activity was measured by a colorimetric assay. Gene expressions of TF were measured by quantitative polymerase chain reaction. RESULTS: Treatment with tafamidis dose-dependently reduced the expression and activity of TNFα-induced TF. This effect was confirmed in cells treated with patients' plasma. Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation was significantly inhibited by tafamidis. Incubation of HAECs with tafamidis and the STAT3 activator colivelin partially rescued the expression of TF. CONCLUSIONS: Treatment with tafamidis lowers the thrombotic potential in human primary endothelial cells by reducing TF expression and activity. This previously unknown off-target effect may provide a novel mechanistic explanation for the lower number of thromboembolic complications in ATTR cardiomyopathy patients treated with tafamidis.

Pathophysiology of Cardiac Amyloidosis.

Amyloidosis refers to a heterogeneous group of disorders sharing common pathophysiological mechanisms characterized by the extracellular accumulation of fibrillar deposits consisting of the aggregation of misfolded proteins. Cardiac amyloidosis (CA), usually caused by deposition of misfolded transthyretin or immunoglobulin light chains, is an increasingly recognized cause of heart failure burdened by a poor prognosis. CA manifests with a restrictive cardiomyopathy which progressively leads to biventricular thickening, diastolic and then systolic dysfunction, arrhythmias, and valvular disease. The pathophysiology of CA is multifactorial and includes increased oxidative stress, mitochondrial damage, apoptosis, impaired metabolism, and modifications of intracellular calcium balance.

The Role of Scintigraphy with Bone Radiotracers in Cardiac Amyloidosis.

Cardiac amyloidosis (CA) is caused by the myocardial deposition of misfolded proteins, either amyloid transthyretin (ATTR) or immunoglobulin light chains (AL). The paradigm of this condition has transformed, since CA is increasingly recognized as a relatively prevalent cause of heart failure. Cardiac scintigraphy with bone tracers is the unique noninvasive technique able to confirm CA without performing tissue biopsy or advanced imaging tests. A moderate-to-intense myocardial uptake (Perugini grade ≥2) associated with the absence of a monoclonal component is greater than 99% specific for ATTR-CA, while AL-CA confirmation requires tissue biopsy.

Glioblastoma and Internal Carotid Artery Calcium Score: A Possible Novel Prognostic Partnership?

Purpose: Clinical evidence suggests an association between comorbidities and outcome in patients with glioblastoma (GBM). We hypothesised that the internal carotid artery (ICA) calcium score could represent a promising prognostic biomarker in a competing risk analysis in patients diagnosed with GBM. Methods: We validated the use of the ICA calcium score as a surrogate marker of the coronary calcium score in 32 patients with lung cancer. Subsequently, we assessed the impact of the ICA calcium score on overall survival in GBM patients treated with radio-chemotherapy. Results: We analysed 50 GBM patients. At the univariate analysis, methyl-guanine-methyltransferase gene (MGMT) promoter methylation (p = 0.048), gross total tumour resection (p = 0.017), and calcium score (p = 0.011) were significant prognostic predictors in patients with GBM. These three variables also maintained statistical significance in the multivariate analysis. Conclusions: the ICA calcium score could be a promising prognostic biomarker in GBM patients.

Wild-Type Transthyretin Cardiac Amyloidosis is Not Rare in Elderly Subjects: the CATCH Screening Study.

BACKGROUND: Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) affects older adults and is currently considered as a rare disorder. OBJECTIVE: We investigated for the first time the prevalence of ATTRwt-CA in elderly individuals from the general population. METHODS: General practitioners from Pisa, Italy, proposed a screening for ATTRwt-CA to all their patients aged 65-90 years, until 1,000 accepted. The following red flags were searched: interventricular septal thickness ≥12 mm, any echocardiographic, ECG or clinical hallmark of CA, or high sensitivity-troponin T ≥14 ng/L. Individuals with at least one red flag (n=346) were asked to undergo the search for a monoclonal protein and bone scintigraphy, and 216 accepted. RESULTS: Four patients received a non-invasive diagnosis of ATTRwt-CA. All complained of dyspnea on moderate effort. A woman and a man aged 79 and 85 years, respectively, showed an intense cardiac tracer uptake (grade 3), left ventricular (LV) wall thickening, grade 2 to 3 diastolic dysfunction, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) >1,000 ng/L. Two other patients (a man aged 74 years and a woman aged 83 years) showed a grade 2 uptake, an increased LV septal thickness, but preserved diastolic function, and NT-proBNP <300 ng/L. The prevalence of ATTR-CA in subjects ≥65 years was calculated as 0.46% (i.e., 4 out of the 870 subjects completing the screening, namely 654 not meeting the criteria for Step 2 and 216 progressing to Step 2). CONCLUSIONS: ATTRwt-CA is uncommon in elderly subjects from the general population, but more frequent than expected for a rare disease.

Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is a heart condition mostly found in older adults. ATTRwt-CA is considered a rare disease, although no systematic screening have been performed yet. The study aimed to understand how common this disease is among the general population aged 65 to 90 years in Pisa, Italy. To do this, general practitioners offered screening for ATTRwt-CA to their patients within this age group. The initial step of the screening involved checking for certain warning signs (red flags), like abnormal thickness in a part of the heart called the interventricular septum, unusual heart function observed through various tests, or elevated levels of a specific heart protein. Out of 1,000 individuals who began the screening process, 346 showed at least one of these red flags and were further examined using bone scintigraphy (a type of imaging test) and tests for a specific protein related to this condition. Of these, 216 agreed to proceed with these additional tests. The results showed that four of these patients actually had ATTRwt-CA. Their conditions varied in severity, with some showing more intense signs of the disease on the heart scans, thicker heart walls, and higher levels of heart stress proteins. All four patients experienced mild difficulty in breathing during physical activity. Based on these findings, the study concluded that about 0.46% of elderly individuals in the general population might have ATTRwt-CA, indicating that the disease is somewhat more common in this age group than previously thought.

Prevalence and clinical outcomes of isolated or combined moderate to severe mitral and tricuspid regurgitation in patients with cardiac amyloidosis.

AIMS: Evidence on the epidemiology and prognostic significance of mitral regurgitation (MR) and tricuspid regurgitation (TR) in patients with cardiac amyloidosis (CA) is scarce. METHODS AND RESULTS: Overall, 538 patients with either transthyretin (ATTR, n = 359) or immunoglobulin light-chain (AL, n = 179) CA were included at three Italian referral centres. Patients were stratified according to isolated or combined moderate/severe MR and TR. Overall, 240 patients (44.6%) had no significant MR/TR, 112 (20.8%) isolated MR, 66 (12.3%) isolated TR, and 120 (22.3%) combined MR/TR. The most common aetiologies were atrial functional MR, followed by primary infiltrative MR, and secondary TR due to right ventricular (RV) overload followed by atrial functional TR. Patients with isolated or combined MR/TR had a more frequent history of heart failure (HF) hospitalization and atrial fibrillation, worse symptoms, and higher levels of NT-proBNP as compared to those without MR/TR. They also presented more severe atrial enlargement, atrial peak longitudinal strain impairment, left ventricular (LV) and RV systolic dysfunction, and higher pulmonary artery systolic pressures. TR carried the most advanced features. After adjustment for age, sex, CA subtypes, laboratory, and echocardiographic markers of CA severity, isolated TR and combined MR/TR were independently associated with an increased risk of all-cause death or worsening HF events, compared to no significant MR/TR [adjusted HR 2.75 (1.78-4.24) and 2.31 (1.44-3.70), respectively]. CONCLUSION: In a large cohort of patients with CA, MR, and TR were common. Isolated TR and combined MR/TR were associated with worse prognosis regardless of CA aetiology, LV, and RV function, with TR carrying the highest risk.

Safety and efficacy of levosimendan in patients with cardiac amyloidosis.

BACKGROUND: Patients with cardiac amyloidosis (CA) often experience heart failure (HF) episodes. No evidence is available on inotropic therapy. This study aims to fill this gap by examining the safety and efficacy of levosimendan. METHODS: We retrieved all HF patients receiving ≥1 levosimendan infusion from 2013 to 2023. CA patients were matched with HF patients without CA (controls) based on sex, age, and left ventricular ejection fraction (LVEF). The response to levosimendan was measured as changes in daily urinary output, body weight, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR). RESULTS: CA patients (median age 77 years, 73% men, 59% with ATTR-CA) and controls were compared. Levosimendan infusion was stopped because of hypotension in 2 cases with CA and (in 1 case) worsening renal function, and in 2 controls because of ventricular tachycardia episodes and (in 1 case) hypotension. CA patients showed a trend toward increased daily urinary output (p = 0.078) and a significant decrease in body weight (p < 0.001), without significant changes in NT-proBNP (p = 0.497) and eGFR (p = 0.732). Both CA patients and controls displayed similar changes in urinary output, weight, and eGFR, but NT-proBNP decreased more significantly among controls (p < 0.001). No differences were noted in rehospitalization rates, but CA patients experienced higher mortality at 6 and 12 months (p = 0.003 and p = 0.001, respectively). CONCLUSIONS: Levosimendan appears safe for CA patients needing inotropic support. The diuretic response and weight decrease during hospitalization were comparable between CA patients and matched HF patients, despite the greater mortality of CA patients after discharge.

Stratifying Disease Progression in Patients With Cardiac ATTR Amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive cardiomyopathy. The clinical course varies among individuals and there are no established measures to assess disease progression. OBJECTIVES: The goal of this study was to assess the prognostic importance of an increase in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and outpatient diuretic intensification (ODI) as markers of disease progression in a large cohort of patients with ATTR-CA. METHODS: We evaluated landmark survival analysis based on worsening of NT-proBNP and requirement for ODI between time of diagnosis and a 1-year visit, and subsequent mortality in 2,275 patients with ATTR-CA from 7 specialist centers. The variables were developed in the National Amyloidosis Centre (NAC) cohort (n = 1,598) and validated in the external cohort from the remaining centers (n = 677). RESULTS: Between baseline and 1-year visits, 551 (34.5%) NAC patients and 204 (30.1%) patients in the external validation cohort experienced NT-proBNP progression (NT-proBNP increase >700 ng/L and >30%), which was associated with mortality (NAC cohort: HR: 1.82; 95% CI: 1.57-2.10; P < 0.001; validation cohort: HR: 1.75; 95% CI: 1.32-2.33; P < 0.001). At 1 year, 451 (28.2%) NAC patients and 301 (44.5%) patients in the external validation cohort experienced ODI, which was associated with mortality (NAC cohort: HR: 1.88; 95% CI: 1.62-2.18; P < 0.001; validation cohort: HR: 2.05; 95% CI: 1.53-2.74; P < 0.001). When compared with patients with a stable NT-proBNP and stable diuretic dose, a higher risk of mortality was observed in those experiencing either NT-proBNP progression or ODI (NAC cohort: HR: 1.93; 95% CI: 1.65-2.27; P < 0.001; validation cohort: HR: 1.94; 95% CI: 1.36-2.77; P < 0.001), and those experiencing both NT-proBNP progression and ODI (NAC cohort: HR: 2.98; 95% CI: 2.42-3.67; P < 0.001; validation cohort: HR: 3.23; 95% CI: 2.17-4.79; P < 0.001). CONCLUSIONS: NT-proBNP progression and ODI are frequent and consistently associated with an increased risk of mortality. Combining both variables produces a simple, universally applicable model that detects disease progression in ATTR-CA.

Disease features and management of cardiomyopathies in women.

Over the last years, there has been a growing interest in the clinical manifestations and outcomes of cardiomyopathies in women. Peripartum cardiomyopathy is the only women-specific cardiomyopathy. In cardiomyopathies with X-linked transmission, women are not simply healthy carriers of the disorder, but can show a wide spectrum of clinical manifestations ranging from mild to severe manifestations because of heterogeneous patterns of X-chromosome inactivation. In mitochondrial disorders with a matrilinear transmission, cardiomyopathy is part of a systemic disorder affecting both men and women. Even some inherited cardiomyopathies with autosomal transmission display phenotypic and prognostic differences between men and women. Notably, female hormones seem to exert a protective role in hypertrophic cardiomyopathy (HCM) and variant transthyretin amyloidosis until the menopausal period. Women with cardiomyopathies holding high-risk features should be referred to a third-level center and evaluated on an individual basis. Cardiomyopathies can have a detrimental impact on pregnancy and childbirth because of the associated hemodynamic derangements. Genetic counselling and a tailored cardiological evaluation are essential to evaluate the likelihood of transmitting the disease to the children and the possibility of a prenatal or early post-natal diagnosis, as well as to estimate the risk associated with pregnancy and delivery, and the optimal management strategies.

Screening the health status of people working in a university.

BACKGROUND: We aimed to evaluate the physical and mental well being of people working in our academic institution. METHODS: This online survey targeted professors ( n  = 108), researchers ( n  = 78), technical and administrative staff ( n  = 279) working in the Scuola Superiore Sant'Anna (Pisa, Italy). Twenty-four multiple-choice questions explored the physical and mental health status, the main cardiovascular risk factors and levels of physical activity, the risk of cancer, and eating and drinking habits. RESULTS: Over 1 week, 112 participants out of 465 (24%) completed the survey [69% women, median age 43 years (interquartile range 33-53)]. The physical and mental health were judged as 'poor' by 5% and 13%. Many individuals had at least one cardiovascular risk factor (diabetes, 4%; hypertension, 10%; family history of coronary artery disease before 40 years, 21%; hypercholesterolemia, 24%; current or former smoking habit, 39%), and 6% had all of them. Many participants were rather sedentary: for example, 44% never or hardly ever walked at a quick pace for ≥20 min. As for eating and drinking habits, 36% ate sweets five or six times a week or every day, 15% drank beer and/or wine at least five or six times a week, and 5% drank spirits three or four times a week. CONCLUSIONS: A small but not negligeable proportion of responders complained of 'poor' health, and 65% had at least one cardiovascular risk factor. The global levels of physical activity and eating and drinking habits were globally suboptimal. Educational and screening activities to improve the wellbeing of people working in academia are advisable.