Abstract
Purpose
We described the incidence and ECG factors associated with de novo atrial fibrillation (AF) in patients diagnosed with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) to ...drive tailored arrhythmia screening.
Background
Data on the incidence rate and factors associated with de novo AF in patients with ATTRwt-CA is limited.
Methods
Multicenter, retrospective, observational cohort study performed in six referral centers for CA. All consecutive patients diagnosed with ATTRwt-CA between 2004 and 2020 with >1-year follow up (FU) were enrolled in the study and were divided into three groups according to presence of AF: (1) patients with “known AF”; (2) patients in “sinus rhythm” and (3) patients developing “de novo AF” during FU. Incidence and factors associated with AF in patients with ATTRwt were the primary outcomes.
Results
Overall, 266 patients were followed for a median of 469 days: 148 (56%) with known AF, 84 (31.6%) with sinus rhythm, and 34 (12.8%) with de novo AF. Age and gender were similarly distributed. At multivariable analysis, PR (Hazard Ratio HR: 1.008; 95% CI: 1.001–1.016), QRS (HR: 1.022; 95% CI: 1.002–1.043) and left atrial dilatation >50mm (HR: 3.429, 95% CI: 1.565–7.329) were associated with de novo AF at FU. Patients presenting with at least two risk factors (PR >200ms, QRS >120ms or LAD >50mm) had a higher risk of developing de novo AF compared to patients with no risk factors (HR 14.918; 95% CI: 3.242–31.646).
Conclusions
Incidence of de novo AF in patients with ATTRwt is 20.7%/year. Longer PR and QRS duration and left atrial dilation are associated with arrhythmia onset.
Funding Acknowledgement
Type of funding sources: None.
Background: Weight loss is common in juvenile idiopathic arthritis (JIA) and has been positively correlated with an increase in the production of proinflammatory cytokines. Objective: To assess if ...plasma leptin is a mediator of cytokine dependent decreased food intake during inflammatory diseases and if it is increased in JIA. Methods: Leptin levels were determined in 31 patients with polyarticular disease and in 37 with oligoarticular disease; 32 healthy children served as controls. Results: Patients had significantly reduced body mass index (BMI) compared with controls (17.3 (3) v 19.1 (3) kg/m2; p<0.005). Leptin was significantly lower in patients than controls (8.1 (4.8) v 10.7 (7.3) ng/ml; p = 0.036), but leptin/BMI values were similar. Absolute (8.2 (4.8) v 8 (4.9); p>0.05) and normalised (0.45 (0.24) v 0.47 (0.24); p>0.05) leptin levels were not significantly different between patients with active and inactive disease and between patients with oligoarticular and polyarticular arthritis (7.8 (4.4) v 8.6 (5.3); p>0.05 and 0.45 (0.23) v 0.48 (0.26); p>0.05, respectively). Conclusions: Leptin production per unit of fat mass is similar in patients and controls. The hypothesis that high levels of proinflammatory cytokines that characterise JIA might induce an increase of adipocytes leptin production is not supported by the results. Leptin may be a marker of nutritional status of JIA.
Melatonin plays a role in the regulation of biological rhythms, body temperature presents circadian variations with lower levels during nighttime, when melatonin levels are very high, and thyroid ...hormones influence shiver independent thermogenesis. We have investigated on possible interactions between the hypothalamic-pituitary-thyroid axis and melatonin in the control of body temperature in humans.
Peripheral blood samples for thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone (TSH), free-thyroxine (FT4), melatonin levels determination and body temperature measurements were obtained every four hours for 24-hours starting at 0600 h in a controlled temperature and light-dark environment from ten healthy males, aged 38-65 (mean age +/-s.e. 57.4+/-3.03, mean body mass index +/-s.e. 25.5+/-0.75). We calculated fractional variation and correlation on single time point hormone serum levels and tested whether the time-qualified data series showed consistent pattern of circadian variation.
A statistically significant difference was evidenced for the fractional variation of daytime TSH serum levels (0600 h-1000 h vs. 1000 h-1400 h, p=0.01, 1000 h-1400 h vs. 1400 h-1800 h, p=0.0001, 1400 h-1800 h vs. 1800 h-2200 h, p=0.001) and for the fractional variation of FT4 serum levels at 1800 h-2200 h vs. 2200 h-0200 h (p=0.02). FT4 serum levels correlated positively with TRH serum levels at 1000 h (r=0.67, P=0.03) and at 1400 h (r=0.63, p=0.04), negatively with TSH serum levels at 2200 h (r=-0.67, p=0.03), negatively with melatonin serum levels at 2200 h (r=-0.64, p=0.04) and at 0200 h (r=-0.73, p=0.01). TRH serum levels correlated positively with TSH serum levels at 0200 h (r=0.65, p=0.04) and at 0600 h (r=0.64, p=0.04). Body temperature correlated positively with FT4 serum levels at 1000 h (r=0.63, p=0.04) and negatively with melatonin serum levels at 0200 h (r=-0.64, p=0.04). A clear circadian rhythm was validated for body temperature (with acrophase in the morning) and melatonin, TRH and TSH secretion (with acrophase at night), while FT4 serum level changes presented ultradian periodicity (with acrophase in the morning).
Changes of TSH serum levels are smaller and those of FT4 are greater at night, when melatonin levels are higher, so that the response of anterior pituitary to hypothalamic TRH and of thyroid to hypophyseal TSH may be influenced by the pineal hormone that may modulate the hypothalamic-pituitary-thyroid axis function and influence the circadian rhythm of body temperature.
Transthyretin-mediated (ATTR) amyloidosis is a progressive and fatal disease caused by TTR amyloid accumulation in organs and tissues. Patients with hereditary or wild-type ATTR amyloidosis ...frequently develop cardiomyopathy, as demonstrated by cardiac biomarkers and imaging. Patisiran, an IV RNAi therapeutic that inhibits synthesis of wt and variant TTR, is approved for the treatment of hATTR amyloidosis with polyneuropathy.
Patisiran can benefit a range of disease-relevant measures in patients with ATTR amyloidosis with cardiomyopathy.
Patients were 18–85 yrs old with evidence of cardiac amyloidosis by echocardiography, either ATTR amyloid deposition on tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with cardiomyopathy, and with prior hospitalization for heart failure due to ATTR amyloidosis or clinical evidence of heart failure. Patients were randomized (1:1) to receive patisiran IV 0.3 mg/kg or placebo Q3W for 12 months. The primary endpoint was change from baseline in 6-MWT at Month 12 (M12) with patisiran vs placebo. Exploratory parameters at M12 included changes in cardiac biomarkers, echocardiographic parameters of cardiac structure and function, and Tc scintigraphy parameters.
APOLLO-B enrolled 360 patients (patisiran, n=181; placebo, n=179): median age (range) age, 76.0 (41, 85) yrs; male, 89%; wtATTR, 80%; on tafamidis at baseline, 25%. Patisiran showed a significant benefit compared with placebo in the 6-MWT (median 95% CI change from baseline: patisiran, -8.15 -16.42, 1.50; placebo, -21.35 -34.05, -7.52; Hodges-Lehmann estimate of median difference: 14.69 0.69, 28.69; p=0.0162). Patisiran demonstrated favorable trends in change from baseline of NT-proBNP (adjusted geometric mean fold change ratio 95% CI: 0.8 0.73, 0.89; nominal p=1.825 × 10–5) and troponin I (LS mean SEM difference: -29.9 20.7; nominal p=0.1491) at M12 vs placebo. Patisiran also demonstrated a trend towards benefit in change from baseline of most evaluated echocardiographic parameters at M12 vs placebo. Patisiran-treated patients who were evaluable for scintigraphy (n=37) experienced a reduction (37.8%) or no change (62.2%) in Perugini grade at M12 compared with baseline (3 8.1% patisiran patients reduced from baseline by ≥2 Perugini grades). Among evaluable placebo patients (n=28) at M12, none experienced a reduction from baseline in Perugini grade, and 1 (3.6%) increased in grade. Patisiran demonstrated an acceptable safety profile; AEs were mostly mild or moderate in severity, and there were no no cardiac safety concerns.
Exploratory analyses after 12 months provide further evidence for the potential benefit of patisiran treatment on cardiac biomarkers and manifestations of cardiac amyloid involvement in patients with ATTR amyloidosis. The long-term impact of patisiran on these measures will be assessed in the ongoing APOLLO-B open-label extension (NCT03997383).
Osteoprotegerin (OPG) serves as a soluble decoy receptor for RANKL to inhibit osteoclast formation and activity. Hormones such as PTH and glucocorticoids have been reported to decrease OPG ...concentrations, while estrogens, transforming growth factor b, related bone morphogenic factor and thrombopoietin reportedly enhance the OPG production in the osteoblastic and bone stromal cells. Since bone turnover shows a prominent circadian rhythm in laboratory animals and humans, with bone resorption increasing at night, we investigated the time structure of circulating OPG concentrations in a group of nine healthy subjects (six women and three men; in the age range of 26–49 years). Blood samples for OPG determination were collected every 4 h for 24 h on the same day, starting at 08:00 in the morning. Data were analyzed by inferential statistical procedures, including the single and population-mean cosinor. A 12-h component was found to characterize serum OPG concentrations (P = 0.038) with peak concentrations around noon and midnight. No statistically significant circadian rhythm of OPG concentrations could be found by cosinor in our study population. The mean 24-h OPG concentration was higher in women than in men (mean ± S.E.: 3.13 ± 0.44 vs. 1.94 ± 0.26 pmol/l, Student t = 2.325, P = 0.053). Since PTH concentrations also exhibit a bimodal pattern along the 24-h scale, PTH may be tested as a putative determinant of the observed changes in serum concentrations of osteoprotegerin.
CSES (China Seismo-Electromagnetic Satellite) is a Chinese–Italian scientific space mission dedicated to monitor the variations of the main parameters of the topside ionosphere (electric and magnetic ...fields, plasma parameters, charge particle fluxes) caused by either natural emitters – especially earthquakes – or artificial ones.
The CSES satellite was successfully launched from the Jiuquan Satellite Launch Center located in the west of Inner Mongolia on February 2nd, 2018, and it is now orbiting under nominal conditions. The expected mission lifetime amounts to 5 years. CSES is the first element of a multi-satellite monitoring system; several satellites are scheduled for the next few years.
The High-Energy Particle Detector (HEPD) is the main contribution of the Italian collaboration to the mission. It was designed and built in order to detect electrons in the energy range between 3 and 100 MeV, protons between 30 and 200 MeV, and light nuclei in the MeV energy window.
The electronics of the detector was designed following stringent requirements on mechanical and thermal stability, power consumption, radiation hardness and double redundancy. The system successfully went through the space qualification tests. In this paper, we describe the HEPD electronics, the space qualification tests performed before launch, and the in-flight performance of the detector.
CSES (China Seismo-Electromagnetic Satellite) is a Chinese-Italian space mission dedicated to monitoring of variations of the electromagnetic field and waves, plasma parameters, and particle fluxes ...induced by natural sources and artificial emitters in the near-Earth space. The satellite was launched from the Jiuquan Satellite Launch Center in the Gobi desert (Inner Mongolia, China) on 2, 2018. The expected mission lifetime amounts to 5 years.
The Italian contribution to the mission includes the design and construction of the High-Energy Particle Detector (HEPD), aimed to detect electrons in the energy range between 3 and 100 MeV and protons between 30 and 200 MeV, as well as light nuclei in the MeV energy range.
In this paper, we describe the calibration procedures applied to HEPD based on data acquired during two tests at accelerator laboratories, which were performed on HEPD Flight Model prior to the delivery to China for final integration. An additional acquisition of cosmic muons was performed in order to better characterize the detector response before launch.
Hereditary transthyretin amyloidosis (ATTRv) is a multisystemic, rare, inherited, progressive and adult-onset disease, affecting the sensorimotor nerves, heart, autonomic function and other organs. ...The actual scenario of pharmaceutical approaches for ATTRv amyloidosis includes five main groups: TTR stabilizers, TTR mRNA silencers, TTR fibril disruptors, inhibitor of TTR fibril seeding and gene therapy. Patisiran is a small, double-stranded interfering RNA encapsulated in a lipid nanoparticle, able to penetrate into hepatocytes, where it selectively targets TTR mRNA, reducing TTR production. We report and discuss 9 cases of different patients with ATTRv amyloidosis successfully managed with patisiran in the real clinical practice. Literature data, as well as the above presented case reports, show that this drug is effective and safe in improving both neurological and cardiovascular symptoms of ATTRv amyloidosis, and to maintain a good QoL, independently form the stage of the disease and the involved mutation. Recent studies correlated improved functional and biochemical outcomes with a regression of amyloid burden, especially at the cardiac level. Today, patisiran can be considered a valid therapeutic option for the management of patients with ATTRv amyloidosis and polyneuropathy and cardiovascular symptoms.
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