Parameters and algorithms to evaluate cardiac mechanics by conductance catheter

This work is structured as follows: In Section 1 we discuss the clinical problem of heart failure. In particular, we present the phenomenon known as ventricular mechanical dyssynchrony: its impact on cardiac function, the therapy for its treatment and the methods for its quantification. Specifically, we describe the conductance catheter and its use for the measurement of dyssynchrony. At the end of the Section 1, we propose a new set of indexes to quantify the dyssynchrony that are studied and validated thereafter. In Section 2 we describe the studies carried out in this work: we report the experimental protocols, we present and discuss the results obtained. Finally, we report the overall conclusions drawn from this work and we try to envisage future works and possible clinical applications of our results. Ancillary studies that were carried out during this work mainly to investigate several aspects of cardiac resynchronization therapy (CRT) are mentioned in Appendix. -------- Ventricular mechanical dyssynchrony plays a regulating role already in normal physiology but is especially important in pathological conditions, such as hypertrophy, ischemia, infarction, or heart failure (Chapter 1,2.). Several prospective randomized controlled trials supported the clinical efficacy and safety of cardiac resynchronization therapy (CRT) in patients with moderate or severe heart failure and ventricular dyssynchrony. CRT resynchronizes ventricular contraction by simultaneous pacing of both left and right ventricle (biventricular pacing) (Chapter 1.). Currently, the conductance catheter method has been used extensively to assess global systolic and diastolic ventricular function and, more recently, the ability of this instrument to pick-up multiple segmental volume signals has been used to quantify mechanical ventricular dyssynchrony. Specifically, novel indexes based on volume signals acquired with the conductance catheter were introduced to quantify dyssynchrony (Chapter 3,4.). Present work was aimed to describe the characteristics of the conductancevolume signals, to investigate the performance of the indexes of ventricular dyssynchrony described in literature and to introduce and validate improved dyssynchrony indexes. Morevoer, using the conductance catheter method and the new indexes, the clinical problem of the ventricular pacing site optimization was addressed and the measurement protocol to adopt for hemodynamic tests on cardiac pacing was investigated. In accordance to the aims of the work, in addition to the classical time-domain parameters, a new set of indexes has been extracted, based on coherent averaging procedure and on spectral and cross-spectral analysis (Chapter 4.). Our analyses were carried out on patients with indications for electrophysiologic study or device implantation (Chapter 5.). For the first time, besides patients with heart failure, indexes of mechanical dyssynchrony based on conductance catheter were extracted and studied in a population of patients with preserved ventricular function, providing information on the normal range of such a kind of values. By performing a frequency domain analysis and by applying an optimized coherent averaging procedure (Chapter 6.a.), we were able to describe some characteristics of the conductance-volume signals (Chapter 6.b.). We unmasked the presence of considerable beat-to-beat variations in dyssynchrony that seemed more frequent in patients with ventricular dysfunction and to play a role in discriminating patients. These non-recurrent mechanical ventricular non-uniformities are probably the expression of the substantial beat-to-beat hemodynamic variations, often associated with heart failure and due to cardiopulmonary interaction and conduction disturbances. We investigated how the coherent averaging procedure may affect or refine the conductance based indexes; in addition, we proposed and tested a new set of indexes which quantify the non-periodic components of the volume signals. Using the new set of indexes we studied the acute effects of the CRT and the right ventricular pacing, in patients with heart failure and patients with preserved ventricular function. In the overall population we observed a correlation between the hemodynamic changes induced by the pacing and the indexes of dyssynchrony, and this may have practical implications for hemodynamic-guided device implantation. The optimal ventricular pacing site for patients with conventional indications for pacing remains controversial. The majority of them do not meet current clinical indications for CRT pacing. Thus, we carried out an analysis to compare the impact of several ventricular pacing sites on global and regional ventricular function and dyssynchrony (Chapter 6.c.). We observed that right ventricular pacing worsens cardiac function in patients with and without ventricular dysfunction unless the pacing site is optimized. CRT preserves left ventricular function in patients with normal ejection fraction and improves function in patients with poor ejection fraction despite no clinical indication for CRT. Moreover, the analysis of the results obtained using new indexes of regional dyssynchrony, suggests that pacing site may influence overall global ventricular function depending on its relative effects on regional function and synchrony. Another clinical problem that has been investigated in this work is the optimal right ventricular lead location for CRT (Chapter 6.d.). Similarly to the previous analysis, using novel parameters describing local synchrony and efficiency, we tested the hypothesis and we demonstrated that biventricular pacing with alternative right ventricular pacing sites produces acute improvement of ventricular systolic function and improves mechanical synchrony when compared to standard right ventricular pacing. Although no specific right ventricular location was shown to be superior during CRT, the right ventricular pacing site that produced the optimal acute hemodynamic response varied between patients. Acute hemodynamic effects of cardiac pacing are conventionally evaluated after stabilization episodes. The applied duration of stabilization periods in most cardiac pacing studies varied considerably. With an ad hoc protocol (Chapter 6.e.) and indexes of mechanical dyssynchrony derived by conductance catheter we demonstrated that the usage of stabilization periods during evaluation of cardiac pacing may mask early changes in systolic and diastolic intra-ventricular dyssynchrony. In fact, at the onset of ventricular pacing, the main dyssynchrony and ventricular performance changes occur within a 10s time span, initiated by the changes in ventricular mechanical dyssynchrony induced by aberrant conduction and followed by a partial or even complete recovery. It was already demonstrated in normal animals that ventricular mechanical dyssynchrony may act as a physiologic modulator of cardiac performance together with heart rate, contractile state, preload and afterload. The present observation, which shows the compensatory mechanism of mechanical dyssynchrony, suggests that ventricular dyssynchrony may be regarded as an intrinsic cardiac property, with baseline dyssynchrony at increased level in heart failure patients. To make available an independent system for cardiac output estimation, in order to confirm the results obtained with conductance volume method, we developed and validated a novel technique to apply the Modelflow method (a method that derives an aortic flow waveform from arterial pressure by simulation of a non-linear three-element aortic input impedance model, Wesseling et al. 1993) to the left ventricular pressure signal, instead of the arterial pressure used in the classical approach (Chapter 7.). The results confirmed that in patients without valve abnormalities, undergoing conductance catheter evaluations, the continuous monitoring of cardiac output using the intra-ventricular pressure signal is reliable. Thus, cardiac output can be monitored quantitatively and continuously with a simple and low-cost method. During this work, additional studies were carried out to investigate several areas of uncertainty of CRT. The results of these studies are briefly presented in Appendix: the long-term survival in patients treated with CRT in clinical practice, the effects of CRT in patients with mild symptoms of heart failure and in very old patients, the limited thoracotomy as a second choice alternative to transvenous implant for CRT delivery, the evolution and prognostic significance of diastolic filling pattern in CRT, the selection of candidates to CRT with echocardiographic criteria and the prediction of response to the therapy.

The gaseous environment of radio galaxies: a new perspective from high-resolution x-ray spectroscopy

It is known that massive black holes have a profound effect on the evolution of galaxies, and possibly on their formation by regulating the amount of gas available for the star formation. However, how black hole and galaxies communicate is still an open problem, depending on how much of the energy released interacts with the circumnuclear matter. In the last years, most studies of feedback have primarily focused on AGN jet/cavity systems in the most massive galaxy clusters. This thesis intends to investigate the feedback phenomena in radio--loud AGNs from a different perspective studying isolated radio galaxies, through high-resolution spectroscopy. In particular one NLRG and three BLRG are studied, searching for warm gas, both in emission and absorption, in the soft X-ray band. I show that the soft spectrum of 3C33 originates from gas photoionized by the central engine. I found for the first time WA in 3C382 and 3C390.3. I show that the observed warm emitter/absorbers is not uniform and probably located in the NLR. The detected WA is slow implying a mass outflow rate and kinetic luminosity always well below 1% the L(acc) as well as the P(jet). Finally the radio--loud properties are compared with those of type 1 RQ AGNs. A positive correlation is found between the mass outflow rate/kinetic luminosity, and the radio loudness. This seems to suggest that the presence of a radio source (the jet?) affects the distribution of the absorbing gas. Alternatively, if the gas distribution is similar in Seyferts and radio galaxies, the M(out) vs rl relation could simply indicate a major ejection of matter in the form of wind in powerful radio AGNs.

Accretion disk winds in active galactic nuclei: an X-ray view

This Thesis focuses on the X-ray study of the inner regions of Active Galactic Nuclei, in particular on the formation of high velocity winds by the accretion disk itself. Constraining AGN winds physical parameters is of paramount importance both for understanding the physics of the accretion/ejection flow onto supermassive black holes, and for quantifying the amount of feedback between the SMBH and its environment across the cosmic time. The sources selected for the present study are BAL, mini-BAL, and NAL QSOs, known to host high-velocity winds associated to the AGN nuclear regions. Observationally, a three-fold strategy has been adopted: - substantial samples of distant sources have been analyzed through spectral, photometric, and statistical techniques, to gain insights into their mean properties as a population; - a moderately sized sample of bright sources has been studied through detailed X-ray spectral analysis, to give a first flavor of the general spectral properties of these sources, also from a temporally resolved point of view; - the best nearby candidate has been thoroughly studied using the most sophisticated spectral analysis techniques applied to a large dataset with a high S/N ratio, to understand the details of the physics of its accretion/ejection flow. There are three main channels through which this Thesis has been developed: - [Archival Studies]: the XMM-Newton public archival data has been extensively used to analyze both a large sample of distant BAL QSOs, and several individual bright sources, either BAL, mini-BAL, or NAL QSOs. - [New Observational Campaign]: I proposed and was awarded with new X-ray pointings of the mini-BAL QSOs PG 1126-041 and PG 1351+640 during the XMM-Newton AO-7 and AO-8. These produced the biggest X-ray observational campaign ever made on a mini-BAL QSO (PG 1126-041), including the longest exposure so far. Thanks to the exceptional dataset, a whealth of informations have been obtained on both the intrinsic continuum and on the complex reprocessing media that happen to be in the inner regions of this AGN. Furthermore, the temporally resolved X-ray spectral analysis field has been finally opened for mini-BAL QSOs. - [Theoretical Studies]: some issues about the connection between theories and observations of AGN accretion disk winds have been investigated, through theoretical arguments and synthetic absorption line profiles studies.

Non invasive assessment of right ventricle in patients with operated tetralogy of Fallot

The objective of this study was to evaluate right ventricular function in patients with right ventricular volume overload in patients with (tetralogy of Fallot, and pulmonary atresia + VSD ) underwent corrective surgery; with echocardiography measure that can be easily applied; and to study the relationship between ProBNP and the contractile function of the right ventricle, dilated right atrium, and the consequences of pulmonary insufficiency . Methods: The study included 50 patients (50% males, mean age 30.64 ± 13.30 years) with prior cardiac surgical intervention of TDF (90%) or pulmonary atresia + VSD (10%). (49 pz) have performed a cardiac MRI and clinical evaluation, (47 pz) echocardiogram, (48 pz) ECG, (34 pz) a cardiopulmonary exercise testing, (29 pz) a dosage of ProBNP. Results: The S-wave velocity (p <0.0001), the TAPSE (p <0.0001) correlated significantly with RVEF estimated by cardiac MRI. The VO2 max was 27.93 ± 12.91 ml / kg / min, 15% of patients had VE/VCO2 The peak> 35. ProBNP correlated positively and significantly with the area of the right atrium (p = 0.0001), and negative and significant with VO2 max (p = 0.04). Those who have increased pulmonary insufficiency (PVR fraction> 30%) have a significantly increased RVED volume (p = 0.01), reduced VO2 max (p = 0.04), and lower ejection fraction of LV (p = 0.02) than the group of patients with PVR ≤ 30. Conclusion: The TAPSE and S-wave velocity are fundamental and may become the technique of choice for routine assessment of RV systolic function in adult patients with TOF. The monitoring of the Pro BNP is probably a choice, given the simplicity and their information that correlate with the test cardiopulmonary. In view of the ventricular-ventricular interaction, so measures to maintain or restore the functioning of the pulmonary valve could preserve biventricular function.

L'Amiloidosi transtiretino correlata ereditaria: profilo clinico, fisiopatologico e storia naturale

Background. Hereditary transthyretin (TTR)-related amyloidosis (ATTR) is mainly considered a neurologic disease. We assessed the phenotypic and genotypic spectrum of ATTR in a non-endemic, Caucasian area and evaluated prevalence, genetic background and disease profile of cases with an exclusively cardiac phenotype, highlighting possible hints for the differential diagnosis with hypertrophic cardiomyopathy (HCM) and senile systemic amyloidosis (SSA) Methods and Results. In this Italian multicenter study, 186 patients with ATTR were characterized at presentation. Thirty patients with SSA and 30 age-gender matched HCM patients were used for comparison. Phenotype was classified as: exclusively cardiac (n= 31, 17%), exclusively neurologic (n= 46, 25%), mixed cardiac/neurologic (n=109, 58%). Among the 8 different mutations responsible for an exclusively cardiac phenotype, Ile68Leu was the most frequent (23/31). Five patients with an exclusively cardiac phenotype developed mild abnormalities at neurological examination but no symptoms during a 36 [14−50] month follow-up. Exclusively cardiac phenotype was characterized by male gender, age > 65 years, heart failure symptoms, concentric left ventricular (LV) “hypertrophy” and moderately depressed LV ejection fraction. This profile was similar to SSA but relatively distinct from HCM. Compared to patients with a mixed phenotype, patients with a exclusively cardiac phenotype showed a more pronounced cardiac involvement on both echocardiogram and ECG. Conclusion. A clinically relevant subset of Caucasian ATTR patients present with an exclusively cardiac phenotype, mimicking HCM or SSA. Echocardiographic and ECG findings are useful to differentiate ATTR from HCM but not from SSA. The role of liver transplantation in these patients is questionable.

La cardiomiopatia aritmogena come causa di scompenso cardiaco e trapianto di cuore

Scopo dello studio: la cardiomiopatia aritmogena (CA) è conosciuta come causa di morte improvvisa, la sua relazione con lo scompenso cardiaco (SC) è stata scarsamente indagata. Scopo dello studio è la definizione della prevalenza e incidenza dello SC, nonché della fisiopatologia e delle basi morfologiche che conducono i pazienti con CA a SC e trapianto di cuore. Metodi: abbiamo analizzato retrospettivamente 64 pazienti con diagnosi di CA e confrontato i dati clinici e strumentali dei pazienti con e senza SC (NYHA III-IV). Abbiamo analizzato i cuori espiantati dei pazienti sottoposti a trapianto presso i centri di Bologna e Padova. Risultati: la prevalenza dello SC alla prima osservazione era del 14% e l’incidenza del 2,3% anno-persona. Sedici pazienti (23%) sono stati sottoposti a trapianto. I pazienti con SC erano più giovani all’esordio dei sintomi (46±16 versus 37±12 anni, p=0.04); il ventricolo destro (VD) era più dilatato e ipocinetico all’ecocardiogramma (RVOT 41±6 versus 37±7 mm, p=0.03; diametro telediastolico VD 38±11 versus 28±8 mm, p=0.0001; frazione di accorciamento 23%±7 versus 32%±11, p= 0.002). Il ventricolo sinistro (VS) era lievemente più dilatato (75±29 ml/m2 versus 60±19, p= 0.0017) e globalmente più ipocinetico (frazione di eiezione = 35%±14 versus 57%±12, p= 0.001). Il profilo emodinamico dei pazienti sottoposti a trapianto era caratterizzato da un basso indice cardiaco (1.8±0.2 l/min/m2) con pressione capillare e polmonare tendenzialmente normale (12±8 mmHg e 26±10 mmHg). L’analisi dettagliata dei 36 cuori dei pazienti trapiantati ha mostrato sostituzione fibro-adiposa transmurale nel VD e aree di fibrosi nel VS. Conclusioni: Nella CA lo SC può essere l’unico sintomo alla presentazione e condurre a trapianto un rilevante sottogruppo di pazienti. Chi sviluppa SC è più giovane, ha un interessamento del VD più severo accanto a un costante interessamento del VS, solo lievemente dilatato e ipocinetico, con sostituzione prevalentemente fibrosa.

Balloon Aortic Valvuloplasty as Bridge-to-Decision in High Risk Patients with Severe Aortic Valve Stenosis

Background. A sizable group of patients with symptomatic aortic stenosis (AS) can undergo neither surgical aortic valve replacement (AVR) nor transcatheter aortic valve implantation (TAVI) because of clinical contraindications. The aim of this study was to assess the potential role of balloon aortic valvuloplasty (BAV) as a “bridge-to-decision” in selected patients with severe AS and potentially reversible contraindications to definitive treatment. Methods. We retrospectively enrolled 645 patients who underwent first BAV at our Institution between July 2007 and December 2012. Of these, the 202 patients (31.2%) who underwent BAV as bridge-to-decision (BTD) requiring clinical re-evaluation represented our study population. BTD patients were further subdivided in 5 groups: low left ventricular ejection fraction; mitral regurgitation grade ≥3; frailty; hemodynamic instability; comorbidity. The main objective of the study was to evaluate how BAV influenced the final treatment strategy in the whole BTD group and in its single specific subgroups. Results. Mean logistic EuroSCORE was 23.5±15.3%, mean age was 81±7 years. Mean transaortic gradient decreased from 47±17 mmHg to 33±14 mmHg. Of the 193 patients with BTD-BAV who received a second heart team evaluation, 72.5% were finally deemed eligible for definitive treatment (25.4%for AVR; 47.2% for TAVI): respectively, 96.7% of patients with left ventricular ejection fraction recovery; 70.5% of patients with mitral regurgitation reduction; 75.7% of patients who underwent BAV in clinical hemodynamic instability; 69.2% of frail patients and 68% of patients who presented relevant comorbidities. 27.5% of the study population was deemed ineligible for definitive treatment and treated with standard therapy/repeated BAV. In-hospital mortality was 4.5%, cerebrovascular accident occurred in 1% and overall vascular complications were 4% (0.5% major; 3.5% minor). Conclusions. Balloon aortic valvuloplasty should be considered as bridge-to-decision in high-risk patients with severe aortic stenosis who cannot be immediate candidates for definitive percutaneous or surgical treatment.

Alterazioni strutturali e funzionali nelle diverse eziologie di amiloidosi cardiaca: analisi dei parametri ecocardiografici ed emodinamici invasivi e loro ruolo prognostico

Background e scopo: Tradizionalmente la cardiomiopatia amiloidotica (CA) è stata considerata una cardiomiopatia restrittiva, ma studi recenti hanno evidenziato il ruolo anche della disfuzione sistolica nella sua fisiopatologia. In questo contesto recente, raramente è stato indagato il profilo emodinamico invasivo. Lo scopo dello studio è stato quello di caratterizzare il profilo emodinamico, strutturale e funzionale della CA nelle tre principali eziologie (amiloidosi da catene leggere (AL), amiloidosi transtiretino-relata (ATTR) mutata (ATTRm) e ‘wild-type’ (ATTRwt)), valutare le differenze del profilo ecocardiografico ed emodinamico nelle fasi diverse di malattia ed esplorare il ruolo prognostico delle principali variabili cliniche e strumentali nella CA. Metodi e risultati: Abbiamo analizzato retrospettivamente i dati di 224 pazienti con CA (AL, n=93; ATTRm, n=66; ATTRwt, n=65). Rispetto all'ATTRwt, i pazienti con AL presentano un minor interessamento morfologico cardiaco, ma dati emodinamici paragonabili, caratterizzati da elevate pressioni di riempimento biventricolari e riduzione della gittata sistolica. L’ATTRm, nonostante il profilo ecocardiografico analogo all’ATTRwt, mostra un quadro emodinamico migliore. Gli indici di funzione diastolica e sistolica longitudinale del ventricolo sinistro (Vsn) sono alterati fin dagli stadi iniziali della malattia, mentre la frazione di eiezione (FEVsn) rimane preservata nella maggior parte dei pazienti, anche nelle fasi avanzate (FEVsn 50 [37-60]%; FEVsn <40% nel 28% dei pazienti NYHA III / IV). All'analisi multivariata, età, NYHA III/I, eziologia AL, frazione di contrazione miocardica (MCF), indice cardiaco (CI) e pressione atriale destra (RAP) sono indipendentemente associati a eventi clinici avversi. Conclusioni Questo studio conferma la complessa fisiopatologia della CA, in cui la disfunzione diastolica è accompagnata da una funzione sistolica longitudinale anormale sin dalle fasi iniziali della malattia. L'AL e l'ATTRwt, nonostante diversi gradi di alterazioni morfologiche, hanno un profilo emodinamico simile; l'ATTRm, invece, presenta un quadro emodinamico migliore. Tra i parametri strumentali, MCF, CI e RAP emergono come predittori significativi di eventi avversi.

Myotonic syndromes: analysis of factors with pathogenetic and prognostic significance

Background: The natural history of Myotonic Dystrophy type 1 is largely unclear, longitudinal studies are lacking. Objectives: to collect clinical and laboratory data, to evaluate sleep disorders, somatic and autonomic skin fibres, neuropsychological and neuroradiological aspects in DM1 patients. Methods: 72 DM1 patients underwent a standardized clinical and neuroradiological evaluation performed by a multidisciplinary team during 3 years of follow-up. Results: longer disease duration was associated with higher incidence of conduction disorders and lower ejection fraction; higher CVF values were predictors for a reduced risk of cardiopathy. Lower functional pulmonary values were associated with class of expansion and were negatively associated with disease duration; arterial blood gas parameters were not associated with expansion size, disease duration nor with respiratory function test. Excessive daytime sleepiness was not associated with class of expansion nor with any of the clinical parameters examined. We detected apnoea in a large percentage of patients, without differences between the 3 genetic classes; higher CVF values were predictors for a reduced risk of apnoea. Skin biopsies demonstrated the presence of a subclinical small fibre neuropathy with involvement of the somatic fibres. The pupillometry study showed lower pupil size at baseline and a lower constriction response to light. The most affected neuropsychological domains were executive functions, visuoconstructional, attention and visuospatial tasks, with a worse performance of E1 patients in the visuoperceptual ability and social cognition tasks. MRI study demonstrated a decrease in the volumes of frontal, parietal, temporal, occipital cortices, accumbens, putamen nuclei and a more severe volume reduction of the isthmus cingulate, transverse temporal, superior parietal and temporal gyri in E2 patients. Discussion: only some clinical parameters could predict the risk of cardiopathy, pulmonary syndrome and sleep disorders, while other clinical aspects proved to be unpredictable, confirming the importance of periodic clinical follow-up of these patients.

Probing the innermost regions of AGN via time-resolved spectral analysis

The dynamics and geometry of the material inflowing and outflowing close to the supermassive black hole in active galactic nuclei are still uncertain. X-rays are the most suitable way to study the AGN innermost regions because of the Fe Kα emission line, a proxy of accretion, and Fe absorption lines produced by outflows. Winds are typically classified as Warm Absorbers (slow and mildly ionized) and Ultra Fast Outflows (fast and highly ionized). Transient Obscurers -optically thick winds that produce strong spectral hardening in X-rays, lasting from days to months- have been observed recently. Emission and absorption features vary on time-scales from hours to years, probing phenomena at different distances from the SMBH. In this work, we use time-resolved spectral analysis to investigate the accretion and ejection flows, to characterize them individually and search for correlations. We analyzed XMM-Newtomn data of a set of the brightest Seyfert 1 galaxies that went through an obscuration event: NGC 3783, NGC 3227, NGC 5548, and NGC 985. Our aim is to search for emission/absorption lines in short-duration spectra (∼ 10ks), to explore regions as close as the SMBH as the statistics allows for, and possibly catch transient phenomena. First we run a blind search to detect emission/absorption features, then we analyze their evolution with Residual Maps: we visualize simultaneously positive and negative residuals from the continuum in the time-energy plane, looking for patterns and relative time-scales. In NGC 3783 we were able to ascribe variations of the Fe Kα emission line to absorptions at the same energy due to clumps in the obscurer, whose presence is detected at >3σ, and to determine the size of the clumps. In NGC 3227 we detected a wind at ∼ 0.2c at ∼ 2σ, briefly appearing during an obscuration event.

Cross-population radio galaxies as a test of the jet-accretion relationship

Radio galaxies (RGs) are extremely relevant in addressing important unknowns concerning the interaction among black hole accretion, radio jets, and the environment. In the classical scheme, their accretion rate and ejection of relativistic jets are directly linked: efficient accretion (HERG) is associated with powerful edge-brightened jets (FRIIs); inefficient accretion (LERG) is associated with weak edge-darkened jets (FRIs). The observation of RGs with an inefficient engine associated with edge-brightened radio emission (FRII-LERGs) broke this scheme. FRII-LERGs constitute a suitable population to explore how accretion and ejection are linked and evaluate the environment's role in shaping jets. To this aim, we performed a multiwavelength study of different RGs catalogs spanning from Jy to mJy flux densities. At first, we investigated the X-ray properties of a sample of 51 FRIIs belonging to the 3CR catalog at z<0.3. Two hypotheses were invoked to explain FRII-LERGs behavior: evolution from classical FRIIs; the role of the environment. Next, we explored the mJy sky by studying the optical-radio properties of hundreds of RGs at z<0.15 (Best & Heckman 2012 sample). FRII-LERGs appear more similar to the old FRI-LERGs than to the young FRII-HERGs. These results point towards an evolutive scenario, however, nuclear time scale changes, star population aging, and kpc-Mpc radio structure modification do not agree. The role of the Mpc environment was then investigated. The Wen et al. 2015 galaxy clusters sample, built exploiting the SDSS survey, allowed us to explore the habitat of 7219 RGs at z<0.3. Most RGs are found to live in outside clusters. For these sources, differences among RG classes are still present. Thus, the environment is not the key parameter, and the possibility of intrinsic differences was reconsidered: we speculated that different black hole properties (spin and magnetic field at its horizon) could determine the observed spread in jet luminosity.

New indicators of star cluster dynamical evolution

This thesis presents a study of globular clusters (GCs), based on analysis of Monte Carlo simulations of globular clusters (GCs) with the aim to define new empirical parameters measurable from observations and able to trace the different phases of their dynamical evolution history. During their long term dynamical evolution, due to mass segregation and and dynamical friction, massive stars transfer kinetic energy to lower-mass objects, causing them to sink toward the cluster center. This continuous transfer of kinetic energy from the core to the outskirts triggers the runaway contraction of the core, known as "core collapse" (CC), followed by episodes of expansion and contraction called gravothermal oscillations. Clearly, such an internal dynamical evolution corresponds to significant variations also of the structure of the system. Determining the dynamical age of a cluster can be challenging as it depends on various internal and external properties. The traditional classification of GCs as CC or post-CC systems relies on detecting a steep power-law cusp in the central density profile, which may not always be reliable due to post-CC oscillations or other processes. In this thesis, based on the normalized cumulative radial distribution (nCRD) within a fraction of the half-mass radius is analyzed, and three diagnostics (A5, P5, and S2.5) are defined. These diagnostics show sensitivity to dynamical evolution and can distinguish pre-CC clusters from post-CC clusters.The analysis performed using multiple simulations with different initial conditions, including varying binary fractions and the presence of dark remnants showed the time variations of the diagnostics follow distinct patterns depending on the binary fraction and the retention or ejection of black holes. This analysis is extended to a larger set of simulations matching the observed properties of Galactic GCs, and the parameters show a potential to distinguish the dynamical stages of the observed clusters as well.

Characterization and natural history of different phenotypes in hereditary transthyretin amyloidosis: 40-year experience at a single Italian referral center

- Aims: Hereditary Transthyretin Amyloidosis (ATTRv) is one of the leading etiologies of systemic amyloidosis with more than 135 mutations described and a broad spectrum of clinical manifestations. We aimed to provide a systematic description of a population of individuals carrying pathogenic mutations of transthyretin (TTR) gene and to investigate the major clinical events during follow up. - Methods: Observational, retrospective, cohort study including consecutive patients with mutations of TTR gene, admitted to a tertiary referral center in Bologna, Italy, between 1984 and 2022. - Results: Three hundred twenty-five patients were included: 106 asymptomatic carriers, 49 cardiac phenotype, 49 neurological phenotype and 121 mixed phenotype. Twenty-three different mutations were found, with Ile68Leu (41.8%), Val30Met (19%), and Glu89Gln (10%) being the most common. After a median follow-up of 51 months data from 290 subjects were analyzed; among them 111 (38.3%) died and 123 (42.4%) had a major clinical event (death or hospitalization for heart failure). Nine (11.5%) of the 78 asymptomatic carriers showed signs and symptoms of the disease. Carriers had a prognosis comparable to healthy population, while no significant differences were seen among the three phenotypes adjusted by age. Age at diagnosis, NYHA functional class, left ventricular ejection fraction, mPND score and disease-modifying therapy were independently associated with survival. - Conclusions: This study offers a wide and comprehensive overview of ATTRv from the point of view of a tertiary referral center in Italy. Three main phenotypes can be identified (cardiac, neurological and mixed) with specific clinical and instrumental features. Family screening programs are essential to identify paucisymptomatic affected patients or unaffected carriers of the mutation, to be followed through the years. Lastly, disease-modifying therapy represents an evolving cornerstone of the management of ATTRv, with a great impact on mortality.