Thèses sur le sujet « Cardiac amyloidosi »

Tra i pazienti con diagnosi iniziale di cardiomiopatia ipertrofica afferiti a Centri di Riferimento per le Cardiomiopatie, l’AC è la malattia non riconosciuta più comune con una prevalenza complessiva del 9%, e che aumenta con l'età (dall'1% nella fascia di età tra i 40-49 anni al 26% sopra gli 80 anni). Nella popolazione generale ≥55 anni più del 7% ha almeno un reperto ecocardiografico suggestivo di AC e l’ispessimento del setto interatriale è quello più frequente. I pazienti con elevato sospetto di AC (≥3 reperti) rappresentano l’1% della popolazione generale e il 4,9% di quelli con cuore non dilatato, ipertrofico e con FE normale.<br>Among patients with initial diagnosis of HCM, cardiac amiloidosis has a prevalence of 9% and it increases with age. In the general population > 55 yo more than 7% has echocardiographic suspicion of the disease and echocardiography has an important role in the early diagnosis of the disease

Introduction: Waldenström's macroglobulinemia is a hematological neoplasm belonging to the group of monoclonal gammopathies, which includes systemic symptoms and those related to an increase in M paraprotein. Objective: To describe a case of cardiac amyloidosis associated with macroglobulinemia. Clinical case: Male patient who was admitted for asthenia, dysphonia, and who, during his evolution, developed progressive dyspnea, heart failure and pleural effusion. Additionally, echocardiography showed myocardial granular pattern, while pleural biopsy was positive for Congo red staining. Subsequently, he received treatment with bortezomib, dexamethasone and rituximab, with favorable evolution. Conclusions: In this disease, early diagnosis is an important advantage for survival. Therefore, its management is palliative of cardiac manifestations. The present case shows a diagnostic challenge, in which the less frequent etiologies of heart failure must be taken into account.<br>Revisión por pares

Background: Hereditary transthyretin amyloidosis (ATTR) is a lethal disease in which misfolded transthyretin (TTR) proteins accumulate as insoluble aggregates in tissues throughout the body. A common mutation is the exchange of valine to methionine at place 30 (TTR V30M), a form endemically found in the northern parts of Sweden. The main treatment option for ATTR amyloidosis is liver transplantation as the procedure halts production of mutated transthyretin. The disease is associated with marked phenotypic diversity ranging from predominant cardiac complications to pure neuropathy. Two different types of fibril composition – one in which both fragmented and full-length TTR are present (type A) and one consisting of only full-length TTR (type B) have been suggested to account for some phenotypic differences. Cardiac amyloidosis is associated with increased myocardial thickness and the disease could easily be mistaken for other entities characterised by myocardial thickening, such as sarcomeric hypertrophic cardiomyopathy (HCM). The aims in this thesis were to investigate echocardiographic characteristics in Swedish ATTR amyloidosis patients, and to identify markers aiding in differentiating ATTR heart disease from HCM. Another objective was to examine the impact of fibril composition and sex on the phenotypic variation in amyloid heart disease. Methods: A total of 122 ATTR amyloidosis patients that had undergone thorough echocardiographic examinations were included in the studies. Analyses of ventricular geometry as well as assessment of systolic and diastolic function were performed, using both conventional echocardiographic methods and speckle tracking technique. ECG analysis was conducted in study I, allowing measurement of QRS voltage. In study I and study II ATTR patients were compared to patients with HCM. In addition, 30 healthy controls were added to study II. Results: When parameters from ECG and echocardiography were investigated, the results revealed that the combination of QRS voltage &lt;30 mm (&lt;3 mV) and an interventricular/posterior wall thickness quotient &lt;1.6 could differentiate cardiac ATTR amyloidosis from HCM. Differences in degree of right ventricular involvement were also demonstrated between HCM and ATTR amyloidosis, where ATTR patients displayed a right ventricular apical sparing pattern whereas the inverse pattern was found in HCM. Analysis of fibril composition revealed increased LV wall thickness in type A patients compared to type B, but in addition type A women displayed both lower myocardial thickness and more preserved systolic function as compared to type A males. When cardiac geometry and function were evaluated pre and post liver transplantation in type A and B patients, significant deterioration was detected in type A but not in type B patients after liver transplantation. Conclusions: Increasing awareness of typical cardiac amyloidotic signs by echocardiography is important to reduce the risk of delayed diagnosis. Our classification model based on ECG and echocardiography could aid in differentiating ATTR amyloidosis from HCM. Furthermore, the apical sparing pattern found in the right ventricle may pose another clue for amyloid heart disease, although it requires to be studied further. Furthermore, we disclosed that type A fibrils, male sex and increasing age were important determinants of increased myocardial thickness. As type A fibril patients displayed rapid cardiac deterioration after liver transplantation other treatment options should probably be sought for this group of patients.

Cardiac amyloidosis is a condition characterised by infiltration of the myocardium with fibrillar proteins. Transthyretin (TTR) is a plasma protein that may form amyloid fibrils and the V122I mutant form of TTR is associated with isolated cardiac amyloidosis. Previous studies have estimated a 4% V122I allele frequency in African Americans. The prevalence of cardiac transthyretin amyloidosis (ATTR) V122I in the British population is not known. I was awarded a British Heart Foundation Clinical Research Fellowship to investigate the diagnosis and prevalence of ATTR V122I in the UK population. More than one million people of Afro-Caribbean ethnicity live in the Greater London area, and in the local ward of Wandsworth make up more than 10% of the population (2011 census data). The prevalence of ATTR V122I at St George's Hospital was high, affecting 12% of all Afro-Caribbean heart failure patients aged ~60 years. The estimated incidence of ATTR V122I in Afro-Caribbean subjects in the St George's Hospital catchment area was over twice the reported incidence of amyloidosis of all types in the general, predominantly Caucasian, UK population. The clinical phenotype is characterised by resistant heart failure, increased wall thickness and diastolic dysfunction on echocardiography and poor outcomes (median survival 29 months). The ECG had poor sensitivity to detect ATTR V122I because 25% of patients present with left ventricular hypertrophy criteria, contrary to the reported low voltage complexes widely reported in AL amyloidosis. Cardiovascular magnetic resonance (CMR) imaging demonstrated extensive late gadolinium enhancement (LGE) and I developed a novel LGE scoring system to differentiate ATTR from AL amyloidosis with high accuracy. A simple diagnostic algorithm to detect new cases of ATTR amyloidosis was retrospectively employed at a separate tertiary heart failure clinic and demonstrated that 5.2% of elderly black patients had ATTR amyloidosis, having previously been given a diagnosis of hypertensive heart failure. Improved detection of ATTR amyloidosis is increasingly important as novel treatments are now undergoing phase 3 clinical trial assessment and newly diagnosed patients now have the potential for disease modifying therapies. This will have implications for counselling and family screening of this inherited autosomal dominant condition in the future.

The left atrium (LA) plays an important role in the modulation of LV filling and contributes to LV stroke volume with atrial contraction. Despite this important role, much research to date has been focused on the ventricles in disease, rather than the atria. In recent years there has been increasing interest and excitement in the function of the LA in normal and disease states – no longer is the LA secondary to the left ventricle (LV). The LA has three major functions: reservoir, conduit and contractile. The LA acts as a reservoir during ventricular systole as it fills with blood via the pulmonary veins and expands in size, subsequently, the mitral valve opens and the conduit phase is this passing of blood from the LA to the LV due to a small pressure gradient. Lastly, atrial systole, or the ‘atrial kick’, provides further augmentation of the LV stroke volume at the end of ventricular diastole. Methods for non-invasive assessment of these LA functions have been limited due to echocardiographic technology and the cumbersome nature data collection for these parameters. Prior techniques included assessment of LA size, phasic changes in LA size or volume as well as a variety of Doppler parameters which provided a cruder assessment of the LA functions. Strain is a unitless measurement of myocardial deformation and can be applied to assess the three LA functions in more detail. Contemporary strain research uses 2D-speckle tracking echocardiography (STE), where strain represents a fraction change in myocardial length relative to baseline and is expressed as a percentage. As strain technology surges forward with now dedicated LA strain software packages, the importance of the left atrium has become increasingly recognised. Improved strain technology has allowed easier and more widely available assessment of the three LA functions. Several studies have now documented normal LA strain values in large populations, and specifically, variations due to age and gender. Multiple literature reviews and guideline documents from cardiac imaging bodies have provided a standardised basis for acquisition of LA strain and the language used to describe LA functions and strain values. Previously, different gating techniques, software and terminology made comparison of literature more challenging. Interest and guidance from these peak bodies such as the European society of cardiovascular imaging confirms the importance of LA strain moving forward. There are many disease states which impact upon LA function and further study of LA strain in these areas may allow identification of subclinical atrial disease and impact on diagnostic or treatment pathways. In reviewing the literature, this thesis examines the current knowledge for clinical applications of LA strain in various pathologies/disease states. To contribute to current LA strain research, this thesis goes on to investigate the reproducibility of the LA strain technique, comparing strain readers of different expertise. This is an important step for uptake of LA strain into widespread use. The study showed LA strain was highly reproducible by a novice strain reader using multi-vendor analysis software and secondly, that there was good interobserver reproducibility between novice and experts. The thesis goes on to investigate the use of LA strain in a specific clinical scenario - cardiac amyloidosis (CA). Cardiac amyloidosis is a condition leading to amyloid protein deposition in cardiac tissue and subsequent organ dysfunction. Recent studies have shown that CA leads to LA dysfunction and abnormal LA strain and strain rate values. Given many different conditions can lead to reduction in LA strain, further investigation into changes and degree of LA dysfunction with CA compared to mimicking pathologies is of importance. Ventricular hypertrophy due hypertension can make differentiation of cardiac amyloidosis difficult using echocardiography alone – particularly when clinical history of hypertension is not previously known. The second original research study confirms a severe reduction in LA function in patients with cardiac amyloidosis, concordant with that seen in other studies. Additionally, LA function in CA was significantly worse compared to the hypertensive group, despite similar increases in LV wall thickness. Therefore, LA strain may provide incremental value in differentiating cardiac amyloidosis from increased LV wall thickness secondary to hypertension. Further investigation with larger cohorts and comparison between strain values in CA and other infiltrative pathologies should be considered to improve observe how specific this severe reduction in LA strain values is for CA compared to other infiltrative pathologies causing increased LV wall thickness. LA strain is a promising emerging tool, the applications of which will be further explored in this thesis.<br>Thesis (Masters)<br>Master of Philosophy (MPhil)<br>School of Medicine<br>Griffith Health<br>Full Text

Background Hereditary transthyretin amyloid (ATTRm) amyloidosis is a systemic disease mainly affecting the peripheral nervous system and the heart. The disease is inherited in an autosomal dominant manner with a varying penetrance. It is caused by mutations in the transthyretin (TTR) gene. Today more than 100 disease causing mutations are known. The V30M mutation that is endemic in northern Sweden is the best studied and comprises the majority of the reported disease cases in the world. In ATTRm amyloidosis caused by the V30M mutation two distinct sub populations are seen, one with disease onset early in life and a mainly neuropathic disease and the other with late onset disease and both neuropathic disease and a progressive cardiomyopathy. These phenotypical findings have in Swedish patients been tied to differences in amyloid fibril composition. Generally, patients with early onset disease have amyloid fibrils containing only full length transthyretin (type B) whereas patients with late onset disease have amyloid containing both full length and fragmented transthyretin (type A). Until recently, the only available treatment for the disease has been liver transplantation. Patients with type A fibrils, especially males, have significantly worse survival after liver transplant due to progressive amyloid cardiomyopathy. Furthermore, it appears that type A fibrils may be the most common finding in other mutations. This thesis work aims to in depth investigate the impact amyloid fibril composition has on cardiac manifestations of the disease and on the outcome of available and novel modalities for cardiac amyloid imaging. Methods The four studies included in the thesis were done as part of the on going clinical research at the Swedish centre for transthyretin amyloidosis in Umeå.  Patients in whom amyloid fibril composition had been determined were included. Available echocardiographic data were analysed to find predictors for left ventricular hypertrophy and systolic function as measured by strain analysis in a large cohort of 105 patients (paper I). Serial 12-lead electrocardiograms from 98 patients were gathered and retrospectively interpreted and analysed to investigate the impact of amyloid fibril composition and disease progression on frequency and development of ECG abnormalities (paper IV).  DPD scintigraphy, cardiac biomarkers, clinical data and echocardiograms were analysed in a cohort of 53 consecutive patients. to assess the impact of amyloid fibril composition on the outcome of DPD scintigraphy and its relationship with cardiac hypertrophy. (paper II). To evaluate the usefulness of positron emission tomography (PET) using the amyloid specific tracer PIB, 10 patients, five with each fibril type, were selected and examined. The patients selected had a similar age of onset and similar echocardiographic findings (paper III). Results Paper I: Type A fibrils, male gender and age were independent factors associated with increased LV thickness. The distribution of amyloid fibril composition did not differ between the sexes, but in patients with type A fibrils, females had lower median cardiac wall thickness (p&lt;0.01and better left ventricular septal strain (p=0.04).The gender differences were not apparent in patients with type B fibrils. Paper II: Ninety-seven per cent of patients with type A fibrils had pathological cardiac DPD uptake compared to none of the patients with type B fibrils. Among patients with normal septal thickness, none of 15 patients with type B fibrils had positive scintigraphy compared with 2 out of 2 with type A fibrils (P&lt;0.01) Cardiac biomarkers, demographic data and cardiac biomarkers were significantly different, but could not differentiate between type A and type B fibrils in individual patients. Paper III: All patients had pathological cardiac PIB retention. In patients with type B fibrils the retention was significantly higher (p&lt;0.01) than in patients with type A fibrils. Based on the selection criteria, no significant differences were seen in various echocardiographic measurements. Paper IV: All patients had a high prevalence of AV-blocks, LAH and anterior infarction pattern. Patients with type A fibrils had significantly more electrocardiographic abnormalities compared to those with type B fibrils, both at an early stage of diseases and at later follow up. Conclusion Type A fibrils are associated with more pronounced cardiac involvement, which appear to be more severe in males than in females. In study II we showed that DPD scintigraphy appears to be a very good tool for non-invasive determination of amyloid fibril composition. Papers III and IV show that patients with type B amyloid have cardiac involvement even without echocardiographic or DPD-scintigraphic evidence of amyloid cardiomyopathy and that ECG abnormalities are common irrespectively of amyloid fibril composition, and increase with time for both groups.

Familial amyloidotic polyneuropathy (FAP), found in the northernmost counties in Sweden, is a rare, lethal and inherited amyloidosis. The disease is caused by mutated transthyretin (TTR). The mutation is characterized by an exchange of valine for methionine at position 30 (ATTRVal30Met). FAP is characterised by progressive polyneuropathy affecting both the peripheral and autonomic nervous system (ANS). Cardiac arrhythmia and autonomic disturbances are common as well as gastrointestinal symptoms: such as constipation and diarrhoea. Today, orthotopic liver transplantation (LTx) is the only treatment to stop the progression of FAP. The rationale for this is because 95% of TTR is synthesized by the liver, a liver transplantation should abolish the production of new mutated amyloidogenic TTR. The first liver transplantation for FAP was performed in Sweden 1990. Heart complications and autonomic disturbances are common in FAP patients both before and after liver transplantation. The aim of the present study was three-fold: to determine whether liver transplantation affects the natural course of cardiac arrhythmias and cardiac autonomic function; to predict the risk of ventricular arrhythmias; and to elucidate heart rate variability (HRV) patterns by power spectrum analysis and Poincaré plots. In total, ninety-seven Swedish FAP patients were included in the studies. The patients underwent 24-hours electrocardiography (Holter) recordings, and/or signal averaged electrocardiography (SAECG) and heart rate variability. The study showed that many patients developed cardiac arrhythmias and conduction disturbances after LTx. Approximately 25 percent of patients were pacemaker treated after LTx. The SAECG recordings disclosed that many FAP patients had ventricular late potentials (LP) compared with healthy subjects, and that LP were associated with nonsustained ventricular arrhythmia. Analyses of heart rate variability (HRV) showed reduced autonomic function in the majority of patients. Some patients had high HRV with broadband power spectra and Poincaré graphs with a fan or complex pattern. These novel findings could be an indicator of ECG abnormalities (subtle atrial arrhythmia) in FAP patients instead of reflecting normal cardiac autonomic modulation. The HRV studies also showed that LTx preserves cardiac autonomic function in FAP. In conclusion, cardiac arrhythmias, late potentials and reduced heart rate variability were common in Swedish patients with FAP, whether they underwent liver transplantation or not. The absence of LP may indicate a low risk for ventricular tachycardia in FAP patients.

L’Hypertrophie Ventriculaire Gauche (HVG) est actuellement mise en évidence par échographie. Cet examen fournit des informations anatomo-fonctionnelles mais ne permet pas de déterminer l’étiologie des HVG, ce qui engendre de graves erreurs de diagnostic et de prise en charge thérapeutique. Les HVG sont classiquement séparées en 2 catégories :1. pathologies hypertrophiques induites par la modification structurelle et fonctionnelle des cardiomyocites qui tend à compenser des insuffisances cardiaques liées par exemple à des problèmes d’hypertension artérielle, de rétrécissement aortique ou de CardioMyopathies Hypertrophiques sarcomériques ;2. pathologies infiltratives correspondant au dépôt de protéines dans la matriceextracellulaire principalement dues à différentes formes d’amyloses cardiaquesNotre hypothèse est que les différents mécanismes physiopathologiques (hypertrophique ou infiltratif) pourraient se traduire dans l’image par des propriétés spécifiques du speckle échographique. Nous avons donc développé un travail d’analyse de la texture de ces images afin de discriminer les différentes HVG.Dans cette étude, la base de données de 4795 images est divisée en une base d’apprentissage de 3770 images et une base de test de 1025 images. L’analyse de texture des images est faite par les ondelettes de Gabor avec 8 orientations, 7 tailles et 5 niveaux de décomposition. Ensuite, les caractéristiques statistiques de premier et deuxième ordre sont extraites des images. Le nombre des caractéristiques est réduit pour la base d’apprentissage en appliquant l’Analyse en Composantes Principales (ACP) suivie par l’analyse discriminante linéaire (ADL) pour une séparation supervisée des classes. Les caractéristiques extraites pour la base de test sont projetées sur les vecteurs propres sélectionnés au cours de l’apprentissage. L’ADL est appliquée à ce niveau pour la classification des données du test et la qualité de cette classification est évaluée. Les résultats obtenus sont bons (qualité totale de classification de 95,51%) et sont suivis d’une étape de cross-validation afin de vérifier la robustesse de notre méthode. A cette étape, les bases de données de l’apprentissage et du test sont mélangées et 50 combinaisons différentes sont évaluées. La même méthode décrite précédemment est appliquée. La cross-validation montre une variation de la qualité de classification (entre 30% et 99.96%) probablement due à l’hétérogénéité des caractéristiques texturelles pour les patients d’une même classe que l’on peut expliquer par des degrés différents d’avancement dans la pathologie.Ces travaux montrent qu’une analyse de texture des images échocardiographiques peut permettre de déterminer des bio-marqueurs aptes à discriminer différentes cardiopathies qui s’expriment par une HVG. Ce résultat peut avoir des retombées très importantes dans la détection précoce des amyloses cardiaques, maladies engendrant un fort taux de mortalité souvent dû à un retard de diagnostic et prise en charge des patients par un centre expert<br>Left-Ventricular Hypertrophy (LVH) is currently detected through echocardiography. The latter imaging modality provides anatomical and functional information. However, it does not allow the determination of the HVG etiology. This can, in turn, lead to dangerous errors in the diagnosis and treatment planning of the disease. LVH pathologies are separated into two categories:- Hypertrophic pathology caused by the structural and functional modification of cardiomyocytes that lead to cardiac failure related, for example, to arterial hypertension problems, aortic narrowing or sarcomeric hypertrophic cardiomyopathies.- Infiltrative pathologies corresponding to protein deposits on the extracellular matrix, mainly due to different forms of cardiac amyloidosisOur hypothesis is that different physiopathological mechanisms (hypertrophic or infiltrative) can be translated in the image through properties specific to echographic speckle. We have therefore developed the work of texture analysis of such images in order to discriminate the different types of LVH.In this study, the database of 4795 images is divided into a learning database of 3770 images and another testing database of 1025 images. The textural analysis of these images is done using Gabor wavelets with 8 orientations, 7 sizes and 5 decomposition levels. Next, the statistical characteristics of first and second orders are extracted from the filtered images. The number of characteristics is reduced for the learning database by applying Principal Component Analysis (PCA) followed by Linear Discriminant Analysis (LDA) for a supervised separation of the classes. The extracted characteristics for the test database are projected on the eigenvectors selected in the learning step. LDA is applied at this level for the test data classification, and the quality of this classification is evaluated. The obtained results are good (total classification quality of 95.51%). A step of cross-validation follows in order to verify the robustness of our method. At this stage, the learning and testing databases are mixed, and 50 different combinations are evaluated. The same method described previously is then applied. The cross-validation shows a variation in the classification quality (between 30% and 99.96%) probably due to the heterogeneity of the texture characteristics for the patients of the same class explained by different disease advancement stages.This work shows that the textural analysis of echocardiographic images can permit the determination of bio-markers suitable to discriminate different LVH cardiopathies. Our results can have a very important impact on the early detection of cardiac amyloidosis, a pathology causing a considerable rate of mortality often due to a belated diagnosis and support by the centers of expertise

A amiloidose cardíaca por transtirretina era até recentemente considerada uma doença intratável. Contudo, esta patologia sub-diagnosticada viu um aumento do interesse na investigação com múltiplos novos tratamentos, incluindo os primeiros fármacos de algumas classes, a aproximarem-se rapidamente das fases finais de investigação, com o tafamidis e o patisiran já aprovados pelos reguladores Europeu e Americano. Os novos fármacos incluem pequenas moléculas estabilizadoras, fármacos silenciadores do gene, disruptores das fibras amilóides e anticorpos monoclonais. Esta revisão pretende reunir as opções terapêuticas para amiloidose cardíaca por transtirretina atuais e iminentes, determinar se algum destes fármacos reúne a evidência necessária para se tornar o foco da gestão da amiloidose cardíaca por transtirretina e identificar questões relevantes ainda por responder pela evidência disponível atualmente.<br>Transthyretin cardiac amyloidosis was until recently considered an untreatable disease. However, this underdiagnosed pathology experienced a surge in research interest with multiple novel treatments, including several first-in-class drugs rapidly approaching the final stages of investigation, with tafamidis and patisiran already approved by the European and American regulators. Novel drugs include small molecule stabilizers, gene silencing drugs, amyloid fibril disruptors, and monoclonal antibodies This review aims to capture a comprehensive picture of the current and upcoming therapeutic options for cardiac transthyretin amyloidosis, to ascertain if any of these drugs gather the necessary evidence to become the staple of transthyretin cardiac amyloidosis management and to identify relevant questions yet to be answered by currently available evidence.

A amiloidose cardíaca por transtirretina era até recentemente considerada uma doença intratável. Contudo, esta patologia sub-diagnosticada viu um aumento do interesse na investigação com múltiplos novos tratamentos, incluindo os primeiros fármacos de algumas classes, a aproximarem-se rapidamente das fases finais de investigação, com o tafamidis e o patisiran já aprovados pelos reguladores Europeu e Americano. Os novos fármacos incluem pequenas moléculas estabilizadoras, fármacos silenciadores do gene, disruptores das fibras amilóides e anticorpos monoclonais. Esta revisão pretende reunir as opções terapêuticas para amiloidose cardíaca por transtirretina atuais e iminentes, determinar se algum destes fármacos reúne a evidência necessária para se tornar o foco da gestão da amiloidose cardíaca por transtirretina e identificar questões relevantes ainda por responder pela evidência disponível atualmente.<br>Transthyretin cardiac amyloidosis was until recently considered an untreatable disease. However, this underdiagnosed pathology experienced a surge in research interest with multiple novel treatments, including several first-in-class drugs rapidly approaching the final stages of investigation, with tafamidis and patisiran already approved by the European and American regulators. Novel drugs include small molecule stabilizers, gene silencing drugs, amyloid fibril disruptors, and monoclonal antibodies This review aims to capture a comprehensive picture of the current and upcoming therapeutic options for cardiac transthyretin amyloidosis, to ascertain if any of these drugs gather the necessary evidence to become the staple of transthyretin cardiac amyloidosis management and to identify relevant questions yet to be answered by currently available evidence.

Although a rare disease, light chain (LC) amyloidosis (AL) is the most common systemic amyloidosis in developed countries. It is caused by an overproduction of immunoglobulin LC proteins in bone marrow plasma cells. In AL amyloidosis, LCs that are prone to misfolding and insolubility will aggregate, form fibrils, and deposit themselves in various tissues, thereby causing organ dysfunction. The most fatal manifestation of AL amyloidosis is associated with cardiac involvement, defined by the presence of extracellular AL amyloid deposits within the heart. Cardiac amyloid infiltration typically leads to diastolic dysfunction followed by heart failure and has a median survival of approximately 6 months from the time of diagnosis if untreated. Clinical observation suggests that a reduction in circulating LCs results in an improvement in heart failure symptoms despite minimal changes in amyloid deposition. This has led to the concept that LCs themselves are cytotoxic to cardiomyocytes. Recent studies indicate that AL LCs induce oxidative stress, cellular dysfunction, and apoptosis (programmed cell death) in cardiomyocytes via a p38α mitogen-activated protein kinase (MAPK) mechanism. They may therefore be a target for amyloidosis therapy. By understanding how LCs cause cardiac dysfunction, we can target this process with therapies and utilize downstream measures of LC activity as diagnostic and prognostic tools. The objective of this study was to determine the role of autophagy in AL amyloidosis. Autophagy is the intracellular process of degrading aging or dysfunctional cellular components. Autophagy can be beneficial by preventing proteotoxicity and providing nutrients, amino acids, and other necessities during times of cellular stress. On the other hand, increased autophagy, like apoptosis, may mediate cellular death depending on the type of stimulus and its duration. Autophagy is induced by a variety of stimuli, including oxidative stress. AL has been demonstrated to increase reactive oxygen species (ROS), and it is unknown if autophagy mediates cardiomyocyte dysfunction in AL cardiac amyloidosis. We thus sought to determine if it is a factor in amyloid cardiotoxicity. We explored the ERK1/2, p38, and JNK MAPK pathways in particular, since MAPK signaling cascades regulate several transcription factors involved in the cell cycle and p38α has been implicated in ROS-induced cardiac AL amyloidosis. Adult rat ventricular myocytes (ARVM) were harvested from healthy adult male rats and exposed to a variety of experimental conditions in vitro. ARVM were treated with vehicle control, human LC obtained from a patient without cardiac involvement, a positive control (aldosterone), and human AL light chains obtained from a patient with AL cardiac amyloidosis in the presence or absence of UO126, SB203580, or SP600125 (specific inhibitors of ERK1/2, p38, and JNK, respectively). The resulting protein expression levels of autophagy indicators LC3II and ATG4B in cardiomyocytes were analyzed by Western blotting. The ratio of phosphorylated to total ERK1/2 protein expression was also explored. We found that AL light chains did not contribute to autophagy via the ERK1/2, p38, or JNK pathways. In contrast to our previous unpublished findings, the protein levels of autophagy indicators in AL-treated ARVM did not differ from vehicle control levels, suggesting that AL did not activate autophagy. However non-cardiomyopathic light chains (LC) did increase LC3II expression in ARVM, despite their human source exhibiting no clinical indications of cardiac involvement. This implies that autophagy induced by non-cardiomyopathic LCs may be beneficial and protect against the development of the cardiotoxicity seen in AL cardiac amyloidosis. Further studies are necessary to understand the effect of autophagy in the heart and its role in cardiac amyloidosis. Continuing to explore the underlying mechanisms of AL light chain toxicity will contribute to the development of diagnostic, prognostic, and treatment strategies for AL amyloidosis.

Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina<br>A amiloidose por depósito de transtirretina (ATTR) é cada vez mais reconhecida como causa importante de insuficiência cardíaca com fração de ejeção preservada. Com o advento de terapêutica farmacológica dirigida, a necessidade de testes de diagnóstico não invasivos capazes de distinguir ATTR de outros tipos de amiloidose tornou-se clara. Evidência crescente tem vindo a demonstrar que a imagiologia em medicina nuclear, particularmente com bifosfonatos, tem potencial neste contexto. O objetivo desta revisão sistemática é estudar a utilidade da imagiologia em medicina nuclear no diagnóstico, prognóstico, e avaliação clínica de doentes com ATTR.Foi realizada uma pesquisa de artigos publicados entre 1 de Janeiro de 2008 e 4 de Julho de 2018 em duas bases de dados, PubMed e Embase. Na Pubmed foram combinados 3 algoritmos de pesquisa: 1- "Radionuclide Imaging"[Mesh] AND "Amyloidosis"[Mesh] AND ("TTR" OR "ATTR" OR "transthyretin"); 2- ("amyloid" OR "amyloidosis") AND ("TTR" OR "ATTR" OR "transthyretin") AND ("scintigraphy" OR "SPECT" OR "SPET" OR "PET" OR "postitron-emission tomography" OR "radionuclide imaging" OR "nuclear medicine"); e 3 - "Amyloidosis/diagnostic imaging"[Mesh] AND "Heart Diseases/diagnostic imaging"[Mesh] AND ("TTR" OR "ATTR" OR "transthyretin"). Na Embase a seguinte equação foi utilizada: 'attr amyloidosis'/exp AND 'radiodiagnosis'/exp.Artigos avaliando técnicas de imagem de medicina nuclear em doentes com ATTR, nomeadamente acuidade diagnóstica, relação com outros exames complementares, semiologia e/ou prognóstico foram considerados elegíveis. Após a aplicação de critérios de exclusão definidos, um total de 44 estudos observacionais e uma revisão sistemática com meta-análise foram avaliados. A qualidade dos artigos foi avaliada através de check-lists do Oxford Centre for Evidence-based Medicine.A cintigrafia com bifosfonatos como o 99mTc-DPD, o 99mTc-PYP e o 99mTc-HMDP revelou adequada acuidade para o diagnóstico de cardiopatia por ATTR. São necessários mais dados para validar o seu potencial papel na avaliação do prognóstico destes doentes. A atividade cardíaca com o 123I-MIBG parece correlacionar-se com o prognóstico de doentes com ATTR. Em relação ao 18F-florbetapir, 18F-florbetabeno, 18F-NaF e 11C-PIB, os poucos estudos disponíveis indicam que estes marcadores são capazes de diagnosticar AC mas não de distinguir os seus tipos. A falta de ensaios aleatorizados e controlados, bem como a heterogeneidade dos protocolos de imagem utilizados nos diferentes estudos são pontos a resolver de modo a obter evidência mais robusta e de maior qualidade.<br>Cardiac transthyretin-related amyloidosis (ATTR) is increasingly recognized as a cause of heart failure with preserved systolic function. Following the recent emergence of promising targeted therapy, the growing need for non-invasive diagnostic tools capable of discerning ATTR from other types of amyloidosis has been made evident. An increasing amount of evidence has shown that nuclear medicine imaging, particularly with bone-seeking radiotracers, has the potential to be such a tool. The purpose of this systematic review is to access the utility of nuclear medicine imaging techniques not only in the diagnosis, but also in the prognosis and clinical evaluation of patients with cardiac ATTR.A search of studies published between 1 January 2008 and 4 July 2018 was performed on two databases, PubMed and Embase. On Pubmed 3 search algorithms were combined: 1 - "Radionuclide Imaging"[Mesh] AND "Amyloidosis"[Mesh] AND ("TTR" OR "ATTR" OR "transthyretin"); 2 - ("amyloid" OR "amyloidosis") AND ("TTR" OR "ATTR" OR "transthyretin") AND ("scintigraphy" OR "SPECT" OR "SPET" OR "PET" OR "postitron- emission tomography" OR "radionuclide imaging" OR "nuclear medicine"); and 3 - "Amyloidosis/diagnostic imaging"[Mesh] AND "Heart Diseases/diagnostic imaging"[Mesh] AND ("TTR" OR "ATTR" OR "transthyretin"). On Embase the following algorithm was used: 'attr amyloidosis'/exp AND 'radiodiagnosis'/exp.Studies evaluating nuclear medicine imaging techniques in patients with cardiac ATTR, in regard to diagnostic accuracy, prognostic impact and/or relationship with clinical status were considered eligible. Following the application of defined exclusion criteria, a total of 44 observational studies and 1 systematic review with meta-analysis were analyzed. The Oxford Centre for Evidence-based Medicine check-lists were used to assess the quality of the studies.Scintigraphy using bone-seeking radiotracers such as 99mTc-DPD, 99mTc-PYP and 99mTc-HMDP revealed adequate accuracy for the diagnosis of cardiac ATTR. More data is needed to further validate the potential role of these tracers in prognostic assessment. Cardiac activity of 123I-MIBG seems to correlate with the prognosis of patients with cardiac ATTR. The few studies with 18F-florbetapir, 18F-florbetaben, 18F-NaF and 11C-PIB have shown that these tracers are can diagnose cardiac amyloidosis but are unable to distinguish its type. The lack of randomized controlled trials and the heterogeneity of imaging protocols used in different studies need to be addressed in order to obtain more robust evidence-based data.

Speckle tracking echocardiography (STE) is a relatively new imaging modality that enables the direct measurement of active contractile myocardial tissue in an offline analysis. This is accomplished through a software algorithm that tracks collections of acoustic markers, known as 'speckles', that are unique to a given section of myocardium. By measuring the displacement of these 'speckles' as the heart contracts and relaxes, STE produces parameters of the strain, or percent change in length, exhibited by the myocardium. As multiple studies have shown, this strain data produced by tracking of the global left atrium has the ability to accurately assess the physiologic functions of the atrium as a reservoir, conduit and booster pump in the cardiac cycle. Despite these valuable correlations, there are noted problems with STE regarding acoustic cluttering and disappearance of 'speckles' that can occur as the selected region of interest moves out of the field of view or becomes obscured. These problems may be increased when tracking an extended region of myocardium. Therefore, this present study sought to test a new method of assessing left atrial function with STE strain analysis by focusing on a concise region of the atrium, specifically the interatrial septum. To test this, the echocardiograms of 37 patients were obtained and grouped according to the designation of their cardiac function as normal (n=11), abnormal (n=12), or exhibiting signs of cardiac amyloidosis (n=14). In all patients, STE strain analysis was performed on the both the global left atrium and the interatrial septum. Measurements of the mean peak strain observed in the resultant strain curves were recorded for both STE scans of each patient. The curves produced by the tracking the segments of the entire atrium (6 segments) and interatrial septum (3 segments) were compared based on the exhibited changes in strain seen in the relative shapes of the curves, as well as the spread of the segmental strain curves about the calculated mean strain curve. Additionally, the number of segments that were either unsuccessfully or incorrectly tracked was recorded as a measure of the accuracy of STE. As a final step, the interatrial strain curves of four selected patients in the various states of ventricular diastolic dysfunction were chosen and compared with data obtained from scans of mitral flow echocardiography and tissue Doppler imaging (TDI) in an attempt to correlate the exhibited changes in strain shown in the interatrial septum with the physiologic functions of the atrium during ventricular diastole. The results showed that the mean peak strain of the global atrial strain trace decreased from normal (41.32%±10.8) to abnormal (21.69%±13.8) to the amyloid group (10.41%±6.9). This trend was echoed in the mean peak strain measured in the interatrial septum, as measured in normal (64.2%±15.6), abnormal (28.37%±13.4) and amyloid groups (12.21%±12.1). When the strain curves of the entire atrium and interatrial septum were compared, they demonstrated similar patterns in the timing of changes in strain, however the strain curves of the individual interatrial septum segments showed a much more concise grouping about the mean strain curve and were less likely to exhibit discordant segmental strain curves that deviated from the pattern established by all other segments in the trace. Additionally, within the STE scans of the global atrium, the interatrial septum exhibited a higher percentage of successfully tracked segments than did the lateral atrial wall; this trend was universally exhibited in all three groups. Finally, the interatrial septum strain curves, mitral flow echocardiography and TDI scans all demonstrated similar indications of left atrial function in the four selected patients. Ultimately, STE strain analysis of the interatrial septum appears to be a more accurate method of tracking the atrial myocardium than STE tracing of the global left atrium. Furthermore, it shows viable potential as a method for assessing the global physiologic function of the left atrium, as indicated by the similarities between the trends exhibited by these STE scans and the data gathered from scans produced by mitral flow echocardiography and TDI.

Amyloidosis is a term used for a whole group of diseases caused by deposition of a substance called amyloid into different tissues. Amyloid may be produced by a range of pathologic processes. Heart affliction is typical for only several types of amyloidoses. Heart involvement is then the patient`s prognosis major limiting factor. Diagnosis of heart amyloidosis is difficult especially for nonspecific symptoms and nonspecific findings obtained during common diagnostic procedures. The aim of this thesis was to evaluate usefulness of novel diagnostic methods, namely cardiac magnetic resonance with gadolinium enhancement and a simplified echocardiographic evaluation of left ventricular longitudinal strain, in diagnosing amyloid cardiomyopathy. In our first study we examined 22 patients with light chain amyloidosis by echocardiography and also with cardiac magnetic resonance with late gadolinium enhancement. We compared morphologic and functional parameters acquired by magnetic resonance examination, which is considered a gold standard for morphologic and functional measurements, with values obtained by echocardiographic measurement. Afterwards we evaluated the presence and eventually pattern of late gadolinium enhancement during cardiac magnetic resonance exam. From acquired data we conclude that the...