Thèses sur le sujet « Miocardite acuta »

BACKGROUND: L'identificazione di marcatori affidabili associati a eventi dopo una miocardite acuta (AM) è clinicamente rilevante per pianificare un futuro follow-up. Abbiamo cercato di chiarire la performance prognostica dei marcatori di risonanza magnetica cardiaca (CMRI) precedentemente descritti, tra cui l'aumento tardivo del gadolinio settale (LGE), rispetto all'evidenza della frazione di eiezione ventricolare sinistra (LVEF) <50% sulla CMRI basale, rispetto alla presentazione clinica complicata (CCP) della AM (definita come la presenza di aritmie ventricolari sostenute [SVT] o LVEF <50% al primo ecocardiogramma di presentazione fulminante). METODI: Abbiamo valutato 248 pazienti AM con insorgenza di sintomi cardiaci <30 giorni prima del ricovero, aumento della troponina e CMRI coerente con la diagnosi di miocardite (tempo mediano dal ricovero alla CMRI di 6 giorni). I pazienti sono stati raccolti retrospettivamente tra febbraio 2006 e aprile 2019 da 6 ospedali Lombardi con un follow-up mediano di 1708 giorni (primo - terzo quartile [Q1-Q3], 1000-2751). Abbiamo valutato la performance prognostica di LGE settale vs. LVEF<50% su CMRI vs. CCP. RISULTATI: La popolazione dello studio aveva un'età mediana di 34 anni (Q1-Q3: 23-41) con una prevalenza maschile dell'87,1% e una LVEF mediana del 61% (Q1-Q3, 55-66%) alla CMRI basale. Tredici pazienti (5,2%) hanno sperimentato almeno un evento cardiaco maggiore (tra cui morte cardiaca, trapianto di cuore (N=1), arresto cardiaco resuscitato (N=3), SVT (N=5), o ricovero per insufficienza cardiaca (N=5). Tra questi 13 pazienti, 10 (76,9%) avevano LGE settale, 8 (61,5%) avevano LVEF<50%, su CMRI, e 12 (92,3%) avevano un CCP. La migliore performance per questi marcatori prognostici era il valore predittivo negativo (NPV) che variava tra 0,98 e 0,99 per CCP, mentre il valore predittivo positivo era basso, tra 0,14 e 0,25 per LVEF<50%. CONCLUSIONI: Abbiamo confermato che il tasso di eventi cardiaci maggiori dopo una AM è relativamente basso, e LGE settale, LVEF<50% su CMRI, e CCP sono significativamente associati agli eventi nel follow-up. Il risultato più rilevante è l'alto NPV di questi marcatori per identificare i pazienti senza eventi dopo una AM. Questa osservazione può aiutare i medici a monitorare i pazienti dopo una AM ed impostare un corretto monitoraggio nel follow-up sulla base di tali dati all'esordio.
BACKGROUND: Identifying reliable markers associated with events after acute myocarditis (AM) is clinically relevant to planning a future follow-up. We aimed to clarify the prognostic performance of previously described cardiac magnetic resonance imaging (CMRI) markers including septal late gadolinium enhancement (LGE), versus evidence of left ventricular ejection fraction (LVEF)<50% on baseline CMRI, vs. complicated clinical presentation (CCP) of AM (defined as the presence of sustained ventricular arrhythmias [SVT] or LVEF <50% on the first echocardiogram of fulminant presentation). METHODS: We assessed 248 AM patients with onset of cardiac symptoms <30 days before admission, increased troponin, and CMRI consistent with myocarditis (median time from admission to CMRI of 6 days). The patients were retrospectively collected between February 2006 and April 2019 from 6 hospitals with a median follow-up of 1708 days (first to third quartile [Q1-Q3], 1000-2751). We assessed the prognostic performance of septal LGE vs. LVEF<50% on CMRI vs. CCP. RESULTS: The study population had a median age of 34 years (Q1-Q3: 23-41) with a male prevalence of 87.1% and a median LVEF of 61% (Q1-Q3, 55-66%) on baseline CMRI. Thirteen patients (5.2%) experienced at least one major cardiac event (including cardiac death, heart transplantation (N=1), aborted cardiac death (N=3), SVT (N=5), or heart failure hospitalization (N=5). Among these 13 patients, 10 (76.9%) had septal LGE, 8 (61.5%) had LVEF<50%, on CMRI, and 12 (92.3%) had a CCP. The best performance for these prognostic markers was the negative predictive value (NPV) ranging between 0.98 and 0.99 for CCP, while predictive value was low, ranging between 0.14 and 0.25 for LVEF<50%. CONCLUSIONS: We confirmed that the rate of major cardiac events after an AM is relatively low, and septal LGE, LVEF<50% on CMRI, and CCP are significantly associated with events. The most relevant finding is the high NPV of these markers to identify patients without events after an AM. This observation can help clinicians to monitor the patients after an AM, in fact, patients without these markers had an uneventful follow-up.

Historical Background. “Angina pectoris” has been known since in ancient Egyptian time. Ebers Papyrus (1500 BC) wrote in a passage ".... If you examine a man for heart disease, he complains of pain in the arm, chest and part of the heart ....". This is the beginning of the long journey that takes us to the 1912 description of the myocardial infarction by coronary thrombosis by James Herrick, the 1962 subsequent birth of the first coronary care unit by Desmond Julian and finally in 1981 to the most modern Chest Pain Unit. Research continues to evaluate new aspects that could lead to the discovery of new strategies to reduce mortality rate of this disease. Background and aims. Preinfarction angina (defined as angina onset within 24 hours from the myocardial infarction) gives protection to the myocardium by reducing infarct size, and limiting left ventricular remodeling. The purpose of this study was to evaluate patients with acute coronary syndrome with ST elevation, and in particular subgroups. We compared patients with preinfarction angina (API +) to those without preinfarction angina (API-) with regard to ventricular function, end-diastolic volume and in-hospital clinical outcome. All these patients are followed up for one year under echocardiography and clinical settings, in order to assess whether any protective effects that are present during the hospital stay persist after one year. Methods and results. We evaluated over a period of two years 448 consecutive patients admitted to the Coronary Care Unit for acute coronary syndrome with ST elevation. Regardless of treatment received, of these patients we analyzed in greater detail a homogeneous subgroup, which had a significant lesion on left anterior descending coronary artery. Of these patients we performed a clinical and echocardiographic follow-up to a year. This study excluded patients enrolled in other studies. Our population was divided as follows: 112 patients, representing 25%, had suffered preinfarction angina (API +) within 24 hours from myocardial infarction, the remaining 336 (75%) had had no angina in the last 24 hours (API-). The two groups compared (API + versus API-) showed no significant differences in age, sex, risk factors (hypertension, high cholesterol, diabetes, family history of coronary artery disease, smoking). With regard to the treatment we found that the API + group had been treated more frequently with primary angioplasty compared to the API- group (88% vs 79%, p = 0.025). With regard to the in-hospital outcome group API+ compared to API- had a significantly reduced length of stay (9 ± 4 days vs 11 ± 9 days, p = 0.004), lower presence of arrhythmias (20% vs 32%, p = 0.015 ), less presence of heart failure (6% vs 14%, p = 0.035) and with regard to data echocardiography: ventricular function was better in group API + (ejection fraction 51 ± 7 % vs 48 ± 9%, p = 0.003) in correspondence to a lower end-diastolic volume (58 ± 11 ml/m2 vs 62 ± 17 ml/m2, p = 0.005) In a one year clinic follow up the number of admissions in other departments was significantly reduced (15% vs 25% p= 0.04) in the group API+, there is no statistical difference regarding the other parameters evaluated between outcome and preinfarction angina even if they are suggestive of a better prognosis in presence of the latter (one year survival 98% in API+ vs 93% in API-). So, considering the well known benefits of revascularization with primary angioplasty and thinking that they may cover the benefits of preinfarction angina, we evaluated a very homogeneous subgroup of 277 patients who had a critical lesion on the left anterior descending coronary artery. Of these, 30% was API +, while the remaining 70% were API-. There were no significant differences with regard to clinical variables. There were no significant differences with regard to the treatment received, while confirming the data of better in-hospital prognosis of group API + compared to API- with reduced hospital stay (9 ± 4 days vs 13 ± 10 days, p = 0.01), a lower presence of arrhythmias (20% vs 32%, p = 0.03), less presence of heart failure (7% vs 17%, p = 0.029) and also with regard to echocardiography: ventricular function was greater in the API + (50 ± 8% vs 46 ± 9%, p = 0.00) at a lower end-diastolic volume (59 ± 12 ml/m2 vs 64 ± 18 ml/m2, p = 0.018). Survival at one year did not differ significantly in the two groups (API + 97% vs API- 94%), it remained an improved ejection fraction (52 ± 9 % vs 48 ± 9 %, p = 0.010) without significant differences in relation to the end-diastolic volume (67 ± 16 ml/m2 vs 69 ± 18 ml/m2). Preinfarction angina by multivariate analysis was an independent predictor of lower presence of arrhythmias (OR 0.48 with 95% CI 0.25-0.93, p = 0.03), fewer episodes of heart failure (OR 0.33 with 95% CI 0.12-0.91, p = 0.03) and reduced hospital stay (in-hospital decreased of -2.62 ± 1.21 days, p = 0.03). Concerning to the echocardiographic data obtained at the discharge preinfartion angina was also protective, with better ventricular function (higher left ventricular ejection fraction 3.21 ± 1.14%, p = 0.01), and reduced diastolic volume (decreased end diastolic volume -5.20 ± 2.26 ml/m2, p = 0.02). Multivariate analysis of the data obtained during the follow up has shown a better ventricular function also at the echocardiography performed at 1 year (2.96 ± 1.44, p = 0.03). At the clinical follow-up at one year we have seen that the presence of preinfarction angina has played a protective role with regard to new episodes of acute coronary syndrome (6 cases vs. 22, OR 0.27) and episodes of heart failure (0 cases vs 5). Conclusions. Preinfarction angina has a certain protective effect with regard to in-hospital outcome, as it is associated with a lower presence of arrhythmias, fewer episodes of heart failure and reduced hospitalization, API+ patients, in despite of equal treatment, also have better sistolic ventricular function with less volume than API- patient . At the echocardiography obtained during the follow up ventricular function is improved in the API + group and our data show a protective role of preinfarction angina even with regard to new episodes of acute coronary syndrome and new episodes of heart failure.
Premessa storica. Già al tempo degli egizi, nel papiro di Ebers (1500 a.C.) è riconoscibile la descrizione dell'angina pectoris da un passo che dice: “.... se esamini un uomo per malattia del cuore, egli si lamenta per dolore al braccio, al petto e ad una parte del cuore....”. Da qui ha inizio il lungo cammino che ci porterà alla descrizione dell’infarto nel 1912 da trombosi coronarica da parte di James Herrick, alla successiva nascita delle prime Unità coronariche nel 1962 per opera di Desmond Julian e le più moderne Chest Pain Unit nel 1981. La ricerca continua a valutare nuovi aspetti che possano portare al rinvenimento di nuove strategie per ridurre la mortalità causata da questa malattia. Background e obiettivi. L’angina preinfartuale (intesa come angina comparsa nelle 24 ore precedenti l’infarto miocardico acuto) conferisce una protezione al miocardio riducendo le dimensioni dell’infarto, e limitando il rimodellamento ventricolare sinistro. Lo scopo di questo studio è valutare i pazienti che si presentano con sindrome coronarica acuta con sopraslivellamento del tratto ST, e in particolare alcuni sottogruppi, confrontando i pazienti con angina pre-infartuale (API+) e quelli senza (API-) per quanto riguarda la funzione ventricolare, il volume telediastolico e gli outcome clinici intraospedalieri e a distanza di un anno, per poter valutare se gli eventuali effetti protettivi presenti durante la degenza si mantengano anche nel tempo. Metodi e risultati. Abbiamo valutato in un arco temporale di due anni 448 pazienti consecutivi ricoverati in Unità Coronarica per sindrome coronarica acuta con ST sopraslivellato (SCA ST sopra) indipendentemente dal trattamento ricevuto. Di questi abbiamo poi analizzato più approfonditamente un sottogruppo omogeneo, che presentava lesione emodinamicamente significativa su ramo discendente anteriore della coronaria sinistra. Di questi pazienti è stato eseguito un follow-up clinico ed ecocardiografico ad un anno. Sono stati esclusi dal presente lavoro pazienti arruolati per altri studi. La nostra popolazione risultava così suddivisa: 112 pazienti, corrispondenti al 25 %, avevano presentato angina pre-infartuale (API+) nelle 24 ore precedenti l’infarto miocardico, i restanti 336 (75 %) non avevano avuto episodi anginosi nelle ultime 24 ore (API-). I due gruppi confrontati ( API+ vs API-) fra di loro non hanno dimostrato differenze significative per quanto riguardava l’età, il sesso, i fattori di rischio (ipertensione arteriosa, ipercolesterolemia, diabete, familiarità per coronaropatia, fumo). I due gruppi sono stati confrontati per quanto riguarda il trattamento ed è risultato che il gruppo API+ era stato trattato più frequentemente con angioplastica primaria rispetto al gruppo API- (88% vs 79% con p=0.025). Per quanto riguarda l’outcome intraospedaliero nel gruppo API+ rispetto a quello API- è risultata significativamente ridotta la durata della degenza (9±4 giorni vs 11±9 giorni con p=0.004), la presenza di aritmie ( 20% vs 32% con p= 0.015), la presenza di scompenso (6% vs 14% con p=0.035) e per quanto riguarda i dati ecocardiografici: la funzione ventricolare era migliore nel gruppo API+ (frazione di eiezione 51±7% vs 48± 9% con p= 0.003) in corrispondenza di un minor volume telediastolico (58 ± 11 ml/m2 vs 62 ± 17 ml/m2 con p = 0.005). Nel follow up ad un anno è risultato significativamente ridotto il numero di ricoveri in altro reparto (15% vs 25% con p=0.04), non vi è significatività statistica per quanto riguarda gli altri parametri valutati tra outcome e angina pre IMA anche se sono suggestivi di una migliore prognosi nel caso di angina pre IMA (sopravvivenza ad un anno API+ 98% vs API- 93%). Considerando i noti vantaggi legati alla rivascolarizzazione con angioplastica primaria e pensando che questi potessero offuscare i vantaggi legati all’angina-preinfartuale, abbiamo valutato un sottogruppo particolarmente omogeneo di 277 pazienti che avevano come caratteristica una lesione critica su discendente anteriore. Di questi il 30% aveva presentato API+, mentre il restante 70% era API-. Anche in questo gruppo non vi erano differenze significative per quanto riguardava età, sesso, fattori di rischio associati (ipertensione arteriosa, diabete, ipercolesterolemia, familiarità per coronaropatia, fumo) e malattie concomitanti (insufficienza renale cronica, broncopneumopatia cronica ostruttiva). Non risultavano differenze significative per quanto riguarda il trattamento ricevuto, mentre si confermavano i dati di miglior prognosi intraospedialiera nel gruppo API+ rispetto a quello API- con ridotta degenza ospedaliera (9±4 giorni vs 13±10 giorni, con p=0.01), la presenza di aritmie ( 20% vs 32% con p= 0.03), la presenza di scompenso (7% vs 17% con p=0.029) e anche per quanto riguarda i dati ecocardiografici: la funzione ventricolare era maggiore nel gruppo API+ (frazione d’eiezione 50± 8% vs 46± 9% con p = 0.00) in corrispondenza di un minor volume telediastolico (59 ± 12 ml/m2 vs 64 ± 18 ml/m2 con p = 0.018). Nel follow up ad un anno la sopravvivenza non presentava differenze statisticamente significative nei due gruppi (API+ 97% vs API- 94%), mentre si manteneva una miglior frazione di eiezione (52± 9 % vs 48± 9 % con p = 0.010) senza differenze significative per quanto riguarda il volume telediastolico (67 ± 16 ml/m2 vs 69 ± 18 ml/m2). All’analisi multivariata l’angina pre-infartuale risultava predittore indipendente di minor presenza di aritmie (OR 0.48 con 95%CI 0.25-0.93, p=0.03), minori episodi di scompenso (OR 0.33 con 95%CI 0.12-0.91, p=0.03) e ridotta degenza (degenza ridotta di -2.62±1.21 giorni con p=0.03). Risultava protettiva anche per quanto riguarda i dati ecocardiografici ottenuti in dimissione con miglior funzione ventricolare (frazione di eiezione aumentata di 3.21±1.14 % con p=0.01), e minor volume telediastolico (volume telediastolico ridotto di -5.20±2.26 ml/m2 con p=0.02). L’analisi multivariata dei dati ottenuti nel follow up ha dimostrato come si mantenga predittore di migliore funzione ventricolare anche nell’ecocardiogramma eseguito ad 1 anno (frazione di eiezione aumentata 2.96±1.44 % con p=0.03). Per quanto riguarda il follow up clinico ad 1 anno abbiamo visto che la presenza di angina pre-infartuale ha svolto un ruolo protettivo per quanto riguarda nuovi episodi di sindrome coronarica acuta (6 casi vs 22, OR 0.27) e per episodi di scompenso cardiaco (0 casi vs 5). Conclusioni. L’angina pre-infartuale risulta avere un effetto protettivo certo per quanto riguarda l’outcome intraospedaliero, in quanto porta ad una minor presenza di aritmie, minori episodi di scompenso e minori giorni di degenza, inoltre i pazienti API+ hanno a parità di trattamento una migliore funzione ventricolare con minor volume telediastolico rispetto ai pazienti API-. Per quanto riguarda il follow up ad un anno la funzione ventricolare risulta migliore nel gruppo API+ e i nostri dati mostrano un ruolo protettivo dell’angina pre-infartuale anche per quanto riguarda nuovi episodi di sindrome coronarica acuta e nuovi episodi di scompenso.

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Dados epidemiológicos, experimentais e clínicos têm sugerido que a doença periodontal, especialmente a periodontite crônica, pode constituir um fator de risco para doenças cardiovasculares isquêmicas. A proposta deste estudo foi investigar a associação entre a doença periodontal e o infarto agudo do miocárdio (IAM) em indivíduos adultos. Uma revisão de literatura de estudos de caso-controle que estudaram essa associação foi sumarizada em uma meta-análise que demonstrou uma chance em dobro para ocorrência de desfechos cardiovasculares isquêmicos em presença da doença periodontal (OR = 2,52; IC 95%: [2.10 3.00], p< 0, 001). Uma estimativa próxima foi obtida por meio de um estudo de caso-controle com uma amostra de 621 indivíduos com 40 anos ou mais, que avaliou a chance de desenvolver o infarto agudo do miocárdio em portadores de doença periodontal do tipo periodontite. As co-variáveis investigadas foram: idade, sexo, raça/cor auto referida, nível de escolaridade, renda per capita, condição marital, prática de atividade física, hábito de fumar presente e passado, consumo de álcool, índice de massa corporal, nível glicêmico, colesterol total e frações, relação cintura-quadril, hipertensão arterial sistêmica. Os resultados encontrados mostraram que os portadores de doença periodontal tiveram uma chance quase em dobro de desenvolver infarto agudo do miocárdio em relação a indivíduos sem doença periodontal, mesmo após ajustar por hábito de fumar, nível de escolaridade, ocupação, diabetes e nível de HDL-colesterol tanto quando comparada a controles comunitários (ORajustada=1,89; IC 95%: [1,11- 3,28], p=0,018), quanto a controles hospitalares (ORajustada=1,92; IC 95% :[1,14-3,23], p=0,015). Ao se estimar a associação de periodontite crônica e níveis plasmáticos de proteína C-reativa em um sub-amostra (n=359), observou-se uma associação positiva e significante (ORajustada= 2,26; IC 95%: [1.30 - 3.93]), considerando também o efeito da idade, nível de escolaridade, sexo, gênero, hábito de fumar, HDL-colesterol e diabetes. Assim, no grupo estudado a exposição à DP aumentou a chance de ocorrência do IAM, bem com da proteína Creativa, independentemente de outros fatores, o que reafirma que a doença periodontal pode ser um marcardor ou um fator de risco para o aparecimento de alterações cardiovasculares isquêmicas, havendo necessidade de estudos adicionais para confirmação da relação causal entre elas.
Salvador

Background: STEM-AMI outcome is a Phase III, multicenter, randomized, controlled, open label study. The aim pof this study is to demonstrate that G-CSF therapy addition to state of the heart treatment (pharmacological and non pharmacological) is safe and significantly improves clinical outcome in patient with reduced left ventriocular EF after successful reperfusion for anterior acute MI. The previous randomized, single blind, phase II study (STEM-AMI trial) demonstrate that administration of G-CSF in “acute phase” of anterior MI with signifiant left ventricular disfunction (EF <45%) can attenuate unfavourable post-infarction remodelling. Since adverse remodelling is the mein predictor of prognosis, the ability of G-CSF to attenuate unfavourable post-infarction remodelling is expected to improve in these patients event-free survival. -EF is known to be unreliable as marker of efficacy of therapy. Many study in acute coronary syndrome demonstrate that global strain directly correlates with the scar area and it is a great predictor of post-infarction remodelling and adverse events as HF or death. -Many studies demonstrated that myocardial strain 2D can quantify infarction area and scar and can predict the possibility of ventricular function improvement. Prymary Objectives: The aim pof this study is to demonstrate that G-CSF therapy addition to state of the heart treatment (pharmacological and non pharmacological) is safe and significantly improves clinical outcome in patient with reduced left ventriocular EF after successful reperfusion for anterior acute MI. The evaluation with myocardial 2D strain may be useful to achieve more information about the possible EF improvement and scar reduction. Overview of study: Phase III, multicentre, randomized, controlled, open label study. We studied patients in the HSG Monza Hospital, randomizzazion 1:1 with a web-based system. Patient will be required to attend 6 study assesment during the follow up that will be of 24 months. Treatment: Five (5) mcg/Kg of G-CSF (Filgastrim) has been administreted subcutaneously in the abdomen b.i.d. for 6 days (from day 0 to day 5) to the patient randomized to active treatment, starting within 24 hours after successful PCI and reperfusion. Population: Patients affected by acute anterior STEMI undergoing primary PCI or PCI rescue with persistent occlusion of coronary artery; Time symptom-to-balloon ≥ 2 h e ≤ 24 h if symptoms persist, TIMI flow post PCI>2; Evidence of left ventricular dysfunction (EF biplane <45%) 24h after revascularization; aged >18 years and < 75 years; informed consent signed. State of art: Enrollment is over. Data analysis in progress

Introducción y objetivos: La miocarditis es una enfermedad inflamatoria del miocardio, secundaria a una infección vírica en la mayoría de los casos. El diagnóstico de certeza se establece por la biopsia endomiocárdica (BEM), aunque al tratarse de una técnica invasiva, su uso está muy restringido en la población pediátrica. El cuadro suele resolverse de forma espontánea, pero algunos pacientes pueden fallecer o presentar una disfunción ventricular severa que precise trasplante cardíaco. Ningún tratamiento ha demostrado mejorar el pronóstico. El objetivo de este estudio es revisar las características de una serie de pacientes pediátricos con miocarditis aguda, describir su evolución, los criterios de mal pronóstico y la utilidad y los riesgos de las diferentes técnicas diagnósticas, como la BEM. Describiremos la utilidad del tratamiento antiviral e inmunosupresor en una población seleccionada de pacientes. Material y métodos: revisamos todos los pacientes < 18 años que han ingresado en el Hospital Materno Infantil de la Vall d´Hebron con el diagnóstico de miocarditis aguda desde abril de 2007 hasta septiembre de 2018. Se revisan las características clínicas y demográficas, los resultados de las diferentes exploraciones complementarias así como la utilidad de la BEM en esta población. Se comparan los resultados inmunohistoquímicos de la BEM con los observados en pacientes con miocardiopatía de origen genético. Se estudia la efectividad del tratamiento médico comparando la evolución de los pacientes tratados con la de una cohorte histórica de características similares que no recibieron tratamiento específico. Resultados: 41 pacientes (25 varones, 16 mujeres, edad mediana 25 meses) presentaron 42 episodios de miocarditis. El diagnóstico se realizó por BEM en 14/42 casos (33.3%), por resonancia magnética en 27/42 (64.3%) y por clínica en 1/42 paciente (2.4%). Con una mediana de seguimiento de 47 meses (entre 7 y 140 meses), se produjo una resolución completa del cuadro con normalización de la FEVI y del DTDVI en 33/42casos (78.5%). El virus más frecuentemente implicado fue el PVB19 (9/42 casos, 21.4%) seguido por el enterovirus (5/42 casos, 11.9%). Fallecieron 4/41 pacientes (9.7%) y 5/41 (12.2%) precisaron un trasplante cardíaco. En el análisis univariado, los factores que se relacionaron con una peor evolución (fallecimiento del paciente o trasplante) fueron la necesidad de ECMO al ingreso (p=0.041), una fracción de eyección del ventrículo izquierdo (FEVI) inferior al 35% (p=0.02) y la disfunción del ventrículo derecho (p=0.02). En el análisis multivariado sólo la FEVI tuvo significación estadística (p=0.007). En cuanto a los hallazgos anatomopatológicos se observó que ningún dato era específico de miocarditis aguda y que 3/5 pacientes (60%) con miocardiopatía dilatada de origen genético cumplían los criterios de inmunohistológicos de miocarditis. Desde febrero de 2015, los casos más graves recibieron tratamiento con inmunosupresión o antiviral en función del resultado anatomopatológico y de la PCR vírica en la BEM. En total fueron tratados 9 pacientes y su evolución se comparó con una cohorte histórica de 11 pacientes de características similares. La supervivencia libre de trasplante al año fue del 100% en el grupo tratado vs el 63% (p=0.042). A largo plazo, 8/9 pacientes tratados evolucionaron a la curación completa frente a 6/11 (88.9% vs 54.5%, p=0.095) Conclusiones: una FEVI<35% es el único facor de riesgo asociado a una mayor mortalidad o a un mayor riesgo de trasplante. La BEM es una técnica segura y útil para el diagnóstico de miocarditis aguda en la población pediátrica. El tratamiento específico guiado por los resultados de la BEM mejora la FEVI y la evolución de los pacientes a corto plazo.
Introduction and objectives: Acute myocarditis is an inflammatory disease of the myocardiumdue to a viral infection in majority ofcases. Diagnosis is performed by obtaining anendomyocardial biopsy (BEM), however it is an invasive technique; its use is not very common in pediatrics. The disease usually resolves itself spontaneously, but some patients may die or have severe ventricular dysfunction, which requires a heart transplant. No treatment has demonstrated to improve the prognosis yet. The aim of this study is to check the characteristics of a series of pediatric patients with acute myocarditis, describe their outcome, the criteria of poor prognosis and the usefulness and risks of different diagnostic techniques, such as BEM. We will describe the usefulness of antiviral and immunosuppressive treatment in a selected population of patients. Material and methods: We reviewed all cases of persons under the age of 18 who had been admitted to Vall d'Hebron Hospital with the diagnosis of acute myocarditis between April 2007 and September 2018. We reviewed clinical and demographic characteristics, diagnostic tests as well as the usefulness of the BEM in this population. Immunohistochemical results of BEM were compared with those observed in a patient population with inheritedcardiomyopathy. The effectiveness of medical treatment was studied by comparing the outcome of treated patients with that of a historical cohort of similar characteristics that did not receive any specific treatment. Results:41 patients (25 men, 16 women, median age 25 months) presented 42 episodes of myocarditis. The diagnosis was performed by BEM in 14/42 cases (33.3%), magnetic resonance in 27/42 (64.3%) and through clinical presentation in 1/42 patient (2.4%). With a median follow-up of 47 months (between 7 and 140 months), a complete resolution of the situation with normalization of left ventricular ejection fraction (LVEF) and left ventricular end diastolic volume (LVEDD) occurred in 33/42 cases (78.5%). The most frequently implicated virus was PVB19 (9/42 cases, 21.4%) followed by enterovirus (5/42 cases, 11.9%). Four patients died (9.7%) and 5/41 (12.2%) required a heart transplant. In the univariate analysis, the factors that were associated with a poor outcome (death or transplant) were the need for ECMO at admission (p = 0.041), LVEF less than 35% (p = 0.02) and right ventricular dysfunction (p = 0.02). In the multivariate analysis, only the LVEF had statistical significance (p = 0.007). Regarding the anatomopathological findings, it was observed that no data were specific for acute myocarditis and that 3/5 patients (60%) with genetic cardiomyopathy met the immunohistological criteria of myocarditis. From February 2015 the patients with the most severe illness were treated with immunosuppression or antiviral treatment based on the anatomopathologicalresults and the viral PCR in the BEM. A total of 9 patients were treated and their outcomewas compared with a historical cohort of 11 patients with similar characteristics. Transplant-free survival at one year was 100% in the treated group vs. 63% (p = 0.042). In the long term, 8/9 treated patients were able to fully recover in comparison to 6/11 patients of the other group who received standard treatment (88.9% vs. 54.5%, p = 0.095) Conclusions: LVEF <35% is the only risk factor associated with a higher mortality or a higher risk of transplantation. BEM is a safe and useful diagnostic tool in the pediatric population with acute myocarditis. The specific treatment based on the results of the BEM improves LVEF and the outcome of patients in the short term.

L'infarto miocardico in assenza di coronaropatia ostruttiva (MINOCA) è definito dall'evidenza di infarto miocardico acuto spontaneo e dalla documentazione angiografica di stenosi coronariche <50%. Negli ultimi anni, sono stati fatti grandi progressi nei campi dell'epidemiologia, patofisiologia, diagnosi, stima della prognosi e terapia di questa condizione. Finora, tuttavia, la definizione di MINOCA è piuttosto eterogenea in quanto condizioni specifiche come la miocardite e la sindrome di Takotsubo sono state spesso incluse, generando così risultati contrastanti. Questa tesi di dottorato si articola in quattro parti: parte I, Introduzione; parte II, Caratteristiche e prognosi; parte III, MINOCA e morte cardiaca improvvisa; parte IV, MINOCA e terapia farmacologica. Lo scopo di questo lavoro è di valutare alcuni degli aspetti più controversi relativi a questa condizione, in particolare per quanto riguarda la prognosi e la terapia farmacologica per i pazienti affetti da MINOCA.
Myocardial infarction and non-obstructed coronary arteries (MINOCA) is defined by the evidence of a spontaneous acute myocardial infarction and angiographic documentation of coronary stenosis <50% in any potential infarct related artery, after having excluded clinically overt causes for the acute presentation. The introduction of this new concept was meant to fill a gap in knowledge and to encourage discovery of putative pathophysiological mechanisms. In recent years, great advances have been made in the fields of epidemiology, pathophysiology, diagnosis, prognosis estimation and therapeutics of this condition. So far, however, the definition of MINOCA is rather heterogeneous as specific cardiac conditions such as myocarditis and Takotsubo syndrome are included thus generating conflicting results. This doctoral dissertation is divided in four sections: part I, Introduction; part II, Characteristics and Prognosis; part III, MINOCA and Sudden Cardiac Death; part IV, MINOCA and Pharmacological Therapy. The aim of this work is to assess some controversial aspect of this condition, in particular with regards to the prognosis and pharmacological therapy for patients affected by MINOCA.

The endothelium plays a pivotal role in the development of cardiovascular disease (CVD) and emerging evidence indicates that pathological blood vessel responses and endothelial dysfunction are associated with metabolic alterations in endothelial cells (ECs). This project aims at performing a complete characterization of the metabolic profiles of an endothelial pathological Acute Myocardial Infarction (AMI) model of 8 patients. The results discussed throughout this thesis are part of this attempt, and brought to the identification of the insights and causes of the AMI pathology, as a consequence of the metabolic alterations related to the endothelium dysfunction which occurs in patients. Due to patients variability, finding a single and clear mechanism among all is quite hard to grasp. However, we have been able to find some metabolic feature to be exploited as possible biomarker for the identification of this CVD. Patients cells presented a low proliferation rate and unveiled a dependence to mitochondrial metabolism, which results in an increased ROS-oxidative stress. Consequently, these cells express increased level of glutathione that supplies the antioxidant defense and prevent ROS (Reactive oxygen species) accumulation. Glutamine seems to play a key role in this AMI model; first of all it is necessary for these cells to display a proper mitochondrial function and in addition, it is required for the synthesis of glutathione as antioxidant against the high level of ROS detected. Additionally, finding a higher content of glutaminase C (GAC) in patients, has opened the possibility that these cells rely more on glutaminase reaction for their survival, and this dependence gathered with the augmented need to neutralize the acidic pH , which results from the increased lactate production, by the ammonia molecules released from glutamine metabolism. This findings point that in AMI model is occurring a metabolic adaptation similar to the Warburg effect, usually described in cancer cells. In the frame of finding the same origin among different pathologies ,in the second part of this work we focused on the crosstalk between dysfunctional endothelium and tumor microenvironment. Moreover, nowadays there is an increasing interest in supporting the existence of a link between cardiovascular pathologies and cancer. One of the wide possibilities which lies these two lethal morbidities is a an alteration of the DNA repair system, crucial for the recovery of the healthy cells against the diseased ones, when a pathological event takes place. Through this study we found that: alternative splicing governs cell‐type regulated expression of variant forms of mRNAs and their encoded proteins that exert differential function. So, employing cancer cell model in which distinct tumor cell subpopulations display differentiated epithelial or mesenchymal phenotype, we have identified alternatively spliced mRNAs with potential impact on the self‐renewal capacities of these cell subpopulations. More in details, among all the genetic characters which can be involved in this process, we provide evidences that RAP80 (UIMC1), an adaptor protein with critical functions in homology-dependent DNA repair (HDR), is expressed as alternatively spliced isoforms in epithelial and mesenchymal cells, as a function of ESRP1/2 expression. More specifically, we have found that the ratio of expression of a full-length isoform to a short isoform of RAP80 is significantly higher in epithelial cells than mesenchymal cells in a prostate cancer cell model for EMT. RAP80 contains a region required for interaction with Abraxas , a core component of the BRCA1-A complex involved in DNA-damage repair. We propose that the ratio of full-length RAP80 to the short isoform lacking AIR is a new mechanism for the regulation of HDR mediated by BRCA1. A higher long/short RAP80 isoform ratio will favor, and lower ratios will counter, the recruitment of BRCA1-A complexes to DSBs.

.Recently cardiac magnetic resonance (CMR) has been proposed as a comprehensive tool for AMI evaluation, since it provides data about regional myocardial wall motion, viability, perfusion and direct visualization of myocardial necrosis. In this respect, the aims of this study performed in AMI patients treated with primary angioplasty (PCI), were: 1.to clarify the impact of reperfusion time on pregression of myocardial damage; 2.to assess the predictive value of CMR features on ventricular post-AMI remodelling; 3.to investigate, with contrast-CMR, the pathological basis of the persistence of ST-segment elevation after AMI; 4.to evaluate the effects of current therapy on CMR detection of necrosis and microvascular injury; 5.to evaluate the correlation between angiographic indexes of myocardial perfusion after primary PCI, and anatomical features on CMR and in particular the correlation between the staining phenomenon and the presence of severe microvascular damage (SMD); 6.to investigate the possibility to detect intramyocardial hemorrhage after AMI by T2-weighted image on CMR, to establish its contribution to the delayed hypoenhanced core, traditionally referred only to microvascular obstruction. We also aimed to correlate radiolagical findings of myocardial hemorrhage with hystological features ex vivo in two died patients. In AMI patients with impaired coronary perfusion undergoing PCI, the risk of transmural necrosis (TN) and SMD seems to increase with the duration of the ischemic time. Also, the amount of TN results as a major determinant of LV remodeling and function, with significant additional predictive value to infarct size and SMD. The evaluation of effects of current therapy with Abciximab demonstrated that SMD seems related to TN without any influence of antiplatelet therapy. In addition, presence of SMD seems the most powerful determinant of persistent ST-segment elevation on ECG. In our experience the angiographic assessment of lack of myocardial perfusion correlates with microvascular damage and extent of infarct
I pazienti inclusi nello studio dal dicembre 2005 all’ottobre 2008 sono stati 300. Per ogni paziente sono stati raccolti i dati di MRI insieme a dati clinici, ecocardiografici, elettrocardiografici ed agiografici. 1.Il primo studio, condotto su una serie di pazienti selezionati in base ad un flusso TIMI preprocedurale inferiore a 3, ha dimostrato che la durata dell’ischemia miocardica rappresenta il maggior determinante della transmuralità di necrosi e della presenza di danno microvascolare. In particolare nei 64 pazienti analizzati, con un tempo medio di ischemia di 190±110 min; l’analisi multivariata ha confermato che il ritardo nel trattamento riperfusivo era correlato sia con la transmuralità di necrosi (odds ratio per 30 min, 1.37, p = 0.032), sia con la presenza di severo danno microvascolare (odds ratio per 30 min, 1.21; p = 0.021), entrambi valutati mediate MRI. 2.Nei primi 76 pazienti è stata inoltre valutata l’influenza della transmuralità di necrosi, dell’infarct size e della presenza di zone di ostruzione microvascolare sul rimodellamento ventricolare: analizzando tutti questi parametri è emerso in questa prima serie di pazienti che la transmuralità di necrosi è il maggior determinante del remodeling; l’infarct size e l’ostruzione microvascolare alla MRI presentavano un valore predittivo aggiunto rispetto alla transmuralità stessa. In questa esperienza preliminare i volumi ventricolari sono stati valutati mediante follow-up ecocardiografico con una media di 6±1 mesi dall’evento acuto. In particolare all’analisi univariata la necrosi transmurale, la severa ostruzione microvascolare, l’infarct size ed I livelli di troponina I (valori di picco) risultavano direttamente correlati con il rimodellamento ventricolare ed inversamente associati alla frazione d’eiezione al follow-up (p <0.001). All’analisi mutlivariata, solo la necrosi transmurale ed i livelli di troponina I emergevano come predittori indipendenti di rimodellamento ventricolare. Inoltre la necrosi transmurale si dimostrava un più potente predittore di rimodellamento, sia in termini di volumi ventricolari (R2 = 0.19), sia di funzione sistolica (R2 = 0.16). 3.Raccogliendo i dati clinici dei pazienti anche durante il follow-up è stato possibile anche raccogliere i dati inerenti gli eventi maggiori, in particolare il decesso per cause cardiache: due dei soggetti seguiti nel follow-up sono stati oggetto di una analisi comparativa delle immagini alla MRI nel post-AMI con i reperti autoptici ed istologici, nonché con i dati derivati dalle MRI eseguite ex-vivo in questi stessi pazienti. Dall’analisi delle immagini T1 e T2 pesate è emerso che le aree ipointense identificate come core ipointenso nell’ambito dell’area di necrosi ed attribuite fino ad allora solo a fenomeni di no-reflow intravascolare, in realtà corrispondevano a zone di vera emorragia intramiocardica. In particolare le aree a basso segnale osservate nelle sequenze T2 ex-vivo, correlavano fortemente con l’emorragia quantificata all’istologia (R = 0.93, p = 0.0007). 4.Un analisi successiva si è proposta di valutare il peso delle nuove terapie antiaggreganti sulla genesi di tale fenomeno. I nostri dati indicano come la presenza di aree ipointense dopo gadolinio siano più legate alla presenza di necrosi transmurale piuttosto che all’impiego di farmaci antiaggreganti per via infusiva come l’Abciximab. In particolare suddividendo i pazienti in due gruppi in base all’impiego di Abciximab, i pazienti in cui tale strategia terapeutica è stata messa in atto presentavano una transmuralità di necrosi pari a 3.03±2.8 segmenti rispetto ai 3.09±2.9 (p=0,9) del gruppo controllo; analogamente la presenza di severa ostruzione microvascolare non si associava ad una terapia specifica impiegata (1.05±1.5 versus 1.06±1.8 segmenti). All’analisi multivariata la severa ostruzione microvascolare risultava correlata esclusivamente con la transmuralità di necrosi (O.R. 1.5; p<0,001) e l’età (O.R. 1.1; p=0.02), ma non alla somministrazione di Abciximab. 5.Un successivo sviluppo è stato quindi quello di valutare in vivo l’incidenza, a partire dalle osservazioni desunte dai due casi autoptici, dell’infarto emorragico definito come stria mesoventricolare ipointensa in T2 ed in T1 (all’interno dell’hyperenhancement tardivo della cicatrice post-infartuale): nella nostra casisistica, analizzando solo i casi di AMI transmurale, è emerso che circa il 37% degli IMA presentava fenomeni di emorragia intramiocardica. 6.Infine abbiamo confrontato, indipendentemente dall’estensione della necrosi, i tradizionali parametri angiografici di mancata perfusione miocardica dopo PTCA ( flusso TIMI e Mycardial Blush Grade MBG) con la presenza alla MRI di aree di no- reflow (identificate come aree di hypoenhancment tardivo). E’ emersa una significativa correlazione (p< 0.001) tra scarsa o assente riperfusione all’angiografia e presenza alla MRI di zone di ostruzione del microcircolo. Inoltre all’interno dei pazienti con MBG. pari a 0 è stato possibile identificare i casi con staining angiografico, indicativo di “spandimento” di mezzo di contrasto nel muscolo cardiaco: tale reperto risultava strettamente associato, anche da un punto di vista topografico, con la presenza di hypoenhancement tardivo, e quindi con segni MRI di emorragia intramiocardica. Conclusioni Il nostro lavoro ha permesso di identificare mediante uno studio prospettico, consecutivo, tutti i dati inerenti la caratterizzazione tissutale mediante MRI del miocardio dopo AMI. Successivi studi di follow-up già in corso in una casistica così numerosa forniranno il reale significato prognostico di queste osservazioni.

Els últims anys s’ha reduït la mortalitat intrahospitalària de l’infart agut de miocardi, en part, gràcies als tractaments de reperfusió, la fibrinòlisi i posteriorment l’intervencionisme coronari percutani. Recentment s’ha invertit de forma significativa en el tractament de la fase aguda de l’infart amb elevació del segment ST amb la creació de xarxes assistencials que prioritzen l’angioplàstia primària com a teràpia de reperfusió com el codi IAM a Catalunya. L’objectiu del codi IAM és que tots els pacients amb IAMEST rebin el tractament de reperfusió més indicat (d’elecció intervencionisme coronari percutani) en els intervals de temps adequats. El codi IAM va entrar en funcionament al juny del 2009. La implementació del codi IAM es va correlacionar amb un augment del percentatge de IAMEST tractats amb teràpia de reperfusió que va passar del 64% al 89%, mitjançant l’ús generalitzat de l’angioplàstia primària (99% respecte 44%, p < 0,001). El codi IAM també es va correlacionar amb un descens significatiu de la mortalitat intrahospitalària (del 7,2% al 2,5%, p < 0,001) si bé no es van apreciar diferències significatives en la mortalitat a llarg termini. Pel que fa a la mortalitat intrahospitalària, es va objectivar com el descens de la mortalitat es va anar produint al llarg del temps de forma progressiva. Per aquest motiu es va afegir aquesta tendència en el temps a l’anàlisi multivariat. El descens de la mortalitat intrahospitalària objectivat en l’era post-Codi IAM va quedar neutralitzat en afegir al model el tractament mèdic òptim (post-Codi IAM: OR 1,14, IC 95% 0,32 – 4,08, p = 0,840), suggerint que el tractament mèdic pot ser tan important com la reperfusió per disminuir la mortalitat intrahospitalària. Després de la implementació del codi IAM es va apreciar com només un 62% dels pacients tenien un control adequat de la pressió arterial, un 29% tenien el cLDL per sota dels nivells desitjats, un 60% dels fumadors havien deixat de fumar i un 36% dels diabètics tenien la hemoglobina glicosilada dins els marges de referència a l’any del seguiment. Dels malalts que van sobreviure als 6 mesos de l’IAMEST, un 6% van morir i 11% van reingressar per causa cardiovascular després de 20 mesos. L’absència de determinació de cLDL i cHDL en el seguiment es va associar amb un pitjor pronòstic a llarg termini. D’altra banda, també es va avaluar el control de la dislipèmia en la primera analítica de seguiment després d’una síndrome coronària aguda i la utilitat d’una eina clínica de fàcil aplicabilitat (les taules de Masana) per millorar el control de la dislipèmia. Als quatre mesos d’una síndrome coronària aguda, un 45% dels pacients va assolir l’objectiu de cLDL, essent aquest percentatge major quan el tractament fou planificat segons les recomanacions de Masana (56% respecte 30%, p < 0,001). En l’anàlisi multivariant, el gènere masculí (p < 0,001), l’absència de dislipèmia prèvia (p < 0,001) i l’aplicació de les taules de Masana (p = 0,007) foren predictors independents per assolir el cLDL objectiu. Les troballes d’aquests treballs ens haurien de fer reconsiderar l’actitud i el tractament dels pacients amb IAMEST: mentre la implementació del codi IAM s’ha acompanyat de millores en el maneig i pronòstic en la fase aguda, el potencial benefici pronòstic a llarg termini podria estar interferit per un control inadequat dels factors de risc cardiovascular. Els nostres resultats suggereixen que caldria unir esforços per promoure la implementació adequada de les mesures de prevenció secundària. En aquest context, l’ús d’eines de fàcil aplicabilitat com les taules de Masana per ajustar la teràpia hipolipemiant pot millorar el control de la dislipèmia en aquests pacients que, a dia d’avui, és clarament insuficient.
In recent years, the in-hospital mortality of ST-elevation acute myocardial infarction (STEMI) has been decreased, in large part, mostly due to reperfusion therapy, initially fibrinolytic treatment and later, primary percutaneous coronary intervention (PPCI). Recently, the treatment of the acute phase of the STEMI has been significantly invested with the creation of healthcare reperfusion networks that prioritize PPCI, such as codi IAM (STEMI ntework) in Catalonia. The purpose of the STEMI network is to ensure that every patient with STEMI receives the most appropriate reperfusion therapy with the appropriate time intervals through a territorial sectorisation of the flow of patients. STEMI network became operative in June 2009. The implementation of STEMI network was correlated with an increase in the percentage of STEMI patients treated with reperfusion therapy that went from 64% to 89% due to the widespread use of PPCI (99% with respect to 44%, p < 0.001). STEMI network was also associated with a significant decrease in in-hospital mortality (from 7.2% to 2.5%, p < 0.001) although no significant differences were appreciated in long-term mortality. Regarding in-hospital mortality, there was a progressive decrease over the years, this tendency was added to multivariate analysis. The decrease in in-hospital mortality observed after implementation of STEMI network was neutralized when incorporating optimal medical treatment to the model (post STEMI code: OR 1.14, 95% CI 0.32 - 4.08, p = 0.840), suggesting that optimal medical treatment can be as important as reperfusion to decrease in-hospital mortality. After the implementation of STEMI network, only 62% of the patients had blood pressure under control, 29% had LDL cholesterol below the desired levels, 60% of smokers had quitted smoking and 36% of diabetic patients had glycosylated haemoglobin within the therapeutic objective after one-year follow-up. The accumulated mortality of 6-months survivors was 6% and 11% of patients were readmitted by cardiovascular disease at 20 months of clinical follow-up. Additionally, an inadequate assessment of LDL cholesterol and HDL cholesterol levels was associated with less favourable long-term cardiovascular outcome after STEMI. On the other hand, usefulness of an easy clinical applicability tool (like Masana tables) to improve the control of dyslipidaemia after an acute coronary syndrome was assessed. After 4 months of follow-up, 45% of patients achieved the objective of LDL cholesterol, being this percentage highest when treatment was planned according to Masana recommendations (56% with respect to 30%, p < 0,001). In multivariate analysis, male gender (p < 0.001), the absence of previous dyslipidaemia (p < 0.001) and the application of Masana tables (p = 0.007) were independent predictors to achieve LDL cholesterol objective. Our findings should make us reconsider the current therapeutic yield of urgent myocardial reperfusion strategies in the setting of a STEMI: while the implementation of assistance networks (such as the STEMI code program) has improved the acute management of STEMI, the potentially beneficial impact of such strategies may be limited by a suboptimal long-term implementation of the secondary prevention strategies. In this sense, usefulness of an easy clinical applicability tool (like Masana tables) can help clinicians achieve dyslipidaemia control which nowadays is clearly insufficient.

Les malalties cardiovasculars representen la principal causa de discapacitat i mort en el conjunt de la població espanyola. Els supervivents d’un primer episodi d’infart agut de miocardi presenten un risc elevat de mort i de nous episodis isquèmics. El pronòstic per la supervivència a llarg termini després d’un infart agut de miocardi, ha millorat per l’ús estès de procediments de revascularització, tractaments farmacològics efectius i per la prevenció secundària com la rehabilitació cardíaca. Malgrat que els programes de rehabilitació cardíaca són una recomanació de classe I en les guies de pràctica clínica, aquesta es troba infrautilitzada amb una baixa derivació dels pacients als programes. Tot i això, encara existeix controvèrsia sobre si és millor un programa supervisat o no supervisat. Per aquest motiu es va plantejar aquest treball, l’objectiu del qual és analitzar l’efecte d’un programa estructurat de rehabilitació cardíaca sobre el rati de mortalitat, de nous esdeveniments isquèmics i el control sobre els factors de risc cardiovasculars en pacients que han patit un recent infart agut de miocardi. Per la realització dels treballs que constitueixen la present tesi s’ha compartit la mateixa metodologia, basada en el registre FRENA (Factores de Riesgo y Enfermedad Arterial). Aquest registre reflecteix la pràctica clínica habitual en pacients afectes d’un infart agut de miocardi i proporciona coneixements sobre la història natural de la malaltia arterioscleròtica en una població no seleccionada de pacients. En el primer treball es van incloure 1.043 pacients que havien presentat un recent infart agut de miocardi i es van dividir en dos grups segons la participació o no en un programa de rehabilitació cardíaca. En el segon treball es van incloure 1.124 pacients afectes d’infart agut de miocardi i es van classificar segons la realització d’exercici físic supervisat o exercici físic no supervisat. En ambdós treballs es va comparar el rati de mortalitat, de nous esdeveniments isquèmics i el control sobre els factors de risc cardiovasculars. En el primer anàlisi els resultats confirmen que els pacients infartats que participen en programes de rehabilitació cardíaca presenten una menor mortalitat comparat amb els pacients que no participen en programes de rehabilitació cardíaca. No és varen trobar diferències en ambdós grups pel que fa al control dels factors de risc cardiovasculars. Cal destacar que segons els resultats del segon treball, després d’aplicar un anàlisi de propensió, l’efecte de l’exercici supervisat i no supervisat és el mateix sobre el resultat del control dels factors de risc cardiovasculars, però els pacients que realitzen exercici físic supervisat presenten un menor rati d’esdeveniment compost (nous esdeveniments isquèmics i mortalitat). Aquests resultats aporten informació novedosa sobre el paper de l’exercici físic supervisat en pacients amb malaltia coronària. Aquests resultats poden representar una aportació important en el disseny dels programes de rehabilitació cardíaca basats en l’exercici físic.
Cardiovascular diseases represent the main cause of disability and death in the whole of the Spanish population. High risk of death and new ischemic events affect the survivors of a first episode of acute myocardial infarction. The prognosis for long-term survival after a myocardial infarction has been improved by the use of revascularization procedures, effective pharmacological treatments and secondary prevention such as cardiac rehabilitation. Although cardiac rehabilitation programs are a class I recommendation in clinical practice guidelines, they appear to be vastly underused with poor referral. However, controversy about which program (supervised versus non-supervised exercise training) is better still exists. Therefore, the aim of this work is to analyze the effect of a comprehensive cardiac rehabilitation program on the mortality rate, subsequent ischemic events rate and control of cardiovascular risk factors in patients who have suffered a recent myocardial infarction. The methodology used in both studies is based on the FRENA (Factores de Riesgo y Enfermedad Arterial, Risk Factors and Arterial Disease) registry. This registry reflects usual clinical practice and the real-world clinical situation in patients with an acute myocardial infarction and provides knowledge about the natural history of artery disease with an unselected patient population. In the first study, 1043 patients with recent acute myocardial infarction were recruited. They were divided into two groups according to the participation or not participation in a cardiac rehabilitation program. In the second study, 1124 patients with recent myocardial infarction were recruited. They were classified according to use of supervised or non-supervised exercise. Both papers compared the mortality rate, subsequent ischemic events rate and the control of cardiovascular risk factors. The results of the studies confirm that patients in cardiac rehabilitation had a significantly lower risk of death. There were no differences among subgroups in the control of cardiovascular risk factors. Note that, according to the results of the second study, after using a propensity analysis, the effect of supervised and non-supervised exercise over the control of cardiovascular risk factors was the same. However, patients participating in supervised exercise training had a significant decrease in the composite outcome of subsequent ischemic events and death. These results provide novel information about the role of supervised exercise in patients with coronary artery disease. These results may represent an important contribution in designing cardiac rehabilitation programs based on exercise.

En els últims anys, l'ús generalitzat de la troponina en els serveis d'urgències, ha permès la seva detecció en pacients amb diagnòstics clínics diferents a la síndrome coronària aguda (SCA). L'objectiu d'aquesta tesi va ser establir el valor pronòstic d'una troponina I (cTnI) elevada en el seguiment dels pacients atesos en un servei d'urgències i que no són diagnosticats de SCA, estudiant també, el seu valor pronòstic en els pacients donats d'alta directament des d´urgències. També ens plantegem identificar aquells pacients amb diagnòstic d'infart de miocardi (IM) tipus 2 i injúria miocàrdica no isquèmica i comparar la seva mortalitat i esdeveniments cardiovasculars adversos en el seguiment. Per respondre a aquests objectius es va realitzar un estudi de cohorts observacional i retrospectiu en el qual es van incloure pacients atesos al servei d'urgències de l'Hospital Universitari Joan XXIII als que es va sol·licitar almenys una determinació de cTnI. Es van identificar les variables demogràfiques, clíniques i analítiques de l'episodi agut, així com les troballes electrocardiogràfiques i les principals exploracions cardiològiques realitzades. Hem observat que els pacients amb troponina I elevada no diagnosticats de SCA van tenir pitjor supervivència que els pacients amb SCA i els pacients amb cTnI negativa. A més, la cTnI constitueix un marcador independent associat a mortalitat en el seguiment dels pacients que són donats d'alta directament des d´urgències. Finalment, una alta proporció de pacients atesos en urgències amb cTnI positiva compleixen criteris diagnòstics d'IM tipus 2. Els pacients amb diagnòstic d'IM tipus 2 i injúria miocàrdica no isquèmica es caracteritzen per tenir un perfil clínic similar, una elevada taxa de mortalitat i menor proporció de reingrés per SCA en comparació als pacients amb diagnòstic d'IM tipus 1.
En los últimos años, el uso generalizado de la troponina en los servicios de urgencias (SU), ha permitido su detección en pacientes con diagnósticos clínicos diferentes al síndrome coronario agudo (SCA). El objetivo de esta tesis fue establecer el valor pronóstico de una troponina I (cTnI) elevada en el seguimiento de los pacientes atendidos en un SU y que no son diagnosticados de SCA, estudiando a su vez, su valor pronóstico en los pacientes dados de alta directamente desde urgencias. También nos planteamos identificar a aquellos pacientes con diagnóstico de infarto de miocardio (IM) tipo 2 e injuria miocárdica no isquémica y comparar su mortalidad y eventos cardiovasculares adversos en el seguimiento. Para responder a estos objetivos se realizó un estudio de cohortes observacional y retrospectivo en el que se incluyeron pacientes atendidos en el SU del Hospital Universitario Joan XXIII a quienes se solicitó al menos una determinación de cTnI. Se identificaron las variables demográficas, clínicas y analíticas del episodio agudo, así como los hallazgos electrocardiográficos y las principales exploraciones cardiológicas realizadas. Hemos observado que los pacientes con troponina I elevada no diagnosticados de SCA tuvieron peor supervivencia que los pacientes con SCA y los pacientes con cTnI negativa. Además, la cTnI constituye un marcador independiente asociado a mortalidad en el seguimiento de los pacientes que son dados de alta directamente desde urgencias. Finalmente, una alta proporción de pacientes atendidos en los SU con cTnI positiva cumplen criterios diagnósticos de IM tipo 2. Los pacientes con diagnostico de IM tipo 2 e injuria miocárdica no isquémica se caracterizan por tener un perfil clínico similar, una elevada tasa de mortalidad y menor proporción de reingreso por SCA en comparación a los pacientes con diagnóstico de IM tipo 1.
Recently, the widespread use of troponin in emergency services has allowed its detection in patients who are not diagnosed with acute coronary syndrome (ACS). The aim of this thesis was to establish the prognostic value of an elevated troponin I (cTnI) in follow-up of patients admitted to the emergency department and without ACS, also studying, its prognostic value in patients discharged directly from the emergency department. We also aimed to identify patients with diagnosis of type 2 myocardial infarction and non-ischaemic myocardial injury and to compare their mortality and cardiovascular events at follow-up. In order to respond to these objectives, an observational and retrospective cohort study was carried out, including all patients admitted at the emergency department in the Hospital Universitario Joan XXIII, and who underwent at least one cTnI determination. We identified the demographic, clinical and analytical variables of the acute episode, as well as the electrocardiographic findings and the main cardiological explorations performed. We found that patients with high troponin levels and without ACS had higher rates of mortality than patients with ACS and patients with negative troponin. In addition, cTnI is an independent predictor associated with mortality in follow-up of patients discharged directly from the emergency department. Finally, a high percentage of patients admitted in the emergency department with high levels of cTnI meet diagnostic criteria for type 2 IM. Patients with a final diagnosis of type 2 myocardial infarction and non-ischemic myocardial injury have a comparable clinical profile, higher rates of mortality and lower readmission rates for ACS compared with patients with type 1 myocardial infarction.

Background Reperfusion is the mainstay treatment for patients presenting with ST-elevation myocardial infarction (STEMI). Nevertheless, reperfusion itself may exacerbate myocardial injury, a process termed “reperfusion injury”. Post-conditioning (PostC) has been suggested to reduce myocardial damage during primary percutaneous coronary intervention (PPCI), nevertheless clinical experience is limited. Objectives We aimed to review all the known strategies to limit the reperfusion injury; moreover we explored the cardioprotective effect of mechanical postconditioning conducting a randomized trial aimed to evalutate infarct size (IS) at cardiac magnetic resonance (CMR) in STEMI patients treated by PPCI. Methods A total of 78 patients with first STEMI (aged 59±12 years) referred for PPCI, were stratified for STEMI location and randomly assigned to conventional PPCI or PPCI with PostC. All patients, with occluded infarct related artery and no collateral circulation, received abciximab intravenously before PPCI. After reperfusion by effective direct stenting, control subjects underwent no further intervention, while in treated patients PostC was performed within 1 minute of reflow by 4 cycles of 1-minute inflation and 1-minute deflation of the angioplasty balloon. Primary end-point was IS reduction, expressed as percentage of left ventricle mass assessed by delayed enhancement on CMR at 30±10 days after index PPCI. Results All baseline characteristics but diabetes (p=0.06) were balanced between groups. Postconditioning patients trended towards a larger IS compared to those treated by standard PPCI (20±12% vs 14±10%, p=0.054). After exclusion of diabetics, PostC group still showed a trend to larger IS (p=0.116). Major adverse events seem to be more frequent in PostC group irrespective to diabetes status (p=0.053 and p=0.080, respectively). Conclusions This prospective, randomized trial suggests that PostC did not have the expected cardioprotective effect and, on the contrary, it might harm STEMI patients treated by PPCI plus abciximab. (Clinical Trial Registration-unique identifier: NCT01004289).
Razionale dello studio La terapia riperfusiva è la via principale per il trattamento di pazienti che si presentino con infarto miocardico con sopraslivellamento del tratto ST (ST-elevation myocardial infarction, STEMI). Tuttavia, la riperfusione di per sé può esacerbare il danno miocardico, un processo denominato “danno da riperfusione”. Il post-conditioning (PostC) é un processo che sembra possa ridurre il danno miocardico da riperfusione durante angioplastica primaria (primary percutaneous coronary intervention, PPCI), ciò nonostante l’esperienza clinical è limitata. Scopo dello studio Presentare e discutere tutte le strategie note in grado di limitare il danno riperfusivo; inoltre, valutare gli effetti cardioprotettivi del postconditioning ischemico meccanico mediante un trial clinico controllato randomizzato arruolante pazienti con STEMI e inviati a PPCI, con endpoint primario le dimensioni dell’infarto (infarct size, IS) finale alla risonanza magnetica cardiaca (cardiac magnetic resonance, CMR). Metodi Un totale di 78 pazienti con primo STEMI (età 59±12 anni) inviati per PPCI, sono stati stratificati per sede dello STEMI e successivamente randomizzati a PPCI convenzionale o PPCI con PostC. Tutti i pazienti, con arteria responsabile dell’infarto occlusa e assenza di circolo collaterale, hanno ricevuto abciximab endovena prima della PPCI. Successivamente alla riperfusione, avvenuta con tecnica direct stenting, i soggetti di controllo non sono stati sottoposti ad ulteriori interventi, mentre i soggetti nel gruppo PostC hanno rivevuto, entro un minuto dalla riperfusione, 4 cicli di 1 minuto di rigonfiaggio e 1 minuto di sgonfiaggio del pallone usato per l’angioplastica. L’endpoint primario oggetto dello studio, la riduzione dell’IS finale, veniva espresso come percentuale della massa ventricolare sinistra affetta, come possibile riconoscere ad una CMR con mezzo di contrasto eseguita a 30±10 giorni di distanza dalla procedura di PPCI indice. Risultati Tutte le caratteristiche di base, ad eccezione del diabete (p=0.06), risultavano ben bilanciate tra i gruppi di trattamento. I pazienti nel gruppo postconditioning tendevano ad avere un IS maggiore quando paragonati a quelli sottoposti a PPCI convenzionale (20±12% vs 14±10%, p=0.054). Dopo esclusione dei pazienti diabetici, il gruppo di pazienti PostC sembrava ancora associato ad IS finali di maggiori dimensioni (p=0.116). Gli eventi avversi cardiovascolari maggiori sono risultati essere più frequenti nel gruppo PostC, indipendentemente dal loro status diabetico (p=0.053 e p=0.080, rispettivamente). Conclusioni Questo trial clinico randomizzato prospettico suggerisce che il PostC non ha l’effetto cardioprotettivo atteso e, invece, potrebbe pure nuocere a pazienti affetti da STEMI e sottoposti a PPCI ed infuzione di abciximab. (Numero identificativo unico di registrazione del trial al sito clinicaltrial.gov: NCT01004289).

Introduction and Objectives: The adverse remodeling of the left ventricle (LV) after ST-elevation acute myocardial infarction (STEMI) is a complex phenomenon characterized by different phases. Firstly, the infarct expands during the healing process through thinning and enlargement of necrotic area; secondarily, there is a global LV volume increase and systolic dysfunction that involves the remote myocardium through hypertrophy, apoptosis and interstitial collagen deposition. Several studies found a close correlation between infarct size and LV remodeling; others associated the adverse remodeling with the following development of congestive heart failure, ventricular arrhythmias and cardiovascular death. The ability of novel echocardiographic parameters of myocardial strain to predict the extent and transmurality of myocardial necrosis after STEMI suggests their possible role in predicting the subsequent LV remodeling. In this thesis, we report the results of a prospective study aimed to determine the predictive value of the various two- (2D) and threedimensional (3D) strain components for LV remodeling and clinical outcome in patients with first recanalized STEMI. Methods: We enrolled a consecutive cohort of 64 patients treated with a primary percutaneous coronary intervention after first STEMI, at a single centre. All patients underwent a comprehensive 2D and 3D echocardiogram at pre-discharge and after 13±2 months to assess LV volumes and function. 2D and 3D strain components were measured by speckle tracking analysis. LV adverse remodeling was defined as relative increase of end-systolic volume >15% respect to basal measurement. Results: Seventeen (27%) patients showed unfavourable remodeling at the follow-up visit. Among clinical data, peak Troponin I value and Killip class at admission were significantly related to adverse remodeling. Pre-discharge less negative 2D- and 3D peak global longitudinal (GL) and 3D end-systolic global area (GA) strain resulted independent determinants of unfavourable LV remodeling. Using ROC curves, a 2D GL strain less negative than a cut-off value of -14.2% showed a sensibility of 73% and a specificity of 61% to predict unfavourable LV remodeling (AUC 0.74, 95% CI 0.61-0.87; p=0.005). Predischarge 2D GL strain was also predictive, at limits of significance, of the composite clinical end point (death, overt heart failure and unstable angina) (p=0.057). Conclusions: Despite optimal medical therapy, LV negative remodeling remains a relatively frequent process after a STEMI, at a mid-term follow-up. Predischarge 2D- 3D GL and GA strain are significant predictors of unfavourable LV remodeling and adverse clinical outcome in patients with first recanalized STEMI. The measurement of these non-invasive, reproducible and unexpensive parameters of LV myocardial function helps to select a sub-population of survivors STEMI patients who may need a closer follow-up and a more aggressive management.
Introduzione e obiettivi: Il rimodellamento avverso del ventricolo sinistro (VS) dopo un infarto miocardico acuto con sopraslivellamento del tratto ST (STEMI) è un fenomeno complesso caratterizzato da diverse fasi. Dapprima l’espansione infartuale avviene durante il periodo di cicatrizzazione attraverso l’assottigliamento e dilatazione della regione necrotica; successivamente vi è un rimodellamento globale del VS che coinvolge il cosiddetto miocardio remoto tramite ipertrofia eccentrica, apoptosi e deposizione di fibre collagene interstiziali. Diversi studi hanno trovato una stretta correlazione fra entità e transmuralità della necrosi miocardica con il rimodellamento del VS; altri hanno associato il rimodellamento avverso con lo sviluppo di insufficienza cardiaca congestizia, aritmie ventricolari e morte cardiovascolare. La capacità dei nuovi indici di deformazione miocardica (strain) di stimare l’estensione e transmuralità di necrosi dopo uno STEMI suggerisce il loro possibile ruolo predittivo di rimodellamento avverso del VS. In questa tesi, vengono riportati i risultati di uno studio prospettico volto a determinare la capacità dei diversi indici di strain bi- (2D) e tridimensionali (3D) nel predire il rimodellamento avverso del VS e la prognosi clinica in pazienti affetti da infarto miocardico acuto e sottoposti a ricanalizzazione percutanea. Metodi: Abbiamo arruolato 64 pazienti trattati con angioplastica primaria per primo STEMI, in un singolo centro. Tutti i pazienti sono stati sottoposti ad ecocardiogramma 2D e 3D predimissione e dopo un periodo medio di 13 ± 2 mesi, per la stima dei volumi e frazione di eiezione del VS. Sono stati inoltre determinati gli strain globali 2D e 3D del ventricolo sinistro misurati con la tecnica speckle tracking. Il rimodellamento avverso del VS è stato definito come incremento relativo del volume telesistolico >15% rispetto alla misura predimissione. Risultati: In diciassette (27%) pazienti è stato documentato un rimodellamento avverso del VS all’ecocardiogramma di follow-up. Fra i dati clinici analizzati, il picco di troponina I e la classe Killip all’ingresso sono stati significativamente correlati a rimodellamento avverso del VS. Un valore ridotto (meno negativo) degli strain longitudinale 2D e 3D e dell’area strain 3D sono risultati predittori indipendenti di rimodellamento avverso del VS. Dall’analisi delle curve ROC, un valore di strain longitudinale 2D meno negativo di -14.2% ha mostrato una sensibilità ed una specificità del 73% e 61% rispettivamente nel prevedere il rimodellamento avverso del VS (AUC 0.74, 95% CI 0.61-0.87; p=0.005). L’entità dello strain longitudinale 2D predimissione è stata inoltre correlata ad un end-point composito di morte cardiovascolare, scompenso cardiaco ed angina instabile (p=0.057). Conclusioni: Nonostante terapia medica ottimale, il rimodellamento avverso del VS dopo STEMI risulta un evento relativamente frequente ad un follow-up di medio termine. Gli strain longitudinali 2D e 3D ed area strain 3D del VS, valutati predimissione, sono risultati indicatori di rimodellamento avverso del ventricolo sinistro e prognosi clinica sfavorevole in una coorte di pazienti affetti da primo infarto miocardico acuto, sottoposto a ricanalizzazione mediante angioplastica primaria. La misura non invasiva, riproducibile e a basso costo di questi parametri di funzione sistolica del ventricolo sinistro può aiutare nell’individuare una sottopopolazione di soggetti sopravvissuti ad uno STEMI che necessitano di uno stretto monitoraggio clinico ed un trattamento più aggressivo.

[ES] Las intervenciones actuales utilizadas en el ámbito clínico durante el infarto agudo de miocardio (IAM) se centran en la revascularización de la zona isquémica. Entre dichas estrategias, la angioplastia coronaria, procedimiento por el cual se utiliza un catéter para desobstruir la arteria ocluida, es el método más utilizado. Sin embargo, se ha descrito este proceso (conocido como reperfusión) desencadena un daño adicional en el miocardio, por lo que la combinación de dicha intervención con moléculas cardioprotectoras resulta de gran interés para tratar de reducir el tamaño del infarto. El presente trabajo propone dos nuevas moléculas con el fin de precondicionar el área isquémica antes de la reperfusión en el contexto del IAM. La primera estrategia propuesta se ha basado en el aporte de un ácido graso (diDHA) en la zona isquémica antes de la reperfusión para tratar de reducir el estrés de los cardiomiocitos y el número de células muertas antes de la reperfusión. Además, se han sintetizado nanoconjugados basados en la unión covalente de diDHA a un unido covalentemente a un esqueleto polimérico (ácido poli-L-glutámico, PGA) con el fin de incrementar la estabilidad del diDHA y conseguir una liberación controlada de la molécula. Los resultados obtenidos mostraron que la formulación PGA-diDHA6.4 fue la más optimizada, mostrando un mejor efecto en el precondicionamiento de los cardiomiocitos antes de la reperfusión en términos de reducción de apoptosis, generación de especies reactivas de oxígeno y mantenimiento de la función mitocondrial in vitro. Además, dicho nanoconjugado también mostró un modesto efecto terapéutico cuando se administró en modelos in vivo de isquemia-reperfusión en ratas y cerdos, reduciendo el tamaño final de infarto respecto a los grupos control. La segunda estrategia terapéutica propuesta se ha centrado en aumentar el potencial terapéutico de las vesículas celulares de pequeño tamaño (SEV o exosomas) procedentes de medio condicionado de células madre estromales (MSC). Numerosos estudios han descrito el papel terapéutico de factores paracrinos secretados por las MSC, donde se incluyen tanto factores solubles como vesículas extracelulares (EV) y, en especial, SEV. Diversas estrategias, como la modificación genética o precondicionamiento de estas células, han sido utilizadas para aumentar el potencial terapéutico de las mismas. En este trabajo se ha propuesto la modificación genética de las MSC con el objetivo de enriquecer las SEV en proteínas de interés que pudiesen potenciar el efecto terapéutico de las SEV nativas. En base a estudios previos, donde se ha visto que la oncostatina-M (OSM) podría jugar un papel anti-fibrótico en el contexto del IAM, se decidió incorporar dicha proteína en la superficie de las SEV derivadas de MSC mediante su fusión con proteínas presentes de forma natural en la superficie de las SEV, con el objetivo de desencadenar una respuesta en las células diana. La modificación de la secuencia de la OSM y su fusión con la tetraspanina CD81 permitieron cargar de manera efectiva la OSM en la superficie de las SEV, y los resultados preliminares en fibroblastos ventriculares cardíacos mostraron un efecto funcional beneficioso con respecto a los SEV control y los enriquecidos en CD81, reduciendo la tasa de proliferación de las células en condiciones de ayuno, y modificando la expresión y la liberación de la proteína telo-Col1α1 en las células después de ser estimuladas con TGFβ-1, α-dextrano y ácido ascórbico-L-sulfato En resumen, dos nuevas estrategias terapéuticas avanzadas libres de células han sido propuestas en el presente trabajo, donde se han mostrado resultados preliminares prometedores para reducir el daño en el miocardio tras el IAM en términos de reducción de apoptosis de cardiomiocitos y de activación de fibroblastos car
[CA] Les intervencions actuals utilitzades en l'àmbit clínic durant l'infart agut de miocardi (IAM) se centren en la revascularització de la zona isquèmica. Entre aquestes estratègies, l'angioplàstia coronària, procediment pel qual s'utilitza un catèter per a desobstruir l'artèria oclosa, és el procés més utilitzat. No obstant això, s'ha descrit que aquest procés (conegut com a reperfusió) desencadena un mal addicional en el miocardi. En conseqüència, la combinació d'aquesta intervenció amb molècules cardioprotectores resulta de gran interés per a tractar de reduir la grandària de l'infart. El present treball proposa dues noves molècules amb potencial cardioprotector en el context del IAM. Com a primera estratègia terapèutica, s'ha proposat l'aportació d'un àcid gras (diDHA) a la zona isquèmica del miocardio abans de la reperfusió per a tractar de reduir l'estrés dels cardiomiocitos i el nombre de cèl·lules mortes abans de la reperfusió. A més, s'han sintetitzat nanoconjugats basats en la unió covalent de diDHA a un esquelet polimèric (àcid poli-L-glutàmic, PGA) amb la finalitat d'incrementar l'estabilitat del diDHA i aconseguir un alliberament controlat de la molècula. Els resultats obtinguts van mostrar que la formulació PGA-diDHA6.4 va ser la més efectiva, mostrant un millor efecte en el precondicionament dels cardiomiocitos abans de la reperfusió en termes de reducció d'apoptosi, generació d'espècies reactives d'oxigen i manteniment de la funció mitocondrial in vitro. A més, el nanoconjugat PGA-diDHA6.4 també va mostrar un modest efecte terapèutic quan es va administrar en models in vivo d'isquèmia-reperfusió en rates i porcs, reduint la grandària final d'infart respecte als grups control. La segona estratègia proposada s'ha centrat en potenciar l'efect terapèutic de vesícules extracelul·lars de xicoteta grandària (SEV o exosomes) que son secretades per cèl·lules mare estromales. Nombrosos estudis han descrit el paper terapèutic de factors paracrinos secretats per les MSC, on s'inclouen tant factors solubles com vesícules extracelul·lars (EV) i, especialment, les SEV. Diverses estratègies, com la modificació genètica o el precondicionament de les MSC, s'han estudiat per augmentar el potencial terapèutic d'aquestes cèl·lules. En aquest treball, es va pensar en la modificació genètica de les MSC amb l'objectiu d'enriquir les SEV en proteïnes d'interés que pogueren potenciar l'efecte terapèutic de les SEV natives. Sobre la base d'estudis previs, on s'ha vist que la oncostatina-M (OSM) podria jugar un paper anti-fibròtic en el context del IAM, es va decidir incorporar aquesta proteïna en la superfície de les SEV derivades de MSC mitjançant la seua fusió amb proteïnes presents de manera natural en la superfície de les SEV, amb l'objectiu de desencadenar una resposta en les cèl·lules diana. La modificació de la seqüència de la OSM i la seua fusió amb la tetraspanina CD81 van permetre carregar de manera efectiva la OSM en la superfície de les SEV, i els resultats preliminars en fibroblastos ventriculars cardíacs van mostrar un efecte funcional respecte als SEV control i els enriquits en CD81, reduint la taxa de proliferació de les cèl·lules en condicions de dejuni, i modificant l'expressió i la secreció de la proteïna telo-Col1α1 en les cèl·lules després de ser estimulades amb TGFβ-1, α-dextran i àcid ascòrbic-L-sulfat, simulant una activació dels fibroblastos in vitro. En resum, dues noves estratègies terapèutiques avançades lliures de cèl·lules han sigut proposades en el present treball, on s'han mostrat resultats preliminars prometedors per a reduir el mal en el miocardi després del IAM en termes de reducció d'apoptosi de cardiomiocitos i d'activació de fibroblastos cardíacs.
[EN] Current therapeutic approaches against acute myocardial infarction (AMI) are focused on myocardial ischemic zone revascularization. The most common strategy is called primary angioplasty, in which a catheter is introduced to unblock the affected artery and restore blood flux, in a process called reperfusion. Nevertheless, an additional injury on cardiac tissue is caused after reperfusion, and the combination of primary angioplasty with the use of cardioprotective molecules has emerged as a potential strategy to reduce cardiac tissue injury. Two new cell-free therapeutic strategies to preconditionate myocardial ischemic area before reperfusion have been proposed to reduce cardiac injury after AMI. The first therapeutic strategy proposed consisted on the input of a free fatty acid (di-docosahexaenoic acid, diDHA) covalently bound to a polymeric backbone (poly-L-glutamic acid, PGA) in order to increase diDHA solubility and stability and modulate its effect on target cells. Results showed that PGA-diDHA6.4 conjugate administration during ischemia protected cardiomyocytes from reperfusion-induced injury, as apoptotic number of cells and oxidative stress was reduced, and mitochondrial function was less affected when compared to untreated cells. In addition to this, PGA-diDHA6.4 also showed therapeutic effects when locally administered in an ischemia-reperfusion in vivo model in rats and pigs, where a modest reduction of area at risk was observed compared to control groups. The second cell-free strategy proposed in this work was focused on enhancing the therapeutic potential of small extracellular vesicles (SEV or exosomes) isolated form mesenchymal stromal cells (MSC) conditioned media. Previous studies have described the therapeutic potential of paracrine factors released by MSC, where both soluble factors and vesicular components are included. In particular, SEV have gained special attention. Several stretegies, such as genetic modification or cell preconditioning, have been tested to enhance the MSC therapeutic potential. In this work, it was proposed MSC genetic modification in order to load proteins of interest on SEV and potentiate its native therapeutic potential. Based on previous findings, where it has been described a potential anti-fibrotic role of oncostatin-M (OSM) in AMI context, we decided to incorporate OSM on SEV surface by its fusion to CD81 tetraspanin, a protein naturally loaded on SEV surface, in order to trigger functional effects on target cells. OSM sequence modification was necessary in order to load the protein on SEV surface efficiently, and preliminary data showed that modified OSM-CD81 loaded on SEV had a functional effect on human ventricular cardiac fibroblasts. Concretely, decrease of proliferation rate after starvation and telo-Collagen1α1 location pattern modification was observed after stimulation with a pro-fibrotic cocktail (containing TGFβ-1, α-dextran and ascorbic-L-acid sulphate) in vitro when cells were treated with modified OSM-CD81- SEV compared to ctrl and CD81-loaded SEV treatments. Overall, two new advanced cell-free therapies with preliminary promising results have been proposed in order to reduce myocardial injury after AMI in terms of cardiomyocytes apoptosis reduction and fibrosis mitigation.
Tejedor Gascón, S. (2021). Development of new advanced therapies to mitigate ischemia-reperfusion-induced injury during acute myocardial infarction [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/171487
TESIS

El término síndrome coronario agudo (SCA) abarca aquellas situaciomes en donde hay un compromiso súbito de perfusión miocàrdica generado por un déficit absoluto o relativo en la circulación arterial coronaria. El electrocardiograma (ECG) de 12 derivaciones es la prueba inicial mas importante, accesible y fácil de realizar en cualquier escenerario que identifica en los primeros instantes a aquellos pacientes que presentan el Síndrome Coronario Agudo con Elevación del Segmento ST (SCAEST) o aparción de novo de un bloqueo de rama izquierda . Diferentes estudios y autores afirman que el tratamiento de los SCA requiere una rápida identificación toda vez que aquellos pacientes con infarto de miocardio (IAM) y con elevacion del segmento ST (IAMEST) o aparición de novo de bloqueo de rama izquierda se benefician del restablecimiento precoz del flujo coronario, ya sea mediante la trombòlisis endovenosa o la angioplastia coronaria transluminal percutània primaria ICPp. El plantearse iniciar un proyecto de codigo de activación vendrá dado básicamente por la necesidad de priorizar la atención a determindos pacientes con patologias tiempo-dependiente, ya sea delante de situaciones en que se ve superada la capacidad de resolución del equipo sanitario o ya sea porquè se requiere una actuación específica o especializada El Código Infarto (Codi IAM) se inició el 1 de junio de 2009 (Instrucció CatSalut 04/2009) con el fin de implantar el tratamiento de reperfusión en red, basado en la intervención coronaria percutánea primaria, a los pacientes con infarto de miocardio y elevación del segmento ST, siguiendo las recomendaciones de las Guías de la Sociedad Europea de Cardiología. El objetivo del Código IAM pretendre extender el tratamiento de reperfusión (fibrinólisis endovenosa, angioplàstia primaria y de rescate) al maximo numero de pacientes con infarto agudo de miocardio con elevación del segment ST (IAMEST) y establece la angioplastia primaria como el tratamiento de elecció durante las 24 horas del dia como protocolo único para toda Cataluña. En esta tesis que lleva por titulo IMPACTO DE LA REGULACIÓN ADMINISTRATIVA EN LA FASE PREHOSPITALARIA DEL PROGRAMA DE COORDINACIÓN “CODIGO INFARTO AGUDO DE MIOCARDIO” EN CATALUÑA se han reclutado 28.933 pacientes con diagnóstico de IAMEST (en el periodo comprendido desde el 1 de enero de 2008 hasta el 31 de octubre de 2016 con el anàlisis de los servicios atendidos por el Sistema de Emergències Mèdiques en dicho período) hemos analizado si la implantación de un protocolo de coordinación (Código Infarto IAM) entre los diferentes niveles asistenciales (en el ámbito prehospitalario y hospitalario) para la atención de pacientes con infarto agudo de miocardio con elevación del segmento ST (IAMEST) y que incluye la regulación administrativa de los flujos de pacientes y la coordinación sanitaria, mejora el proceso asistencial, en la fase prehospitalària y principalment en los tiempos de activación, actuación y transporte al hospital de referencia ICPp, así como si disminuye las complicaciones clínicas de estos pacientes tanto en Servicios primarios (via publica y domicilios) y servicios interhospitalarios (entre hospitales sin capacidad ICPp a hospitales con capacidad ICPP) De los resultados hay que destacar que el aumento progresivo y consolidado de los servicos primarios, y por consiguiente disminución de las alertas hospitalarias para realizar traslados interhospitalarios, en pacientes con IAMEST es uno de los resultados de la aplicación del código IAM. El motivo de esta mejora ha sido fundamentalmente en el traslado directo al centro con capacidad de ICPp (centro útil versus centro cercano) en un 26,5 % en servicios primarios y en un 2.8% en servicios interhospitalarios. En el año 2016 un 98,6% de los pacientes asistidos en servicios primarios de SEM llegan en los tiempos establecidos por el codigo IAM a centros con capacidad ICPp desde la realización e interpretación del ECG.
The term acute coronary syndrome (ACS) encompasses those situations where there is a sudden compromise of myocardial perfusion generated by an absolute or relative deficit in the coronary arterial circulation. The 12-lead electrocardiogram (ECG) is the most important initial test, accessible and easy to perform in any scenario that identifies in the first instants those patients who present with Acute Coronary Syndrome with ST segment elevation (STEMI) or new appearance a left bundle branch block. Different studies and authors affirm that the treatment of ACS requires rapid identification since those patients with myocardial infarction (AMI) and with ST segment elevation (STEMI) or emergence of new left bundle branch block benefit from early reestablishment the coronary flow, either through intravenous thrombolysis or primary percutaneous transluminal coronary angioplasty PCI. The idea of ​​initiating an activation code project will basically be given by the need to prioritize care for certain patients with time-dependent pathologies, either in front of situations in which the resolving capacity of medical team resolution is overcomed or because requires specific or specialized action The Myocardial Infarction Code (Code AMI) was started on June 1, 2009 (CatSalut Instruction04/2009) in order to implant the reperfusion treatment in the assistencial net, based on primary percutaneous coronary intervention, to patients with myocardial infarction and Elevation of the ST segment, following the recommendations of the Guidelines of the Cardiology European Society. The objective of the IAM Code is to extend reperfusion treatment (intravenous fibrinolysis, primary angioplasty PCI and rescue) to the maximum number of patients with acute myocardial infarction with ST segment elevation (STEMI) and establish primary angioplasty PCI)( as the treatment of choice during 24 hours a day as a single protocol for all of Catalonia. In this Thesis entitled " ADMINISTRATIVE IMPACT REGULATION IN PRE-PHOSPITAL PHASE OF THE COORDINATION PROGRAM ACUTE CORONARY CODE AMI IN CATALONIA”, 28,933 patients with a diagnosis of STEMI have been recruited (in the period from 1 January 2008 Until October 31, 2016, with an analysis of services provided by the Emergence Medical System EMS in that period). We analyzed whether the implementation of a coordination protocol (Code AMI) between different levels of care (in the prehospital setting and hospital) for the care of patients with acute ST-segment elevation myocardial infarction (STEMI), which includes the administrative regulation of patient flows and health coordination, improves the care process, in the prehospital stage and mainly in the times of activation, performance and transport to the primary PCI reference hospital, as well as if it reduces clinical complications of these patients in both Primary services (public and home) and interhospital services (between hospitals without primary PCI capacity to hospitals with primary PCI capacity) As a results, it should be highlighted that the progressive and consolidated increase of primary services, and consequently a decrease in hospital alerts for interhospital transfers, in patients with STEMI is one of the results of the application of the AMI code. The reason for this improvement was mainly in the direct transfer to the center with primary PCI capacity (useful center versus near center) in 26.5% in primary services and 2.8% in interhospital services. In 2016, 98.6% of the patients assisted in primary services of SEM arrive at the time established by the code IAM to centers with capacity primary PCI from the realization and interpretation of the ECG.

La prevalenza dell’obesità sta crescendo in modo sostanziale sia nei Paesi sviluppati sia in quelli in via di sviluppo. Negli ultimi anni si è sviluppato un vasto consenso sul fatto che una perdita di peso corporeo del 10% sia in grado di ridurre significativamente le complicanze mediche (quali le patologie cardiovascolari) e i fattori di rischio associati all’eccesso ponderale. Tuttavia, la progressiva diffusione di sovrappeso e obesità e l’assenza di una strategia di trattamento efficace costituiscono un terreno fertile per il proliferare di differenti modelli interventistici. Ad oggi, il programma di intervento più diffuso rimane la “dietoterapia prescrittiva”. La terapia di gruppo (cognitivo-comportamentale) si è dimostrata negli ultimi anni più efficace nel trattamento dell’obesità rispetto all’intervento prescrittivo. Lo studio vuole valutare l'efficacia di un intervento educazionale di gruppo (trattamento B) in un campione di soggetti con diagnosi di sovrappeso e obesità (BMI > 24,9 kg/m2) che sono incorsi in un primo episodio di infarto miocardico acuto (sia STEMI sia NSTEMI), confrontato con l'approccio dietoterapico prescrittivo classico (trattamento A). L’outcome primario dello studio è la riduzione del 5-10% del peso corporeo a 6-12 mesi dall’inizio del trattamento. Gli outcome secondari invece sono i seguenti: l’identificazione in prevenzione secondaria di nuovi biomarcatori periferici con significato prognostico-predittivo, da utilizzare in prevenzione primaria; l’identificazione di un marcatore periferico per il grasso epicardico che correli con lo spessore di EAT. Da Novembre 2013 a Settembre 2015 sono stati arruolati 90 pazienti. I pazienti che avevano dato il loro consenso scritto e che soddisfacevano le caratteristiche di inclusione sono stati randomizzati ad uno dei due trattamenti. Il trattamento educazionale di gruppo si è dimostrato essere più efficace della dietoterapia prescrittiva classica in termini di perdita di peso (in A, Δpeso T1-T6: -2,83%; in B, Δpeso T1-T6: -4,89%; in A, Δpeso T1-T12: +3,50%; in B, Δpeso T1-T12: -6,45%) e di miglioramento della composizione corporea sia nel breve che nel lungo termine. Tale intervento nutrizionale necessità tuttavia di essere perfezionato ulteriormente sulla base del costrutto della CBT, da adeguare alla condizione di cardiopatia ischemica. I risultati relativi allo spessore di EAT mostrano una riduzione dello stesso sia a sei che a 12 mesi per entrambi i trattamenti, con una percentuale di efficacia pressoché raddoppiata per i pazienti sottoposti ad intervento educazionale di gruppo (in A, ΔEAT-TS T1-T6: -5,00%; in B, ΔEAT-TS T1-T6: -18,84%; in A, ΔEAT-TS T1-T12: -11,67%; in B, ΔEAT-TS T1-T6: -30,43%), suggerendo la necessità di approfondire il ruolo del grasso epicardico nell’insorgenza della cardiomiopatia ischemica e del suo potenziale diagnostico e prognostico-predittivo utile in prevenzione primaria. Inoltre, la Serglicina si è dimostrata essere un buon marcatore di correlazione con lo spessore del grasso epicardico (p value T6 = 0,023; p value T12 = 0,002; p value andamento temporale = 0,003), da proporre eventualmente nella routine diagnostica con significato prognostico/predittivo di rischio cardiovascolare obesità viscerale-correlato. I dati ottenuti in merito ai livelli di espressione plasmatica di Chemerina e Greline suggeriscono altresì un ruolo attivo di queste molecole nei processi pro-infiammatori e cardiorigenerativi, rispettivamente. Sarebbe pertanto interessante approfondire il grado di correlazione esistente tra Chemerina e danno tissutale, nonché tra le Greline e il loro potere cardiorigenerativo, al fine di inserire i loro dosaggi nella pratica clinica con significato prognostico/predittivo di rischio cardiovascolare.

Parvoviruses is a viral disease characterized by an acute hemorrhagic gastroenteritis, caused by a canine parvovirus (CPV) that is stable in the environment, able to bear pH variations and high temperatures. It is resistant to many common disinfectants and can survive for many months in contaminated areas. There are two common clinical forms of the disease: the myocardial and the gastroenteric. This work had as objective to analyse microscopically the cardiopathy cases, diagnosticated macroscopically during the necropsy of dogs with parvovirus detected in faeces. In the 100 samples send to the Histopathology Laboratory, from the University of Uberaba, they get in the left ventricular myocardium the following alterations: myocarditis 38%, hemorrhage 43%, hyaline degeneration 21% and hyperemia 79%. Having been carried out the Qui-Quadrado test with a significance level of 0,05, we can conclude that there is association (p = 0,02) between the infected animals with the parvoviruses virus and the histopathologyc alterations observed in the left ventricular myocardium.
Parvovirose é uma enfermidade viral caracterizada por gastroenterite hemorrágica aguda, cujo agente etiológico é parvovírus canino (PVC), vírus estável no ambiente, capaz de suportar variações de pH e temperaturas altas, resistente a vários desinfetantes comuns, podendo sobreviver por muitos meses em áreas contaminadas. Há duas formas clínicas comuns da doença: a miocárdica e a gastroentérica. No Brasil a doença eclodiu subitamente na população canina no ano de 1978. Objetiva-se com este trabalho analisar microscopicamente o miocárdio de cães com teste de detecção de antígenos parvovírus nas fezes. Das 100 amostras do miocárdio ventricular esquerdo, enviadas ao Laboratório de Histopatologia da Universidade de Uberaba, foram observadas as seguintes alterações: miocardite 38%, hemorragia 43%, degeneração hialina 21% hiperemia 79%. Ao realizar o teste Qui-Quadrado com nível de significância de 0,05, concluiu-se que existe associação (p = 0,02) entre animais infectados com o vírus da parvovirose e as alterações histopatológicas observadas no miocárdio ventricular esquerdo.
Mestre em Ciências Veterinárias

La posición socioeconómica y la práctica de actividad física (AF), como estilo de vida, son dos determinantes que influyen en la salud individual y poblacional. En esta tesis se ha analizado la relación y la tendencia en el periodo 1995-2005 de estos dos determinantes con los factores de riesgo cardiovascular (FRCV) y el riesgo de infarto agudo de miocardio (IAM). Se han utilizado datos de tres estudios transversales de base poblacional (1995-2000-2005) realizados en la población de Girona y que incluyen más de 9.000 individuos y datos de un estudio caso-control que incluye más de 1.000 casos de IAM y 1.000 controles. Se ha demostrado que las clases sociales menos favorecidas tienen mayor prevalencia de FRCV, no obstante, las diferencias entre clases en relación al conocimiento, tratamiento y control de los FRCV clásicos que existían en 1995, han desaparecido. Sin embargo, las diferencias entre clases están aumentando durante el periodo analizado respecto a los estilos de vida (tabaquismo, sobrepeso/obesidad y sedentarismo). En relación a la práctica de AF, la prevalencia de sedentarismo ha disminuido de 1995 a 2005. La edad, el género femenino y la clase social menos favorecida se asocian con mayor prevalencia. Al analizar la relación dosis-respuesta de la AF y la salud cardiovascular, se ha observado que la AF ligera no se asocia con un mejor perfil de FRCV pero si con menor riesgo de IAM en mayores de 64 años. La AF moderada-intensa mejora los perfiles de los FRCV con un beneficio máximo en 600-700 MET•minuto/semana y disminuye el riesgo de IAM con un beneficio máximo en 1.500-2.000 MET•minuto/semana.
Socioeconomic status and physical activity practice (PA) (as lifestyle) are two major factors in individual and population health. In this thesis, we analyzed the relationship and the trend in the period 1995-2005 of both two determinants with cardiovascular risk factors and myocardial infarction risk. We used data from three independent population-based cross-sectional studies performed in Girona across 1995-2005 period with 9,546 individuals and data from population based age- and sex-matched case-control study with 1,000 cases and 1,000 controls. This thesis shows that the lower social classes have higher prevalence of cardiovascular risk factors, however, differences in awareness, treatment and control of classical cardiovascular risk factors between groups have disappeared and the disparities in healthy lifestyles between groups are widening. The prevalence of sedentary lifestyle has decreased in the period. Age, female gender and lower educational level were associated with a higher prevalence of physical inactivity. Light intensity PA reduced myocardial infarction risk in subjects older than 64 years and moderate-high intensity PA were associated with a better cardiovascular risk factors profile with a maximum benefit around 600-700 MET・min/week and also with a lower myocardial infarction risk with a maximum benefit around 1500-2000 MET・min/week.

Introduction: Achieving optimal times of reperfusion in STEMI patients transferred for primary percutaneos coronary intervention (PCI) remains a challenge, particularly in geographically disperse regions. Our goal was to create a prediction model of STEMI diagnosis - wire crossing time and perform an internal validation. Methods: Prospective cohort study of patients admitted to the critical care unit (2007-2018) diagnosed with STEMI who required to be transferred to PCI center. An analysis was carried out to identify the predictive variables leading to a delay in STEMI diagnosis -wire crossing times. Afterwards, a prediction model was created and an internal validation of this model was performed. Results: A total of 1.049 patients were included during the study period. The delaying predictive factors were: severe Killip on admission (Killip ≥3) (OR 1,100 IC 95% (1,048-1,155) p=0,0001), coronary artery bypass grafting (OR 1,241 IC 95% (1,119-1,377) p <0,001), out-of-hospital cardiac arrests (OR 1,150 IC 95% (1,078-1,228) p <0,001), lateral ischemia (OR 1,065 IC 95% (1,030-1,102) p=0,0002), first medical contact in a non-PCI center (OR 1,225 IC 95% (1,174-1,279) p<0,001), primary healthcare center (OR 1,183 IC 95% (1,131-1,238) p<0,001), home care (OR 1,077 IC 95% (1,026-1,131) p=0,003) and distance (Km) from PCI center; < 40 Km (OR 1,034 IC 95% (1,026-1,043) p<0,001) and >40 Km (OR 1.079 IC 95% (1,066-1,092) . Internal validation showed a square R of 0.355 and a correlation of 0.6. The area under the curve to predict time >120 minutes was 0.785. Conclusions: STEMI diagnosis-wire crossing time predictor variables were identified and included in a prediction model. Internal validation was success. This tool could be useful in clinical practice when taking relevant decisions in STEMI patients
Introducció: És difícil aconseguir temps òptims d´angioplàstia primària (AP) en un percentatge de pacients amb IAMEST procedents del medi extra-hospitalari o d'hospitals sense programa d'AP. Disposar d'una eina de predicció del temps d'AP desde el diagnòstic podria ser útil. El nostre objectiu va ser crear un model de predicció del temps d'ECG diagnòstic-pas de guia i realitzar una validació d'aquest model. Mètode Estudi de cohorts prospectiu de pacients ingressats a la unitat de cures crítiques cardiològiques (2007-2018) amb IAMEST, tractats amb AP i que van requerir ser traslladats a un centre amb disponibilitat d'hemodinàmica. Es va realitzar un anàlisi per identificar les variables predictores de demora de l'ECG diagnòstic- pas de guia, es va crear un model de predicció d'aquest temps i una validació interna del model. Resultats Es van incloure un total de 1.049 pacients en l'estudi. Les variables incloses en el model de predicció van ser la insuficiència cardíaca greu a l'ingrés (Killip ≥3) (OR 1,100 IC 95% (1,048-1,155) p = 0,0001), la cirurgia cardíaca prèvia de bypass (OR 1,241 IC 95% (1,119-1,377) p <0,001), la mort sobtada extrahospitalària (OR 1,150 IC 95% (1,078-1,228) p <0,001), la localització lateral de l'IAM (OR 1,065 IC 95% (1,030-1,102) p = 0, 0002), el primer contacte amb hospital sense disponibilitat d'hemodinàmica (OR 1,225 IC 95% (1,174-1,279) p <0,001), centre d'atenció primària (OR 1,183 IC 95% (1,131-1,238) p <0,001), domicili ( OR 1,077 IC 95% (1,026-1,131) p = 0,003) i finalment la distància al centre amb hemodinàmica; <40 Km (OR 1,034 IC 95% (1,026-1,043) p <0,001) i> 40 km (OR 1.079 IC 95% (1,066-1,092) p <0,001). La validació interna va mostrar un R quadrat de 0,355 i una correlació de 0,6. L'àrea sota la corba per a temps superiors a 120 minuts va ser de 0,785. Conclusions Identificades les variables predictores del temps ECG diagnòstic-pas de guia es va crear un model de predicció, amb una validació interna satisfactòria, que pot ser útil en la presa de decisions clíniques en el IAMEST

La aterosclerosis, engrosamiento de la pared arterial, puede progresar gradualmente hasta complicarse con la aparición de un trombo ocasionando una obstrucción brusca de una arteria con obliteración del flujo en el órgano irrigado por dicha arteria. Según su localización, esta oclusión puede dar lugar a un accidente cerebrovascular (CVA), una obstrucción arterial periférica o a un síndrome coronario agudo (ACS). Dentro de los ACS podemos encontrar la angina inestable, el infarto agudo de miocardio con y sin elevación de ST y la muerte súbita. Estas manifestaciones agudas de la enfermedad cardíaca comparten un mismo fenómeno patofisiológico: la aterotrombosis coronaria y resultan de una isquemia aguda del miocardio. Aunque se han producido grandes avances en el tratamiento de esta enfermedad, la medicina actual no es capaz de predecir el riesgo de sufrir patología cardiovascular. Pese a la gran influencia de los factores de riesgo clásicos tales como la dislipemia, la diabetes, la hipertensión y la obesidad, una proporción importante de los eventos ocurren en individuos que no presentan ninguno de estos factores. De ello deriva la actual necesidad de identificar nuevos biomarcadores que mejoren la predicción global de riesgo de enfermedad cardiovascular. En los últimos años la proteómica se ha convertido en una estrategia básica para el estudio del perfil proteico y de asociaciones proteicas complejas en una muestra biológica. Mediante el uso de técnicas proteómicas se pueden determinar modificaciones en la estructura de una proteína, así como sus niveles de expresión y la presencia de modificaciones post-traduccionales, que pueden estar asociadas a una patología determinada y tener valor diagnóstico, pronóstico y terapéutico. Se han propuesto muchas moléculas como marcadores de la aterotrombosis, pero los resultados no son consistentes y la mayoría de ellos no ha llegado a utilizarse en la práctica clínica. Por eso cada vez hay una mayor necesidad de integrar las técnicas proteómicas en el descubrimiento de nuevos biomarcadores lo que permitirá conocer nuevos mediadores y vías patofisiológicas sin una asociación previa a las patologías cardiovasculares. En este trabajo se han aplicado técnicas de proteómica diferencial para el estudio de los cambios que se dan a nivel sérico en la fase aguda tras un infarto agudo de miocardio (AMI) de nueva presentación. Mediante la comparación del perfil proteómico de pacientes AMI e individuos sanos se han detectado importantes cambios en el patrón de distribución de dos grupos de proteínas: relacionadas con el metabolismo de las lipoproteínas de alta densidad (HDL) y relacionadas con el metabolismo del retinol, vía no asociada hasta el momento con el AMI. Dentro de las proteínas del metabolismo de las HDL encontramos cambios en la fase aguda post-AMI en la apolipoproteína J y la transtiretina (TTR). Ésta última también muestra cambios en situaciones de alto riesgo cardiovascular como la hipercolesterolemia familiar. A su vez, también se han detectado cambios en la proteína mayoritaria de las HDL, la apolipoproteína A-I, pero en este caso en una fase más tardía post-AMI y en pacientes diabéticos. Las proteínas relacionadas con el metabolismo del retinol que muestran un perfil diferencial son la TTR y la proteína plasmática de unión a retinol (RBP4). En una segunda parte de este trabajo se han estudiado los cambios proteómicos que se dan a nivel de tejido cardíaco en un modelo experimental porcino de AMI y se ha encontrado por primera vez una asociación de la vía de señalización del receptor del hidrocarburo de arilo con el daño producido por la reperfusión posterior a un AMI.. Además se ha visto que la aplicación de un procedimiento cardioprotector como es el post-condicionamiento isquémico atenua la activación de dicha vía inducida por la reperfusión.
Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality. Atherosclerosis, the underlying mechanism of cardiovascular diseases, progresses gradually until the blood flow is compromissed leading to the precipitaton of an acute ischemic event such as acute coronary syndrome (ACS) or ictus. Identifying subjects at risk of developing an acute ischemic event remains one of the great challenges of cardiovascular medicine. Classical approaches, such as the presence of cardiovascular risk factors, are unable to accurately predict cardiovascular events. During the last years several studies have been focussed on the search for new plasma biomarkers of acute ischemic events. Although many potential molecules have been described, the results have not been consistent enough and most of them are not used in clinical practice. Until now, the only group of accepted biomarkers for the diagnosis of acute myocardial ischemic events are troponins. Nevertheless, these structural proteins are released to the circulation as a consequence of an irreversible injury of the myocardium. Therefore there is still a need for the identification of new biomarkers that will allow the early detection of an ischemic event before the irreversible necrosis of the myocardium occurs. Proteomic technologies allow the identification of molecules related to new pathways that together with traditional markers could act as a multibiomarker for diagnosis, prognosis and treatment, and therefore become a key tool for the development of new approaches in the prevention of cardiovascular diseases. In this study by applying proteomic technologies such as bi-dimensional electrophoresis we have compared the serum proteomic profile of patients with an acute new-onset myocardial infarction (AMI) to that of healthy individuals and found important changes in two main group of proteins: HDL-related proteins (apolipoproteins J and A-I, and TTR) and retinol metabolism associated proteins (TTR and RBP4). In a second part of the work by the study of proteomic changes that occur in the myocardial tissue after an AMI in a swine experimental model we have found, for the first time, an association of the aryl hidrocarbon receptor signalling pathway with the reperfusion injury after an AMI. Moreover, we have found an attenuation of the same pathway in response to a cardioprotective approach such as ischemic post-conditioning.