Thèses sur le sujet « Acute myocarditi »

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.

Acute myocarditis is an acute inflammatory syndrome characterized by myocardial damage and dysfunction often due to a viral infection followed by a variable development over time. There are currently no specific treatments and standard treatments for heart failure are generally applied. The inflammasome is a recently identified macromolecular structure that occupies a central role in the amplification of the inflammatory response and promotion of cell death during acute and chronic infections. We hypothesized the formation of the inflammasome in acute myocarditis. To investigate, samples of patients were collected from the Cardiomyopathy Registry in Trieste, with 12 cases of biopsy-proven myocarditis and 11 cases of autopsy-proven myocarditis stained for major components of the inflammasome through immunofluorescence; 10 of the 12 (83.3%) biopsy cases and 8 of the 11 (72.7%) autopsy cases presented formation of the inflammasome in a variety of cells including resident cells (i.e. cardiomyocytes, endothelial cells, fibroblasts) and infiltrating cells (i.e. leukocytes) while varying in intensity and distribution. Control samples of 5 subjects not presenting with any acute cardiac events showed no formation of the inflammasome. While further studies should look to elucidate the correlation of inflammasome-formation and progression of disease, this finding paves the way for further insight into the pathophysiology of acute myocarditis.

Acute myocardial infarction (AMI) results in the activation of the innate immune system with monocytes playing critical roles in both the initial inflammation following myocardial ischaemia and subsequent recovery. Monocytes are a heterogeneous cell population and observations from experimental models demonstrate that immediately following myocardial injury, classical inflammatory monocytes, which are highly phagocytic, are recruited to ischaemic myocardium from the bone marrow and spleen and peak at 48 hours. This is followed by the recruitment of non-classical monocytes that are involved in repair and healing, peaking at day 5. The monocyte response in humans following AMI is currently poorly understood. Due to their central role in the pathogenesis of AMI, monocytes are attractive both as potential biomarkers to inform of extent of myocardial injury (and recovery) and also as therapeutic targets with the specific targeting of monocytes in experimental models resulting in reduced infarction size and improved LV remodelling. However, in spite of these promising results and our greater understanding of the pathogenesis of AMI, no immune-modulating therapeutic has been translated into routine clinical practice. We therefore hypothesized that characterisation of the monocyte response to AMI by flow cytometry and gene expression profiling in both experimental models and humans would give novel insights into underlying biological processes and function (both locally in the myocardium and systemically), identify novel therapeutic targets, enable their use as cellular biomarkers of disease, and test conservation between species validating the experimental model for future investigation. Classical inflammatory monocytes were found to significantly increase in the peripheral blood 48 hours following AMI in both mice and humans, with the magnitude of the monocyte response correlating with the extent of myocardial injury in both species. Gene expression profiling of peripheral circulating monocytes following AMI identified a number of candidate genes, biological pathways and upstream regulators that were conserved between species and that could represent novel therapeutic targets. Furthermore, in an experimental model of AMI, leukocytes appeared to have effects beyond the ischaemic myocardium, with leukocyte recruitment in remote myocardium and in kidneys associated with elevated inflammatory markers and endothelial activation.

Coronary heart disease (CHD) is the single biggest cause of death in the United Kingdom1. Primary percutaneous coronary intervention (primary PCI) has transformed the early treatment of acute myocardial infarction (MI), improving outcome by rapidly re-opening the occluded coronary artery, with a larger mortality benefit and reduced risk compared with thrombolysis. Despite these advances, and even with the optimal treatment, some patients still sustain substantial myocardial damage leading to mortality and morbidity. MicroRNAs (miRs) are short non-coding RNAs with a role in regulating protein synthesis. Some miRs are cardiospecific, can be detected in plasma after a myocardial infarction and show promise as biomarkers and insights into the mechanisms of myocardial injury. In this work, as part of the Oxford Acute MI (OxAMI) Programme, a cohort of patients recruited at the time of ST elevation MI underwent detailed clinical and microRNA analysis at the time of myocardial infarction. This work was validated using separate discovery and validation cohorts. The source of detected miRs was further analysed in an in-vitro endothelial cell culture model and by measuring miRs released into the venous drainage of the heart, the coronary sinus. In the Discovery Cohort, miRs previously shown to be increased in myocardial infarction (e.g. miR-1, -133a, -499) were detectible in plasma after myocardial infarction, and this was confirmed in the validation cohort. Other miRs with a similar relationship were also identified (e.g. miR-30a, -378a, 125b). Microvascular obstruction was found to be associated with increased infarct size and also with release of microRNAs correlating with infarct size suggesting a link between microvascular obstruction and myocardial necrosis. Analysis of paired coronary artery and coronary sinus samples showed that these miRs increased down the myocardial gradient, suggesting myocardial release. The culmination of this work was to use the experimental findings from circulating plasma, cultured endothelial cells and coronary sinus experiments to design a microRNA panel using a blood sample taken six hours after admission to use in a regression model which was more predictive of final infarct size than troponin alone.

The aim of this thesis was to determine if the neutrophil played a significant role in acute myocardial infarction in man. Firstly methods for isolating and radiolabelling neutrophils were developed. These, along with measurement of established markers of neutrophil activation and free radical activity were used to assess neutrophil involvement in myocardial infarction in man. The single-step isolation procedure developed provided a simple and easy means of isolating an essentially 'pure' preparation of cells with a minimum of 'handling'. That this method resulted in isolation of a viable cell population was evidenced by normal kinetics and uptake into sites of infection and inflammation in vivo. In collaboration with others it was shown that the acute inflammatory response to myocardial infarction may be imaged in man using radiolabelled autologous neutrophils. The time interval from onset of pain to injection of labelled cells was the only factor shown to determine the outcome of imaging and suggests that the stimulus for cell recruitment may be early and transient. Detection of increased neutrophil elastase by radioimmunoassay and the non-peroxide diene conjugated isomer of linoleic acid by high performance liquid chromatography in the plasma of these patients demonstrated increased neutrophil activation and free radical activity in acute myocardial infarction in man. Coronary reperfusion, effected by intravenous thrombolysis, might be thought to be associated with increased neutrophil activation but the results showed a reduction in the intensity of the inflammatory response as assessed by uptake of radiolabelled autologous neutrophils, abolition of the late peak of neutrophil activation and a similar degree of free radical activity between patients treated with and without thrombolysis. This is consistent with a reduction rather than an exaggeration of the inflammatory response and conflicts with current views on 'reperfusion injury'.

Unplanned readmissions to the hospital are a problem faced by most health care organizations in the United States; hospitals are penalized for such readmissions. The project site identified high readmission rates for patients who were discharged after acute myocardial infarction (AMI), making careful transition home a necessity for post-AMI patients. The focus of this quality improvement (QI) project was implementation of an early follow-up appointment of AMI patients following discharge. The purpose of this project was to evaluate the effectiveness of changing follow-up appointments for patients with an AMI from 14-30 days to 7-14 days post discharge to reduce unplanned readmission rates. Bandura’s self- efficacy theory provided the theoretical framework for this project. An evaluation of the QI project was completed by comparing patient readmission rates 6 months before and 6 months after implementation of the early follow-up appointments. Data analysis demonstrated that the readmission rate was not improved in the first 6 months post QI project implementation. Using the plan-do-check-act process, a multifactorial approach was recommended to refine the QI project and address the system-wide readmission rates. The implications of this project for positive social change include providing early analysis of the readmission QI project, which allowed the hospital to restructure the QI approach and improve the plan for preventing readmission.

Acute myocardial infarction (AMI) is the leading cause of death worldwide. Currently, the best method of treating cardiac ischemia is early reperfusion which, itself, induces myocardial damage. The mTOR complex is a key regulator of cardioprotection against cell stressors. We hypothesized that reperfusion therapy with Rapamycin, a potent mTOR inhibitor, would reduce infarct size in adult mouse hearts. Rapamycin was administered at the onset of reperfusion following 30 min in situ LAD ligation. After 24 hours of reperfusion, myocardial infarct size and apoptosis were significantly reduced in rapamycin-treated mice compared to control. Rapamycin inhibited pro-apoptotic protein Bax and phosphorylation of ribosomal protein S6 (target of mTORC1), while it induced phosphorylation of AKT (target of mTORC2). Rapamycin also induced phosphorylation of ERK, while significantly reduced phosphorylation of p38. Thus, our study shows that reperfusion therapy with Rapamycin provides cardioprotection through induction of the phosphorylation of Akt and ERK.

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 standard 12-lead ECG remains the cornerstone of immediate clinical triage In patients presenting pre-hospital or to an Emergency Department with acute ischaemic-type chest pain at rest However, this non-invasive test is well known to have poor diagnostic sensitivity for acute coronary artery occlusion. Previous research conducted at the Royal Victoria Hospital Belfast has shown the utility of extended lead systems, i.e. the body surface potential map (BSPM). in improving the diagnostic performance of the ECG in this regard. Despite advances in cardiac biomarkers, there remain a variety of high-risk populations where these biomarkers are of reduced initial diagnostic value and/or their measurement may result in an unnecessary delay to acute myocardial infarction diagnosis. The primary aim of this thesis is to evaluate the BSPM in these groups, namely those patients with: • Negative cardiac biomarkers at presentation; • ST-segment depression only on ECG at presentation; • Typically 'balanced ischaemia' on ECG, i.e. in left main coronary artery stenosis; • Ventricular Fibrillatory cardiac arrest; and • Extreme Body Mass Index.

Background: Influenza is an important global cause of morbidity and mortality. Though some cardiac complications of influenza, such as myocarditis, are well-recognised, its role as a trigger for acute cardiovascular events is less clear. Improved understanding of this relationship will add to evidence to support appropriate prevention and treatment strategies. Methods: I investigated evidence that influenza and acute respiratory infections could trigger acute myocardial infarction (AMI) through a systematic literature review and meta-analysis (chapter 2) and original research studies (chapters 3-7). These were an ecological weekly time series study using Poisson regression models adjusted for temporal and environmental confounders in England & Wales and Hong Kong (chapter 3); two self-controlled case series analyses using the General Practice Research Database linked to influenza surveillance data (chapter 4) and to cardiac disease registry and hospitalisation data (chapter 5); a case control study in AMI patients and surgical controls during the 2009 influenza pandemic in London (chapter 6); an exploratory mechanistic study (chapter 7). Key findings: • Acute respiratory infections, and seasonal influenza, triggered AMI • A triggering effect may be greater for influenza than for other respiratory infections (p=0.011) • AMI risk was highest in the first three days after acute infection – adjusted incidence ratio 4.19 (95% CI 3.18-5.53) – and persisted for around 28 days • The proportion of AMI deaths due to seasonal influenza ranged from 3-5%, rising to 13% in periods of highest influenza circulation • The relative risk of AMI after acute respiratory infection was highest in people aged ≥80 years • Influenza vaccination protected against some adverse cardiac outcomes in people with existing cardiovascular disease Conclusions: Reducing the burden of influenza would benefit cardiovascular health. Questions remain about key groups to target, as well as the optimal type and delivery of interventions to reduce influenza-associated AMI risk.

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.

Abstract Ischemic heart disease is one of the leading cause of death in the Western world. There is convincing evidence that stem cell therapy improves cardiac function and reduces the scar formation following an acute myocardial infarction (AMI). The mechanisms involved in the recovery remain partly unknown. Direct injection of stem cells into myocardium is a widely used transplantation technique though there are few details available about the behavior of cells after transplantation. A cardiac explant culture model simulating tissue stress was developed in this study to examine in detail the properties of the stem cells after their transplantation. The migration range in myocardium and the number of adherent stem cells increased with time. In vitro and in vivo studies revealed that after their administration, the stem cells became localized in the slit-like spaces, such as in the capillaries. Even though the study outcomes regarding the impact of stem cell therapy in recovery after AMI have been largely promising, the results of the clinical studies have proved to be more controversial. If one wishes to evaluate the true contribution of the stem cell therapy to the recovery, it is essential to devise a reliable study method for cell targeting. Here, iron labeled stem cells in combination with magnetic resonance imaging (MRI) were used. The MRI data corresponded to the histological results. Thus, it is concluded that MRI is a feasible method for monitoring the effectiveness of cell targeting. Stem cell treatment was shown to increase cardiac function at three weeks after AMI. If there was a high number of stem cells in cardiac tissue after transplantation, this predicted a greater improvement in cardiac function. Improper stem cell injection may lead to leakage of the stem cells out of the myocardium, leading to unreproducible study results. Inflammation modulating factors secreted by the stem cells are considered as key mechanisms in the recovery after AMI. There were differences in the cytokine levels between the stem cell treated and control groups in a clinical and in vivo animal study i.e. stem cell therapy exerted a balancing effect on the inflammatory process, a crucial component in the optimal recovery after AMI. The present study reveals many properties of stem cells, importance of cell targeting and the influence of stem cell therapy on cytokine levels after AMI
Tiivistelmä Iskeeminen sydänsairaus on yksi yleisimmistä kuolinsyistä länsimaissa. Tutkimusten mukaan kantasoluterapia parantaa sydämen toimintakykyä ja pienentää akuutin sydäninfarktin jälkeen sydämeen muodostuvan arpikudoksen määrää. Paranemiseen liittyvät mekanismit ovat edelleen osittain tuntemattomia. Kantasolujen ruiskutus suoraan sydämeen on paljon käytetty menetelmä, vaikka solujen käyttäytymistä ei tunneta tarkkaan.Tutkimuksessa kehitetyn kudoksen stressitilaa simuloivan sydänkudoksen kasvatusmenetelmän avulla tutkittiin siirrettyjen kantasolujen toimintaa yksityiskohtaisesti. Kantasolujen vaeltaman matkan sydänkudoksessa ja kiinnittyneiden kantasolujen lukumäärä havaittiin kasvavan ajan kuluessa. In vitro ja in vivo tutkimuksissa havaittiin kantasolujen sijaitsevan ruiskutuksen jälkeen rakomaisissa paikoissa kuten pienissä verisuonissa. Vaikka tutkimustulokset kantasoluterapian hyödyistä paranemisen suhteen ovat pääosin lupaavia, kliinisten tutkimusten tulokset ovat ristiriitaisia. Todellisen kantasoluhoidon vaikutuksen arvioimiseksi tarvitaan luotettava menetelmä varmistamaan kantasolujen hakeutuminen vaurioalueelle. Tässä tutkimuksessa rautaleimattujen kantasolujen paikantamisessa käytetty magneettikuvantaminen vastasi histologisia löydöksiä. Magneettikuvantaminen todettiin käyttökelpoiseksi menetelmäksi solujen paikallistamisessa. Kantasoluhoidon osoitettiin parantavan sydämen toimintakykyä kolme viikkoa akuutin sydäninfarktin jälkeen. Suuri kantasolumäärä sydänkudoksessa siirron jälkeen ennusti parempaa toipumista. Puutteellisesti suoritettu kantasoluruiskutus voi johtaa kantasolujen vuotamiseen pois sydänkudoksesta aiheuttaen vaihtelevuutta tutkimustuloksiin. Kantasolujen erittämiä tulehdusta sääteleviä tekijöitä pidetään tärkeimpänä mekanismina paranemisprosessissa. Tutkimus osoitti eroavaisuuksia kantasoluhoidetun ja kontrolliryhmän välillä. Kliinisessä ja koe-eläintutkimuksessa kantasolusiirrolla todettiin tulehdusreaktiota tasapainottava vaikutus, mikä on tärkeää optimaalisen sydänlihaskudoksen paranemisen kannalta akuutin sydäninfarktin jälkeen. Tutkimus toi esiin monia kantasolujen ominaisuuksia, solujen paikantamisen tärkeyden ja kantasoluhoidon vaikutuksen sytokiinipitoisuuksiin akuutin sydäninfarktin jälkeen

Abstract There is a need to identify patients with an increased risk of dying after acute myocardial infarction (AMI), because sudden cardiac death (SCD) and potentially fatal ventricular tachyarrhythmias can be prevented by an implantable cardioverter-defibrillator, or in some cases, with aggressively optimized drug or revascularization therapy. The present study was designed to study the predictive power of non-invasive risk markers and all-cause, cardiac and arrhythmic mortality in 700 consecutive post-AMI patients discharged alive with optimal medication according to contemporary guidelines. Detrended fluctuation analysis of heart rate variability (HRV) predicted all-cause mortality beyond clinical variables as well as left ventricular function in post-AMI patients. The predictive power of the short-term scaling exponent α1 was higher than that of the traditional indexes of HRV (for α1 < 0.65, the risk ratio (RR) in multivariate analysis was 5.1, with 95% confidence intervals (CI) 2.9-8.9; p < 0.001). HRV results from a conventional 24-hour electrocardiographic (ECG) recording system differed significantly when compared to a system with a higher sampling frequency. The difference was generally more pronounced in post-AMI patients than in healthy subjects. The presence of sustained T-wave alternans during a predischarge exercise test after AMI was not a marker of mortality. However, the inability to perform an exercise test or to reach the heart rate of 105 beats/min predicted independently all-cause (RR 9.3, 95% CI 2.0-43.3, p < 0.01) and cardiac mortality (RR 11.1, 95% CI 2.4-50.8, p < 0.01). High levels of natriuretic peptides were associated with both sudden and non-sudden cardiac mortality. B-type natriuretic peptide provided more specific independent information on the risk for subsequent SCD (RR 3.9, 95% CI 1.2-12.3, p < 0.05) than non-SCD. SCDs occurred mainly more than 18 months after AMI, and the proportion of SCD was less than 40% of all cardiac deaths. Common arrhythmia markers such as the presence of ventricular premature beats or episodes of nonsustained ventricular tachycardia during ambulatory recordings, the time domain parameters of HRV, baroreflex sensitivity, QT dispersion and QRS complex duration provided only limited predictive power on the risk of SCD or arrhythmic events in patients with optimized beta-blocking therapy. Many risk variables previously considered to predict SCD were better predictors of non-SCD than SCD. Conclusions: 1. The epidemiological pattern of SCD was different from that reported previously. 2. Many arrhythmia risk markers provided only limited information on the risk of SCD. 3. Short-term fractal scaling exponent α1 provided potentially useful information on the risk for all-cause mortality, and BNP was useful in predicting the risk of SCD in a post-AMI population with optimized therapy.

Background: Younger adults have been identified as an emerging ‘at-risk’ population with a rising prevalence of cardiac risk factors and hospitalization for acute myocardial infarction (AMI). Coupled with this is an unexplained excess early AMI mortality risk in younger women compared to younger men. Self-perceived health status (symptoms, physical function and disease perception) has been proposed as a contributing factor; however, not much is known about sex differences in health status outcomes of younger adults post AMI. The overarching goal of this thesis is to enhance our understanding of AMI in younger adults (20-55 years). The main objectives are: 1) to examine sex differences and 10-year trends in AMI hospitalization and early AMI mortality, and to determine whether the sex gap in early AMI mortality has changed in recent years, and 2) to examine the sex differences and changes in health status during the first year following AMI. Methods: The age- and sex-specific 10-year trends in AMI hospitalization and 30-day AMI mortality were based on population-based, administrative data in British Columbia (BC) and assessed using negative binomial and logistic regression, respectively. Sex differences and changes in health status were assessed using prospectively collected data on 286 younger AMI patients, in BC. Linear and generalized linear mixed models were used to assess health status changes. Results: Between 2000-2009, younger adults, particularly women, did not experience the same declining AMI hospitalization rates as older adults. Furthermore, for early AMI mortality, the observed sex differences among younger adults persisted, even after adjusting for comorbidities. While health status in both men and women diminished in the first month following AMI, driven by worse angina and physical function, it improved thereafter. Younger women consistently had significantly worse cardiac-related physical function, disease perception, and overall physical and mental health than younger men during the first year; however, the changes in health status were similar in men and women. Conclusions: The findings highlight a persistent sex difference in early mortality and health status following AMI among younger adults. The first month after AMI is a critical period to intensify support and treatment in order to improve outcomes.

A left ventricular thrombus develops in approximately 40% of patients following an anterior myocardial infarction. Embolization from these thrombi has been regarded as the most important cause of stroke following a myocardial infarction. The occurrence and characteristics of left ventricular thrombi and stroke after anterior myocardial infarction may, however, have changed after the introduction of aspirin and thrombolytics as standard therapy. The occurrence of left ventricular thrombi was examined in 99 patients with an acute anterior myocardial infarction, 74 of whom were treated with streptokinase. Thrombi were equally common in the thrombolysis group (46%, 95% confidence interval [Cl], 35-57%) as in the non-thrombolysis group (40%, 95% Cl, 21-59%). The risk of thrombus formation was related to the degree of left ventricular segmental dysfunction. Using serial echocardiographic examinations, the formation and resolution of thrombi was found to be highly dynamic. The majority of thrombi diagnosed during the hospital stay had resolved at follow-up one month later, irrespective of treatment with streptokinase or anticoagulants. The development of new thrombi was, however, observed at every follow-up examination interval. One-hundred-and-twenty-four patients suffering a stroke within 28 days of an acute myocardial infarction were identified in the northern Sweden MONICA stroke registry between 1985 and 1994. The overall event rate of ischemic myocardial infarction-related stroke was 1.07%. The risk of a stroke was highest duringt he first 5 days after the infarction. Only approximately half the strokes were preceded by an anterior myocardial infarction. In a case-control analysis, atrial fibrillation (chronic or new onset), ST elevation and a history of a previous stroke were found to be independent predictors of stroke. There was a long-term trend towards a lower incidence and event rate for myocardial infarction-related stroke. Clinical stroke characteristics were examined in 103 patients with a first-ever stroke within 28 days of a myocardial infarction and compared with stroke characteristics in 206 control subjects without a recent myocardial infarction. The sudden onset of neurological symptoms, an impairment of consciousness, a progression in neurological deficits and a stroke of the total anterior circulation infarction subclass were more common in cases than in controls. The risk of a recurrent stroke during one year of follow-up was not influenced by a recent myocardial infarction, but patients who had suffered a myocardial infarction had markedly higher mortality. To conclude, thrombolytic treatment does not reduce the occurrence of left ventricular thrombi after a myocardial infarction. The risk of thrombus formation is related to the extent of the myocardial injury. The development and resolution of thrombi is a highly dynamic process. There is a long-term trend towards a lower incidence and event rate of ischemic stroke after a myocardial infarction. Although the clinical stroke characteristics differ, they are not specific enough to differentiate between patients with and without a recent myocardial infarction.

S. 1-84: sammanfattning, s. 85-136: 5 uppsatser

digitalisering@umu

This study investigated whether acute myocardial ischemia of the anterior left ventricular wall induced an increase in cardiac sympathetic efferent nerve activity and thereby affected regional myocardial blood flow and contractile function.

The intramyocardial injection of biomaterials is an emerging therapy for myocardial infarction. Computational methods can help to study the mechanical effect s of biomaterial injectates on the infarcted heart s and can contribute to advance and optimise the concept of this therapy. The distribution of polyethylene glycol hydrogel injectate delivered immediately after the infarct induction was studied using rat infarct model. A micro-structural three-dimensional geometrical model of the entire injectate was reconstructed from histological micro graphs. The model provides a realistic representation of biomaterial injectates in computational models at macroscopic and microscopic level. Biaxial and compression mechanical testing was conducted for healing rat myocardial infarcted tissue at immediate (0 day), 7, 14 and 28 days after infarction onset. Infarcts were found to be mechanically anisotropic with the tissue being stiffer in circumferential direction than in longitudinal direction. The 0, 7, 14 and 28 days infarcts showed 443, 670, 857 and 1218 kPa circumferential tensile moduli. The 28 day infarct group showed a significantly higher compressive modulus compared to the other infarct groups (p= 0.0055, 0.028, and 0.018 for 0, 7 and 14 days groups). The biaxial mechanical data were utilized to establish material constitutive models of rat healing infarcts. Finite element model s and genetic algorithms were employed to identify the parameters of Fung orthotropic hyperelastic strain energy function for the healing infarcts. The provided infarct mechanical data and the identified constitutive parameters offer a platform for investigations of mechanical aspects of myocardial infarction and therapies in the rat, an experimental model extensively used in the development of infarct therapies. Micro-structurally detailed finite element model of a hydrogel injectate in an infarct was developed to provide an insight into the micromechanics of a hydrogel injectate and infarct during the diastolic filling. The injectate caused the end-diastolic fibre stresses in the infarct zone to decrease from 22.1 to 7.7 kPa in the 7 day infarct and from 35.7 to 9.7 kPa in the 28 day infarct. This stress reduction effect declined as the stiffness of the biomaterial increased. It is suggested that the gel works as a force attenuating system through micromechanical mechanisms reducing the force acting on tissue layers during the passive diastolic dilation of the left ventricle and thus reducing the stress induced in these tissue layers.

Includes bibliographical references.
Acute inferior myocardial infarction is generally associated with a benign course and low in-hospital mortality. However, a group of patients with high degree atrioventricular block has significantly increased mortality. Although some of the prognostic factors associated with increased mortality have been identified, the explanations for these remain less than satisfactory.

Mestrado em Materiais e Dispositivos Biomédicos
Acute Myocardial Infarction (AMI) is the leading cause of death and disability in industrialized countries and is expected to become so in emerging countries by 2020. AMI is one of the main diseases with the highest rate of misdiagnosis. Of the majority of patients that arrive to the Emergency Department (ED) with cardiac pain and other symptoms suggestive of myocardial infarction, only a small portion actually may experience an Acute Myocardial Infarction. Therefore, diagnosing Acute Myocardial Infarction within such a large proportion of patients with cardiac pain is indeed a diagnostic challenge. For the correct diagnosis, it is essential to collect blood samples from the patient for the measurement of cardiac biomarkers, namely cardiac troponin I and cardiac troponin T. In this thesis, it is proposed a new type of biosensor for the early and reliable diagnosis of Acute Myocardial Infarction based on the use of metallic nanoparticles attached with aptamers as new Surface Enhanced Raman Scattering (SERS) platforms for the specific detection of cardiac troponin-I. Firstly, gold and silver colloidal nanoparticles (NPs) were synthesized via the classical citrate reduction method and later characterized to assess the quality of the substrate. Larger gold nanoparticles (AuNPs) with sizes ranging from 35-96 nm were also prepared by a seed-mediated growth method. The detection of cardiac troponin I proceeded with the addition of the protein at lower concentrations to the metallic colloids. The final results showed that AuNPs with larger sizes are good candidates to be used as SERS platforms for the detection of cardiac troponin I, because they have presented the highest enhancement of the Raman signals of the protein. These experiments have shown that larger AuNPs are definitely most suitable for this kind of applications. Peak bands were found to be attributed from characteristic bands present in proteins.
O Enfarte Agudo do Miocárdio é a principal causa de morte e de incapacidade nos países desenvolvidos e prevê-se que seja também nos países em desenvolvimento até 2020. O Enfarte Agudo do Miocárdio é uma das principais patologias com a maior taxa de erro no diagnóstico. Entre a maioria de pacientes que se apresenta com dor torácica ou outro sintoma sugestivo de Enfarte Agudo do Miocárdio, apenas uma pequena porção de pacientes realmente manifesta a patologia. Deste modo, diagnosticar um Enfarte Agudo do Miocárdio numa larga proporção de pacientes com dor torácica é de facto um desafio para os clínicos. Para o correto diagnóstico é essencial que se colete uma amostra de sangue do paciente para a medição de biomarcadores cardíacos sobretudo as troponinas cardíacas I e T. Nesta tese propõe-se um novo tipo de biossensor para o diagnóstico precoce e fiável de Enfarte Agudo do Miocárdio que se baseia na funcionalização de aptâmeros à superfície de nanopartículas metálicas como novas plataformas de SERS (Surface Enhanced Raman Scattering) para a deteção específica da troponina cardíaca I. Numa primeira fase, nanopartículas de ouro e de prata foram sintetizadas pela via clássica de redução com citrato e subsequentemente caracterizadas para determinar a qualidade dos substratos obtidos. Nanopartículas com tamanhos que rondam os 35-96 nm foram igualmente sintetizadas pelo processo de crescimento mediado por sementes. A deteção da troponina cardíaca I passou pela adição de baixas concentrações de proteína aos coloides metálicos. Os resultados finais demonstraram que as nanopartículas de ouro com tamanhos superiores aparentam ser bons candidatos a substratos para SERS para a deteção da troponina cardíaca-I, uma vez que apresentaram melhor intensificação de sinais de Raman da proteína. Estes testes permitiram concluir que as nanopartículas de ouro de maiores dimensões são de facto mais adequadas para este tipo de aplicações. Os picos obtidos podem ser atribuídos a bandas características encontradas nas proteínas.

Myocardial infarction remains an important cause of death and disability in Scotland. Although initial mortality is largely a consquence of arrhythmias, after the first few hours mortality and morbidity is closely related to the extent of myocardial damage and subsequent ventricular dilatation. This thesis discusses means of reducing left ventricular dysfunction after myocardial infarction. The first two sections describe a placebo controlled double blind clinical trial of oral therapy with captopril or isosorbide mononitrate initiated early after myocardial infarction and continued for 28 days. Left ventricular function and volume as assessed by echocardiography, radionuclide ventriculography or magnetic resonance imaging was similar in the placebo and vasodilator groups at 5 weeks. Even the placebo group showed a trend to a decrease in ventricular diameter. In contrast to many similar studies most of these patients (88% ) received thrombolysis, perhaps resulting in a population with little tendency to ventricular dilatation. Clinical outcome (death, cardiogenic shock) was significantly better in the captopril group, suggesting this agent may have a role for high risk patients (possibly those with persisting coronary occlusion). However there was no evidence that vasodilator therapy reduced infarct size as quantified by tomographic radionuclide imaging. In addition the acute inflammatory response, as reflected by measures of neutrophil activation and free radical lipid attack, was not modified by vasodilator therapy. The last two sections focus on coronary artery reperfusion. A detailed study of 17 patients with myocardial infarction found streptokinase therapy caused complement and neutrophil activation, particularly in those that did not reperfuse. This inflammatory activation may lead to a detrimental increase in infarct size. The pattern of complement activation was consistent with plasmin mediated proteolytic activation rather than an antigen-antibody reaction.

There is substantial evidence to suggest that the sympathetic nervous system is intimately involved in the development of ventricular arrhythmias during acute myocardial ischaemia. Nevertheless factors controlling myocardial noradrenaline (NA) release during ischaemia are only partly understood. Therefore, the effect or duration and severity of ischaemia on neuronal NA release (left stellate ganglion stimulation, 5Hz) was studied using a perfused, innervated rat heart model. The effect of ischaemia on presynaptic inhibition by α-adrenergic, muscarinic and purinergic receptors was also examined. There is higher density of α-adrenoceptors in female tissues but it is not clear whether there is a gender difference in presynaptic inhibitory mechanisms. NA overflow progressively declined during 10 min stop-flow ischaemia, but was maintained for up to 60 min during less severe ischaemia (95% flow reduction). α-Adrenergic or purinergic antagonists increased NA overflow during low-flow but not stop-flow ischaemia. In normoxic hearts, neuronal NA overflow was inhibited by vagal nerve stimulation (VS, 15 Hz) but not after 10 min low-flow or 1-5 min stop-flow ischaemia. The loss of VS-induced inhibition of NA overflow during ischaemia may be due to enhanced α-adrenergic presynaptic inhibition of acetylcholine release, since an α-adrenoceptor antagonist could restore this effect. The inhibitory effect of the muscarinic agonist methacholine on NA overflow was also attenuated by low-flow or stop-flow ischaemia, indicating a dysfunction of muscarinic presynaptic receptors. The effect of gender on α-adrenergic presynaptic inhibition of neuronal NA release was also studied. In normoxic hearts, NA overflow by control nerve stimulation was similar. The α-adrenergic inhibitor rauwolscine potentiated NA overflow more in female (F) than in male (M) hearts, both during normoxia and ischaemia. Ovariectomy attenuated α-adrenergic presynaptic inhibition of NA overflow. During normoxia, presynaptic inhibition of neuronal NA overflow by VS was greater in F than in M hearts but methacholine reduced NA overflow equally in F and M hearts. In conclusion, sympathetic nerve stimulation leads to ischaemic-reperfusion arrhythmias. The antiarrhythmic effect of VS and of dietary polyunsaturated fatty acids cannot be explained by presynaptic modulation of NA release. Cardiac neuronal function, especially sympathetic neurotransmitter release and presynaptic modulation, is affected by the severity of ischaemia, parasympathetic nervous activity and gender.

BACKGROUND: Ischaemic heart disease is the leading cause of mortality and morbidity in the developed world. Cardiovascular magnetic resonance (CMR) is a non-invasive imaging modality providing in vivo myocardial tissue characterisation and quantification. We aimed to validate CMR in the field of interventional cardiology as a tool for guiding patient selection and management to the assessment of the results of interventions both in the acute and chronic settings. METHODS AND RESULTS: We investigated the impact of primary angioplasty delay on the presence and extent of myocardial salvage, microvascular obstruction and infarct size. We found that “time is muscle”, and that shorter time to reperfusion was associated with smaller infarct size (p=0.05), less microvascular obstruction (p=0.04) and a greater amount of salvaged myocardium (p=0.003). Microvascular obstruction was then used as an endpoint in a prospective randomised trial assessing the impact of a thrombectomy device as adjunctive therapy in primary PCI. The incidence and extent of microvascular damage was significantly reduced in the thrombectomy group compared to standard primary PCI (p=0.0005). CMR can identify 2 degrees of microvascular damage: early or persistent microvascular dysfunction. The latter was the strongest predictor of LV remodelling (p=0.03), it was predicted by infarct size (p=0.002), and infarct healing (shrinkage) occurred to a greater extent (p<0.006). We validated the clinical use of CMR perfusion in a cohort of patients with chronic coronary occlusion whose management is currently controversial. CMR identified myocardial viability and inducible myocardial ischaemia in a significant percentage of patients, guided revascularisation that reduced ischaemic burden (p<0.0001) with improvements in left ventricular function (p<0.0001) and health outcome measures (p<0.0001). Finally, improved CMR perfusion image quality was pursued with a new imaging protocol but this demonstrated increased incidence of artefacts (p<0.001) and lower diagnostic accuracy compared to the standard technique. CONCLUSIONS: Cardiovascular magnetic resonance provides in vivo myocardial tissue characterisation that can potentially not only guide treatment but also assess its effects. The result of this work suggests that CMR could emerge as a clinical valuable technique in numerous interventional clinical settings within acute to chronic myocardial ischaemia, in addition to providing surrogate endpoints for clinical trials.