In 2015, American Heart Association (AHA) reported that 1 in 9 deaths are attributed to Heart failure (HF), the number one killer in the world. While advancements in interventional cardiology in conjunction with pharmacotherapies have significantly reduced the rate of mortality following MI, there has been a corresponding rise in chronic heart failure (CHF) in surviving patients, largely attributed to the limited regenerative capacity of the heart and the inadequate healing response. Myocardial ischemic injury triggers an exuberant local and systemic inflammation, and the extent and quality of the cardiac wound healing process is intricately tied to the delicate equilibrium of this inflammatory response. While cardiac regeneration is an important goal, it is imperative in the meantime to explore therapeutic strategies that target these inflammatory mediators of early cardiac repair. These interventions to influence and improve cardiac wound healing can represent a new therapeutic window to halt the progression of heart failure between the few hours that may be used to limit infarct size by reperfusion and an irreversible non-contractile cardiac scar. This dissertation examines three therapeutic delivery strategies aimed at modulating the immune response to enhance cardiac repair in rodent models MI: 1) Polyketal nanoparticles as siRNA delivery vehicles for antioxidant therapy; 2) Spherical nucleic acid particles for anti-inflammatory therapy and; 3) Bioactive PEG (polyethyleneglycol)-based hydrogel for immunomodulation. The work presented here applies novel nucleic acid delivery strategies for cardiac gene silencing and has contributed to new knowledge with regard to modulating the immune response following MI.

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Σκοπός: Ο σκοπός της παρούσας μελέτης ήταν να ερευνηθεί κατά πόσο η ανάσπαση του τμήματος ST και η θετικοποίηση του κύματος Τ στις Q – απαγωγές του ΗΚΓ κατά τη διάρκεια της δοκιμασίας κόπωσης πρό της εξόδου από το νοσοκομείο, μπορούν να συνεισφέρουν στη κλινική αντιμετώπιση των ασθενών με πρόσφατο έμφραγμα μυοκαρδίου. Εισαγωγή: Η κλινική σημασία αυτών των ΗΚΓ ευρημάτων παραμένει αμφισβητούμενη, παρά το γεγονός ότι σε αρκετές μελέτες σχετίζεται με την ύπαρξη μυοκαρδιακής βιωσιμότητας όπως και λειτουργικής αποκατάστασης μετά από επαναγγείωση. Από τη στιγμή που η επιλογή των ασθενών που συμμετέχουν σε κάθε μελέτη μπορεί να εξηγήσει τα διαφορετικά αποτελέσματα, η αξία αυτών των ευρημάτων στη τωρινή εποχή της θρομβόλυσης πρέπει να διευκρινισθεί. Μέθοδος: Στη μελέτη έλαβαν μέρος 101 ασθενείς, ηλικίας 58+11 έτη, με πρόσφατο, πρώτο, ανεπίπλεκτο Q – έμφραγμα μυοκαρδίου (εκ των οποίων 56% ήταν πρόσθια, 57% θρομβολυμένα με κλάσμα εξώθησης αριστεράς κοιλίας 43 + 7%). Οι ασθενείς προ της εξόδου από το νοσοκομείο υποβάλλονταν σε υπομεγίστη δοκιμασία κόπωσης. Ακολούθως, σε απουσία σοβαρής ισχαιμίας, διενεργείτο διαδοχικά μελέτη δυναμικής ηχοκαρδιογραφίας με χρήση δοβουταμίνης (DSE), σπινθηρογράφημα μυοκαρδίου με θάλλιο – 201 (201Tl-SPECT) και αγγειογραφία των στεφανιαίων αρτηριών. Αποτελέσματα: Οι ασθενείς με ανάσπαση του τμήματος ST στη μέγιστη κόπωση έχουν μεγαλύτερης έκτασης εμφράγματα (peak CPK 2351+1465 versus 1671+1132 U/L, p<0.05) και περισσότερο επηρεασμένη συστολική λειτουργία με κριτήριο τον αριθμό των μυοκαρδιακών τμημάτων με συμπεριφορά ουλώδους ιστού τόσο στη δυναμική ηχοκαρδιογραφία με χρήση δοβουταμίνης (p<0.05) όσο και στο σπινθηρογράφημα μυοκαρδίου με θάλλιο – 201 (p<0.01). Η επίπτωση βιωσιμότητας και / ή ισχαιμίας δεν διέφερε στις δύο ομάδες. Τα αποτελέσματα ήταν παρόμοια και στη χαμηλής φόρτισης κόπωση. Η εντόπιση του εμφράγματος στο πρόσθιο τοίχωμα και η παρουσία > 3 τμημάτων με συμπεριφορά ουλής στη DSE ήταν μεταξύ των ανεξάρτητων θετικών προβλεπτικών παραγόντων της ανάσπασης του ST στη μέγιστη άσκηση. Η θετικοποίηση του κύματος Τ απεδείχθει το ίδιο αναποτελεσματική στη πρόβλεψη βιωσιμότητας και / ή ισχαιμίας. Κατά τη διάρκεια της μακρόχρονης κλινικής παρακολούθησης που ακολούθησε (31+13 μήνες), η συχνότητα των συμβαμάτων ήταν χαμηλή (8 % για θάνατο ή μη θανατηφόρο ΟΕΜ) και δεν διέφερε μεταξύ των ομάδων. Συμπέρασμα: Σε ασθενείς με πρόσφατο Q – έμφραγμα μυοκαρδίου, χωρίς κλινικά και ΗΚΓ κριτήρια σημαντικής υπολειπομένης ισχαιμίας, οι ανασπάσεις του διαστήματος ST κατά την δοκιμασία κοπώσεως εκφράζουν την μεγάλη έκταση του εμφράγματος. Η δυνατότητα αυτών των ST/T μεταβολών του ΗΚΓ να συνεισφέρουν στη ανίχνευση βιωσιμότητας και ισχαιμίας και στη διαστρωμάτωση κινδύνου αυτών των ασθενών , αποδεικνύεται χαμηλή. Τά κλασσικά κλινικά κριτήρια που χρησιμοποιούνται και σήμερα αποδεικνύονται ιδιάτερα αποτελεσματικά στη επιλογή των ασθενών χαμηλού κινδύνου. / Objectives: The aim of this prospective study was to investigate whether ST segment elevation and T wave normalization in Q-wave leads on pre-discharge exercise electrocardiogram (ECG) can contribute to patient management after recent myocardial infarction (MI) Background: The clinical relevance of these exercise ECG changes remains controversial despite accumulating evidence of their association with myocardial viability as well as functional recovery after revascularization. Since patient selection may explain the discordant results across the studies, the value of these ST/T abnormalities in the thrombolytic era should be better defined. Methods: One-hundred one patients, aged 58+11 years, with a recent, first, uncomplicated Q-wave MI (56% anterior, 57% thrombolyzed, ejection fraction 43+7%) underwent predischarge, submaximal treadmill testing followed, in the absence of severe ischemia, by dobutamine stress echocardiography, thallium-201 single photon emission computed tomography and coronary angiography. Results: Patients with, as compared with those without ST elevation at peak exercise had more severe infarctions (peak creatine kinase 2351+1465 versus 1671+1132 U/L, p<0.05) and more extensively impaired left ventricular contractility due to scar tissue as based on the number of segments with scar on echocardiography (p<0.05) or scintigraphy (p<0.01). However, the incidence of myocardial viability and ischemia was not different between the two groups. Results were similar for ST elevation at low level exercise. Anterior infarction location and at least three scarred segments on dobutamine stress echocardiography were among the independent predictors of ST elevation at peak ergometric exercise. T wave normalization was similarly inaccurate in identifying viability or ischemia. Over long-term follow-up of 31+13 months, the event rate was low ( 8 % for death or nonfatal MI) and did not differ between groups with or without these exercise-induced ST/T wave changes. Conclusions: In patients after acute, Q-wave MI without severe ischemia according to clinical and standard ECG criteria, exercise-induced ST elevation is associated with larger infarctions. The contribution of these ST/T changes to identify patients with myocardial viability or ischemia and for risk stratification is poor. In-hospital management of these patients based on routine clinical practice is sufficient for selection of a population with a relatively low long-term risk.

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Coronary heart disease (CHD) remains the single leading cause of natural death worldwide. Despite significant advances in the diagnosis and treatment, CHD accounts for 1 out of every 6 deaths in the United States. Myocardial infarct (MI) as a result of CHD causes irreversible damage to the heart through the loss of viable myocardial tissue. Patients surviving the initial MI are at risk of developing heart failure due to lost contractile function and adverse cardiac remodeling. Improvement in the survival rates for MI have led to an increase in the incidence of heart failure, affecting approximately 5 million people in the United States. Although treatment of heart failure has improved, the mortality rates of heart failure remain high with 1 in 5 dying within the first year of diagnosis and 50% dying within 5 years. The cost of caring for heart failure patients ranks number one in Medicare. Oxidative stress plays an important role in the etiology and pathophysiology of CHD and heart failure. The transcription factor Nrf2 is a master regulator of cellular antioxidant defense mechanisms, controlling the expression of numerous antioxidant and detoxification genes through the Antioxidant Response Element (ARE) in the promoter regions. The cytoprotective effects of Nrf2 have been demonstrated in a variety of organs and disease states; however, the role of Nrf2 in the heart and heart disease has not been defined. The work presented here defines roles of Nrf2 in limiting cardiac injury and the progression to heart failure (Chapter II), protecting cardiac myocytes from oxidative stress through the preservation of mitochondria (Chapter III), and mediating the infarct reducing effects of statins, one of the most prescribed pharmacological agent (Chapter IV). In order to investigate a role of Nrf2 in the pathology of ischemic injury in the heart, a mouse model of ischemia and myocardial infarct by occlusion of the left anterior descending coronary artery was used. Nrf2 knockout mice subjected to ischemia/reperfusion injury experienced a larger infarct size than wild-type mice. Furthermore, mice lacking Nrf2 experienced a higher mortality rate and an accelerated progression to heart failure, indicated by severely compromised contractile function and reduced cardiac output, within 10 days following an MI. Morphological examination revealed maladaptive remodeling, including myocyte hypertrophy, heart enlargement, and dilated left ventricle, in Nrf2 KO mice that was absent in WT mice. Analysis of cardiac function by echocardiogram revealed increased left ventricular mass, increased systolic volume, decreased fraction shortening, reduced ejection fraction, and decreased cardiac output in Nrf2 KO mice. Nrf2 KO mice also demonstrated expression of biomarkers of heart failure, such as expression of fetal gene program, with elevated levels of β-MHC, ANF, and BNP mRNA in the myocardium. Interestingly, a lack of immune cell infiltrate and myofibroblasts as well as a deficiency in collagen deposition were observed in the infarcted region of hearts from Nrf2 KO mice. These data indicate that Nrf2 plays an important role in protecting the myocardium from ischemic injury and the progression to heart failure. Lack of Nrf2 response results in deficiency of wound healing and instead initiation of maladaptive remodeling, leading to heart failure. Mitochondria are key sources of reactive oxygen species (ROS) generation, as well as important targets for ROS-induced cell injury. Cardiac myocytes have the highest content of mitochondria among all cell types and can be particularly susceptible to mitochondrial dysfunction due to the high metabolic demand associated with the contractile function of the heart. With cardiomyocytes (CMCs) isolated from neonatal rats and kept under tissue culture conditions, mitochondria exist in elaborated networks. Such networks were replaced by predominately individual punctate mitochondria 24 hours after exposure to a sublethal dose of H₂O₂. Mitochondrial morphology was altered with membrane swelling and disorganization of inner cristae with areas of condensation. Disrupted mitochondrial morphology was associated with a loss of membrane potential and decreased expression of mitochondrial proteins involved in the electron transport chain, such as cytochrome b and cytochrome c. Nrf2 overexpression prevented H₂O₂ from inducing morphological changes in mitochondria and the reduction of cytochrome b and cytochrome c expresssion. Although Nrf2 is known as a transcription factor regulating antioxidant and detoxification genes, Nrf2 overexpression did not significantly reduce the level of protein oxidation as measured by carbonyl formation. Instead, we found that Nrf2 localizes to the outer mitochondrial membrane, suggesting a direct role of Nrf2 in mitochondrial protection. As further evidence of a direct role in mitochondrial protection, a cell-free system of mitochondria isolated from the myocardium of Nrf2 knockout mice were more sensitive to permeability transition, an indicator of mitochondrial dysfunction. Combined, these data suggest that Nrf2 protects mitochondria from oxidant injury likely through direct interaction with mitochondria. In the clinic, statins are now commonly administered for patients experiencing MI or CHD. Statins have become mainstays in the treatment of hypercholesterolemia and atherosclerosis as inhibitors of the rate limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase. In addition, statins have been shown to elicit pleiotropic effects, including plaque stabilization, maintenance of endothelial function, anti-inflammatory actions, and antioxidant capabilities, independent of effects on cholesterol synthesis. Recently, these pleiotropic effects have been implicated in providing acute protection against ischemia and reperfusion injury, which has led to the use of high dose statins clinically before revascularization of an ischemic event. I have found that administration of atorvastatin in mice induced Nrf2 protein levels in the heart, brain, lung, and liver. While atorvastatin reduced infarct size following an MI in wild-type mice, this protective effect was lost in mice lacking Nrf2. Failure of atorvastatin to protect against MI in Nrf2 knockout mice indicates that Nrf2 plays a critical role in mediating the protective effects of acute statin treatment. Nrf2 induction by statins is a novel discovery. In order to understand the mechanism of such statin effect, I used an in vitro cell system, in which a variety of statins, atorvastatin, simvastatin, lovastatin, and pravastatin, were found to elevate Nrf2 protein levels. Elevation of Nrf2 by statins was independent of increased protein stability or transcriptional regulation. Instead, statins increased Nrf2 mRNA association with ribosomal complexes and induced Nrf2 protein through a translational mechanism. Recruitment of Nrf2 mRNA to ribosomes and induction of Nrf2 protein was dependent on activation of PI3 kinase. These studies provide evidence that Nrf2 plays a critical role in protecting cardiac myocytes and the heart from oxidative stress and MI. In the absence of Nrf2, mice experienced worse cardiac injury following MI and quickly advanced to heart failure. Mechanistically, this work has identified a novel role of Nrf2 in preserving mitochondrial morphology and integrity during oxidative stress through a direct interaction with the outer mitochondrial membrane. Finally, a newly defined role of Nrf2 induction by statins in mediating protection against MI by acute statin therapy indicates that modulation of Nrf2 may represent a viable pharmacological target for cardiac protection in humans.

Background: Heart disease remains the leading cause of morbidity and mortality worldwide. Typical symptoms of heart disease are lacking in nearly one-third of patients with acute myocardial infarction (AMI). Simplified ECG assessment via lead I by various handheld and smartphone-based electrocardiogram (ECG) devices may be used for rapid screening without the traditional delays, privacy concerns, or costs of 12-lead ECG recording in patients who are asymptomatic or have atypical symptoms. The purpose of this DNP project was to compare ECG data from lead I to the standard 12-lead ECG to determine its potential efficacy as an early screening tool for AMI. Methods: This project compared ECGs in 84 patients with cardiac diagnoses, 66 (78.6%) had acute myocardial infarction with abnormal 12-lead ECGs and 18 (22.6 %) were without AMI or abnormal findings on the standard 12-lead ECG. ST-segment and T-wave amplitude and characteristics were compared between infarction territories. Results: Lead I in those with abnormal ECGs had a mean ST-segment deviation from baseline of 1.0 ± 0.7 mm, which was significantly different than those with normal ECGs (mean 0.1 ± 0.3 mm)(p = .000). The mean T-wave amplitude in patients with abnormal ECGs was 0.7 ± 1.3 mm, which was a significant reduction compared to those with normal ECGs group of 2.2 ± 1.5 mm (p = .000). Conclusion: ST-segment deviations and reduction in T-wave amplitude are significant indicators of acute myocardial infarction in lead I ECG, the same vector used in handheld single-lead ECG devices.

Syfte: Syftet med studien var att undersöka hur vanligt det är med stress och depression efter genomgången hjärtinfarkt. Vidare planeras att undersöka samband mellan stress och depression samt också eventuella skillnader mellan könen för hur stress och depression upplevs efter genomgången hjärtinfarkt. Metod: Patienter som varit inlagda för hjärtinfarkt vid Akademiska sjukhuset i Uppsala inkluderas i studien. Patienterna skall ha genomgått hjärtinfarkt och/eller PCI och/eller CABG. De tre enkäterna Vardagslivets stress, Känsloläge samt MADRS användes. Frekvenser och korrelationer beräknades med IBM SPSS Statistics version 19. Tillstånd för studien söktes hos klinikchef. Resultat: Antalet patienter i studien är 18. Förekomsten av självskattad depression efter hjärtinfarkt uppmättes till 6%. Självskattad stress varierade mellan patienterna, dock skattade 33%, höga nivåer av stress. Skillnader i hur kvinnor och män upplever stress och depression efter genomgången hjärtinfarkt kunde inte bestämmas i denna studie. Ett signifikant svagt samband mellan stress och depression visades dock (r = 0,52, p= 0,029). Slutsats: Patienter med nyligen genomgången hjärtinfarkt kan uppleva depression i efterförloppet. Att behandla depressionen kan ge ökad livskvalitet. / Objective: The aim of this study was to investigate the frequency of depression and stress after a myocardial infarction. Other aims were to study the relationship between stress and depression and also differences between the sexes in their experience of stress and depression after a myocardial infarction. Method: Patients being hospitalized at Akademiska sjukhuset in Uppsala, Sweden were included in the study. Patients with a myocardial infarction and/or coronary angioplasty and/or coronary bypass surgery were included. Three questionnaires The Everyday Life Stress Scale, The Depressive Mood Scale and MADRS where used. Frequencies and correlations were calculated using IBM SPSS Statistics version 19. Permission for the study was sought from the clinic manager. Result: 18 participants were included in the study. The frequency of self estimated depression after a myocardial infarction was 6%. The frequency of self estimated stress varied throughout the population but 33% estimated their stress as high. Differences in stress and depression between women and men could not be determined in this study. A weak significant correlation between stress and depression was however shown (r = 0,52, p= 0,029). Conclusion: Patients who have gone through a myocardial infarction can experience depression afterwards. Treating depression can improve quality of life.

In the present study clinical performance of new highly cardiospecific biochemical markers of myocardial injury was investigated and these markers were compared with conventional enzymes. The multimarker risk assessment score index, including biochemical markers of myocardial injury, inflammation and haemostasis, was developed for the prognosis of patients after ACS. The prognostic value of BNP concentration changes in predicting LV remodeling and dysfunction after MI was evaluated along with other biochemical markers of myocardial injury.