Background: Patients with pre-existing vascular disease are known to have worse outcomes after acute myocardial infarction (AMI). However, there is limited data for outcomes stratified by type and number of vascular territories involved. Methods: Using the Nationwide Inpatient Sample (2015–2017), we examined outcomes of AMI in patients with pre-existent vascular disease stratified by number as well as types of diseased beds including all five major vascular sites: cardiac, cerebrovascular, renal, aortic and peripheral vascular disease (PVD). Multivariable logistic regression was used to determine the adjusted odds ratios (aOR) of adverse outcomes and invasive procedure utilization. Results: Out of 2,184,614 AMI admissions, 49.7% had pre-existent vascular disease. The odds of major adverse cardiovascular and cerebrovascular events (MACCE), mortality, ischemic stroke and major bleeding incrementally increased and was highest in those with ≥3 vascular sites involved (aOR for MACCE 1.16, CI 1.13–1.19; mortality 1.3, CI 1.26–1.34; stroke 1.15, CI 1.1–1.2; major bleeding 1.21, CI 1.16–1.25). Amongst those with a single pre-existent diseased vascular bed, the adjusted odds of MACCE appeared to be higher in those with PVD (1.28, CI 1.26–1.31), aortic disease (1.24, CI 1.19–1.29), and cerebrovascular disease (1.22, CI 1.2–1.25). Patients with pre-existent vascular disease had a lower overall likelihood of undergoing invasive revascularization procedures. Conclusions: Approximately half of the population presenting with AMI have pre-existent vascular disease. There is an incremental increase in adverse outcomes with increasing number of diseased vascular beds, with further differences in outcomes and utilization of invasive procedures based on sub-types of sites involved.

Aims: There are limited data on the management and outcomes of chronic liver disease (CLD) patients presenting with acute myocardial infarction (AMI), particularly according to the subtype of CLD. Methods: Using the Nationwide Inpatient Sample (2004-2015), we examined outcomes of AMI patients stratified by severity and sub-types of CLD. Multivariable logistic regression was performed to assess the adjusted odds ratios (aOR) of receipt of invasive management and adverse outcomes in CLD groups compared with no-CLD. Results: Of 7 024 723 AMI admissions, 54 283 (0.8%) had a CLD diagnosis. CLD patients were less likely to undergo coronary angiography (CA) and percutaneous coronary intervention (PCI) (aOR 0.62, 95%CI 0.60-0.63 and 0.59, 95%CI 0.58-0.60, respectively), and had increased odds of adverse outcomes including major adverse cardiovascular and cerebrovascular events (1.19, 95%CI 1.15-1.23), mortality (1.30, 95%CI 1.25-1.34) and major bleeding (1.74, 95%CI 1.67-1.81). In comparison to the non-severe CLD sub-groups, patients with all forms of severe CLD had the lower utilization of CA and PCI (P <.05). Among severe CLD patients, those with alcohol-related liver disease (ALD) had the lowest utilization of CA and PCI; patients with ALD and other CLD (OCLD) had more adverse outcomes than the viral hepatitis sub-group (P <.05). Conclusions: CLD patients presenting with AMI are less likely to receive invasive management and are associated with worse clinical outcomes. Further differences are observed depending on the type as well as severity of CLD, with the worst management and clinical outcomes observed in those with severe ALD and OCLD.

Excerpt: Dr Meier and colleagues1 present intriguing data that individuals with a first acute myocardial infarction (AMI) were less likely than matched controls to have used tetracycline antibiotics or quinolones in the previous 3 years. The authors raise the possibility that organisms susceptible to these antibiotics may be involved in the pathogenesis of coronary heart disease. However, several methodological limitations lead to other possible explanations for the observed associations.

Ischemic cardiomyopathies, such as myocardial infarction (MI), are a leading cause of heart failure in both men and women throughout the world. Despite timely intervention post-MI, the loss of viable myocardium can lead to global remodeling and loss of function in many patients due to the limited regenerative potential of heart tissue. Thus, there is a critical need to better understand the repair mechanisms involved and to develop new preventative and reparative therapies for treating MI and preventing progression to heart failure. Methylglyoxal (MG) is a highly reactive dicarbonyl metabolite of glycolysis and the main precursor of advanced glycation end-products (AGEs), which can cause oxidative stress and wound healing delay. MG was shown to play an important causative role in the cellular changes, adverse remodeling and functional loss of the infarcted heart. This suggests MG as a target for therapy to restore cell-ECM signaling, inhibit oxidative stress and improve cardiac function post-MI. The aim of this PhD project was to develop new biomaterial therapies that can reduce the effects of MG, decrease oxidative stress, enhance electrical conductivity and improve cardiac contractility and function post-MI. There were three primary objectives: 1) To develop an injectable antioxidant and hydrogel system for minimizing the effects of MG and promoting cardiac repair post-MI; 2) To synthesize a nanoparticle system for targeted delivery of Glyoxalase-1 (Glo1) enzyme to cardiac tissue for reducing the accumulation of MG, limiting adverse remodeling and preserving cardiac function following MI; and 3) To design a sprayable nano-therapeutic that uses surface engineered custom designed multi-armed peptide grafted nanogold for on-the-spot coating of infarcted myocardial surface for increasing contractility of the myocardium post-MI. In the first study, a fisetin-loaded collagen type I hydrogel (fisetin-HG) was injected intramyocardially in mice at 3h post-MI, and compared to fisetin-alone, hydrogel-alone, or saline treatment. The fisetin-HG treatment increased the level of glyoxalase-1 (the main MG-metabolizing enzyme), reduced MG-AGE accumulation, and decreased oxidative stress in the MI heart, which was associated with smaller scar size and improved cardiac function. Treatment with fisetin-HG also promoted neovascularization and increased the number of pro-healing macrophages in the infarct area, while reducing the number of pro-inflammatory macrophages. The second study revealed that when delivered intravenously at 3h post-MI, our Glo1-loaded nanoparticles specifically targeted the damaged cardiac tissue, led to improved cardiac function, protected cell viability and limited infarct expansion by reducing oxidative stress post-MI. Lastly, the third study showed that, when applied at 1-week post-MI, the sprayed nanogold treatment remained at the treatment site for at least 28 days with no significant off-target organ infiltration. Our results demonstrated a remarkable increase in cardiac function, muscle contractility, and myocardial electrical conductivity post-MI. Overall, these findings show that reducing MG levels through both increased activity of Glo1 and direct MG scavenging as well as increasing cardiac contractility may be a promising approach to limit adverse cardiac remodeling, prevent damage, and preserve the function of the infarcted heart

Ataxia-telangiectasia mutated kinase (ATM), a serine/threonine kinase primarily located in the nucleus, is typically activated in response to DNA damage. Individuals with mutations in ATM gene develop a disease called Ataxia telangiectasia (AT). These individuals are more susceptible to ischemic heart disease and metabolic disorder. Our lab has previously shown that ATM plays a critical role in β-adrenergic receptor (β-AR) - and myocardial infarction (MI)-stimulated myocyte apoptosis and cardiac remodeling. This study tested the hypothesis that ATM plays a critical role in cardiac autophagy and glucose metabolism following MI and ischemia, respectively. Early during MI (4 hours after its onset) and 4 hours post-treatment with ATM inhibitor KU-55933, ATM deficiency resulted in autophagic impairment in the heart and in cardiac fibroblasts, respectively. Such autophagic changes in the heart and in cardiac fibroblasts associated with the activation of GSK-3β and mTOR, and inactivation of Akt and AMPK. ATM deficiency also augmented autophagy in the infarct region of the heart 28 days post-MI as well as in cardiac fibroblasts treated with ATM inhibitor KU-55933 for 24 hours. Autophagic changes in the infarct region during ATM deficiency associated with enhanced Akt, Erk1/2, and mTOR activation. Additionally, the lack of ATM accelerated glycolysis and gluconeogenesis and augmented TCA cycle metabolism under non-ischemic conditions. Following a 20 minute global ischemic period, the glycolytic pathway, not the gluconeogenic pathway, was down-regulated during ATM deficiency which was found to be associated with alterations in TCA cycle metabolism. Such metabolic rearrangements associated with changes in the phosphorylation of Akt, GSK-3β, and AMPK alongside alterations in Glut4 protein expression. Thus, ATM deficiency impairs autophagy early after the onset of MI and in cardiac fibroblasts treated with ATM inhibitor KU-55933 for 4 hours. In contrast, ATM deficiency appears to augment autophagy late post-MI in the infarct region of the heart and in cardiac fibroblasts treated with ATM inhibitor KU-55933 for 24 hours. Lack of ATM alters glucose and TCA cycle metabolism with and without ischemia. Such findings implicate ATM as a key player in autophagic changes in the heart in response to MI as well as in glucose metabolism under non-ischemic and ischemic conditions.

Transplanted embryonic stem (ES) cells following myocardial infarction (MI) contribute to limited cardiac repair and regeneration with improved function. Therefore novel strategies are still needed to enhance the efficacy by which ES cells differentiate into cardiac cell types and inhibit adverse remodeling in the infarcted myocardium. Our studies evaluate whether genetic manipulation of transplanted ES cells employing miR- 1, a pro-cardiac microRNA, and TIMP-1, an anti-apoptotic and anti-fibrotic protein, will enhance cardiac myocyte differentiation, inhibit native cardiac apoptosis, and reduce fibrosis in the infarcted myocardium. Furthermore, we assess levels of associated pro- (caspase-3, PTEN) and anti-(Akt) apoptotic proteins as well as a pro-fibrotic protein (MMP-9) in the post-MI and cell transplanted heart. microRNAs (miRs) have emerged as critical regulators of various physiological processes including development, differentiation, metabolism, and death. Indeed, miR- 1 plays an integral role in early cardiac development in Drosophila and mice as well as mediates differentiation of cardiac myocytes in vitro. To that end, we generated ES cells overexpressing miR-1 (miR-1-ES cells), transplanted them into the infarcted myocardium, and evaluated their impact on cardiac myocyte differentiation, myocardial repair, and left ventricular dysfunction post-MI. We provide evidence demonstrating enhanced cardiac myocyte commitment of transplanted miR-1-ES cells in the mouse infarcted heart as compared to ES cell and culture media transplanted hearts. Assessment of apoptosis revealed overexpression of miR-1 in transplanted ES cells protected host myocardium from MI-induced apoptosis through activation of p-Akt and inhibition of caspase-3, PTEN, and superoxide anion production. A significant reduction iv in interstitial and vascular fibrosis was quantified in miR-1-ES and ES cell transplanted groups compared with control MI. However, no statistical significance between miR-1- ES cell and ES cell groups was observed. Finally mice receiving miR-1-ES cell transplantation post-MI had significantly improved heart function compared with respective controls. Our data suggests miR-1 drives cardiac myocyte differentiation from transplanted ES cells and inhibits apoptosis post-MI ultimately giving rise to enhanced cardiac repair, regeneration, and function. Next, we assessed the role of miR-1-ES cells in a chronic model of MI as research has shown that apoptosis occurs not only hours but months following ischemia. 4 weeks following transplantation into the infarcted myocardium, we provide evidence demonstrating reduced cardiac apoptosis in miR-1-ES cell transplanted hearts compared to respective controls. Moreover, we show significant elevation of p-Akt levels and diminished PTEN levels in hearts transplanted with miR-1-ES cells as determined by enzyme-linked immunoassays. Finally, using echocardiography, we reveal mice receiving miR-1-ES cell transplantation post-MI had significantly improved cardiac function compared with animals transplanted with ES cell and culture media. Our data suggests that miR-1, when overexpressed in transplanted ES cells, has the capacity to inhibit apoptosis long term while attenuating contractility loss. In addition to enhancing cardiac-specific donor cell differentiation, improving the efficacy by which stem cells promote cell survival and repair in the host myocardium is imperative in the pursuit of refining and optimizing stem cell therapy. To that end, we overexpressed TIMP-1, an endogenous inhibitor of apoptosis and fibrosis, in ES cells (TIMP-1-ES cells), transplanted them into infarcted myocardium, and evaluated their v impact on adverse cardiac remodeling. Immunofluorescence, TUNEL staining, caspase-3 activity, ELISAs, histology, and echocardiography were used to assess apoptosis, fibrosis, and heart function. Hearts transplanted with TIMP-1-ES cells demonstrated a reduction in apoptosis as well as an increase in p-Akt activity compared with ES cells or culture media controls. Interstitial and vascular fibrosis was significantly decreased in the TIMP-1-ES cell group compared to controls. Furthermore, MMP-9, a key pro-fibrotic protein, was significantly reduced following TIMP-1-ES cell transplantation. Echocardiography data showed fractional shortening and ejection fraction were significantly improved in the TIMP-1-ES cell group compared with respective controls. Our data suggest that transplanted ES cells overexpressing TIMP- 1 attenuate adverse myocardial remodeling and improve cardiac function compared with ES cells. Overall, our data suggest that genetic manipulation of ES cells following transplantation in the infarcted heart enhances cardiac myocyte differentiation, inhibits apoptosis and fibrosis as well as improves cardiac function.

Doxorubicin (DOX) is the antineoplastic drug of preference used to treat a wide variety of malignancies, with high survival rates among treated patients. However, the benefits of this drug have become less appealing due to the side effects that occur such as DOX-induced cardiomyopathy (DIC) and an increased risk of myocardial infarction (MI). Therefore, there is an urgent need to explore the therapeutic options to treat DIC. In this context, adult stem cells have been used as a source to reduce cardiomyocyte apoptosis in DIC; however, the effects of transplanted embryonic stem (ES) cells and induced pluripotent stem (iPS) cells in DIC post MI are unknown. As a result, we wanted to understand how transplanted ES and iPS cells and the factors released by them inhibit apoptosis and improve cardiac function in DIC post MI. C57BL/6 mice were divided into five groups: Sham, DOX-MI, DOX-MI+cell culture (CC) media, DOX-MI+ES cells, and DOX-MI+iPS cells. Mice were treated with DOX (12 mg/kg, cumulative dose) followed by left coronary artery ligation to induce MI. ES or iPS cells (5 x 104 ) were delivered into the peri-infarct region. At day 14 post-MI, echocardiography was performed, mice sacrificed, and hearts harvested for further analyses. To investigate if protective effects are provided by factors released from ES and iPS cells in DIC, we performed in vitro studies using condition media (CM) obtained from ES or iPS cells to treat DOX-induced cardiotoxicity in H9c2 cells. Our data reveal that apoptosis was significantly inhibited in the ES and iPS cell transplanted hearts as well as ESCM and iPSCM treated cells compared with the untreated controls. Furthermore, a significant increase in levels of Notch-1, Hes1, and pAkt survival protein were observed. Decreased levels of PTEN, a negative regulator of Akt pathway, along with improved iv heart function were also observed in the stem cell transplanted groups. In conclusion, our data show that transplantation of ES and iPS cells blunt DOX-induced apoptosis in vivo, which is associated with improved cardiac function. Moreover, decreased apoptosis in both in vitro and in vivo models is mediated by the Notch pathway.

Bakgrund: Hjärtinfarkt är en av de vanligaste förekommande sjukdomarna som framför allt drabbar vuxna och är en av de främsta orsakerna till ökad dödlighet i Sverige och över hela världen. Att uppleva en hjärtinfarkt är en händelse som förändrar livet. Genom att beskriva kvinnors upplevelser av hur deras liv påverkas efter en hjärtinfarkt och kan sjuksköterskor ge personcentrerad vård och hjälpa patienter återställa hälsa och välbefinnande. Syfte: Syftet var att beskriva kvinnors upplevda livssituation efter att ha genomgått en hjärtinfarkt. Metod: En litteraturöversikt där 14 artiklar granskades och analyserades. Resultat: Litteraturöversiktens centrala fynd sammanställdes i följande kategorier. Begränsningar i vardagen, känslor av rädsla och osäkerhet, förlust av identitet, förändringar i relationer och det sexuella livet, och anpassning och acceptans till det nya livet. Sammanfattning: Litteraturöversikten visar att många kvinnor upplever förändringar i sin identitet och självbild till följd av sin hjärtinfarkt eftersom att de måste anpassa sig till de nya livssituationerna och inte längre kan leva som de brukade. Förändringar i relationer och sexliv förekommer också hos många kvinnor som konsekvens av den rädsla och begränsningar de upplever efter en hjärtinfarkten. Många kvinnor har också svårt att anpassa sig till sitt nya liv och hitta en balans på grund av alla dessa faktorer. / Background: Heart attack, or myocardial infarction, is one of the most common diseases that mainly affect adults and is one of the most common causes of mortality in both Sweden and globally. Experiencing a heart attack is a life-changing event. By exploring women’s experiences of how their lives are affected by heart attacks nurses can provide person-centered care and help patients restore their health and well-being. Aim: The aim was to describe women’s lived experiences of their life situations after a heart attack. Method: A literature review where 14 articles were reviewed and analyzed. Results: The central findings of this literature review were compiled in the following categories; limitations in the everyday life, emotions of fear and anxiety, loss of identity, changes in relationships and the sexual life, and adaptation and acceptance of the new life. Summary: This literature review indicates that many women experience changes in their identity and self-image as a result of their heart attack because they have to adapt to new life situation and cannot live as they used to. Changes in relationships and the sexual life are also common among women as consequences of the fear and limitations they experience following their heart attacks. Many women also find it difficult to adapt to a new life and find balance because of all these factors.

Rationale: G protein-coupled receptor (GPCR) kinases (GRKs) are important regulators of cardiac function whose primary role is the phosphorylation of GPCRs and attenuation of downstream signaling, and GRK2 is upregulated after cardiac stress, injury, and during heart failure (HF). Recent studies have identified novel non-GPCR roles for GRKs such as cytoskeletal assembly, insulin signaling, fibrosis and pro-death signaling. One of the most compelling discoveries regarding novel roles of GRK2 in HF pathogenesis is its mitochondrial translocation (mtGRK2) following cardiac injury, which is associated with increased ROS production, decreased FA metabolic oxygen consumption, and pro-death signaling. Moreover, this localization is dependent on phosphorylation of serine 670 (S670) by kinases such as ERK1/2. Of note, expression of a GRK2 C-terminus peptide, βARKct, which contains S670 but no kinase domain or activity, is cardioprotective following injury in part due to inhibition of endogenous mtGRK2. This is significant because growing evidence demonstrates that cardiomyocyte metabolism is regulated by levels and activities of individual mitochondrial proteins Objective: This study sought to identify mitochondrial proteins which GRK2 interacts with either basally or after injury- or stress-induced translocation, and to determine whether functional regulation of mitochondrial function via phosphorylation of these proteins contributes to the phenomenon of bioenergetic defects during the development of HF. Methods and Results: Co-immunoprecipitation of GRK2 in vitro from primary ventricular cardiomyocytes and a human transformed cardiomyocyte-derived cell line was followed by liquid-chromatography mass-spectroscopy identification of all GRK2- interacting proteins. We followed this with proteomics analysis using DAVID and iv Ingenuity software to identify main pathways altered by GRK2 during stress or injury, focusing on mitochondrial dysfunction which revealed that GRK2 interacts with all major components of the electron transport chain (ETC). Using recombinant proteins as well as in vitro and in vivo models of myocardial infarction (MI), we demonstrate that GRK2 is able to phosphorylate the catalytic barrel of mitochondrial ATP synthase (complex V). Moreover, reduction of GRK2 levels in vivo using a GRK2 knockdown mouse model appears to protect against injury-induced bioenergetic deficits, whereas increased GRK2 levels in a transgenic GRK2 overexpression mouse model reveals both baseline deficits in ATP production as well as worsened post-MI outcomes. Conclusions: These collective data highlight the significance of the mitochondrial GRK2 interactome as a driver of cardiac bioenergetic deficits, particularly as a response to MI injury which progresses to HF. Given the current lack of effective HF treatments, this highly novel mechanism of GRK2 regulation of the mitochondrial ETC emphasizes the need for GRK2-targeting therapies for treating HF. / Molecular & Cellular Biosciences

Atherosclerosis is a major cause of cardiovascular disease, which is among the leading causes of death globally. Elevated plasma concentration of low density lipoprotein (LDL) cholesterol is a risk factor for atherosclerosis, while a high plasma level of high density lipoprotein (HDL) cholesterol is considered protective. Uptake of HDL cholesterol by hepatocytes during reverse cholesterol transport, and athero-protective signaling induced by HDL in other cells are mediated by the scavenger receptor class B, type 1 (SR-B1). SR-B1 deficiency in mice that are susceptible to atherosclerosis results in exacerbation of atherosclerosis, and in mice with mutations in apolipoprotein E (apoE), renders mice uniquely susceptible to occlusive coronary artery (CA) atherosclerosis and myocardial infarction. In this thesis, the impact of a lack of SR-B1 on the development of atherosclerosis is characterized in otherwise wild type mice, and in mice that also lack the LDL receptor (LDLR). We demonstrate that after prolonged feeding of a high fat, high cholesterol cholate-containing diet, SR-B1 knockout (KO) mice develop similar levels of diet-induced atherosclerosis to LDLR KO mice and apoE KO mice in traditionally susceptible arteries, and significantly more atherosclerosis in arteries that are typically resistant to plaque development, such as the CAs. SR-B1/LDLR double KO mice develop extensive occlusive CA atherosclerosis accompanied by myocardial infarction, and exhibit reduced iv survival compared to LDLR KO control mice when fed a variety of atherogenic diets. In both SR-B1 single KO and SR-BI/LDLR dKO mice, CA atherosclerosis is accompanied by splenomegaly, elevated numbers of circulating leukocytes and increased expression of VCAM-1 in CA endothelium. Interestingly, removal of the spleen has no effect on circulating leukocyte numbers or atherosclerosis in SR-B1/LDLR dKO mice, suggesting the enlarged spleens in SR-B1 deficient mice do not influence atherosclerosis in these animals. We conclude that SR-B1 is important for the protection against atherosclerosis in mice, particularly in CAs. This is likely through roles in multiple cell types including hepatocytes, endothelial cells and bone marrow-derived cells. Future studies should focus on evaluating the impact of cell-specific SR-B1 activity in different cell types on murine atherosclerotic CA disease. / Thesis / Doctor of Philosophy (PhD)