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.

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lschemic disease in form of ischemic heart disease (IHD), ischemic stroke and peripheral arterial disease (PAD) due to atherosclerosis represents a massive clinical and economic burden to healthcare and is currently the number one cause of death in the world. Treatment modalities for peripheral arterial disease include bypass surgery involving autologous vein or synthetic materials such as ePTFE. Long term patency of small diameter vascular grafts used for infra-inguinal reconstructions, however, is below 50 % 5 years after implantation. Therefore, novel vascular graft concepts and materials are needed. The concept of transmural in vivo endothelialisation of vascular grafts holds great promise for increasing long term patency. To achieve complete luminal endothelial cell coverage and optimal integration of the porous synthetic graft material into the host tissue, transmural ingrowth of tissue and vasa vasorum might have to be facilitated. Since VEGF1ss and PDGF-BB are growth factors known to stimulate and consolidate angiogenesis, this PhD thesis hypothesized, that neovascularisation of porous polyurethane (PU) can be increased by delivery of vascular endothelial growth factor (VEGF1ss) and platelet derived growth factor (PDGF-BB). To prove this hypothesis, subcutaneous implantation of PU discs was established as a valid, reproducible, relatively simple and quantifiable neovascularisation model. Three different ways of growth factor delivery were investigated. The gene encoding for human VEGF15s was cloned into the genome of adeno associated viruses (AAV), which served as a vector for gene transduction of autologous wound healing cells in vivo using the "Gene Activated Matrix" approach. Genetically modified matrix embedded AAV-VEGF155 was loaded into porous PU and transduced autologous ingrowing wound cells. In contrast to the excellent transduction efficiency in myocytes, AA V showed a poor tropism for wound healing cells. The second approach to increase neovascularisation into porous PU was the surface modification of PU by covalent attachment of nitrous acid degraded heparin. Neovascularisation into the biomaterial was increased by 77 % after 10 days of subcutaneous implantation. Since certain angiogenic growth factors show a high affinity for heparin, additional loading of heparin surface modified PU with VEGF165 increased neovascularisation even further up to 115 % at 10 days compared to control. Dual growth factor delivery of VEGF 165 and PDGF-BB not only initiated increased vascularisation of porous PU, but also created a stable vascular network 2 months after implantation. In contrast, PU loaded with VEGF165 alone showed regression of total vascular area of 61 % compared to vascular area at 10 days. Thirdly, to study the effects of controlled, prolonged growth factor delivery, a "Neovascularisation Construct" was developed which was implanted subcutaneously in rats. The construct consisted of an osmotic mini pump and a tube of porous PU lined with ePTFE, into which a defined amount of VEGF16s was pumped for 10 days. After implantation, granulation tissue was growing into the pores of the PU and neovascular area was increased up to 265 % compared to PBS control. Furthermore, using different growth factor concentration, a dose dependency was shown. In addition, this thesis investigated the functional perfusion of the micro vascular network growing into PU by four different vascular quantification techniques. lntravital perfusion with biotinylated lycopersicon esculentum followed by microscopical analysis, vascular corrosion casting quantified by scanning electron microscopy as well as the novel micro-CT analysis of silicone rubber perfused vessels were compared to conventional immunhistochemical analysis of endothelial cells by CD31. Interestingly, PBS perfused "Neovascularisation Constructs" showed a relatively poor perfusion; therefore CD31 immunohistochemistry "overestimated" functional neovascularisation 3 fold. All perfusion techniques indicated a strong effect of VEGF 165 delivery on vessel perfusion (10 to 20 fold increases of vascular area and volume compared to PBS control). Micro-CT scanning was shown to be an excellent tool to study micro vascular networks in a three-dimensional fashion across the whole length of the sample in a limited amount of time and to provide reliable and reproducible data on vessel density, vascular volume, and connectivity. Since resolution is still limited today to about 10 μm using a commercially available bench top scanner, this new technology still needs to be complemented by immunohistochemistry and perfusion studies such as lectin perfusion and corrosion casting. In summary, the induction of neovascularisation was achieved by heparin surface modification alone, which was even increased through additional delivery of growth factors into the biomaterial PU. The development of a stable micro vascular network at 2 months was achieved and the functionality was shown using four different, independent techniques including the novel micro-CT scanning of neovascularisation into biomaterials. Towards the development of an in vivo, spontaneously and transmurally endothelialising vascular graft with superior long-term patency further investigations are necessary. As an initial step, increased spontaneous neovascularisation of the possible graft material polyurethane was achieved. Future steps are clearly indicated to study the translation of increased neovascularisation of the biomaterial polyurethane towards increased endothelialisation in a vascular graft model.

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Dengue virus infection affects the heart structurally and functionally. Clinical manifestations of cardiac complications secondary to dengue virus infection vary from self-limiting arrhythmias to severe myocardial infarction, leading to hypotension, pulmonary edema, and cardiogenic shock. However, we report a case of dengue hemorrhagic fever (DHF) complicated by a complete heart block. A female with DHF due to dengue virus serotype 2, presented to the emergency department with fever, headache, rash, and fatigue followed by an episode of syncope. She was found to have a third-degree atrioventricular block, with pulseless polymorphic ventricular tachycardia. Patient was resuscitated and a temporary trans-venous pacemaker was placed. She reverted back to normal sinus rhythm after 4 days of syncope and was subsequently discharged from the hospital after complete resolution of symptoms, without the need for a permanent pacemaker. Physicians are warranted to have high index of suspicion for dengue virus infection as an etiology in patients with acute cardiovascular compromise, especially in tropical areas.

Background-Heart failure (HF) is the leading cause for hospital readmission. Hospice care may help palliate HF symptoms but its association with 30-day all-cause readmission remains unknown. Methods and Results-Of the 8032 Medicare beneficiaries hospitalized for HF in 106 Alabama hospitals (1998-2001), 182 (2%) received discharge hospice referrals. Of the 7850 patients not receiving hospice referrals, 1608 (20%) died within 6 months post discharge (the hospice-eligible group). Propensity scores for hospice referral were estimated for each of the 1790 (182+1608) patients and were used to match 179 hospice-referral patients with 179 hospice-eligible patients who were balanced on 28 baseline characteristics (mean age, 79 years; 58% women; 18% non-white). Overall, 22% (1742/8032) died in 6 months, of whom 8% (134/1742) received hospice referrals. Among the 358 matched patients, 30-day all-cause readmission occurred in 5% and 41% of hospice-referral and hospice-eligible patients, respectively (hazard ratio associated with hospice referral, 0.12; 95% confidence interval, 0.06-0.24). Hazard ratios (95% confidence intervals) for 30-day all-cause readmission associated with hospice referral among the 126 patients who died and 232 patients who survived 30-day post discharge were 0.03 (0.04-0.21) and 0.17 (0.08-0.36), respectively. Although 30-day mortality was higher in the hospice referral group (43% versus 27%), it was similar at 90 days (64% versus 67% among hospice-eligible patients). Conclusions-A discharge hospice referral was associated with lower 30-day all-cause readmission among hospitalized patients with HF. However, most patients with HF who died within 6 months of hospital discharge did not receive a discharge hospice referral.

Background: The incidence of ventricular fibrillation (VF) out-of-hospital cardiac arrest (OHCA) treated by first responders has declined over the past decade. Since VF OHCA occurs primarily in the setting of severe coronary artery disease, primary and secondary prevention strategies may in part account for the decline. However, such strategies may not have a similar impact on non-ischemic arrest. Methods: All Rochester Minnesota residents who presented with a VF OHCA from 1991 to 2004, treated by emergency medical services (EMS), were included in the study. Incidence rates were calculated based on the population for Rochester during the time period. Changes over time were tested using Poisson regression models. The significance of the trends was estimated according to the Mantel-Haenszel test for association, and two-tailed p-values reported. Results: The overall incidence of EMS-treated VF OHCA in Rochester during the study period was 10.6 per 100,000 (95% CI 9.1-11.8). The incidence decreased significantly (p < 0.001) over the study period [1991-1994: 18.2/100,000 (95% CI 13.4-21.9); 1995-1999: 11.8/100,000 (95% CI 10.4-17.9); 2000-2004: 8.7/100,000 (95% CI 6.0-13.0)]. The incidence of VF OHCA with ischemic heart disease also declined [1991-1994: 13.4/100,000 (95% CI 8.9-16.9); 1995-1999: 11.1/100,000 (95% CI 8.2-15.9); 2000-2004: 5.5/100,000 (95% CI 3.8-8.2), p < 0.001]. In contrast, the incidence VF OHCA with non-ischemic heart disease increased [1991-1994: 2.1/100,000 (95% CI 1.13-3.1); 1995-1999: 2.3/100,000 (95% CI 1.9-3.7); 2000-2004: 2.9/100,000 (95% CI 2.0-3.4), p < 0.001]. Conclusion: The incidence of VF OHCA is declining. The decline is attributable to the reduction of VF cardiac arrest with ischemic heart disease; suggesting an impact of treatment strategies targeted at coronary artery disease. The relative increasing incidence of non-ischemic VF OHCA suggests that more efforts are required to minimize mortality in this cohort population.

Osteopontin (OPN) expression increases in the heart during hypertrophy and heart failure. Here, we studied the role of OPN in pressure overload-induced hypertrophy and analyzed the signaling pathways involved in hypertrophy. Aortic banding (AB) was performed in a group of wild-type (WT) and OPN knockout (KO) mice to induce pressure overload. Left ventricular (LV) structural and functional remodeling was studied 1 month after AB. AB increased OPN and β1 integrin (a receptor for OPN) protein expression in WT-AB group. Hypertrophic response as measured by increased heart weight-to-body weight ratio and myocyte cross-sectional area was significantly increased in WT-AB and KO-AB groups when compared with their respective shams. However, the increase was significantly higher in WT-AB. Re-expression of atrial natriuretic factor was only detected in WT-AB group. LV end-diastolic pressure-volume curve obtained using Langendorff perfusion analysis exhibited a leftward shift in WT-AB group, not in KO-AB. LV-developed pressures measured over a range of LV volumes were significantly increased in WT-AB, not in KO-AB mice. Increased phosphorylation of c-Jun N-terminal kinases, p38 kinase, Akt, and glycogen synthase kinase-3β was significantly higher in WT-AB when compared with KO-AB group. Increased OPN expression may play an essential role in modulating compensatory cardiac hypertrophy in response to chronic pressure overload.

Background: Despite Rheumatic Heart Disease (RHD) contributing to an estimated disease burden in 2019 of 40 million people and 285 500 deaths, few studies document the characteristics and outcomes in children. We undertook a sub-analysis of children from the multi-centre prospective two-year global Rheumatic Heart Disease Registry (REMEDY) to document their presentation, clinical characteristics and outcomes. Methods: Nine-hundred and twenty-one children were enrolled into the REMEDY registry among the 3,343 symptomatic RHD patients from 25 hospitals in 12 African countries, India and Yemen and followed up over 24 months to assess characteristics, complications and outcome. Results: More than half of the children enrolled in the REMEDY study presented with severe valvular heart disease; 60% had more than one valve involved, 30% were classified as NYHA class III/IV and 17.7% died within 24 months. Just over 20% of children were not on penicillin prophylaxis. Although 20% met criteria for surgery, only less than 9% (n=78, 8.5%) had had percutaneous or surgical intervention with half from upper-middle-income countries. The major risk factors associated with mortality included older age (Hazard Ratio (HR): 1.01, p=0.001) and atrial fibrillation or flutter (HR: 2.3, p=0.028). Female gender(HR: 0.68, p=0.062) and education level above primary school (HR: 0.88, p=0.68) did not confer significant protection. However, a past medical history of ARF conferred some protection against mortality (HR: 0.61, p=0.031). In follow-up, 30% (n=238, 29.6%) of children experienced an adverse cardiovascular event, nearly 15% (n=114, 14.1%) were hospitalised and six young women became pregnant during the study period. Conclusion: Children with RHD in low- and middle-income countries are severely affected, with significant mortality and morbidity. The use of penicillin was suboptimal and the substantial need for surgery is evident. Our findings support the recommendations of the World Health Assembly (WHA) Resolution 71.14 passed in May 2018 for consistent provision of penicillin, integrated collaborative efforts focused on children and adolescent health as well as access to specialised services including cardiac surgery.

The present study addressed cognitive biases in anxiety and depression using the emotional Stroop task, and explored both the affective space and autonomic underpinnings of these disorders. In previous studies, anxiety has been associated with both an attentional bias toward threat information and low cardiac vagal control, as reflected in heart rate variability (HRV) indices. Depression has been linked to a memory bias for negative information; however, findings of low HRV for depression are mixed. The high comorbidity of these disorders renders such findings as difficult to interpret. In the present study, it was hypothesized that the negative affect groups (anxious, depressed, comorbid anxious/depressed) would have lower vagally mediated HRV across tasks compared to the control group and that the anxiety and depression groups would show biases for group specific words on the Stroop task. Results for the Stroop tasks generally support previous findings of an attention bias in anxiety. The comorbid anxiety/depression group generally showed lower vagal control across tasks compared to the other groups, although comparisons between the "pure" anxiety and depression groups and the controls were not significant. It is suggested that this is because the comorbid group had higher depression and anxiety than either of the "pure" groups. / Master of Science