| 1. |
- Nijm, Johnny, 1969-
(författare)
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Inflammation and cortisol response in coronary artery disease
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atherosclerosis is characterized by a chronic inflammation, involving autoimmune components, in the arterial wall. An increase in proinflammatory activity relative to anti-inflammatory activity is considered to cause a progression of the disease towards plaque instability and risk of atherothrombotic events, such as acute coronary syndrome (ACS). Cortisol, the end product of the hypothalamus-pituitary-adrenal (HPA) axis, is a powerful endogenous anti-inflammatory mediator. Disturbances in the HPA axis have been reported in chronic inflammatory/autoimmune diseases, like rheumatoid arthritis. The aim of this thesis was to study various markers of systemic inflammation in patients with acute and stable conditions of coronary artery disease (CAD) and relate these findings to the cortisol response.Both patients with ACS and patients with stable CAD had high levels of C-reactive protein (CRP), interleukin (IL)-6 and IL-1 receptor antagonist, compared with healthy controls. In addition, patients with stable CAD had significantly more neutrophil-platelet aggregates than controls, as a possible indicator of neutrophil activation.The cortisol response was determined in two different cohorts of CAD patients; one consisting of patients with a first-time myocardial infarction and one consisting of patients with long-term stable CAD. From the acute phase to 3 months, the patients with a myocardial infarction showed a higher 24-h cortisol secretion and a flattened diurnal slope caused by higher cortisol levels in the evening, as compared with healthy controls. The patients with long-term stable CAD showed similarly high levels of cortisol in the evening. The levels of evening cortisol were strongly correlated with CRP and IL-6. When exposed to acute physical or acute psychological stress at 3 months, the ACS patients showed a markedly blunted cortisol response compared with healthy controls. Following the stress tests, a significant increase in CRP was observed in the patients but not in the controls, indicating a failure of the HPA axis to compensate for stress-induced inflammation in CAD.In the ACS patients, the time course of matrix metalloproteinases (MMPs) and their tissue inhibitor TIMP-1 was determined during the 3 months follow-up. A major finding was that the MMP-9 and TIMP-1 levels remained significantly higher in the patients at all time points compared to the controls. MMP-9 and TIMP-1, but not MMP-2, MMP-3 or MMP-7, were related to inflammatory activity, as assessed by CRP and IL-6. MMP-9 and TIMP-1 showed significant correlation with evening cortisol, even after adjustment for CRP and IL-6, lending further support for a link between ´high´ flat cortisol rhythm and systemic inflammatory activity.The activation status of neutrophils in stable CAD was further examined by measuring the expression, affinity state and signalling capacity of b2-integrins and the innate production of reactive oxygen species (ROS). However, the neutrophils in patients were not more activated in vivo than were cells in healthy controls, neither were they more prone to activation ex vivo. The data rather indicated an impaired function of neutrophils in stable CAD.The neutrophils in CAD patients showed a significantly lower number of total glucocorticoid receptors (GRs) and a lower GRa:GRb ratio compared to healthy controls, indicating a chronic over activation of the HPA axis and, possibly, a state of glucocorticoid resistance. Moreover, the evening cortisol levels in patients were associated with an overexpression of annexin-1, the ´second messenger´ of glucocorticoid action. In contrast to neutrophils in controls, the neutrophils in patients also showed a hyper responsiveness to exogenous annexin-1 resulting in impaired neutrophil function.To conclude, clinically stable CAD was associated with a systemic inflammatory activity, involving a high MMP-9:TIMP-1 ratio and an increased inflammatory response to acute stress but not any activation of neutrophils. This inflammatory activity was associated with a dysregulated cortisol secretion, defined by a flat diurnal rhythm and a blunted cortisol response to stress. Although the clinical relevance remains to be verified, an intriguing hypothesis is that a hyporesponsive HPA axis favours the development towards plaque instability.
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| 2. |
- Steer, Peter
(författare)
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Lipids and Endothelium-Dependent Vasodilation
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Impaired endothelium-dependent vasodilation (EDV) is associated with atherosclerotic cardiovascular disease as well as several of its risk factors. The aim of the present thesis was to investigate how lipids influence EDV in the vascular bed of the human forearm. Apolipoprotein B was inversely associated with both EDV and endothelium-independent vasodilation (EIDV) in healthy subjects aged 20-69 years. HDL cholesterol was associated with the EDV to EIDV ratio (EFI). Small LDL particles and antibodies against oxidized LDL were not associated with endothelial vasodilatory function. The EFI in young, healthy subjects was positively associated with alpha-linolenic acid proportion, but inversely associated with myristic acid in men only. Eicosapentaenoic acid was positively associated with EDV, whereas dihomo-gamma-linolenic acid was inversely associated with both EDV and EIDV in men. Acute elevation of long-chain fatty acids with Intralipid®/heparin infusion in young, healthy subjects impaired EDV after 2 h. This impairment could be prevented by co-infusing vitamin C, diclophenac or L-arginine. Acute elevation of both medium-chain and long-chain fatty acids during Structolipid®/heparin infusion did not impair EDV. An ordinary meal (34 E% fat) transiently attenuated EDV at 1 hour. No attenuation in EDV was observed after meals containing 20 and 3 E% fat. These findings show that the endothelial vasodilatory function is associated with fatty acid profile in serum in the fasting state and during acute fatty acid elevation, as well as with apolipoprotein B and HDL cholesterol. Furthermore, lowering dietary fat content to 20 E% or less preserves endothelial vasodilatory function and might therefore protect against atherosclerosis.
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| 3. |
- Ulvenstam, Anders, 1975-
(författare)
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Cardiovascular events after acute coronary syndrome with special reference to ischemic stroke
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Acute coronary syndrome (ACS) encompasses acute myocardial infarction (AMI) and unstable angina (UA). It is a global major cause of morbidity and mortality in both the short and long terms. The risk for recurrent ischemic cardiovascular (CV) events and death after ACS depends on patient factors at presentation, revascularization and secondary prevention measures. Of these, ischemic stroke (IS) is a feared and potentially devastating complication that confers suffering for the individual patient and an economic burden on society. ACS and secondary prevention treatment have gone through dramatic improvements during recent decades. These improvements, together with an improved risk factor profile in the general population, have led to lower morbidity and halved mortality. ACS and IS share many risk factors. Most of our knowledge about prognosis and risk of recurrent ischemic events after ACS is based on clinical trials and it is uncertain whether these findings can be translated to the general population. Aims: The study aims were as follows: to estimate the rate, time trends, risk factors and effects on mortality of IS after an AMI during the decades that ACS and secondary prevention treatment improved; to study wether the switch from the antiplatelet agent clopidogrel to ticagrelor influenced post-AMI IS risk in patients treated with PCI, based on data from the SWEDEHEART register; and to estimate the long-term rate of subsequent CV events after ACS in an unselected cohort of ACS patients, based on the ACS-population in the Nurse-based Age- independent Intervention to Limit Evolution of Disease After Acute Coronary Syndrome (NAILED-ACS) study. Methods: In papers I–IV, data from the SWEDEHEART register were merged with the Swedish National Patient Register (NPR) to identify patients with AMI and subsequent ischemic stroke. In paper V, data were obtained from the NAILED-ACS study. Survival analysis with Kaplan–Meier estimates and hazard ratios for risk factors with Cox proportional hazards regression models were calculated in all five studies. When appropriate, propensity scores and competing risk analyses were used to adjust for baseline differences and a high overall mortality rate, respectively. Results: The overall IS rates at 30 days and 1 year after AMI were 2.1 and 4.1% respectively, during the study period (1998–2008). The rate of IS after AMI decreased over time, both at 30 days and at 1 year, with relative risk reductions (RRRs) of 11% at 30 days and 20% at 1 iii year respectively, when comparing the beginning and end of the study period. AMI complicated by IS within 1 year had a higher mortality rate than AMI without IS (36.5 vs. 18.3%). The mortality rates decreased during 1998– 2008, by 9.4% in patients with IS and 7.5% in those without IS.The introduction of dual antiplatelet therapy (DAPT) with ticagrelor instead of clopidogrel was associated with a 21% relative risk reduction of IS within 1 year after AMI in patients treated with PCI. The rate of recurrent CV events (CV death, AMI and IS) after ACS during the first year was 10.3% and remained high during a median follow-up time of 4.7 years, at 28.6%.Predictors of increased risk of recurrent ischemic events were older age, female sex, previously established CV and cerebrovascular disease, hypertension, atrial fibrillation, diabetes mellitus, heart failure and renal disease. Reperfusion and revascularization procedures in the acute phase as well as evidence-based secondary prevention treatment were associated with a protective effect against recurrent ischemic events. Conclusion: The results reported in this thesis indicate an overall high rate of recurrent CV events after ACS based on a contemporary, unselected population of ACS patients. IS a relatively rare, but serious complication after AMI that confers a substantially increased mortality risk. The rate and mortality risk of IS after AMI have decreased over time. Improved, evidence-based treatment, both in the acute phase and in the long term, has most likely reduced the post-ACS risk of recurrent ischemic events in general and more specifically of IS. The switch from clopidogrel to ticagrelor was associated with a small, but statistically significant reduction in IS risk in PCI-treated AMI patients.
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