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- Ward, Liam, 1989-
(författare)
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Sex differences in atherosclerosis and exercise effects
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cardiovascular disease (CVD) is the leading cause of death globally, with atherosclerosis being the main cause of cardiovascular diseases. Atherosclerosis is an inflammatory disease of the blood vessel wall, which over time will cause thickening and hardening of the vessel wall. Atherosclerosis can result in catastrophic vascular events, such as myocardial infarction and stroke. There are distinct sex differences in CVD mortality at different ages, before menopause women have a lower mortality of CVD in comparison to men, which equalises after menopause. In addition to sex differences in the incidence of CVD, there are also distinct sex differences in the phenotype of atherosclerotic plaques, with men generally developing more severe and vulnerable plaques that are at risk of rupture.This thesis aimed to investigate the sex differences in atherosclerosis, in particular how the proteome and pathophysiology differs. In addition, we sought to investigate the potential benefit of an exercise programme, in reducing CVD risks, using a randomised controlled trial including postmenopausal women.Sex differences in atherosclerosis were first investigated via proteomic analysis of human carotid endarterectomy samples. Initially, five intraplaque biopsies were taken from distinct atheroma regions, including; internal control, fatty streak, plaque shoulder, plaque centre, and fibrous cap. Protein extracts from these biopsies were subjected to analysis by mass spectrometry. The novel sampling method was successful in reducing the effect of plaque heterogeneity, a limitation in previous proteomic studies of atherosclerosis, and a number of previously unreported proteins were identified in human carotid atheroma. In addition to this, with the inclusion of multivariate statistical modelling, it was found that 43 proteins significantly discriminated the carotid atheroma between men and women. These proteins were grouped by function, and it was found that atheroma from men was associated with the increased abundance of inflammatory response proteins, including phospholipase-A2 membrane associated and lysozyme C, and atheroma from women was associated with increased abundance of blood coagulation, complement activation, and transport proteins, notably including; antithrombin-III, coagulation factor XII, and afamin. In addition, differences were also ii observed in the abundance of iron metabolism related proteins. These sex differences were further expanded upon from a pathophysiological perspective. Immunohistochemistry stainings of ferritin and transferrin receptor 1 were found significantly increased in the atheroma from men. Moreover, the levels of plasma haemoglobin were also significantly increased in men and were associated with the development of more vulnerable and severe plaque types. The more vulnerable and severe plaque types were also associated with significantly greater macrophage infiltration. In summary, these results are indicative of men developing atheroma with greater inflammation that are more vulnerable, due to increased iron and inflammatory proteins and macrophage infiltration, whereas atheroma from women develop with less inflammation and a more stable phenotype.The randomised controlled clinical trial aimed at investigating the effects of resistance training (RT), over a 15-week period, in postmenopausal women. Plasma samples were obtained at week-0 and week-15 of the study period, and analyses were performed primarily using a series of immunoassays. Results showed that women participating in RT, with good compliance, were associated with significant decreases in plasma levels of ferritin, lipids, and inflammatory adipokines. These results suggest that the use of regular RT may be a beneficial intervention in reducing the levels of body iron, lipids, and inflammation, all of which are risk factors for the development of CVD. However, validation studies are required in a larger cohort of postmenopausal women, in addition to the inclusion or complementary studies in middle-aged men.In summary, the works included in this thesis further expand on the current knowledge of sex differences in atherosclerosis, and also provides information on the potential of an exercise intervention to beneficially reduces the effects of known risk factors of CVD.
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| 2. |
- Nilsson, Sigrid, 1997-
(författare)
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Vasomotor Symptoms, Cardiovascular Risk and the Role of Physical Activity in Midlife Women
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The menopausal transition is, for most women, accompanied by hot flushes and night sweats (i.e., vasomotor symptoms, VMS). VMS has been associated with a worsened cardiovascular risk profile, but whether VMS constitutes an independent risk marker for developing subclinical atherosclerotic cardiovascular disease (ASCVD) is still uncertain. Visceral adipose tissue (VAT) contributes more to systemic low-grade inflammation than abdominal subcutaneous adipose tissue (ASAT), enhancing atherosclerosis development. Physical activity is an effective behavioral strategy to maintain and improve cardiovascular health. Whether a resistance training intervention (RTI) could reduce low-grade inflammation and VAT volume in postmenopausal women with VMS remains unclear, and whether the RTI-associated effects could be maintained over time requires further investigation.Material and Methods: This thesis is based on three studies. Study 1 was conducted on a subset of participants from the cross-sectional population-based Swedish CArdioPulmonary BioImage Study (SCAPIS), including women 50-64 years of age. The women underwent comprehensive cardiovascular assessments and completed an extensive female-specific questionnaire. VMS was assessed on a 4-point scale. Subclinical ASCVD was detected via coronary computed tomography angiography (CCTA), computed tomography (CT), and carotid ultrasound. Study 2 is a sub-study of 65 postmenopausal women with VMS and low physical activity, randomized to either three days/week of an RTI or unchanged physical activity for 15 weeks. Women underwent anthropometric measurements, magnetic resonance imaging (MRI), and blood sampling at baseline and after 15 weeks. During the last followup contact in Study 2 after two years, 35 women agreed to attend an additional clinic visit to reevaluate cardiovascular risk markers, marking the inception of Study 3.Results: Of 2995 women included in Study 1, 14.2% reported severe VMS (n = 425), 18.1% moderate VMS (n = 543), and 67.7% no or mild VMS (n = 2027). Current or previous severe VMS, but not moderate VMS, was significantly associated with CCTA-detected coronary atherosclerosis, with odds ratio (OR) before and after multivariable adjustment 1.36, 95% confidence interval (CI) 1.08 – 1.72 and 1.33, 95% CI 1.02 – 1.72, respectively. This association was only present for >5 years durations of severe VMS or when the onset of severe VMS occurred before menopause. Adjustment for menopausal hormone therapy strengthened the association for women with severe VMS >5 years (OR 1.67, 95% CI 1.16 – 2.40). Women compliant with an RTI had compared to a control group (CG), decreased adiponectin (p < 0.01), ASAT (p < 0.01), VAT (p < 0.01), total abdominal adipose tissue (TAAT) (p < 0.01) and fat ratio (p <0.001). Furthermore, an RTI reduced moderate to severe VMS frequency to six months post-intervention compared to a CG, but did neither contribute to preserved cardiovascular health markers nor improved health-related quality of life (HRQoL) after two years compared to a CG.Conclusions: There is a need for extra vigilance regarding cardiovascular risk factors in the group of women suffering from severe VMS. Implementing a 15-week RTI in these women could counteract the VAT redistribution and alter the frequency of moderate to severe VMS with maintained effects up to six months.
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| 3. |
- Sundell, Micaela, 1989-
(författare)
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Epidemiological and Clinical Aspects of Hormonal Contraception and Menopausal Hormone Therapy in Women
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The main indications for therapy with female sex hormones are contraception and menopausal hormone therapy (MHT). The aim of this thesis was to investigate the use of hormonal contraception and MHT in different populations of women in Sweden, 2000–2021. The use of contraception in women with obesity was studied. The use of MHT in Sweden over time was studied and different run-in periods were validated to define an incident MHT user. We also investigated the risk of pulmonary embolism (PE) in women using MHT, including considerations regarding administration form, treatment duration and type of progestin used. Women with premature or early menopause after bilateral oophorectomy were studied with regard to dispensed MHT.Material and Methods: The studies were based on different data sources including electronical medical records, national mandatory health registers, and a national quality register (GynOp). The use of MHT over time was studied using defined daily doses (DDD) per 1,000 women per day, one-year prevalence and incidence proportion. The definition of an incident drug user was validated by calculating the predictive value of different run-in periods.Results: The most prescribed contraceptive method in women with obesity was progestin-only pills (44%), but 21% were prescribed combined hormonal contraceptives contrary to Swedish and European guidelines. Incident users with obesity were significantly more likely to discontinue their contraceptive method within one year, compared with normal weight women. The use of MHT decreased significantly after the turn of the century. In the 50–54 years age interval, the dispensed amount decreased from 282 DDD/1,000 women per day in 2000, to 77 in 2006. It then stabilised around 50 DDD/1,000 women per day during 2010 to 2017. The one-year prevalence followed the same pattern, with a plateau 2010–2016. From 2017, an increase in MHT dispensations was observed. A run-in period of 18 months had a PV of 88% in the 50 to 54 years age group and was found to be suitable and reliable for defining incident users of MHT at the ages close to menopause. The risk of PE was significantly increased in users of oral MHT, but not transdermal. The risk was highest in first-ever users (OR 2.32; 95% CI, 1.34–4.00) and was considerably lower in women who may have used MHT previously (OR 1.38; 95% CI, 1.01–1.89). 69% of all women with a bilateral oophorectomy had at least one dispensation of MHT within one year after surgery. Within this treated group the estimated treatment time constituted 63% of the remaining time to natural menopause.Conclusions: Progestin-only pills was the most prescribed contraceptive method in women with obesity, but many women with obesity were prescribed combined hormonal contraceptives contrary to clinical guidelines. The use of MHT decreased significantly after the turn of the century, but has increased since 2017 in the age groups close to menopause. The classifications used for prevalent and incident drug use are of importance to the results. The risk of pulmonary embolism is increased in users of oral but not transdermal MHT. There seems to be a significant undertreatment with hormone therapy in women with premature, surgical menopause.
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