| 1. |
- Vavruch, Camilla
(författare)
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Leptin and the Intersection of Cardiovascular Disease, Metabolism, and Adipose Tissue
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- According to the World Health Organization, cardiovascular disease (CVD) is a group of disorders of the heart and blood vessels, and it is the leading cause of death worldwide. The risk factors for CVD are divided into two major classes: non-modifiable (age, gender, family history) and modifiable (including tobacco use, type 2 diabetes mellitus (T2DM), physical inactivity, unhealthy diet, abdominal obesity, high cholesterol, dyslipidemia, and stress). Because CVD is a major cause of mortality and morbidity, new and clinically useful biomarkers of cardiovascular risk are of essence. Since obesity is a risk factor for CVD, new ways to achieve weight loss are also important. In this thesis, the focus is on leptin, a metabolic hormone with a pivotal function in the balance of appetite and satiety, and inducing weight loss. The adipose tissue releases leptin, with plasma levels of leptin reflecting the total adipose mass. Since it is related to both fat mass and cardiovascular risk, and is pro-inflammatory, it has been studied as a potential link between obesity, inflammation, hypertension, and vascular function. In paper I, we aimed to see if repeated cold exposure increased metabolic rate and/or brown adipose tissue (BAT) volume in humans. Out of 28 recruited participants, we allocated 16 to expose themselves to cold for one hour every day for six weeks, while 12 were controls, instructed to avoid cold exposure. Through magnetic resonance imaging, we found that supra-clavicular BAT volume had increased in an on-treatment analysis of the cold exposure group. In paper II, we used baseline data from 720 participants in “Cardiovascular Risk factors In Patients with Diabetes—a Prospective study in Primary care” (CARDIPP), all of whom had T2DM and were 55-66 years old at recruitment. We followed patients for incidence of ischemic heart disease (IHD) mortality and morbidity for 4-7 years, using the national Swedish Cause of Death and Hospitalization Registries. Our study showed that serum leptin levels related positively to the hazard ratio in both men and women, and predicted IHD independently of age, HbA1c, BMI, systolic blood pressure, and LDL/HDL-cholesterol ratio. This supports the use of serum leptin in patients with T2DM to add independent prognostic information in terms of IHD. When adding pulse wave velocity (PWV) and intima-media thickness to the model as markers of arterial stiffness, the finding of increased risk of IHD related to leptin levels remained statistically significant in men, but not in women. In paper III, we aimed to discover novel associations between leptin and circulating proteins, to possibly link leptin with the development of CVD in patients with T2DM. Using proximity extension assay, we investigated associations between 88 plasma proteins in the CARDIPP population. We replicated the associations passing the significance threshold in patients with T2DM in an independent cohort and found that adipocyte fatty acid binding protein (A-FABP) was significantly associated with leptin in both cohorts, more so in men than women. A-FABP can be found in white adipocytes and macrophages, and some studies have identified it as a circulating biomarker for metabolic syndrome, T2DM, and cardiovascular events. Finally, in paper IV, we analyzed data from 1 658 men and 1 678 women aged 50 to 65 when included in “The Swedish CardioPulmonary bioImage Study” (SCAPIS), focusing on leptin and its possible correlation with PWV. In bivariate correlations, we found log transformed leptin, and inflammatory markers IL-6, IL-18, and CRP, were all correlated in both men and women. In a multivariable linear regression, log transformed leptin correlated positively with PWV, independently of home blood pressure, smoking, non-HDL, BMI, T2DM, and IL-6, IL-18, and CRP. This suggests it may be possible to use leptin as a marker for PWV and arterial stiffness.In conclusion, this thesis provides new insights into leptin and its potential associations with other circulating proteins, and its connection to cardiovascular disease and inflammation, both in patients with T2DM and in healthy subjects. It also provides more insight into brown adipose tissue.
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| 2. |
- Kentson, Magnus
(författare)
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Fatigue and Peripheral Muscle Dysfunction: Studies on Vitamin D Status, Muscle Metabolism and Systemic Inflammation in Patients with COPD : Aspects of COPD severity beyond FEV1 and exacerbations
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundThe severity of Chronic Obstructive Pulmonary Disease (COPD) is usually described in terms of forced expiratory volume in one second (FEV1) and number of exacerbations. However, COPD is a complex disease with different ways of expression, involving pulmonary symptoms, extra pulmonal manifestations and comorbidities, which altogether affect the patient by contributing to reduced functional capacity, increased shortness of breath, reduced health-related quality of life and increased mortality. Systemic inflammation is common in COPD and can potentially constitute a link between the lungs and other organs. The aim of this thesis was to broaden the aspects of COPD severity beyond FEV1 and exacerbations by studying fatigue, the role of vitamin D, nutritional factors, systemic inflammation and peripheral muscle function in patients with COPD. Methods and ResultsIn paper I, we included 101 patients with COPD, and 34 control subjects. Assessment of experience of fatigue, functional limitation due to fatigue, and the relationships to physiological, psychological and situational variables and quality of life (QoL) were evaluated. We found that experience of fatigue was highly prevalent (72% versus 56% in control subjects) and a troublesome symptom in COPD. Patients with COPD and fatigue had lower lung function, shorter walking distance, more dyspnoea, anxiety and depressive symptoms and poorer health status compared to patients without fatigue (all p < 0.01). Several contributing factors were identified to experience of fatigue and functional limitations of fatigue with dyspnoea, depressive symptoms and insomnia as the most prominent factors. No clear association with systemic inflammation was found. Paper II evaluated vitamin D status in 66 patients with advanced COPD (28 with long-term oxygen therapy (LTOT)) and 47 control subjects. 25-hydroxyvitamin 25(OH)D were deter-mined in early fall in a short period of seven weeks. Questionnaires about COPD symptoms, general health, lifestyle, dietary habits and QoL were answered. Lung function tests and blood sampling including systemic inflammatory markers, carotenoids and protein carbonylation (PC) were assessed. The peak annual 25(OH)D of COPD patients was significantly lower than in the control subjects, but there was no significant difference between COPD patients with and without LTOT. Among vitamin D-deficient COPD patients, 25(OH)D correlated positively with lung function, blood oxygenation, food portion size, Mediterranean Diet Score and Ultra-violet Score and negatively with dyspnoea and DOSE-index, a composite index for COPD se-verity. Ongoing vitamin D supplementation was the single most important intervention to maintain 25(OH)D levels <50 nmol/L. In paper III, we evaluated in the same cohort as paper II oxidative damage and levels of carotenoids. Patients with COPD (±LTOT) did not demonstrate increased oxidative damage. Com-pared with the control group, levels of several carotenoids were significantly lower in COPD, and the diet contained significantly less fruit and vegetables. Lycopene correlated positively with saturation and lutein correlated positively with some inflammatory markers but negatively with IL-6, an important marker for systemic inflammation. The study highlights the importance of dietary factors in COPD. In paper IV, 32 patients with COPD answered questionnaires, and were subjected to lung function tests and blood analysis including systemic inflammatory markers. Magnetic resonance imaging (MRI) for analysis of whole-body and thigh muscle composition was performed. Bioenergetics in the resting thigh muscle, (PCr/Pi ratio), were analysed using 31phosphorus magnetic resonance spectroscopy (31P-MRS). We found that adverse muscle composition was common in the COPD group. Clinical characteristics reflecting COPD severity were all associated with a raise of the PCr/Pi ratio in the thigh muscle. Increased MFIa correlated positively to systemic inflammatory markers, negative to physical activity and PCr/Pi ratio. We compared the COPD group with a virtual control group from UK Biobank (n= 3200). ConclusionsSevere COPD is much more than airway obstruction and exacerbations. The presence of fatigue is associated, as well as vitamin D status and nutritional factors, with important clinical out-comes reflecting COPD severity. Adverse muscle composition is common in COPD and there seems to be a link between systemic inflammation, muscle fat infiltration and bioenergetics.
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| 3. |
- Vergara, Marta, 1976-
(författare)
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Impact of different interventions on cardiovascular risk factors
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obesity and related complications such as diabetes mellitus type 2 (T2DM) and cardiovascular events, are a growing major health problem worldwide. Achieving a negative energy balance by increasing physical activity in combination with reduced caloric intake, is the most common approach in weight reduction strategies, something that is difficult to maintain in the long term. Other possible strategy to increase energy expenditure could be enhancing resting metabolic rate (RMR) by increasing energy consumption in muscle tissue.Regular exercise is often recommended as part of the treatment and prevention of cardiovascular disease (CVD) and it is expected to ameliorate risk factors associated with the metabolic syndrome, such as glucose and insulin metabolism, lipid profile and blood pressure. However, extreme exercise performance seems to have potential unbeneficial effects on inflammation, oxidation, and cardiac health. We intended to study the impact of a more common way of exercise in different cardiovascular risk factors and how natural antioxidants, protein supplementation or hypercaloric diet could influence the results. In patients with already established T2DM, it is important to find new and easy to manage markers for CVD, as it is the main cause of morbidity and mortality in this patient group. Even if quality of life (QoL) is strongly related to CVD in patients with T2DM, it is still not incorporated in routinary clinical assessments.Paper I: Resistance training (RT) performed by healthy men for three months, increased lean body-mass and RMR. The increase of RMR was dependent on both an increase in muscle mass and a higher RMR per kg of muscle tissue. Even if it was equally efficient to combine training with whey protein supplementation or with increased energy intake, hyperalimentation with an extra intake of a fast-food resulted in an impaired cardiovascular profile, with reduced insulin sensitivity and higher ApoB levels. Thus, regularly performed RT could be helpful in the treatment of obesity by increasing RMR.Paper II: Regularly running 5 km for 4 weeks resulted in a positive outcome, leading to lower insulin and triglyceride levels, higher HDL cholesterol, and a tendency to lower inflammation when compared with a period of minimal physical activity. However, Troponin-T, marker of myocardial injury, was detectable after a 5 km race at maximal speed in almost half of the races. Consuming blueberries showed a cardioprotective effect, blunting troponin-T release and improving the lipid profile. Less positive was the increase of fasting glucose in consumers of blueberries, which could be an indirect effect of concomitant diet. Paper III: Running 5 km at maximal speed may not be as advantageous for cardiovascular health as expected, at least when looking at the acute effects of a single race in healthy young individuals. A relative short race seemed to reduce insulin sensitivity and despite increased insulin levels, glucose was higher directly after the race compared with a resting day. Indeed, we found elevated cortisol and Troponin-T levels after the races, which suggests that running a distance that is common among recreational runners, may not be fully advantageous for cardiovascular health when performed in a strenuous way.Paper IV: We investigated if selected questions regarding the domains "general mental health and well-being" and "vitality", from QoL measurement instrument SF-36, could predict cardiovascular events and death in patients with T2DM in primary care. These two questions: "During the last 4 weeks, did you feel full of pep?" and "During the last 4 weeks, did you have a lot of energy?" were shown to be markers for major adverse cardiovascular events (MACE) independently of traditional vascular risk factors as well as arterial stiffness.
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| 4. |
- af Geijerstam, Peder, Doktorand, 1983-
(författare)
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Home Blood Pressure in Health and Disease
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hypertension is the most common preventable cause of premature all-cause mortality, primarily from cardiovascular disease (CVD). Individuals with dysglycemia, including prediabetes and diabetes, are at increased risk. Licorice intake raises blood pressure (BP) through the effects of glycyrrhizic acid (GA), but the true limit of safe intake is uncertain. Home BP has several benefits over BP measured at a clinic, including a higher predictive value for CVD. By combining office and home BP, it is possible to diagnose masked hypertension (MH), in which home but not office BP is elevated, and white coat hypertension (WCH), in which office but not home BP is elevated. The aim of this thesis was to advance our knowledge on home BP in relation to dysglycemia, markers of CVD, and licorice intake. The first 3 papers used data from the Linköping cohort of the prospective Swedish CArdioPulmonary bioImage Study (SCAPIS). Study IV was a randomized controlled cross-over study. Data was obtained from questionnaires, blood samples and office and home BP measurements. In studies I-III, pulse wave velocity (PWV), coronary artery calcium score (CACS), and carotid artery plaques as markers of CVD were also included. In Study I, we examined 5025 men and women aged 50-64 years old for the relation between dysglycemia and home BP. Both the systolic office and home BP measurements were positively as-sociated with dysglycemia. Participants with dysglycemia vs normoglycemia more often had MH. The findings were in line with previous research and strengthened the association between dysglycemia and MH. In Study II, we examined the associations between MH and markers of CVD in 4122 individuals without BP-lowering treatment. Of participants, 4.2% had MH, and these were more often men and had higher BMI than those with normotension. Participants with MH also had higher odds for CACS ≥100, an as-sociation which has previously been suggested as a trend.In Study III, we examined the relation between soluble P-se-lectin (sP-selectin) as a measure of thrombotic activity, plasma high-sensitivity C-reactive protein (hsCRP) as a measure of inflammation, and home BP in 4548 participants. Both markers were higher in each hypertension phenotype compared with sustained normotension. The quartile of participants with the highest sP-se-lectin values had higher odds for CACS ≥100 and carotid artery plaques. The association between sP-selectin and sustained hyper-tension was novel and not affected by adjustments for hsCRP. In Study IV, 28 healthy participants aged 18-30 years old were evaluated for the effects of a daily intake of licorice containing 100 mg of GA compared with a control product for 2 weeks. During the licorice intake period, the systolic home BP increased with 3.1 mmHg, and the suppression of serum aldosterone and plasma renin levels indicated that this was due to the licorice intake. In conclusion, this thesis further strengthens the idea that both home and office BP measurements have values beyond that of the other, and that home BP may be most valuable in individuals with dysglycemia and obesity, and in men. Finally, licorice may be more potent than previously known, suggesting the need for increased awareness.
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| 5. |
- Carlsson, Axel C, et al.
(författare)
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Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes : a proteomics approach
- 2020
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 25:1, s. 37-43
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Tidskriftsartikel (refereegranskat)abstract
- Background: Diabetic kidney disease (DKD) is a leading risk factor for end-stage renal disease and is one of the most important risk factors for cardiovascular disease in patients with diabetes. It is possible that novel markers portraying the pathophysiological underpinning processes may be useful.Aim: To investigate the associations between 80 circulating proteins, measured by a proximity extension assay, and prevalent DKD and major adverse cardiovascular events (MACE) in type 2 diabetes.Methods: We randomly divided individuals with type 2 diabetes from three cohorts into a two-thirds discovery and one-third replication set (total n = 813, of whom 231 had DKD defined by estimated glomerular filtration rate <60 mg/mL/1.73 m2 and/or urinary albumin-creatinine ratio ≥3 g/mol). Proteins associated with DKD were also assessed as predictors for incident major adverse cardiovascular events (MACE) in persons with DKD at baseline.Results: Four proteins were positively associated with DKD in models adjusted for age, sex, cardiovascular risk factors, glucose control, and diabetes medication: kidney injury molecule-1 (KIM-1, odds ratio [OR] per standard deviation increment, 1.65, 95% confidence interval [CI] 1.27-2.14); growth differentiation factor 15 (GDF-15, OR 1.40, 95% CI 1.16-1.69); myoglobin (OR 1.57, 95% CI 1.30-1.91), and matrix metalloproteinase 10 (MMP-10, OR 1.43, 95% CI 1.17-1.74). In patients with DKD, GDF-15 was significantly associated with increased risk of MACE after adjustments for baseline age, sex, microalbuminuria, and kidney function and (59 MACE events during 7 years follow-up, hazard ratio per standard deviation increase 1.43 [95% CI 1.03-1.98]) but not after further adjustments for cardiovascular risk factors.Conclusion: Our proteomics approach confirms and extends previous associations of higher circulating levels of GDF-15 with both micro- and macrovascular disease in patients with type 2 diabetes. Our data encourage additional studies evaluating the clinical utility of our findings.
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| 6. |
- Ström, Edvin, 1992-
(författare)
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Influence of fruit, meal distribution and dental health on cardio-metabolic risk
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Fruit is often recommended as a snack between meals and a main component of the cardioprotective Mediterranean diet. The sugar content might be of concern since it theoretically could lead to hepatic fat accumulation and affect dental status negatively. Dental status is associated with cardiovascular disease, but subjective dental health’s association has barely been studied. The aim of this thesis was to study dietary recommendations, as in fruit consumption and meal frequency, and their effect on cardio-metabolic risk factors and dental status. Another aim was to study dissatisfaction with teeth as a marker of cardiovascular risk in type 2 diabetes. Methods Paper I-II studied the effect of extra fruit or nuts as a snack between meals on hepatic fat content and dental status. A study population of 30 young, healthy, normal-weight participants were recruited and randomized to each intervention by 1:1 allotment. The amount of hepatic fat content (HFC) was quantified by MRI-examination. Dental status was investigated by the same licensed dentist. In both cases were examinators blinded to the allotted intervention. Other parameters were markers cardiometabolic risk, inflammatory markers, and vitamin levels. Paper III is a randomized cross-over study with the primary outcome of post-prandial energy expenditure after varying meal frequency and fat- /carbohydrate content in fourteen study participants. In parallel the hormones ghrelin and GLP-1 were measured as secondary outcomes. There were 4 types of test meals served with either a single large drink of 750 kcal or divided into five smaller drinks (150 kcal) with the same total energy content in a series every 30 minutes for 2.5 hours. Macronutrient content was varied by low- or high carbohydrate content (54.9 E%/20.0 E%). Protein content was similar (9.9 E%). The remainder of energy was from fat. Paper IV explored the association between dissatisfaction with teeth and major adverse cardiovascular events (MACEs) defined as hospitalization or death due to myocardial infarction or stroke in a population of 601 available cases with type 2 diabetes in primary care. The Cox regression was adjusted for age, sex, inflammation, BMI, duration of diabetes, HbA1c, total cholesterol, office systolic blood pressure, prior MACE, currently smoking, marital status, being born in Sweden, self-reported stress, and self-reported happiness. Paper V investigated the association of self-reported frequency of consumed bananas, apples/pears, and oranges/citrus fruit with office- and home blood pressure in a study population of 2 283 available participants. Adjustments were made for the covariates sex, age, BMI, smoking, alcohol consumption, salt consumption, educational level, physical activity, HbA1c, total cholesterol and S-creatinine levels in a multivariable linear regression. Subgroup analysis by sex was also performed. Results In paper I there was no change in HFC in either group. There was a decrease in number of deep gingival pockets in the fruit group with a statistically significant different change compared to the nut group as sign of a potentially improved dental status. In paper III post-prandial energy expenditure was higher after one large drink compared to the series of smaller drinks and the drinks with high-carbohydrate content. GLP-1 levels were higher after the large drink, while similar with varying fat-/carbohydrate content. Ghrelin did not differ at any test occasion at group level. Paper IV revealed an increased risk of MACE when dissatisfied with teeth independent of sex, age, and inflammation. When also adjusting for cardiovascular risk factors and socio-psychological factors the increased risk was attenuated. Paper V showed an independent association between lower systolic- and diastolic home blood pressures for apples/pears and oranges/citrus fruits in total study population. Diastolic home blood pressure was independently associated with all types of fruit consumption in women only. Conclusions Fruit as snack in addition to habitual diet in quantities greater than the minimum recommended amount did not increased HFC. Periodontal status was improved in the fruit group with a statistically significant change compared to the nut group. The acute effects of a large meal compared to a series of smaller and high-carbohydrate content resulted in a higher post-prandial energy expenditure. Dissatisfaction with teeth could help determine cardiovascular risk associated with a range of biological and social factors. Fruit consumption was independently associated with lower home blood pressure, predominately diastolic blood pressure in women. There is an undeniable opportunity for future collaboration between health care and dental health care to further expand the knowledge and increase the evidence behind dietary recommendations promoting general- and dental health.
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| 7. |
- Barmano, Neshro, 1980-
(författare)
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Structured management, Symptoms, Health-related Quality of Life and Alcohol in Patients with Atrial Fibrillation
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting at least 2.9 % of the Swedish population. Although AF is associated with increased risk of ischaemic stroke, there have been many reports on the underuse of oral anticoagulants (OAC) and non-adherence to guidelines in other areas as well. AF is also associated with disabling symptoms and decreased health-related quality of life (HRQoL), but some patients are asymptomatic. The reasons for the great variation of symptoms remain unclear. Furthermore, although research on AF has increased, studies have mainly focused on treatment, while studies on risk factors, such as alcohol consumption, have only recently gained attention.The aim of this thesis was to investigate whether structured care of patients with AF could improve guideline adherence and HRQoL compared to standard care, and to determine which factors affect symptoms and HRQoL prior to treatment with radiofrequency catheter ablation (RFA), as well as improvement after RFA. Furthermore, we aimed to examine the associations of alcohol consumption with cardiac biomarkers, the size of the left atrium (LA), and re-ablation.This thesis is based on two studies. In the ‘Structured Management and Coaching – Patients with Atrial Fibrillation’ (SMaC-PAF) study, 176 patients were recruited to the intervention group, receiving a structured follow-up programme, and 146 patients were recruited to the control group, receiving standard care. The two groups were compared in regard to adherence to guidelines and patient-reported outcome measures (PROMs) assessing symptoms and HRQoL.In the ‘Symptom burden, Metabolic profile, Ultrasound findings, Rhythm, neurohormonal activation, haemodynamics and health-related quality of life in patients with atrial Fibrillation’ (SMURF) study, 192 patients referred for their first RFA of AF were included. PROMs questionnaires were filled out, echocardiography was performed, and cardiac biomarkers were analysed. Alcohol consumption was assessed through interview and through analysis of ethyl glucuronide in hair (hEtG). AF recurrence and re-ablation within 12 months were examined.In the first study, after one year, 94% (n=112) and 74% (n=87) of patients with indication for OAC in the intervention and the control groups, respectively, actually received treatment with OAC (p <0.01). Both groups improved in anxiety and HRQoL scores over the year, but in the intervention group, arrhythmia-specific symptoms were less frequently experienced and the SF-36 scores were more similar to the norm population.In the second study, the most important predictors of arrhythmia-related symptoms and HRQoL prior to RFA were anxiety, depression and low-grade inflammation, while frequent AF attacks prior to RFA, freedom from AF recurrence after RFA, female gender, no enlarged LA, absence of diabetes, and the presence of heart failure were significant predictors of improvement in symptoms and HRQoL after RFA. Men with hEtG ≥7 pg/mg had higher levels of cardiac biomarkers, larger LA volumes and a higher re-ablation rate than men with hEtG <7 pg/mg, while no such findings were present in women.In conclusion, structured management was superior to standard care in patients with AF, emphasising the importance of structured care, adjusted to local requirements, in order to improve the care and well-being of patients with AF. Although the reasons for the great variety of symptoms in patients with AF still are not yet fully understood, it seems that psychological factors and inflammation play a role, and that improvement in symptoms and HRQoL after RFA is influenced by gender, diabetes, heart failure, LA size and the frequency of attacks before, as well as freedom from AF after, RFA. Finally, alcohol consumption corresponding to hEtG ≥7 pg/mg was associated with higher levels of cardiac biomarkers, larger LA size and a higher rate of re-ablation in men, implying that men with an hEtG-value ≥7 pg/mg have a higher risk for LA remodelling that could potentially lead to a deterioration of the AF situation.
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