| 1. |
- Lilja, Mikael
(författare)
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Trends in obesity and type 2 diabetes : ethnic aspects and links to adipokines
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Objective The prevalence of obesity and related diseases such as type 2 diabetes mellitus (T2DM) is increasing worldwide, and the Asian Indian population seems to be particularly susceptible to developing T2DM, even at a low body mass index (BMI). In Sweden, the age-adjusted prevalence of diabetes has not increased despite increasing self-reported obesity. However, modern data on the prevalence of obesity and T2DM in Scandinavia are absent.The biochemical links between obesity and subsequent T2DM are unknown, but the adipocyte-derived hormones leptin and adiponectin (adipokines) have been suggested as potential links because they both are related to insulin and glucose physiology. Some studies have found leptin to be an independent predictor of T2DM in men but not in women, although these results are inconsistent. In contrast, adiponectin has more consistently been linked to development of T2DM in both men and women. Furthermore, the leptin–adiponectin ratio may predict incident T2DM better than either of the two hormones separately.The aims of this thesis were to describe time trends in obesity and T2DM in northern Sweden, to evaluate leptin and adiponectin as predictors of deterioration in glucose metabolism including T2DM, and to evaluate leptin as a risk marker regarding ethnic differences, circ-annual variation, and intra-individual stability. Materials and methods Three large population surveys were used, the Northern Sweden MONICA (MONitoring of Trends and Determinants in CArdiovascular Disease) study, the Västerbotten Intervention Programme (VIP), and the Mauritius Non-Communicable Disease Study. Within the MONICA study, six cross-sectional surveys were performed in Sweden’s two northernmost counties, Norrbotten and Västerbotten, between 1986 and 2009. A total of 1000 men and 1000 women ages 25–64 years, also including from 1994 250 men and 250 women ages 65–74 years, were independently chosen for each survey. The overall participation rate was 75%. In 1999, a reinvestigation was performed in 74% of all participants from the three first surveys. Data from the MONICA surveys were used in papers I and IV and data from the reinvestigation survey in paper II. VIP is an ongoing population intervention program that started in the mid-eighties targeting cardiovascular risk factors and has covered the whole county of Västerbotten since 1991. Inhabitants are invited the years they turn 40, 50, and 60 years old, and the annual participation rate has varied between 48% and 67%. A subset (n=1780) from VIP was used in paper II for the circ-annual leptin analysis, and VIP data linked to the diabetes register in Västerbotten (DiabNorr) were used in a case referent study (640 patients with T2DM) in paper III. The Mauritius Non-Communicable Disease Study was performed in 1987 in 10 randomly selected (with probability proportional to size) population clusters. All eligible adults ages 25–74 years were invited, and the participation rate was 86% (n=5083). In 1992, a follow-up survey was performed in 49% of the initial participants. The Mauritius survey data were used in paper II. Results I. BMI increased in men ages 25–74 years and in women ages 25–44 years in northern Sweden between 1986 and 2004. The prevalence of obesity (BMI 30) increased in men ages 25–44 and 55–74 years and in women ages 25–44 years. The prevalence of obesity increased from 10.4% to 19.1% in men and from 12.9% to 17.9% in women ages 25–64 years. Waist circumference (WC) decreased in women of all ages and in men ages 55–64 years between 1986 and 1990. After 1990, WC increased again, and the prevalence of abdominal obesity rose markedly in women ages 25–64 years. II. Differences in circulating levels of leptin, leptin per BMI unit (leptin/BMI), and leptin per cm in WC (leptin/waist) were tested in men and women of Asian Indian, Creole (African), and Caucasian ethnicity. Asian Indian men and women had the highest leptin concentrations and Caucasian men and women the lowest while Creole men and women had intermediate values for leptin, leptin/BMI, and leptin/waist. No circ-annual variation in leptin concentrations was seen in Caucasians. The intra-individual test– retest stability for leptin was equal in men and women of different ethnicities, over 5–13 years, with an intra-class correlation of 0.65–0.82. III. High adiponectin concentrations predicted decreased risk of T2DM in both insulin-sensitive and insulin-resistant men and women, whereas high leptin levels predicted increased risk for T2DM only in insulinsensitive men. A high leptin–adiponectin ratio predicted T2DM in both men and women, and men with a high ratio had a shorter time to diagnosis than those with a low ratio. IV. In northern Sweden, fasting and post-load glucose increased in women ages 24–65 years with 0.2 mmol/l and 0.7 mmol/l, respectively, between 1990 and 2009. Consequently, the prevalence of impaired fasting glucose and impaired glucose tolerance (IGT) rose from 4.5% to 7.7%, and from 7.8% to 14.5%, respectively. In men, post-load glucose increased at 0.5 mmol/l, and the prevalence of IGT rose from 3.5% to 10.1%. The prevalence of diabetes did not increase. An independent relationship between leptin and changes in fasting and post-load glucose was seen in men but not in women. Conclusion An increasing obesity and concomitant deterioration in glucose metabolism was seen in northern Sweden in the period studied. High adiponectin concentrations predicted a decreased risk of T2DM in both men and women, whereas high leptin concentrations predicted an increase in fasting and post-load glucose as well as an increased risk of T2DM in men but not in women. Individual insulin resistance status modified the association between leptin and T2DM, and the leptin–adiponectin ratio may add further predictive information beyond the measures of the separate hormones. In relation to traditional anthropometric measures of obesity, Asian Indian men and women had the highest and Caucasians the lowest concentrations of leptin while Creole (African) men and women had intermediate levels. As a risk marker, leptin has a high intra-individual stability, equal in men and women and among different ethnicities over 5–13 years with no circ-annual variation.
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| 2. |
- Andersson, Jonas, 1969-
(författare)
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Adipose tissue as an active organ : blood flow regulation and tissue-specific glucocorticoid metabolism
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Despite advances in the treatment of atherosclerosis, cardiovascular disease is the leading cause of death worldwide. With the population getting older and more obese, the burden of cardiovascular disease may further increase. Premenopausal women are relatively protected against cardiovascular disease compared to men, but the reasons for this sex difference are partly unknown. Redistribution of body fat from peripheral to central depots may be a contributing factor. Central fat is associated with hyperlipidemia, hyperglycemia, hypertension, and insulin resistance. Two possible mediators of these metabolic disturbances are tissue-specific production of the stress hormone cortisol and adipose tissue blood flow (ATBF). The aim of this thesis was to determine the adipose tissue production of cortisol by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and to investigate the regulation of ATBF. Materials and Methods: Cortisol release was estimated by labeled cortisol infusions and tissue-specific catheterizations of subcutaneous and visceral adipose tissue (VAT) in men. We investigated ATBF by 133Xe-washout and its relation to autonomic activity, endothelial function, adipose tissue distribution, and adipokines in different groups of women. We further investigated the effect of two diets and of weight loss on ATBF in women. Results: We demonstrated significant cortisol release from subcutaneous adipose tissue in humans. Splanchnic cortisol release was accounted for entirely by the liver. Cortisol release from VAT (to the portal vein) was not detected. ATBF decreased according to increasing weight and postmenopausal status, and the level of blood flow was associated with nitric oxide (NO) activity and autonomic activity. ATBF was also highly associated with leptin levels and both subcutaneous adipose tissue and VAT areas. After 6 months of diet and weight reduction, a significant difference in ATBF was observed between diet groups. Conclusions: Our data for the first time demonstrate the contributions of cortisol generated from subcutaneous adipose tissue, visceral tissues, and liver by 11β-HSD1. ATBF is linked to autonomic activity, NO activity, and the amount of adipose tissue (independent of fat depot). Postmenopausal overweight women exhibited a loss of ATBF flexibility, which may contribute to the metabolic dysfunction seen in this group. Weight loss in a diet program could not increase the ATBF, although there were ATBF differences between diet groups. The results will increase understanding of adipose tissue biology and contribute to the development of treatment strategies targeting obesity and obesity-related disorders.
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| 3. |
- Eriksson, Maria, 1965-
(författare)
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Adipocyte-derived hormones and cardiovascular disease
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obesity is increasing globally and related to major changes in lifestyle. This increase is associated with an increased risk of cardiovascular disease (CVD). Knowledge about adipose tissue as a metabolic-endocrine organ has increased during the last few decades. Adipose tissue produces a number of proteins with increased body weight, many of which are important for food intake and satiety, insulin sensitivity, and vessel integrity, and aberrations have been related to atherosclerosis. Notably, the risk for developing CVD over the course of a lifetime differs between men and women. In Northern Sweden, men have a higher risk for myocardial infarction (MI). However, the incidence is declining in men but not in women. These sex differences could be due to functional and anatomical differences in the fat mass and its functions. The primary aim of this thesis was to evaluate associations between the adipocyte-derived hormones leptin and adiponectin, and fibrinolysis and other variables associated with the metabolic syndrome, and particularly whether these associations differ between men and women. Another aim was to evaluate these associations during physical exercise and pharmacological intervention (i.e. enalapril). Finally, whether leptin and adiponectin predict a first MI or sudden cardiac death with putative sex differences was also investigated. The first study used a cross-sectional design and included 72 men and women recruited from the WHO MONICA project. We found pronounced sex differences in the associations with fibrinolytic variables. Leptin was associated with fibrinolytic factors in men, whereas insulin resistance was strongly associated with all fibrinolytic factors in women. The second study was an experimental observational study with 20 men exposed to strenuous physical exercise. During exercise, leptin levels decreased and adiponectin levels increased, and both were strongly associated with an improved fibrinolytic capacity measured as decreased PAI-1 activity. Changes in insulin sensitivity were not associated with changing adiponectin levels. The third study was a randomised, double-blind, single centre clinical trial including 46 men and 37 women who had an earlier MI. The study duration was one year, and participating subjects were randomised to either placebo or ACE inhibitor (i.e. enalapril). Circulating leptin levels were not associated with enalapril treatment. During the one-year study, changes in leptin levels were associated with changes in circulating levels of tPA mass, PAI-1 mass, and tPA-PAI complex in men, but not vWF. These associations were found in all men and men on placebo treatment. In women on enalapril treatment there was an association between changes in leptin and changes in vWF. In the fourth study, the impact of leptin, adiponectin, and their ratio on future MI risk or sudden cardiac death was tested in a prospective nested casecontrol study within the framework of the WHO MONICA, Västerbotten Intervention Project (VIP), and Västerbotten Mammary Screening Program (MSP). A total 564 cases (first-ever MI or sudden cardiac death) and 1082 matched controls were selected. High leptin, low adiponectin, and a high leptin/adiponectin ratio independently predicted a first-ever MI, possibly with higher risk in men in regards to leptin. The association was found for non-fatal cases with ST-elevation MI. Subjects with low adiponectin levels had their MI earlier than those with high levels. In conclusion, the adipocyte-derived hormones leptin and adiponectin are related to the development of CVD with a sex difference, and fibrinolytic mechanisms could be possible contributors to CVD risk.
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| 4. |
- Ljungberg, Johan, 1968-
(författare)
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Cardiovascular risk factors in aortic stenosis
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Aortic stenosis (AS) is the most common hemodynamic significant valvular heart disease and affects about 2% of the population. The incidence increases with age. When symptoms of the stenotic aortic valve disease eventually occur the 2-year mortality exceeds 50%. Aortic valve replacement (AVR) by surgery or by catheter intervention is the only known treatment. The causes of AS are only partly known, despite that the disease has been known since the beginning of 17th century. In younger individuals, a bicuspid valve is present in about 80% of the cases. The traditional cardiovascular risk-factors for ischemic heart disease have been linked to AS, and the histology of the stenotic aortic valve and the atherosclerotic plaques shares several features such as inflammation, lipid deposition and calcification. High levels of the lipoprotein Lp(a) has been linked to both atherosclerosis and AS, and a causal relation with AS is supported by Mandelian randomisation. End-stage renal disease is associated with increased risk of AS but if early impairment increases the risk is not known.Material and methods: We identified 799 patients with surgery for valvular heart disease and/or disease of the ascending aorta with a prior participation in one of three large population based health surveys in northern Sweden (Västerbotten Intervention Program [VIP], MONItoring Of trends and Determinants in CArdivascular Disease survey [MONICA], and the Mammary Screening Project [MSP]). For each case, four referents matched by age, gender, type and date of survey, and geographical area were randomly selected. From the health surveys, data on cardiovascular risk-factors and health history as well as measurements of anthropometry, blood pressure, glucose and cholesterol levels were retrieved. Each case was carefully validated and data from pre- and perioperative assessments were collected. The presence of coronary artery disease (CAD) was determined from the preoperative coronary angiogram. Apolipoproteins B and A1, Lp(a), creatinine and cystatin C were analysed in samples obtained at the initial survey. As this is a matched case-referent study where cases and referents had the same follow-up duration within strata, logistic regression using the conditional maximum likelihood routine designed for matched analysis was used to estimate odds ratios (ORs) with 95% confidence intervals. Studied variables were tested in uni- and multivariable models.Results: Paper 1: Of the identified 799 cases with questionnaires, 322 were primarily operated for AS, 91 for aortic regurgitation, 181 for mitral regurgitation, 131 for disease of ascending aorta, 52 for CAD (and for concomitant valvular or aortic disease). The remaining 22 had various indications for valvular heart surgery and were excluded. Altogether 38% of patients were women. Aortic stenosis: Hypertension (OR 1.87 [1.37–2.54]), diabetes (OR 1.78 [1.01–3.11]) and total cholesterol (OR 1.64 [1.07–2.49]) were associated with future AVR. After exclusion of concomitant CAD, none of the these risk-factors remained significant. Aortic regurgitation: None of the cardiovascular risk-factors was associated with increased risk for aortic regurgitation demanding surgery, whereas high levels of cholesterol were associated with reduced risk for surgery (OR 0.29 [0.12–0.71]). Mitral regurgitation: High levels of cholesterol associated with surgery for mitral regurgitation (OR 1.74 [1.01–3.00]), but not in those without CAD. Disease of the ascending aorta: Hypertension (OR 2.42 [1.44–4.06]) and previous smoking (OR 1.97 (1.12–3.49]) related to increased risk for surgery of the ascending aorta, whereas diabetes was inversely associated with surgery (OR 0.09 [0.01–0.73]). Excluding CAD, only diabetes remained protective (OR 0.24 [0.07–0.81]). Paper 2: 322 patients underwent AVR, and 70 had surgery before the age of 60 years and 252 had surgery after 60 years of age. After exclusion of patients with CAD, 49 and 82 patients remained in these age groups. Arterial hypertension associated with future AVR in those operated before the age of 60 years regardless of concomitant CAD or not (OR 3.40 [1.45–7.93] and OR 5.88 [1.46–23.72]). In those older than 60 years at surgery and with concomitant CAD, all traditional cardiovascular risk factors associated with surgery, but in those without concomitant CAD, only impaired fasting glucose (IFG) was associated with surgery (OR 3.22 [1.19–8.76]). Paper 3: 336 patients having surgery for AS. Lipoprotein(a) [Lp(a)] was independently associated with surgery in those with concomitant CAD (OR 1.29 [1.07–1.55]), but not in those without CAD. A high Apo B/A1 ratio was associated with surgery in patients with CAD (OR 1.43 [1.16–1.76]), but not in those without. Paper 4: The same cohort as in paper 3 was examined. Renal function was estimated by the ratio between glomerular filtration rates (eGFR) obtained from cystatin C and creatinine, and a low ratio indicates early impairment of renal function (“shrunken pore syndrome”). A high ratio independently associated with lower risk for future AVR (OR 0.84 [0.73–0.97]). Protective effect was seen in women but not in men (0.74 [0.60–0.92] and 0.93 [0.76 [0.76–1.13], respectively). After stratification for CAD, the association remained significant in women with CAD but not in men with CAD (0.60 [0.44–0.83] and 0.96 [0.76 [0.75–1.23], respectively).Conclusion: The traditional cardiovascular risk-factors associated with future surgery for valvular heart disease and for surgery of the ascending aorta, however with a clear difference if there was concomitant CAD or not. Arterial hypertension was a major risk factor for surgery for AS in younger patients without CAD, whereas impaired fasting glucose (IFG) associated with surgery in elderly patients without CAD. High levels of Lp(a) and a high Apo B/A1 ratio were associated with future AVR only in patients with concomitant CAD. Similarly, early renal impairment expressed as low ratio of eGFR by cystatin C and by creatinine (“shrunken pore”) associated with future AVR.
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| 5. |
- Tossavainen, Erik, 1977-
(författare)
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In the hands of ohm : hemodynamic aspects in pulmonary hypertension
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Congestive heart failure (CHF) is one of the most challenging diseases in terms of health care demand and mortality, in the western world. Despite major breakthroughs in the fields of diagnosis and treatment over the three last decades, the management of CHF still remains challenging.CHF is defined as inability of the heart to supply sufficient blood flow to meet the needs of the body. This definition however, may be an oversimplification of a complex pathophysiological process since patients with overt CHF may have normal, or even supernormal cardiac output at the expense of increased filling pressures, which subsequently leads to the development of post capillary pulmonary hypertension (PH). In the presence of advanced CHF, clinical signs and symptoms are obvious at rest. However, the majority of affected individuals do not experience any discomfort at rest and may demonstrate normal findings when assessed. Small increases in systemic blood pressure and or venous return, caused by activity may result in severe elevation of filling pressures if left ventricular compliance is significantly decreased. This example highlights the need to perform cardiac investigations during stress to provoke symptoms. Increased pulmonary vascular resistance (PVR), commonly found in pre-capillary PH, is a condition that shares many symptoms with CHF, and is also associated with poor prognosis. Even though the disease is located within the lung vessels, it is highly important and challenging task differentiating pre- and post-capillary PH. Since treatment differs considerably and may be detrimental in case of misdiagnosis, additional sensitive and reliable screening methods are crucial to aid in differentiation.Methods: Out of the four studies included in this thesis, three were conducted solely at Norrland’s University Hospital, while patients in the third study were recruited and examined at Uppsala Akademiska Hospital. All included patients had idiopathic dyspnea and were admitted for right heart catheterization (RHC), which is gold standard with regards to hemodynamics. Echocardiographic examinations were performed simultaneously with RHC, except in the Uppsala study, wherein echocardiography were performed within 3 days to the RHC.Echo-Doppler derived pulmonary artery acceleration time (PAcT) is an easily assessed parameter, indicating elevated pulmonary artery systolic pressure (PASP) and pulmonary artery resistance (PVR). PAcT was tested as a screening method for identification and differentiation of pre and post- capillary PH in a cohort of 56 patients (study 1).The ability to calculate PVR non-invasively, using novel echocardiographic measurements, was made by replacing the invasive pressure and flow components that constitutes the foundation of the PVR = (mean pulmonary artery pressure – Pulmonary capillary wedge pressure (PCWP)) /cardiac output), with novel echocardiographic measurements. PVR = mPAP-Chemla – Left atrial strain rate during atrial systole (LASRa) / Cardiac Output-Echo (study 2).Invasively measured left ventricular filling pressure in response to passive leg lifting, and its ability to predict pathological increase in left ventricular filling pressures during supine bicycling, was tested in a population of 85 patients with normal left ventricular ejection fraction (LVEF) and suspicion of CHF based on NT-proBNP levels alone were investigated (Study 3).Finally, an evaluation of standard and novel Doppler echocardiographic parameters, potentially useful in identifying patients who may develop increased filling pressures during passive leg lifting (PLL), was carried out (study 4).Results:Study 1: PAcT correlated negatively with pulmonary artery systolic pressure (PASP) (r = -0.60, p < 0.001) and PVR (r = -0.57, p < 0.001). PAcT of <90 ms had a sensitivity of 84% and a specificity of 85% in identifying patients with PVR ≥ 3.0 WU. Regardless of normal or elevated left sided filling pressures, PAcT differed significantly in patients with normal, compared to those with elevated levels of, PVR (p < 0.01). A significant difference was also found on comparison of the PAcT/PASP ratio (p < 0.01), with a lower ratio among patients with PVR ≥ 3.0. WU.Study 2: We prospectively used Doppler and 2D echocardiography in 46 patients with sinus rhythm which revealed that left atrial strain rate during atrial systole (LASRa) had the highest significant positive correlation with PCWP (r2 = 0.65, P < 0.001). By adopting a linear line of best-fit, LASRa may therefore be substituted for PCWP. Subsequently, LASRa was substituted into the PVR equation. This novel echocardiographically derived PVR calculation, significantly correlated with RHC generated PVR values (r2 = 0.69, P < 0.001) and minor drift (+0.1WU) when assessed by Bland Altman analysis.Study 3: Only 22% (11/51) of patients with elevated NT-proBNP had PCWP above normal levels at rest. However, in response to PLL, 47% of patients developed elevated PCWP, and the majority of this 47% subsequently developed pathological pressure levels while performing supine cycling exercise. Thus, the likelihood of developing high LVFPs during exercise could be determined by PLL, with a sensitivity and specificity of 90%.Study 4: At rest, left atrial volume indexed to body mass index (BMI) (LAVI) and mitral deceleration time (DT) were independently related to PCWP during PLL. However, during PLL univariate regression analysis revealed LASRa (β = -0.77, P <0,001) and E/LVSRe (β = 0.47, P < 0,021) most related to PCWPPLL. Multiple regression analysis fortified LASRa and E/LVSRe as relevant independent parameters useful in the assessment of filling pressure during PLL.Conclusion: A PAcT < 90ms is strongly suggestive of increased PVR (>3.0 WU). Based on study 1, there is clear evidence suggesting that these findings apply irrespective of LVFPs. PAcT can potentially serve as a rapid screening tool for estimation of PVR, however, is not useful if the exact level of PVR is required. In this case, an established PVR calculation method is preferred, and could be performed with higher precision by inclusion of echocardiography derived LASRa as a surrogate measure of PCWP. Insufficient LV compliance results in the inability to cope with increased cardiac preload. Nt-proBNP is secreted when the myocardium is stretched, however only a small portion of patients within the CHF group (study 3) had a high PCWP at rest. Nearly half of the study population with elevated NT-proBNP showed increased PCWP during PLL, which is indicative of underlying ventricular stiffness. By performing this preload increasing maneuver, patients predisposed to developing high filling pressure during supine cycling could be identified with high sensitivity and specificity. Echocardiography, in comparison with RHC, is more accessible, safer and requires less resources and time, thus is an appealing option in the quest to identify additional, non-invasive methods reflective of invasive pressures, which could be useful in the assessment of filling pressure during different loading conditions. LAVI at rest, LASRa and E/LVSRe during PLL, proved independently related to PCWP during PLL.
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