<p>Diss. (sammanfattning) Umeå : Umeå universitet, 1995, härtill 5 uppsatser</p> / digitalisering@umu

Acute haemorrhage is a leading cause of death in trauma. Young women (YW) seem more susceptible to hypovolemic circulatory stress than young men (YM), but the underlying mechanisms are not clear. Elderly subjects are more vulnerable to haemorrhage, with a decreased defence of central blood volume in elderly men, but the defence has not been evaluated in elderly women  (EW). The aims were to assess differences in cardiovascular responses to hypovolemic circulatory stress, emphasizing compensatory mechanisms to maintain central blood volume in YW, EW and in women prone to vaso‐vagal reaction (VW). Lower body negative pressure (LBNP) was used as a model for haemorrhage and to create acute hypovolemic stress. Volumetric techniques were used to assess venous compliance, capacitance and capillary fluid exchange both caused by LBNP in the calf and the response to maintain central blood volume. LBNP induced a comparable hypovolemic stimulus in YW and YM, with lower calf venous compliance and capacitance but higher net capillary fluid filtration in YW. YW responded with smaller vasoconstriction without association between P‐NE and peripheral vascular resistance in contrast to YM. Venous capacitance response was decreased with time in YW. Further, net capillary fluid absorption from peripheral tissues to central circulation was decreased in YW in response to hypovolemic stress. All in all, this indicates less efficiency to defend central blood volume in young women. Calf venous compliance and capacitance was maintained in EW compared to YW but capillary filtration was decreased, implying reduced capillary function with age. With increasing transmural pressures however, filtration and capillary filtration coefficient (CFC) increased indicating increased capillary susceptibility to transmural pressure load in dependent regions with age. Heart rate increase was attenuated in EW while peripheral vascular conductance was maintained suggesting reduced cardiovagal baroreceptor function in response to hypovolemia with age. Venous capacitance response and fluid absorption from peripheral tissues to central circulation were decreased with age, indicating less efficiency to defend central blood volume. LBNP induced a slower hypovolemic stimulus in VW compared with nonvagal women. Further, the cardiopulmonary baroreflex was less efficient, and the venous capacitance response from peripheral tissues to central circulation was decreased, which may explain their susceptibility to orthostatic challenge.

digitalisering@umu.se

The spectrum of cardiovascular diseases is the leading cause of morbidity and mortality globally. Early assessment and treatment of these conditions, acquired as well as congenital, is therefore of paramount importance.   The human heart has a great ability to adapt to various hemodynamic conditions by cardiac remodeling. Pathologic cardiac remodeling can occur as a result of cardiovascular disease in an effort to maintain satisfactory cardiac function. With time, cardiac function diminishes leading to disease progression and subsequent heart failure, the end-point of many heart diseases, associated with very poor prognosis.   Within the normal cardiac ventricles blood flows in highly organized patterns, and changes in cardiac configuration or function will affect these flow patterns. Conversely, altered flows and pressures can bring about cardiac remodeling. In congenital heart disease, even after corrective surgery, cardiac anatomy and thereby intracardiac blood flow patterns are inherently altered. The clinically most available imaging technique, ultrasound with Doppler, allows only for one-directional flow assessment and is limited by the need of clear examination windows, thus failing to fully assess the complex three-dimensional blood flow within the beating heart. Cardiovascular magnetic resonance imaging (CMR) with phase-contrast has the ability to acquire three-dimensional (3D), three-directional time resolved velocity data (3D + time = 4D flow data) from which visualization and quantification of blood flow patterns over the complete cardiac cycle can be performed. Four functional blood flow components have previously been defined based on the blood route and distribution through the ventricle, where the inflowing blood that passes directly to the outflow is called Direct flow. From these components, various quantitative measures can be derived, such as component volumes and kinetic energy (KE) throughout the cardiac cycle. In addition, the 4D flow technique has the ability to quantify and visualize turbulent flow with increased velocity fluctuations in the heart and vessels, turbulent kinetic energy (TKE).   The technique has been developed and evaluated for assessment of left ventricular (LV) blood flow in healthy subjects and in patients with dilated dysfunctional left ventricles, showing significant changes in blood flow patterns and energetics with disease. There is however still no study addressing the gap in the spectrum from the healthy cohorts to patients with moderate to severe left ventricular remodeling. In Paper III, 4D flow CMR was utilized to assess LV blood flow in patients with subtle LV dysfunction, and a shift in blood flow component volumes and KE was seen from the Direct flow to the non-ejecting blood flow components.   In patients with both left- and right-sided acquired and congenital heart disease, right ventricular (RV) function is of great prognostic significance, however this ventricle has historically been somewhat overseen. With its complex geometry, advanced physiology and retrosternal location, assessment of the RV is still challenging and the right ventricular blood flow is still incompletely described. In Paper I, the RV blood flow in healthy subjects was assessed, and the proportionally larger Direct flow component was located in the most basal region of the ventricle and possessed higher levels of KE at end-diastole than the other flow components suggesting that this portion of blood was prepared for efficient systolic ejection. In Paper II, the blood flow was assessed in the RV of patients with subtle primary LV disease, and even if conventional echocardiographic or CMR RV parameters did not show any RV dysfunction, alterations of flow patterns suggestive of RV impairment were found in the patients with the more remodeled LVs.   With improvements of the cardiovascular health care, including the surgical techniques, the number of adult patients with surgically corrected complex congenital heart diseases increases, one of which is tetralogy of Fallot (ToF). Surgical repair of ToF involves widening of the pulmonary stenosis, which postoperatively may cause pulmonary insufficiency and regurgitation (PR). Disturbed or turbulent flow patterns are rare in the healthy cardiovascular system. With pathological changes, such as valvular insufficiency, increased amounts of TKE have been demonstrated. Turbulence is known to be harmful to organic tissues and could be significant in the development of ventricular remodeling, such as dilation and other complications seen in Fallot patients. In Paper IV, the RV intraventricular TKE levels were assessed in relation to conventional measures of PR. Results showed that RV TKE was increased in ToF patients with PR compared to healthy controls, and that these 4D flow-specific measures related slightly stronger to indices of RV remodeling than the conventional measures of PR.   4D flow CMR analysis of the intracardiac blood flow has the potential of adding to pathophysiological understanding, and thereby provide useful diagnostic information and contribute to optimization of treatment of heart disease at earlier stages before irreversible and clinically noticeable changes occur. The flow specific measures used in this thesis could be utilized to detect these alterations of intracardiac blood flow and could thus act as potential markers of progressing ventricular dysfunction, pathological remodeling or used for risk stratification in adults with early repair tetralogy of Fallot. Visualizations of intracardiac flow patterns could provide useful information to cardiac/thoracic surgeons pre- and post-operatively.

<p>2022-03-21</p>

SAMMANFATTNING Bakgrund: Hjärtinfarkt är en av våra vanligaste folksjukdomar som drabbar den vuxna befolkningen och är en vanlig dödsorsak. Sjukdomen kan vara ärftligt betingad men är även en välfärdssjukdom, där det går att påverka riskfaktorer för att insjukna och återinsjukna i hjärtinfarkt. Syfte: Syftet var att beskriva sekundärpreventiva omvårdnadsåtgärder i primärvården för att förebygga återinsjuknande i hjärtinfarkt hos vuxna. Metod: En litteraturstudie med strukturerad systematisk sökstrategi som är baserad på 12 stycken kvantitativa vetenskapliga artiklar med experimentell design. Sökningen gjordes i databasen PubMed. Kvalitetsgranskning skedde med hjälp av Joanna Briggs Checklist for Randomized control trials. Huvudresultat: De flesta studierna visade att interventioner i form av stöd och utbildning gav positiva effekter på återinsjuknande i hjärtinfarkt och patientrelaterade riskfaktorer. Genom interventioner kan de uppnå högre livskvalité, minskat återinsjuknande, hälsosammare liv med mindre stress, bättre motionsvanor, lägre BMI, minskat rökande, bättre följsamhet till läkemedelsanvändning och bättre egenvårdsförmåga. Interventionerna bestod av olika utbildningsprogram som sjuksköterskeledda egenvårdsprogram eller teoribaserade program, webbaserade fjärrutbildningar, telefonapplikationer, telefonuppföljningssamtal, handböcker, mail eller hemutbildningskit med informationsbroschyrer. Denna litteraturstudie visar att genom sekundärpreventiva omvårdnadsåtgärder så kan patienternas hälsa förbättras och de får högre livskvalité och mindre risk att återinsjukna i hjärtinfarkt. Genom att ge patienten information, utbildning och råd så kan sjuksköterskan vägleda och stödja patienterna att utveckla sin förmåga till egenvård. Detta stämmer överens med Orems teori om egenvårdsbalans. Slutsats: Utbildningsinsatser i någon form efter en hjärtinfarkt har visat ge goda effekter på patienters hälsa och minska risken för återinsjuknande.  Nyckelord: förebyggande hälsovård, hjärtinfarkt, hälsofrämjande arbete, sekundär sjukdomsprevention.

Background As a major cause of morbidity and mortality treatment of venous thromboembolism is important, with the correct use of anticoagulants it is possible to greatly reduce both mortality and morbidity. Warfarin is among the most widely used anticoagulants being effective in treatment and prevention of venous thromboembolism with few negative side effects other than bleeding complications. With a narrow therapeutic window warfarin treatment requires constant monitoring and adjustments to stay effective without an increased bleeding risk. The aim of this thesis was to study the efficacy and safety of warfarin treatment in venous thromboembolic disease. Methods Using AuriculA, the Swedish national quality register for atrial fibrillation and anticoagulation, a cohort was created of patients registered with warfarin treatment during the study time January 1st 2006 to December 31th 2011, including all different indications for anticoagulation. In all four studies the study design was retrospective with information added to the cohort from the Swedish national patient register about background data and endpoints in form of bleeding complications in all studies and thromboembolic events in study 1 and 2. In study 3 and 4 information was added from the cause of death register about occurrence of death and in study 3 cause of death. In study 3, information from the prescribed drugs register about retrieved prescriptions of acetylsalicylic acid was added. Results In study 1 the mean TTR was found to be high both among patients managed at primary healthcare centres and specialised anticoagulation clinics at 79.6% and 75.7%. There was no significant difference in rate of bleeding between the two types of managing centres being 2.22 and 2.26 per 100 treatment years. In study 2 no reduction in complication rate with increasing centre TTR was seen for patients with atrial fibrillation with few centres having centre TTR below 70% (2.9%), in contrast to previous findings by Wan et al(1). For those with warfarin due to VTE where a larger proportion of the centres had centre TTR below 70% (9.1%) there was a reduction in complication rate with increasing centre TTR. Among the 13859 patients with treatment for VTE in study 3 age (HR 1.02, CI 95% 1.01-1.03), hypertension (HR 1.29, CI 95%1.02-1.64), Cardiac failure (HR 1.55, CI 95% 1.13-2.11), chronic obstructive pulmonary disease (HR 1.43, CI 95% 1.04- 1.96), alcohol abuse (HR 3.35, CI 95% 1.97-5.71), anaemia (HR 1.77, CI 95% 1.29-2.44) and a history of major bleeding (HR 1.75, CI 95% 1.27-2.42) increased the risk of bleeding during warfarin treatment. In study 4 both those with high iTTR and those with low INR variability had a low rate of bleedings at 1.27 (1.14-1.41) or 1.20 (0.94-1.21) per 100 treatment years compared to those with low iTTR and high INR variability having a rate of bleeding at 2.91 (2.61-3.21) or 2.61 (2.36-2.86) respectively. Those with the combination of both low iTTR and high INR variability had an increased risk of bleeding, hazard ratio HR 3.47 (CI 95 % 2.89-4.17). The quartile with both the lowest iTTR and the highest INR variability had an increased risk of bleeding with a hazard ratio 4.03 (3.20-5.08) and 3.80 (CI 95%, 3.01-4.79) compared to the quartile with the highest iTTR and lowest INR variability. Conclusion It is possible to achieve a safe warfarin treatment both in specialised anticoagulation centres and in primary health care. At initiation of treatment some of the patients at high risk of bleeding can be identified using knowledge about their background. With the use of quality indicators as TTR and INR variability during treatment those at high risk of complications can be identified and analysing treatment quality on centre level gives an opportunity to identify improvement areas among managing centres. With the addition of new treatment options warfarin can still be the most suitable option for some patients, being safe and effective when well managed.

The major polyunsaturated fatty acid (PUFA) in the western diet is linoleic acid (LA), which is considered to be the major source of tissue arachidonic acid (AA), the principal precursor for the vaso-active eicosanoids via the cyclooxygenase enzymatic pathway. However, dietary AA may contribute significantly to tissue levels of AA in humans, leading to an increase in the production of eicosanoids, particularly the platelet aggregating, vasoconstricting, thromboxane (TXA2), hence increasing thrombosis risk. The aims of this study were to determine the extent to which dietary AA contributed to prostacyclin (PGI2) and TXA2 production in vivo and whether dietary long chain (LC) n-3 PUFA have a modulating influence on the metabolism of AA to these vaso-active eicosanoids. A gas chromatography -mass spectrometry (GCMS) method for urinary PGI2-M determination and a tandem GCMS/MS method for urinary TXA2-M determination were perfected for use within our laboratory (with the assistance of Dr Howard Knapp, University of Iowa and Professor Reinhard Lorenz, Ludwig Maximilian's University, Munich, respectively). An initial animal study compared the in vitro production of PGI2 by aorta segments with the whole body in vivo production of PGI2 in rats fed ethyl arachidonate or the ethyl ester of eicosapentaenoic acid (EPA), at levels many times higher than encountered in human diets. During AA feeding both measures of PGI2 increased, although in vitro TXA2 production was not affected. EPA feeding lowered in vitro TXA2 and in vivo PGI2. Prior to determining the effects of AA and LC n-3 PUFA in humans, a study was carried out to determine the AA and LC n-3 PUFA content of foods and from these, an estimate of the mean daily intake of AA and other LC PUFA. Eggs, organ meats and paté were found to be the richest sources of AA. Of the meat and fish analysed, white meat was found to be relatively rich in AA but poor in LC n-3 PUFA. Lean red meat, particularly kangaroo had similar LC n-3 PUFA and AA content. Fish, although rich in AA, had extremely high levels of LC n-3 PUFA. The calculated mean daily intakes of AA in Australian adults was 130mg (males) and 96mg (females). For total LC n-3 PUFA intake, the mean daily values were 247mg (males) and 197mg (females). Two human pilot studies involving dietary intervention trials examined the effects of dietary AA and AA plus long chain n-3 PUFA on thrombosis risk, gauged by the change in the ratio of PGI2 / TXA2 as well as alterations to other recognised risk factors, such as lipoprotein lipids and platelet aggregation. The desired dietary amounts of AA and LC n-3 PUFA were achieved in the first study by combining food items with known levels of each fatty acid. In the second study, where a diet with approximately equal quantities of AA and LC n-3 PUFA was being examined, kangaroo meat was consumed, following a low-fat vegetarian diet used as a baseline. Diets rich in AA alone (~500mg/day) increased plasma phospholipid (PL) AA levels, PGIi and TXA2 production. When foods containing equal quantities of AA and EPA (∼500mg/day of each) were fed to subjects PGI2 increased, with no change in TXAs production. Low fat vegetarian diets lowered PGI2 production, the level of which was reestablished by an AA rich diet (∼300mg AA/day + ∼260mg/day LC n-3 PUFA) of kangaroo meat. However, TXA2 production was not altered. A final, larger human dietary intervention trial then examined the effects of diets relatively rich in AA alone, AA plus LC n-3 PUFA and LC n-3 PUFA, on the ratio of PGI2/TXA2- The dietary sources of these fatty acids were white meat, red meat and fish, respectively. Each contained a mean level of AA of ∼140mg/day, with varying LC n-3 PUFA levels (59, 161 and 3380mg/day, respectively). Neither meat diet altered PGI2 or TXA2 production significantly, despite increasing serum PL AA levels. The fish diet resulted in a decrease in the serum and platelet PL AA/EPA ratio and TXA2 production, thus increasing the PGI2 / TXA2 ratio. These results would indicate that stores of AA in the body are sufficiently high to have effectively saturated the cyclooxygenase pathway for production of both PGI2 and TXA2, thus making any small change in the plasma level of AA due to 'normal' dietary levels, inconsequential. However, as seen in the rat study and the two pilot studies higher dietary levels of AA can increase both PGI2 and TXA2 production. Increases in platelet levels of EPA and DHA were associated with a decrease in TXA2 production, or the maintenance of a constant TXA2 level, while AA tissue levels and PGI2 production increased. This suggests a possible inhibitory effect of LC n-3 PUFA on the metabolism of AA to TXA2, particularly in platelets. From these short term studies, conducted over 2-3 week periods, it can be concluded that diets rich in lean meats can raise plasma AA levels but do not affect TXA2 or PGI2 production, hence are not pro-thrombotic. Diets rich in long chain n-3 PUFA from fish, raise plasma EPA and DHA levels, lower TXA2 production and are anti-thrombotic. Diets which combine equal quantities of AA and LC n-3 PUFA appear to increase PGI2 production while keeping TXA2 production constant. In order for these LC PUFA to have a significant effect on eicosanoid production the dietary intake of these fatty acids through foods such as red meat or white meat would have to be higher than average current Australian consumption levels.

This thesis addresses the health economic evaluation of community-based interventions against cardiovascular disease (CVD), with special emphasis on the Västerbotten Intervention Project (VIP), run since 1985. The framework is a simple evaluation model consisting of two parts; the selection and measurement of empirical consequences caused by the project under evaluation (e.g. changes in mortality, well-being, use of resources) and a set of values (e.g. efficiency, equity) aimed at assessing the goodness of these consequences. The project’s effects on CVD were predicted by means of risk factors measured in Norsjö between 1985-1990, applied to an epidemiological model based on a logistic risk equation derived from the Framingham population. Cost per life-years saved ranged from £14 900 to net savings, depending on the assumptions. The favourable cost-effectiveness in this kind of intervention has earlier been predicted from theoretical models, but this is the first study based on real experiences from contemporary community-based interventions against CVD. Furthermore, all social classes have benefited from the intervention. Also potential adverse effects in the form of excess mortality due to low cholesterol levels were investigated, and they were negligible in comparison with the health gains. The value of an intervention from a citizen’s perspective was investigated through an interview study (n≈100) in accordance with the contingent valuation method. Great expectations concerning mortality effects on the community level and future savings in health care were good predictors for assigning the intervention a high value. On the contrary, personal benefits in the form of a decreasing risk for CVD had no positive association with the value of the intervention. Hence, the consequences that the cost-effectiveness analysis accounts for - mortality and savings - coincide with the most valuable consequences from the citizen's perspective. In a democracy, the set of values used to determine the success or failure of a programme like a prevention project must agree with values held by the majority of the citizens. Therefore, the attitudes to ethical values among Swedish politicians (n≈450) responsible for health care have been mapped. The support for the health maximization principle was weak, and a trade-off between efficiency and equity was preferred. About 70% of the respondents were prepared to sacrifice health gains to achieve increased equity. / digitalisering@umu

Ischemic heart disease (IHD) is a leading cause of global mortality. Emerging evidence suggests a potential role of the gut microbiome in IHD development. The present study explored the association between alpha diversity, representing microbial richness and evenness, and IHD, as well as the relationship between specific gut microbial species and IHD risk. The study uses a longitudinal design with data from the two cohorts within the Swedish Infrastructure for Medical Population-based Life-course and Environmental Research (SIMPLER). Survival analysis is employed to calculate the hazard rate for all associations. Because of thecompositionality of the gut microbiome species-level data a centered log-ratio (CLR) transformation is applied before the main analysis. We find no associations between alpha diversity and risk of IHD in the age and sex-adjusted model as well as in the main model adjusted for age, sex, smoking, education, physical activity, hypertension, high cholesterol, and intakes of fish, red and processed meat, fermented dairy, fruit and vegetables and alcohol. Five species are found to be statistically significantly associated with IHD in the main model before correction for multiple testing, which is statistically non-significant after the correction.