Today, invasive coronary angiography is still the gold standard to perform the diagnosis of coronary artery disease. But it is an invasive procedure that carries non negligible morbidity (1.5%) and mortality (0.15%), and results in high costs. Less invasive and more cost-effective techniques are highly desirable. Over the past 15 years, substantial advances have been made in non-invasive cardiac imaging. In the first part of this work, we prospectively evaluated the diagnostic accuracy of 40-slice multidetector CT (MDCT) to detect coronary artery disease prior to cardiac valve surgery in 82 patients. On a per-patient basis, MDCT correctly identified 14/15 patients with (sensitivity 93%) and 60/67 patients without coronary disease (specificity 90%). Performing invasive angiography only in case of abnormal CT might have avoided invasive angiography in 60/82 (73%) patients without coronary disease. Thus, MDCT could be potentially useful in the preoperative evaluation of such patients, allowing to avoid systematic cardiac catheterization in a large number of patients. Magnetic resonance coronary angiography (MRCA) has also emerged as a promising alternative due to the lack of ionizing radiation and absence of iodinated contrast injection. Therefore, we compared diagnostic accuracy of whole-heart MRCA and MDCT, against QCA, to identify >50% stenosis basis in 77 patients. WH-MRCA acquisition failed in a high number of patients. This was caused by an unstable breathing pattern or drift of the diaphragm position. Because of higher success rate, MDCT had higher diagnostic accuracy than WH-MRCA to detect coronary stenosis. Thus MDCT is superior to WH-MRCA, however WH-MRCA can perform as well as CT in interpretable segments with adequate image quality. In the second part of this work, to evaluate whether MDCT and cardiac magnetic resonance (cMR) might allow simultaneous assessment of aortic valve area (AVA), we compared measurements of AVA by MDCT to cMR, transesophageal and transthoracic echocardiography. AVA by MDCT and cMR correlated highly with AVA by other techniques. In our study, we compared 3 planimetric approaches to AVA calculated by the continuity equation using TTE. We did observe excellent correlations between planimetric and continuity equation-derived AVA, but all 3 planimetric measures were found to overestimate continuity equation AVA. A potential explanation for this observation could be that we measure different aortic valve orifices. Indeed planimetric techniques measure the true dimensions of the anatomical orifice, whereas the continuity equation measures the "effective" orifice area. The ability of MDCT and cMR to accurately assess aortic valve area at the time of non-invasive coronary imaging, places these techniques in a strong position for the comprehensive assessment of such patients. However, despite these good results, it must nonetheless be emphasized that to be acceptable in daily clinical practice, a strategy in which invasive coronary angiography would not be performed systematically but rather selectively in only a subset of patients, requires a perfect sensitivity for disease detection in individual patients. Unfortunately, the present work shows that MDCT and WH-MRCA have not yet reached such a level of accuracy. Finally, these tests are not a substitute for other imaging techniques in all cardiovascular conditions. Unlike an echocardiogram machine, the MRI and MDCT scanners cannot be brought to the bedside of an acutely ill patient.

In patients with unstable coronary artery disease, this study evaluated the degree of inflammation and coagulation activity, relations to myocardial cell damage, prognosis, and influences of randomisation to 72 h infusion with three different doses of inogatran, a direct thrombin inhibitor (n=904), or unfractionated heparin (n=305). Anticoagulant treatment effects were evaluated with aPT time. In inogatran treated patients with aPT times ≥ 44 s (median), the 7-days event rate - death, myocardial infarction or refractory angina – was 11.6 %, compared to 6.6 % with aPT times < 44 s (p=0.01). Higher aPT times was related to improved outcome during heparin treatment. Markers of inflammation, i.e. fibrinogen and C-reactive protein (CRP), and coagulation, i.e. prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), soluble fibrin (SF) and D-dimer were analysed in serial samples (n=320). High fibrinogen, F1+2 and D-dimer levels persisted at 30 days. Patients with myocardial damage, detected by elevated troponin, had higher levels of all markers except TAT. Ischemic events occurred at 30 days in 17 % of patients with high (pre-treatment top tertile) and 8.5 % of patients with lower fibrinogen levels (p=0.03), while high CRP levels only were related to increased mortality. At 30 days, patients with high compared to low pre-treatment levels of TAT or SF had 40 % lower event rate. Patients with early decreased compared to raised F1+2 or TAT levels during treatment had 50 % lower 30-days event rate (p<0.05). Conclusions: The aPT time is an inappropriate indicator of antithrombotic efficacy. The raise in fibrinogen in the acute phase is sustained, and indicates risk of thrombosis and new ischemic events. The pronounced CRP elevation is transient, but associated with increased mortality. Higher coagulation activity may identify patients with a thrombotic condition as the major cause of instability, who are best responders to anticoagulant therapy. However, reactivation of coagulation activity with raised risk of ischemic events is a concern at cessation of treatment.

Stroke is the third leading cause of morbidity and mortality in the industrialized world. Subarachnoid hemorrhage (SAH), the least common form of stroke, is one of the most demanding diseases treated in neurointensive care units. Cerebral ischemia may develop rapidly, and has a major influence on outcome.To be able to save parts of the brain that are at risk for ischemic brain damage, there is a need for reliable monitoring techniques. Understanding the pathophysiology of cerebral ischemia is a prerequisite both for the correct treatment of these diseases and for the development of new monitoring techniques and treatment modalities. The main aim of this thesis was to gain insight into the mechanisms of cerebral ischemia by studying early hemodynamic and metabolic changes with positron emission tomography and neurochemical changes with microdialysis. A secondary aim was to evaluate the potential of these techniques for detecting ischemia and predicting the degree of reversibility of ischemic changes. Early changes in cerebral blood flow (CBF) and metabolism (CMRO2) were studied with repeated positron emission tomography in an experimental model (MCAO) of transient focal ischemia, and in SAH patients. CMRO2 was superior to CBF in discriminating between tissue with irreversible damage and tissue with the potential for survival in the experimental model. A metabolic threshold of ischemia was found. Neurochemical changes in the ischemic regions were studied simultaneously with microdialysis. Extracellular concentrations of glucose, lactate, hypoxanthine, glutamate and glycerol were measured, and the lactate/pyruvate (LP) and lactate/glucose ratios were calculated. Changes in all the microdialysis parameters were related to the degree of ischemia (severe ischemia or penumbra). Especially the LP ratio and glycerol were found to be robust and specific markers of ischemia. In the patients, hemodynamic and metabolic changes were common, but diverse in the acute phase of SAH, and it was suggested that these changes may contribute to an increased vulnerability for secondary events and the development of secondary ischemic brain damage.

Randomised controlled trials (RCT) have demonstrated a net benefit of carotid endarterectomy (CEA) in stroke prevention for patients with severe carotid artery stenosis as compared to best medical treatment. Results in routine clinical practice must not be inferior to those in the RCTs. The carotid arteries are clamped during CEA which may impair the cerebral perfusion. The aim of this thesis was to assess population-based outcomes from CEA, investigate risk factors for perioperative complications/late mortality and to evaluate effects of carotid clamping during CEA. In the Swedish vascular registry 6182 CEAs were registered during 1994-2003. Data on all CEAs were retrieved, analysed and validated. In the validation process no death or disabling stroke was unreported. The perioperative stroke or death rate was 4.3% for those with symptomatic and 2.1% for asymptomatic stenosis (the latter decreasing over time). Risk factors for perioperative complications were age, indication, diabetes, cardiac disease and contralateral occlusion. Median survival time was 10.8 years for the symptomatic and 10.2 years for the asymptomatic group. Tolerance to carotid clamping during CEA under general anaesthesia was evaluated in 62 patients measuring cerebral oximetry, transit time volume flowmetry and stump pressure. High internal carotid artery flow before clamping and low stump pressure was associated with decreased oxygenation after clamping suggesting shunt indication. In 18 patients undergoing CEA, jugular bulb blood samples demonstrated significantly altered levels of marker for inflammatory activation (IL-6) and fibrinolytic activity (D-dimer and PAI-1) during carotid clamping as compared to radial artery levels. This indicates a cerebral ischaemia due to clamping although clinically well tolerated. In conclusion, the perioperative outcome after CEA in Sweden compared well with the RCTs results. Tolerance to carotid clamping may be evaluated by combining stump pressure and volume flow measurements. Although clinically tolerated clamping may induce a cerebral ischaemic response.

Kvantifisering av hjertets muskelfunksjon med tøyning og tøyningshastighet målt med ultralyd for vurdering av koronar sykdom. Automatisert metode versus manuell ved akutt hjerteinfarkt og ultralyd stress test. Vanligvis måles hjertets muskelfunksjon med ultralyd, en mye brukt metode for å diagnostisere hjertesykdommer. Vurderingen av muskelfunksjonen baserer seg i dag på en subjektiv visuell gradering av bevegelsen av hjertemuskelen, og dette krever erfaring. En ny automatisert diagnostisk ultralydsmetode basert på måling av hastigheten i hjertemuskelen gir et kvantitativt mål på muskelens tøyning og sammentrekning. Den nye metoden gir ny og mer detaljert informasjon om hjertets funksjon og om pasientens prognose enn vanlig ultralydsvurdering. Den nye metoden er mer presis ved oppfølgning etter hjerteinfarkt. Et hjerteinfarkt gir nedsatt bevegelse av muskelen og måles med den nye metoden som nedsatt hastighet som muskelen forkortes med. Små forandringer i den skadde hjertemuskelen, ikke alltid synlige for øyet, kan mer nøyaktig følges over tid med den nye metoden. Utbredelsen av hjerteinfarktet kan også vurderes mer nøyaktig. Det samme gjelder når angina vurderes under belastning. Når en pasient ikke kan sykle eller gå på tredemølle brukes en medisinsk belastningstest. Ved å belaste hjertet med et medikament som øker hjertemuskelens arbeid samtidig med en ultralydundersøkelse, kan vi oppdage redusert blodforsyningsreserve i hjertet. Stresstesten hjelper til med å vurdere om en trang blodåre bør åpnes etter et hjerteinfarkt, og til å vurdere pasienters risiko for hjertekomplikasjoner før en større operasjon. Den nye metoden gir i tillegg mer informasjon om den langsiktige prognosen sammenlignet med den gamle metoden. Vi har funnet at den nye ultralydsmetoden er mer presis (gir større diagnostisk treffsikkerhet i diagnostikk av koronarsykdom) sammenlignet med den gamle. Måling av sammentrekningshastigheter i hjertemuskelen ble utviklet og testet på Institutt for sirkulasjon og bildediagnostikk ved NTNU av Andreas Heimdal og Asbjørn Støylen i 1998. Metoden trengte teknisk videreutvikling og testing i et større pasientmateriale. Metoden har ikke fått stor utbredelse på sykehusene pga støyfylte kurver og tidskrevende analyser, men med denne automatiserte metoden blir brukervennligheten større som muliggjør klinisk bruk. / Paper I and II preprinted with kind permission of Elsevier, sciencedirect.com

Even if popliteal artery aneurysm (PAA) is the most common peripheral aneurysm, no single surgeon or institution has enough patients to study this disease with appropriate scientific methods, and no population-based investigation exists. PAA epidemiology, treatment, management, and outcome were studied in a population-based study of 571 patients (717 legs) primarily operated on for PAAs and 100 episodes of preoperative thrombolysis in Sweden between 1987 and 2002. Patients were identified in the Swedish Vascular Registry and case-records were reviewed. Information on amputation and survival was obtained for all patients, and 190 patients were re-examined with ultrasound, after mean 7.2 years (range 2-18) Median age was 71 years; 5.8% were women. Patients with unilateral PAA had AAA in 28%, increasing to 38% when PAAs were bilateral. Crude survival was 91.4% at one and 70% at five years, significantly lower than among age and sex matched controls. The cumulative incidence for operation of PAA in Sweden was estimated to 8.3/million person year. One-year amputation-rate was 8.8 %, increasing to 11% after follow-up (7.2 years). Independent risk factors for amputation within one year were poor run-off, age, emergency procedure, and prosthetic graft. Run-off was improved by preoperative thrombolysis among 87% of legs, when acute ischemia. After surgical repair with a medial approach the risk of late expansion of the aneurysm was 33%, with a posterior approach 8% , p=0.014. Among 190 re-examined patients, 108 (57%) had at least one additional aneurysm at index-operation, increasing to 131 (68%) at re-examination, the total number of aneurysms increasing by 42% (from 244 to 346). Conclusions: Multiple aneurysms are common among patients operated on for PAA. Preoperative thrombolysis improves run-off and decreases the amputation-rate in PAAs with acute ischemia. Vein grafts do better than prosthetic grafts, especially when a long bypass is needed. Posterior approach, when possible, reduces the risk of late expansion. A complete examination of the aorto-iliac and femoro-popliteal arteries is warranted at the time of surgery. All patients should be kept under life-long surveillance in order to detect and treat newly developed aneurysms timely. Normal arterial segments should be re-examined after three years.

Pulmonary hypertension syndrome (PHS) in broiler chickens adequately represents idiopathic pulmonary arterial hypertension (IPAH) in humans, a condition that affects 300 new patients each year in the US. The factors that trigger IPAH are poorly understood but an increase in reactive oxygen species in the circulation coincides with the onset of these conditions. Broiler chickens (n=583) were fed a control diet (CTL), containing 3,200 kcal of ME / kg of feed, 23% CP, 1.55% (wt / wt) Arginine (Arg) and 40 IU of VE (alpha-tochopherol) / kg of feed; a high-Arg diet (HA), CTL diet plus 0.8% (wt / wt) supplemental L-Arg HCl; or a high Arg and vitamin diet (AEC), the HA diet plus 200 IU ?-tochopherol / kg of feed and 500 mg of ascorbic acid / L of drinking water 500 mg ascorbic acid / L of water (exp. 1 and 2) or Kg feed (exp. 3). Supplemented broilers were either exposed to hypobaric hypoxia or had a primary bronchus occluded (PBO) to induce PHS. Also, medial thickness was assessed in male broiler and Leghorn (n =80) chickens fed a CTL diet and subjected to pulmonary artery occlusion (PAO). The results show that supplementation with Arg and VE plus VC have an additive effect on the velocity at which the pulmonary arterial pressure returned to basal levels in hypoxic chickens challenged with epinephrine. Also, supplementation increased xanthine oxidase (XO) activity in the vicinity of the pulmonary endothelium with no effect on NAD(P)H-oxidase activity or oxidative stress in hypoxic chickens subjected to PBO. These enzymes are upregulated in humans with IPAH. Furthermore, supplementation reduced pulmonary artery reactivity to phenylephrine in hypoxemic broilers. Unsupplemented broiler chickens had a lower specific lung weight compared to unsupplemented Leghorns. Hypoxemic broilers showed thicker resistant pulmonary arteries and were more hypertensive than hypoxemic Leghorns. Leghorns were more hypoxemic and resistant to PHS than broilers. In conclusion, Arg and VE plus VC show an additive effect in the improvement of cardiovascular performance of hypoxemic broilers as well as in restoring reactivity to phenylephrine in hypoxemic pulmonary rings. Also, supplementation shows an additive effect in restoring XO activity in hypoxic broilers. Leghorns had a better ventilation capacity and better pulmonary vasodilation capacity than broiler chickens.

Sex steroids in general and estrogens in particular – in addition to their effects on the reproductive organs – affect a large number of crucial bodily functions, including “higher” brain functions. Neuropeptides constitute the phylogenetically oldest neurotransmitter system and are currently thought to act mainly during stress, disease or injury. The concentration of galanin is i.a. up-regulated by injury to the nervous system and by estrogen. The main focus of the present thesis was to investigate whether the reported neuroprotective effect of 17β-estradiol in experimental animal stroke models is partially mediated through its effects on galanin and if galanin per se exerts neuroprotective effects in stroke. An exploratory study of the effects of sex steroid concentrations due to gender and pubertal development showed differences in concentrations of i.a. the neuropeptides galanin and neuropeptide Y also in brain regions of female rats important for higher brain functions, including hippocampus and cortex, brain regions not directly involved in reproduction. Puberty brings about changes in several hormonal mechanisms, and our studies showed that the major effect on the concentrations of galanin in various brain regions of ovariectomized (ovx) rats, was brought about by 17β-estradiol. The pathophysiological mechanisms involved in thrombolysis – the current treatment of choice in human stroke – attempts the re-establishment of perfusion (reperfusion) to the lesioned area of the brain. This prompted us to develop a reperfusion stroke model in rats designed to be mild, focal and transient, allowing long-term observation periods of animals thriving well postoperatively. Mortality and morbidity during and after the middle cerebral artery (MCA) occlusion are important confounding factors crucial for the results. Changing anaesthesia from intraperitoneally administered chloral hydrate to isofl urane inhalation anaesthesia using endotracheal intubation and controlled ventilation markedly reduced the mortality rate from 25% to 10.6%, which was even further reduced down to 2.7 % by successively improved surgical skills. Contrary to our initial hypothesis, long-term 17β-estradiol treatment resulted in larger ischemic lesions in our stroke model compared to control treatment. After 3 days the cerebral ischemic lesion area was doubled after 17β-estradiol treatment in rats subjected to 60 min microclip occlusion of the MCA followed by reperfusion. A similar, but not statistically signifi cant difference was found after 7 and 14 days. Three groups studying different types of experimental animal stroke and different doses of 17β-estradiol treatment have recently also demonstrated lack of neuroprotection by 17β-estradiol treatment. Furthermore, large epidemiological clinical studies have recently also reported an increased risk and poorer outcome in postmenopausal women subjected to hormone replacement therapy. The concentrations of galanin-like immunoreactivity in extracts of punch biopsies from the penumbra area after transient MCA occlusion were found unchanged, but were decreased (p=0.015) in the apparently undamaged ipsilateral hippocampus. Galanin administered by continuous intracerebroventricular infusion (2.4 nmol/day) resulted in a 30% larger ischemic lesion compared to controls, measured 7 days after the MCA occlusion. Taken together, these results indicate that galanin in the brain is primarily a factor reacting to ischemic injury rather than a neuroprotective factor in its own right. Very limited information is available about the steady state serum concentrations of 17β-estradiol in response to different modes of administration to rats for days and weeks. The need for this information has become especially apparent during recent years due to the observable dichotomy of estrogens effects – neuroprotective or not – in the various animal models of brain ischemia reported in the current scientific literature. The cause of this dichotomy is likely to be found in the experimental setup, including the mode of administration of 17β-estradiol. Delayed steady state of serum 17β-estradiol concentrations were found when comparing two common modes of exogenous administration of 17β-estradiol – slow-release osmotic pumps vs. daily subcutaneously injections of 17β-estradiol solved in sesame oil – to ovx rats during 2 times 6 weeks crossover treatment. Steady state was reached at week 4 in the daily injections group compared to at week 6 in the slow release osmotic pumps group. Once steady state was reached, the concentration was the same in both groups for the reminder of the experiment (in total 12 weeks). / On the day of the public defence of the doctoral thesis, the status of article V was: Available on line since 24th of May 2005.

Syftet med studien var att undersöka hur patienter som haft en hjärtinfarkt och/eller genomgått en kranskärlsoperation skattar sin oro och nedstämdhet före och efter ett års hjärtrehabilitering samt om det fanns skillnader mellan mäns och kvinnors skattningar. Enkäter innehållande patienters självskattning av oro och nedstämdhet före och efter hjärtrehabilitering, Hospital Anxiety and depression scale (HAD), samlades in från Hälsoinvest i Högbo. Författarna till denna studie valde att samla in enkäter från 1996- 2001. För att få delta i hjärtrehabiliteringen måste patienterna vara i arbetsför ålder och haft hjärtinfarkt och/eller genomgått kranskärlsoperation samt vara icke rökare. HAD- formuläret innehöll sju frågor rörande oro och sju frågor rörande nedstämdhet. Undersökningsgruppen bestod av 115 personer: 34 kvinnor och 81 män. Medelåldern på deltagarna var 52,4 år (range = 33-61 år). Huvudresultatet visade att deltagarna signifikant hade minskat graden av oro och nedstämdhet över tid. Det fanns inga signifikanta skillnader mellan mäns och kvinnors skattningar av oro och nedstämdhet före eller efter hjärtrehabilitering. Kvinnor respektive män minskade signifikant sin grad av oro och nedstämdhet över tid. Denna studie indikerar att hjärtrehabilitering behövs för att minska patienters oro och nedstämdhet i samband med kranskärlssjukdom.

Background Even though more than 600 stroke treatments have been shown effective in preclinical studies, clinically proven treatment alternatives for cerebral infarction remain scarce. Amongst the reasons for the discrepancy may be methodological shortcomings, such as high mortality and outcome variability, in the preclinical studies. A common approach in animal stroke experiments is that A) focal cerebral ischemia is inflicted, B) some type of treatment is administered and C) the infarct sizes are assessed. However, within this paradigm, the researcher has to make numerous methodological decisions, including choosing rat strain and type of surgical procedure. Even though a few studies have attempted to address the questions experimentally, a lack of consensus regarding the optimal methodology remains. Methods We therefore meta-analyzed data from 502 control groups described in 346 articles to find out how rat strain, procedure for causing focal cerebral ischemia and the type of filament coating affected mortality and infarct size variability. Results The Wistar strain and intraluminal filament procedure using a silicone coated filament was found optimal in lowering infarct size variability. The direct and endothelin methods rendered lower mortality rate, whereas the embolus method increased it compared to the filament method. Conclusions The current article provides means for researchers to adjust their middle cerebral artery occlusion (MCAo) protocols to minimize infarct size variability and mortality. / <p>Funding Agencies|County Council of Ostergotland, Sweden||</p>