Peripheral vascular diseases such as peripheral artery disease (PAD) and critical limb ischemia (CLI) are growing at an ever-increasing rate in the Western world due to an aging population and the incidence of type II diabetes. A growing economic burden continues because these diseases are common indicators of future heart attack or stroke. Common therapies are generally limited to pharmacologic agents or endovascular therapies which have had mixed results still ending in necrosis or limb loss. Therapeutic angiogenic strategies have become welcome options for patients suffering from PAD due to the restoration of blood flow in the extremities. Capillary sprouting and a return to normoxic tissue states are also demonstrated by the use of angiogenic cytokines in conjunction with bone marrow cell populations. To this point, it has been determined that spatial and temporal controlled release of growth factors from vehicles provides a greater therapeutic and angiogenic effect than growth factors delivered intramuscularly, intravenously, or intraarterialy due to rapid metabolization of the cytokine, and non-targeted release. Furthermore, bone marrow cells have been implicated to enhance angiogenesis in numerous ischemic diseases due to their ability to secrete angiogenic cytokines and their numerous cell fractions present which are implicated to promote mature vessel formation. Use of angiogenic peptides, in conjunction with bone marrow cells, has been hypothesized in EPC mobilization from the periphery and marrow tissues to facilitate neovessel formation. For this purpose, controlled release of angiogenic peptides basic fibroblast growth factor (FGF-2) and granulocyte-colony stimulating factor (G-CSF) was performed using tunable ionic gelatin hydrogels or fibrin scaffolds with ionic albumin microspheres. The proliferation of endothelial cell culture was determined to have an enhanced effect based on altering concentrations of growth factors and method of release: co-delivery versus sequential. Scaffolds with these angiogenic peptides were implanted in young balb/c mice that underwent unilateral hindlimb ischemia by ligation and excision of the femoral artery. Endpoints for hindlimb reperfusion and angiogenesis were determined by Laser Doppler Perfusion Imaging and immunohistochemical staining for capillaries (CD-31) and smooth muscle cells (alpha-SMA). In addition to controlled release of angiogenic peptides, further studies combined the use of a fibrin co-delivery scaffold with FGF-2 and G-CSF with bone marrow stem cell transplantation to enhance vessel formation following CLI. Endpoints also included lipophilic vascular painting to evaluate the extent of angiogenesis and arteriogenesis in an ischemic hindlimb. Tissue engineering strategies utilizing bone marrow cells and angiogenic peptides demonstrate improved hindlimb blood flow compared to BM cells or cytokines alone, as well as enhanced angiogenesis based on immunohistochemical staining and vessel densities.

The site of confluence of the artery and the portal vein in the liver still appears to be controversial. Anatomical studies suggested a presinusoidal or an intrasinusoidal confluence in the first, second or even final third of the sinusoids. The objective of this investigation was to study the problem with functional biochemical techniques. Rat livers were perfused through the hepatic artery and simultaneously either in the orthograde direction from the portal vein to the hepatic vein or in the retrograde direction from the hepatic vein to the portal vein. Arterial how was linearly dependent on arterial pressure between 70 cm H2O and 120 cm H2O at a constant portal or hepatovenous pressure of 18 cm H2O. An arterial pressure of 100 cm H2O was required for the maintenance of a homogeneous orthograde perfusion of the whole parenchyma and of a physiologic ratio of arterial to portal how of about 1:3. Glucagon was infused either through the artery or the portal vein and hepatic vein, respectively, to a submaximally effective ''calculated'' sinusoidal concentration after mixing of 0.1 nmol/L. During orthograde perfusions, arterial and portal glucagon caused the same increases in glucose output. Yet during retrograde perfusions, hepatovenous glucagon elicited metabolic alterations equal to those in orthograde perfusions, whereas arterial glucagon effected changes strongly reduced to between 10% and 50%. Arterially infused trypan blue was distributed homogeneously in the parenchyma during orthograde perfusions, whereas it reached clearly smaller areas of parenchyma during retrograde perfusions. Finally, arterially applied acridine orange was taken up by all periportal hepatocytes in the proximal half of the acinus during orthograde perfusions but only by a much smaller portion of periportal cells in the proximal third of the acinus during retrograde perfusions. These findings suggest that in rat liver, the hepatic artery and the portal vein mix before and within the first third of the sinusoids, rather than in the middle or even last third.

This thesis describes the management of patients treated with mechanical circulatory support devices for short- or long-term use. Twenty-four patients suffering from postcardiotomy heart failure were treated with a minimally invasive axial flow pump. The device was effective in unloading the failing left ventricle and in maintaining an adequate systemic circulation. The principles of perioperative monitoring, and pharmacological therapy are outlined. The pump was also used as an alternative to the heart-lung machine in conjunction with coronary artery bypass surgery. Together with a short-acting β-blocker, esmolol, the heart was decompressed and heart motion was reduced, facilitating bypass surgery on the beating heart. The anesthesiological considerations using this method are described. An implantable left ventricular assist device was used as a bridge to heart transplantation in 10 patients. We were interested in assessing the possibility to establish such a treatment program at a non-transplanting center. A multidisciplinary approach was enabled thanks to the organization of our Heart Center and due the close collaboration with our transplant center at Lund University. As one of the first centers in Europe, we established a well-functioning program with good results. Nine out of 10 of the bridge patients, with treatment times varying between 53 to 873 days, survived pump treatment and were eventually transplanted. The device proved to be powerful enough to support the failing heart and enable rehabilitation of the patients. Outpatient management became simpler when using the electrical device with belt-worn batteries. The uncertain durability and the high risk of device-related complications are shortcomings that limit its potential for more permanent treatment of heart failure. A new generation of small implantable axial blood flow pumps has therefore been developed. The principles of these pumps are based on the first generation axial flow pumps evaluated in this thesis. After several years of basic research and experimental studies, the first human implants have been performed. In the thesis, the hemodynamic effects of such a novel axial flow pump have been evaluated in an acute heart failure model. This technology holds great promise, both as a bridge to heart transplantation, and as a permanent circulatory support system. / On the day of the public defence the status of the article IV was: Submitted for publication.

Sleep is a basic need, important to physical and psychological recovery. Insomnia implies sleep-related complaints, such as difficulty falling asleep, difficulty staying asleep, early awakening, or non-restorative sleep (NRS) in an individual who has adequate circumstances and opportunity to sleep.  Insomnia is also related to impairment of daytime functions. The prevalence of reported sleep disturbances varies between 15% and 60% in patients with coronary artery disease (CAD) up to five years after intervention. Disturbed sleep may have a negative impact on self-care capacity and behaviours. Little attention has been given to evaluation of sleep promotion through individualized non-pharmacological interventions among CAD patients. The overall aim of this thesis was to describe the impact of sleep quality and disrupted sleep on health-related quality of life (HRQoL) in patients with stable CAD, in comparison to a population-based group. The objective was also to evaluate an individualized non-pharmacological programme to promote self-care in sleep. Four studies were conducted during seven years, starting in 2001. Patients from six hospitals in the south of Sweden were invited to participate. In addition, an age and gender matched population-based group was randomly selected during the same period as the patients and was used for comparison with the CAD patients in two of the studies. Data was collected through interviews, self-reported questionnaires, a study specific sleep diary and actigraphy registrations. A pretest-posttest control design was used to evaluate whether an individualized non-pharmacological intervention programme could promote self-care in sleep-activity in CAD patients. The results showed a high prevalence of insomniac CAD patients out of whom a large proportion were non-rested insomniacs. This showed that NRS is one of the core symptoms of insomnia. On the other hand there were weak or non-significant gender differences with increasing insomnia severity. Severe insomniac CAD patients displayed a two or threefold higher presleep arousal or anxiety score and were more limited in taking physical exercise than the general population. Generally low sleep efficiency (SE%) was revealed in the studies, particularly among severe non-rested insomniac CAD patients. Among CAD patients, the individualized non-pharmacological programme to promote self-care in sleep-activity indicated improvements in sleep and HRQoL. This thesis elucidates the importance of focusing on the individual’s perception of their sleep-activity and health in their local context and supporting self-care management. Furthermore, it is of importance that nurses set individual goals together with the patient in order to increase self-efficacy to promote HRQoL.

In contrast-enhanced magnetic resonance angiography (CE-MRA),vascular signal is produced by the acquisition of a T1-weighted magnetic resonance imaging scan while the presence of a contrast agent induces a low T1 in blood. In this thesis,CE-MRA of the aortoiliac arteries was evaluated.Different contrast agents and techniques for synchronisation of the scan with the contrast bolus passage were assessed. In 30 patients with clinically suspected iliac artery stenoses,contrast-enhanced magnetic resonance angiography was compared with duplex ultrasound scanning and digital subtraction x-ray angiography (DSA),with intraarterial pressure measurements as reference method. No statistically significant differences in sensitivity or specificity were observed between the techniques regarding the detection of hemodynamically significant iliac stenoses. The use of multiplanar reformats and source images in the MRA examinations was of value for the differentiation between high-grade stenoses and occlusions. With DSA as reference method, MRA had significantly higher sensitivity and specificity than duplex for the detection of ≥50% stenoses. In fourteen patients examined with iliac artery MRA, differences in contrast arrival time of up to 7 s was observed between the aorta and the common femoral artery.A dual-station timing technique adjusting for this difference was found feasible. Compared with a fluoroscopically triggered technique (n=13),which is used in clinical rotine, the dual-station technique was more reliable for the visualisation of distal vessels. In a clinical phase II study comparing different doses of t he contrast agent gadobenate dimeglumine for the enhancement of iliac artery MRA, a significant improvement in subjective diagnostic quality compared with time-of-flight MRA was found at all doses from 0.025 mmol/kg.An increasing trend with dose was observed up to a dose level of 0.05-0.1 mmol/kg. In a phase I clinical study on the intravascular, iron oxide contrast agent NC100150 Injection, a positive dose response was observed for abdominal vascular enhancement, with the highest contrast-to-noise ratio observed at 4.0 mg Fe/kg bw at 1.5 T and at 2.5-4 mg Fe/kg bw at 0.5 T.At 1.5 T higher R2*values were calculated for the aorta than for the IVC.

α1- and α2-Adrenoceptors are involved in various physiological events in the eye: blood flow regulation, aqueous humor dynamics and pupil regulation. The α1- and α2-adrenoceptors can be further subdivided into six subtypes (α1A, α1B, α1D, α2A , α2B, and α2C ). Currently available α1- and α2-adrenergic drugs are not selective for the different subtypes and some ocular adrenergics have undesirable side-effects, both local and systemic. A better understanding of the subtype distribution in the eye would be useful when designing new drugs with greater efficacy and fewer adverse effects; this applies especially to the treatment of glaucoma. The purpose of the thesis was therefore to identify and localize the different subtypes of α1- and α2-adrenoceptors in the eye. The identities of the α1-adrenoceptor subtypes were studied in various parts of pig and albino rabbit eyes by radioligand binding. In the pig retina and in the albino rabbit iris, ciliary body and retina, mixed populations of α1A- and α1B-adrenoceptors were localized. In the rabbit choroid only the α1A-adrenoceptor subtype was detected. The α2-adrenoceptor subtypes were also characterized by radioligand binding, in different parts of the pig eye. In the iris, ciliary body and choroid, only α2A-adrenoceptors were localized, while in the retina, mostly α2A-adrenoceptors and a minor population of α2C-adrenoceptors were identified. High densities of α2A-adrenoceptors were found in the ciliary body and choroid. The effect of α2-adrenoceptor agonists on the porcine ciliary artery was studied on a small-vessel myograph. α2-Adrenoceptor agonists proved to be potent vasoconstrictors in the porcine ciliary artery and it was found that the vasoconstriction induced by brimonidine was mediated by the αA-adrenoceptor.

Transesophageal echocardiography (TEE) has become a useful tool in monitoring the heart in patients during open-heart surgery. This study was undertaken to evaluate whether it is feasible to use TEE to assess left ventricular myocardial viability in anesthetized patients scheduled for coronary artery bypass grafting (CABG). A total of 84 patients were studied. To test myocardial viability, TEE and a low-dose dobutamine stress regimen were used. Echocardiographic data were analyzed off-line using a visual or semiautomatic analysis of segmental left ventricular wall motion (LVWM). Visual assessment was performed by readers blinded to the sequence of events. The agreement between readers in visual analysis of segmental LVWM in the transgastric short-axis view was 73% or higher. Segmental LVWM assessed by TEE was compared to hemodynamic data obtained by thermodilution pulmonary artery catheter (PAC) and coronary angiographic data. Also, using the same low-dose dobutamine stress regimen, TEE findings in the anesthetized patient perioperatively were compared with preoperative transthoracic echocardiography (TTE) findings in the awake patient. TEE was found to be feasible and adequate for testing left segmental ventricular viability. A concomitant increase in stroke volume assessed by PAC and decrease in LVWM-score assessed by TEE was found with dobutamine stimulation. Abnormal segmental LVWM corresponded to angiographically stenosed supplying coronary artery vessels. During dobutamine stimulation, 69% of the corresponding segments responded which is a sign of viability. The LVWM response to preoperative TTE and perioperative TEE dobutamine stress was comparable except for a significant difference in the apical segments. This study showed that perioperative TEE dobutamine stress could be used to test left ventricular viability and was also a valuable supplement to PAC, angiography and TTE. The acquired knowledge is important and suggest that further development of transesophageal ultrasound technology is warranted.

Renal artery stenosis (RAS) is a potentially curable cause of hypertension and azotemia. Besides intra-arterial renal angiography there are several non-invasive techniques utilized to diagnose patients with suspicion of renal artery stenosis. Removing the stenosis by revascularization to restore unobstructed blood flow to the kidney is known to improve and even cure hypertension/azotemia, but is associated with a significant complication rate. To visualize renal arteries with x-ray techniques a contrast medium must be used. In a randomized, prospective study the complications of two types of contrast media (CO2 and ioxaglate) were compared. CO2 was not associated with acute nephropathy, but induced nausea and had lower attenuation differences compared to Ioxaglate. Acute nephropathy was related to the ioxaglate dose and the risk was evident even at very low doses if the patients were azotemic with creatinine clearance <40 ml/min. Evaluating patients for clinically relevant renal artery stenosis can be done utilizing several non-invasive techniques. MRA was retrospectively evaluated and shown to be accurate in detecting hemodynamically significant RAS. In a prospective study of 58 patients, evaluated with four methods for renal artery stenosis, it was shown that MRA and CTA were significantly better than ultrasonography and captopril renography in detecting hemodynamically significant RAS. The standard of reference was trans-stenotic pressure gradient measurement, defining a stenosis as significant at a gradient of ≥15 mmHg. The discrepancies were mainly found in the presence of borderline stenosis. The outcome of percutaneous revascularization procedures showed a technical success rate of 95%, clinical benefit in 63% of treated patients, 30-day mortality 1.5% and major complication rate of 13%. The major complication rate for patients with baseline serum creatinine >300µmol/l was 32%. Our results compare favorably with published studies and guidelines.

This study was undertaken to investigate the involutional changes of the uterus and uterine cavity by ultrasound (US), gray-scale and Doppler, after normal delivery, and to compare with the corresponding findings from women with puerperal complications, particularly retained placental tissue (RPT). The overall design was exploratory and prospective, with the use of descriptive statistics for analysis. Forty-two women with uncomplicated vaginal term delivery were examined on post-partum days 1, 3, 7, 14, 28 and 56. The AP diameters of the uterus and uterine cavity and morphological findings were recorded. The maximum AP diameters of the uterus and uterine cavity diminished from 92.0 mm on day 1 to 38.9 mm at day 56 and from 15.8 mm at day 1 to 4.0 mm at day 56, respectively. The uterus was most often empty in the early and late puerperium while a mixed echo pattern over the whole cavity was found during mid puerperium (I). Seventy-nine women with secondary post partum hemorrhage (SPH) were examined on the day they presented with clinical symptoms. US revealed an echogenic mass in the uterine cavity in 17 of 18 patients treated surgically and histology confirmed placental tissue in 14 of these. Sixty-one patients with either an empty cavity or mixed echo pattern had an uneventful puerperal course after conservative treatment (II). AP diameters and morphological findings for 55 women with endometritis, 28 after caesarean section and 20 after manual evacuation of the placenta overlapped extensively with normal references (III). The physiological vascular involution studied in 45 women after normal delivery showed that PI and RI indices did not change significantly until day 28 postpartum. The presence of at least one uterine artery notch was found in 13.3% of the women at day 1 and in 90.6% at day 56 postpartum (IV). PI and RI values were measured and compared with reference values in 20 women with clinical suspicion of RPT who were to undergo surgical evacuation. Mean resistance indices were below the 10th percentile for eight of these 20 women, but overlapping was considerable. Doppler US has limited value as a diagnostic tool for RPT. The absence of a hyper-vascular area in the myometrium does not exclude RPT but an echogenic mass in the cavity is a sign of RPT (V).

Kranskärlsoperationen är för patienten en stor händelse som leder till många frågor och funderingar. Tidigare forskning har visat att patienter som genomgått en ranskärlsoperation har stort behov av information. Vårt syfte med studien var att beskriva informationen vid en kranskärlsoperation. Studien gjordes som en itteraturstudie. Resultatet av studien utföll i tre kategorier, informationsmetoder, vad informationen innehöll samt olika faktorer som påverkade patientinformationen. Information gavs skriftligt, muntligt, som videofilm, med Internet eller av en patient som tidigare gjort en kranskärlsoperation, ofta i kombination med varandra. Vad patienten ville att informationen skulle innehålla varierade från person till person beroende på i vilken fas patienten befann sig, pre- eller postoperativt. Flera faktorer framkom som var av betydelse. Det var viktigt för patienterna att personalen tog sig tid att lyssna och svara på frågor och funderingar. Patienter med litet socialt nätverk hade större behov av information än andra med stort socialt nätverk. En annan betydelsefull sak var att patienterna lätt skulle kunna komma i kontakt med kompetent personal både innan operationen och efter utskrivningen. Slutsatsen av resultatet var att informationen bör vara individuellt anpassad utifrån varje patients behov. Fortsatt forskning behövs för utveckling av en god patientinformation kring patienternas upplevelse av olika sorters informationssätt, samt att utveckla kontakt med patienter som tidigare gjort en kranskärlsoperation / Coronary artery bypass is for the patient a major event leading to many questions and concerns. Previous research has shown that patients who have undergone coronary artery bypass have great needs of information. Our aim of this study was to describe information before and after a coronary artery bypass. The study was done as a literature review. The results of the study were distributed into three categories, information methods, information content and the various factors that affect patient information. Information was given in writing, orally, by video, by Internet or by a patient previously undergoing a coronary artery surgery, usually in combination with each other. What the patient wanted the information should contain varied from person to person depending on what stage the patient was, pre- or postoperatively. Several factors emerged that were relevant. It was important for the patients that the staff took the time to listen and respond to questions and concerns. Patients with small social networks had a greater need for information than others with larger social network. Another important thing was that patients could easily get in touch with competent personnel both before surgery and after discharge. The conclusion of the result was that the information should be individualized based on each patient's needs. Continued research is needed to develop good patient information on patients' experience of different types of information means, and to develop contact with patients who have previously done a coronary artery bypass.