Infective endocarditis (IE) is a rare but complex disease that is fatal if untreated. With a modern combination of antimicrobial therapy and heart valve surgery, mortality is still 10-20 %. The structure of the endocarditis vegetation impedes the penetration of phagocytic cells such as monocytes and granulocytes. This leads to high bacterial counts inside the vegetation and the need for long treatment courses with a combination of intravenously administered bactericidal antibiotics. The aim of this thesis was to study the changes in epidemiology, management, and mortality at our hospital between 1980 and 2001, and to identify prognostic factors associated with mortality. To assess the issue of referral bias, differences between referred episodes and episodes from our local community were studied. Additional aims were to study the occurrence of the pro-chemotactic cytokines IL-8 and TNF-α in heart valves and vegetations during the active phase of IE, and to study the effect of the glycopeptide antibiotic vancomycin in dense staphylococcal cultures in vitro. As it is a rare and complex disease, management of IE is usually complicated for non-specialists. For this reason a computerised decision support system for IE was developed and evaluated. Between 1980 and 2001, the occurrence of Staphylococcus aureus IE and the use of early heart valve surgery increased significantly, regardless of whether the episodes were referred or of local origin. Glycopeptide antibiotics, mainly vancomycin, were used more frequently, especially among referred patients. Referred patients were younger, predominantly male, had more complications, and received surgical treatment more often than patients from our local community. The reason for the lower frequency of female patients in the referral cohort cannot be explained by more comorbidity or fewer complications. The differences between referred and local episodes seen in our study highlight the need for assessment and adjustment for referral bias in IE studies (Paper I). In six patients who needed early heart valve surgery, the largest numbers of IL-8-containing cells, and the greatest amount of inflammation, were seen in patients with short preoperative antimicrobial treatment courses. No such relationships were seen with respect to TNF-α-containing cells. The IL-8-containing cells and the inflammatory cells were predominantly scattered in the heart valve stroma or in the margin of the vegetation (Paper II). The primary effect of IL-8 is to stimulate chemotaxis of polymorphonuclear neutrophil granulocytes. This indicates that there is no deficiency of IL-8 in the area close to the vegetation as a cause of the localised agranulocytosis often present inside the vegetation. Our study revealed a need for computerised decision support systems (DSSs) in the field of IE, but to be used in clinical practice these DSSs need be part of knowledge bases covering larger domains (Paper IV). Some of our initial ideas described in Paper III, especially the use of Internet technology and the combination of rule-based advice and explanatory hypertext, will probably be included in these knowledge bases. In vitro, there is a rapid reduction of free vancomycin in broth containing dense staphylococcal cultures. Consequently, there is a simultaneous increase in broth MICs, particularly in high inocula, which is not caused by a development of resistance (Paper V). These findings need further evaluation in vivo, but indicate that the dosing regimen of vancomycin is of particular importance in staphylococcal infections with dense inocula, e.g. infective endocarditis. Diabetes mellitus and moderate to severe heart failure were independent risk factors for 6-month mortality in left-sided, Duke definite IE episodes, regardless of referral or local origin of the episodes. Early heart valve surgery had a positive impact on the 6-month mortality in the referral cohort of episodes, which may be due to referral bias (Paper VI).

<p>A more global analysis of the outcome of heart valve surgery is desirable to reflect the actual benefit for the patient. This thesis focuses on the preoperative assessment of the patient, and the outcome after surgery with regard to operative mortality, long-term survival, valve-related complications, and quality of life. </p><p>Magnetic resonance imaging and echocardiography were comparable in assessing severe mitral regurgitation, but did not agree in measuring regurgitant fraction. Natriuretic peptides correlated well to regurgitant fraction on magnetic resonance imaging and to PISA and vena contracta on echocardiography. </p><p>The risk of death, myocardial injury and postoperative heart failure after valve surgery has decreased over the last decade whereas the proportion older patients has increased. </p><p>Survival is reduced after mitral valve replacement in patients with severe symptoms whereas patients with less symptoms have excellent survival. Older patients are more often severly symptomatic at the time of mitral valve surgery. </p><p>Event-free survival is superior in patients with a mechanical prosthesis, but not influenced by valve type in older patients. A mechanical prosthesis is associated with a higher risk of bleeding < 5 years from surgery, especially in older patients; and a bioprosthesis is associated with a higher risk of thromboembolism > 5 years from surgery. Ageing with a mechanical prosthesis implied an increased risk for an adverse event, this was not true for bioprostheses. </p><p>Quality of life after complicated heart valve surgery resulted in reduced physical health but equal mental health compared to uncomplicated controls.</p>

A more global analysis of the outcome of heart valve surgery is desirable to reflect the actual benefit for the patient. This thesis focuses on the preoperative assessment of the patient, and the outcome after surgery with regard to operative mortality, long-term survival, valve-related complications, and quality of life. Magnetic resonance imaging and echocardiography were comparable in assessing severe mitral regurgitation, but did not agree in measuring regurgitant fraction. Natriuretic peptides correlated well to regurgitant fraction on magnetic resonance imaging and to PISA and vena contracta on echocardiography. The risk of death, myocardial injury and postoperative heart failure after valve surgery has decreased over the last decade whereas the proportion older patients has increased. Survival is reduced after mitral valve replacement in patients with severe symptoms whereas patients with less symptoms have excellent survival. Older patients are more often severly symptomatic at the time of mitral valve surgery. Event-free survival is superior in patients with a mechanical prosthesis, but not influenced by valve type in older patients. A mechanical prosthesis is associated with a higher risk of bleeding &lt; 5 years from surgery, especially in older patients; and a bioprosthesis is associated with a higher risk of thromboembolism &gt; 5 years from surgery. Ageing with a mechanical prosthesis implied an increased risk for an adverse event, this was not true for bioprostheses. Quality of life after complicated heart valve surgery resulted in reduced physical health but equal mental health compared to uncomplicated controls.