Cardiovascular & Haematological Disorders - Drug Targets - Volume 9, Issue 4, 2009

Infective endocarditis (IE) is a microbial infection of the endocardium. In subacute IE, the previously-damaged damaged surface of cardiac valve becomes the starting point for the deposition of platelets and the formation of a platelet-fibrin clot. IE develops after bacteria enter the bloodstream and colonize the clot. Platelets and fibrin mount up over the bacteria, increasing the size of the vegetation. As additional layers of fibrin are added, leukocytes are incapable to break through the vegetation. Treatment with antibiotics can also be problematic because the bacteria within the vegetation often become less metabolically active, and many antibiotics require active bacterial growth to be effective. The overall incidence of infective endocarditis is 1.7 to 4.0 per 100,000 population and in adults older than 50 years, it exceeds 15 per 100,000 population. However, the precise incidence of IE is difficult to determine because case definitions have diverged from decade to decade, among different authors, and among different medical facilities. Moreover, the incidence of predisposing conditions (eg, rheumatic heart disease and injection drug use) has wandered over time and among different areas. Sex and age have an impact on the incidence of IE. Men prevail in most series, with male-to-female ratios ranging from 3:2 to 9:1. Almost 50-60% of cases of acute IE do not necessitate an underlying heart condition to be present. The microorganisms most accountable for the development of acute IE (e.g. S. aureus) are exceedingly virulent and able to colonize normal heart valves. The incidence of acute IE has been progressively rising and now surpasses the number of subacute IE cases. The patients who are more susceptible to IE comprise of those with congenital heart defects, rheumatic heart disease, the elderly, immunocompromised and AIDS patients, intravenous drug abusers (IVDA) and patients with a malignancy. Mitral valve prolapse is the most common (30%) predisposing condition found in young adults, and bicuspid aortic valve is the most common underlying congenital condition (15%). Rheumatic heart disease currently accounts for less than 20% of cases, but 6% of these patients develop IE in their lifetimes. In 75% of cases of IVDA IE, no underlying valvular abnormalities are noted, and 50% of them involve the tricuspid valve. Prosthetic valve endocarditis (PVE) accounts for 10-20% of all cases of IE, and in the long run, 5% of mechanical and bioprosthetic valves become infected. Mechanical valves are more likely to be infected within the first 3 months of implantation, and bioprosthetic valves are more likely to be infected after the first year. The mitral valves are more vulnerable than those in the aortic area. Analogous to PVE are infections of implantable pacemakers (PMs) and cardioverter -defibrillators. Usually, these devices are infected within a few months of implantation. The principle causative agents include Streptococcus viridans (55%), Staphylococcus aureus (30%), Enterococcus (6%) and HACEK bacteria, although on occasions it can also be caused by fungi. Antibiotics are usually administered intravenously for 2-6 weeks and duration usually depends on the pathogen%s virulence. 15-25% of patients with IE are treated surgically. Removal of an infected valve is necessary when antibiotic therapy fails, there are persistent vegetations after systemic embolization or vegetations increase their size after antimicrobial treatment, in valvular dysfunction and in fungal endocarditis.

Revised guidelines for the prevention of infective endocarditis published by the American Heart Association in 2007 do not support the indiscriminate use of antibiotic prophylaxis for dental procedures. However, they still recommend the use of prophylaxis for high-risk patients before dental treatments likely to cause bleeding. Given the high prevalence of bacteremia of dental origin due to tooth-brushing, mastication or other daily activities, it appears unlikely that infective endocarditis from oral microorganisms can be completely prevented. A good oral health status and satisfactory level of oral hygiene are sufficient to control the consequences of the systemic spread of oral microorganisms in healthy individuals. However, caution is still needed and prophylactic antibiotics must be administered to susceptible or medically compromised patients. This review briefly outlines the current concepts of odontogenic bacteraemia and antibiotic prophylaxis for patients undergoing dental treatment.

Infective endocarditis (IE) is a rare but severe disease with high mortality, and results most often from the combination of bacteraemia and a predisposing cardiac condition. American Heart Association (AHA) and other national and international organizations have made recommendations for the prevention of IE, although no randomised clinical trial has confirmed its efficacy. The current tendencies of IE prophylaxis, based on 2007 AHA guidelines and recent medical bibliography are presented in our review.

Infective endocarditis (IE) is a lethal disease if not promptly treated with antibiotics, either in association with surgery or not. The incidence of disease has not decreased over the last decades due to the change of risk conditions. Complications of IE may involve cardiac structures when the infection spreads within the heart, or extra cardiac ones when the cause is usually from embolic origin; they may also be due to medical treatment or to the septic condition itself. A lot of complications occur in most of patients. The literature reports one complication of IE in 57%, two in 26% and three or more in about 14% of patients examined. The frequency of specific complications depends on variables as the infecting pathogen, duration of disease before therapy and type of treatment. However it is often difficult to assess the true incidence of complications because the published reviews in literature are frequently based on retrospective chart reviews and different diagnostic criteria are used. The decision over either indication or timing of surgery should be individualized and based on a multidisciplinary approach involving at least cardiologists and cardiac surgeons. Congestive heart failure (CHF) is the most important complication of IE, which has the greatest impact on prognosis. Periannular abscesses are a relatively common complication of IE (42% to 85% of cases during surgery or at autopsy respectively), associated with a higher morbidity and mortality. Systemic embolization occurs in 22% to 50% of cases ; emboli may involve major arteries, mostly affecting the central nervous system, but also other organs. Splenic abscess is a rare complication of IE, due to direct seeding of spleen by an embolus or bacterial seeding of a bland infarction. Neurological complications develop in 20% to 40% of patients with IE and represent a dangerous subset of complications. Mycotic aneurysms are rare, resulting from diffusion of infection to the vessel wall. Actually the clinical profile, the best treatment (medical or surgical approach) and outcome of complicated IE are not well defined. Changing trends in aetiology of IE with emerging infections from Staphylococci, bacteria of the HACEK group and Fungi have resulted in an increased frequency of culture negative IE. Sepsis or persistent fever, despite appropriate antimicrobial therapy, recurrent emboli, heart failure or new pathologic murmurs suggest haemodynamic impairment and/or infection extending beyond the valve leaflet or prosthetic valvular annulus. The course of the disease will consequently get worse with an increasing need of surgery. Patients who develop abscesses are more likely to undergo surgery than those who do not (84-91% vs 36%), and also their in-hospital mortality rate is higher (19% vs 11%). A prompt detection of complications often allows an earlier surgical treatment which represents the best way to improve the outcome. The introduction of molecular methods techniques has increased the ability to identify the causal agents of IE, mostly in cases of culture negative endocarditis. Echocardiography, mainly from transesophageal (TEE) approach, has significantly improved the evaluation of IE allowing to detect the specific signs of the disease as vegetations, abscesses, valve insufficiency, prosthetic valve dehiscence, fistulas. In our 3rd referral Hospital (Lancisi Heart Hospital, Ancona, Italy) we performed a follow-up (mean 8,26 years) of 15 patients with periannular complications associated with IE. The long term follow-up showed low mortality rate, high incidence of reintervention, improved New York Heart Association (NYHA) class in survivors and no changes of the lesions at the echocardiographic examination, suggesting that periannular complications have not significantly influenced the overall survival in our patients at the follow-up.

Prosthetic valve endocarditis (PVE) is a grave medical entity with potentially fatal end results. The disease encompasses a rather small but, in the same time, vital part of IE incidents that is probable to be augmented in future years. PVE occurs in 1-4% of valve recipients during the first year following valve replacement, and in approximately 1 % per year afterwards. The type of prosthetic valve (mechanical versus bioprosthetic) seems not having an impact on the rate of development of IE and it is comparable in both groups (0.8 cases per year of follow-up). The pathogenetic mechanisms, pathogens implicated, clinical features and diagnostic approach of PVE will be reviewed here, along with the antibacterial and potential surgical treatment and prevention of the disease.

Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of liver damage and alteration of hepatic enzymes. NAFLD is strongly associated with metabolic syndrome and obesity. It is characterized by fat accumulation in the liver that may progress throughout hepatic steatosis and inflammation (non-alcoholic steatohepatitis [NASH]) toward cirrhosis and liver failure. In the last decade several studies suggested that NAFLD is an independent cardiovascular risk factor that increases cardiovascular mortality. At present, several studies investigating possible therapeutic approaches are ongoing. The present review is focused on the current and promising treatments of NAFLD.

Much of the morbidity and mortality of sickle cell anemia is accounted for by a chronic vasculopathy syndrome. There is currently no identified therapy, interventional or prophylactic, for this problem. For two reasons, development of an effective therapeutic approach will require a systems biology level perspective on the vascular pathobiology of sickle disease. In the first place, multiple biological processes contribute to the pathogenesis of vasculopathy: red cell sickling, inflammation and adhesion biology, coagulation activation, stasis, deficient bioavailability and excessive consumption of NO, excessive oxidation, and reperfusion injury physiology. The probable hierarchy of involvement of these disparate sub-biologies places inflammation caused by reperfusion injury physiology as the likely, proximate, linking pathophysiological factor. In the second place, most of these sub-biologies overlap with each other and, in any case, have multiple points of potential interaction and transactivation. Consequently, an approach modeled upon chemotherapy for cancer is needed. This would be a truly multi-modality approach that hopefully could be achieved via employment of relatively few drugs. It is proposed here that the specific combination of a statin with suberoylanilide hydroxamic acid would provide a suitable, broad, multi-modality approach to chemo-prophylaxis for sickle vasculopathy.

CD44, short for cluster of differentiation 44, is an adhesion molecule of the hyaluronate receptor family. Expressed on the surface of most vertebrate cells, it functions as a receptor for several extracellular matrix components, e.g., hyaluronan, collagen, laminin, fibronectin, and osteopontin. CD44 has in recent years been intensively studied in connection with different forms of cancer, where CD44 may regulate invasiveness and tumor progression. Although major functions involve adhesion and migration, CD44 also affects leukocyte homing and recruitment, phagocytosis, matrix remodeling, proliferation, and apoptosis. As such, CD44 is an interesting putative molecule in cardiovascular drug therapy. Accumulating evidence from human studies point to CD44 as involved in inflammatory diseases such as atherosclerosis and human abdominal aneurysms. To date, several animal studies have shown that the role of CD44 in atherogenesis may vary depending on experimental model. In this Review, we trace CD44 and its potential role in the context of cardiovascular diseases by highlighting both human and animal studies that may help us understand; is CD44 a new cardiovascular drug target or merely an innocent bystander?