when treating patients with fever of unknown origin who have heart disease or a history of open heart surgery , physicians must consider infective endocarditis ( ie ) as a differential diagnosis . recent epidemiological modifications of ie include its mode of acquisition and microbiological profile . the drastic restrictions in indications for ie prophylaxis have been reported unassociated with an increased incidence of ie ; however , temporal trend analysis has shown a significant increase in ie in patients without previously detected heart disease . thorough understanding of the clinical features of these patients is needed to prevent ie , a condition with an unacceptably high mortality rate . moreover , the relative association of undiagnosed , clinically silent mitral valve prolapse , bicuspid aortic valves , and apparently normal valves with mild valvular dysfunction with the development of ie remains elusive . although blood cultures and cardiac imaging with echocardiography are considered the cornerstones of ie diagnosis , clinical suspicion and the integration of all clinical and laboratory data are also important . traditionally , ie has been suspected in patients with previously detected heart disease or a history of open heart surgery who develop fever , generalized weakness , have weight loss , and/or evidence of systemic embolism . endocardial damage due to significant shear stress caused by underlying heart disease that results in non - bacterial thrombotic endocarditis has traditionally been considered a prerequisite for bacteremia and the successful development of vegetation . based on this paradigm , and despite recent drastic restrictions in its indications , patients with previously detected heart disease or a history of open heart surgery have been the main target of ie prophylaxis . however , even in 20-year - old studies from the netherlands and france that used the old von reyn diagnostic criteria ,  40% of patients diagnosed with ie had no previous history of predisposing heart disease of any type ; ie was the first clinical presentation in these patients ( table 1 ) . similarly , a study from spain confirmed this finding , with 40% of patients having no history of heart disease . groups of patients without previous underlying heart disease have been found to differ in clinical characteristics , including vegetation site , major infecting microorganism , and mortality rate . after excluding intravenous drug abusers and patients with pacemakers , selton - suty et al .   found that ie affected the aortic valve more frequently , with a higher prevalence of group d streptococci ( bovis ) and no difference in mortality . by contrast , castillo et al .   found that in patients with pacemakers , vegetation was more frequent in the right cardiac chamber and the mitral valve than in the aortic valve , and that the prevalence of staphylococcus aureus was higher and mortality rates were significantly lower . two recent studies have shown a temporal trend of ie in patients without previously recognized underlying heart disease . three successive population surveys from france showed that the rate of ie patients without previously detected heart disease increased from 34% in 1991 to 49% in 1999 ( p < 0.001 ) and remained stable at 47% in 2008 ( fig . in a recent analysis of 328 consecutive korean patients with ie in a tertiary referral hospital , 76% ( 249 patients ) had no prior medical history of underlying heart disease at the time of hospitalization for ie . temporal trend analysis showed that the trend of ie developing in patients without predisposing underlying heart disease did not change during the study period ( fig . these discrepancies may have been due to differences in inclusion criteria and study settings ( a national survey versus an observational study in a single - center ) . although it has been well recognized that a significant proportion of patients with ie have no previously diagnosed predisposing conditions , clinical data regarding underlying unrecognized cardiac lesions associated with the development of ie in these patients are limited . since imaging modalities such as echocardiography have been utilized to diagnose these conditions for fewer than 20 years , the absence of imaging data has been a critical flaw in many clinical studies , even recent population - based surveys . undiagnosed mitral valve prolapse or a bicuspid aortic valve have been suggested as major causes of unrecognized cardiac lesions associated with ie development . in a recent report using a modern diagnostic criteria for ie with transesophageal echocardiography being performed in more than 95% of patients , an ' apparently normal - looking valve , ' defined as minimally thickened valvular leaflets with normal valvular function or trivial valvular regurgitation , was found to be the second most common underlying condition associated with ie development following mitral valve prolapse . of 249 patients without prior medical history of underlying heart disease , ie developed in an apparently normal - looking valve in 64 patients ( 26% ) , whereas the remaining 185 patients had clinically silent valvular or congenital heart disease with mitral valve prolapse being the most common underlying disease entity ( n = 82 , 44% ) . other underlying disease entities included bicuspid aortic valve ( n = 29 ) , rheumatic valvular heart disease ( n = 21 ) , calcified aortic stenosis ( n = 21 ) , and congenital heart disease ( n = 14 ) . this study is not the first to highlight the clinical importance of an apparently normal - looking valve in ie development , as a single - center study from the mid-1980s found that 27% of study subjects with ie had no significant underlying cardiac disease . healthcare associated infective endocarditis ( haie ) is another new epidemiologic trend of ie , and ie of an apparently normal - looking valve can be associated with both nosocomial ( fig . 3 ) haie . however , a recent report found that , interestingly , community - acquired ie involving an apparently normal looking valve ( fig . the increasing clinical impact of this type of ie must be considered carefully , because neglecting this increasing proportion of ie patients may negatively impact their mortality rate . compared to ie in patients with clinically silent valvular or congenital heart disease , patients with ie of apparently normal valves tend to be older with a higher incidence of diabetes and end - stage renal disease on hemodialysis , larger vegetation size , higher european system for cardiac operative risk evaluation ii ( euroscore ii ) , more frequent involvement of the aortic and tricuspid valve , and higher rates of ie with staphylococcal and enterococcal infection ( table 2 ) . surgery was performed less frequently in these patients due to their poorer medical status , which resulted in higher mortality . since the 1980s , the prevalence of rheumatic valvular heart disease and congenital heart disease as predisposing factors to the development of ie has decreased rapidly in industrialized countries . mitral valve prolapse has emerged as the most common underlying cardiac condition leading to ie in developed countries . ie involving an apparently normal - looking valve has also been described as a prototype of ie in intravenous drug abusers , characterized by minimal thickening or deformation of the right - sided tricuspid valve . few clinical studies have described ie of apparently normal - looking valves in non - drug abusers and it remains unclear whether this pattern should be regarded as a relatively new trend associated with an increased incidence of haie . however , one report based on clinical data obtained more than 30 years ago showed that apparently normal - looking valves , as a clinical feature of ie , were more common in non - drug abusers than in drug abusers ( 59% vs. 41% ) . in that study , staphylococcal infections predominated in non - drug abusers with ie of apparently normal - looking valves , whereas streptococcal infections predominated in patients with mitral valve prolapse . the prevalence of co - existing illnesses - including severe vascular disease , metastatic malignancy , and renal failure - was significantly higher ( as high as 40% ) in non - drug abusers with ie of an apparently normal - looking valve than in patients with mitral valve prolapse and ie . the overall reported incidence of ie in an apparently normal - looking valve in non - drug abusers was 16% in a study performed in the early 1980s   and was 20% in a recent study , suggesting that clinicians remain unaware of this important finding in ie patients . the pathophysiologic mechanism involving the development of non - haie or community - acquired ie in an apparently normal - looking valve with predominant staphylococcal infection is not yet clearly understood . a recent large population - based survey analyzing ie epidemiology after the recent drastic restrictions in indications for ie prophylaxis clearly showed an increase in the incidence of staphylococcal ie , especially in patients without previously detected underlying heart disease . that finding was thought to be due to the increased number of patients with prosthetic valve ie , pacemaker ie , and diabetes mellitus , all of which are associated with staphylococcal bacteremia . the higher prevalences of non - haie and community acquired ie than haie in a recent report , excluding prosthetic valve and pacemaker ie , suggests that catheter- or device - related blood infections associated with increased healthcare or medical interventions alone can not explain the contemporary trend in ie patterns . recently , increased age at the time of diagnosis of left - sided ie is reported to be associated with less valvular impairment ( insufficiency and perforation ) and a more favorable microbiological profile . additionally , s. aureus ie is more common in younger patients , suggesting the important role of patients ' age in determining clinical characteristics . age - dependent changes in host - defense mechanisms or underlying cardiac conditions may be important , as may age - dependent increases in clinically silent pre - existent valvular regurgitation without structural abnormalities on two - dimensional echocardiography . moreover , age - dependent increases in cardiac valvular abnormalities that met previous ie prophylaxis guidelines have been observed . the rates of mitral and tricuspid regurgitation were similar , with the rate of aortic regurgitation slightly lower , and these findings differed from the affected sites of vegetation in clinical studies . minor injury to the valvular endocardium may occur more frequently in left - sided cardiac valves inherently exposed to relatively high pressure , making these valves more vulnerable to the development of non - bacterial and/or bacterial thrombotic endocarditis with cumulative bacteremia or repeat intravenous injection of particulate material . a recent report suggested that bacteremia prevention is essential even in patients without previously detected predisposing heart disease to reduce the unacceptably high in - hospital mortality rate in patients with ie . a large proportion of patients with ie have no previous history of underlying heart disease . analysis of underlying disease showed that undetected mitral valve prolapse was the most common disease , followed by an apparently structurally normal valve . haie developed in less than half of patients with ie in an apparently normal - looking valve . community - acquired ie involving an apparently normal - looking valve in patients with no history of underlying heart disease has been inappropriately neglected . the higher mortality rate and larger vegetation size observed in these patients warrants repartition of at - risk groups for better targeting of ie prophylaxis to improve clinical outcomes .
infective endocarditis ( ie ) has been increasingly diagnosed in patients without previously detected predisposing heart disease , but its clinical features have yet to be fully determined . a recent single - center study including echocardiographic images and surgical findings investigated the incidence of undiagnosed , clinically silent valvular or congenital heart diseases and healthcare - associated infective endocarditis ( haie ) . the study confirmed that a large proportion of patients with ie have no previous history of heart disease . 
 analysis of underlying disease in these patients showed that undetected mitral valve prolapse was the most common disease , followed by an apparently structurally normal valve . 
 the patients who developed ie of apparently structurally normal valves had different clinical characteristics and worse outcomes . 
 ie involving a structurally normal valve was associated with both nosocomial and non - nosocomial haie , whereas community - acquired ie was more frequent than haie . 
 the pathophysiologic mechanism involving the development of non - haie or community - acquired ie due to predominantly staphylococcal infection in an apparently structurally normal valve is not yet clearly understood . 
 structurally normal valves are not necessarily free of regurgitation or abnormal turbulence and , given the dynamic nature and fluctuating hemodynamic effects of conditions such as poorly controlled hypertension , end - stage renal disease , and sleep apnea , further investigation is necessary to evaluate the potential role of these diseases in the development of ie . 
 an apparently normal - looking valve is associated with ie development in patients without previously recognized predisposing heart disease , warranting repartition of at - risk groups to achieve better clinical outcomes .