**5. Structurally normal native cardiac valves**

**2. Predisposing cardiac disease: a changing epidemiology**

material [5, 6].

18 Advanced Concepts in Endocarditis

**disease**

response [8].

cedures considered high-risk [7].

Since mid-last century, the epidemiology of IE has continued to change across high-income countries (HIC), from predominantly young patients with rheumatic heart disease (RHD) to the current era of an ageing population with IE, infrequent RHD and prevalent degenerative valve disease (DVD). A history of acute rheumatic fever (ARF) in patients with IE had declined from ~38 to 22.5% in the 30 years up to 1967 [1]. By the 1980s, this had reduced to 6% [2]. According to data from the International Collaboration on Endocarditis—Prospective Cohort Study (ICE-PICS), DVD is the most common underlying pathology in IE, with significant mitral regurgitation (MR) and aortic regurgitation (AR) accounting for 43.3 and 26.3% of cases, respectively, compared with rheumatic mitral valve, present in only 3.3% cases. Prosthetic valve endocarditis (PVE) accounts for up to 22.2% of cases [3], whilst the prevalence of cardiac device-related infective endocarditis (CDRIE) has increased along with health-care associated IE (HCAIE) [4]. Endocarditis patterns in congenital heart disease (CHD) have changed due to patients surviving into adulthood with more complex disease, the availability of improved surgical techniques and implantation of prosthetic

The 2015 European Society of Cardiology IE management guidelines now consider the following cardiac conditions to pose the highest risk of IE: (i) prosthetic cardiac valves and/or repairs with prosthetic material, (ii) previous IE, (iii) cyanotic CHD, and (iv) any CHD that has been repaired for up to 6 months post procedure or indefinitely if a residual defect or valve incompetence persists. Repair or intervention includes both surgical and transcatheter procedures. Antibiotic prophylaxis is recommended for these patients when exposed to pro-

**3. Estimating risk of infective endocarditis: methodological issues**

**4. Pathogenesis of infective endocarditis with underlying cardiac** 

to the difficulties faced in drawing generalised conclusions.

There are methodological challenges with investigating risk of acquiring IE. Two major limitations are: i) low incidence of IE in the general population and ii) selection bias associated with tertiary referral hospitals. Variations in study design and methodology also contribute

The major predisposing categories of underlying cardiac pathology are DVD, CHD and RHD. Platelet-fibrin aggregates form on damaged or inflamed endothelium, resulting in nonbacterial thrombotic endocarditis (NBTE), a precursor of IE [8]. Microorganisms are able to attach to this nidus via adhesion molecules and stimulate a host inflammatory Infective endocarditis does occur in some patients without pre-existing known structural abnormalities. Whether the valves were completely normal is uncertain. Early degenerative changes can be present without clinical detection [17]. Modern-era echo with high image resolution and careful scrutiny of valve morphology and function, has the potential to shed more light on this research question.

There is an increasing prevalence of IE involving structurally normal cardiac valves, accounting for 26–43% of native left-sided IE cases [2, 18, 19]. Sun et al. [18] reported the commonest underlying cardiac predisposition was mitral valve prolapse (MVP) followed by normal valves (26%). Olmas et al. [20] found in an IE cohort, normal left-sided native valves in 39.8% of patients aged >65 years and in 53.8% of those aged ≤65 years, whilst DVD comprised 23.4% of the cohort. However, details regarding Doppler valve function were not available. This is important, for even normal valves may be regurgitant, exposing endothelium to shearing forces. Limitations include assessing valves for pre-existing pathology when already involved by infection and absence of pathological correlation to exclude subtle underlying pathology. In vitro studies have demonstrated certain microorganisms can attach to and/or be internalised by healthy valve endothelium, however in vivo, animal studies have required trauma to the endothelium to initiate IE following an inoculum of bacteria [9]. This raises the question—are the valves 'normal' or are there subtle pathological changes or haemodynamic disturbance, which predispose to IE. This was also raised by Que and Moreillon [21] and Baddour et al. [9].

cusps, from early adulthood, most pronounced on the noncoronary cusp, (ii) ridge-like thickening at the base of cusps where mechanical forces are highest; occurs in early adulthood in 20–40% persons, and (iii) commissural adhesion, due to fibroelastic hyperplasia, affecting 10–20% of older persons [28]. With ageing, endothelial dysfunction and hemodynamic stress lead to degenerative changes, inciting an inflammatory process, not unlike atherosclerosis. Histological changes include subendothelial thickening, lipid and protein accumulation, inflammatory cell proliferation, fibrosis and calcification within the valve fibrosa [29]. The process is accelerated over the age of 55 years, and onset in males is marginally earlier than females [28]. Initially there is no significant restriction to cusp opening and the diagnosis of

The Role of Modern-Era Echocardiography in Identification of Cardiac Risk Factors for Infective…

http://dx.doi.org/10.5772/intechopen.75760

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The presence of aortic sclerosis (focal thickening, no commissural fusion, peak velocity <2.0 m/s) is associated with an increased risk of death [30]. Caution should be exercised not to over diagnose sclerosis on echo [31]. Artefactual thickening and echogenicity can appear with harmonic imaging and over-gained signals. Optimising transthoracic (TTE) image settingsand use of both harmonic and fundamental frequencies can overcome these limitations [31]. Transoesophageal imaging has higher resolution and anatomical detail is

Eventually large calcified deposits occupy the body of the leaflet and can extend into the ventricular septum, the ventricular surface of the anterior mitral valve leaflet (AMVL) and are associated with mitral annular calcification (MAC). Cusp motion becomes restricted and aortic stenosis (AS) ensues. Ulcerations and thrombi may form, being a potential mimicker of IE [16, 32], and may form a nidus for infective endocarditis. There is a paucity of data on IE occurring with aortic sclerosis, although empirically, the risk is very small. Endocarditis of calcific trileaflet AS is relatively uncommon. According to Delahaye [33] 27/366 cases of native valve IE were pure AS. Risk is higher in patients with BAV and/or AR. In a study from the Mayo clinic [10], 310 native valves were excised for IE and it was reported 59% had no calcification. Mild-moderate and severe calcification was present in 37% and 5%, respectively. The most common underlying cardiac structural abnormalities were BAV (38% of 170 aortic valves) and MVP (43% of 120 mitral valves). This finding would suggest that IE is less common in severely calcified valves [10]. Another study with pathologic correlation found pre-existing calcification

present in 27% of valves with IE, though numbers in the study were small [11].

Acquired degenerative changes of the AV leaflets can occur secondarily in the context of conditions leading to annuloaortic dilatation. In this pathology, the leaflets come together at the free edges rather than the zone of coaptation, leading to focal thickening, and increased risk

Acquired age-related fenestrations form within the lunular region of the aortic semilunar cusps, adjacent to the commissures, often in association with myxomatous AV disease.

aortic sclerosis is confirmed with echo.

superior [31].

of NBTE and IE [17].

*6.1.1.3. Fenestrations*

*6.1.1.1. Aortic sclerosis and echocardiography*

*6.1.1.2. Aortic stenosis and risk of endocarditis*

To assess normal valve thickness according to age, 200 normal valves were reviewed at autopsy [22]. There was approximately double the thickness of the aortic cusps and mitral leaflets with age [22]. In a separate study, transoesophageal echo (TOE) identified normal MV thickness overall to be ≤3 mm and AV≤2 mm in those aged <60 years [23]. The prevalence of normal valves with physiological regurgitation was investigated in a retrospective echocardiographic study of 1333 patients without a history of cardiac disease or hypertension [24]. Physiological MR and TR were defined as structurally normal valves on 2-D imaging, with a regurgitant jet area occupying <20% of the left atrial (LA) area and <5 cm2 within the right atrium (RA), respectively. Aortic regurgitation with jet to LVOT width ratio <25% and normal leaflets was considered physiological. Non-organic MR was detected in 1/3rd or patients aged 10–19 years and approximately 2/3rd of persons aged >30 years. Non-organic TR was identified in over 4/5th of persons across all age cohort groups (10–89 years). Non-organic AR was present in <10% of patients under 50 years, with an increase in prevalence corresponding to each decade, up to 46% of those aged 80–89 years [24].

#### **5.1. Risk of endocarditis in normal valves with physiological regurgitation**

Data is not readily available on the risk of IE in patients with left-sided non-organic regurgitation. However, one study did assess the risk of IE in structurally normal right-sided cardiac valves in adult patients with CHD and pulmonary hypertension (PHTN) [25]. Both TVs and PVs had physiological regurgitation. The presence of PHTN was responsible for increased regurgitant velocities across the valves and thought to mimic the haemodynamic forces experienced by incompetent left-sided valves. High velocity flow was defined as PR jet ≥3.2 m/s and TR≥4.7 m/s. A small subset of valves was inspected at necropsy with the majority of TVs and minority of PVs revealing mild nodular degenerative changes along leaflet closure margins. The echocardiograms were said to be normal in appearance. There were 0.61 and 7.17 cases of IE per 1000 patient-years in the normal valve group compared to the CHD control group, respectively. The risk was therefore small, but inconclusive due to insufficient patient numbers [25].
