**6. Degenerative valve disease**

#### **6.1. Degenerative disease of the aortic valve**

The prevalence of nonrheumatic AS increases with ageing [26]. In a cohort of older patients with IE, the prevalence of acquired MR and AS was reported as 57 and 28% respectively, compared with 38 and 10% in patients <65 years [26, 27].

#### *6.1.1. Fibro-calcific degeneration*

Age-related findings often begin on the aortic valve in early or middle adulthood and include the following: (i) noduli arantii—fibroelastic proliferation on the ventricular surface of the 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 aortic sclerosis is confirmed with echo.

#### *6.1.1.1. Aortic sclerosis and echocardiography*

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

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

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

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

The prevalence of nonrheumatic AS increases with ageing [26]. In a cohort of older patients with IE, the prevalence of acquired MR and AS was reported as 57 and 28% respectively, com-

Age-related findings often begin on the aortic valve in early or middle adulthood and include the following: (i) noduli arantii—fibroelastic proliferation on the ventricular surface of the

within the right

a regurgitant jet area occupying <20% of the left atrial (LA) area and <5 cm2

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

risk was therefore small, but inconclusive due to insufficient patient numbers [25].

each decade, up to 46% of those aged 80–89 years [24].

**6. Degenerative valve disease**

*6.1.1. Fibro-calcific degeneration*

**6.1. Degenerative disease of the aortic valve**

pared with 38 and 10% in patients <65 years [26, 27].

Baddour et al. [9].

20 Advanced Concepts in Endocarditis

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 superior [31].

#### *6.1.1.2. Aortic stenosis and risk of endocarditis*

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 of NBTE and IE [17].

#### *6.1.1.3. Fenestrations*

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. Fenestrations are found in approximately 5% of females and 10–20% of males, mostly present from the age of <45 years with a minor increase in prevalence over time, in males [28]. They are not routinely identified on echo because of their location above the line of closure. Fenestrations result in valvular regurgitation in the following circumstances: (i) spontaneous rupture resulting in a flail cusp, (ii) fenestration enlarges to extend below the zone of coaptation and/or (iii) reduced leaflet coaptation, such as prolapse or root dilatation, when the fenestration is no longer 'sealed-off' within the cusp closure zone [34, 35]. The risk of IE associated with fenestrations or valvular perforations is unknown.

the chordal apparatus [28]. The following changes may be noted at the posterior leaflet: (i) puckered scars—infrequent at 3–5%, > 65 years, (ii) fibro-elastic hyperplasia (mitral opacity) of the atrial surface in ~20%, >65 years and, (iii) mucoid or myxomatous degeneration (~ 5–10%) ± prolapse, with increased proteoglycans in the spongiosa layer [28]. The condition shows a slight increase with age in the milder forms. Severe forms of mucoid change were not related to age [28]. Fibroelastic deficiency (FED) is seen more commonly in the elderly and can

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Mitral annular calcification (MAC) is common in the elderly though can occur prematurely in certain other conditions such as hypertrophic cardiomyopathy (HCM), PMD, diabetes and renal disease. MAC commonly involves the posterior annulus and parallels AV calcification, with a sharp rise >55 years [28]. Normal sphincteric action of the annulus is altered and MR ensues [17]. Inflammation accompanies MAC and complications such as ulcerative erosion, thrombus formation, systemic embolic, liquefaction necrosis, infected vegetations and abscess formation occur with increased frequency [34, 39]. With large protruding MAC deposits, it is theorised there is alteration of local blood flow, predisposing to NBTE and IE [39]. Mitral stenosis can also occur as calcium encroaches on the leaflets. Vegetations form at the base of the mitral leaflet [39] rather than the leaflet closure line, as seen with typical regurgitant lesions [17] and are localised accurately with 3-D echo. Although MAC predisposes to IE, the exact

Mitral valve prolapse (MVP) most commonly occurs due to PMD. Secondary myxomatous degeneration can occur in other conditions, such as RHD and age-related degeneration. Additional causes of prolapse include congenital and papillary muscle dysfunction. The 'middle' tissue layer of healthy valves, the spongiosa, normally thickenings towards the leaflet/cusp margins and this is not a pathological finding [16]. With pathological myxomatous changes, there is diffuse increase in deposition of glycosaminoglycans in leaflets, cusps, chords and annuli and thrombi may form [16]. In a study from China, echocardiography (either TTE or TOE) correctly identified valve prolapse and thickening in 85% of patients in

In a landmark study, data was collected from a healthy population comprising the offspring of the original Framingham study group [40]. Echocardiographic criteria (2-D) used in the study were as follows: (i) prolapse - superior displacement of the mitral leaflet(s) >2 mm above the atrioventricular annular plane in the long-axis window, (ii) classic MVP - at least 2 mm prolapse with leaflet thickness ≥5 mm and, (iii) non-class MVP – ≥2 mm prolapse with leaflet thickness <5 mm [40]. A total of 2.4% met criteria for prolapse. Classic MVP was found in 1.3% of persons and non-classic MVP in 1.1% [40], with mean age mid 50s and a slight female preponderance. Mean MR volume was mild in the classic group and a trace in the nonclassic and control groups. Severe MR was only found in the classic groups and comprised

lead to leaflet prolapse and/or chordal rupture.

*6.2.2. Myxomatous mitral valve disease and prolapse*

which myxomatous disease was confirmed pathologically [37].

*6.2.2.1. Prevalence of mitral prolapse and regurgitation in healthy individuals*

risk is unknown.

7% of cases [40].

#### *6.1.1.4. Lambl's excrescences*

Lambl's excrescences increase in prevalence with age and may become incorporated into the noduli arantii [28]. They are located along the lines of cusp closure of left-sided (high pressure) valves. They are composed of a fibro-elastic core with an endothelial layer covering the surface. There is associated turbulence and relative stasis of blood flow, which predisposes to formation of NBTE and IE [34]. Although the risk of IE is unknown, empirically it is uncommon. Occasionally Lambl's excrescences can mimic vegetation and lead to a false-positive diagnosis of IE. However, Lambl's are usually identified as thin single or multiple filamentous strands on echo, which help differentiate them from typical vegetations and papillary fibroelastomas.

#### *6.1.2. Myxomatous degeneration*

Primary myxomatous degeneration (PMD) of the AV is less common than of the MV. In cases of significant 'pure' AS, it has been said to be the primary underlying pathology in up to 10–36% of subjects [38], however other pathological studies examining excised regurgitant aortic valves have reported much lower rates of PMD, at 2% [36] and in a more recent clinicopathological correlation study from China, 3% (35 of 1080 excised aortic valves) [37]. Histological findings include degeneration of the fibrosa layer, disruption of collagen fibres and deposition of mucopolysaccharides [37]. The cusps are susceptible to developing fenestrations adjacent to the commissures and with time, the prolapsing cusps develop thickening of the free margin, thought secondary to chronic trauma from the regurgitant jet [38]. The incidence of endocarditis with this pathology is unknown, however empirically, high velocity regurgitant jets increase the risk of IE.

#### **6.2. Degenerative disease of the mitral valve**

#### *6.2.1. Mitral valve sclerosis and age-related changes*

Mitral valve sclerosis is commonly encountered in the elderly and characterised by leaflet thickening. In patients >60 years, the leaflets are at least twice the thickness compared to early adulthood [22]. The following changes are frequently noted on the anterior leaflet: (i) senile sclerosis - nodular thickening on the atrial surface of the closing edge, up to age of 65 years, (ii) atheromatosis—age-related lipoid deposition (yellow plaque) on the ventricular aspect of the base of the leaflets extending towards and sometimes involving the chordal apparatus [28]. The following changes may be noted at the posterior leaflet: (i) puckered scars—infrequent at 3–5%, > 65 years, (ii) fibro-elastic hyperplasia (mitral opacity) of the atrial surface in ~20%, >65 years and, (iii) mucoid or myxomatous degeneration (~ 5–10%) ± prolapse, with increased proteoglycans in the spongiosa layer [28]. The condition shows a slight increase with age in the milder forms. Severe forms of mucoid change were not related to age [28]. Fibroelastic deficiency (FED) is seen more commonly in the elderly and can lead to leaflet prolapse and/or chordal rupture.

Mitral annular calcification (MAC) is common in the elderly though can occur prematurely in certain other conditions such as hypertrophic cardiomyopathy (HCM), PMD, diabetes and renal disease. MAC commonly involves the posterior annulus and parallels AV calcification, with a sharp rise >55 years [28]. Normal sphincteric action of the annulus is altered and MR ensues [17]. Inflammation accompanies MAC and complications such as ulcerative erosion, thrombus formation, systemic embolic, liquefaction necrosis, infected vegetations and abscess formation occur with increased frequency [34, 39]. With large protruding MAC deposits, it is theorised there is alteration of local blood flow, predisposing to NBTE and IE [39]. Mitral stenosis can also occur as calcium encroaches on the leaflets. Vegetations form at the base of the mitral leaflet [39] rather than the leaflet closure line, as seen with typical regurgitant lesions [17] and are localised accurately with 3-D echo. Although MAC predisposes to IE, the exact risk is unknown.

#### *6.2.2. Myxomatous mitral valve disease and prolapse*

Fenestrations are found in approximately 5% of females and 10–20% of males, mostly present from the age of <45 years with a minor increase in prevalence over time, in males [28]. They are not routinely identified on echo because of their location above the line of closure. Fenestrations result in valvular regurgitation in the following circumstances: (i) spontaneous rupture resulting in a flail cusp, (ii) fenestration enlarges to extend below the zone of coaptation and/or (iii) reduced leaflet coaptation, such as prolapse or root dilatation, when the fenestration is no longer 'sealed-off' within the cusp closure zone [34, 35]. The risk of IE associated

Lambl's excrescences increase in prevalence with age and may become incorporated into the noduli arantii [28]. They are located along the lines of cusp closure of left-sided (high pressure) valves. They are composed of a fibro-elastic core with an endothelial layer covering the surface. There is associated turbulence and relative stasis of blood flow, which predisposes to formation of NBTE and IE [34]. Although the risk of IE is unknown, empirically it is uncommon. Occasionally Lambl's excrescences can mimic vegetation and lead to a false-positive diagnosis of IE. However, Lambl's are usually identified as thin single or multiple filamentous strands on echo, which help differentiate them from typical vegetations and papillary

Primary myxomatous degeneration (PMD) of the AV is less common than of the MV. In cases of significant 'pure' AS, it has been said to be the primary underlying pathology in up to 10–36% of subjects [38], however other pathological studies examining excised regurgitant aortic valves have reported much lower rates of PMD, at 2% [36] and in a more recent clinicopathological correlation study from China, 3% (35 of 1080 excised aortic valves) [37]. Histological findings include degeneration of the fibrosa layer, disruption of collagen fibres and deposition of mucopolysaccharides [37]. The cusps are susceptible to developing fenestrations adjacent to the commissures and with time, the prolapsing cusps develop thickening of the free margin, thought secondary to chronic trauma from the regurgitant jet [38]. The incidence of endocarditis with this pathology is unknown, however empirically, high

Mitral valve sclerosis is commonly encountered in the elderly and characterised by leaflet thickening. In patients >60 years, the leaflets are at least twice the thickness compared to early adulthood [22]. The following changes are frequently noted on the anterior leaflet: (i) senile sclerosis - nodular thickening on the atrial surface of the closing edge, up to age of 65 years, (ii) atheromatosis—age-related lipoid deposition (yellow plaque) on the ventricular aspect of the base of the leaflets extending towards and sometimes involving

with fenestrations or valvular perforations is unknown.

*6.1.1.4. Lambl's excrescences*

22 Advanced Concepts in Endocarditis

fibroelastomas.

*6.1.2. Myxomatous degeneration*

velocity regurgitant jets increase the risk of IE.

**6.2. Degenerative disease of the mitral valve**

*6.2.1. Mitral valve sclerosis and age-related changes*

Mitral valve prolapse (MVP) most commonly occurs due to PMD. Secondary myxomatous degeneration can occur in other conditions, such as RHD and age-related degeneration. Additional causes of prolapse include congenital and papillary muscle dysfunction. The 'middle' tissue layer of healthy valves, the spongiosa, normally thickenings towards the leaflet/cusp margins and this is not a pathological finding [16]. With pathological myxomatous changes, there is diffuse increase in deposition of glycosaminoglycans in leaflets, cusps, chords and annuli and thrombi may form [16]. In a study from China, echocardiography (either TTE or TOE) correctly identified valve prolapse and thickening in 85% of patients in which myxomatous disease was confirmed pathologically [37].

#### *6.2.2.1. Prevalence of mitral prolapse and regurgitation in healthy individuals*

In a landmark study, data was collected from a healthy population comprising the offspring of the original Framingham study group [40]. Echocardiographic criteria (2-D) used in the study were as follows: (i) prolapse - superior displacement of the mitral leaflet(s) >2 mm above the atrioventricular annular plane in the long-axis window, (ii) classic MVP - at least 2 mm prolapse with leaflet thickness ≥5 mm and, (iii) non-class MVP – ≥2 mm prolapse with leaflet thickness <5 mm [40]. A total of 2.4% met criteria for prolapse. Classic MVP was found in 1.3% of persons and non-classic MVP in 1.1% [40], with mean age mid 50s and a slight female preponderance. Mean MR volume was mild in the classic group and a trace in the nonclassic and control groups. Severe MR was only found in the classic groups and comprised 7% of cases [40].

#### *6.2.2.2. Prevalence and risk of mitral prolapse in endocarditis*

Mitral valve prolapse occurs in 7–30% of cases of native valve IE, nearly always in the presence of MR and associated with redundant leaflets. Of note, NBTE forms on atrial aspect of thickened, redundant leaflets [17]. In a large clinicopathological correlation study of 120 native mitral valves excised due to IE, 43% had a history of prolapse [10]. The estimated risk of IE is shown in **Table 1**. Recent data published by Katan et al. [41] found a higher incidence of IE in MVP compared to earlier publications, thought in part due to the previous overestimation of true MVP in healthy individuals using less stringent diagnostic methods [41].

increasing gradually with age [28]. The mild age-related degenerative changes of the PV are

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Recently published research estimates the incidence of adult congenital heart disease (ACHD) associated IE is 1.0–1.33 cases per 1000 patient-years and in children (0–18 years), 0.41 cases per 1000 patient-years. Cumulative first incidence of IE, from birth to 18 years, was shown to be 6.1/1000 [5, 50, 51]. According to published data from the USA, the estimated incidence in children is lower, at 0.05–0.12 cases per 1000 patient-years [52, 53]. Interestingly, Marom et al. found 18% of children with IE had no underlying structural heart disease and no identifiable

Incidence rate in complex CHD has recently been published by Kuijpers et al. [5], 2017. Incidence of IE (per 1000 patient-years) reported according to lesion-specific pathology include: pulmonary atresia (PA) with ventricular septal defect (VSD), 7.84; double outlet right ventricle (DORV), 3.59; Marfans, 2.35; univentricular heart (UVH), 1.9; Tetralogy of Fallot (ToF), 1.8; congenitally corrected transposition (cTGA), 0.93; transposition, 0.89; and Ebstein's anomaly, 0.7.

Overall estimated incidence of IE with a VSD in ACHD is 1.0–1.33 and for children, 0.41 per 1000 patient-years (**Table 2**). In another study, the incidence was reported at 1.86 in adults and 1.06 in children, per 1000 patient-years (p = 0.06) [55]. The majority of studies have identified the following risk factors: i) unrepaired VSD ii) co-existent AR and, iii) residual defect at site of VSD repair. It has not been unequivocally proven a restrictive defect carries a higher risk. A VSD associated with AR carries a 2x relative risk (incidence increase from 1.25 up to 3.48/1000) [55], whilst a VSD that has undergone secondary aneurysmal transformation to form a Gerbode defect (LV-LA shunt) carries a risk of 5 per 1000 patient-years [56]. In one study, non-operated VSD's carried a 2.6x risk (0.73 versus 1.87/1000 patient-years) [55].

Secundum ASD IE incidence is estimated at 0.23 for children and 0.28–0.64/1000 patient-years in adults (**Table 2**). A higher than expected risk was likely due to concomitant valve disease or misdiagnosed primum defects [50]. Isolated ASD is rarely associated with infective endocarditis [57]. The risk in adults with atrioventricular septal defect (AVSD) is estimated at

**7.1. Overall incidence of endocarditis in congenital heart disease**

risk factors, compared to earlier published rates, ranging from 2.5–19% [54].

**7.2. Incidence of endocarditis in complex congenital heart disease**

not typically associated with IE.

**7. Congenital heart disease**

**7.3. Endocarditis in simple shunts**

*7.3.1. Ventricular septal defect*

*7.3.2. Atrial septal defect*

0.89 per 1000 patient-years (**Table 2**).

#### *6.2.2.3. Mitral prolapse—echocardiographic predictors of endocarditis risk*

Mitral regurgitation confirmed on echo and/or typical murmur, has been shown to be a predictor of risk in studies that have specifically assessed this variable (**Table 1**). In the study by Katan et al. [41], no cases of IE occurred in patients without a history of MR during follow-up. Nishimura et al. [47], found redundant leaflets (i.e. M-mode thickness ≥5 mm) were associated with IE, though numbers were small. Marks et al. [48] also confirmed classic MVP with leaflet thickening ≥5 mm (2-D echo) and redundancy was associated with IE risk over non classic MVP.

#### **6.3. Degenerative disease of the right-sided cardiac valves**

Gross degenerative changes of the right-sided valves are uncommon compared to the higherpressure environment of left-sided valves. The TV often undergoes only minimal change, with nodular thickening along the closing edge of the anterior valve leaflet. Mild diffuse leaflet thickening may occur in middle age; though in a minority of patients (>65 years), may become moderate or severe [28]. Myxoid degeneration of TV leaflets occurs occasionally [49], with TV prolapse (TVP) and PMD occurring in about 4% of cases [37, 40] . The risk of IE in TVP is unknown.


The pulmonary valve (PV) remains translucent and thin in the vast majority. Nodular thickening (noduli Morgani) along the centre part of the closing margin occurs in <50% of subjects,

**Table 1.** Risk of infective endocarditis associated with mitral valve prolapse and regurgitation.

increasing gradually with age [28]. The mild age-related degenerative changes of the PV are not typically associated with IE.
