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In: Perspectives in Aortic Valve Disease ISBN: 978-1-53618-769-4
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Editor: Giovanni Concistrè © 2020 Nova Science Publishers, Inc.
Chapter 6
AORTIC VALVE ENDOCARDITIS:
EPIDEMIOLOGY, TREATMENT AND OUTCOMES
Michele Danilo Pierri
Jacopo Alfonsi, Luca Montecchiani and Marco Di Eusanio
Cardiac Surgery Department, Lancisi Cardiovascular Center,
Polytechnic University of Marche, Ancona, Italy
Infective endocarditis (IE) is an infrequent pathology, but burdened with high
mortality. In recent years, it has been manifesting more frequently in older patients and
relating to degenerative heart valve dysfunctions. Furthermore, it is increasingly linked to
aggressive and antibiotic resistant microorganisms and to health related procedures.
Localization of infection in the aortic valve is the most frequent. It can concern both
native valve and artificial ones and, more recently, there have been many reported cases
regarding percutaneously implanted valves. Frequently, aortic IE is complicated by an
extension of the infection to the annulus with the formation of abscesses, fistulas and
prostheses detachments.
The diagnosis of the aortic valve IE is based on clinical findings, culture tests and
echocardiography examinations. New laboratory and radiological methods (also based on
biological markers) have recently been proposed to increase the chances of having a more
accurate diagnosis, especially in uncertain cases.
Aortic IE therapy is primarily based on antibiotic therapy; surgical therapy is
indicated mainly in complicated forms with heart failure or uncontrolled infection. Early
surgical therapy seems to have better results, but the question of the ideal timing remains
unsolved, especially in patients with recent neurological damage.
Surgical treatment may consist in the replacement of the valve, with biological or
mechanical prostheses, with the repair of abscesses and pseudoaneurysms with patches
or, in the case of more destructive forms, in the replacement of the entire aortic root with
homografts, stentless valves and conducts or valved conduits. Despite the increase in the
age of the patients and the presence of comorbidities, outcome after surgical therapy have
improved over time, even though mortality remains high and the rate of recurrences isn’t
Corresponding Author’s Email: micheledanilo.pierri@ospedaliriuniti.marche.it.
, Mariano Cefarelli, Paolo Berretta,
ABSTRACT
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negligible. Surgical mortality is particularly high in prosthetic valve endocarditis and
percutaneously implanted valves.
Due to the complexity of the management and the challenges it poses, the creation of
a multidisciplinary team devoted specifically to diagnosing and treating IE is
recommended.
Keywords: endocarditis, aortic valve disease, surgical treatment
INTRODUCTION
Infective endocarditis (IE) is the infection of the endocardial surface, particularly the
valves, implanted cardiac devices, prosthetic valves and intravascular conduit. It is an
infrequent condition with high mortality rates, ranging between 15% and 30% [1].
IE was described initially by Osler in 1885 [2] when it was inevitably fatal. With the
advent of antibiotic therapy, its mortality decreased, but still remained high; in more recent
times, the diffusion of antibiotic-resistant and aggressive strains (frequently related to health
care procedures) poses an additional challenge for its treatment. Early surgery was seen as a
therapeutic option for IE especially in more aggressive and disruptive cases and, recently, a
more aggressive surgical approach was suggested along with the expansion of the indications
and anticipating the surgical timing in order to improve the prognosis. Often aortic valve IE is
considered in the context of the so-called “Left heart endocarditis.” However, number and
anatomy of the leaflets, pressure differences across the valve and etiology, represent
important differences in the characteristics of the two valves.
In this chapter we will focus on the aortic valve IE involvement, its epidemiology,
treatment and outcome.
CLASSIFICATION
The above mentioned “left heart endocarditis” involving the left heart structures is
opposed to the “right heart endocarditis” involving tricuspid and pulmonary valves.
Clinically, IEs are divided in sub-acute and acute forms, the first having more attenuated
symptoms.
Another important classification differentiates between IE of native valve (NVE) and IE
of implanted valvular prostheses (PVE). The latter is further sub-divided in early and late IE
depending on whether they develop within a year after the implantation of the affected
prosthesis or later. Alternatively, PVE can be classified as early-onset (within 60 days of
surgery), intermediate-onset (from 60 to 365 days) and late-onset (over 1 year after surgery).
IE can also be classified as “community acquired” or related to “health care exposure”:
the former occurs more frequently and is related to streptococci while the latter frequently
consists of staphylococci infections developed in the setting of health care with invasive
procedures, intravenous lines, and implantable devices and frequently having an acute
expression [3-6].
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EPIDEMIOLOGY
The incidence of IE is of 3-10 cases every 100.000 units per year, but there are
significative geographical differences [7-9].
In the USA, it is of 7.7 cases every 100.000 units per year in recent years [10]. A study
based on the National Registry of Hospital Discharge reported a Spanish incidence of 5.56
cases per 100.000 units in 2014 [11]. During the same year, a Danish registry [12] reported
7.55 cases every 100.000 units while in Italy Cresti et al. [13] found 4.6 cases every 100.000
in the period between 1998 and 2014.
According to some [12, 14], there is an increasing trend of IE; some attribute these
changes to the modified guideline suggestions about endocarditis prophylaxis [15], but the
rise could also be a consequence of the aging population, increasing morbidity and expansion
of health care invasive procedures.
Left side endocarditis are more frequent (90-95%) than right sided endocarditis and NVE
are more common (90%) than PVE. Multiple valve endocarditis are infrequent.
The incidence of aortic involvement compared to the mitral one varies in different reports
with conflicting results: Murdoch et al. [16] found an involvement of mitral valve in 41% of
the cases and aortic valve in 37,6%; Olmos et al. [17] found no differences between the two
valves; Ilaho Moreira et al. [18] reported a major incidence in aortic valve (55,7% vs 35%).
IE is associated with about half of cases with degenerative valve pathology (mainly
mitral prolaxe and calcific aortic stenosis), but the number of cases with absence of previous
valve disease is increasing, probably due to health care associated procedures and implantable
devices. In recent times, there are increasing rates of IE reported on percutaneously implanted
prostheses [19, 20].
Among the valvular congenital disease, bicuspid aortic valves play a prominent role,
having a significant diffusion and increased susceptibility to IE in the adult population [21].
PHYSIOPATHOLOGY
The initial primer of IE is bacteremia. Microorganisms can enter the bloodstream as a
consequence of multiple conditions both medical and not: tooth extraction, urinary
catheterization, body piercing, procedures on the gastrointestinal, genitourinary o respiratory
tracts. Bacteremia can occur frequently during daily activities [10]. Bacteremias resulting
from health care are a growing cause of IE, accounting for an estimate 25% of cases in recent
years [16].
The second phase is adhesion to cardiac structures: normally, endothelium is resistant to
bacterial adhesion, but, given certain conditions, it becomes altered and vulnerable. In almost
50% of IE there is a previous, underlying predisposition, particularly a valve dysfunction
[16]; in these cases there is an alteration of the blood flow that leads to endothelial damage as
a consequence of shear stress and jet lesions. Damaged endothelium is the basis for micro
thrombi formations, which, in turn, can be colonized by bacteria or fungi with the
development of conglomerates that progressively grow due to bacterial multiplication and
platelet and fibrin deposition. Some bacteria, particularly gram positive, can adhere to
damaged endothelium with the mediation of proteins called adhesins. Platelet, fibrin,
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thrombus and colonizing bacteria grow to develop vegetations that are the “hallmark” of
infective endocarditis [22, 23]. During this process, many microorganism (including
staphylococci, streptococci and enterococci) produce biofilm, a polysaccharide slime-like
matrix. Biofilm protects bacteria from the immunitary response and antibiotics [24, 25].
In native aortic valve endocarditis, vegetations are frequently found on the ventricular
side of the valve. The extension of the infection beyond the aortic leaflets can lead to the
formation of abscess (paravalvular cavity of a diameter of 1 cm or more), aorto-ventricular
dehiscence, ventricular septal defect, fistula and extension to mitral or tricuspid valve.
In mechanical prostheses, the infective process initiates in the periannular site with
frequent abscess formation while, in biologic valves, the process is mainly localized to the
leaflets with rupture and perforation, but the annulus can be involved as well [26] (Figure 1).
A B
Figure 1A and 1B. Large endocarditic vegetations on explanted (A) and in situ (B) biological
valve prosthesis.
MICROBIOLOGY
Eighty-ninghty percent of IEs are caused by gram positive microorganism. Streptococci
are a frequent cause of community acquired IEs; they cause subacute endocarditis, but, more
recently and in compromised patients, can be clinically more aggressive. Enterococci are also
frequent cause of IE and are more associated with health care related IE, but the most
common cause of IE in developed country is Staphylococcus aureus that accounts for 30% of
cases [16, 27] and causes an aggressive form, with high mortality and morbidity [28].
Coagulase negative staphylococci (CoNS) are frequent in PVE, but can also cause NVE
[29] and are frequently methicillin resistant. 5-10% of IE are caused by gram negative
bacteria of the HACECK group (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella,
Kingella) while fungi account for about 1% of cases.
The raise of antibiotic resistance in microorganisms responsible for IE has created more
difficulty in their antibiotic management. Infection by methicillin resistant Staphylococcus
aureus (MRSA) is now epidemic in many western countries and vancomycin resistance is
also very frequent [30, 31].
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The analysis of the Swedish register on infectious endocarditis (SRIE) published in 2019
[32] is one of the few publications that examines the data of the native endocarditis of the
aortic valve separately from those of the mitral one. In this cohort, the major causative agent
of endocarditis on the aortic valve is Streptococci alpha hemolytics, responsible for 33% of
cases, followed by Staphylococcus aureus in 31%; enterococci are cause of 14% of aortic IEs.
Mitral endocarditis have a different distribution with a greater and significant presence of
staphylococcus aureus and a lower representation of enterococci. This difference is explained
by the differences in pressure and calcification of the two valves with different strategies of
aggression of the host tissue by Staphylococci and enterococci.
SYMPTOMS
There are many variations in the modality of clinical presentation of IE: some patients
rapidly develop sepsis (mainly in IE caused by Staphylococcus aureus) while others present
nonspecific, subacute symptoms.
Cardiac symptoms are related to the valve incompetence or stenosis or both and to the
disruption of left ventricular outflow tract. Patients may be asymptomatic or complaining
asthenia and/or dyspnea, having more or less nuanced signs of decompensation up to frank
decompensation and cardiogenic shock. Aortic valve endocarditis with annular extension can
cause an atrioventricular block due to the disruption of conduction system [33].
Cerebral complications are the most severe extracardiac complications of IE, as well as
the most frequent (occurring in 15 to 20% of patients) [34, 35]: macro or micro-emboli with
ischemic or hemorrhagic strokes, transient ischemic attacks or asymptomatic embolisms or
infection aneurysms. Emboli can also involve the lungs, spleen and the peripheral vessels
[36].
Other symptoms occasionally occur as glomerulonephritis or rheumatic manifestations.
Some of the “classic” systemic peripheral symptoms of IE, like Janeway lesions (hemorrhagic
plaque on palm and soles) or Osler’s node and splinter hemorrhage are now considered rare
[16].
DIAGNOSIS
Diagnosis of IE is difficult due to the high number of variations in clinical presentation
with many nonspecific symptoms. It is based on the presence of clinical signs,
microbiological findings and heart morphological examination (mainly performed with
echocardiography).
Fever in patients with previous cardiac valve pathology and/or new or modified cardiac
murmur can drive the diagnosis, same for the presence of vascular and immunological
phenomena as emboli, Janeway lesion, Roth’s spot, Osler nodes. Other generic non-specific
clinical signs that occasionally occur are poor appetite and weight loss.
Blood cultures results represent an important point for the diagnosis of endocarditis.
Culture tests should be multiple, at least 3, and taken before starting antibiotic therapy [37].
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A relevant number IE have negative cultures: their rate range between 2 to 30% or more
and are mainly related to assumption of antibiotic therapy before blood collection, but may
also be consequence of infection caused by intracellular microorganism or fungi [21, 38, 39].
There are newer techniques that can allow causative diagnosis also when cultures are
negative, as spectroscopy [40], serological test and the search for bacterial ribosomal RNA
using the Polymerase Chain Reaction (PCR) [41].
In a recent literature review [42], it has been pointed out that sensitivity and specificity of
PCR was 96% to 100%, greater than blood cultures, but the method is mainly applicable to
valve tissue removed from patients who have undergone cardiac surgery.
Echocardiography is of paramount importance in IE diagnosis: the key finding for the
echocardiography diagnosis of IE are vegetation, abscesses, and prostheses dehiscence.
(Figures 2, 3)
Figure 2. TEE shows a large aortic vegetation floating in left ventricle.
Figure 3. Aortic valve endocarditis with paravalvular psudoaneyrsm formation, transesophageal
echocardiographic view.
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The transthoracic echocardiography (TTE) is less invasive, but has low sensitivity,
especially in the case of PVE for which the sensitivity is 40-70%. On the contrary, the
transesophageal echocardiography (TEE) is more invasive and may require sedation or
anesthesia, but has greater specificity in both NVE and PVE. TEE sensitivity and specificity
in NVE vegetation’s detection is respectively 90-100% and 100% and sensitivity of 77-90%
in PVE diagnosis [43, 44].
The role of three-dimensional echocardiography is increasing. Its ability to reconstruct
the volumes of irregular masses can be useful to evaluate the true dimensions of vegetations,
perivalvular extension of the infection, prosthetic valve dehiscence, and valve perforation
[45].
In uncertain cases, new diagnostic systems are emerging: computed tomography (CT)
scans and combination of CT scan with metabolic imaging systems as 18-fluorodeoxyglucose
positron emission tomography (18FDG-PET) or leukocyte scintigraphy (SPECT).
CT is useful in the study of anatomy, particularly in the paravalvular regions, in IE
complication and in the cases of PVE when the artifacts caused by artificial valve can make
echocardiography difficult [46, 47] (Figure 4).
Figure 4. Transverse images from an 65-year-old woman with PVE: (A) integrated 18F-FDG-PET–CT;
(B) 18F-FDG-PET–CT. High FDG uptake was observed at the level of the aortic prosthesis.
Metabolic tracers show areas of metabolic activity (PET) or inflammation (SPECT). In
the cases of PVE, PET has a sensitivity and specificity of 70-80% and 80-90% respectively
while for SPECT are reported values of 90% and 100%. [48-50]. Results are not good for the
diagnosis of NVE: Ricciardi et al. examining 7 patients with suspected NVE found that 18F-
Michele Danilo Pierri, Mariano Cefarelli, Paolo Berretta et al.
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Major
Criteria
Blood colture
positive
Typical micro-organisms consistent with IE from 2 separate blood
cultures – S. aureus, S. viridans, S. bovis (gallolyticus), HACEK
group, community acquired enterococci, in the absence of primary
foci
r
Persistently positive blood culture for organisms that are typical
causes of IE: ≥2 positive blood cultures from blood samples
drawn >12 hours apart
r
For organisms that are more commonly skin contaminants: 3 or a
majority of ≥4 separate blood cultures (with first and last drawn
atleast 1 hour apart)
r
Single positive blood culture for Coxiella burnetii or phase I IgG
antibody titre >1:800
Evidence of
endocardial
involvment
r
Positive echocardiogram (vegetation, abscess)
New valvular regurgitation or dehiscence
Minor
Criteria
Fever > 38ºc
Immunologic phenomena (glomerulonephritis, Osler’s nodes, Roth’s
spots, Rheumatoid factor)
Vascular phenomena (major arterial emboli, septic pulmonary
infarcts, mycotic aneurysm, intracranial hemorrhage, conjuntival
hemorrhage, Janeway lesions)
Predisposition (preexistence of cardiac lesions or IV drug user)
Positive blood culture but not meeting major criteria or serologic
evidence of active infection with organism consistet with IE
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FDG-PET–CT failed to detect the infection in all cases [51]. Limits in the usefulness of
metabolic imaging systems include the inability to discriminate between inflammation and
infection, which leads to the risk of false positives in the first months after valve prostheses
implantation, in the cases of post-pericardiotomy syndrome and prosthetic valve thrombosis.
Duke criteria are widely used as help for the diagnosis in the modified form to take into
account the echocardiography morphological characteristics Duke algorithm, on the basis of a
combination of major criteria (echocardiographic and microbiological) and minor criteria,
grades the probability of having an endocarditis as defined, possible or rejected [52] (Table
1). Duke criteria has a sensitivity between 70 and 79% in IE diagnosis [53].
In a Spanish study [48] the integration of CT/PET data increased the sensitivity of Duke
Criteria from 51% to 91% in cases of suspected PVE.
Table 1. Modified Duke criteria. Modified from Li JS et al.
TREATMENT
The treatment of patients with suspected or confirmed infective endocarditis should be
provided by a multidisciplinary team with expertise in cardiology, cardiac surgery, and
infectious disease. Successful treatment is dependent on eradication of the causative agent,
which requires prolonged bactericidal antibiotic treatment. Guidelines indicate empiric and
microorganism-specific antibiotic protocols [3, 54]. Because of the antibiotic resistance and
tolerance and the drug’s difficulty in penetrating vegetations and biofilm, treatment for IE
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should be prolonged for almost 4-6 weeks with endovenous administration drugs in
combination and at full dosage.
This entails an evident commitment of the health structures, with a significant impact on
costs, also due to the need to keep the patient hospitalized.
For this reason, alternative antibiotic therapy modalities are being investigated, for
example by switching to an oral antibiotic regimen after an initial phase of endovenous
antibiotic therapy. A Danish multi center study [55] has recently used a mixed regimen of this
sort with good results. The 400 patients examined had IE caused by Staphylococcus aureus,
streptococci, enterococci, Staphylococci coagulase negative. However, patients with MRSA
and those with cardiac abscesses and other infection sites were excluded.
Another promising field is that of long-acting lipoglycopeptide antibiotics such as
dalbavancin and oritavancin which can be administered once a week [56].
SURGERY
Indication
Aggressive antibiotic therapy is essential to solve many cases of life-threatening
endocarditis and is often able to eradicate the disease.
However, in many cases of ineffectiveness of medical therapy or complicated forms of
IE, surgical therapy is required. The role of surgery for the treatment of bacterial endocarditis
has gradually increased also thanks to the publication of encouraging surgery results.
Indication for surgery are summarized in the periodically updated guidelines of American and
European cardiology societies [3, 4] (Table 2).
A revision of reports about IE’s surgical treatment (Imad M Tleyjeh et al. 2007) showed
an increase in surgical cases of 7% per year from 1960 to 2000. Nonetheless, about 50% of
patients with IE need surgery [57] and about 25% of patients with appropriate surgical
indication according to current guidelines denied surgery [58].
The European cardiology society guidelines have indications relating to surgical timing
[3]. Surgery is indicated on emergency bases (within 24 hours) in all cases complicated with
refractory pulmonary edema or cardiogenic shock; urgent surgery (within few days) is
indicated if there is evidence of poor hemodynamic tolerance; elective surgery when there
aren’t signs of cardiac decompensation.
Critical hemodynamic instability can be caused by acute aortic valve regurgitation or
stenosis and fistula in cardiac chambers or pericardium. Since heart failure and cardiogenic
shock are two of the strongest predictors of fatal outcome, early diagnosis and early surgery
can be useful to lower the operative risk. Inability to control the infection despite optimal
antibiotic therapy is indication of urgent treatment. Uncontrolled infection can have systemic
expression as persistent fever o local expressions as increase volume of vegetation,
development of pseudo aneurysms, fistula or perivalvular abscess. If the causative germ is
difficult to eradicate, aggressive or with multiple antibiotic-resistances, surgery should be
undertaken on elective or urgent basis.
Michele Danilo Pierri, Mariano Cefarelli, Paolo Berretta et al.
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2015 ESC Guidelines
Class
2014 AHA Guideline
Class
Heart failure
NVE o PVE causing refractory
pulmonary oedema of cardiogenic
shock
I
Valve dysfunction causing
heart failure
I
NVE o PVE causing symptoms of
heart failure or ecochardiographic
signs of poor haemodinamic tolerance
I
Uncontrolled
infection
Locally uncontrolled infection
(abscess, false aneurysm, fistula,
enlarging vegetation)
I
Hearth block or abscess
I
Infection caused by fungi o
multiresistant organisms
I
Resistant organysms
I
Persisting positive blood cultures
despite appropriate antibiotic therapy
and adequate control of septic
metastatic foci
IIa
Persistent infection/Relapsing
infection
I
PVE caused by staphylococci or nonHACEK gram-negative bacteria
IIa
Prevention
of embolysm
vegetations > 10 mm after one or
more embolic episode despite
appropriate antibiotic therapy
I
Recurrent emboli and
persistent vegetation despite
appropriate antibiotic therapy
Ia
vegetations >10 mm, associated with
severe valve stenosis or regurgitation,
and low operative risk
IIa
isolated very large vegetations (>30
mm)
IIa
isolated large vegetations (>15 mm)
and no other indication for surgery
IIb
Large mobile vegetation
(native valve)
IIb
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Table 2. Indication to surgery
Embolic complications develop in 20 to 50% of the patients and are related to migration
of vegetations [59, 60]. Vegetation’s embolization can occur at any time, but seems to be
more frequent during the initial weeks and before the beginning of the antibiotic therapy.
There is a relation between vegetation’s size and its mobility with risk of embolization [36].
Current guidelines indicate a class IIa recommendation for surgery in patients with
vegetation > 10 mm when associated with severe valvular regurgitation or stenosis, but
indicate that surgery in patients without valvular dysfunction and large vegetation (>15 mm)
for the prevention of embolisms may be considered.
The concept of early surgery has gained popularity over time, also thanks to the
improvement of surgical techniques and its good results. The topic was revived by the recent
publication [61] of a prospective randomized study comparing early surgery versus
conventional treatment in patients with left-sided IE. In this study, 37 patients underwent
early surgery (within 48 hours after randomization) and 39 followed a conventional treatment
timing. In the early surgery group, there was a reduced composite end point of death from any
cause and embolic events, supported mainly by reduction in systemic embolisms.
There is no uniformity in the definition of “early surgery.” Some define it as surgery
performed in the “acute phase”, during the course of antibiotic therapy, others as surgery
within 7 days of diagnosis; others shift the timing to 10 days from diagnosis, others two
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