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38
CHAPTER 3 Valvular Heart Disease
factors may combine to create a pro-remodeling milieu by activation of local
fi broinfl ammatory pathways such as the renin–angiotensin aldosterone system
(RAAS). It has previously been well documented that diseased aortic valves and
atheromatous plaques contain a complete and fully functional RAAS system
(including renin, angiotensin, angiotensin-converting enzyme [ACE], and angio-
tensin receptors) and that myocardial angiotensin II expression may be more
related to local synthesis rather than reuptake from the systemic circulation.
10,11
Regional variation in the expression of such pathways may account for the wide
phenotypic variation seen in patients with traditional risk factors: some develop
atherosclerotic disease, some develop aortic stenosis, and others may have
both diseases concomitantly.
10
Endothelial disruption, an early process in the development of atheroma
and its subsequent complications (acute coronary syndromes), also appears
to be a critical early event in aortic stenosis.
7
It is considered that this event
occurs prior to both aortic valve “atheromatosis” and leafl et calcifi cation and
that it gives rise to an infl ux of activated infl ammatory cells (including T lym-
phocytes, polyclonal plasma cells, macrophages, and mast cells) as well as cells
with osteoblast-like activity.
12
Infl ammatory infi ltrates are found in degenera-
tive aortic valves (similar to atheroma), and these contribute to the formation
of lipid deposits and calcifi c foci. Immunohistochemical analysis has enabled a
more precise characterization of the typical subpattern of cellular infi ltrate in
calcifi c aortic valve stenosis, namely CD4 T lymphocytes, CD20 B lymphocytes,
and lambda-positive plasma cells.
4
Extracellular matrix remodeling, including
collagen synthesis and elastin degradation by enzymes, such as matrix met-
alloproteinases, underlies leafl et and vascular stiffening.
13
Further studies into
the underlying pathophysiology of both atherosclerosis and aortic stenosis
highlight pivotal roles for diminished endothelial nitric oxide activity and for
infl ammatory activation/redox stress that ultimately culminate in activation of
pro-calcifi c stimuli.
14,15
Not unexpectedly, therefore, the presence or absence of calcifi cation car-
ries a very important prognostic role in both diseases. For example, the extent
of aortic valve calcifi cation in aortic stenosis is a strong predictor of clinical
events (namely death or need for valve replacement due to symptoms), while
in the absence of aortic valve calcifi cation, the likelihood of adverse events is
very low.
16
Once the aortic valve becomes at least moderately calcifi ed, event
rates are known to increase signifi cantly, with about half of patients experienc-
ing an adverse cardiovascular event within 2 years, regardless of age. Similarly
with atherosclerotic disease, the extent of coronary calcifi cation is predictive of
long-term prognosis,
17
while the absence of coronary calcifi cation is associated
with only a very low risk of future cardiovascular events.
18
The subject of whether drugs already proven to ameliorate atherosclerotic
disease might slow the rate of progression of aortic stenosis has been addressed
in a number of experimental studies and in observational and randomized con-
trolled trials.
14
In particular, focus has been drawn to statins (drugs known to
halt the progression of and perhaps even induce the regression of athero-
sclerotic plaques) as well as inhibitors of the renin–angiotensin– aldosterone
pathway. In an experimental model of aortic stenosis in rabbits produced by
a high-cholesterol diet, statin therapy reduced aortic valve uptake of oxidized
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CHAPTER 3 Valvular Heart Disease
low-density lipoprotein and led to reduction in infl ammation and calcifi cation
of the leafl ets.
19
In a prospective study of asymptomatic patients with mod-
erate aortic stenosis, statin therapy was shown to delay the progression of
diastolic dysfunction and to reduce levels of natriuretic peptides.
20
Multiple
retrospective studies indicated that in an era when statins were indicated for
more severe hyperlipidemia, statin therapy was associated with reduced pro-
gression of stenosis compared to those not receiving therapy.
21–23
However,
multiple prospective randomized clinical trials, including SALTIRE, SEAS, and
ASTRONOMER, failed to demonstrate any signifi cant effect of statin therapy
on the progression of aortic stenosis, as refl ected by annualized increases in the
mean aortic valve pressure gradient, decreases in the aortic valve area, or the
need for aortic valve replacement.
24–26
Hypotheses advanced as to why statin
therapy in these prospective trials failed to affect stenosis progression despite
the apparent importance of hyperlipidemia as a risk factor for aortic stenosis
include the inclusion of patients with more advanced calcifi ed disease, which is
less amenable to therapy, and the exclusion of patients from these trials with
more severe hyperlipidemia, in whom guidelines now mandate use of statin
therapy anyway (as they could not be ethically randomized to absence of statin
therapy).
Other drug classes, namely ACE inhibitors and angiotensin receptor block-
ers (ARBs) have also received attention. Although formerly perceived to be
relatively contraindicated in aortic stenosis, a more recent large observational
study suggested that both ACE inhibitor therapy and ARB therapy were asso-
ciated with an improved survival and a lower risk of cardiovascular events in
patients with aortic stenosis.
27
In addition, ARB therapy has been associated
with improved reverse remodeling after aortic valve replacement.
28
Overall to
date, however, no prospective trials to assess ACE inhibitor therapy or ARB
therapy in aortic stenosis have been carried out, and until further data are avail-
able, the consensus opinion is that no medical treatments as of yet are defi ni-
tively proven to prevent or delay the progression of aortic stenosis.
29
Given the pathophysiological similarities described, it is also perhaps not
surprising that many of the current candidate biomarkers for aortic stenosis
were identifi ed largely through connecting parallels with atherosclerotic dis-
ease.
30
Apoplipoprotein E4 has been associated with an increased likelihood of
aortic stenosis and coronary artery disease.
31
Brain natriuretic peptide (a prog-
nostic marker in atherosclerotic disease) also correlates with aortic valve dis-
ease severity and progression,
32
whereas studies of C-reactive protein levels in
aortic stenosis, important in prognostication in coronary artery disease, have
had mixed results.
33,34
Comparable overlap exists for the homeostatic hormone
leptin and the regulator of calcifi cation remodeling osteopontin.
35,36
While val-
vular calcifi cation has been linked to the development and progression of aortic
stenosis and is more prevalent in those with either reduced bone density or
increased bone turnover, therapeutic intervention with bisphosphonates did
not affect disease progression in a large retrospective study.
37
Although not yet
ongoing, a defi nitive assessment of the true impact of specifi c bisphosphonates
on aortic stenosis will likely only become clear within the setting of a random-
ized clinical trial. Future directions to aid early disease intervention in athero-
sclerotic and aortic valve disease include ongoing translational work to better
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40
CHAPTER 3 Valvular Heart Disease
understand molecular and cellular mechanisms as well as the development of
new specifi c biomarkers and noninvasive imaging-based diagnostics to better
detect disease onset and progression.
Thrombotic risks associated with valvular heart
disease
Stroke risk is an important clinical complication of valvular heart disease with a
wide variety of potential underlying etiologies, including intracardiac thrombosis
(most commonly in the setting of atrial fi brillation), infective emboli (typically
in the setting of infective endocarditis), calcifi c emboli (most often iatrogenic
in the setting of aortic stenosis), and prosthetic valve thrombosis (discussed
further below). The risk of stroke is higher with stenotic valve disease com-
pared to regurgitant lesions and again signifi cantly higher in the setting of mitral
stenosis versus aortic stenosis.
For patients with surgical valve disease, the choice of valve type (biopros-
thetic versus mechanical) is an important decision. Valve replacement is never a
complete cure but rather results in a new set of problems and the potential for
prosthesis-related complications. In particular, thromboembolism and bleed-
ing from chronic anticoagulation are ongoing risks for those with mechanical
valves, whereas valve degeneration and the need for subsequent surgery are
major risks for those with bioprosthetic valves. For patients with mechanical
valves, the annual risk of stroke is 0.7 percent on warfarin, 2.2 percent on aspi-
rin, and 4 percent with no anticoagulation.
38
To minimize the thrombotic risk after mechanical valve placement, antico-
agulation with heparin is indicated as a bridge to warfarin therapy as soon as the
risk of postoperative bleeding is considered acceptable. Warfarin levels can be
particularly diffi cult to manage in the early postoperative period as patients can
be more sensitive to fl uctuating International Normalized Ratio (INR) levels
due to reductions in plasma albumin resulting in decreased warfarin-binding
capacity, as well as an increased likelihood of adverse drug interactions from
the use of other medications after surgery, such as antibiotics. The intensity of
warfarin therapy (target INR) is infl uenced by multiple factors, including the
type of valve, the site of valve placement, and the presence or absence of other
risk factors for thrombus formation. These include concomitant atrial fi brilla-
tion, a history of previous thromboembolism, left ventricular dysfunction, and
a hypercoagulable state. In the presence of any such risk factors, antiplatelet
therapy is indicated in addition to warfarin (in the absence of a high risk of
bleeding). The addition of low-dose aspirin to warfarin in such circumstances
has been shown to signifi cantly reduce the risk of major systemic embolism and
overall mortality, albeit with an increased risk of bleeding.
39
It is important to
remember that new antithrombotic agents such as direct thrombin inhibitors
have not been approved for use to prevent thrombosis in patients with heart
valve prostheses, particularly in the setting of atrial fi brillation.
The risk of thromboembolism is particularly high early after prosthetic valve
placement; therefore, it is recommended that any elective noncardiac surgery
be deferred at least for the fi rst 3 months after surgery.
40
Guidelines have been
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41
CHAPTER 3 Valvular Heart Disease
formulated to offer advice on recommended specifi c procedures when antico-
agulation needs to be discontinued in patients with prosthetic valves, includ-
ing careful bridging with heparin therapy and avoidance of any routine use of
vitamin K.
41
Prosthetic mechanical valve thrombosis is associated with a high mortality,
even with prompt emergency medical or surgical intervention. It should be
suspected in any patient with a prosthetic valve who develops symptoms of
heart failure, especially in the setting of an unexpected rise in the transval-
vular gradient from either baseline or established normal values for valves of
that type, size, and location. The most common risk factor for prosthetic valve
thrombosis is noncompliance with anticoagulant therapy.
42
The most frequently
affected valve location for prosthetic thrombosis is the tricuspid valve, followed
by the mitral and aortic valves, respectively. Echocardiography remains the gold
standard for diagnosis of prosthetic valve thrombosis, while cine-fl uoroscopy
can be very useful to assess valve motion. With regard to therapeutics, options
lie between fi brinolytic therapy and reoperation.
29
Unfortunately, both choices
are associated with a high risk of complications and a high mortality rate.
42,43
Fibrinolytic therapy is recommended for thrombosis of right-sided prostheses,
or for thrombosis of left-sided prostheses when either surgery is considered
too high risk or is not available, or in lower-risk patients (NYHA class I or II)
with a small clot burden (less than 80 mm
2
). For higher-risk patients (NYHA
class III or IV) or if there is a large clot burden, prosthetic valve thrombosis is
best managed by reoperation.
29
Pharmaceutical manufacturers of recently developed anticoagulants have
not yet sought approval for these agents in the prophylaxis of prosthetic valve
thrombosis, opting for more common indications such as prophylaxis of throm-
bosis in the setting of nonvalvular atrial fi brillation and deep vein thrombo-
sis. Advances in medical therapy to yield better outcomes with regard to the
prevention of prosthetic valve thrombosis await clinical trials of non-warfarin
agents.
Transcatheter aortic valve replacement (TAVR)
Indicated for selected high-risk patients with aortic stenosis, transcatheter
aortic valve replacement (TAVR) is an increasingly performed procedure that
has now been carried out in over 40,000 patients worldwide.
44
Research and
development of the underlying technology has undergone a particularly rapid
evolution and now forms the subject of an expert consensus document.
45
The
greatest experience to date in the United States is with the Edwards Sapien
Valve, a 23-mm or 26-mm trileafl et bovine pericardial valve mounted on a
cobalt chromium alloy balloon-expandable stent, which received U.S. Food
and Drug Administration (FDA) approval in November 2011, following regis-
try experience as well as evaluation in the randomized controlled “Placement
of AoRTicTraNscathetER Valve” (PARTNER) studies
46–48
(Figs. 3.1 and 3.2).
These industry-sponsored trials were designed for FDA premarket approval
and assessed TAVR versus standard therapy, including balloon aortic valvu-
loplasty in patients unsuitable for surgery (cohort B) and as an alternative to
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42
CHAPTER 3 Valvular Heart Disease
surgical aortic valve replacement in high-risk patients (cohort A).The cohort
B dataset was set up as a superiority trial design, while the cohort A dataset
involved a non-inferiority trial design and included patients who underwent an
anterograde transapical approach (due to severe peripheral artery disease or
the presence of severe aortic calcifi cation that would carry an increased stroke
risk with use of the standard retrograde femoral approach). All-cause mortality
at 1 year was found to be superior in the TAVR group of cohort B (30.7 per-
cent versus 50.7 percent; HR 0.55 [0.40–0.74], p < 0.001) and non-inferior in
the TAVR group of cohort A (24.2 percent versus 26.8 percent; p = 0.44).
However, despite these results, an important concern with regard to TAVR
outcomes relates to stroke risk.
The risk of stroke is dependent on the means of assessment used, and the
Valve Academic Research Consortium (VARC), comprising key physician
experts, U.S. FDA representatives, and device manufacturers, met to formalize
consensus defi nitions including that for stroke to facilitate evaluation of TAVR
outcomes.
49
Diagnostic criteria were established for stroke with goals includ-
ing consideration of prior surgical valve literature, pathophysiological mecha-
nisms, and clinical relevance. Using these criteria, an analysis of neurological
events by a clinical events committee revealed an increased risk of all stroke
in the TAVR group of cohort B of 6.7 percent at 30 days versus 1.7 percent,
p = 0.03, and 10.6 percent at 1 year versus 4.5 percent in the standard therapy
group, p = 0.04.
47
Of note, the actual reported number of post-TAVR strokes
AB
CD
Figure 3.1 Transesophageal images of TAVR. (A) Long axis (120 degree) view demon-
strating severe calcifi c aortic stenosis. (B) Pre-dilation of the stenosis using balloon aortic
valvuloplasty. (C, D) Biplane views following successful device implantation.
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CHAPTER 3 Valvular Heart Disease
A
B
C
Figure 3.2 Fluoroscopic images of TAVR. (A) Pre-dilation of the stenosis using balloon
aortic valvuloplasty (see arrow). (B) Careful positioning of device using rapid ventricular
pacing (see arrow). (C) Successful device implantation (see arrow).
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CHAPTER 3 Valvular Heart Disease
published in the FDA executive summary (updated June 2011) was even higher:
7.3 percent at 30 days and 11.2 percent at 1 year.
50
Some of the increased
stroke effect with TAVR in cohort B may simply be related to longer survival.
However, another issue worth considering (which may have served to blunt
the increased post-TAVR stroke risk) was the unequal distribution of baseline
characteristics to the advantage of TAVR. For example, in the TAVR group,
the rate of atrial fi brillation was 33 percent versus 49 percent in the standard
therapy group, p = 0.04, while corresponding logistic EuroSCOREs were 26
versus 30, p = 0.04. Furthermore, a large percentage (24 percent) of the stan-
dard therapy group received aortic balloon valvuloplasty, an invasive procedure
with a signifi cant stroke risk. In the TAVR group of cohort A, there was also
an increased risk of all stroke of 5.5 percent at 30 days versus 2.4 percent in
the surgical AVR group, p = 0.04, and 8.3 percent at 1 year versus 4.3 percent,
p = 0.04.
48
Published registry data concur with the trial data with an increased
incidence of early stroke of a magnitude similar to that seen in PARTNER.
51
Of
note, in other studies that have used more sensitive means of stroke detection
such as magnetic resonance imaging, the incidence of cerebral ischemic lesions
after TAVR has been reported to be as high as 84 percent.
52
However, the vast
majority of such radiological lesions seem not to be clinically apparent and their
relevance is not fully understood.
With regard to post-TAVR stroke, those occurring within 30 days of device
implantation are felt to be directly attributable to the actual prosthetic valve
procedure, while those occurring more remotely are felt to be more likely
related to comorbid risk factors such as age, hypertension, diabetes, or other
cardiac conditions, including atrial fi brillation. In PARTNER cohort B, 9/14
(64 percent) of the major strokes occurred within the fi rst 30 days, while in
cohort A, the corresponding fi gure was 13/17 (76 percent). Pathophysiological
mechanisms for these earlier procedure-related events have been proposed to
involve embolization of calcium, thrombus, or atherosclerotic emboli from the
valve site, ascending aorta, or aortic arch; hypotension related to either rapid
ventricular pacing or procedural hemodynamic instability; or traumatic aortic
dissection. However, no apparent explanation has been proven to explain the
concerning continuing increased risk of remote stroke following TAVR.
There is a concern that outside the constraints of trial protocols such as
PARTNER, the stroke signal may become stronger, particularly when dissemi-
nated to less experienced operators and centers.
53
The average age of patients
in both cohorts of PARTNER was 83 years. While it is not possible to extrap-
olate the results of PARTNER outside the study population, any increase in
stroke risk over standard therapy would likely be magnifi ed in younger and/or
lower-risk patients with fewer comorbidities and longer life expectancy.
Factors that may help to prevent TAVR-related strokes include careful
patient selection, increased procedural experience of the operator and center,
creation of multidisciplinary “heart teams” within clinical practice, improved
device characteristics including reduced catheter and valve sizes, optimal
periprocedural management, and the development of hybrid procedure
rooms.
54
The use of embolic protection devices has also been investigated with
a view to reducing procedural stroke by transient fi ltration of cerebral blood
fl ow. Capture of debris in more than half of patients provides evidence for the
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45
CHAPTER 3 Valvular Heart Disease
potential to reduce the procedural cerebral embolic burden when utilizing such
devices during TAVR.
55
Patients are administered periprocedural heparin with subsequent preven-
tive therapy of aspirin and clopidogrel for 6 months after the TAVR procedure.
Treatment of post-TAVR stroke depends on etiology (ischemic versus hemor-
rhagic), timing (how soon after the procedure it has occurred), and stroke
severity. For example, hemorrhagic strokes generally require reversal of the
effects of antiplatelet or anticoagulant medications. On the other hand, throm-
bolysis or mechanical clot retrieval might be considered for acute periproce-
dural ischemic strokes, particularly if associated with a moderate to severe
neurological insult. Antiplatelet therapy alone is generally considered for minor
strokes in the absence of atrial fi brillation or intracardiac thrombus.
An off-label indication of TAVR technology that is receiving much recent
interest is the prospect of “valve in valve” implantation.
56
Should this prove
to be useful, it could dramatically change decision making with regard to
choice of prosthetic valve. For example, rather than opting for the durability
of a mechanical prosthesis and consequent need for anticoagulation, one could
envisage an alternative choice of bioprosthesis without anticoagulation, which
could be followed by “valve in valve” implantation should the bioprosthesis fail.
While progress to date in TAVR technology has been rapid and impressive,
the need to combat stroke risk remains a signifi cant challenge and will need to
remain center stage as the focus of future developments before this therapy
can become more widely applicable.
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