Review
European Heart Journal (2005) 26, 1596–1605
doi:10.1093/eurheartj/ehi304
Atherosclerotic renovascular disease in chronic heart
failure: should we intervene?
Ramesh de Silva1*, Nikolay P. Nikitin1, Sunil Bhandari2, Anthony Nicholson3, Andrew L. Clark1,
and John G.F. Cleland1
1
Academic Cardiology, University of Hull, Castle Hill Hospital, Castle Road, Cottingham, East Yorkshire, HU16 5JQ , UK;
Department of Nephrology, Hull Royal Infirmary, Hull, East Yorkshire, HU3 2JZ, UK; and 3 Department of Vascular Radiology,
Leeds General Infirmary, Leeds, West Yorkshire, LS1 3EX, UK
2
Received 9 July 2004; revised 10 January 2005; accepted 31 March 2005; online publish-ahead-of-print 26 May 2005
See page 1576 for the editorial comment on this article (doi:10.1093/eurheartj/ehi375)
KEYWORDS
Heart failure;
Renovascular disease;
Intervention
Renal artery stenosis (RAS) is most commonly caused by atherosclerosis, which is also the most common
cause of chronic heart failure (CHF). One-third of patients with CHF are reported to have significant
renovascular disease. The presence of RAS confers a worse outcome in studies of hypertension and coronary disease, though data are lacking for patients with CHF. As the kidney is intricately involved in the
fluid retention that occurs in CHF, an adverse effect of RAS on outcome would be expected. Presentations of RAS in CHF include flash pulmonary oedema, hypertension, worsening of CHF, and worsening
renal function. RAS commonly progresses and may cause worsening of renal function in patients with
CHF and previously stable renal function. A variety of investigations that can safely and accurately
identify RAS in CHF are available, although none is recommended in current guidelines for the management of CHF. Treatment for RAS, whether for hypertension, for renal dysfunction, or for pulmonary
oedema, is at the discretion of the physician due to the lack of adequate randomized controlled
trials demonstrating the efficacy and safety of intervention. As it is not clear how RAS should be
managed in CHF, screening cannot be advocated. Currently, a multicentre randomized outcome trial,
which includes a cohort of patients with RAS and CHF, is in progress to provide answers in this area
of uncertainty.
Introduction
Sources and selection criteria
Atherosclerosis is a common cause of chronic heart failure
(CHF).1 It can affect both the coronary and renal arteries.
It is possible that renal artery stenosis (RAS) caused by
atherosclerosis plays a significant role in the pathophysiology and progression of CHF in some patients. RAS can
cause pulmonary oedema and clinical CHF in the absence
of obvious, major cardiac dysfunction. Benefit from renal
revascularization in this setting, using either percutaneous
or surgical techniques, has been suggested in case
reports,2,3 but such treatment is not mentioned in the
guidelines of heart failure.4,5 No randomized studies addressing the role of renal revascularization in patients with
CHF and RAS exist. This review outlines the epidemiology,
clinical presentations, and management strategies currently
adopted for patients with atherosclerotic renovascular
disease (AVRD), with a particular emphasis on patients
with coexistent heart failure. We will discuss why prospective randomized studies in this setting are important.
We performed literature searches using MEDLINE, Embase,
and the Cochrane register from inception to November
2004 using keywords such as ‘renal artery stenosis’, ‘atherosclerotic renovascular disease’, and ‘ischaemic nephropathy’, alone and in combination with ‘heart failure’ and
‘flash pulmonary oedema’. Review articles, randomized controlled trials, major observational trials, and original work
published in peer reviewed journals were accessed. In
addition, the reference lists of the articles accessed were
scrutinized to identify further papers not identified by the
original search strategy.
* Corresponding author. Tel: þ44 1482 624073; fax: þ44 1482 624085.
E-mail address: [email protected]
Presentations of ARVD
Renovascular disease is often asymptomatic. Clinical
presentations include hypertension, progressive renal dysfunction, a marked rise in serum creatinine with therapeutic
blockade of the renin–angiotensin–aldosterone system
(RAAS), atheroembolic disease, proteinuria, flash pulmonary
oedema, and CHF.6 It is possible that the majority of
patients with ARVD will present with heart failure, in turn
taken as a manifestation of coronary artery disease and
& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: [email protected]
RAS and CHF
chronic hypertension. It may be difficult to distinguish such
patients from those with heart failure but without ARVD.
Case reports and small series suggest that patients with
RAS may also present with flash pulmonary oedema or CHF
without coronary disease, although no large case-series
exist. Patients with flash pulmonary oedema present with
sudden onset of acute pulmonary oedema (APO) associated
with acute systemic and pulmonary hypertension. These
are often elderly patients and may be less likely to be investigated for underlying RAS. The electrocardiogram and renal
function, as indicated by serum creatinine, are often normal
and left ventricular systolic function is often preserved.7
Other patients with bilateral ARVD may present with CHF
and left ventricular systolic dysfunction without evidence
of coronary disease, or with diastolic ventricular dysfunction
in the presence of hypertension and impaired renal
function.8
Hypertension is the most common presentation of RAS.
One to five per cent of all patients with hypertension
will have RAS.9 Renovascular hypertension carries a worse
cardiovascular
prognosis
than
other
hypertensive
conditions.10 A renovascular cause for hypertension is
suggested by many features, although none is diagnostic.11,12 These include a younger age of presentation in
the absence of a positive family history, resistant
hypertension, deteriorating blood pressure control in compliant patients, presence of atherosclerosis in other vascular
trees, reversible early deterioration of renal function following initiation of angiotensin converting enzyme (ACE)inhibitors with reversal on subsequent withdrawal, renal
impairment with minimal proteinuria, and .1.5 cm difference in kidney size on ultrasonography.3,8 Clinical prediction
rules have been devised to identify hypertensive patients
who have a high probability of having RAS,14,15 and simple
and readily determined clinical and laboratory patient
characteristics are associated with severe RAS in populations
at risk.16
Renal dysfunction is another common manifestation of
RAS. Six per cent of all patients entering a dialysis
program and 14% of those over the age of 50 had RAS as
the cause of their renal failure.17 Other data suggest that
RAS may be the underlying cause of renal failure in up to
25% of patients over the age of 60.18 A rapid increase [e.g.
a rise in serum creatinine .44 mmol/L (0.5 mg/dL) if the
initial serum creatinine is ,177 mmol/L (2.0 mg/dL) or a
rise in .88 mmol/L (1.0 mg/dL) if the baseline creatinine
exceeds 177 mmol/L (2.0 mg/dL)], or .20% increase in
serum creatinine following introduction of an ACE-inhibitor
are both markers of underlying RAS.19
Epidemiology of ARVD
Aetiology
ARVD accounts for 90% of RAS.20 As coronary disease
also accounts for most cases of heart failure due to left
ventricular systolic dysfunction,21,22 it is likely that atherosclerosis is the most common cause of coexistent RAS in
patients with heart failure. Ischaemic heart disease may
make a less important, and hypertension a greater, contribution to the development of heart failure in patients with
preserved left ventricular systolic function.23,24 However,
the aetiology of RAS in such cases is also likely to be
1597
atherosclerotic. Other less common aetiologies of RAS
include fibromuscular dysplasia, aortic or renal artery dissection, non-specific aortoarteritis, thrombotic or cholesterol embolization, collagen vascular disease, neurofibramotosis, trauma, post-transplantation stenosis, and
post-radiation fibrosis.12
Prevalence
The prevalence of RAS increases with age,25 diabetes,26 aortoiliac occlusive disease, and hypertension,27 though no
population-based estimates currently exist.28 Prevalence
rates of 5, 10, 24, and 30% have been reported in patients
with hypertension,9,29 stroke,30 peripheral vascular
disease,31 and coronary artery disease,32,33 respectively.
The only published study to our knowledge reporting the
prevalence of RAS in CHF involved an elderly population
with heart failure34 in which 86 patients over the age of
70 years (mean 77.5 years, 49% women) were investigated.
Previous therapy with ACE-inhibitors and a serum creatinine
level .300 mmol/L (3.4 mg/dL) were exclusion criteria.
However, a selection bias existed in this study as all patients
were screened using captopril renography and only 53
patients underwent magnetic resonance angiography. RAS
.50% was present in 29 (34%) of the patients studied.
Prognosis
RAS augurs a worse outcome in studies of hypertension and
coronary disease, predominantly due to coronary and cerebrovascular events rather than renal failure, but data are
lacking in patients with heart failure. In patients with essential hypertension, 5-year mortality in two prospective
studies was 7% higher in patients with RAS than in wellmatched patients35 and 23% higher than in the general population.36 In patients investigated for coronary artery disease
with angiography, 4-year survival was 21% higher in patients
without renal artery involvement than in the group with
RAS.10 In another study, patients with peripheral vascular
disease and coexisting RAS of .50% at angiography had a
2-year mortality of 33%.37 Patients with CHF and renal dysfunction do have a worse prognosis38,39 but it is not clear
whether renal dysfunction is a useful marker of RAS in this
setting or that the presence of RAS itself alters outcome.
Pathophysiology
Experiments conducted by Goldblatt et al. 40 on the effects
of renal-artery constriction in animals led to the recognition
that RAS may cause hypertension. A haemodynamically significant unilateral stenosis increases renin secretion from
the juxta-glomerular apparatus (JGA), causing sodium and
water retention by the ipsilateral kidney, both through
direct actions of angiotensin II and via aldosterone synthesis.41 The ischaemic kidney also acts as a direct stimulus
to the sympathetic nervous system (SNS) with subsequent
release of norepinephrine.42 A normal contralateral kidney
suppresses its renin secretion and a pressure natriuresis
occurs, restoring intravascular volume. Natriuresis fails to
occur in the presence of bilateral RAS or abnormal contralateral kidney function43 (Figure 1 ). Volume overload can
occur due to kidneys ‘protected’ by bilateral stenosis
failing to mount a pressure natriuresis to high arterial pressures.3,44 It is possible that in heart failure, a condition often
1598
R. de Silva et al.
Figure 1 Pathophysiology in the development of pulmonary oedema. Failure of pressure natriuresis occurs in the presence of significant contra-lateral renal
artery stenosis or a diseased kidney.
associated with reduced arterial pressure, failing baroreflexes, and altered renal pathophysiology, there is also a
failure of pressure-natriuresis, making such patients more
susceptible to salt and water retention.45 This may manifest
as recurrent episodes of flash pulmonary oedema,46 characterized by hyper-reninaemia,47 which may occur in the presence of normal left ventricular systolic function.7 However,
diastolic dysfunction may be a contributing factor. Other
mechanisms may contribute to the progression of CHF in
patients with significant ARVD (Table 1 ).
The pathophysiology of the renal impairment in patients
with RAS is multifactorial. Intrarenal atheroma, cholesterol
embolization, hypertensive damage, and ischaemic damage
all contribute.74 An abnormal serum creatinine value
reflects loss of .50–60% of functioning nephrons. As the
kidneys are a paired organ system, an abnormal serum creatinine in a patient with unilateral RAS suggests concomitant
dysfunction of the contralateral kidney. Possible causes
include renal parenchymal damage, atheroembolic renal
disease,75 and hypertensive nephrosclerosis (intrarenal
artery stenosis), which is a more common manifestation of
ARVD than involvement of the extra-renal vasculature.76
Natural history of ARVD
ARVD tends to progress from unilateral to bilateral, from
stenosis to occlusion, and from normal to elevated serum
creatinine concentrations.77 In one study using duplex
Table 1 Mechanisms that may contribute to the progression of
CHF in ARVD
Reduced cardiac baroreceptor reflex sensitivity48
Increased sympathetic nerve activity49
Hyperhomocysteinemia50
Attenuation of nitric oxide induced endothelium-dependent
vasodilation51
Increased oxidative stress52
Excess production of endothelin and vasopressin53
Low density lipoprotein oxidation54
ultrasound, 23% of subjects with ,60% unilateral stenosis
had progressed to .60% at the end of 1 year; in patients
with .60% stenosis, 5% developed total occlusion at 1 year
and 10% developed total occlusion at 2 years.78 A prospective study in patients with hypertension and/or renal insufficiency showed that arteries classified as normal at baseline
had progressed to a high-grade stenosis (60%) in one-third
of cases after 5 years.79 Patients with unilateral disease
have a 49% risk of developing bilateral disease within 2
years.80 However, the use of treatments and life-style modifications proved to reduce the progression of atherosclerosis
were not uniform in these observational reports. The natural
history of RAS in patients with CHF is unknown. Progression
of RAS may be truncated by the demise of the patient and it
RAS and CHF
is unclear to what extent progression of RAS may be responsible for this.
Investigations for RAS
As it is often not clear that diagnosis of RAS will alter management, investigation of suspected RAS is not always mandatory. When investigations are planned, information about
the site, degree, and haemodynamic significance of the
lesion is required to try to ensure that treatment is worthwhile.81 However, no universally accepted definition for significant RAS exists, as anatomical narrowing does not
necessarily correlate with functional impairment. Lesions
causing ,50% stenosis are probably haemodynamically insignificant,82 lesions that are 50% are likely to have only minor
haemodynamic effects,83 and lesions between 50 and 70%
are probably haemodynamically significant.84 A stenosis
between 50 and 80% is thought to be significant if a translesional peak pressure gradient of .20 mmHg or a mean of
10 mmHg is found using Doppler wire interrogation of the
lesion.81,85
Non-invasive tools used to diagnose ARVD include colour
coded duplex sonography (CDS), captopril renography,
computed tomographic angiography (CTA), and gadolinium
enhanced magnetic resonance angiography (MRA). Digitalsubtraction, arterial-phase renal angiography remains
the ‘gold standard’ for diagnosis, providing information
about the site and severity of stenosis, and guiding
appropriate revascularization strategies. It is, however, an
invasive procedure with associated risks, and suggestions
have been made that it should be restricted for angioplasty
and stenting only, and not for confirming suspected
ARVD.86
CDS is operator dependent with sensitivity and specificity
approaching 95% for the detection of lesions .50% in dedicated laboratories.87 A formula derived using Doppler ultrasonography [the renal resistance-index calculated as follows:
1 2 (end-diastolic velocity/maximal systolic velocity) 100]
may identify patients who will benefit from intervention.88
Captopril renography uses non-invasive scintigraphic
assessments of renal function before and after administration of captopril.89 Administration of captopril reduces
the angiotensin II dependent efferent arteriolar resistance
that is increased in RAS to maintain glomerular filtration
rate. This vasodilation leads to a reduction of transcapillary
forces, therefore reducing the glomerular filtration rate in
the kidney. A substantial reduction in renal function following captopril administration with reversal of the effect on
cessation of the drug indicates the presence of haemodynamically significant RAS. It is both sensitive (80–95%) and
specific (50–94%) but does not provide information about
the anatomy of the renal arteries. However, the sensitivity
of the test is insufficient in the presence of renal failure,
bilateral RAS and renin-independent hypertension.86 Other
nuclear imaging techniques are used for evaluating total
and single kidney glomerular filtration rates. They can be
used to look for early manifestations of ischaemic nephropathy and to assess the functional significance of an
anatomical lesion.90
CTA has sensitivity and specificity rates of 95%,91 and
using techniques such as spiral CTA, it may be even superior
to standard angiography.92 Functional information is available using faster scanners, with the ability to quantify
1599
renal perfusion and segmental renal function.93 However, a
major limitation is the risk of nephrotoxicity from the use
of contrast agents.
Gadolinium enhanced MRA has a 100% sensitivity and 89%
specificity compared with conventional angiography.94,95
Detection rates for RAS are comparable to those for CTA.96
Future developments may allow dynamic assessment of
the anatomy and functional effects of a lesion during the
same assessment,97 and studies assessing aortic spiral
blood flow may have a role in identifying those patients
most suitable for renal revascularization.98 Major disadvantages of MRA are the cost and duration of the test, difficulty
in visualizing the distal, intrarenal vessels, false-positive
artefacts due to respiration, peristalsis and tortuous
vessels, and overestimation of the severity of RAS.94,99 It is
also not useful in monitoring patients following renal
artery stenting due to stent artefact.100 Advantages
include the high sensitivity of MRA, the lack of ionizing radiation and the ability for use in the presence of renal impairment, as the contrast agents are not nephrotoxic.101,102
Treatment of ARVD
The rationale for intervention in patients with RAS is based
on the progressive natural history of the condition. Despite
little evidence,103 in the presence of significant RAS and
normal sized ipsilateral kidneys, renal revascularization is
conventionally offered in the following settings: severe
hypertension resistant to medical therapy, rapidly progressive renal failure with no other obvious cause, recurrent flash
pulmonary oedema, and worsening renal function (WRF) in
the presence of ACE-inhibitors or angiotensin receptor
blockers.104–111
Heart failure
Anecdotal reports, case reports, and retrospective case
series (Table 2 ) support a benefit of treating RAS in the presence of CHF or flash pulmonary oedema. The majority of
reports involved patients with significant bilateral RAS or
unilateral RAS with a non-functioning contralateral kidney.
Whether revascularization will improve the symptoms of
heart failure in a patient with unilateral disease and two
functioning kidneys is unclear. No randomized or observational study has prospectively assessed the outcome of
renal revascularization for RAS in patients with CHF.
Hypertension
Reversal of hypertension by nephrectomy for unilateral
renal disease was first demonstrated in 1937.112 Vascular
reconstruction was later found to have the same effect in
selected cases.86 With the advent of percutaneous transluminal renal angioplasty (PTRA), revascularization has become
an acceptable mode of treatment. However, interpretation
of trials of percutaneous revascularization in hypertension
is difficult, due to different selection criteria, different definitions of improvement and variable, often short, duration
of follow up. The studies are also limited by small patient
numbers, lack of control subjects and failure to standardize
anti-hypertensive therapy or methods of blood pressure
measurement.
Only three randomized controlled trials comparing PTRA
with medical therapy for the treatment of hypertension
1600
Table 2 Reports of renal revascularisation for chronic heart failure and/or acute pulmonary oedema in the presence of renal artery stenosis
Authors and year of
publication
Number
of cases
Heart
failure
presentation
Coronary
artery
disease
Left ventricular
systolic
dysfunction
ACE-inhibitor use
Renal artery stenosis
degree
Intervention
CHF
endpoints
Pickering et al. 19883
11
APO
Yes 5/11
No
10/11 no further APO
6
CHF
Yes
Yes
1
APO
Unknown
Unknown
Yes with WRFa
4 PTRA, 1 surgery,
one none
PTRA
Undefined clinical improvement
Palmar et al. 198955
Messina et al. 199256
17
APO
Yes 11/17
Yes 6/17
Unknown
7 Bilateral, 2 unilateral
to SFK, 2 unilateral
Severe bilateral or
unilateral to SFK
Severe unilateral to
SFK
Severe bilateral
8 PTRA, 3 surgery
Meissner et al. 19882
Yes 8/11 showed
WRFa
Yes with WRFa
Missouris et al. 199357
2
CHF
Unknown
Yes
Yes with WRFa
Diamond 199358
3
APO
Yes 1/3
No
Yes 1/3 with WRFa
5
APO
Yes 2/5
No
Unknown
1
1
CHF
APO
No
No
Yes
No
Unknown
No
28
CHF
Yes 24/28
Yes 22/28
Unknown
Planken et al. 199863
2
APO
Yes 1/2
Yes 1/2
Yes 1/2
Farmer et al. 199964
1
APO
Unknown
No
No
19 APO, 6 CHF
Yes 15/25
Yes 4/25
Unknown
APO
CHF
Unknown
Unknown
Yes
Unknown
Unknown
Yes with WRFa
APO
APO
APO
APO
CHF and APO
Yes
Yes
No
Unknown
Unknown
No
Unknown
Unknown
Unknown
Unknown
Yes
Yes with WRFa
Unknown
Unknown
Yes 6/39
APO
APO
CHF
Unknown
Yes
Yes
No
No
Yes
Unknown
Yes with WRFa
Yes with WRFa
Weatherford et al. 199759
Ducloux et al. 1997
Kwan et al. 199761
60
Khosla et al. 199762
Bloch et al. 199965
25
1
9
Walker et al. 20017
Hoieggen et al. 200168
Mansoor et al. 200169
Duclos et al. 200270
Gray et al. 200271
1
1
1
2
39
Basaria et al. 200272
Aslam et al. 200373
Brammah et al. 200344
1
1
1
SFK, single functioning kidney; NYHA, New York Heart Association, SOB, shortness of breath.
a
Definition varies between case reports.
.70% Stenosis, 8
unilateral, 20 bilateral
1 Severe unilateral to
SFK, 1 severe bilateral
Severe unilateral
stenosis of vein graft
to SFK
22 Bilateral, 3 unilateral
Severe unilateral
4 Severe bilateral,
5 severe unilateral
Severe unilateral
Bilateral
Severe bilateral
Critical RAS
18/39 Severe bilateral,
21/39 Severe
unilateral to SFK
Bilateral RAS
Bilateral RAS
Severe unilateral,
occluded contralateral
Surgery
Surgery
Bilateral PTRA
PTRA and
bilateral stents
28 PTRA with
stent
2 PTRA
No APO over mean follow-up
2.4 years
Echo normalised in one, free from
heart failure in other
2/3 no further APO
No APO over mean follow-up
57 months
Undefined clinical improvement
Unknown
16/28 improvement in NYHA class
No recurrence of APO at follow-up
PTRA
No APO at 2-month follow-up
25 PTRA and stent
18/25 no recurrence, 3 with APO,
4 with CHF at 1 year
No symptoms at 1 month
Unspecified improvement
PTRA
8 PTRA, 1 surgery
PTRA
PTRA
PTRA
PTRA and stents
26 PTRA and stent
No further APO
Unknown
No SOB at 3 years
Symptom free at 6 months
Reduction in hospitalization for
heart failure
PTRA and stents
PTRA and stent
Unilateral PTRA
and stent
No further APO at 3-year follow-up
No further APO at 6-month follow-up
No further CHF
R. de Silva et al.
Bhardwaj et al. 200066
Missouris et al. 200067
Severe unilateral to
SFK
2 Severe bilateral, 1
severe unilateral to SFK
1 Severe bilateral, 4
severe unilateral to SFK
Severe bilateral
Severe bilateral
1 PTRA, 16
surgery
1 PTRA, 1 surgery
No further APO before discharge
RAS and CHF
exist.107–109 A combined total of 210 patients were followedup for a period of 6–12 months, and a meta-analysis of the
trials has recently been published.110 In the majority of
cases, the only advantage for patients treated with PTRA
was a reduction in their drug regime, though this was not
observed in patients with pre-existing renal failure. A subgroup of patients with bilateral RAS had better control of
their blood pressure with PTRA. No long-term benefit on
the preservation of renal function was demonstrated in
these trials.
Renal disease
One study suggested that up to 15% of elderly hospitalized
patients had ischaemic nephropathy leading to end stage
renal disease often as a result of atherosclerotic extraparenchymal RAS.17 Another observational study suggested
that revascularization prevented further decline in the
function and size of kidneys with RAS.113 PTRA may
also relieve severe proteinuria secondary to RAS.114
Observational trials of patients with renal dysfunction
showed that PTRA may delay the need for renal replacement therapy or allow dialysis to be discontinued in
some patients.115 However, revascularization can also be
associated with a decline in renal function,116 and as
noted earlier, randomized trials of hypertension failed to
show any benefit on renal function.
Predicting outcome of treatment
Owing to the limited success of PTRA in treating both hypertension and renal impairment, it is important to identify
patients whose blood pressure and/or renal function
improve following successful correction of RAS.14,117 A
shrunken kidney, a kidney with cortical necrosis or a
kidney proven by biopsy to have irreversible damage will
not benefit from revascularization.118 Factors that affect
outcome include the severity of RAS, the procedure used
to treat RAS, radiocontrast nephrotoxicity, atheroembolism119 and the presence of underlying renal parenchymal
disease.117 Reasons for lack of benefit include long term
exposure to the effects of high blood pressure leading to
irreversible renal and vascular damage (hypertensive
nephrosclerosis)120 and suboptimal vessel dilation when analysed using intravascular ultrasound.121
Modern PTRA with stenting may be safer and more
beneficial, but this cannot be assumed.122,123 PTRA with
stenting has higher rates of procedural success and lower
rates of restenosis than PTRA alone.124,125 A randomized
comparison of PTRA and PTRA with stent placement for
the treatment of atherosclerotic ostial RAS showed vessel
patency rates of 57 vs. 88% and restenosis rates of 48 vs.
14%, respectively.126 However, there was no difference
between the two groups in terms of blood pressure
reduction or improvement of renal function.
Complications
Despite improvement in PTRA techniques, failure rates are
still appreciable. A meta-analysis from the early 1990s
showed an overall rate of residual stenosis .50% in 12% following PTRA.127 Another review of 1417 angioplasties
carried out in 20 experienced centres showed an overall
rate of technical failures of 30%, increasing to 45% for
1601
ostial lesions.128 Early complications include recoil of
aorto-ostial plaques and dissections111,129 and late complications include persisting encroachment of aortic atheroma
and restenosis. At 6–12 months, restenosis rates of 27–100%
have been reported.130 A high incidence of technical failure
occurs despite apparent visual success following PTRA. With
the use of stents, complication rates range from 18 to
33%,131 and include dissections, sub-acute thrombosis, and
restenosis. Restenosis rates of 11–39% occur at 1 year
follow up.132,133 This is due to myointimal hyperplasia124
and is common with increasing age and ostial lesions.134
Treatment options for restenosis include PTRA with or
without stent placement, excimer laser-assisted angioplasty, rotational atherectomy, brachytherapy, and surgical
end-atherectomy.73,135,136 Technological advances such as
the use of drug eluting stents and atheroembolic protection
devices may reduce both the early and late complication
rates associated with PTRA.137
Surgery
Reconstructive surgery has similar effects to PTRA and stenting in lowering blood pressure, although the former may
offer greater improvement in renal function, but with a
higher mortality rate of 3–6%.138,139 Surgical revascularization is performed in patients with occluded renal arteries
to functioning kidneys supplied by collaterals, and in the
presence of aneurysmal or occlusive diseases of the abdominal aorta.140 Uncontrolled studies suggest that surgical
intervention may reduce nephrotic range proteinuria and
delay the need for renal replacement therapy.141
The management of hemodynamcally insignificant lesions
remains uncertain. It would appear logical to try to prevent
the progression of atheroma using treatment that is
believed to be effective for the coronary and cerebral circulation (e.g. smoking cessation, LDL-cholesterol ,100 mg/dL,
blood pressure ,140/85 mmHg, ACE-inhibition if tolerated,
low-dose aspirin, folate administration).86 A randomized
trial is underway to determine the effects of statins, antihypertensive agents, and anti-platelet agents, with or
without stent placement, upon the progression of renal dysfunction caused by ARVD.142
CHF and renovascular disease
Should intervention be offered to CHF patients with
atherosclerotic RAS?
The few randomized trials looking at cardiovascular outcomes in ARVD use blood pressure and renal function as endpoints. They were underpowered to determine whether
revascularization improved cardiovascular outcomes.
Anecdotal reports exist (Table 2 ) on the safety and efficacy
of renal angioplasty for RAS in the presence of CHF and/or
flash pulmonary oedema but randomized controlled trials
are lacking. When the balance of risk and benefit is in
doubt, randomized trials are required. Until the answers
to the trials are known, it would seem appropriate to use
renal revascularization as an intervention of last resort
rather than a preferred treatment.
1602
Should clinicians screen routinely for RAS
in patients with CHF?
Before adopting a screening test, it is important to know
the approximate prevalence of the condition to ensure
that screening is a good use of resources and that detection will benefit patients by changing management.
Neither of these conditions has been adequately fulfilled
in patients with heart failure. Consequently, there is
no clinical imperative to screen. However, clinical indicators, such as cardiac and renal failure in the presence
of hypertension, presence of atherosclerosis in other
vascular trees, reversible early deterioration of renal function following initiation of and subsequent withdrawal of
ACE-inhibitors and .1.5 cm difference in kidney size on
ultrasonography will make the diagnosis of RAS more
likely.8,13
Should ACE-inhibitors be used in patients with heart
failure and ARVD, and if so can high doses be
tolerated?
ACE-inhibitors reduce morbidity and mortality in CHF143
with some evidence of a greater benefit with higher
doses.144 Deteriorating renal function is an important
cause for the under-use of ACE-inhibitors. Approximately
2% of patients entering randomized controlled trials will
have ACE-inhibitors withdrawn for WRF.145 However, as
patients with elevated serum creatinine were excluded
and patients were younger than the epidemiological mean
age, the true risk in the community may be higher. It is
unclear what proportion of trial patients had ARVD or
indeed whether the presence of ARVD predicts WRF when
ACE-inhibitors are introduced.34 For the moment, it would
seem appropriate to treat patients with heart failure and
RAS with an ACE-inhibitor. If renal dysfunction develops,
then trying to reduce treatments other than the ACEinhibitor, in order to restore renal afferent arteriolar perfusion pressure, is the appropriate first response.146 If
renal dysfunction continues to deteriorate the choices
include renal revascularization,139,147 treatment with a
combination of hydralazine and nitrates148 or withdrawal
of the ACE-inhibitor. In patients with no prior diagnosis
of RAS, recommendations that withdrawal of an ACE-inhibitor should occur only when the rise in creatinine exceeds
30% above baseline within the first 2 months of initiation
have been made.149 However, a rise in serum creatinine
that gradually improves with time is a normal haemodynamic response following the initiation of ACE-inhibitors
in patients with heart failure. Successful stenting of the
renal arteries may permit the use of high dose ACEinhibitors provided renal function continues to be monitored
closely150,151 though ‘prophylactic’ stenting of RAS to
reduce the risk of ACE-inhibitor-induced renal dysfunction
does not seem justified given the imperfect relationship
between RAS and WRF.
Should we expect mortality and morbidity benefits
from intervening?
WRF indicates a poorer prognosis in CHF38,39 but it is not
clear that either renal function or outcome can be improved
by renal revascularization either for unilateral or bilateral
disease.103 The United Kingdom Medical Research Council’s
R. de Silva et al.
ASTRAL (Angioplasty and STent for Renal Artery Lesions)
trial152 comparing revascularization (PTRA with or without
stent insertion) and medical management and which
includes patients with RAS requiring treatment, whether
for renal dysfunction or for hypertension, may provide
some answers. The study will investigate symptoms, renal
and cardiac function and major morbidity and mortality
and include a substantial subgroup of patients with heart
failure. To date, however, there are no randomized controlled trials primarily designed to prospectively assess the
outcome of renal artery revascularization in patients with
significant ARVD and CHF.
Conclusion
Heart failure is a systemic disease caused by cardiac dysfunction. Sometimes the cardiac dysfunction may itself be
secondary to disease in other organs, including the kidney.
When cardiac dysfunction cannot be corrected, and even
sometimes when it can, it is appropriate to identify other
non-cardiac targets for therapeutic interventions.
Successful management of heart failure requires a multidisciplinary approach making it one of the most interesting and
fruitful areas of clinical research and practice. It is surprising that so little is known about the causes and management
of renal dysfunction in heart failure. It is possible that ARVD
plays an important role in both respects.
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