British Journal of Anaesthesia 93 (1): 74±85 (2004)

DOI: 10.1093/bja/aeh167 Advance Access publication May 14, 2004

Heart failure
J. J. Magner and D. Royston*

Department of Anaesthesia and Intensive Care Medicine, Royal Brompton and Hare®eld NHS Trust,
Hare®eld Hospital, Hare®eld, Middlesex, UB9 6JH, UK
*Corresponding author. E-mail: dave@tharg.demon.co.uk

Br J Anaesth 2004; 93: 74±85

Keywords: complications, heart, failure; equipment, assist devices; treatment

Congestive heart failure is a complex clinical syndrome
characterized by impaired ventricular performance, exercise
intolerance, a high incidence of ventricular arrhythmias and
shortened life expectancy. Congestive heart failure is
common and is estimated to affect ®ve million people in
the US, 300 000 of whom die per year.34 Hospitalizations
and mortality from heart failure have increased steadily
since 1968, despite the overall improvement in mortality
from cardiovascular disease. Among adults over 65 yr of
age, heart failure is the commonest reason for admission to a
hospital.11
Heart failure may occur suddenly or develop gradually
and is the ®nal common pathway of a variety of primary
cardiovascular disease entities. Coronary artery disease and
hypertension are the two major risk factors for the
development of heart failure in the elderly. Other common
aetiologies include diabetes mellitus, valvular heart disease,
especially aortic stenosis and mitral regurgitation, and non-
ischaemic myopathies.8 It is often multifactorial, but
speci®c independent risk factors are male gender, hyper-
tension, coronary artery disease, diabetes mellitus and age.7
At present, the only cure for end-stage congestive heart
failure is cardiac transplantation.
Heart failure can be broadly subdivided into two distinct
forms (although other classi®cation schemes exist) and
distinguishing between the two forms is often dif®cult. The
®rst form is termed diastolic dysfunction or diastolic heart
failure and is due to inadequate ventricular relaxation
preventing adequate end-diastolic ®lling. This type of heart
failure affects the left ventricle. The second is the more
common systolic dysfunction or systolic heart failure due to
inadequate force generation to eject blood normally. This
type of heart failure can affect either ventricle but failure of
the left heart is more common.
Pathophysiology of heart failure
The principle problems associated with the aging and failing
heart are changes in shape, associated with chamber
enlargement, and ventricle wall thickness and stiffness. As
humans age they progressively lose cardiac myocytes. Their
maximal heart rate and cardiac output decrease, while
systemic vascular resistance and left ventricular (LV)
stiffness, systolic arterial pressure and LV wall thickness
increase.4 Myocellular hypertrophy and increased myocel-
lular mass result from increased wall stress and reduction of
contractility; this in turn leads to chamber enlargement due
to cell slippage and sarcomere growth.5
Increased interstitial ®brosis and cross-linking of
collagen in the heart are also associated with aging and
this contributes to increased LV stiffness.54 In addition,
prolongation of isovolaemic relaxation time and slowing of
the rate at which calcium is sequestered by the sarcoplasmic
reticulum after myocardial relaxation result in poor LV
relaxation. The compliance and early diastolic ®lling of the
left ventricle is decreased and, because LV relaxation is
impaired, a signi®cantly greater percentage of LV ®lling is
due to atrial contraction.4 In addition to the decreased early
diastolic ®lling, increased LV stiffness and prolonged
relaxation time cause raised LV pressures at rest and during
exercise.53
The major neurohumoral systems activated in response to
a reduction in cardiac output are the sympathetic nervous
system and renin±angiotensin±aldosterone (RAA) system.
In addition, modi®cations to endothelin receptors, natriure-
tic peptides and tumour necrosis factor receptors are now
recognized to be involved in the secondary response.5
Stimulation of the sympathetic nervous system causes
peripheral vasoconstriction and retention of sodium and
water by the kidney.22 Plasma norepinephrine levels
correlate directly with prognosis in congestive heart failure
patients.22 Sympathetic activity also activates the RAA.
While these responses have an initial bene®t to the patient,
they also compound the injury to the heart so that in heart
failure the re¯ex activation of the neurohumoral systems
eventually contributes to detrimental effects instead of
maintaining arterial pressure and cardiac output. LV

Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2004
 Heart failure and its management

remodelling and LV systolic dysfunction occur as a

consequence of activation of neurohumoral activation.
These deleterious effects are related to alterations in
afterload, preload, stretch, increased wall tension, inter-
stitial collagen deposits and through direct toxic effects.
Increased wall tension and myocardial oxygen consump-
tion, together with reduced subendocardial perfusion,
combine to reduce myocyte shortening and with remodel-
ling, the LV dilates and becomes more spherical.

Diagnosis
The signs and symptoms of heart failure include tachy-
cardia, decreased exercise tolerance, shortness of breath,
peripheral and pulmonary oedema and cardiomegaly. There
are a number of precipitating factors for acute-on-chronic
organ failure. Examples include inadequate compliance
with medication, hot weather, uncontrolled hypertension,
anaemia, infection with fever, hypoxia, alcohol intake,
myocardial infarction (MI), pulmonary embolism, renal
insuf®ciency and thyroid abnormalities.5 One of the most
common precipitating factors is the development of an
arrhythmia, especially an atrial arrhythmia. The prevalence
of atrial ®brillation increases with age from 5% at age 60 yr
to about 22% by the age of 90 yr.6 Atrial ®brillation may
suddenly worsen heart failure by reducing cardiac output
because of a shortened diastolic ®lling time and a loss of the
atrial kick that was contributing to late diastolic ®lling. The
single most useful diagnostic test in the evaluation of
patients with heart failure is echocardiography, particularly
transoesophageal echocardiography (TOE) coupled with
Doppler ¯ow studies. These tests determine whether the
primary abnormality is pericardial, myocardial or valvular,
and if myocardial, whether the dysfunction is primarily
systolic or diastolic. The functional information gained from
the echocardiogram is the measurement of LV ejection
fraction; patients with an ejection fraction less than 40% are
generally considered to have systolic dysfunction. In
addition, the echocardiogram allows for the quantitative
assessment of the dimensions, geometry, thickness and
regional motion of the right and left ventricles and the
qualitative evaluation of the atria, pericardium, valves and
vascular structures. Such a comprehensive evaluation is
important, since it is not uncommon for patients to have
more than one cardiac abnormality that can cause or
contribute to the development of heart failure.
LV size is assessed by measuring the inside diameter at
the junction of the basal and mid third at end diastole. This
value should be less than 5.5 cm with a wall thickness of
1.2 cm or less at end diastole. Systolic LV global function
can be assessed quantitatively or qualitatively.
Fractional area change (FAC) is a two-dimensional TOE
equivalent of ejection fraction. It is obtained by measuring
the LV chamber cross-sectional area at the transgastric mid
short axis view at end-systole and end-diastole to get the
end-diastolic area (EDA) and end-systolic area (ESA).
Fig 1 Schematic diagram showing ¯ow rate from the left atrium to the
left ventricle through the mitral valve during diastole. In the normal state
there is signi®cant passive ¯ow in the early period of diastole (E wave)
that is enhanced by the ¯ow associated with atrial contraction (A wave).
With mild or early diastolic dysfunction without a signi®cant increase in
left atrial pressure, there is impaired relaxation slowing the early passive
¯ow. As heart failure progresses, the left atrial pressure will rise in an
attempt to overcome the impaired relaxation of the ventricle to early
passive ®lling. Although the balance in ¯ow rates appears to be similar
to a normal ¯ow pattern, the deceleration in the early ¯ow is more abrupt
because of impaired ®lling of the stiff ventricle. With impaired relaxation
without elevated ®lling pressures, it is simple to appreciate that adequate
ventricular ®lling requires the atrial contraction. IVRT, isovolaemic
relaxation time.
FAC=EDA±ESA/EDA and is normally greater than 0.5.
This method is not as accurate when regional wall motion
abnormalities are present. A qualitative assessment is done
by examination of all areas of the ventricle and estimation of
ejection fraction as normal (>55%), mildly decreased,
moderately decreased, moderately severely decreased or
severely decreased (<25%). This method in experienced
hands correlates well with other non-echocardiographic
methods of ejection fraction measurement such as ventri-
culography.
Diastolic LV function can be assessed using pulse wave
Doppler echocardiography. The transmitral in¯ow velocity
pro®le during diastole in the normal patient has an `E' wave
corresponding to early passive ®lling of the ventricle,
followed by an `A' wave corresponding to atrial contraction
(Fig. 1). Impaired relaxation patterns with decreased peak
E-to-A velocity ratio and prolonged E wave deceleration
time signify mild diastolic dysfunction. A restrictive
pattern, with raised ®lling pressures and severe diastolic
dysfunction, is associated with an increased peak E-to-A
velocity ratio and decreased E wave deceleration time. A
period where the mitral in¯ow pattern appears normal may
occur as diastolic dysfunction progresses from mild to
severe. The pulmonary venous in¯ow velocity pro®le may
help to distinguish between these two.

75
 Magner and Royston

Table 1 The four stages of heart failure (A±D) as de®ned by the Joint Task Force of the American College of Cardiology and American Heart Association.35
HF, heart failure; LV, left ventricular

Stage Description Examples Implications

A Patients at high risk of developing HF Systemic hypertension Risk of

because of the presence of conditions Coronary artery disease anaesthesia/surgery is
that are strongly associated with the Diabetes mellitus related to underlying condition
development of HF. These patients
should have no identi®ed structural or
functional abnormalities of the
pericardium, myocardium or cardiac
valves and have never shown signs or
symptoms of HF

B Patients who have developed structural LV hypertrophy or ®brosis Risk of

heart disease that is strongly associated LV dilatation or hypocontractility anaesthesia/surgery related
with the development of HF but who Asymptomatic valvular heart disease to underlying condition;
have never shown signs or symptoms Previous myocardial infarction optimizing therapy before
of HF surgery is most important

C Patients who have current or prior Dyspnoea or fatigue due to LV systolic High risk of
symptoms of underlying HF associated dysfunction decompensation and
with underlying structural heart disease Asymptomatic patients who have adverse cardiac outcome
undergone treatment for prior
symptoms of HF

D Patients with advanced structural heart Patients who are frequently Extreme risk for
disease and marked symptoms of HF at hospitalized for HF and cannot be anaesthesia; patient will
rest despite maximal medical therapy and safely discharged from the hospital usually present in an
who require specialized interventions Patients in the hospital awaiting heart intensive care setting or
transplantation specialist unit
Patients at home receiving continuous
i.v. support for symptom relief or being
supported with a mechanical
circulatory assist device
Patients in a hospice setting for the
management of HF

Management remove contributing factors might include treatment of

No cure exists for most people with heart failure but much
can be done to make physical activity more comfortable and
improve the quality and duration of life. The American
College of Cardiology and American Heart Association
have described four stages of heart failure (Table 1).34
Patients in stage A have a known risk factor. Those in stage
B are known to have LV dysfunction but have not developed
heart failure. Those in stage C have current or previous
evidence of heart failure with known LV dysfunction and
the stage D patients have refractory end-stage heart failure.
Although this is a useful classi®cation to differentiate
between various management strategies, it is also obvious
that the symptomatic and pathological development of heart
failure is on a continuum.
The three approaches to therapy are intended to: (i) treat
the underlying cause; (ii) remove contributing factors that
can worsen heart failure, and (iii) treat the heart failure
itself. Surgical interventions include heart surgery for
valvular or coronary artery disease. Medical treatment to
infection and intervention for an overactive thyroid.
Patients with stage-A heart failure without contraindica-
tions, who have exercise-limiting angina pectoris or
frequent angina at rest should have angiography with a
view to revascularization. A few patients with ischaemia of
effort present not with chest pain but with shortness of
breath. These patients also warrant investigation and
possible angiography. Patients with stage-B heart failure
and haemodynamically signi®cant valvular regurgitation or
stenosis are candidates for valve replacement or repair.
Anaesthetic considerations for stage-A patients undergo-
ing cardiac or major non-cardiac surgery mainly centre
around the therapy they are receiving. The majority will be
being treated for hypertension (diuretics, angiotensin-con-
verting enzyme (ACE) inhibitors and beta blockers),
diabetes, or both.34
For stage B-heart failure, all measures used for stage A
are recommended. If ACE inhibitors and beta blockers have
not already been started their addition to the patient's
medication should be considered. Patients are usually

76
 Heart failure and its management
anticoagulated with oral anticoagulants to an international
normalized ratio of 2±3. Medications such as non-steroidal
anti-in¯ammatory drugs (NSAIDs) and all antiarrhythmic
drugs other than beta blockers, digoxin and amiodarone
should be stopped as they aggravate heart failure.34
Anaesthetic implications for patients with impaired
ventricular function or stage-C heart failure
If the patient does present for surgery that is unrelated to
their heart failure, the two principal cardiovascular events to
control during anaesthesia are myocardial depression and
peripheral vasodilatation. Any changes in either of these
variables should be minimized. Historically drugs such as
etomidate and ketamine have been suggested as useful in
this regard. However, there is a lack of evidence to support
these in the patient whose cardiac condition has been
optimized with currently advocated preoperative pharmaco-
logical interventions.
The majority of patients with impaired LV function are
dependent on their preload to maintain ventricular ®lling
and many patients with heart failure also rely on increased
sympathetic tone to maintain tissue perfusion and cardiac
output. Patients with severe impairment of LV function are
therefore extremely sensitive to changes in the ®ne balance
in which they exist. Moreover, the underlying cardio-
myopathy leading to heart failure has different aetiology
and thus different problems of management.
Cardiomyopathy is associated with a high incidence of
heart failure and may be restrictive, dilated or hypertrophic.
Restrictive cardiomyopathy is the most dif®cult to deal
with and is characterized by stiff ventricles that impair
ventricular ®lling; pronounced right heart failure is a
frequent problem. If the technique of general anaesthesia
produces myocardial depression, vasodilatation and reduced
venous return allied to increased intrathoracic pressure from
IPPV, then this may lead to circulatory arrest. Spontaneous
ventilation is therefore preferred while maintaining an
elevated right heart pressure by administration of ¯uid.
Dilated cardiomyopathy manifests as a large, poorly
contractile heart, with stroke volume preserved by dilatation
and increased LV end-diastolic volume. Functional mitral
and tricuspid incompetence is common due to the dilatation
of the annulus of the valve, and exacerbates the problem.
Arrhythmias are frequent and may be life-threatening.
Amiodarone is the drug of choice to treat these arrhythmias
as it has the least myocardial depressant effect.14
Inhalational anaesthetics reduce myocardial contractility
in a dose-dependent manner, but effects differ between the
different agents. Iso¯urane is a popular anaesthetic for
patients undergoing coronary revascularization and appears
to have certain cardioprotective properties. Sevo¯urane,
unlike iso¯urane and des¯urane, does not induce a
tachycardia. Recent human studies have also suggested
that iso¯urane and sevo¯urane have cardioprotective effects
similar to those induced by ischaemic precondition-
77
ing.24 70 71 Because of the extreme sensitivity to negative
inotropic agents, these patients frequently require inotropic
support.14
Hypertrophic cardiomyopathy is characterized by out¯ow
tract obstruction produced by septal hypertrophy. Impaired
diastolic function is an important feature, and diastolic
®lling of the ventricles may rely on atrial systole (`atrial
kick') for up to 75% of end-diastolic volume (Fig. 1),
therefore sinus rhythm is very important. Tachycardia may
also be a problem, as it reduces diastolic ®lling time of both
the coronaries and the ventricle. Inotropic support may
worsen out¯ow obstruction and increase myocardial oxygen
demand at the same time as lessening oxygen supply by
increasing ventricular wall tension.14 In general, vasodila-
tors that do not induce a tachycardia should be useful here.
Interventions with grade-D heart failure
These patients are most likely to present to the anaesthetist
in intensive care rather than for elective surgery, as
mortality following anaesthesia and surgical interventions
in this group is extremely high.
Pharmacological interventions
The cardiac glycosides have been the mainstay of treatment
for those with chronic heart failure.14 Their mechanisms of
action leading to subjective reduction in symptoms in heart
failure are multiple.42 In addition to effects on ion exchange
channels, it is hypothesized that digoxin also provides a
reduction in the sympathetic hyperactivity associated with
congestive heart failure.27 Diuretics should be given for
patients with evidence of ¯uid retention, and spirinolactone
is often used in patients with recurrent symptoms and
preserved renal function. Patients should also be treated
with neurohormonal blockade with an ACE inhibitor (or
angiotensin receptor blocker in patients with persistent
cough or angioedema) and a beta blocker. Calcium channel
blockers (except amlodipine) and NSAIDs should not be
given.
The basis of added therapy in advanced heart failure is
interventions to increase inotropy and reduce preload.
Inotropy
The fundamental mechanism to improve inotropy is to
increase myocyte intracellular cyclic AMP. Figure 2 shows
the various pathways that can be used to achieve this effect.
In the acute setting the usual inotropic support is from
catecholamines acting through the beta adrenoceptor. I.V.
dobutamine has been used for short-term support in severe
heart failure and LV dysfunction, but older patients treated
with dobutamine commonly develop arrhythmias,60 and
there is evidence that an increased rate of ventricular
arrhythmias and subsequent mortality are associated with
use of dobutamine. The FIRST study showed that long-term
use of dobutamine in heart failure patients was an
 Magner and Royston

Fig. 2 An increase in myo®bril contractility is related to an increase in ionized calcium (Ca2+) concentration. In turn, Ca2+ ¯ux is relayed to increased
cyclic AMP (cAMP). Increase in cAMP can be induced by a number of pathways, shown as outline boxes. Those discussed in the review are
metabolic substrate enhancement, stimulation of adenylate cyclse through beta-adrenoceptor stimulation and prevention of breakdown of cAMP by
administration of a phosphodiesterase inhibitor. Na+, sodium ions.

independent predictor of mortality, and did not improve
quality of life.52
Phosphodiesterase inhibitors (PDI) have become another
mainstay of treatment but recent trials have shown an
increased mortality in patients with congestive heart
failure,55 and patients with heart failure and abnormal LV
ejection fraction;21 55 68 however, they remain in use for
acute heart failure. The principal problem with these agents
is that with prolonged i.v. administration the associated
peripheral arterial dilatation leading to hypotension may be
dif®cult to control.
Recently there has been a resurgence of interest in the use
of nutritional and metabolic support in heart failure.
Nutritional supplements (such as coenzyme Q10, carnitine,
taurine and antioxidants) have been the subject of small-
scale studies. The administration of glucose-insulin-potas-
sium (GIK) may be of bene®t. First suggested as an
intervention for improving ventricular function and redu-
cing infarct size in the 1970s,44 57 GIK's popularity waned
because of concerns about various safety issues.50 However
in 1987, a study advocated the use of GIK following
coronary thrombolysis with streptokinase, stating that its
use improved ejection fraction and reduced segmental wall
motion abnormalities.63
A further approach to improving carbohydrate utilization
is to cause the myocyte to metabolize carbohydrate as its
principal substrate in preference to fatty acids. One
approach to increase glucose oxidation is to inhibit fatty
acid oxidation; three agents that work in this manner are
trimetazidine, etomoxir and ranolizine. Trimetazidine is
widely available for clinical use.43 It optimizes cardiac
metabolism by inhibition of fatty acid oxidation through
inhibition of mitochondrial palmitoylcarnitine oxidation,
while only partially inhibiting pyruvate oxidation and
preserving mitochondrial oxidation.26 37 A European
collaborative working group on trimetazidine has under-
taken a number of trials. These have con®rmed earlier
®ndings for this class of compound and showed that in
patients with angina, the effects of trimetazidine are not
only equivalent to nifedipine23 and propranol25 but also that
it does not reduce coronary blood ¯ow or rate pressure
product. It is synergistic with diltiazem in reducing angina
and appears to be effective in patients with LV dysfunc-
tion.65 Patients with chronically dysfunctional myocardium
have also been studied, and administration of trimetazidine
caused signi®cant improvement in function and symptoma-
tology.65 Evidence therefore suggests that agents such as
trimetazidine improve the dysfunctional heart without
increasing oxygen demand and may have an important
therapeutic role.
L-carnitine and its analog proprionyl L-carnitine increase
glucose oxidation and bene®t myocardial function by
reducing mitochondrial acetyl CoA.64 Animal studies have
demonstrated a myocardial bene®t,28 and a multicentre trial
showed that L-carnitine may reduce ventricular end-
diastolic pressure and slow the progression of LV dilatation
in patients who have suffered an MI.35
Direct stimulation of the pyruvate dehydrogenase (PDH)
complex to increase glucose oxidation may also be effect-
ive, and the prototype drug in this class is dichloroacetate,

78
 Heart failure and its management

Fig 3 Increased smooth muscle relaxation leads to vasodilatation, related to an increase in cyclic guanosine monophosphate (cGMP). Two clinically
relevant pathways (shown as outline boxes) can induce an increase in cGMP. Soluble guanylate cyclase is activated by nitric oxide (NO) derived
endogenously or from donors such as glyceryl trinitrate and nitroprusside. Particulate guanylate cyclase is stimulated by human brain natriuretic factor
(hBNP; nesiritide1). GTP, guanosine triphosphate; O2, oxygen

which acts by inhibiting PDH kinase and therefore prevents
inhibition of the PDH complex. This drug has been shown
clinically to have bene®cial effects in patients with LV
functional abnormalities in heart failure.12
Reduced preload
The mechanism for reduction in vascular tone that may
bene®t patients with heart failure is to increase the
intracellular concentration of cyclic guanosine mono-
phosphate (cGMP), leading to smooth muscle relaxation
and vasodilation. This is usually achieved using a nitrate
vasodilator or sometimes with sodium nitroprusside
infusion.
As an alternate, human brain natriuretic peptide (hBNP)
binds to the particulate guanylate cyclase receptor of
vascular smooth muscle and endothelial cells, leading to
increased intracellular concentrations of cGMP and smooth
muscle cell relaxation (Fig. 3).
A form of hBNP has been produced using recombinant
technology and is available as the compound nesiritide.46
Nesiritide has been shown to relax isolated human arterial
and venous tissue that had been precontracted with either
endothelin-1 or the alpha-adrenergic agonist, phenylephr-
ine. In human studies involving patients with heart failure,
nesiritide produced dose-dependent reductions in pulmon-
ary capillary wedge pressure (PCWP) and systemic arterial
pressure. In animals, nesiritide had no effects on cardiac
contractility or on measures of cardiac electrophysiology
such as atrial and ventricular effective refractory times or
atrioventricular node conduction. Naturally occurring atrial
natriuretic peptide, a related peptide, increases vascular
permeability in animals and humans and may reduce
intravascular volume. The effect of nesiritide on vascular
permeability has not been studied.
Nesiritide achieves the majority of its effect within 15 min
of injection.46 The offset of the haemodynamic effect of
nesiritide is longer than the kinetic half-life would predict.
For example, in patients who developed symptomatic
hypotension in the VMAC trial,1 half of the recovery of
systolic arterial pressure toward the baseline value after
discontinuation or reduction of the dose of nesiritide was
observed in about 60 min. When higher doses of nesiritide
were infused, the duration of hypotension was sometimes
several hours.
Non-pharmacological interventions in heart failure
Synchronized pacing
Sudden cardiac death due to arrhythmias is a common
problem in patients with heart failure. Such patients should
be treated aggressively, and sinus rhythm, which is crucial
in those patients who rely on synchronized atrial systole for
ventricular ®lling, should be restored, and rate optimized,
typically to a rate of about 80 beats min±1.
In chronic atrial ®brillation, the use of TOE facilitates
earlier cardioversion by allowing examination of the heart
and especially the atrial appendages for clot, and therefore
safe DC cardioversion without anticoagulation.
Optimization of the synchronization of myocardial con-
traction has been studied recently, with promising results.13
Many patients with chronic heart failure have ECG evidence

79
 Magner and Royston
of an interventricular conduction delay, which may worsen
LV systolic dysfunction; this is most often in the form of left
bundle branch block. This is caused by asynchronous
ventricular contraction and occurs in up to one-third of
chronic heart failure patients.17 Permanent pacing has been
used for many years to treat symptomatic bradycardia and
may be useful to alleviate heart failure associated with heart
block.18 A number of studies have examined the use of dual
chamber pacing in heart failure patients to improve cardiac
performance. Results have varied, with apical right-sided
pacing causing worsening haemodynamics or poorer LV
function.31 40 These effects are thought to be a result of
asynchrony of the ventricles, so many centres now advocate
pacing from the interventricular septum in the hope of
providing a more physiological pattern of contraction. From
this grew the idea that cardiac resynchronization could be
achieved with biventricular pacing. Signi®cant improve-
ment can be shown in patients who have cardiac
resynchronization through atrial-synchronized biventricular
pacing.2 17 41 This is achieved through the use of dual
chamber pacing placed in the usual way (transvenous), with
a third wire, also transvenous, placed in the LV venous
circulation via the coronary sinus. Biventricular pacing has
been shown to allow the heart to contract more ef®ciently to
increase LV ejection fraction and cardiac output while
consuming less oxygen.51 Other bene®ts include increased
diastolic ventricular ®lling time, decreased PCWP and
reduced mitral regurgitation.18 Newer devices allow more
control of atrioventricular contraction for further optimiza-
tion of function. Several clinical trials have studied the use
of biventricular pacing in left bundle branch block. The
MUSTIC and MIRACLE studies showed signi®cant
improvements in quality-of-life scores, exercise tolerance,
peak oxygen uptake and ejection fraction with biventricular
pacing.17 41 There were also impressive reductions in
hospital admission and hospital stay. Mortality data from
the COMPANION study showed a reduction in mortality of
20% in the biventricular pacing group; the trial was
consequently halted.15 In those who had implantable
biventricular cardiac de®brillators, the all-cause mortality
was reduced by 40%. The CARE heart failure study is
underway, but evidence thus far seems to show a de®nite
bene®t in morbidity and mortality with biventricular
pacing.19
Unfortunately as many as 20% of those patients who
ful®ll the criteria for biventricular pacing derive no bene®t
from it, and new techniques of patient selection are being
sought.59 The current criteria that suggest greatest bene®ts
following biventricular pacing and internal cardiode®bril-
lator implantation are systolic heart failure, non-reversible
causes for failure, a patient who is highly symptomatic and
has optimized medical therapy, and should be in sinus
rhythm with signi®cant mitral regurgitation, and ventricular
dysynchrony (left bundle branch block induced by right
ventricular apical pacing).18
80
Implantable cardioverter de®brillators are being advo-
cated in heart failure because severe LV failure, an
independent predictor of cardiac mortality, causes death
by progressive heart failure or malignant ventricular
arrhythmias.18 The National Institute for Clinical
Evidence has recommended the use of these devices in
cases of high-risk heart failure, following the publication of
large randomized controlled trials showing bene®ts in
mortality in high-risk ischaemic patients.49 The MADIT-II
trial showed a relative risk reduction of 31% in heart failure
patients with ischaemic heart disease and poor LV function
when automatic de®brillators were implanted.48
Biventricular pacing and implantable cardioverter de®-
brillators have also been used in the acute setting; a case
report of a patient weaned from cardiopulmonary bypass
with biventricular pacing was published recently,39 and bi-
atrial pacing has been used to prevent recurrence of atrial
®brillation in the intensive care unit after surgery.29
Surgical ventricular restoration
Anterior myocardial infarction leads to changes in the
ventricular architecture and volume. The proposed patho-
physiology is for the development of dyskinesia or akinesia
that leads to heart failure by myocardial dysfunction of the
remote muscle.9 Ventricular remodelling is designed to
return the ventricle to a more normal shape. Patients
undergoing anterior ventricular endocardial restoration
showed signi®cant improved 18-month survival and reduc-
tion in hospital re-admission when associated with coronary
revascularization or mitral valve repair.9 The Surgical
Treatment of Heart Failure Trial has been started and will
investigate long-term outcomes of patients with heart failure
and abnormal LV ejection fraction.
Mechanical assistance
This is a more radical and invasive method of support and
protection of the failing heart. Mechanical assist devices are
designed to decrease the mechanical work of the heart and
improve coronary perfusion. The main problem for the
clinician is to assess how much potential the patient's heart
function (together with the resultant multi-organ failure
related to the low output state) has for recovery and if a
mechanical support device will achieve this. The increasing
variety and availability of these devices will allow the
selection of the most appropriate system for each patient.
Predictability of the device's performance and available
resources are essential for effective use of mechanical
support.47
Intra-aortic balloon counterpulsation, commonly referred
to as an intra-aortic balloon pump (IABP), has been the
mainstay of perioperative short-term treatment of the failing
heart. Although IABPs are not suitable for all critically ill
patients, their use is becoming more widespread, with good
results reported.13 Further study on balloon pump use has
generated evidence that may allow the use of an IABP on an
 Heart failure and its management
ambulatory, longer term basis.20 36 IABP is a proven
technology that is often used as a comparator to assess the
ability of other systems to unload the heart and maintain
coronary ®lling whilst maintaining cardiac output. It is an
effective treatment for intractable angina and cardiogenic
shock,32 and has been shown to have a considerable bene®t
in cases of acute MI in combination with either percuta-
neous transluminal coronary angioplasty or thrombolysis.10
However, dopamine has been shown to be more effective in
the case of myocardial stunning following resuscitation.67
For perioperative protection, it is clear that the effectiveness
of IABP is greatest when introduced before surgery:
institution 2 h before surgery conveyed a highly signi®cant
bene®t when compared with institution at weaning from
cardiopulmonary bypass.45 Other modalities of protection
(pharmacological and metabolic modulation) should always
accompany IABP use.47 The overall morbidity (e.g. limb
ischaemia or bleeding) from IABP use is 3±5%, and risk
must be balanced against bene®ts.
LV assist devices (LVAD) have become increasingly
used for end-stage heart failure because of the shortage of
organs available for transplantation. While certain devices
have been approved by the US Food and Drug
Administration (FDA) for short-term support or as a bridge
to transplant, none has received a licence for permanent
replacement therapy. The REMATCH trial sponsored by the
US National Institutes of Health was designed to compare
permanent LVAD placement against optimal medical
management in patients not suitable for cardiac transplan-
tation.61 62 Analysis of data from these studies showed a
48% reduction in the risk of death from any cause in the
group that received LVADs compared with the medical-
therapy group. The survival rate at 1 yr was 52% in the
device group and 25% in the medical-therapy group, and at
2 yr was 23% and 8%, respectively. The frequency of
serious adverse events in the device group was 2.35 times
that in the medical-therapy group, with a predominance of
infection, bleeding and malfunction of the device.
Indications for device placement include postcardiotomy
shock, acute MI and myocarditis. In many cases, short-term
support as a bridge to recovery is replaced by a longer-term
device as a bridge to transplant. Reduced ventricular
function before surgery may mean that longer-term devices
are used at the outset. One of the most common indications
is severe cardiogenic shock associated with acute coronary
syndrome.56 Revascularization is often not appropriate in
these patients, and a bridge to transplant is required. The
Shock trial demonstrated the ineffectiveness of medical and
surgical revascularization in these patients, but device
implantation is not yet considered the optimal option.
Patients with long-term heart failure awaiting transplanta-
tion frequently receive implants because of clinical
deterioration. More time is provided to evaluate these
patients because of their chronic clinical deterioration, and
this approach often allows a period for recovery of end-
organ failure before transplantation. Patients considered
81
ineligible for transplantation may be improved by the
implantation of a device to the point where they can be
listed for transplantation.69 More recently, a team at
Hare®eld Hospital has been using an aggressive medical
therapy including the anabolic beta-adrenoceptor agonist
clenbuterol. This has been associated with exceptional
recovery of the patient's native heart function, allowing
removal of the LVAD without clinical deterioration.33
Patient selection is critical. Early implantation in a patient
soon to receive an organ, or with a chance of recovery,
subjects the patient to an expensive and complex procedure
with its own morbidity and mortality. Conversely, a delay in
device placement may result in multi-organ failure that
precludes further intervention for the patient. The decision-
making process is complicated and clinically challenging.
The appropriate device to implant depends on variables such
as the planned duration of support, patient body surface area
and need for uni- or bi-ventricular support. Criteria have
been developed to help these decisions. Haemodynamic
elements include systolic arterial pressure, PCWP and
cardiac index, with consideration of inotropic or balloon
pump support, or both. Other end-organ function, including
cognitive function, are essential considerations.
Preoperative factors that have an impact on LVAD effect-
iveness include ventilatory support, coagulopathy, right
heart function, infection and renal function.69 Most patients
with heart failure have mild pulmonary hypertension, which
resolves over time with placement of an LVAD and
unloading of the left heart. However, the right heart may
not be able to tolerate this reactive pulmonary hypertension
and may need support for a few days. Right heart failure can
be catastrophic and support can be with inotropic agents
(typically PDIs are used as ®rst-line intervention because of
their combined inotropic and vasodilator actions) or right
VAD insertion. The simplest protection is to ensure that the
patient's cardiac index is not raised precipitously following
LVAD placement, which might cause the right ventricle to
fail.69
Temporary neurological damage is not a contraindication
to device placement where there are reasonable grounds to
expect recovery, but if there is no recovery the patient
should not receive a transplant. Aortic valvular insuf®ciency
is a contraindication, as the low pressure ventricle will allow
a preferential ¯ow of pumped blood in a circuit from the left
ventricle through the device and back to the aortic root
rather than around the body. The valve lea¯ets may be sewn
together when a device that does not require valve opening
is implanted. Aortic stenosis may be repaired if myocardial
recovery is possible, and this may convey some protection
in the event of device failure.69 Mitral stenosis or regurgi-
tation should also be corrected and a tricuspid annuloplasty
ring may be placed to prevent the development of
insuf®ciency. A patent foramen ovale must be diagnosed
and closed, as with unloading of the left atrium signi®cant
intracardiac right-to-left shunting may occur.
 Magner and Royston
Choice of device
Devices can be divided into site of placement (extra- and
intra-corporeal) and type of ¯ow generator system (centri-
fugal, axial and diaphragm). Centrifugal pumps utilize the
pump mechanism of standard heart bypass. Two of the most
common are the Biomedicus Bio-pump and the Sarns/3M
Centrifugal system; new centrifugal systems include the
bearingless Levitronix system. These drive systems are
magnetically coupled to an external power source and pump
¯ow is related to rotation speed. They can be used uni- or bi-
ventricularly. Their main disadvantages are the need for
heparinization, dif®culty in chest closure, the need for
intensive monitoring and inability to generate pulsatile ¯ow.
They are used primarily as a bridge to recovery in
cardiogenic shock, but may be followed by a longer-term
device if recovery does not occur in 7±14 days.
Examples of other extracorporeal devices include the
Thoratec/Pierce-Donachy device and the Abiomed Bi-
ventricular support (BVS) 5000. The Abiomed is a pneu-
matic device with two pumps, each with two chambers: the
top (atrial) ®lls by gravity, and the lower (ventricular) has a
bladder that is compressed with gas to expel the contained
blood. The machine can generate ¯ows up to 6 litre min±1
and the central console regulates the ¯ow based on preload
®lling. The device is approved for post-cardiotomy support
but has been used for bridging to transplantation; it is
relatively safe, being ®lled passively, and simple to
maintain in the patient. It provides pulsatile ¯ow. Its
disadvantages include a ®xed stroke volume that may be
problematic in the very small or large patient, the need for
anticoagulation, the requirement for intensive care unit
support and the inability for patient mobilization. This
device is ideal for short-term support (average 7 days) and
as a bridge to recovery or to transplantation. The Thoratec/
Pierce-Donachy VAd can also be used for left, right or
bi-ventricular support. It is a polyurethane-lined, pneuma-
tically driven, pusher-plate device, with a stroke volume of
65 ml and generates ¯ows up to 7 litre min±1. The pump
itself is extracorporeal but like the BVS 5000, the chest may
be closed over the in¯ow and out¯ow cannulae, which exit
the body through the abdominal wall. The cannulae have a
coating to allow reduced levels of anticoagulation This
device is approved for post-cardiotomy support and is
frequently used as a bridge to transplant. It has been
implanted for up to 515 days, and has been reported as
having up to 38% weaning rate in some studies. Advantages
include versatility and suitability for small patients. It is the
only device approved for those in need of longer support.
Disadvantages include infective risk with the abdominal
exit site, anticoagulation need and a large cumbersome drive
console.69
Intracorporeal devices include the Novacor Left
Ventricular Assist System (LVAS) and The Heartmate
LVAD systems. The Novacor is FDA approved for bridge to
transplant. This device works by a dual pusher plate with a
polyurethane-lined blood-contact surface and two porcine
82
valves. Flows are up to 10 litre min±1 with a stroke volume
of 70 ml. Similar to the Heartmate system, it is only
available as a left-sided support device and it can be
triggered with ECG or intrinsic ventricular contractile
synchronization. Newer devices may become completely
implantable, but for now drive gases and electrical
connections to the device that is implanted in the abdominal
cavity must pass through the skin. Patients under 60 kg in
weight are usually considered too small for implantation of
this device. Advantages include the almost free ambulation
so that selected patients can be discharged home.
Anticoagulation is the primary drawback of LVAS, and
despite this being adequate based on laboratory criteria, the
incidence of thrombotic stroke is high (about 26%). The
percutaneous line is a route for infection, as with
the Heartmate and other transcutaneous systems.
Reliability is excellent and support has been up to 4 yr.69
The Heartmate LVAD is available in two versions: the
implantable pneumatic (IP) and vented electric (VE). The
device is unique in that it uses a sintered titanium housing
that stimulates formation of a pseudo-intimal layer. This is
combined with xenograft valves to avoid the need for
anticoagulation. The IP device is driven by a pneumatic
driver and is thus less portable than the VE device. An
external pneumatic pump may drive the IP device in an
emergency, since it is vented. Flow rates as high as 10 litre
min±1 can be achieved and the stroke volume is 85 ml; there
are two modes. The driveline is tunnelled and exits the
abdomen. Advantages include a very low rate of throm-
boembolic events (2.7%) despite the avoidance of anti-
coagulation.66 A hand pump can operate both devices in the
event of a failure, and patients can be discharged home
while awaiting an organ. Disadvantages include limitation
on patient size, percutaneous driveline and the requirement
for another type of device if right-sided support is required.
These devices have proven themselves reliable and versa-
tile, and patients who go on to transplantation do as well as
those who have transplantation initially.16
Implantable axial ¯ow pumps (Jarvik 2000, DeBakey
VAD, Kriton and the Heartmate II) are the latest technology
to be employed. These systems are very light, simple, small,
lack valves, can generate ¯ows up to 10 litre min±1 and have
minimal blood contact areas.38 They show minimal
haemolysis but require anticoagulation (except the
Kriton). The Kriton is exceptional as it has a pump with
no mechanical wear, and therefore no heat, and no area of
stagnant blood to stimulate clotting. The main advantage of
these pumps is their small size, which simpli®es implant-
ation and explantation, and makes them suitable for smaller
patients. Their simplicity should aid reliability but in the
event of a failure, replacement is the only option. These
devices are in clinical use now and are under evaluation.
There is some concern that these devices are not pulsatile
and this may have implications for end organs, but this is a
theoretical issue and the evidence appears good in studies to
date.58
 Heart failure and its management
Postoperative management of patients after implantation
is often dif®cult because of multiple organ dysfunction.
Bleeding and worsening right ventricular disease contribute
to dif®cult patient management. Avoidance of transfusion
where possible in patients who will be transplanted, and the
implications for pulmonary vascular resistance with trans-
fusion, are major concerns. Aprotinin has been shown to be
effective in reducing bleeding in these patients30 and
anticoagulation is only begun after surgery when patients
have ceased to bleed. Right-hearted failure is the most
dangerous complication of LVAD insertion, as mentioned
previously; an atrial pressure above 20 mm Hg with a low
PCWP are cardinal signs. Inhaled nitric oxide may be
valuable in this setting. Pacing, biventricular if indicated,
may also be instituted. Biventricular support will be
necessary if aggressive pharmacological support is unsuc-
cessful despite careful regulation of left-sided ¯ows.69
Vasodilatory hypotension is common in these patients and if
traditional vasopressors fail, arginine vasopressin may be
useful.3
Summary
The heart failure epidemic is now a major cause of mortality
and morbidity and is responsible for many hundreds of
thousands of deaths throughout the world each year.
Anaesthetists and intensivists encounter this condition on
an almost daily basis and not infrequently it contributes to or
causes the death of the patients for whom we are respon-
sible. However, our understanding of this complex illness is
steadily improving and the medical armamentarium to
alleviate symptoms and improve outcome is expanding.
New surgical and medical treatments and new and more
sophisticated medical devices all have the potential to
prolong and improve the lives of heart failure patients.
Future therapy for this distressing condition holds out much
promise.
References
1 Intravenous nesiritide vs nitroglycerin for treatment of
decompensated congestive heart failure: a randomized
controlled trial. JAMA 2002; 287: 1531±40
2 Abraham WT, Fisher WG, Smith AL, et al. Cardiac
resynchronization in chronic heart failure. N Engl J Med 2002;
346: 1845±53
3 Argenziano M, Choudhri AF, Oz MC, et al. A prospective
randomized trial of arginine vasopressin in the treatment of
vasodilatory shock after left ventricular assist device placement.
Circulation 1997; 96: II-286±90
4 Aronow W. Effects of aging on the heart. In: Tallis R, Fillit H,
Broccklehurst J, eds. Brocklehurst's Textbook of Geriatric Medicine
and Gerontology. Edinburgh: Churchill Livingstone, 1998; 255±62
5 Aronow WS. Epidemiology, pathophysiology, prognosis and
treatment of systolic and diastolic heart failure in elderly
patients. Heart Dis 2003; 5: 279±94
6 Aronow WS, Ahn C, Gutstein H. Prevalence of atrial ®brillation
and association of atrial ®brillation with prior and new
83
thromboembolic stroke in older patients. J Am Geriatr Soc
1996; 44: 521±3
7 Aronow WS, Ahn C, Kronzon I. Comparison of incidences of
congestive heart failure in older African-Americans, Hispanics
and whites. Am J Cardiol 1999; 84: 611±12, A9
8 Aronow WS, Ahn C, Kronzon I, Koenigsberg M. Congestive
heart failure, coronary events and atherothrombotic brain
infarction in elderly blacks and whites with systemic
hypertension and with and without echocardiographic and
electrocardiographic evidence of left ventricular hypertrophy.
Am J Cardiol 1991; 67: 295±9
9 Athanasuleas CL, Stanley AW Jr, Buckberg GD, et al. Surgical
anterior ventricular endocardial restoration (SAVER) in the
dilated remodeled ventricle after anterior myocardial infarction.
RESTORE group. Reconstructive Endoventricular Surgery,
returning Torsion Original Radius Elliptical Shape to the LV. J
Am Coll Cardiol 2001; 37: 1199±209
10 Barron HV, Every NR, Parsons LS, et al. The use of intra-aortic
balloon counterpulsation in patients with cardiogenic shock
complicating acute myocardial infarction: data from the National
Registry of Myocardial Infarction 2. Am Heart J 2001; 141: 933±9
11 Berry C, Murdoch DR, McMurray JJ. Economics of chronic heart
failure. Eur J Heart Fail 2001; 3: 283±91
12 Bersin RM, Wolfe C, Kwasman M, et al. Improved hemodynamic
function and mechanical ef®ciency in congestive heart failure
with sodium dichloroacetate. J Am Coll Cardiol 1994; 23: 1617±24
13 Bosenberg C, Royston D. Protect the heart in the intensive care
unit ± but how? Curr Opin Crit Care 2002; 8: 417±20
14 Bovill J. Anesthesia for patients with impaired ventricular
function. Semin Cardiothorac Vasc Anesth 2003; 7: 49±54
15 Bristow MR, Feldman AM, Saxon LA. Heart failure management
using implantable devices for ventricular resynchronization:
Comparison of Medical Therapy, Pacing and De®brillation in
Chronic Heart Failure (COMPANION) trial. COMPANION
Steering Committee and COMPANION Clinical Investigators. J
Card Fail 2000; 6: 276±85
16 Cantanese K, Morales D. Outpatient left ventricular assist
therapy. In: Goldstein D, Ox M, eds. Cardiac Assist Devices.
Armonk, NY: Futura, 2000: 153±65
17 Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite
biventricular pacing in patients with heart failure and
intraventricular conduction delay. N Engl J Med 2001; 344:
873±80
18 Chow AW, Lane RE, Cowie MR. New pacing technologies for
heart failure. BMJ 2003; 326: 1073±7
19 Cleland JG, Daubert JC, Erdmann E, et al. The CARE-HF study
(CArdiac REsynchronisation in Heart Failure study): rationale,
design and end-points. Eur J Heart Fail 2001; 3: 481±9
20 Cochran RP, Starkey TD, Panos AL, Kunzelman KS. Ambulatory
intraaortic balloon pump use as bridge to heart transplant. Ann
Thorac Surg 2002; 74: 746±51
21 Cohn JN, Goldstein SO, Greenberg BH, et al. A dose-dependent
increase in mortality with vesnarinone among patients with
severe heart failure. Vesnarinone Trial Investigators. N Engl J
Med 1998; 339: 1810±16
22 Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as
a guide to prognosis in patients with chronic congestive heart
failure. N Engl J Med 1984; 311: 819±23
23 Dalla-Volta S, Maraglino G, Della-Valentina P, Viena P, Desideri
A. Comparison of trimetazidine with nifedipine in effort angina: a
double-blind, crossover study. Cardiovasc Drugs Ther 1990; 4
(Suppl 4): 853±9
24 De Hert SG, ten Broecke PW, Mertens E, et al. Sevo¯urane but
 Magner and Royston
not propofol preserves myocardial function in coronary surgery
patients. Anesthesiology 2002; 97: 42±9
25 Detry JM, Sellier P, Pennaforte S, et al. Trimetazidine: a new
concept in the treatment of angina. Comparison with
propranolol in patients with stable angina. Trimetazidine
European Multicenter Study Group. Br J Clin Pharmacol 1994;
37: 279±88
26 Fantini E, Demaison L, Sentex E, Grynberg A, Athias P. Some
biochemical aspects of the protective effect of trimetazidine on
rat cardiomyocytes during hypoxia and reoxygenation. J Mol Cell
Cardiol 1994; 26: 949±58
27 Ferguson D. Sympathetic mechanisms in heart failure. Circulation
1993; 87: 68±75
28 Ferrari R, Anard I. Utilisation of propionyl L-carnitine for the
treatment of heart failure. In: de Jong J, Ferrari R, eds. A New
Therapeutic Approach to Cardiac Diseases. Dordrecht: Kluwer
Academic, 1995; 323±36
29 Gerstenfeld EP, Khoo M, Martin RC, et al. Effectiveness of
bi-atrial pacing for reducing atrial ®brillation after coronary
artery bypass graft surgery. J Intervent Cardiol Electrophysiol 2001;
5: 275±83
30 Goldstein DJ, Oz MC, Smith CR, et al. Safety of repeat aprotinin
administration for LVAD recipients undergoing cardiac
transplantation. Ann Thorac Surg 1996; 61: 692±5
31 Hochleitner M, Hortnagl H, Ng CK, Gschnitzer F, Zechmann W.
Usefulness of physiologic dual-chamber pacing in drug-resistant
idiopathic dilated cardiomyopathy. Am J Cardiol 1990; 66:
198±202
32 Hollenberg SM. Cardiogenic shock. Crit Care Clin 2001; 17:
391±410
33 Hon JK, Yacoub MH. Bridge to recovery with the use of left
ventricular assist device and clenbuterol. Ann Thorac Surg 2003;
75: S36±41
34 Hunt SA, Baker DW, Chin MH, et al. ACC/AHA Guidelines for
the Evaluation and Management of Chronic Heart Failure in the
Adult: Executive Summary A Report of the American College of
Cardiology/American Heart Association Task Force on Practice
Guidelines (Committee to Revise the 1995 Guidelines for the
Evaluation and Management of Heart Failure): Developed in
Collaboration With the International Society for Heart and Lung
Transplantation; Endorsed by the Heart Failure Society of
America. Circulation 2001; 104: 2996±3007
35 Iliceto S, Scrutinio D, Bruzzi P, et al. Effects of L-carnitine
administration on left ventricular remodeling after acute anterior
myocardial infarction: the L-Carnitine Ecocardiogra®a
Digitalizzata Infarto Miocardico (CEDIM) Trial. J Am Coll Cardiol
1995; 26: 380±7
36 Jeevanandam V, Jayakar D, Anderson AS, et al. Circulatory
assistance with a permanent implantable IABP: initial human
experience. Circulation 2002; 106: I183±8
37 Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal
drug trimetazidine shifts cardiac energy metabolism from fatty
acid oxidation to glucose oxidation by inhibiting mitochondrial
long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2000; 86:
580±8
38 Kaplon RJ, Oz MC, Kwiatkowski PA, et al. Miniature axial ¯ow
pump for ventricular assistance in children and small adults. J
Thorac Cardiovasc Surg 1996; 111: 13±18
39 Kleine P, Doss M, Aybek T, Wimmer-Greinecker G, Moritz A.
Biventricular pacing for weaning from extracorporeal circulation
in heart failure. Ann Thorac Surg 2002; 73: 960±2
40 Linde C, Gadler F, Edner M, et al. Results of atrioventricular
synchronous pacing with optimized delay in patients with severe
congestive heart failure. Am J Cardiol 1995; 75: 919±23
84
41 Linde C, Leclercq C, Rex S, et al. Long-term bene®ts of
biventricular pacing in congestive heart failure: results from the
MUltisite STimulation in cardiomyopathy (MUSTIC) study. J Am
Coll Cardiol 2002; 40: 111±18
42 Lonn E, McKelvie R. Drug treatment in heart failure. BMJ 2000;
320: 1188±92
43 Lopaschuk G, Manzilli M. Mode of action of trimetazidine and
other metabolic agents in the treatment of ischaemic heart
disease. Semin Cardiothorac Vasc Anesth 2003; 7: 91±6
44 Mantle JA, Rogers WJ, Smith LR, et al. Clinical effects of glucose-
insulin-potassium on left ventricular function in acute myocardial
infarction: results from a randomized clinical trial. Am Heart J
1981; 102: 313±24
45 Marra C, De Santo LS, Amarelli C, et al. Coronary artery bypass
grafting in patients with severe left ventricular dysfunction: a
prospective randomized study on the timing of perioperative
intraaortic balloon pump support. Int J Artif Organs 2002; 25:
141±6
46 Mills RM, Hobbs RE. Nesiritide in perspective: Evolving
approaches to the management of acute decompensated heart
failure. Drugs Today (Barc) 2003; 39: 767±74
47 Mol B. Mechanical support in acute perioperative heart failure:
Are assist devises smart enough to heal the heart? Semin
Cardiothorac Vasc Anesth 2003; 7: 105±9
48 Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a
de®brillator in patients with myocardial infarction and reduced
ejection fraction. N Engl J Med 2002; 346: 877±83
49 National Institute for Clinical Excellence. Guidance on the use of
implantable cardioverter de®brillators. Technological appraisal
guidance no. 11. London: NICE, 2000; 15
50 Neely JR, Grotyohann LW. Role of glycolytic products in damage
to ischemic myocardium. Dissociation of adenosine triphosphate
levels and recovery of function of reperfused ischemic hearts.
Circ Res 1984; 55: 816±24
51 Nelson GS, Berger RD, Fetics BJ, et al. Left ventricular or
biventricular pacing improves cardiac function at diminished
energy cost in patients with dilated cardiomyopathy and left
bundle-branch block. Circulation 2000; 102: 3053±9
52 O'Connor CM, Gattis WA, Uretsky BF, et al. Continuous
intravenous dobutamine is associated with an increased risk of
death in patients with advanced heart failure: insights from the
Flolan International Randomized Survival Trial (FIRST). Am Heart
J 1999; 138: 78±86
53 Ogawa T, Spina RJ, Martin WH 3rd, et al. Effects of aging, sex and
physical training on cardiovascular responses to exercise.
Circulation 1992; 86: 494±503
54 Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy
of the aging human heart. Myocyte loss and reactive cellular
hypertrophy. Circ Res 1991; 68: 1560±8
55 Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone
on mortality in severe chronic heart failure. The PROMISE Study
Research Group. N Engl J Med 1991; 325: 1468±75
56 Park SJ, Nguyen DQ, Bank AJ, Ormaza S, Bolman RM 3rd. Left
ventricular assist device bridge therapy for acute myocardial
infarction. Ann Thorac Surg 2000; 69: 1146±51
57 Rackley CE, Russell RO Jr, Rogers WJ, et al. Clinical experience
with glucose-insulin-potassium therapy in acute myocardial
infarction. Am Heart J 1981; 102: 1038±49
58 Reddy RC, Goldstein AH, Pacella JJ, et al. End organ function with
prolonged nonpulsatile circulatory support. Asaio J 1995; 41:
M547±51
59 Reuter S, Garrigue S, Barold SS, et al. Comparison of
characteristics in responders versus nonresponders with
 Heart failure and its management
biventricular pacing for drug-resistant congestive heart failure.
Am J Cardiol 2002; 89: 346±50
60 Rich MW, Woods WL, Davila-Roman VG, et al. A randomized
comparison of intravenous amrinone versus dobutamine in older
patients with decompensated congestive heart failure. J Am
Geriatr Soc 1995; 43: 271±4
61 Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term mechanical
left ventricular assistance for end-stage heart failure. N Engl J
Med 2001; 345: 1435±43
62 Rose EA, Moskowitz AJ, Packer M, et al. The REMATCH trial:
rationale, design and end points. Randomized Evaluation of
Mechanical Assistance for the Treatment of Congestive Heart
Failure. Ann Thorac Surg 1999; 67: 723±30
63 Satler LF, Green CE, Kent KM, et al. Metabolic support during
coronary reperfusion. Am Heart J 1987; 114: 54±8
64 Schonekess BO, Allard MF, Lopaschuk GD. Propionyl L-carnitine
improvement of hypertrophied heart function is accompanied by
an increase in carbohydrate oxidation. Circ Res 1995; 77: 726±34
65 Sellier P. The effects of trimetazidine on ergometric parameters
in exercise-induced angina. Controlled multicenter double blind
versus placebo study. Arch Mal Coeur Vaiss 1986; 79: 1331±6
85
66 Slater JP, Rose EA, Levin HR, et al. Low thromboembolic risk
without anticoagulation using advanced-design left ventricular
assist devices. Ann Thorac Surg 1996; 62: 1321±7
67 Tennyson H, Kern KB, Hilwig RW, Berg RA, Ewy GA. Treatment
of post resuscitation myocardial dysfunction: aortic
counterpulsation versus dobutamine. Resuscitation 2002; 54:
69±75
68 Uretsky BF, Jessup M, Konstam MA, et al. Multicenter trial of oral
enoximone in patients with moderate to moderately severe
congestive heart failure. Lack of bene®t compared with placebo.
Enoximone Multicenter Trial Group. Circulation 1990; 82:
774±80
69 Williams M, Oz M, Mancini D. Cardiac assist devices for end-
stage heart failure. Heart Dis 2001; 3: 109±15
70 Zaugg M, Lucchinetti E, Garcia C, et al. Anaesthetics and cardiac
preconditioning. Part II. Clinical implications. Br J Anaesth 2003;
91: 566±76
71 Zaugg M, Lucchinetti E, Uecker M, Pasch T, Schaub MC.
Anaesthetics and cardiac preconditioning. Part I. Signalling and
cytoprotective mechanisms. Br J Anaesth 2003; 91: 551±65