Download Prevention and Management of Chronic Heart Failure in Patients at

Prevention and Management of Chronic
Heart Failure in Patients at Risk
Livio Dei Cas,
MD,
Marco Metra, MD, Savina Nodari, MD, Alessandra Dei Cas,
and Mihai Gheorghiade, MD
MD,
The prevalence and incidence of chronic heart failure
(HF) have now reached epidemic proportions. However,
the issue of the prevention of HF has been raised only
recently. New US guidelines have introduced a new
classification system that includes 4 categories: patients
at risk, patients with asymptomatic left ventricular dysfunction, patients with symptomatic HF, and those with
refractory HF. Because coronary artery disease is the
major cause of HF, its risk factors are also those of HF.
Hypertension favors the development of HF through accelerated atherosclerosis and increased left ventricular
wall stress and hypertrophy. Left ventricular hypertrophy is also a powerful risk factor for HF, independent of
blood pressure. Angiotensin-converting enzyme (ACE)
inhibitors, ␤-blockers, and diuretics are the antihypertensive agents that have been associated with favorable
effects in patients with overt HF. Therefore, they may be
preferred in the prevention of this syndrome. Diabetes is
the most frequent noncardiac comorbidity of HF and is
independently associated with an increased risk. Normalization of glycemic and glycosylated hemoglobin
levels is a desirable goal of treatment. However, no
direct evidence exists in the prevention of HF. A greater
control of the other risk factors (eg, hypertension, hyperlipidemia) is, on the other hand, particularly important. ␤-Blockers and ACE inhibitors have both been
shown to have favorable effects across all spectrums of
severity of HF. The ACE inhibitor ramipril has also been
shown to prevent the development of HF in patients at
risk without left ventricular dysfunction. The role of antiplatelet agents, warfarin, and statins is clear in the
prevention of the coronary artery disease. However, it
has not been adequately assessed in patients with HF
and awaits the results of ongoing trials. 䊚2003 by
Excerpta Medica, Inc.
Am J Cardiol 2003;91(suppl):10F–17F
he increase in the mean age of the general population and the improvement in the treatment of the
T
major cardiovascular diseases have caused a progres-
been identified: (1) stage A—patients at high risk for
developing HF but without any structural heart disease; (2) stage B—patients with cardiac dysfunction
but who have never developed symptoms of HF; (3)
stage C—patients with past or current symptoms of
HF; and (4) stage D—patients with end-stage disease.2
This classification scheme is similar to that used
with malignancies and emphasizes the progressive
nature of HF, with patient status generally worsening
from a particular stage to the next stage. It also points
out the importance of the therapeutic interventions at
an earlier stage of the disease, when they are primaryprevention procedures that may halt the development
of HF and its excessive morbidity and mortality. The
treatments used to reduce the incidence of HF exacerbations and the consequent hospitalizations when
the symptoms have already developed may be considered as secondary prevention of HF.1,2 In this review,
we will focus only on the primary prevention of HF
(secondary prevention is the current treatment of
symptomatic HF, aimed at improvement of symptoms
but also, and often mainly, at improvement of prognosis).
Coronary artery disease is the single most common
cause of HF,6 –9 with a significant increase in the
number of patients who can be identified (from 29% to
40%) when coronary angiography is systematically
used in addition to clinical criteria.9 Isolated hypertension is regarded as the primary cause of HF in a
minority of patients; however, it frequently coexists
with coronary artery disease.6 –9 Idiopathic dilated car-
sive increase in the prevalence and incidence of
chronic heart failure (HF). Despite numerous studies
on risk factors and the prevention of coronary artery
and cerebrovascular diseases, the issue of the prevention of HF has been brought to attention only recently.1–3 In the latest update of the guidelines of the
European Society of Cardiology4 and in the latest
edition of a major textbook of cardiovascular diseases,5 the treatment of patients with asymptomatic left
ventricular dysfunction or mildly symptomatic HF has
been differentiated from that of patients with symptomatic and advanced HF. However, it was only in the
latest revised version of the American College of
Cardiology/American Heart Association (ACC/AHA)
guidelines2 that the issue of the prevention of HF has
been highlighted. These guidelines have, for the first
time, introduced a new approach to the classification
of HF, emphasizing both the evolution and progression of this syndrome. There are 4 stages that have
From the Cattedra di Cardiologia, Università di Brescia, Brescia, Italy;
and the Division of Cardiology, Northwestern University Medical
School, Chicago, Illinois, USA.
This work was supported in part by Cassa di Risparmio delle
Provincie Lombarde from the Centro per lo Studio del Trattamento dello
Scompenso Cardiaco of the University of Brescia, Brescia, Italy.
Address for reprints: Marco Metra, MD, Cattedra di Cardiologia,
c/o Spedali Civili, P.zza Spedali Civili, 25100 Brescia, Italy. E-mail:
[email protected].
10F
©2003 by Excerpta Medica, Inc.
All rights reserved.
0002-9149/03/$ – see front matter
doi:10.1016/S0002-9149(02)03369-6
diomyopathy is the second most frequent cause of HF,
followed by valve disease, alcoholic cardiomyopathy,
cor pulmonale, and hypertrophic and restrictive cardiomyopathy. Because hypertension and coronary artery disease and, above all, their combination are the
main causes of most cases of HF, it is clear that
primary prevention of HF actually corresponds to the
prevention of coronary artery disease and its risk
factors.
HYPERTENSION
Hypertension is a major risk factor for HF. In the
20-year follow-up study of the 5,143 subjects included
in the original Framingham Heart Study and the Framingham Offspring Study,10 hypertension antedated
the development of HF in 91% of the subjects. After
adjustment for age and other risk factors, the hazard
for developing HF was about 2-fold in men and 3-fold
in women with hypertension compared with those
without hypertension; hypertension accounted for
only 39% of cases of HF in men compared with 59%
in women. Similarly, in the National Health and Nutrition Examination Survey Epidemiologic Study
(NHANES), hypertension alone was associated with a
1.40 relative risk (RR) of HF (95% confidence interval
[CI], 1.24 to 1.59; p ⬍0.001) at multivariate analysis
with a population-attributable risk of 10.1%.8 Antecedent hypertension increases the risk of HF also in
patients who have developed a myocardial infarction.
In a study involving 1,093 consecutive patients with
acute myocardial infarction, those with antecedent
hypertension had greater neurohumoral activation, left
ventricular dilatation, and incidence of symptomatic
HF and HF hospitalizations.11 Most studies primarily
evaluated diastolic blood pressure; however, more recent data from the Systolic Hypertension in the Elderly Program (SHEP) have shown the importance of
the pulse pressure in elderly patients with isolated
systolic hypertension. In this study, a 10-mm Hg increment in the pulse pressure was associated with a
14% increase in the HF risk (95% CI, 0.05 to 0.24),
and this risk remained significant at multivariate analysis, after adjustment for the other covariates and
mean blood pressure values.12
The 2 main mechanisms through which hypertension causes HF are (1) accelerated atherosclerosis and
(2) elevated left ventricular wall stress, with secondary neurohumoral activation and left ventricular hypertrophy. In addition to coronary atherosclerosis, hypertension may predispose one to myocardial ischemia also through an increase in coronary resistance
secondary to endothelial dysfunction, decreased coronary reserve, augmented interstitial and perivascular
collagen, and abnormalities in the responsiveness of
the coronary vessels to vasoactive substances.13 Left
ventricular mass is linearly related to the level of
blood pressure. However, it is influenced by other
factors, such as age, sex, race, body weight and height,
salt and alcohol intake, and neuroendocrine factors
(eg, the renin–angiotensin–aldosterone system and
sympathetic nervous system, insulin, growth hormone
activation). Left ventricular hypertrophy is a wellknown risk factor for death, major cardiovascular
events,14 and HF,15 both in the normotensive subjects
and, to a greater extent, in hypertensive patients. In
addition, an increased left ventricular mass is an independent predictor of a worse outcome at later stages
of the disease, as shown by its independent prognostic
value in patients with asymptomatic and symptomatic
left ventricular systolic dysfunction studied in the
Study of Left Ventricular Dysfunction (SOLVD) trials.16 The relation between left ventricular mass and
the incidence of major cardiovascular events is linear
without any threshold value, and it persists after adjustment for other risk factors and blood pressure.
The increase in left ventricular stress and hypertrophy may cause major cardiovascular events through
multiple mechanisms, including (1) myocardial ischemia caused by a disproportionate increase in the
myofibrillar component, perivascular fibrosis, and a
reduction in the coronary vasodilatory capacity; (2)
reduced left ventricular compliance; and (3) potentially malignant tachyarrhythmias. Other mechanisms
that may contribute to the development of left ventricular dysfunction are myocardial fibrosis and fiber
disarray, an acceleration of myocyte death with the
mechanisms of ischemic necrosis and apoptosis, and
the expression of a fetal gene program with a reduced
efficiency of myocardial contraction.13,17 Reduction of
blood pressure and left ventricular hypertrophy is
therefore a desired goal of therapy for HF prevention.
However, the relation between the regression of left
ventricular hypertrophy and prognosis has not yet
been thoroughly assessed. A trial showing the utility
of left ventricular hypertrophy regression was the
Heart Outcomes Prevention Evaluation (HOPE) trial,
which showed an association among the regression of
the electrocardiographic markers of left ventricular
hypertrophy and a lower risk of major cardiovascular
events and the prevention of HF.17
Treatment of both systolic and diastolic hypertension is associated with a reduction in the incidence of
HF. In a systematic review and meta-analysis of 18
controlled studies published in 1997 that included a
total of 48,220 patients, ␤-blocker therapy was associated with an RR of HF of 0.58 (95% CI, 0.40 to
0.84), and high-dose and low-dose diuretic therapies
were associated with risk reductions of 0.17 (95% CI,
0.07 to 0.41) and 0.58 (95% CI, 0.44 to 0.76), respectively, compared with placebo.18 The reduction of the
pulse pressure is also associated with a reduced incidence of HF.19 Treatment of hypertension has already
demonstrated its benefit in the primary prevention of
HF. In fact, the recent finding of a reduction in the
incidence of HF in women has been related to the
better treatment of hypertension.20
Blood pressure should be reduced according to the
specific patient’s risk profile, with the general goal of
a blood pressure measurement ⬍140/85 mm Hg in all
patients and ⬍130/80 mm Hg in patients with diabetes.21,22 Among the different antihypertensive agents,
those that are useful for the treatment of both hyper-
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11F
tension and HF (eg, diuretics, ␤-blockers, and angiotensin-converting enzyme [ACE] inhibitors) should be
preferred.2 Diuretics and ␤-blockers have been widely
shown to be effective in the prevention of HF in the
first trials of antihypertensive therapy.14 More controversial is the effectiveness of the ␣-antagonists. The
doxazosin arm of the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial
(ALLHAT) was prematurely discontinued because
doxazosin administration was associated with an increased risk of major cardiovascular disease and, in
particular, of HF, compared with chlorthalidone treatment (RR, 2.04; 95% CI, 1.79 to 2.32; p ⬍0.001).23
Other data favor the use of ACE inhibitors, rather than
calcium antagonists, for the prevention of HF. The
frequency of development of HF was significantly
lower in the ACE inhibitor group than in the calcium
antagonist group in the Swedish Trial in Old Patients
with Hypertension 2 (STOP Hypertension–2) study
(RR, 0.78; 95% CI, 0.63 to 0.97).24 This trend was
confirmed in a subsequent meta-analysis showing an
increased RR of HF with calcium antagonists compared with both ACE inhibitors (RR, 1.24; 95% CI,
1.00 to 1.55) and diuretics, and ␤-blockers (RR, 1.22;
95% CI, 1.03 to 1.46).25 However, the use of calcium
antagonists has been associated with a reduced incidence of stroke, and no significant difference in the
prevention of HF was observed in another meta-analysis.26
DIABETES
Similar to HF, the number of patients with diabetes
mellitus is progressively increasing. Diabetes is a
large comorbidity of patients with HF. In major clinical trials, it was observed in 20% to 30% of patients27
with higher values (35%) when blood glucose was
measured at baseline and the recent diagnostic criteria
were applied.28 Similar percentages (35% among patients treated by cardiologists, 38% among those
treated by generalists) have been observed when less
selected HF populations, not included in clinical trials,
were studied.29
Diabetes markedly increases the likelihood of HF
in patients without cardiac disease. The Framingham
study was the first study that showed an increased risk
of HF in patients with diabetes, with an incidence of
HF that showed a 4-fold and 8-fold increase in men
and women with diabetes, respectively, compared
with those without diabetes.30 In the NHANES study,
diabetes was independently associated with an increased risk of HF (RR, 1.85; 95% CI, 1.51 to 2.28; p
⬍0.01).8 The association between glycosylated hemoglobin (HbA1c) levels and the incidence of HF was
studied in a large, population-based sample of adult
patients (29,958 men and 22,900 women) with diabetes with no known history of HF observed for a
median duration of 2.2 years. After adjustment for
other risk factors, concomitant therapy, and type and
duration of diabetes, a significant independent association was found between HbA1c levels and incidence
12F THE AMERICAN JOURNAL OF CARDIOLOGY姞
of HF. Each 1% increase in its level was associated
with an 8% increase in the risk of HF hospitalization
or death. An HbA1c level ⱖ10, relative to HbA1c ⬍7,
was associated with 1.56-fold (95% CI, 1.26 to 1.93)
greater risk of HF.31
Diabetes is not only a risk factor for HF in patients
without structural heart disease, but it is also associated with a worse outcome once a cardiac disease (eg,
a myocardial infarction or HF itself) has developed. A
report from the SOLVD trial was the first to identify
diabetes as an independent risk factor of increased
mortality and morbidity in both symptomatic and
asymptomatic patients with HF.32 A further analysis
of this database showed that diabetes was associated
with an increased risk of mortality only in patients
with HF of ischemic origin (RR, 1.37; 95% CI, 1.21 to
1.55; p ⬍0.0001) but not in those with nonischemic
cardiomyopathy.33 In addition, the increased mortality
of patients with ischemic cardiomyopathy, compared
with those with nonischemic cardiomyopathy, was
limited to those with concomitant diabetes.33 Diabetes
mellitus is also associated with an increased risk of HF
and death in patients with an acute myocardial ischemic event.34,35
Many mechanisms may explain both the increased
incidence of HF in patients with diabetes without any
initial cardiac disease and the worse outcome of patients with diabetes in whom a cardiac disease has
developed.27,34 –37 Population-based studies have demonstrated an increased left ventricular mass and wall
thickness with subclinical impairment in left ventricular systolic function, shown by a lower left ventricular fractional shortening, midwall shortening and
stress-corrected midwall shortening, and increased arterial stiffness in patients with diabetes, compared
with those without diabetes.38 Diabetes likely acts on
the intrinsic properties of the myocardium with an
effect that is independent and additive to the more
common and widespread coronary artery disease and
to the associated abnormalities of autonomic function,
with increased sympathetic and decreased vagal stimulation.27,34,37 Accordingly, histology studies have
shown that diabetes is associated with myocyte hypertrophy, perivascular fibrosis, and an increase in matrix
collagen, cellular triglycerides, and cell membrane
lipids, consistent with nonenzymatic glycation of vascular and membrane proteins, increased cellular fatty
acid uptake, and hyperglycemia-induced oxidative
stress.36 Abnormalities of left ventricular diastolic
function with a reduced left ventricular compliance
occur early in the course of diabetes, even before
hypertension, vasculopathy, and even fasting hyperglycemia have developed, thus suggesting that they
are secondary to diabetes.39 Metabolic abnormalities
may also explain the unfavorable synergy observed
between diabetes and coronary artery disease in patients with HF. The impaired glucose uptake caused
by diabetes may, in fact, be particularly deleterious in
patients with concomitant coronary artery disease,
which is, in turn, generally associated with a shift in
myocardial metabolism from free fatty acids to glucose and glycolysis.27,33
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MAY 8, 2003
It is therefore clear how the treatment of diabetes
should reduce both the incidence of new cases of HF
and the morbidity and mortality of patients in whom
HF has already developed. Glycemic and HbA1c serum levels should be controlled and reduced to normal
levels, even with the possibility of untoward effects of
intensive insulin treatment.40 Tighter blood pressure
control with reduction of blood pressure to ⬍130/80
mm Hg has been shown to be associated with a
reduced risk of HF in the United Kingdom Prospective
Diabetes Study (UKPDS).41 In addition, ACE inhibitors can prevent the development of major cardiovascular events and HF in patients with diabetes, even
when they do not have concomitant hypertension.2,42,43
CORONARY ARTERY DISEASE
Epidemiology and mechanisms: Coronary artery
disease is the single most common cause of HF. It was
present in almost 70% of patients included in major
multicenter HF trials,44 and similarly, it was associated with an RR of 8.11 (95% CI, 6.95 to 9.46; p
⬍0.001), with a population-attributable risk of 61.6%
in an epidemiologic study.8 These percentages, although high, likely underestimate the real prevalence
of coronary artery disease. In fact, patients with a
recent myocardial infarction or unstable angina have
been excluded from most of the trials, and coronary
angiography or stress myocardial imaging were not
systematically used either in multicenter trials or in
epidemiologic studies. In a general population– based
study on incident cases of HF, coronary artery disease
was identified as the principal cause in 29% of patients, on the basis of only the clinical criteria, versus
52% of patients when either coronary angiography or
stress perfusion imaging was systematically used.9
Coronary artery disease is important, not only as a
risk factor and a precursor of HF, but also as a variable
associated with a worse outcome in patients in whom
HF has developed. Many studies have shown that
patients with ischemic cardiomyopathy have a worse
prognosis compared with those with nonischemic cardiomyopathy.44 – 46 In addition, new ischemic events
may further worsen the outcome of patients with HF.
In the SOLVD trials, the occurrence of a new myocardial infarction and of unstable angina more than
doubled the 1-year risk of HF hospitalizations (from
8.6% to 20.5% and from 8.4% to 15.3%, respectively).47 These results are likely to be even more significant when patients with a recent ischemic event are
also included, as occurs in clinical practice.
In addition to new ischemic events with new scar
formation, there are many other mechanisms through
which coronary artery disease may cause the progression of left ventricular dysfunction and HF: (1) left
ventricular dysfunction may be secondary to severe
and widespread coronary artery disease causing episodes of reversible ischemia (myocardial stunning) or
a sustained severe reduction of blood flow (myocardial hibernation); (2) the noninfarcted myocardium
may undergo the process of left ventricular remodeling with left ventricular dilatation, spherical conformation, and reduced contractility; and (3) coronary
artery disease may be attended by endothelial dysfunction with reduced release of nitric oxide and prostacyclin and an increased release of toxic factors for
the myocardium, such as angiotensin II and endothelin.44 Endothelial dysfunction may also favor new
acute ischemic events, because it may cause vasoconstriction, smooth muscle cell proliferation and migration, lipid deposition in the vessel wall, and finally,
plaque rupture and thrombosis.44 There is, therefore, a
tight link between the progression of left ventricular
dysfunction and the induction of new ischemic events
in patients with coronary artery disease. However, this
link has been pointed out only recently.44
␤-Blockers and ACE inhibitors— efficacy from prevention to therapy: The 2 classes of drugs that have
been associated with the most favorable effects on the
prognosis of patients with HF, ␤-blockers and ACE
inhibitors, are both characterized by their action both
as neurohumoral antagonists and as powerful antiischemic agents. The long-term administration of
␤-blockers has been associated with a highly significant improvement in symptoms, left ventricular function, morbidity, and mortality in patients with HF
studied in large multicenter controlled trials.2,4,5,48,49
These agents may cause a highly significant improvement in the left ventricular function, with reversal of
the remodeling process.48 –51 Their beneficial effects
on left ventricular function are likely of the greatest
degree that has been obtained in clinical practice to
date, and they represent a main mechanism of their
favorable effects on the prognosis. However, although
the increase in the left ventricular ejection fraction
after ␤-blockade is greater in patients with idiopathic
cardiomyopathy,50,52,53 their beneficial effects on
prognosis are present also, if not primarily, in patients
with ischemic cardiomyopathy.54,55 It is therefore
likely that the prevention of the ischemic events is a
main mechanism of their favorable action. Long-term
␤-blocker administration has been associated with (1)
a decrease in myocardial oxygen consumption, (2) a
shift in myocardial metabolism toward the more favorable glucose, rather than free fatty acid uptake,56
(3) a reduction in lipid accumulation in coronary
plaques, (4) an enhancement of endogenous thrombolysis, and (5) a reduced incidence of plaque rupture and
coronary thrombosis.49,57 In addition to the protection
from the ␤-adrenergic receptor–mediated toxic effects
of the catecholamines on the myocardium, these antiischemic mechanisms of ␤-blockade may reduce the
incidence of new ischemic events and prevent the
development of left ventricular dysfunction and symptomatic HF in patients at risk.
Similar beneficial effects have been described with
ACE inhibitors. In addition, these agents have been
associated with favorable effects on left ventricular
remodeling. Their action seems, however, milder than
that of ␤-blockers.48,57 In contrast, and relatively unexpectedly, ACE inhibitors have been shown to be
powerful anti-ischemic agents. The administration of
A SYMPOSIUM: FROM PREVENTION TO MANAGEMENT OF CHRONIC HEART FAILURE
13F
the ACE inhibitors may (1) reduce myocardial oxygen
consumption through a decrease in afterload, preload,
and left ventricular myocardial mass; (2) improve
myocardial oxygen supply through a reduction in
perivascular and interstitial fibrosis and an improvement in endothelial-dependent vasodilation; (3) inhibit
the migration and proliferation of the smooth muscle
and inflammatory cells, with a slowing of the atherosclerosis progression; and (4) favor endogenous
thrombolysis through its mild antiplatelet action and
the enhancement of the plasminogen activator inhibitor activity. The long-term administration of ACE
inhibitors has been associated with a reduction in the
incidence of ischemic events (reinfarction, unstable
angina, revascularization procedures) in the SOLVD47
and Survival and Ventricular Enlargement (SAVE)
trials58 performed in patients with symptomatic or
asymptomatic left ventricular dysfunction. The best
evidence of the anti-ischemic effects of the ACE inhibitors has been obtained in the HOPE trial, performed in patients at risk of vascular events (previous
cerebral, coronary, or peripheral arterial vascular
event) or with diabetes plus 1 other risk factor and
with the exclusion of patients with left ventricular
dysfunction or HF.42 During a mean follow-up period
of 5 years, treatment with ramipril versus placebo was
associated with a significant reduction in cardiovascular death (6.1% vs 8.1%; RR, 0.74; p ⬍0.001), myocardial infarction (9.9% vs 12.3%; RR, 0.80; p
⬍0.001), revascularization procedures (16% vs
18.3%; RR, 0.85; p ⫽ 0.002), and HF (9% vs 11.5%;
RR, 0.77; p ⬍0.001). The HOPE trial is therefore one
of the first trials that directly addressed the issue of the
prevention of cardiovascular events, including the primary prevention of HF. This trial shows the tight link
between recurrences of vascular ischemic events and
the development of symptomatic HF, and it shows
how the administration of an ACE inhibitor may prevent both these untoward unwanted events.
Antiplatelet agents and coronary revascularization—
the efficacy with prevention and the uncertainty with
treatment: In addition to the administration of ␤-block-
ers and ACE inhibitors, other drugs and procedures
are beneficial for the treatment of coronary artery
disease and thus may prevent the development of HF.
However, the effects of these drugs and procedures
have been assessed mainly in patients without HF and,
in some cases, with evidence of only a mild left
ventricular dysfunction. Therefore, although we know
these procedures are beneficial when used before the
development of left ventricular dysfunction (primary
prevention), data obtained in patients with HF are
more controversial; 2 examples are those of antiplatelet agents and of coronary revascularization. Aspirin is
universally accepted as first-line treatment of coronary
artery disease. However, in addition to some inconsistencies in the data of multicenter trials,57 the results
in the 2 large, long-term aspirin trials, including those
of patients with HF, have not shown significant beneficial effect on mortality in this subgroup.59,60 Aspirin has many potentially unfavorable effects in pa14F THE AMERICAN JOURNAL OF CARDIOLOGY姞
tients with HF. It may reduce prostacyclin production,
increase the vasoconstrictor response to endothelin,
and favor the development of renal failure during the
initiation of ACE inhibitor therapy.57 In addition, the
beneficial effects of ACE inhibitors and ␤-blockers
seem to be reduced, although rather weakly, by the
concomitant aspirin therapy.53,61 Thus, whereas the
favorable effects of aspirin in the prevention of new
ischemic events and, therefore, in the primary prevention of HF are indisputable, its usefulness in patients
with both asymptomatic and symptomatic left ventricular dysfunction are less clear. A large (4,500 patients)
randomized, controlled trial comparing warfarin, aspirin, and clopidogrel in patients with HF is currently
ongoing.62
Similarly, whereas the benefits of the revascularization procedures in the prevention of new coronary
events with secondary left ventricular dysfunction are
well established, their efficacy in patients with symptomatic HF and advanced left ventricular dysfunction
are less clear.57 Patients with HF were excluded from
the first major coronary revascularization trials, and
the data available are from small and selected study
groups, are retrospective, and are not controlled. The
vast majority of the studies indicate the usefulness of
an assessment of myocardial viability in the prediction
of the improvement in left ventricular function and
symptoms after coronary revascularization. However,
no data are available on the effects on mortality, and
the effects of revascularization in patients with low
amounts of viable myocardium at the imaging tests are
not clear.63 Currently, 2 major trials are going to
address these issues. A trial comparing a strategy of
proceeding or not proceeding to coronary investigation leading to revascularization among patients with
HF and meaningful amounts of myocardium, ischemic
or stunned or hibernated, has been recently started in
the United Kingdom (the Heart Failure Revascularization Trial).57 This trial is projected to include approximately 800 patients. A larger trial will be performed
in the United States to compare both the role of an
assessment of myocardial viability and the effects of
revascularization (Surgical Treatment for Ischemic
Heart Failure [STICH]).63 Unlike the previous study,
all patients will undergo coronary angiography in this
last trial. The duration of this trial is projected to be
ⱖ6 years.
Statins: a promise for the future? Patients with
symptomatic HF have been excluded from the previous trials of lipid-lowering therapy. Thus, our knowledge of the role of hyperlipidemia and the effects of
statin treatment are still insufficient. Serum cholesterol is widely recognized as a major risk factor for
coronary artery disease and hence HF. However, patients with symptomatic HF tend to have low cholesterol levels and, in contrast with the results in patients
without HF, low cholesterol, low-density lipoprotein,
and triglyceride levels have been associated with a
worse outcome in patients with HF.64 – 66 The relatively low incidence of new ischemic events in pa-
VOL. 91 (9A)
MAY 8, 2003
tients with advanced HF64 makes the role of lipidlowering therapy even more uncertain.
Statins have many effects potentially useful for the
prevention of HF: (1) they reduce the incidence of
new ischemic events through an increase in plaque
stability and an improvement of endothelial function;
(2) they may inhibit the synthesis of proinflammatory
agents, such as the cytokines and chemokines, which
have been implicated in the pathogenesis of HF; and
(3) they may improve autonomic function, with an
increased parasympathetic drive; downregulate the angiotensin II type 1 receptors; cause neoangiogenesis;
and cause an improvement in transmembrane calcium
influx.64 However, statins also have potentially deleterious effects. In patients with advanced HF, congestion of the splanchnic circulation favors the absorption
of gut endotoxins, such as lipopolysaccharides, which
may then cause the activation of proinflammatory
cytokines, such as tumor necrosis factor-␣.67 Lipoproteins have, from this point of view, a favorable effect
because they may bind to lipopolysaccharides and
neutralize their effects.68 Second, ubiquinone, a coenzyme in mitochondrial oxidative phosphorylation and
an antioxidant (potentially useful in patients with HF),
is synthesized by the 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is the same enzyme that is
inhibited by the statin administration. Accordingly, a
decrease in ubiquinone plasma and, possibly, tissue
levels have been described after statin therapy.68
Although no study has been aimed primarily at the
assessment of the role of statins in HF, favorable
results have been obtained in retrospective analyses of
data from some major trials. The Scandinavian Simvastatin Survival Study (4S) assessed the effects on
the outcome of the administration of simvastatin in
patients with a previous history of coronary artery
disease and no signs or symptoms of HF. Approximately 2% of the 4,444 included patients developed
HF during the 4 years of follow-up, and this event was
associated with a ⬎4-fold increase in mortality compared with the other patients. Simvastatin administration was associated with 20% reduction in the incidence of HF compared with placebo; in patients who
had developed HF, there was a 19% reduction in the
mortality rate compared with placebo.69 Among the
major statin trials, the left ventricular ejection fraction
was measured only in the Cholesterol and Reduction
of Events (CARE) study. In this trial, pravastatin
therapy was equally effective in reducing coronary
events independent of the left ventricular ejection
fraction (⬎0.40 or ⬍0.40). However, patients with a
left ventricular ejection fraction ⬍0.25 were excluded
from this trial. Favorable results have also been obtained in reanalyses of other trials. In the Evaluation
of Losartan in the Elderly (ELITE) II trial, 11% of
patients receiving a statin had a lower mortality compared with the others (10.6% vs 17.6%, p ⬍0.003).
Similar results were obtained in a reanalysis of the
Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTIMAAL).68 Thus,
despite the controversial physiopathologic issues, retrospective analyses of clinical trials seem to indicate
that statins may have favorable effects in the prevention of HF and in HF after it has developed. This last
issue, however, needs to be formally tested in a randomized trial.64,66,68
Other factors: Many other agents have deleterious
effects and may favor the development of HF. They
include smoking, excessive alcohol consumption,
abuse of cocaine or other illicit drugs, mediastinum
radiation therapy, and chemotherapeutic agents, such
as anthracyclines or trastuzumab. Avoidance of all
these factors helps to prevent the occurrence of
chronic HF. On the other hand, patients exposed to
these substances are at risk of developing HF.2 Obesity, traditionally regarded as a coronary risk factor,
has been recently shown to be independently related to
the risk of HF.70
CONCLUSIONS
Chronic HF is a progressive disease. Hence, a
major goal of treatment is not only to improve the
course of HF when it is already symptomatic, but,
even more importantly, to prevent its development in
patients at risk. Because coronary artery disease is the
major cause of HF, risk factors of coronary artery
disease are also those of HF. Hypertension, diabetes,
and left ventricular hypertrophy, however, are also
deleterious through other mechanisms. Other therapies, like statin therapy, may, on the other hand, be
beneficial in other mechanisms in addition to the reduction in coronary events. Thus, the prevention of
HF is an extremely broad and difficult task. Any
significant achievement in the prevention of HF will
be a major step forward in the managment of cardiovascular diseases and in the improvement of human
well-being.
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