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clinical practice
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the authors clinical recommendations.
From the Western Infirmary and the Brit- Approximately 1 to 2% of the population in developed countries has heart failure,
ish Heart Foundation Glasgow Cardio- with the prevalence rising to 10% or more among persons 70 years of age or older.1
vascular Research Centre, University of
Glasgow, Glasgow, United Kingdom. Ad- At least half the patients with heart failure have a low ejection fraction (40% or
dress reprint requests to Dr. McMurray at less).1 This review focuses on the recommended treatment for ambulatory patients
the British Heart Foundation Cardiovas- with systolic heart failure; heart failure with preserved ejection fraction was re-
cular Research Centre, University of Glas-
gow, 126 University Pl., Glasgow G12 8TA, viewed previously in this series.2
United Kingdom, or at j.mcmurray@bio Coronary artery disease is the cause of approximately two thirds of cases of
.gla.ac.uk. systolic heart failure, although hypertension and diabetes are likely to be contrib-
N Engl J Med 2010;362:228-38. uting factors in many cases. Dilated cardiomyopathy may also result from a genetic
Copyright 2010 Massachusetts Medical Society. cause, previous viral infection (recognized or unrecognized), alcohol abuse, or oc-
casionally, chemotherapy (e.g., doxorubicin or trastuzumab).2
The maladaptive changes that occur in surviving myocytes and in the extracel-
lular matrix after myocardial injury lead to pathologic remodeling of the left ven-
An audio version
tricle, with dilatation and impaired contractility. If these changes are left untreated,
of this article is
available at they worsen over time, exacerbated by additional injury (e.g., myocardial infarction)3
NEJM.org and by systemic responses to left ventricular systolic dysfunction, notably activation
of the sympathetic and reninangiotensinaldosterone systems.4 All these responses
have detrimental systemic effects, accounting for the clinical manifestations of the
syndrome of heart failure, including the development and worsening of symptoms,
declining functional capacity, episodes of frank decompensation that result in the
need for hospitalization, myocardial electrical instability, and premature death,
usually due to pump failure or a ventricular arrhythmia (Fig. 1). Since the limited
cardiac reserve of patients with systolic heart failure depends on atrial contraction
and synchronized contraction of the left ventricle, events that affect these functions
(e.g., the development of atrial fibrillation or left bundle-branch block) or that im-
pose an additional hemodynamic load on the failing heart (e.g., anemia) can lead to
acute deterioration. Interruption of left ventricular remodeling and of the systemic
responses to it is the basis of much of the effective treatment of heart failure.
Injury to myocytes
and extracellular
matrix
Neurohumoral Apoptosis,
imbalance, increased
Ventricular altered gene expression,
cytokine expression,
remodeling energy starvation,
immune and inflammatory oxidative stress
changes, altered fibrinolysis
Heart-failure syndrome
ventricle and the heart more generally (a process termed remodeling). These changes, in turn,Draft lead4 to electrical in-
12/23/09
stability, systemic processes resulting in many effects on other organs and tissues, and further McMurray
Authordamage to the
Fig # 1
heart. This cycle, along with intercurrent events, such as myocardial infarction, is believed to cause progressive
Title Patho-physiology of
worsening of the heart-failure syndrome over time. systolic heart failure
ME
DE Solomon
Artist Knoper 1,7,8 Other
Before 1990, as many as 60 to 70% of patients and the results of additional testing.
AUTHOR PLEASE NOTE:
died within 5 years after the diagnosis of systolic symptoms (e.g., orthopneaFigureand paroxysmal
has been noc-
redrawn and type has been
Please check carefully
reset
heart failure, and hospitalization owing to the turnal dyspnea) and signs (e.g., jugular
Issue date 1/21/10 venous dis-
exacerbation of symptoms was frequent.5 Effec- tention, cardiac enlargement, and a third heart
tive treatment has improved both outcomes, sound) have 70 to 90% specificity for the diagno-
with a relative reduction in mortality in recent sis but only 11 to 55% sensitivity.9
years of 20 to 30%.6 Routine cardiac investigations, such as electro-
cardiography and chest radiography, are also in-
S T R ATEGIE S A ND E V IDENCE sensitive, although they may provide other useful
information (Table 1).7,8 For example, left ventricu-
DIAGNOSIS AND EVALUATION lar systolic dysfunction may be seen without car-
The cardinal symptoms (i.e., dyspnea and fatigue) diomegaly on a chest radiograph. Measurement of
and signs (i.e., peripheral edema) of heart failure the plasma concentration of natriuretic peptides
are nonspecific and must be evaluated in light of is recommended, since natriuretic peptides are
the patients history, the findings on examination, secreted in increased amounts by the failing heart,
Table 1. Possible Findings in Patients with Left Ventricular Systolic Dysfunction and Recommendations for Treatment.*
* COPD denotes chronic obstructive pulmonary disease, and RAAS reninangiotensinaldosterone system.
and a normal concentration virtually rules out a classification or the more recent American Heart
diagnosis of heart failure (although this obser- AssociationAmerican College of Cardiology clas-
vation may not hold true in the case of obese sification (Table 2).7,8,12
persons).10 Coexisting conditions that are common in pa-
Transthoracic Doppler echocardiography allows tients with heart failure and that may influence the
for confirmation of the diagnosis, provides in- prognosis and affect treatment decisions should
formation on myocardial and valvular structure be routinely assessed (Table 1). These include con-
and function, and may reveal other important ditions that may have led to the heart failure (e.g.,
findings, such as the presence of a thrombus in ischemic heart disease, hypertension, or diabetes)
a cardiac chamber.7,8 Cardiac magnetic resonance or that may result from either the heart failure
imaging is an alternative to echocardiography in itself (e.g., atrial fibrillation, cachexia, or depres-
difficult cases, such as those in which the qual- sion) or the treatment (e.g., gout induced by diuret-
ity of the ultrasonic image is poor, or in cases in ics). Other common coexisting conditions include
which characterization of the tissue is particu- renal impairment, anemia, and sleep-disordered
larly important (e.g., when myocarditis or an in- breathing.
filtrative myocardial disease is suspected).11 In-
vestigations that are recommended routinely, as T R E ATMEN T OP T IONS
well as those that are useful in selected circum-
stances, are summarized in Table 1.7,8 The goals of treatment are the reduction in symp-
Patients symptoms, including limitations in toms, a decrease in the rate of hospitalization,
activity, can be quantified with the use of the and the prevention of premature death. The cor-
New York Heart Association (NYHA) functional nerstone of treatment is pharmacologic therapy
* The American College of Cardiology (ACC)American Heart Association (AHA) classification is from Hunt et al.8 The
New York Heart Association (NYHA) functional classification is from the Criteria Committee of the New York Heart
Association.12
(Fig. 2). Lifestyle modification such as exercise this treatment requires close monitoring of blood
training, implantable devices, and in selected cas- levels of electrolytes because of the risk of dis-
es, surgery may also be needed. turbances such as hyponatremia. Patients with
refractory edema often have impaired absorption
PHARMACOLOGIC THERAPY of oral diuretics and require intravenous therapy.
Pharmacologic agents include those that provide The requirement for diuretics may decrease as the
relief of symptoms only (i.e., diuretics) and those patients condition improves. Although patients
that also modify the course of the disease (see who have recently presented with symptoms may
below). The dosing and key side effects of medica- quickly become symptom-free with diuretic ther-
tions that have been shown in randomized trials apy, treatment with agents that also modify the
to be effective are listed in Table 3. The random- course of the disease is needed to reduce the risk
ized trials are summarized in Table 1 in the Sup- of progression of the disease.
plementary Appendix, available with the full text
of this article at NEJM.org. Detailed information Agents That Modify the Course of the Disease
that provides guidance on prescribing and moni- Angiotensin-ConvertingEnzyme (ACE) Inhibitors
toring treatments is available.32 ACE inhibitors are the first-line therapy for pa-
tients with systolic heart failure; therapy should
Diuretics for Relief of Symptoms be initiated promptly after diagnosis and contin-
Diuretics provide rapid relief of dyspnea and flu- ued indefinitely. ACE inhibitors reduce ventricu-
id retention.7,8 The lowest dose of diuretic needed lar size, increase the ejection fraction modestly,
to achieve an edema-free state (dry weight) is and reduce symptoms.7,8 Two large trials showed
used. The patients weight should be measured that when patients with NYHA class II, III, or IV
daily, and the dose of the diuretic adjusted to heart failure were treated with enalapril, as com-
maintain the dry weight. Patients can alter the pared with placebo, in addition to diuretics and
timing of the doses for social convenience. digoxin, the rates of admission to the hospital
The combination of a loop diuretic and a were reduced, and there was a relative risk reduc-
thiazide-like diuretic (e.g., metolazone), often in tion for death of 16 to 40%.14,15 In a placebo-con-
conjunction with an aldosterone antagonist trolled trial, enalapril therapy reduced the risk of
treatment that is termed sequential nephron the development of symptomatic heart failure
blockade may be needed to control fluid re- among asymptomatic (NYHA class I) patients with
tention in cases of severe heart failure, although left ventricular systolic dysfunction33 and was su-
Beta-blocker
Yes No
Persisting
symptoms?
Yes No
Yes No Yes No
233
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The n e w e ng l a n d j o u r na l of m e dic i n e
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