NEJM CARDIOVASCULAR DISEASE ARTICLES - Part 10 potx

T h e n e w e ngl a n d j o u r na l o f m e d icine
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2302
report on a study assessing the efficacy of 10 mg
of rosuvastatin daily in patients with heart fail-
ure and left ventricular systolic dysfunction attri-
buted to coronary artery disease. The study, called
the Controlled Rosuvastatin Multinational Trial
in Heart Failure (CORONA), was a randomized,
placebo-controlled trial involving patients who
were at least 60 years of age (mean, 73 years)
who were receiving high rates of evidence-based
therapy for left ventricular systolic dysfunction,
including angiotensin-converting–enzyme inhibi-
tors or angiotensin-receptor blockers and beta-
blockers. As compared with placebo, treatment
with rosuvastatin resulted in no significant dif-
ference in the primary composite outcome of
death from cardiovascular causes, nonfatal myo-
cardial infarction, or nonfatal stroke, even though
the drug was associated with substantial reduc-
tions in levels of low-density lipoprotein (LDL)
cholesterol and high-sensitivity C-reactive protein.
Patients in the rosuvastatin group had signifi-
cantly fewer hospitalizations for cardiovascular
causes, including heart failure; rates of adverse
drug events did not differ between the two study
groups. Rosuvastatin therapy had no effect on the
health status of patients, as assessed on the basis
of New York Heart Association class and the
McMaster Overall Treatment Evaluation question-

naire, which were designated as tertiary outcomes.
Results aside, one might ask whether a study
of a statin for secondary prevention in this pop-
ulation was warranted. Although the numbers of
patients with systolic heart failure who have been
enrolled in previous secondary-prevention trials
have been inadequate to generate robust evidence,
observational studies have suggested benefits of
statin therapy on morbidity and mortality in this
population.
5
Statins also have a favorable effect on
surrogate end points (e.g., endothelial function),
which in theory would be beneficial for patients
with heart failure.
Given these facts, it might be tempting to as-
sume that patients with ischemic left ventricular
systolic dysfunction would accrue benefits from
statins similar to those identified in previous tri-
als. However, there are several reasons to resist this
temptation. First, the limitations of assumptions
based on observational data
6
and surrogates
7
are
well documented. Furthermore, the need to under-
stand specifically the balance of risks and bene-
fits of drug therapy in patients with heart failure
is magnified by particular characteristics of this

population. Although patients with ischemic left
ventricular systolic dysfunction have high rates of
adverse outcomes, their risk of ischemic cardio-
vascular events — outcomes that statins seem most
likely to prevent — may occur less frequently than
in other patients with coronary disease. Moreover,
heart failure disproportionately affects older per-
sons, who often have a substantial risk of coex-
isting illnesses, a factor that raises questions
about the applicability of evidence from clinical
trials involving younger patients with a single,
dominant clinical problem.
8
Finally, typical reg-
imens for this population involve multiple drugs,
both because of the burden of coexisting illness-
es and the number of drugs used to treat heart
failure.
9
The addition of a new drug to an already
complex regimen increases not only the cost but
also the risk of adverse drug interactions. When
coupled with a theoretical concern about possi-
ble adverse drug effects from statins specific to
patients with heart failure,
10
such factors amplify
the need to understand the safety and efficacy of
this therapy.
How, then, can the clinical findings of the

CORONA study be reconciled with the existing
randomized trials of statins in patients with es-
tablished coronary artery disease? First, statins as
a class may not be efficacious in patients with
ischemic left ventricular systolic dysfunction who
are already receiving evidence-based therapy for
heart failure. An attenuated effect of statins could
reflect the distribution of the causes of outcomes
in this population. For example, among patients
in the CORONA study, rates of nonfatal myocardi-
al infarction were about one quarter of the rates
reported in patients in the Prospective Study of
Pravastatin in the Elderly at Risk (PROSPER)
study,
11
a statin trial that enrolled patients whose
mean age was about 75 years and who had a mean
follow-up of about 38 months (as compared with
32.8 months in the CORONA study). It is also im-
portant to point out that the confidence intervals
around the primary end point in the CORONA
study are consistent with as much as a 17% rela-
tive reduction in risk or an absolute risk reduction
of approximately 2%. An absolute benefit of this
magnitude would be clinically significant and is
similar to that identified in PROSPER. Second, it
is possible that even though rosuvastatin low-
ered levels of LDL cholesterol and high-sensitivity
C-reactive protein, the drug does not share the
same benefits regarding important health out-

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editorials
n engl j med 357;22 www.nejm.org november 29, 2007
2303
comes with other statins. Although several stat-
ins have proven clinical efficacy, supporting the
assumption of a class effect, experience with
cerivastatin has shown that such assumptions
can lead us astray. It is reassuring that in the
CORONA study, patients in the rosuvastatin
group had fewer hospitalizations for cardiovascu-
lar causes and no greater risk of adverse events
than did those in the placebo group. Finally, stat-
ins may have less incremental benefit in a popu-
lation of older patients who are at higher risk
for competing events, which could reduce the
likelihood of ascertaining a benefit for specific
cardiovascular outcomes. Although only a minor-
ity of deaths in the CORONA study were desig-
nated as having noncardiovascular causes, deaths
that did not have a clear cause were presumed
to be cardiovascular in nature, potentially lim-
iting the quantification of the magnitude of com-
peting risks.
Future trials may shed light on some of these
unresolved questions. The Justification for the
Use of Statins in Primary Prevention: An Inter-
vention Trial Evaluating Rosuvastatin (JUPITER)
(ClinicalTrials.gov number, NCT00239681) trial
12

should provide additional perspective on the
general effect of rosuvastatin on important
health outcomes in patients without estab-
lished cardiovascular disease. The results of
the Gruppo Italiano per lo Studio della Soprav-
vivenza nell’Insufficienza Cardiaca Heart Fail-
ure Study (GISSI-HF) (ClinicalTrials.gov number,
NCT00336336),
13
a randomized trial in which
patients with heart failure are receiving either
rosuvastatin or placebo, will complement the
findings of the CORONA study. The GISSI-HF
study is also enrolling patients with nonischemic
cardiomyopathies and those with preserved left
ventricular systolic function, both important sub-
groups of the population with heart failure who
were not evaluated in the CORONA study.
The results of the CORONA study highlight
issues that are central to the conduct of trials
involving patients with heart failure. When im-
portant questions are raised about the benefits
and risks of a therapy that is well established in
other populations, it may still be essential to es-
tablish treatment effects in the population with
heart failure. Admittedly, enrolling subjects in
trials that challenge well-established treatment
paradigms may be difficult despite equipoise on
an intellectual level. Second, trials simply must

focus more attention on including patients who
are representative of those seen in clinical prac-
tice. In enrolling older patients, the CORONA
study made important strides, although the pro-
portion of women who were enrolled (less than
25%) was no higher than that in previous heart
failure trials. Finally, because health status (in-
cluding symptom burden and quality of life) pro-
vides a patient-centered understanding of the ef-
fect of any treatment, it should be included as an
outcome in all studies of heart failure. Ideally,
health status outcomes would not be consigned
to tertiary status and would be assessed with
valid, reliable, and clinically sensitive instruments
designed specifically for use in populations with
heart failure.
14
Trials enrolling more representa-
tive populations and assessing a broader range
of outcomes are instrumental to informed deci-
sion making.
15
Meanwhile, enough uncertainty exists about
the mechanisms underlying the primary results of
the CORONA study that clinicians should con-
tinue to prescribe statins for patients with is-
chemic heart failure and left ventricular systolic
dysfunction. Until further evidence accumulates,
we cannot tell to what extent the CORONA study
reflects the limitations of the use of statins for

patients with heart failure, the problems associ-
ated with a particular drug, or the intrinsic chal-
lenges of treating older patients with complex
coexisting illnesses.
Dr. Masoudi reports receiving consulting fees from Amgen,
UnitedHealthcare, and Takeda and grant support from Amgen.
No other potential conflict of interest relevant to this article was
reported.
From the Department of Medicine, Division of Cardiology, Den-
ver Health Medical Center, Denver, and the Department of Med-
icine, Division of Cardiology, University of Colorado at Denver
and Health Sciences Center, Aurora, CO.
This article (10.1056/NEJMe0707221) was published at www.
nejm.org on November 5, 2007.
Randomised trial of cholesterol lowering in 4444 patients
with coronary heart disease: the Scandinavian Simvastatin Sur-
vival Study (4S). Lancet 1994;344:1383-9.
Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for
secondary prevention for patients with coronary and other ath-
erosclerotic vascular disease: 2006 update: endorsed by the Na-
tional Heart, Lung, and Blood Institute. Circulation 2006;113:
2363-72. [Erratum, Circulation 2006;113:e847.]
Krumholz HM, Anderson JL, Brooks NH, et al. ACC/AHA
clinical performance measures for adults with ST-elevation and
non-ST-elevation myocardial infarction: a report of the Ameri-
can College of Cardiology/American Heart Association Task
Force on Performance Measures (Writing Committee to Develop
Performance Measures on ST-Elevation and Non-ST-Elevation
Myocardial Infarction). Circulation 2006;113:732-61.
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Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older
patients with systolic heart failure. N Engl J Med 2007;357:2248-
61.
Foody JM, Shah R, Galusha D, Masoudi FA, Havranek EP,
Krumholz HM. Statins and mortality among elderly patients
hospitalized with heart failure. Circulation 2006;113:1086-
92.
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and ben-
efits of estrogen plus progestin in healthy postmenopausal
women: principal results from the Women’s Health Initiative
randomized controlled trial. JAMA 2002;288:321-33.
Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib
on the progression of coronary atherosclerosis. N Engl J Med
2007;356:1304-16. [Erratum, N Engl J Med 2007;357:835.]
Masoudi FA, Havranek EP, Wolfe P, et al. Most hospitalized
older persons do not meet the enrollment criteria for clinical
trials in heart failure. Am Heart J 2003;146:250-7.
Masoudi FA, Baillie CA, Wang Y, et al. The complexity and
cost of drug regimens of older patients hospitalized with heart
failure in the United States, 1998-2001. Arch Intern Med 2005;
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Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly
individuals at risk of vascular disease (PROSPER): a randomised
controlled trial. Lancet 2002;360:1623-30.
Ridker PM. Rosuvastatin in the primary prevention of cardio-
vascular disease among patients with low levels of low-density
lipoprotein cholesterol and elevated high-sensitivity C-reactive
protein: rationale and design of the JUPITER trial. Circulation
2003;108:2292-7.
Tavazzi L, Tognoni G, Franzosi MG, et al. Rationale and de-
sign of the GISSI heart failure trial: a large trial to assess the ef-
fects of n-3 polyunsaturated fatty acids and rosuvastatin in symp-
tomatic congestive heart failure. Eur J Heart Fail 2004;6:635-41.
Green CP, Porter CB, Bresnahan DR, Spertus JA. Develop-
ment and evaluation of the Kansas City Cardiomyopathy Ques-
tionnaire: a new health status measure for heart failure. J Am
Coll Cardiol 2000;35:1245-55.
Tunis SR, Stryer DB, Clancy CM. Practical clinical trials:
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editorials

Sudden Death after Myocardial Infarction — Who Needs
Prophylaxis, and When?

Alfred E. Buxton, M.D.

Although the age-adjusted mortality from cardio-
vascular disease has declined in recent years, the
number of sudden deaths has risen.

1

According

to data from the Centers for Disease Control and
Prevention, 63 percent of deaths from cardiovas-
cular causes in the United States, or more than
450,000 events, in 1998 were sudden and unex-
pected, most being attributable to coronary disease.
Sudden death is the end result of multiple process-
es, usually manifested electrocardiographically as
ventricular fibrillation or ventricular tachycardia.
The type of arrhythmia observed depends on the
temporal relation to myocardial infarction. In the
acute phase of myocardial infarction, the metabolic
consequences of severe ischemia may trigger ven-
tricular fibrillation, even though ventricular func-
tion was often normal before the event. Such cases
may account for half of sudden deaths.

2

Scar for-
mation after myocardial infarction may lead to the
development of the substrate for intramyocardial
reentry, resulting in ventricular tachycardia, which,
in turn, may precipitate cardiac arrest in the absence
of active ischemia. This type of ventricular tachy-
cardia (usually monomorphic) may develop days or
years after the index infarction. Finally, some pa-
tients have gradual, extensive ventricular remodel-
ing after myocardial infarction, and the remodeling
leads to the syndrome of heart failure. The devel-
opment of heart failure, with its attendant neuro-

hormonal abnormalities, sets the stage for other
mechanisms that may cause ventricular tachycardia
(usually the polymorphic type). Thus, the mecha-
nisms responsible for sudden death vary according
to their temporal relation to myocardial infarction
and multiple other factors, including the presence
or severity of left ventricular dysfunction.
In the prethrombolytic era, multiple variables
were shown to influence the risk of both sudden
and nonsudden death after myocardial infarction.
In a substudy of the Valsartan in Acute Myocardial
Infarction Trial (VALIANT) reported in this issue of
the

Journal,

Solomon and colleagues

3

extend and
reinforce our understanding of factors influencing
the risk of death after acute myocardial infarction.
VALIANT compared the effect of valsartan, capto-
pril, or both on the risk of death in more than
14,000 patients with acute myocardial infarction
complicated by left ventricular dysfunction (de-
fined as a left ventricular ejection fraction of 40 per-
cent or less), heart failure, or both between 1998
and 2001.

4

Several characteristics of the patients
enrolled in the trial are noteworthy. The mean left
ventricular ejection fraction was 35 percent, 28 per-
cent had had a prior myocardial infarction, and ap-
proximately three fourths were in Killip class II, III,
or IV at the time of enrollment.

4

During a median
follow-up of 24.7 months, 7.3 percent of the pa-
tients died suddenly or were resuscitated after car-
diac arrest.

3

Solomon et al. emphasize two major
points: the temporal occurrence of sudden death
after myocardial infarction and the importance and
limitations of the left ventricular ejection fraction
as a risk factor for sudden death.
Clustering of sudden deaths in the early period
after myocardial infarction was noted in the pre-
thrombolytic era.

5

The time course of sudden death
in the modern era has been explored less extensive-
ly, but some work in unselected populations of sur-
vivors of acute myocardial infarction suggests a de-
lay in sudden death to 18 months after the acute
event.

6

This issue is clarified in the current study.
Solomon et al. clearly demonstrate the period of
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2639

highest risk to be the first month after myocardial
infarction (event rate, 1.4 percent), with a dramatic
drop to a fairly constant rate of 0.14 to 0.18 percent
per month thereafter.
The association between a reduced left ventricu-

lar ejection fraction and an increased risk of death
after myocardial infarction has been recognized
for years. In both the prethrombolytic era and the
post-thrombolytic era, the risk of death increases
markedly if the left ventricular ejection fraction is
40 percent or less.

7

At first glance, it may seem sur-
prising that Solomon et al. found the risk of sud-
den death to be similar among patients with a left
ventricular ejection fraction of more than 40 per-
cent and those with an ejection fraction of 30 to 40
percent. This finding is most likely explained by
the fact that in order to enter VALIANT, any patient
with a left ventricular ejection fraction of more than
40 percent would have had to have heart failure, re-
affirming the importance of heart failure as a risk
factor for sudden death.
Although Solomon et al. note a number of sig-
nificant differences between survivors and patients
who died, there were no clinically useful factors
distinguishing those who died suddenly from
those who had a nonsudden death. In other words,
a reduced left ventricular ejection fraction and evi-
dence of advanced heart failure carried an equally
increased risk of sudden and of nonsudden death
and did not have a cause-and-effect relation to ar-
rhythmic events. The importance of this limitation

has implications for preventive therapy. If we are to
use efficacious treatments, such as implantable car-
dioverter–defibrillators (ICDs), in a cost-effective
manner, we need risk-stratification tests that iden-
tify patients whose risk of sudden death significant-
ly exceeds their risk of nonsudden death. To date,
there is only one such test — the electrophysiolog-
ical test.

8

What is the importance of the current study? It
reinforces findings in earlier studies that the risk of
sudden death is greatest in the early period after in-
farction among patients with clinically significant
ventricular dysfunction or heart failure. This point
raises several questions. Should patients with high-
risk characteristics undergo prolonged hospitaliza-
tion after myocardial infarction? An alternative so-
lution, given the observation of Solomon et al. that
risk drops dramatically within six months after
acute myocardial infarction, might be to provide
noninvasive vest defibrillators or automatic exter-
nal defibrillators to high-risk patients for limited
periods. The latter approach is the subject of an on-
going trial sponsored by the National Heart, Lung,
and Blood Institute in selected patients with a re-
cent anterior myocardial infarction. These nonin-
vasive approaches to prophylactic defibrillation are
attractive in light of the results of the Defibrillator

in Acute Myocardial Infarction Trial (DINAMIT),
which demonstrated the failure of ICDs to reduce
the risk of death among high-risk patients with clin-
ically significant left ventricular dysfunction after a
recent myocardial infarction.

9

How do the results of this large, multicenter trial
by Solomon et al. relate to studies demonstrating
the ability of ICDs to prevent sudden death in pa-
tients with chronic coronary heart disease?

10-12

These trials — the Multicenter Automatic Defibril-
lator Implantation Trial (MADIT), the Multicen-
ter Unsustained Tachycardia Trial (MUSTT), and
MADIT-II — were predicated on earlier observa-
tions, similar to those of Solomon et al., that pa-
tients with spontaneous ventricular arrhythmias
and clinically significant ventricular dysfunction
after a recent myocardial infarction have a substan-
tial risk of death. However, a minority of patients
in these trials had a myocardial infarction within
2 years before enrollment: the average times from
myocardial infarction to enrollment were 39 months
in MUSTT and 81 months in MADIT-II. The total
mortality rate in VALIANT after the first year was
approximately 5 percent per year. The rate of sud-

den death or resuscitation after cardiac arrest was
approximately 2.5 percent per year among patients
with a left ventricular ejection fraction of 30 per-
cent or less. After the first year, the total mortality
rates and the rate of sudden death were fairly con-
stant and low. These figures contrast with the total
mortality rates of 11 percent per year in the control
patients with a left ventricular ejection fraction of
less than 30 percent in both MUSTT and MADIT-II.
Thus, event rates in the ICD trials were double
those in VALIANT.
What is the explanation for this difference? In
part, it may be due to the fact that two thirds of the
patients enrolled in MADIT and MUSTT had symp-
tomatic heart failure, as reflected by a New York
Heart Association class of at least II, in addition to
a reduced left ventricular ejection fraction. I suspect
that another reason for the higher rates of events in
the ICD trials is enrollment bias, resulting in the re-
cruitment of patients at very high risk. Why is this
important? Because it suggests that the results of
the ICD trials may not be generalizable to all pa-
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tients meeting the entry criteria for those studies.
The mortality risks observed in the ICD trials may
have been exaggerated because of the manner in
which patients were recruited. Thus, when perform-
ing such studies, we must strive to enroll broad-
based, representative populations, unencumbered
by referral bias.
In summary, the analysis by Solomon et al. is a
useful reality check on the problem of sudden death
among survivors of acute myocardial infarction.
This study documents the natural history of sud-
den death and some of the risk factors for it with
contemporary treatment of myocardial infarction.
The challenge going forward is to translate these
observations into cost-effective preventive therapy.

From the Cardiology Division, Department of Medicine, Brown
Medical School, Lifespan Academic Medical Center, Providence, R.I.

1.

Zheng Z-J, Croft JB, Giles WH, Mensah GA. Sudden cardiac
death in the United States, 1989 to 1998. Circulation 2001;104:
2158-63.

2.

Gorgels APM, Gijsbers C, de Vreede-Swagemakers J, Lousberg
A, Wellens HJJ. Out-of-hospital cardiac arrest — the relevance of
heart failure: the Maastricht Circulatory Arrest Registry. Eur Heart J
2003;24:1204-9.

3.

Solomon SD, Zelenkofske S, McMurray JJV, et al. Sudden death
in patients with myocardial infarction and left ventricular dysfunc-
tion, heart failure, or both. N Engl J Med 2005;352:2581-8.

4.

Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, capto-
pril, or both in myocardial infarction complicated by heart failure,
left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-
906. [Erratum, N Engl J Med 2004;350:203.]

5.

Daly LE, Hickey N, Graham IM, Mulcahy R. Predictors of sud-

den death up to 18 years after a first attack of unstable angina or
myocardial infarction. Br Heart J 1987;58:567-71.

6.

Huikuri HV, Tapanainen JM, Lindgren K, et al. Prediction of
sudden cardiac death after myocardial infarction in the beta-block-
ing era. J Am Coll Cardiol 2003;42:652-8.

7.

Rouleau JL, Talajic M, Sussex B, et al. Myocardial infarction
patients in the 1990s — their risk factors, stratification and survival
in Canada: the Canadian Assessment of Myocardial Infarction
(CAMI) Study. J Am Coll Cardiol 1996;27:1119-27.

8.

Buxton A, Hafley G, Lee K, et al. Relation of ejection fraction and
inducible ventricular tachycardia to mode of death in patients with
coronary artery disease: an analysis of patients enrolled in the Multi-
center Unsustained Tachycardia Trial. Circulation 2002;106:2466-
72.

9.

Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an
implantable cardioverter–defibrillator after acute myocardial infarc-
tion. N Engl J Med 2004;351:2481-8.

10.

Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an
implanted defibrillator in patients with coronary disease at high risk
for ventricular arrhythmia. N Engl J Med 1996;335:1933-40.

11.

Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the
prevention of sudden death in patients with coronary artery disease.
N Engl J Med 1999;341:1882-90. [Erratum, N Engl J Med 2000;342:
1300.]

12.

Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a
defibrillator in patients with myocardial infarction and reduced ejec-
tion fraction. N Engl J Med 2002;346:877-83.

Copyright © 2005 Massachusetts Medical Society.

Adjuvant Chemotherapy for Non–Small-Cell Lung Cancer —
The Smoke Clears

Katherine M.W. Pisters, M.D.

Lung cancer has been the most common cancer in
the world since 1985 and is today the leading cause
of cancer-related death. In 2002, there were 1.35
million new cases and 1.18 million related deaths

worldwide.

1

Non–small-cell lung cancer, the most
common form, accounts for 80 to 85 percent of
cases. Given the size of the problem, the benefit
of adjuvant chemotherapy for non–small-cell lung
cancer, reported by Winton et al. in this issue of
the

Journal,

has tremendous implications.

2

Complete surgical resection is the best hope for
cure in patients with operable non–small-cell lung
cancer, yet the five-year overall survival rate is only
23 to 67 percent, depending on the size of the pri-
mary tumor and the presence or absence of inva-
sion and lymph-node involvement.

3

After surgery,
relapse at distant sites occurs two to three times as
frequently as local recurrence and is most often fa-
tal. Postoperative radiotherapy decreases the rate of

local recurrence in stage IIIA disease but has a det-
rimental effect on survival in patients with stage I
or stage II disease.

4

Adjuvant systemic chemothera-
py directed at micrometastatic disease has an es-
tablished role in the treatment of breast and colon
cancer; however, its use in non–small-cell lung can-
cer has, until now, been controversial.
Decades ago, initial forays into adjuvant therapy
for non–small-cell lung cancer failed — the trials
were poorly designed and used relatively inactive
chemotherapy. The next generation of studies in-
corporated cisplatin (an agent still considered a cor-
nerstone of treatment), but the studies were too
small to detect a benefit.
A 1995 meta-analysis of results from random-
ized trials of adjuvant therapy conducted between
1965 and 1991 showed that treatment with alkylat-
ing agents alone or in combination with radiation
reduced overall survival (an absolute decrease in
the rate of survival of 5 to 7 percent at five years,
and an increase in the risk of death of 15 to 35 per-
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,

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vol. 352 no. 25

Sudden Death in Patients with Myocardial Infarction
and Left Ventricular Dysfunction, Heart Failure, or Both

Scott D. Solomon, M.D., Steve Zelenkofske, D.O., John J.V. McMurray, M.D., Peter V. Finn, M.D.,
Eric Velazquez, M.D., George Ertl, M.D., Adam Harsanyi, M.D., Jean L. Rouleau, M.D., Aldo Maggioni, M.D.,
Lars Kober, M.D., Harvey White, D.Sc., Frans Van de Werf, M.D., Ph.D., Karen Pieper, M.S., Robert M. Califf, M.D.,
and Marc A. Pfeffer, M.D., Ph.D., for the Valsartan in Acute Myocardial Infarction Trial (VALIANT) Investigators
abstract

From the Cardiovascular Division, Brigham
and Women’s Hospital, Boston (S.D.S.,
P.V.F., M.A.P.); Novartis Pharmaceuticals,
East Hanover, N.J. (S.Z.); the Department
of Cardiology, Western Infirmary, Glasgow,
Scotland (J.J.V.M.); Duke University Medi-
cal Center, Durham, N.C. (E.V., K.P., R.M.C.);
University of Wurzburg, Wurzburg, Germa-
ny (G.E.); the National Center for Health
Services, Budapest, Hungary (A.H.); the
University of Montreal, Montreal Heart In-
stitute, Montreal (J.L.R.); Associazione Na-
zionale Medici Cardiologi Ospedalieri Re-
search Center, Florence, Italy (A.M.); the
Department of Cardiology, Rigshospitalet,
Copenhagen (L.K.); the Department of Car-
diology, Green Lane Hospital, Auckland,
New Zealand (H.W.); and Leuven Coordi-
nating Center, Leuven, Belgium (F.V.W.).
Address reprint requests to Dr. Solomon
at the Cardiovascular Division, Brigham

and Women’s Hospital, 75 Francis St., Bos-
ton, MA 02115, or at
harvard.edu.
N Engl J Med 2005;352:2581-8.

Copyright © 2005 Massachusetts Medical Society.

background

The risk of sudden death from cardiac causes is increased among survivors of acute
myocardial infarction with reduced left ventricular systolic function. We assessed the
risk and time course of sudden death in high-risk patients after myocardial infarction.

methods

We studied 14,609 patients with left ventricular dysfunction, heart failure, or both after
myocardial infarction to assess the incidence and timing of sudden unexpected death
or cardiac arrest with resuscitation in relation to the left ventricular ejection fraction.

results

Of 14,609 patients, 1067 (7 percent) had an event a median of 180 days after myocar-
dial infarction: 903 died suddenly, and 164 were resuscitated after cardiac arrest. The risk
was highest in the first 30 days after myocardial infarction — 1.4 percent per month
(95 percent confidence interval, 1.2 to 1.6 percent) — and decreased to 0.14 percent
per month (95 percent confidence interval, 0.11 to 0.18 percent) after 2 years. Patients
with a left ventricular ejection fraction of 30 percent or less were at highest risk in this
early period (rate, 2.3 percent per month; 95 percent confidence interval, 1.8 to 2.8 per-
cent). Nineteen percent of all sudden deaths or episodes of cardiac arrest with resusci-
tation occurred within the first 30 days after myocardial infarction, and 83 percent of all

patients who died suddenly did so in the first 30 days after hospital discharge. Each de-
crease of 5 percentage points in the left ventricular ejection fraction was associated with
a 21 percent adjusted increase in the risk of sudden death or cardiac arrest with resusci-
tation in the first 30 days.

conclusions

The risk of sudden death is highest in the first 30 days after myocardial infarction
among patients with left ventricular dysfunction, heart failure, or both. Thus, earlier im-
plementation of strategies for preventing sudden death may be warranted in selected
patients.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
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udden death is a catastrophic com-

plication of acute myocardial infarction.

1

Al-
though many patients who die from an acute
myocardial infarction do so before reaching the
hospital, those admitted remain at substantial risk
for ventricular arrhythmias. That risk is greatest in
the first few hours, declines rapidly thereafter, and
is influenced by the extent of myocardial injury, re-
current ischemia, electrolyte abnormalities, and
other factors.

2,3

The success of coronary care units
in the 1960s was, in part, related to the early identi-
fication and treatment of life-threatening arrhyth-
mias that occurred in the setting of an acute myo-
cardial infarction. Though the risk of sudden death
is believed to decrease rapidly after infarction, the
extent and time course of this change in risk have

not been well studied, especially since the use of
coronary reperfusion, beta-blockers, and angio-
tensin-converting–enzyme inhibitors has become
widespread.
Reduced left ventricular function is a major risk
factor for death, including sudden death, after myo-
cardial infarction.

4,5

This observation has led to
trials of implantable cardioverter–defibrillators
(ICDs) in patients with a low left ventricular ejec-
tion fraction after infarction.

6

The Multicenter Un-
sustained Tachycardia Trial (MUSTT) demonstrat-
ed the benefit of an ICD in patients with coronary
artery disease, a left ventricular ejection fraction of
40 percent or less, and inducible sustained ventric-
ular tachycardia.

7

The Multicenter Automatic Defi-
brillator Implantation Trial II (MADIT-II)

8

further
showed a benefit of empirical ICD therapy in pa-
tients with a left ventricular ejection fraction of 30
percent or less one month or more after myocardial
infarction. Although these studies enrolled few pa-
tients within six months after they had had a myo-
cardial infarction, the results are reflected in the
current American College of Cardiology–American
Heart Association guidelines for the management
of acute myocardial infarction,

9

which recommend
the implantation of an ICD one month or more after
myocardial infarction in patients with a left ventric-
ular ejection fraction of 30 percent or less and in
those with a left ventricular ejection fraction of 40
percent or less and additional evidence of electri-
cal instability. In contrast, the recently reported
Defibrillator in Acute Myocardial Infarction Trial
(DINAMIT)

10

did not show that the implantation
of an ICD 6 to 40 days after myocardial infarction
reduced the risk of death in patients with a left ven-
tricular ejection fraction of 35 percent or less and

reduced heart-rate variability. Nevertheless, the risk
of sudden death in the early period after myocardial
infarction remains high and has not been well
studied in the modern era.

11

To better delineate the
early and later risk of sudden death after myocar-
dial infarction and the association of these risks with
the left ventricular ejection fraction, we studied pa-
tients enrolled in the Valsartan in Acute Myocardial
Infarction Trial (VALIANT).
VALIANT was a randomized, controlled trial of
treatment with valsartan, captopril, or both in
14,703 patients with a first or subsequent acute
myocardial infarction complicated by heart failure,
left ventricular systolic dysfunction, or both.

12

Pa-
tients were enrolled between December 1998 and
June 2001. All patients had an ejection fraction of
no more than 40 percent or clinical or radiologic
evidence of heart failure complicating their myo-
cardial infarction. For this analysis, we excluded 94
patients because they had already received an ICD
before randomization. All patients gave written in-
formed consent, and the research protocol was ap-

proved by the appropriate review boards. The de-
tails of the patient population and the protocol,
including inclusion and exclusion criteria, have
been reported previously.

12

A central adjudication committee reviewed all
deaths and episodes of cardiac arrest with resusci-
tation in a blinded fashion, using source documen-
tation provided by the site investigators. Deaths
were classified as having cardiovascular or noncar-
diovascular causes, and deaths from cardiovascular
causes were further classified as sudden or due to
myocardial infarction, heart failure, stroke, or an-
other cardiovascular cause. Sudden death was ex-
plicitly defined as death that occurred “suddenly and
unexpectedly” in a patient in otherwise stable con-
dition and included witnessed deaths (with or with-
out documentation of arrhythmia) and unwitnessed
deaths if the patient had been seen within 24 hours
before death but had not had premonitory heart
failure, myocardial infarction, or another clear cause
of death. Cardiac arrest with resuscitation was de-
fined as cardiac arrest from which a patient re-
gained consciousness and subsequent cognitive
function, even briefly.
The median duration of follow-up was 24.7
months. Sudden deaths and episodes of cardiac
arrest with resuscitation were combined for this

analysis. The left ventricular ejection fraction was
determined before randomization (a median of five
s
methods
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sudden death after myocardial infarction

2583

days after myocardial infarction) at the clinical site
in 11,256 patients: echocardiography was used in
9095, radionuclide ventriculography in 272, and
contrast ventriculography in 1889. The analysis of
the incidence and timing of sudden death included
all patients and was related to the left ventricular
ejection fraction in the subgroup of patients for
whom information on the ejection fraction was
available: 3852 with an ejection fraction of 30 per-
cent or less, 4998 with an ejection fraction of 31 to
40 percent, and 2406 with an ejection fraction of

more than 40 percent.
The rates of sudden death were assessed by di-
viding the events in each period by the number of
person-days of exposure and are expressed as the
percentage per month. Baseline clinical character-
istics were compared with the use of Student’s t-test
for continuous variables and the chi-square test for
categorical variables. The risk of sudden death as-
sociated with each decrease of 5 percentage points
in the left ventricular ejection fraction was assessed
in a Cox proportional-hazards model, with adjust-
ment for all known baseline covariates.
Of 14,609 patients, 1067 (7 percent) had an event:
903 patients died suddenly, and 164 were resusci-
tated after cardiac arrest. For 643 of the 1067 pa-
tients (60 percent), this was the first cardiovascular
event after enrollment. Five patients who were re-
suscitated after cardiac arrest died on the day of
resuscitation. The median time to sudden death
or cardiac arrest with resuscitation was 180 days
after myocardial infarction (interquartile range,
50 to 428). Of the 164 patients who were resusci-
tated, 108 (66 percent) were alive at six months and
93 (57 percent) were alive at the end of the trial. As
compared with surviving patients without events,
patients who died suddenly or had cardiac arrest
with resuscitation were significantly older; had
higher baseline systolic and diastolic blood pres-
sures, baseline heart rate, and Killip class; had a
lower left ventricular ejection fraction; were more

likely to have a history of diabetes or hypertension;
and were less likely to have been treated with reper-
fusion therapy, amiodarone, or beta-blockers (Ta-
ble 1). The differences between patients who died
suddenly or were resuscitated after cardiac arrest
and those who died of other causes were much less
clinically apparent.
During the first 30 days after myocardial infarc-
tion, 126 patients died suddenly and 72 patients
were resuscitated after cardiac arrest (representing
19 percent of all patients with such events during
the trial), for an event rate of 1.4 percent per month
(95 percent confidence interval, 1.2 to 1.6 percent).
Eighty-three percent of sudden-death events from
which the patients were not resuscitated occurred
after hospital discharge. Of the patients who were
resuscitated during the first 30 days after myocar-
dial infarction, 74 percent were alive at 1 year. Event
rates and the cumulative incidence of events during
various periods in the study are shown in Table 2.
The rate of sudden death or cardiac arrest with re-
suscitation decreased precipitously during the first
year, declining to 0.14 percent per month (95 per-
cent confidence interval, 0.11 to 0.18 percent) after
year 2.
Figure 1 shows the Kaplan–Meier estimates of
the rate of sudden death or cardiac arrest with re-
suscitation according to the left ventricular ejection
fraction in patients in whom the ejection fraction
was measured. The increased early incidence of

these events was most apparent among patients
with an ejection fraction of 30 percent or less: the
incidence rate during the first 30 days was 2.3 per-
cent per month (95 percent confidence interval, 1.8
to 2.8 percent) (Fig. 1 and 2). Of the 156 sudden
deaths or episodes of cardiac arrest with resuscita-
tion that occurred during the first 30 days, 85 oc-
curred among the 3852 patients with an ejection
fraction of 30 percent or less (54 percent; 1 percent
of all patients with a known left ventricular ejection
fraction). Of the 3852 patients with an ejection frac-
tion of 30 percent or less, 399 (10 percent) died sud-
denly or had cardiac arrest with resuscitation dur-
ing the trial, as compared with 295 of the 4998
patients with an ejection fraction of 31 to 40 per-
cent (6 percent) and 119 of the 2406 patients with
an ejection fraction of more than 40 percent (5 per-
cent). Among the patients with a known left ven-
tricular ejection fraction, 49 percent of all sudden
deaths or cardiac arrests with resuscitation occurred
in patients with an ejection fraction of 30 percent or
less, and this proportion remained relatively con-
stant throughout follow-up.
Among the 399 patients with an ejection fraction
of 30 percent or less who died suddenly or had car-
diac arrest with resuscitation, 85 (21 percent) did
so during the first 30 days after myocardial infarc-
tion, as compared with 50 of 295 such patients with
an ejection fraction of 31 to 40 percent (17 percent)
and 21 of 119 such patients with an ejection frac-

tion of more than 40 percent (18 percent). Never-
theless, even among patients with an ejection frac-
results
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tion of more than 40 percent, the rate of sudden
death or cardiac arrest with resuscitation was more

than six times as high in the first month as after
one year. Although the incidence of sudden death or
cardiac arrest with resuscitation declined markedly
over time in all groups, the relative risk of these
events remained two to three times as high as
among patients with a left ventricular ejection frac-
tion of 30 percent or less as among patients with an
ejection fraction of more than 40 percent, although
overall, the absolute rate after two years was sub-
stantially lower than during the early period. When
the left ventricular ejection fraction was considered
as a continuous variable, each decrease of 5 percent-
age points in the ejection fraction was associated
with a 21 percent increase in the risk of sudden
death or cardiac arrest with resuscitation during the
first 30 days after myocardial infarction (hazard
ratio, 1.21; 95 percent confidence interval, 1.10 to
1.30), after adjustment for all known baseline co-
variates.
The results of our analysis confirm that patients
with left ventricular dysfunction, heart failure, or
both after myocardial infarction are at high risk for
sudden death or cardiac arrest with resuscitation.
The absolute risk is greatest in the early period after
myocardial infarction and among patients with the
lowest ejection fraction and declines significantly
over time, reaching a steady state at approximately
discussion

* Plus–minus values are means ±SD. The body-mass index is the weight in kilograms divided by the square of the height

in meters. Percentages may not sum to 100 because of rounding. CHF denotes congestive heart failure, PCI percutane-
ous coronary intervention, and LVEF left ventricular ejection fraction.

† P values are for the comparison with sudden death or cardiac arrest with resuscitation.

Table 1. Baseline Characteristics of the Patients, According to the Outcome.*
Characteristic
Sudden Death
or Cardiac Arrest
with Resuscitation
(N=1067)
Death from Cause
Other Than
Sudden Death
(N=1905)
P
Value
Survival Free
of Sudden Death
or Cardiac Arrest
with Resuscitation
(N=11,637)
P
Value†

Age (yr)
67.8±11.2 71.4±10.3 <0.001 63.5±11.7 <0.001
Male sex (%) 67 61 0.002 70 0.04
Blood pressure (mm Hg)
Systolic 125.1±18.2 123.5±17.5 0.02 122.3±17.0 <0.001

Diastolic 73.3±12.0 71.9±11.9 0.002 72.3±11.1 0.008
Heart rate (beats/min) 78.1±13.6 78.9±13.7 0.10 75.6±12.5 <0.001
Body-mass index 27.7±5.7 27.1±5.0 0.007 28.0±5.3 0.04
Killip class (%) 0.13 <0.001
I 19 17 30
II 46 47 49
III 26 26 15
IV 9 10 5
Clinical or radiologic evidence
of CHF at entry (%)
83 85 0.10 75 <0.001
Prior myocardial infarction (%) 45 41 0.08 24 <0.001
History of hypertension (%) 64 64 0.96 53 <0.001
History of diabetes (%) 31 32 0.42 21 <0.001
Beta-blocker (%) 61 57 0.07 73 <0.001
Amiodarone (%) 20 19 0.73 8 <0.001
Primary PCI (%) 8 8 0.34 17 <0.001
Thrombolytic therapy (%) 24 25 0.32 38 <0.001
Primary PCI or thrombolytic therapy (%) 30 32 0.25 49 <0.001
LVEF 0.32±0.10 0.33±0.10 0.06 0.36±0.10 <0.001
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sudden death after myocardial infarction

2585

one year. The risk was increased despite the fact that
all patients, according to the study design, were re-
ceiving inhibitors of the renin–angiotensin system
and the majority were receiving beta-blockers and
aspirin.
Several measures may identify patients at high-
est risk for sudden death in the first year after myo-
cardial infarction.

3,13,14

These are an assessment of
the frequency or severity of arrhythmia, including
the incidence of premature ventricular contractions,
nonsustained ventricular tachycardia, dispersion of
the QT interval, and late potentials on signal-aver-
aged electrocardiograms; measures of autonomic
function; and the results of invasive electrophysio-
logical testing.

15-17

The left ventricular ejection frac-
tion, an independent risk factor for sudden death,
is currently the most widely used and robust clini-

cal determinant of risk after infarction and has be-
come the basis for determining a patient’s eligibility
for ICD therapy.

9

However, it is poor at distinguish-
ing between patients who will die from arrhythmia
and those who will die of other cardiovascular
causes.

18

In VALIANT, patients who died suddenly
were similar to those who died of other causes.
Other causes of death included pump failure, recur-
rent myocardial infarction, procedure-related caus-
es, other cardiac causes, and noncardiac causes,
which were relatively rare in this population. Base-
line characteristics that were associated with an in-
creased risk of death from other causes were also
associated with an increased risk of sudden death.
Our inability to distinguish patients who died sud-
denly from those who died of other causes may re-
flect our lack of more sophisticated measures of
the risk of arrhythmia in this study.
The other key determinant of the risk of sudden
death is the time after myocardial infarction. The
absolute risk of sudden death is highest in the first
year after myocardial infarction. Our data suggest

that this risk is greatest within the first week after
myocardial infarction and falls rapidly within the
first month. The increased early rate of sudden
death was highest among patients with the lowest
left ventricular ejection fraction, but the high inci-
dence was not restricted to patients with the lowest
left ventricular ejection fraction. Indeed, the inci-
dence of sudden death in the group with the high-
est ejection fraction was greater in the first 30 days
than was the incidence of sudden death in the group
with the lowest ejection fraction after 90 days. More-
over, patients who died suddenly or had cardiac ar-
rest with resuscitation were in clinically stable con-

* CI denotes confidence interval.

Table 2. Event Rate and Cumulative Incidence of Events during Follow-up.*
Time after
Myocardial
Infarction
No. at Risk
at Beginning
of Interval
No. Who Died
of Any Cause
during Interval Sudden Death or Cardiac Arrest with Resuscitation

No. of Patients Event Rate Cumulative Incidence

%/mo (95% CI)

%

0–30 Days
14,609 589 198 1.4 (1.2–1.6) 1.4
>1–6 Mo 13,997 767 340 0.50 (0.45–0.55) 2.5
>6–12 Mo 13,157 509 211 0.27 (0.23–0.31) 1.6
>1–2 Yr 12,622 754 240 0.18 (0.16–0.20) 2.1
>2–3 Yr 7,926 244 75 0.14 (0.11–0.18) 1.7

Figure 1. Kaplan–Meier Estimates of the Rates of Sudden Death or Cardiac
Arrest with Resuscitation, According to the Left Ventricular Ejection Frac-
tion (LVEF).

The analysis was restricted to patients for whom data on LVEF were available.
0.20
Sudden Death or Cardiac
Arrest with Resuscitation (%)
0.15
0.05
0.10
0.00
1 6 12 24
36
LVEF >40% (n=2406)
LVEF ≤30% (n=3852)
LVEF, 31– 40% (n = 4998)
Months after Myocardial Infarction
No. at Risk 9946262977510,18311,256
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dition and many had recently been discharged from
the hospital. Thus, to prevent sudden death after in-
farction, the ideal strategy must also take into ac-
count patients with a better-preserved left ventricu-
lar ejection fraction (more than 40 percent).
The discriminatory effect of the left ventricular
ejection fraction appears to be greatest in the first

six months after myocardial infarction. Among pa-
tients who survived beyond one year, the annualized
rate of sudden death was still highest in the group
with the lowest left ventricular ejection fraction but
was fairly similar among the three ejection-fraction
groups, although the relative risk remained higher
in the groups with a lower ejection fraction. This ob-
servation, however, should be tempered by the fact
that patients who survive are already at lower risk.
Also, ventricular function was measured relatively
early after infarction, and in some patients, substan-
tial recovery of ventricular function may have oc-
curred with a concomitant decrease in the risk of
sudden death. An additional decline in the left ven-
tricular ejection fraction may occur over time, and
the risk of sudden death at a particular time after
myocardial infarction is more likely to be related to
the ejection fraction at that time than to the ejection
fraction in the periinfarction period.
Although our findings suggest that a strategy of
treating a greater proportion of patients early and
focusing on those with a low left ventricular ejection
fraction later might be the most efficient approach
to minimizing the risk of sudden death after myo-
cardial infarction, the recently reported DINAMIT
showed no benefit of implanting an ICD 6 to 40
days after myocardial infarction in patients with an
ejection fraction of 35 percent or less and evidence
of reduced heart-rate variability.

10

Indeed, in that
trial, a decrease in the rate of death from arrhythmia
was offset by an increase in the rate of death from
other causes.

19

The DINAMIT findings thus did not
provide support for the use of early ICD therapy in a
high-risk population after myocardial infarction
and underscore the fact that patients at increased
risk for sudden death from arrhythmia are also at
increased risk for death from other causes.
Although it is difficult to reconcile the absence
of a benefit in DINAMIT with the substantially in-
creased risk of sudden death we observed in the
early post-infarction period, there were a number
of important differences between the two studies.
Although DINAMIT enrolled patients with a lower
overall left ventricular ejection fraction than did
VALIANT, the average time to enrollment was 18
days after myocardial infarction — 13 days later
than the average enrollment date in VALIANT —
and thus, DINAMIT may have selected for patients
already at lower risk for sudden death. Moreover, at
7.2 percent per year, the overall mortality rate was
lower in DINAMIT than in VALIANT. Although the
rate of death from arrhythmia in the DINAMIT con-

trol group was similar to the rate of sudden death
in VALIANT (3.5 percent and 3.7 percent per year,
respectively), the true rate of death from arrhyth-
mia in our study may have been much higher, since
only unexpected deaths were categorized as sudden,
thereby excluding patients with fatal arrhythmia in
the setting of myocardial infarction or pump failure.
Alternatively, DINAMIT, with only 120 deaths, may
have been statistically underpowered to demon-
strate a clinically important difference between
groups, an interpretation that would suggest the
need for additional studies of ways to prevent sud-
den death from arrhythmia in the early period after
infarction.
It remains unclear whether therapies targeted at
a high-risk population soon after infarction would
reduce the risk of sudden unexpected death, but

Figure 2. Rate of Sudden Death or Cardiac Arrest with Resuscitation
over the Course of the Trial in the Three Categories of Left Ventricular
Ejection Fraction (LVEF).

The analysis was restricted to patients for whom data on LVEF were available.
The average rate (percentage per month) is shown at the midpoint of each
period.
LVEF ≤30% (n=3852)
LVEF, 31– 40% (n=4998)
LVEF >40% (n=2406)
Rate of Sudden Death or Cardiac
Arrest with Resuscitation (%/mo)

1.50
1.75
2.00
1.25
1.00
0.25
0.75
0.50
0.00
Months after Myocardial Infarction
2.25
2.50
1 2 3 4 5 6 12 24 36 48
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sudden death after myocardial infarction

2587

our data provide a rationale for considering early-
intervention strategies, including short-term ther-

apies, in selected patients at risk. This is supported
by the fact that the majority of our patients (74 per-
cent) who were resuscitated during the first 30 days
were alive at 1 year. In addition, although our data
suggest that the overall risk of sudden death or car-
diac arrest with resuscitation increases with a de-
creasing left ventricular ejection fraction, even in
patients with an ejection fraction of more than 40
percent, the risk of sudden death or cardiac arrest
with resuscitation was six times as high in the first
30 days as at 1 year, suggesting a potential role for
early short-term intervention, even in lower-risk pa-
tients. For example, if all sudden deaths could be
prevented, a strategy of treating everyone for 30
days and only those with a left ventricular ejection
fraction of 30 percent or less beyond 30 days in the
VALIANT study would potentially have prevented
or postponed 507 deaths, as compared with 317
deaths with the use of the currently recommended
strategy of treating only those with an ejection frac-
tion of 30 percent or less beyond 30 days. This ap-
proach may not be practical on the basis of current
ICD technology, but such an approach might be
practical and cost-effective in the future, although
it must be noted that current Medicare regulations
do not allow for payment for ICD therapy before 40
days after myocardial infarction.

6

A number of limitations of this analysis should
be noted. First, the left ventricular ejection fraction
was measured locally, not centrally, although local
estimation of the ejection fraction is used to make
clinical decisions. Second, some patients identified
as having died suddenly may have died from causes
such as aortic dissection, pulmonary embolism,
stroke, and especially, reinfarction; in the case of
reinfarction, sudden death may still be due to ar-
rhythmia.

20

Also, since our definition of sudden
death specified prior stability, we may have exclud-
ed many deaths from arrhythmia that occurred in
the setting of myocardial infarction or heart failure.
Finally, although our data may help guide interven-
tional strategies that reduce risk, we did not assess
the efficacy of such strategies.
In summary, we demonstrated that the risk of
sudden death is highest soon after myocardial in-
farction — particularly during the first 30 days.
This risk is greatest among patients with the low-
est left ventricular ejection fraction (30 percent or
less), but even patients with a high ejection frac-
tion (more than 40 percent) are at substantially
increased risk in the early post-infarction period,
as compared with the subsequent risk, and the
discriminatory effect of the left ventricular ejec-

tion fraction declines over time. Although it is not
known whether early ICD therapy would reduce
these risks, taken in the context of recent data dem-
onstrating the benefits of ICD therapy in high-risk
patients,

21

our data suggest the need to consider
implementing strategies to prevent sudden death
in selected patients before the time recommended
by current guidelines.

Supported by a grant from Novartis Pharmaceuticals.

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7.

Buxton AE, Lee KL, Fisher JD, Joseph-
son ME, Prystowsky EN, Hafley G. A ran-
domized study of the prevention of sudden
death in patients with coronary artery dis-
ease. N Engl J Med 1999;341:1882-90. [Erra-
tum, N Engl J Med 2000;342:1300.]

8.

Moss AJ, Zareba W, Hall WJ, et al. Pro-
phylactic implantation of a defibrillator in
patients with myocardial infarction and re-
duced ejection fraction. N Engl J Med 2002;
346:877-83.

9.

Antman EM, Anbe DT, Armstrong PW,
et al. ACC/AHA guidelines for the manage-
ment of patients with ST-elevation myo-
cardial infarction: a report of the American
College of Cardiology/American Heart As-
sociation Task Force on Practice Guidelines
(Committee to Revise the 1999 Guidelines
for the Management of Patients with Acute
Myocardial Infarction). Circulation 2004;
110:e82-e292.

10.

Hohnloser SH, Kuck KH, Dorian P, et
al. Prophylactic use of an implantable car-
dioverter–defibrillator after acute myocar-
dial infarction. N Engl J Med 2004;351:
2481-8.

11.

Huikuri HV, Tapanainen JM, Lindgren K,
et al. Prediction of sudden cardiac death after
myocardial infarction in the beta-blocking
era. J Am Coll Cardiol 2003;42:652-8.

12.

Pfeffer MA, McMurray JJ, Velazquez EJ,
et al. Valsartan, captopril, or both in myo-
cardial infarction complicated by heart fail-
ure, left ventricular dysfunction, or both.
N Engl J Med 2003;349:1893-906. [Erratum,
N Engl J Med 2004;350:203.]

13.

Califf RM, McKinnis RA, Burks J, et al.
Prognostic implications of ventricular ar-
rhythmias during 24 hour ambulatory mon-
itoring in patients undergoing cardiac cath-

eterization for coronary artery disease. Am J
Cardiol 1982;50:23-31.

14.

Myerburg RJ, Kessler KM, Castellanos
A. Sudden cardiac death: epidemiology, tran-
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at RIKSHOSPITALET HF on February 18, 2008 .

n engl j med

352;25

www.nejm.org june

23

,

2005

2588

sudden death after myocardial infarction

sient risk, and intervention assessment.
Ann Intern Med 1993;119:1187-97.

15.

Naccarella F, Lepera G, Rolli A. Arrhyth-
mic risk stratification of post-myocardial in-
farction patients. Curr Opin Cardiol 2000;
15:1-6.

16.

Steinberg JS, Regan A, Sciacca RR, Big-
ger JT Jr, Fleiss JL. Predicting arrhythmic
events after acute myocardial infarction us-
ing the signal-averaged electrocardiogram.
Am J Cardiol 1992;69:13-21.

17.

Kleiger RE, Miller JP, Bigger JT Jr, Moss
AJ. Decreased heart rate variability and its
association with increased mortality after
acute myocardial infarction. Am J Cardiol
1987;59:256-62.

18.

Every N, Hallstrom A, McDonald KM, et
al. Risk of sudden versus nonsudden cardiac
death in patients with coronary artery dis-
ease. Am Heart J 2002;144:390-6.

19.

Hohnloser SH, Connolly SJ, Kuck KH,
et al. The Defibrillator in Acute Myocardial
Infarction Trial (DINAMIT): study protocol.
Am Heart J 2000;140:735-9.

20.

Uretsky BF, Thygesen K, Armstrong
PW, et al. Acute coronary findings at au-
topsy in heart failure patients with sudden
death: results from the Assessment of
Treatment with Lisinopril and Survival
(ATLAS) trial. Circulation 2000;102:611-
6.

21.

Bardy GH, Lee KL, Mark DB, et al.
Amiodarone or an implantable cardiover-
ter-defibrillator for congestive heart failure.
N Engl J Med 2005;352:225-37.

Copyright © 2005 Massachusetts Medical Society.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at RIKSHOSPITALET HF on February 18, 2008 .
New England Journal of Medicine
CORRECTION
Sudden Death in Patients with Myocardial Infarction
and Left Ventricular Dysfunction, Heart Failure, or

Both
Sudden Death in Patients with Myocardial Infarction and Left Ventric-
ular Dysfunction, Heart Failure, or Both . On page 2581, lines 9 and
10 in the Results section of the Abstract should have stated that ``83
percent of all patients who died suddenly in the first 30 days did so
after hospital discharge,´´ rather than ``83 percent of all patients who
died suddenly did so in the first 30 days after hospital discharge,´´ as
printed. We regret the error.
N Engl J Med 2005;353:744
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at RIKSHOSPITALET HF on February 18, 2008 .
n engl j med 355;3 www.nejm.org july 20, 2006
PERSPECTIVE
231
though the Office for Civil Rights
issued guidelines in 2003 that
seem to allow health care facili-
ties to opt out of providing lan-
guage services if their costs are
too burdensome, Title VI provides
no such exemption.
Ad hoc interpreters, including
family members, friends, un-
trained members of the support
staff, and strangers found in wait-
ing rooms or on the street, are
commonly used in clinical en-
counters. But such interpreters
are considerably more likely than
professional interpreters to com-

mit errors that may have adverse
clinical consequences.
1,5
Ad hoc
interpreters are also unlikely to
have had training in medical ter-
minology and confidentiality;
their priorities sometimes con-
flict with those of patients; and
their presence may inhibit dis-
cussions regarding sensitive issues
such as domestic violence, sub-
stance abuse, psychiatric illness,
and sexually transmitted diseas-
es.
5
It is especially risky to have
children interpret, since they are
unlikely to have a full command
of two languages or of medical
terminology; they frequently make
errors of clinical consequence; and
they are particularly likely to avoid
sensitive issues.
1,5
Given the doc-
umented risks associated with the
use of ad hoc interpreters, it is of
concern that the 2003 guidance
from the Office for Civil Rights

states that such use “may be ap-
propriate.”
Later this year, the California
legislature will consider a bill pro-
hibiting state-funded organiza-
tions from using children young-
er than 15 years of age as medical
interpreters. Leland Yee, the Cali-
fornia speaker pro tempore, pro-
posed the bill, prompted by his
experiences interpreting for his
mother and, later, as a child psy-
chologist. The bill requires orga-
nizations receiving state funding
to establish a procedure for “pro-
viding competent interpretation
services that does not involve the
use of children.”
Although this legislation may
emerge as a state model, as an un-
funded mandate, it will have lim-
ited power to improve care. Per-
haps the time has come for payers
to be required to reimburse pro-
viders for interpreter services. The
provision of adequate language
services results in optimal com-
munication, patient satisfaction,
outcomes, resource use, and pa-
tient safety.

1,5
A 2002 report from
the Office of Management and
Budget estimated that it would
cost, on average, only $4.04 (0.5
percent) more per physician visit
to provide all U.S. patients who
have limited English proficiency
with appropriate language services
for emergency-department, inpa-
tient, outpatient, and dental visits.
This seems like a small price to
pay to ensure safe, high-quality
health care for 49.6 million Amer-
icans.
Dr. Flores is director of the Center for the
Advancement of Underserved Children and
a professor of pediatrics, epidemiology,
and health policy at the Medical College of
Wisconsin and the Children’s Research In-
stitute of the Children’s Hospital of Wiscon-
sin, Milwaukee.
Flores G, Laws MB, Mayo SJ, et al. Errors
in medical interpretation and their potential
clinical consequences in pediatric encoun-
ters. Pediatrics 2003;111:6-14.
Flores G, Abreu M, Schwartz I, Hill M.
The importance of language and culture in
pediatric care: case studies from the Latino
community. J Pediatr 2000;137:842-8.

Baker DW, Parker RM, Williams MV,
Coates WC, Pitkin K. Use and effectiveness
of interpreters in an emergency department.
JAMA 1996;275:783-8.
Youdelman M, Hitov S. Racial, ethnic and
primary language data collection: an assess-
ment of federal policies, practices and per-
ceptions. Vol. 2. Washington, D.C.: National
Health Law Program, October 2001.
Flores G. The impact of medical interpret-
er services on the quality of health care: a
systematic review. Med Care Res Rev 2005;
62:255-99.
1.
2.
3.
4.
5.
language barriers to health care in the united states
Taking Heart — Cardiac Transplantation
Past, Present, and Future
Sharon A. Hunt, M.D.
H
eart transplantation hit the
international news with a
splash in December 1967, when
the first human-to-human trans-
plantation was performed in South
Africa by Christiaan Barnard, and
the first transplantation in the

United States, performed by Nor-
man Shumway at Stanford Uni-
versity, followed a month later.
Initial enthusiasm for the proce-
dure was quickly curbed, however,
when it became evident that sur-
vival rates were usually measured
in days or weeks. This poor sur-
vival was due not to poor surgi-
cal technique, but to an inade-
quate understanding of the type
of postoperative complications one
should anticipate and a lack of
tools for addressing these com-
plications when they were rec-
ognized.
A 1971 cover story in Life mag-
azine, entitled “A New and Dis-
quieting Look at Transplants,”
1

reflected the public perception of
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PERSPECTIVE
n engl j med 355;3 www.nejm.org july 20, 2006
232
the field, though the article fo-
cused specifically on the psychosis
the patients experienced in the in-
tensive care unit as a result of sleep

deprivation caused by intense,
round-the-clock surveillance by
anxious clinicians. Problems that
were less easily solved included
the occurrence of allograft rejec-
tion and opportunistic infections.
After the early enthusiasm for
the procedure subsided, a decade
of slow, steady clinical research
ultimately led to some viable so-
lutions for these clinical obstacles,
as well as to the recognition of an
unanticipated hurdle that today
remains the most important fac-
tor limiting long-term survival
after heart transplantation: pre-
mature development of transplant
coronary vasculopathy. Little has
changed in surgical technique
since the 1960s except for the
introduction of the bicaval anasta-
mosis (see figure), which better
preserves the integrity of the si-
nus node and the architecture of
the right atrium. In the 1970s, a
number of developments helped
to make the field ripe for resur-
gence. First, the use of endomyo-
cardial biopsy to confirm a clin-
ical diagnosis of acute allograft

rejection and to document the
adequacy of therapy was validat-
ed.
2
After the introduction of
cyclosporine-based immunosup-
pression in 1980, the clinical di-
agnosis of rejection became much
more problematic, so routine sur-
veillance biopsies of the heart
were introduced; this approach
remains the mainstay of diagno-
sis of rejection for the first one to
three years after transplantation.
A second major advance during
the 1970s was the development of
safe methods for the cold preser-
vation of donor hearts, with cold-
ischemia times of up to three
hours. This development opened
the way to the procurement of
hearts from distant donors, a sys-
tem that is universally used to-
day. In the early days, the donor
had to be transferred to the trans-
plantation center so that the heart
could be harvested in an operat-
ing room adjoining that of the
recipient — a cumbersome and
expensive requirement to which

many families of potential donors
objected.
Subsequent legal recognition
of the concept of brain death led
to the founding of local and then
national organ-procurement sys-
tems with uniformly applied cri-
teria for the allocation of donated
organs. For the past two decades,
the national organ-allocation sys-
tem has been run by the private
United Network for Organ Shar-
ing under contract to the federal
government.
During the same period, rec-
ognition of which opportunistic
infections were to be expected and
their most common presenta-
tions in transplant recipients led
to a highly aggressive approach
to infectious complications and
the institution of effective prophy-
laxis against some of the more
prevalent ones — for example,
the use of trimethoprim–sulfa-
methoxazole against Pneumocystis
carinii infection.
The undisputed leader of the
field during the 1970s was Stan-
ford’s Shumway. Dr. Shumway died

in February of this year, but not
before seeing his vision of the
wider application of heart trans-
plantation become a reality.
3
It had initially been anticipated
that young, healthy donor hearts
would live out their biologic des-
tiny in a new location and not de-
velop coronary artery disease for
many decades. This supposition
was proved invalid in the early
1970s, when a number of early re-
cipients of heart transplants died
from ischemic heart disease.
Pathologically, this disease was
a form of intimal thickening that
was characteristically diffuse, con-
centric, and longitudinal. Since it
was entirely limited to vessels of
the allograft, the intuitive conclu-
sion was that it was immuno-
logically mediated. Subsequent re-
search has suggested that the
process involves an initial immu-
nologic insult to the coronary vas-
culature that can be exacerbated
by nonimmunologic factors, such
as dyslipidemia, diabetes, and
viral infection. The model of graft

vasculopathy has contributed
greatly to an understanding of
the biology of vascular injury and
its sequelae.
Investigations into therapies
for graft vasculopathy have cen-
tered on palliation and preven-
tion. Standard palliative percu-
taneous interventions, including
angioplasty and coronary stent-
ing, have been shown to be safe
and to have some short-term ef-
fectiveness in the occasional pa-
tient with one or more focal cor-
onary narrowings.
4
However, the
technology is not applicable in
the majority of patients with dif-
fuse, distal disease. Pharmacolog-
ic interventions have thus far been
validated mainly for the preven-
tion of this disease. Such inter-
ventions have included statins and
the newer immunosuppressive
agents mycophenolate mofetil and
the mammalian target of rapamy-
cin (mTOR) inhibitors everolimus
taking heart — cardiac transplantation past, present, and future
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n engl j med 355;3 www.nejm.org july 20, 2006
PERSPECTIVE
233
taking heart — cardiac transplantation past, present, and future
A Standard (Biatrial) Heart Transplantation
B Orthotopic Cardiac Transplantation with Bicaval Technique
Arch of aorta
Arch of aorta
Arch of aorta
Pulmonary artery trunk
Superior vena cava
Superior vena cava
Left subclavian
artery
Left common
carotid artery
Brachiocephalic
trunk
Inferior vena cava
Completed transplantation
Completed transplantation
Inferior vena cava
Right atrium
Right atrium
Left atrium
Left atrium
Pulmonary artey trunk
Arch of aorta
Right superior pulmonary vein
Right inferior pulmonary vein

Superior vena cava
Superior vena cava
Left subclavian
artery
Left common
carotid artery
Brachiocephalic
trunk
Inferior vena cava
Inferior vena cava
Right atrium
Left atrium
Left atrium
Standard (Panel A) and New Bicaval (Panel B) Surgical Anastamoses.
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PERSPECTIVE
n engl j med 355;3 www.nejm.org july 20, 2006
234
taking heart — cardiac transplantation past, present, and future
and sirolimus (formerly known as
rapamycin). A single study involv-
ing 46 patients has suggested that
sirolimus has the potential to re-
verse angiographic disease in some
patients with established disease.
5
Most postoperative medical
regimens for cardiac-transplant
recipients now consist of multi-
drug immunosuppression incor-

porating a calcineurin inhibitor
(cyclosporine or tacrolimus), a cell-
cycle agent (usually mycopheno-
late mofetil), and corticosteroids
in the early postoperative period.
Most programs also include a
statin. With increasing frequency,
the mTOR inhibitors are being in-
troduced later after transplanta-
tion, to help spare renal function
by permit-
ting the
use of low-
er doses of
the calci-
neurin in-
hibitors
and to pre-
vent graft vasculopathy. The use
of mTOR inhibitors in the very
early postoperative period is lim-
ited because of concern regarding
potential impairment of wound
healing.
In the 21st century in the
United States, the summation of
all these advances has produced
an annual cohort of approxi-
mately 2000 new transplant re-
cipients, who have an 87 percent

probability of surviving the first
year after transplantation, a
“half-life” in excess of 10 years,
and a high probability of an ex-
cellent
quality
of life.
3

The
number of transplants is strictly
limited by donor availability and
has changed little over the past 15
years, despite a trend toward us-
ing older donors. These 2000 re-
cipients represent a small dent in
the overall population of patients
who are dying of end-stage heart
failure, but for younger patients
without serious coexisting condi-
tions who are willing to submit to
the requirement of a lifetime of
medication and medical care, this
possibility is an outstanding al-
ternative to early death.
The use of xenografts (organs
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n engl j med 355;3 www.nejm.org july 20, 2006
PERSPECTIVE
235

from nonhuman species) has been
viewed as an attractive alternative
to human donors, potentially pro-
viding an unlimited supply of or-
gans. Unfortunately, substantial
immunologic barriers — as well
as concerns regarding the trans-
mission of infectious agents that
are benign in one species but not
in others (as the human immuno-
deficiency virus proved to be) —
have thus far been insurmount-
able. As Dr. Shumway was fond of
saying, “Xenografts are the fu-
ture of transplantation . . . and
always will be.”
However, the future is likely to
hold improvements in the quality
and length of life for heart-trans-
plant recipients, as bench work in
fields such as vascular biology
and immunology translates into
clinical reality. Circumventing the
problem of relentless graft vascu-
lopathy will clearly prolong many
lives. And achievement of the holy
grail of transplantation — im-
mune tolerance or acceptance of
the graft with maintenance of nor-
mal immune function in other

respects — will eventually open
the door to normal lives and life
spans for all transplant recipients.
Dr. Hunt is a professor of cardiovascular
medicine at the Stanford University School
of Medicine, Stanford, Calif.
Thompson T. A new and disquieting look
at transplants: the year they changed hearts.
LIFE. September 17, 1971:56-70.
Caves PK, Stinson EB, Billingham ME,
Shumway NE. Serial transvenous biopsy of
the transplanted human heart: improved
management of acute rejection episodes.
Lancet 1974;1:821-6.
Taylor DO, Edwards LB, Boucek MM, et al.
Registry of the International Society for Heart
and Lung Transplantation: twenty-second of-
ficial adult heart transplant report — 2005.
J Heart Lung Transplant 2005;24:945-55.
Bader FM, Kfoury AG, Gilbert EM, et al.
Percutaneous coronary interventions with
stents in cardiac transplant recipients. J Heart
Lung Transplant 2006;25:298-301.
Mancini D, Pinney S, Burkhoff D, et al.
Use of rapamycin slows progression of car-
diac transplantation vasculopathy. Circula-
tion 2003;108:48-53.
1.
2.
3.

4.
5.
taking heart — cardiac transplantation past, present, and future
Thoughts from the Transition Zone
J. Terrance Davis, M.D.
I
got the call earlier today. A teen-
ager has been on life support at
our hospital while awaiting a heart
transplant. She was running out
of time when we got the offer of
a heart, and it was my job to re-
cover the organ. Before I knew it,
I was arriving at a suburban hos-
pital 600 miles away, accompanied
by my resident and a procurement
technician. When we drove in, it
seemed like any other emergen-
cy department at night.
But as we walked through the
emergency room (ER), all grew
quiet. There were eyes upon us,
and as people stepped aside, I
sensed their ambivalence at our
arrival: “Something good will
come of this. It’s almost over.
What a shame.” In this small hos-
pital, the tragedy of a young life
lost in a motor-vehicle accident
had permeated every department.

This is the donor zone. Teen-
agers stood in the hallways crying
and comforting one another, med-
ical teams had given their all but
to no avail, and the family was
trying to come to grips with the
loss. It is a zone of intense sad-
ness. Out of sight of all this, back
in the operating room, a heart was
beating in a body with no future.
The recovery was routine —
and yet extraordinary. An army of
coordinators had been on the tele-
phone for hours to bring together
people who could maximize the
potential of orphaned organs in
a body that was about to die.
Working side by side, we and an-
other team that was taking the
liver and kidneys divided shared
vessels in the middle. When we
all were ready, I put the cold po-
tassium solution into the heart,
which immediately stopped beat-
ing and turned into a flaccid, pale,
cold, apparently lifeless organ. I
removed the heart from the body,
realizing that this act completed
the process of death and marked
the beginning of a difficult time

in the donor zone.
People here would go home
grieving. But I had much to think
about — no time to reflect. I
thanked everyone, and we jumped
into the waiting ambulance. The
funeral procession for the donor
was yet to come; this was a dif-
ferent sort of journey for a heart
headed to a new home.
Soon, we will enter the recip-
ient zone. It will be permeated by
anticipation, excitement, and hope.
As I walk through that ER, eyes
will once again be on me, but the
message they convey will be dif-
ferent: Good news! They’re wait-
ing for you!
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n engl j med 357;21 www.nejm.org november 22, 2007
2195
clinic a l implications of ba sic r esea rch
T h e n e w e ngl a n d j o u r na l o f me dicine
The Liver X Receptor and Atherosclerosis
James Scott, M.B., B.S.
Cardiovascular disease is the leading cause of
death in the developed world, and it is poised to
become the most widespread health problem
worldwide. Atherosclerosis is the major cause of
cardiovascular disease. An elevated level of plas-

ma low-density lipoprotein (LDL) cholesterol is the
sine qua non for the development of atheroscle-
rosis.
1
People with lifelong low LDL cholesterol
levels are at very low risk for cardiovascular dis-
ease, yet the dramatic reduction of LDL choles-
terol through the use of statin drugs over several
years reduces the risk of heart attack by only 40%,
largely because the disease is already established
when treatment is initiated. Early and prolonged
treatment with statins could further reduce this
risk, but new treatments are also needed.
Consequently, there has been a surge in the
search for new drugs targeted against core athero-
genic mechanisms, but the route to new drugs has
been studded with high-profile failures costing
the pharmaceutical industry billions of dollars.
The basic elements of the problem are pressure
from big pharmaceutical companies, weakened
and underfunded regulatory agencies, and an in-
complete understanding of the target biologic pro-
cesses of the new drugs and their mechanisms of
action. A recent study by Bradley and colleagues,
2

which provides new insight into a not-so-new tar-
get, is therefore welcome.
Cholesterol is a necessary constituent of cell
membranes and a precursor of bile acids and ste-

roid hormones. Multiple mechanisms that have
developed in animals husband cholesterol. Choles-
terol homeostasis is highly susceptible to the glut
of cholesterol in the Western diet and to genetic
disorders, which perturb cholesterol metabolism,
leading to the LDL cholesterol levels observed in
adults that far exceed those in neonates and in
animals in the wild.
Atherosclerosis, a chronic inflammation of the
arterial intima, develops slowly over many years.
It results from the interaction between LDL cho-
lesterol, monocytes and macrophages, T cells, and
smooth-muscle cells of the arterial wall. The cho-
lesterol-engorged macrophage “foam cell” is the
hallmark and agent provocateur of atherosclero-
sis. The early lesions of atherosclerosis, so-called
fatty streaks that can be detected in the first dec-
ade of life, are accumulations of foam cells in the
arterial intima. In advanced fatty, fibrous, ath-
erosclerotic plaques, foam-cell apoptosis produc-
es a cholesterol-rich necrotic core, which makes
plaques prone to rupture and thereby promotes
vascular thrombosis.
The liver X receptors (LXRs) α and β (LXRα
and LXRβ) are master regulators of whole-body
cholesterol homeostasis, intermediary metabolism
and energy balance, and the integration of meta-
bolic and inflammatory signaling. Metabolites of
cholesterol ― oxysteroids ― are natural activat-
ing ligands for the LXRs, each of which is a het-

erodimer made up of either LXRα or LXRβ and
a retinoid X receptor (RXR). LXRα and LXRβ have
different tissue-specific expressions, interactions
with coactivators and corepressors, and nuclear-
import mechanisms (
Fig. 1
). These differences re-
sult in different repertoires of downstream gene
activation. LXRβ is ubiquitously expressed, where-
as LXRα is expressed predominantly in tissues in-
volved in lipid homeostasis in the liver, intestine,
adipose tissue, and macrophages. LXRα and LXRβ
are equally effective in promoting reverse choles-
terol transport from macrophages; they activate
members of the ABC superfamily of membrane
transporters, which transfer cholesterol to high-
density lipoprotein (HDL) particles. They also sup-
press genes involved in macrophage inflammatory
signaling and apoptosis. LXRα and LXRβ also ac-
tivate genes (e.g., the glucokinase gene) that medi-
ate glucose metabolism. Macrophage LXRs there-
by inhibit atherosclerosis, making them highly
attractive targets for drug discovery.
The first generation of nonselective synthetic
LXRα and LXRβ ligands inhibited atherosclero-
Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.
T h e n e w e ngl a n d j o u r na l o f me dicine
n engl j med 357;21 www.nejm.org november 22, 2007
2196
sis in mice deficient in apolipoprotein E, but in-

creased hepatic lipogenesis and plasma triglyceride
levels (
Fig. 1
).
3
In their study, Bradley et al. showed
that mice lacking both LXRα and apolipoprotein E
are protected against atherosclerosis by the ligand
activation of LXRβ, which activates macrophage
cholesterol efflux and elevates levels of HDL
cholesterol; their levels of plasma triglyceride re-
11/06/07
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
Please check carefully
Author
Fig #
Title
ME
DE
Artist
Issue date
COLOR FIGURE
Version 4
Scott
1
LAM
11/22/07
Liver X receptor
BP

SH
GW3965
LXRE
LXRα
or LXRβ
RXR
Nucleus
A Mouse deficient in APOE
Reduced atherosclerosis
Hypertriglyceridemia
Cell membrane
of macrophage
Reverse
cholesterol transport
Antiapoptosis
Lipogenesis
NF-κB transrepression
Cell membrane
of macrophage
Cell membrane
of macrophage
Cell membrane
of macrophage
C Mouse deficient in APOE and LXRα
Atherosclerosis
VLDL
Nucleus
Liver
B Mouse deficient in APOE plus activator of LXR
D Mouse deficient in APOE and LXRα plus activator of LXR

GW3965
Cholesterol metabolites
(oxysterols)
Cholesterol metabolites
(oxysterols)
Cholesterol metabolites
(oxysterols)
Cholesterol metabolites
(oxysterols)
LXRE
LXRα
or LXRβ
RXR
“Protective” gene
expression is weak
“Protective” gene
expression
Reverse
cholesterol transport
NF-κB transrepression
Nucleus
LXRE
LXRβ
RXR
Nucleus
LXRβ
RXR
LXRE
Marked atherosclerosis
Reduced atherosclerosis and

no hypertriglyceridemia
Changes in gene
expression
Weaker “protective” gene
expression than that in mouse
deficient in APOE only
“Protective” gene
expression
Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.
n engl j med 357;21 www.nejm.org november 22, 2007
2197
mained normal.
2
This observation teases out the
biology of the LXRs and suggests that the pursuit
of LXRβ-specific agonist ligands for the treatment
of atherosclerosis may prove to be fruitful.
Such a strategy, however, may not be straight-
forward, because the ligand-binding domains of
the LXRα–RXR and LXRβ–RXR heterodimers are
similar to one another. That said, there is a prec-
edent for more nuanced nuclear-receptor modula-
tors; that is, tamoxifen for the estrogen receptor.
Isoform-specific LXR ligands are under develop-
ment. Another option is to design specific al-
losteric modulators that target divergent do-
mains of the two receptors. Other potential
benefits of LXR agonists may manifest in the
central nervous system: they have ameliorated
Alzheimer’s disease in mouse models,

4
presum-
ably through their effects on cholesterol metab-
olism, inflammation, and γ-secretase activity.
Although the work of Bradley et al. points to
LXRβ as a target for the treatment of atheroscle-
rosis, mice and humans have different gene ex-
pressions in response to LXR activation. Genes
involved in bile-acid production, innate immune
response, and hepatic lipogenesis are regulated
differently in mice and humans. These differences
may have a bearing on the efficacy and toxicity
of LXR ligands in humans. As Alexander Pope ob-
served in his Essay on Man nearly 275 years ago,
“The proper study of mankind is man.”
No potential conflict of interest relevant to this article was re-
ported.
From Imperial College, London.
Brown MS, Goldstein JL. Lowering LDL — not only how low,
but how long? Science 2006;311:1721-3.
Bradley MN, Hong C, Chen M, et al. Ligand activation of
LXRβ reverses atherosclerosis and cellular cholesterol overload
in mice lacking LXRα and apoE. J Clin Invest 2007;117:2337-46.
Joseph SB, McKilligin E, Pei L, et al. Synthetic LXR ligand
inhibits the development of atherosclerosis in mice. Proc Natl
Acad Sci U S A 2002;99:7604-9.
Zelcer N, Khanlou N, Clare R, et al. Attenuation of neuroin-
flammation and Alzheimer’s disease pathology by liver x recep-
tors. Proc Natl Acad Sci U S A 2007;104:10601-6.
Copyright © 2007 Massachusetts Medical Society.

1.
2.
3.
4.
Clinical Implications of Basic Research
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Figure 1 (facing page). Gene Regulation by Liver X
Receptors in the Macrophage.
In the basal state, liver X receptors (LXRs) and reti-
noid X receptor (RXR) heterodimers are bound to liver
X response elements (LXRE) in the promoters of tar-

get genes. Ligand activation leads to cell-specific, tar-
get-gene expression. Atherosclerosis develops in mice
deficient in apolipoprotein E (APOE) (Panel A). In
these models, the LXR dual-agonist, GW3965, induces
macrophage cholesterol efflux (by direct action) and
suppresses macrophage inflammatory genes (by indi-
rect “transrepression” of nuclear factor κB [NF-κB] by
an unknown, presumably nuclear mechanism), there-
by inhibiting atherosclerosis,
3
but it also induces lipo-
genesis and triglyceride-rich very-low-density lipopro-
tein (VLDL) secretion in the liver (Panel B). Bradley et
al.
2
have recently shown that marked atherosclerosis
develops in mice “doubly” deficient in APOE and
LXRα (Panel C); this atherosclerosis is suppressed by
GW3965. In contrast to its effect on mice with intact
LXRα receptors, GW3965 does not induce hypertri-
glyceridemia in these “double-knockout” mice (Panel
D) — indicating that LXRβ is a candidate target for
highly selective, agonist-only drugs to treat atheroscle-
rosis.
Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.
original article
The
new england journal of medicine
n engl j med 355;12 www.nejm.org september 21, 2006
1222

Transcoronary Transplantation of Progenitor
Cells after Myocardial Infarction
Birgit Assmus, M.D., Jörg Honold, M.D., Volker Schächinger, M.D.,
Martina B. Britten, M.D., Ulrich Fischer-Rasokat, M.D., Ralf Lehmann, M.D.,
Claudius Teupe, M.D., Katrin Pistorius, M.D., Hans Martin, M.D.,
Nasreddin D. Abolmaali, M.D., Torsten Tonn, M.D., Stefanie Dimmeler, Ph.D.,
and Andreas M. Zeiher, M.D.
From the Division of Cardiology and Mo-
lecular Cardiology, Department of Medi-
cine III (B.A., J.H., V.S., M.B.B., U.F R., R.L.,
C.T., K.P., S.D., A.M.Z.), Division of He-
matology, Department of Medicine II
(H.M.), and the Department of Diagnos-
tic and Interventional Radiology (N.D.A.),
Johann Wolfgang Goethe University; and
the Institute for Transfusion Medicine
and Immunohematology, Red Cross
Blood Donor Service, Baden–Württem-
berg–Hessen (T.T.) — both in Frankfurt,
Germany. Address reprint requests to Dr.
Zeiher at the Department of Medicine III,
J.W. Goethe University, Theodor-Stern-
Kai 7, 60590 Frankfurt, Germany, or at

Drs. Assmus and Honold contributed equal-
ly to the article.
N Engl J Med 2006;355:1222-32.
Copyright © 2006 Massachusetts Medical Society.
Abstract
Background

Pilot studies suggest that intracoronary transplantation of progenitor cells derived
from bone marrow (BMC) or circulating blood (CPC) may improve left ventricular
function after acute myocardial infarction. The effects of cell transplantation in
patients with healed myocardial infarction are unknown.
Methods
After an initial pilot trial involving 17 patients, we randomly assigned, in a controlled
crossover study, 75 patients with stable ischemic heart disease who had had a myo-
cardial infarction at least 3 months previously to receive either no cell infusion (23
patients) or infusion of CPC (24 patients) or BMC (28 patients) into the patent coro-
nary artery supplying the most dyskinetic left ventricular area. The patients in the
control group were subsequently randomly assigned to receive CPC or BMC, and the
patients who initially received BMC or CPC crossed over to receive CPC or BMC,
respectively, at 3 months’ follow-up.
Results
The absolute change in left ventricular ejection fraction was significantly greater
among patients receiving BMC (+2.9 percentage points) than among those receiving
CPC (−0.4 percentage point, P = 0.003) or no infusion (−1.2 percentage points,
P<0.001). The increase in global cardiac function was related to significantly en-
hanced regional contractility in the area targeted by intracoronary infusion of BMC.
The crossover phase of the study revealed that intracoronary infusion of BMC was
associated with a significant increase in global and regional left ventricular func-
tion, regardless of whether patients crossed over from control to BMC or from CPC
to BMC.
Conclusions
Intracoronary infusion of progenitor cells is safe and feasible in patients with healed
myocardial infarction. Transplantation of BMC is associated with moderate but
significant improvement in the left ventricular ejection fraction after 3 months.
(ClinicalTrials.gov number, NCT00289822.)
Copyright © 2006 Massachusetts Medical Society. All rights reserved.
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progenitor-cell infusion in ischemic heart disease
n engl j med 355;12 www.nejm.org september 21, 2006
1223
C
hronic heart failure is common,
and its prevalence continues to increase.
1

Ischemic heart disease is the principal cause
of heart failure.
2
Although myocardial salvage due
to early reperfusion therapy has significantly re-
duced early mortality rates,
3
postinfarction heart
failure resulting from ventricular remodeling re-
mains a problem.
4
One possible approach to re-
versing postinfarction heart failure is enhance-
ment of the regeneration of cardiac myocytes as
well as stimulation of neovascularization within
the infarcted area. Initial clinical pilot studies
have suggested that intracoronary infusion of pro-
genitor cells is feasible and may beneficially af-
fect postinfarction remodeling processes in pa-
tients with acute myocardial infarction.
5-9
However,

it is currently unknown whether such a treatment
strategy may also be associated with improvements
in cardiac function in patients with persistent left
ventricular dysfunction due to healed myocardial
infarction with established scar formation.
Therefore, in the prospective TOPCARE-CHD
(Transplantation of Progenitor Cells and Recovery
of LV [Left Ventricular] Function in Patients with
Chronic Ischemic Heart Disease) trial, we inves-
tigated whether intracoronary infusion of pro-
genitor cells into the infarct-related artery at least
3 months after myocardial infarction improves
global and regional left ventricular function.
Methods
Patients
Between January 2002 and December 2004, a total
of 92 patients who had had a myocardial infarc-
tion at least 3 months previously were recruited
into the study at a single center. Patients be-
tween 18 and 80 years of age were eligible for
inclusion in the study if they had had a document-
ed myocardial infarction at least 3 months before
inclusion and had a well-demarcated region of
left ventricular dysfunction and a patent infarct-
related artery. Exclusion criteria were the pres-
ence of acutely decompensated heart failure with
a New York Heart Association (NYHA) class of
IV, a history of other severe chronic diseases or
cancer, or unwillingness to participate. The ethics
review board of the Johann Wolfgang Goethe Uni-

versity in Frankfurt, Germany, approved the
protocol; the trial was registered according to the
German Drug Law (accession numbers, 0703/01
and 0704/01); and the study was conducted in
accordance with the Declaration of Helsinki. Writ-
ten informed consent was obtained from each
patient.
Study Design
The study consisted of three phases: a pilot trial
comprising 17 patients (7 receiving progenitor cells
derived from bone marrow [BMC] and 10 receiv-
ing progenitor cells derived from circulating blood
[CPC]); a second phase, in which 75 patients were
randomly assigned to receive intracoronary infu-
sion of BMC (28 patients) or CPC (24) or no cell
infusion (23); and a third phase, in which the 75
randomly assigned patients crossed over to one
of the active treatments if they had originally been
in the control group or to the alternate cell type if
they had initially received intracoronary cell infu-
sion (Fig. 1).
The primary end point of the study was the
absolute change in global left ventricular ejection
fraction (LVEF) as measured by quantitative left
ventricular angiography 3 months after cell infu-
sion. Secondary end points included quantitative
variables relating to the regional left ventricular
function of the target area, as well as left ven-
tricular volumes derived from serial left ventric-
ular angiograms. In addition, functional status

was assessed by NYHA classification. Finally,
event-free survival was defined as freedom from
death, myocardial infarction, stroke, or rehospi-
talization for worsening heart failure. Causes of
rehospitalization during follow-up were verified
by review of the discharge letters or charts of
hospital stays.
Preparation and Transplantation
of Progenitor Cells
For patients assigned to receive CPC, mononuclear
cells were isolated by Ficoll density-gradient cen-
trifugation of 270 ml of venous blood and cultured
for 3 days ex vivo, as previously reported.
6,7,9-12

A mean of 22×10
6
±11×10
6
CPC were infused. For
patients assigned to receive BMC, 50 ml of bone
marrow aspirate was obtained while the pa-
tients were under local anesthesia on the morn-
ing of cell-transplantation day. BMC were iso-
lated by Ficoll density-gradient centrifugation,
as previously reported.
6,7,9
We infused a mean of
205×10
6

±110×10
6
BMC, of which on average less
than 1% were positive for the hematopoietic
progenitor-cell marker CD34.
For cell transplantation, arterial puncture
Copyright © 2006 Massachusetts Medical Society. All rights reserved.
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