Reviews
Current Treatment of
Edward K. Massin, MD
Key words: Cardio-
myopathy, congestive!
drug therapy
From: The Division of
Transplantation, Texas Heart
Institute and St. Luke's
Episcopal Hospital; Baylor
College of Medicine; and
The University of Texas
Medical School, Houston,
Texas
Presented at the 20th
anniversary symposium of
the Texas Heart Institute,
titled "Update Cardiology
1990, " held 24-26 October
1990, at the Westin Galleria
Hotel, Houston, Texas
Address for reprints:
Edward K. Massin, MD,
Suite 2310, 6624 Fannin
Street, Houston, TX 77030
Te= Heart Institutejournal
Dilated Cardiomyopathy
Within the last decade, the treatment for patients with dilated cardiomyopathy has
changed. Clinical management of these patients is aimed at controlling congestive heart
failure, treating arrhythmias, preventing pulmonary and systemic emboli, and managing
chest pain. The goals of treatment for patients with dilated cardiomyopathy are to make
the patient feel better and live longer. To achieve this, we direct treatment to improving
left ventricular function and cardiac output and controlling arrhythmias and thrombo-
emboli. Basic treatment begins with inotropic therapy, preload reduction, and afterload
reduction. For patients with symptomatic disease, we recommend diuretics, digoxin,
and converting enzyme inhibitors for first-line therapy. Patients with arrhythmias may be
treated by the addition of amiodarone, a pacemaker, or an automatic implantable
cardioverter-defibrillator; and most such patients need to be anticoagulated. All patients
need close follow-up for possible drug toxicity associated with their regimens. Heart
transplantation can be considered for patients refractory to medical treatment. Although
the incidence of dilated cardiomyopathy continues to increase, we are learning better
ways to treat it. In the future, new drugs with fewer side effects should be available to
treat, and perhaps impede, the development of dilated cardiomyopathy. (Texas Heart
Institute Journal 1991;18:41-9)
D lilated or congestive cardiomyopathy is characterized by an enlarged heart
with poorly contractile myocardium. The incidence ofdilated cardiomyop-
athy appears to be rising, with estimates that 3 to 10 persons per 100,000
suffer from the disease. Between 10,000 and 20,000 new cases are diagnosed in the
United States each year." 2 Approximately 85% of all deaths in cases of cardiomyop-
athy are attributed to dilated cardiomyopathy. The prognosis for patients with
dilated cardiomyopathy is not good. At 2 years, 500/o of afflicted patients have died.
Although 25% are still alive at 10 years,' for most, the quality of life is poor. More
than 400/o die suddenly.
Cardiac glycosides and diuretics have been considered standard treatment for
patients with dilated cardiomyopathy for many years. Within the last decade,
however, the use of digitalis has been debated. Physicians have achieved improved
results by using additional drugs. Vasodilators, including converting enzyme inhib-
itors, have been used with some success, as have 3-agonists, f3-blockers, phos-
phodiesterase inhibitors, and other inotropic agents. The role of antiarrhythmic
agents in treating patients at high risk for sudden death remains unclear. Anti-
coagulation clearly has a role to play in patients with dilated cardiomyopathy.
Ultrafiltration, mechanical support devices, and heart transplantation can also be
considered for patients refractory to medical regimens.
Thus, the treatment of patients with dilated cardiomyopathy has changed within
the last decade. Now there are options; but with these new options has come con-
troversy. Should digitalis and diuretics remain the first line of defense against this
crippling disease? What is the role of n-blockers? Do antiarrhythmic agents given
routinely decrease the threat of sudden death? Is there really a single treatment for
dilated cardiomyopathy? This paper will attempt to answer some ofthese questions.
Pathogenesis
Dilated cardiomyopathy is characterized by cardiomegaly and dilatation, generally
of both ventricles. Systolic and diastolic function are impaired. There is myocyte
loss with hypertrophy of remaining cells and "cell slippage." Left ventricular wall
thinning is accompanied by sarcomere thickening, increased cell tension, and
worsening contractility. Connective tissue loss may affect wall remodeling and
Treatment of Dilated Cardiomyopathy 41
thereby diminish diastolic function. A number of
conditions appear to be associated with an increased
incidence of dilated cardiomyopathy, including alco-
hol abuse, systemic arterial hypertension, pregnancy
and the puerperium, chemicals toxic to the myocar-
dium, immunologic disorders, and viral infections.3
Each of these conditions can create myocardial
overload by increasing myocardial work or by caus-
ing segmental myocardial loss (as in myocardial
infarction) or generalized myocyte loss (as in cardio-
myopathy). Increased wall stress results in delayed
contraction and relaxation and in ventricular dilation,
further increasing wall stress and initiating a poten-
tially catastrophic pathologic cycle. Hypertrophy and
wall remodeling result in "cell slippage," thinning of
the ventricular wall, loss of myocytes, and reactive
hypertrophy of the remaining cells. Reduced pump
function results in neurohormonal activation and
further complicates the cycle, affecting peripheral
circulation and causing fluid retention. Therapy must
be directed to interruption of this process.
Although virus has never been isolated in human
myocardium, enteroviral genomic fragments have
been found in endomyocardial biopsy tissue in 15%
to 25% of patients with dilated cardiomyopathy or
active myocarditis. I Dilated cardiomyopathy is known
to have occurred following acute viral infection. Most
likely, a relationship exists between viral infections
and immunologic disorders. Disordered cellular im-
munity has been found in patients with dilated car-
diomyopathy.3 4 The viral infection probably triggers
an immunologic reaction at the cellular level that, in
turn, damages myocardial tissue.
Investigators have theorized that viruses may mod-
ify the antigenic properties of the host's myocardial
cells to initiate production of autoantibodies that sub-
sequently impair myocardial function.3 Heart reac-
tive antibodies, antinuclear factors, and bound
gamma globulins have been found in myocardial
tissue. Limas5 6 has reported the presence of circulat-
ing auto-antibodies directed against sarcolemmal
components in patients with dilated cardiomyopathy,
but not in patients with hypertrophic cardiomyopathy.
Limas6 also has reported that a substantial proportion
of patients with idiopathic dilated cardiomyopathy
have autoantibodies directed against the cardiac
,B-adrenergic receptor. He showed that cardiac trans-
plantation resulted in a dramatic decrease in the
ability of the serum to inhibit ligand binding to the
cardiac P-adrenergic receptor.7 Why this occurs re-
mains to be determined, although a genetic predispo-
sition to these autoantibodies is strongly suspected.
If an immune response is at least in part the cause
of dilated cardiomyopathy, successful treatment re-
quires identification of the cardiac proteins that are
targets of the circulating autoantibodies. Investiga-
tors have learned that ejection fraction is lower in the
42 Treatment of Dilated Cardiomyopathy
presence of autoantibodies against mitochondrial
adenine nucleotide translocator (Anti-ANT). I Anti-ANT
is also suspected of inhibiting calcium in the cardiac
myocyte.
Abnormal lymphocyte function has also been re-
ported in dilated cardiomyopathy.8 Histologic studies
have confirmed that parasympathetic function is
impaired in these patients and may predispose to
arrhythmias and sudden death.9 If all of these factors
can be controlled, it may be possible to arrest or
reverse the pathophysiologic processes that cause
dilated cardiomyopathy. Until that time, we must
treat dilated cardiomyopathy aggressively.
Diagnosis
Noninvasive Diagnostic Techniques
Echocardiography often shows increased size of both
ventricles, accompanied by poor contractility and
global, regional, and diastolic dysfunction. Trans-
mitral Doppler velocity recordings and radionuclide
time-activity waves can be used to assess left ven-
tricular filling characteristics. Blood-pool imaging
can be used to confirm dilatation and decreased myo-
cardial contractility.
Thallium scintigraphy techniques may be useful in
diagnosing areas of reversible ischemia. Positron-
emission tomography can distinguish preserved
metabolic activity in poorly perfused myocardium.
Magnetic resonance imaging may be most useful in
evaluating pericardial pathology.
Right ventricular characteristics may have prog-
nostic value, since right ventricular ejection fraction
may better reflect pulmonary capillary wedge pres-
sure and left ventricular filling pressure, parameters
that seem to correlate with symptoms and prognosis.
Invasive Diagnostic Techniques
Catheterization can provide hemodynamic data re-
garding myocardial systolic and diastolic function
and can assess the severity of valvar dysfunction, aid
in discrimination of pericardial disease, and yield
valuable information regarding pulmonary and sys-
temic vascular resistance. Myocardial biopsy can be
useful to differentiate myocarditis from dilated cardio-
myopathy and to diagnose some specific diseases of
the heart muscle. Low ejection fraction, deteriorating
functional class, high levels of plasma norepineph-
rine10 and atrial natriuretic factor (ANF),11 and epi-
sodes of syncope are predictive of early death.
Treatment
Success of treatment must be evaluated in consider-
ation of the fact that 25% to 30% of patients with
congestive heart failure experience symptomatic im-
provement with placebo. Clinical management of
Volume 18, Number 1, 1991
these patients is aimed at controlling congestive heart
failure, treating arrhythmias, preventing pulmonary
and systemic emboli, and, often, at managing chest
pain. Because many of the sequelae of dilated car-
diomyopathy result from depression of myocardial
contractility, treatment is directed at manipulating
vasomotor activity and at improving myocardial con-
tractility. Basic treatment for congestive heart fail-
ure resulting from dilated cardiomyopathy consists
of inotropic therapy, preload reduction, and after-
load reduction (Fig. 1). The effects of angiotensin-
converting enzyme inhibition and P-blockade are
probably more complex. We treat patients who have
life-threatening arrhythmias with amiodarone, pace-
makers, or automatic implantable cardioverter-defib-
rillators, and we give most patients anticoagulants.
We choose therapeutic agents based on severity of
illness and response to initial treatment (Fig. 1). Pa-
tients in stage 1 are in New York Heart Association
(NYHA) class II or III and may be managed as
outpatients, while patients in stage 2 have deterio-
rated to NYHA class III or IV and generally require
hospitalization. Stage-3 patients require mechanical
circulatory support.
Dilated Cardiomyopathy
ARRHYTHMIAS ' THROMBUS-EMBOLUS
TACHYCARDIA
VT
BRADYCARDIA
HEART BLOCK
COUMADIN/HEPARIN
AMODARONE PACEMAKER B-BLOCKADE
SINUS A-FIB
DDD A-FLUTTER_
DDO-R VVI-R
STAGE I
INOTROPIC RX
DIGITALIS
PRELOAD REDUCTION AFTERLOAD REDUCTION
LOOP DIURETICS ACEI
K *SPARING
IV
DOPAMINE
STAGE 2
LONG-ACTING TUBULE HYDRALADNE-NITRATES
DOBUTAME
INOCOR
STAGE 3
MECHANCAL CIRCULATORY SUPPORT
HEART TRANSPLANT
Fig. 1 Protocol for treating dilated cardiomyopathy.
The goals of treatment for patients with dilated
cardiomyopathy are to make the patient feel better
and live longer. Successful treatment implies a de-
crease in numbers of medications and in frequency of
hospital and physician visits, an improvement in ex-
ercise tolerance, and a decrease in expense. Patients
awaiting heart transplantation must remain alive until
an appropriate donor is found, which may require
more than a year of waiting.
Successful treatment generally requires careful mon-
itoring of salt and fluid intake and output. Serum
electrolytes, renal and hepatic function, and drug
levels should be evaluated frequently. Decisions on
drug treatment should take into account the fact that
some drugs have multiple actions.
Texas Hean Institutejournal
Inotropic Therapy
Inotropic agents augment myocardial contractility.
They appear to work in part by increasing intracel-
lular calcium, which in tum reacts with contractile
proteins to generate a greater force of myocardial
contraction.12 ,-agonist inotropic agents act by stim-
ulating production of cyclic adenosine monophos-
phate (cAMP), which in tum facilitates calcium entry
into the myofibrils. Phosphodiesterase inhibitors act
by preventing the breakdown of cAMP. Inotropic
agents produce a dose-responsive increase in cardiac
output with improved renal flow and reduction of
total body salt and water.
Despite theirdocumented beneficial effect on myo-
cardial contractility, chronic use of inotropic drugs
remains controversial. The price for the benefits may
include increased myocardial oxygen consumption
and cardiac workload and the potential for ischemic
injury, arrhythmias, and hepato-renal toxicity.
Digitalis. Although recent studies have con-
firmed that digitalis has a beneficial hemodynamic
effect in patients with congestive failure,"1-15 digitalis
administration remains controversial. A new study
undertaken by the National Heart, Lung, and Blood
Institute and the Department of Veterans Affairs
Cooperative Studies Program (Digitalis Investigation
Group) will evaluate digitalis within the context of
current therapeutic regimens that include widespread
use of angiotensin-converting enzyme (ACE) inhib-
itors. Centers are now being recruited to implement
the protocol in 1,000 patients. Results are expected to
be published in 1996.
We believe that digitalis is useful in the treatment
of congestive failure and administer it to virtually
all of our stage-1 patients. Digitalis increases cardiac
index and lowers pulmonary capillary wedge pres-
sure. While it does have a direct inotropic effect,
its extracardiac effects may be equally important:
venodilation induced by altering baroreceptor re-
sponses and, possibly, inhibition of renin release
from the kidneys. Digitalis is indicated in patients
with left ventricular systolic dysfunction, ventricular
dilatation, advanced NYHA classification, or atrial
tachyarrhythmias. The risk of hypotension associated
with vasodilator use is decreased by using digitalis.
Digitalis is especially useful in patients with heart
failure accompanied by atrial fibrillation or atrial
flutter with rapid ventricular response, or in patients
with paroxysmal atrial tachycardia.
Although there are risks associated with digitalis
therapy, most of the adverse reactions that occur are
reversible and, if treated, do not change long-term
morbidity and mortality. Among more than 4,300
patients in the Boston area who received digitalis in
one study, 12% of patients experienced adverse reac-
tions.'6"17 These studies were done, however, before
digitalis serum levels were monitored routinely and
Treatment of Dilated Cardiomyopathy 43
before adequate treatment for toxicity was devel-
oped; therefore, current morbidity rates would be
even lower. Physicians should monitor patients with
renal failure very carefully, since digoxin toxicity is
more likely to develop in patients who cannot excrete
the drug normally. Patients taking digitalis prepara-
tions require careful monitoring of serum potassium.
In those of our patients with low creatinine clearance
and satisfactory hepatic function, we consider use of
digitoxin.
While the benefits of digitalis glycosides are likely
to be more apparent in patients with more severe
congestive heart failure, 3 large and relatively recent
trials1820 have suggested that digoxin may be benefi-
cial even in mild congestive failure. Patients in each
of these studies showed improved exercise tolerance.
In a study by Arnold,21 digitalis withdrawal resulted in
decreased left ventricular stroke work index and in-
creased pulmonary capillary wedge pressure, effects
that were reversed when treatment with digitalis was
resumed. In patients with congestive heart failure
who have digitalis withdrawn, 15% to 25% will re-
quire its reinstitution.
Dopamine. Dopamine exerts an inotropic effect
on the myocardium through a direct action on a, 3,
and dopamine receptors, or through the release of
norepinephrine from terminal sympathetic neurons.
The effect depends upon the dosage given. At low
dosages (less than 2 gg/kg/min), dopamine activates
dopaminel receptors and increases renal flow while
enhancing coronary artery and cerebrovascular dila-
tion. At moderate dosages (2 to 5 jg/kg/min), dopa-
mine activates ,iS-adrenergic receptors and causes
increased myocardial contractility with little change
of heart rate, and with reduction or no change in
systemic vascular resistance. High doses (5 to 10 ,ug/
kg/min) activate a1-adrenergic receptors and sero-
tonin-sensitive receptors, and increase coronary and
systemic arterial resistance and heart rate. In patients
with severe heart failure, it is important not to give
too much dopamine. Dopamine's strength lies in its
ability, at proper doses, to restore cardiac output
and increase sodium excretion.
In early studies, dopamine infusion rates of 2 to 6
jg/kg/min were found to increase cardiac output
26% while reducing systemic and pulmonary vas-
cular resistance and causing no significant change in
heart rate.22 Left ventricular dp/dt increased by ap-
proximately 58%; glomerular filtration rate, renal
perfusion flow, and sodium excretion all increased
substantially.22'23 Large doses of dopamine may be
used to provide a positive inotropic effect if infusions
of nitroprusside or nitroglycerine are used for vaso-
dilation.
Dobutamine. Dobutamine is a synthetic sympath-
omimetic amine that stimulates the R, 02, and a
receptors, causing an increase in cardiac output with
44 Treatment of Dilated Cardiomyopathy
favorable flow distribution. Unlike dopamine, it does
not cause the release of endogenous norepineph-
rine, nor does it cause significant hypertensive,
vasodilative, or arrhythmogenic effects. Myocardial
contractility is augmented with little net effect on the
systemic vascular bed. Dobutamine is not a renal
vasodilator.
Infusion of dobutamine usually causes clinical
hemodynamic improvement within 72 hours, and
this improvement can last more than 10 months after
discontinuation of the drug. This prolonged benefit
following discontinuation may be due to mitochon-
drial effects24 or to conditioning of the skeletal mus-
cles.25 Because it has prolonged clinical benefit, it
can be used intermittently. Patients awaiting cardiac
transplantation have been kept on intermittent dobu-
tamine for weeks without ill effect. The usual effec-
tive dose of dobutamine is 2.5 to 10 ,ug/kg/min.
Both dopamine and dobutamine are valuable in
treatment of congestive heart failure. Their individual
properties must be recognized to enable appropriate
selection in a given case.
Amrinone (Inocor). Amrinone, a nonglycosidic,
nonsympathomimetic phosphodiesterase inhibitor,
is a bipyridine derivative that produces both positive
inotropic effects and vasodilation. A n-agonist, amri-
none inhibits breakdown of intracellular cAMP by
inhibition of phosphodiesterase. Amrinone increases
cardiac output by direct inotropic effect, by increas-
ing the rate of left ventricular relaxation, and by
decreasing both systemic and pulmonary vascular
resistance. In recommended doses (5 to 10 ,ug/kg/min),
amrinone may augment cardiac output 30% to 50%
while decreasing left ventricular filling pressure 200/o
to 40%.26 As a result of these effects, and of its action
as a vasodilator and the resultant decrease in resting
wall tension, myocardial oxygen consumption may
decrease and patients may note increased exercise
tolerance. Patients who have not responded to cate-
cholamines may respond to amrinone.
Amrinone can be used in combination with other
drugs, including digoxin and catecholamines. The
additive effects of combining these drugs is often
beneficial to patients.27 When used in conjunction
with epinephrine and norepinephrine, cAMP pro-
duction increases, which facilitates calcium entry into
myocardial cells. Amrinone is administered intrave-
nously, since oral administration has been associated
with an increased risk of arrhythmias and sudden
death.28 Administered intravenously, the drug was
associated with a 3% risk of arrhythmias.
Recently, the Prospective Randomized Milrinone
Survival Evaluation (PROMISE) Trial-the first
controlled trial designed to evaluate the effects of a
phosphodiesterase inhibitor on survival-was dis-
continued, a result of adverse effects noted in the
treatment group.
Volume 18, Number 1, 1991
 Summary. We begin inotropic therapy for patients
with dilated cardiomyopathy by prescribing digitalis.
If patients do not respond to digitalis, we give dopa-
mine, dobutamine, or amrinone (or amrinone in com-
bination with dopamine or dobutamine). Dopamine
and dobutamine are not completely interchange-
able, and their effects may be additive. Because of its
mixed inotropic and vasodilatory effects, amrinone
can be added to this drug regimen in patients with
severe heart failure. Amrinone can also be used alone
in patients who are unresponsive to dopamine or
dobutamine.
Diuretics
All patients with dilated cardiomyopathy and conges-
tive heart failure retain sodium and water, which
increases preload and causes pulmonary congestion
and edema. Diuretics are an effective way to rapidly
reduce volume overload and pulmonary congestion.
The diuretic should increase urine output and reduce
left ventricular filling pressure. Diuresis results in
rapid symptomatic relief. We begin treatment with a
loop diuretic and often add a potassium-sparing, or
distal tubule, agent (Fig. 1). Because the loop diuretics
are short acting, patients in stage-2 failure may need
an additional long-acting thiazide to achieve optimal
effect. The dosage can be adjusted by monitoring the
patient's weight and urine volume and by regular
physical examination, with attention to venous pres-
sure, heart rate, S3, liver distention, and edema. It
may be necessary to give a potassium supplement.
All patients should be closely monitored so that they
do not become hypokalemic or hyperkalemic. Not
only can diuretics adversely affect the neurohumoral
system and electrolyte balance, they can also increase
plasma cholesterol, glucose intolerance, and the fre-
quency of ventricular arrhythmias. Rising BUN is
often an indication of excessive reduction of intravas-
cular volume and decreased renal perfusion. When
persistent congestive heart failure is encountered in
this setting, a circulatory support device should be
considered.
Maximal diuretic therapy requires use of a loop
diuretic and agents preventing reabsorption at the
proximal tubule (acetazolamide), at the distal tubule
(thiazide), and at the collecting duct (potassium
sparing).
"Diuretic resistance" in congestive heart failure is
probably most often due to poor oral absorption and
can be overcome by increasing the individual dose
and frequency of oral administration or by giving the
drug intravenously by bolus or continuous infusion.
Apparent resistance should prompt evaluation of in-
trinsic renal function and verification that nonster-
oidal anti-inflammatory drugs are not being used.
Atrial natriuretic factor may play a role in the future
treatment of congestive heart failure.
Texas Heart Institutejournal
Afterload Reduction
Ventricular afterload can be described as the force
opposing left ventricular fiber shortening during left
ventricular ejection.9'" Controlling impedance to
ejection, or afterload reduction, is important in
patients with dilated cardiomyopathy. It may be
particularly advantageous in patients who are hyper-
tensive or who have significant mitral insufficiency.
Of the vasodilators used to reduce afterload, only
ACE inhibitors have been shown consistently to
improve symptoms, exercise capacity, and prognosis
in patients with congestive failure.
ACE Inbibitors. Angiotensin-converting enzyme
(ACE) is responsible for the formation of angiotensin
II from angiotensin I, and for the breakdown of
bradykinin.3' ACE inhibitors dilate arteries constricted
by angiotensin II, thereby lowering systemic vascular
resistance; they also improve left ventricular function
and cardiac output while decreasing preload and
afterload, and favorably influence myocardial "re-
modeling." Blood pressure, heart rate, and myocar-
dial oxygen consumption also decrease. Myocardial
ischemia may be ameliorated. Because ACE inhibi-
tors alter the neurohormonal mechanisms of con-
gestive failure, they have an advantage over other
vasodilators. Administration of ACE inhibitors favor-
ably affects serum levels of prostaglandin, renin, and
aldosterone.
Several double-blind, placebo-controlled, ran-
domized trials have demonstrated the effectiveness
of ACE inhibitors.32'33 In fact, in a large meta-analysis,
ACE inhibitors were the only class ofvasodilators that
consistently improved functional status and increased
patient survival.-' In these patients, the improvement
seen in exercise performance continued over time.
Although more experience is needed before the
effects of ACE inhibitors on mortality can be deter-
mined, preliminary results are encouraging. In the
CONSENSUS trial,32 death rate among patients with
severe congestive heart failure decreased from 44%
at 6 months in the placebo group to 36% at 1 year in
the treatment group. In a recent double-blind study,
Newman and associates35 compared mortality rates in
patients with moderately severe heart failure given
captopril versus placebo. At 90 days, 21% of patients
treated with placebo had died, while only 4% of
patients given captopril had died.
ACE inhibitors may decrease the number of prema-
ture ventricular complexes and lethal arrhythmias,19-'6
although whether or not their use decreases the
incidence of sudden death is yet to be proved. ACE
inhibitors can be given in combination with digitalis
and diuretics. Currently available ACE inhibitors in-
clude captopril, enalapril, and lisinopril.
Side effects have been known to occur in some
patients given ACE inhibitors. First-dose hypotension
may occur in patients with hyponatremia, relative or
Treatment of Dilated Cardiomyopathy 45
absolute intravascular volume depletion, or severe
symptomatic heart failure (NYHA class III or IV), and
in patients given a large initial dose of drug.37 In the
CONSENSUS enalapril trial, 10% of patients dropped
out when the initial dose was 5 mg. When the start-
ing dose was 2.5 mg a day, the first-dose drop-out
rate decreased to 5%. Therefore, in patients at risk
for hypotension, ACE inhibitors should be given in
initial low doses.
Another complication that may occur in suscep-
tible patients is worsening of renal failure. Patients
known to have diabetes and severe intravascular
volume depletion should be given these drugs cau-
tiously. Serum potassium levels must be closely
monitored.
Hydralazine and Isosorbide Dinitrate. Nitrates re-
duce preload, and may induce significant reduction
of systemic and pulmonary venous pressure. Nitro-
prusside may be useful for short-term arteriolar and
venous dilation. We use hydralazine and isosorbide
dinitrate in combination when patients are intolerant
of ACE inhibitors. Administration of a nitrate accom-
panied by hydralazine more effectively increases
cardiac output and lengthens life. These drugs im-
prove conditions of left ventricular loading by arterial
and venous dilation. The Veterans Administration
Cooperative Study on Vasodilator Therapy of Heart
Failure (VHeFT-1)Y8 studied men with moderately
severe heart failure who were receiving standard
therapy. When hydralazine and isosorbide dinitrate
were added to the therapy, the cumulative mortality
at 2 years fell from 34% in the placebo group to 26%
in the treated group, a "mortality-risk reduction" of
25%.
To sum up, the combination of hydralazine with
nitrates seems to improve survival. Afterload reduc-
tion has earned a place as standard therapy of severe
congestive heart failure. ACE inhibitors such as
captopril and enalapril have been shown to be useful
in improvement of hemodynamics, symptoms, and
long-term prognosis.
Three studies are now under way to assess the
effects of vasodilators on mortality in patients with
congestive failure. The largest, Studies of Left Ven-
tricular Dysfunction (SOLVD), will assess the benefits
of enalapril in patients with ejection fractions less
than 35%. The Survival and Ventricular Enlargement
(SaVE) study will compare captopril with placebo in
patients with left ventricular dysfunction after myo-
cardial infarction. Enalapril versus combined hydral-
azine-isosorbide dinitrate therapy will be evaluated
in VHeFT-2. More should be known when the results
of these studies have been reported.
P-blockers. There are few mortality data on
blockers, but because they can block the adverse
effects of high sympathetic activity, they should be
considered in the treatment of patients with refractory
46 Treatment of Dilated Cardiomyopathy
cardiomyopathy. Patients must be selected carefully,
however, because the negative inotropic effects of P-
blockers may worsen heart failure. Two trials have
supported the beneficial effects of 5-blocker therapy
after acute myocardial infarction: the f,-Blocker Heart
AttackTrial39 and the Norwegian Multicenter ,B-Blocker
Trial.40 Used in small doses, n-blockers may favorably
affect ventricular modeling and cause improvement
in hemodynamics. Patients report increased exercise
tolerance. Diastolic filling may improve, and the
harmful effects of catecholamines on the myocar-
dium may be minimized.
Therefore, in patients with dilated cardiomyopathy
who remain symptomatic after conventional therapy,
we consider ,-blockers, especially metoprolol, be-
ginning with a low dose and increasing to a mean
dose of 25 to 50 mg, given twice daily. In a study by
Anderson4" this dosage resulted in a decrease in sud-
den deaths. Until additional studies are completed,
however, extreme care must be taken in selecting
patients and in monitoring dosages of the drug. We
exclude patients with bradycardia and asthma.
Pacemakers. In some patients with dilated cardio-
myopathy, pacemakers can be lifesaving. In our
patients with severe, symptomatic bradycardia, we
implant permanent pacemakers. Selection of the ap-
propriate pacemaker depends upon whether sinus
node function is normal or abnormal. In patients with
stable sinus node function, we use a dual-chamber
pacemaker (DDD or DDD-R). Because this type of
pacemaker produces synchronous atrial and ven-
tricular contractions, it favorably affects cardiac out-
put. Upper-rate limits must be set to prevent angina
and to prevent induction of pacemaker-mediated
tachycardia in patients with retrograde conduction.
In our patients with atrial fibrillation or atrial flutter,
we implant a VVI or a VVI-R ventricular pacemaker,
depending on the patient's activity level. This type of
system may prevent ventricular arrhythmias by over-
driving competitive rhythms.
Complications
Arrhythmias
Despite the progress in therapy for congestive failure,
at least 40% of patients die suddenly, many as a result
of ventricular tachyarrhythmias, either ventricular
tachycardia or ventricular fibrillation. A recent study
of 21 cardiac arrests in 20 patients with advanced
heart failure documented severe bradycardia or elec-
tromechanical dissociation in 13 of the 20 patients.
Precipitating factors included coronary occlusion,
pulmonary embolism, hypokalemia, and hypo-
glycemia in 6 of 13 patients.42 In patients with idio-
pathic dilated cardiomyopathy, 700/o to 95% have
frequent and complex premature ventricular con-
tractions, and 400/o to 800/o have unsustained ventricu-
Volume 18, Number 1, 1991
lar tachycardia. In the VHeFT study,-' 25% to 300/o of
patients with unsustained ventricular tachycardia did
not have symptoms.
Ventricular arrhythmias have been associated with
myocardial fibrosis and hemodynamic stress, both of
which contribute to the reentry phenomena critical to
the development of ventricular arrhythmias. Other
factors associated with ventricular arrhythmias may
be reversible, and include: electrolyte imbalance;
increased plasma norepinephrine, renin, and angio-
tensin levels in the neurohormonal system; and drug
therapy for heart failure. Diuretic drugs, which acti-
vate the sympathetic nervous and renin-angiotensin
systems, exacerbate the loss of potassium and mag-
nesium. Digitalis can cause arrhythmias, as can the
other inotropic agents, such as the phosphodiester-
ase inhibitors.
Electrophysiologic study has been suggested as
a means to determine which patients with dilated
cardiomyopathy are at greater risk for sudden death.
Such study, however, has proved more informative
in patients with coronary artery disease than in
patients with idiopathic dilated cardiomyopathy. An
exception is serial Holter monitoring in patients with
frequent, complex ventricular ectopy, used to deter-
mine whether therapy is necessary.
Antiarrhythmic agents exacerbate arrhythmias in
5% to 200/o of patients treated. Antiarrhythmic agents
can be negative inotropic agents and can worsen
congestive heart failure, leading to altered drug kin-
etics and toxicity. The decision to treat a patient with
these drugs should be based on several factors; most
important is the effect of treatment on length of life.
Despite these complications, we give amiodarone
to our patients with complex ventricular arrhythmias,
when we believe the benefits outweigh the risks. In
a recent study of 84 patients with moderate to severe
congestive heart failure, there was a 100/o mortality
after 1 year in patients treated with amiodarone,
versus a 400/o mortality at 1 year in untreated pa-
tients.43 In a double-blind, placebo-controlled, cross-
over study by Cleland and associates,44 amiodarone,
in contrast to other antiarrhythmic drugs, was shown
to reduce the frequency and complexity of ventricu-
lar arrhythmias. We have found that in low doses (200
mg/day), side effects are limited, and the drug is still
effective in suppressing arrhythmias. Other, more
standard agents are infrequently effective in con-
trolling rhythm.
Patients at high risk of sudden death-particularly
when malignant ventricular arrhythmias have been
documented-should be considered candidates for
an automatic implantable cardioverter-defibrillator
(AICD). Winkle and coworkers45 reported actuarial
survival in 270 patients following AICD implantation
of 92% at 1 year and 74% at 5 years. Worldwide data
are comparable.Y6
Texas Heart Institutejournal
Thromboembolism
Thromboembolism often complicates the clinical
course of patients with dilated cardiomyopathy. At
least 11% to 13% of patients experience embolic
episodes.4748 Emboli occur, in order of decreasing
frequency, in the pulmonary, renal, splenic, and
cerebral circulations.49 A number of factors have
been cited as predisposing patients with dilated
cardiomyopathy to the development of emboli, in-
cluding: alcoholic disease, which leads to a higher
incidence of thromboembolism; mural thrombi, which
occur in 73% of patients with dilated cardiomyop-
athy; arrhythmias, which are associated with emboli
in 33% of patients; and, possibly, a hypercoagulable
state. The number and frequency of emboli increase
as congestive heart failure worsens.
Although there is no concrete evidence that anti-
coagulation decreases the risk of embolism, retro-
spective reports have suggested that this is the case.
Fuster5l noted an 180/o incidence of emboli in patients
who were not on anticoagulants, versus a 00/o inci-
dence in patients who were on anticoagulants. When
anticoagulation was stopped, 4 of 5 patients in his
series developed emboli.
We routinely prescribe coumadin or heparin for
our patients. We monitor protime and liver function
tests while patients are on anticoagulation therapy.
Conclusion
Questions remain regarding the best agents to pre-
scribe for patients with dilated cardiomyopathy and
the best time, in the course of treatment, to adminis-
ter each type of drug. Drugs that have been shown to
improve survival to date include those that reduce
preload and afterload. New drugs are being devel-
oped. For patients with symptomatic disease, we
recommend diuretics, digoxin, and converting en-
zyme inhibitors for first-line therapy. Although digi-
talis and diuretics improve symptoms, they do not
improve survival rates. ACE inhibitors, on the other
hand, have been shown to improve survival. Patients
with arrhythmias may be treated by addition of
amiodarone, a pacemaker, or an automatic implant-
able cardioverter-defibrillator. Most need to be
anticoagulated. Treatment with 5-blockers remains
investigational.
Heart transplantation is the most aggressive treat-
ment for patients with end-stage heart disease result-
ing from dilated cardiomyopathy. In our transplant
population of 380 patients, approximately 43% had
dilated cardiomyopathy. In 15% of these patients,
some form of mechanical support-ultrafiltration,
intraaortic balloon puimp, Nimbus hemopump, left
ventricular assist device, or total artificial heart-was
necessary as a bridge until an acceptable donor organ
could be found. Results of heart transplantation have
Treatment of Dilated Cardiomyopathy 47
improved over the last 10 years with the introduction
of new immunosuppressive regimens that are better
tolerated. Recipient criteria have been relaxed. We
now accept patients into our transplant program into
their 60s. However, the limited supply of donors
favors younger recipients. Permanent heart assist
devices may help some of these patients, and should
be available within the next few years. Much more
work on the artificial heart, however, is needed be-
fore it will be ready for permanent human use.
The incidence of dilated cardiomyopathy contin-
ues to increase. To better treat dilated cardiomyopa-
thy, we must learn more about the pathophysiologic
mechanisms that cause it. New drugs with fewer side
effects must be developed that can treat and possibly
impede dilatation of the cardiac chambers. Until that
time, we believe the best treatment is an intelligent
combination of the drugs available, in doses individu-
alized to patient needs, with close follow-up for toxic
effects.
References
1. O'Connell JB. Immunosuppression for dilated cardiomyop-
athy [editorial]. N EnglJ Med 1989;321:1119-21.
2. Engelmeier RS, O'Connell JB, Scanlon PJ, Gunnar RM.
Chronic 5-blockade in dilated cardiomyopathy. Primary
Cardiology 1987;13:25-46.
3. Wenger NK, Goodwin JF, Roberts WC. Cardiomyopathy and
myocardial involvement in systemic disease. In: Hurst JW,
ed. The heart: arteries and veins. 6th ed. New York: McGraw-
Hill Book Company, 1986:1181-3.
4. Fowles RE, Bieber CP, Stinson EB. Defective in vitro suppres-
sor cell function in idiopathic congestive cardiomyopathy.
Circulation 1979;59:483-91.
5. Limas CJ. The mechanisms of dilated cardiomyopathy: immu-
nological aspects. CHF: Index and Reviews 1990;III:1,24.
6. Limas CJ, Goldenberg IF, Limas C. Autoantibodies against f-
adrenoceptors in human idiopathic dilated cardiomyopathy.
Circ Res 1989;64:97-103.
7. Limas CJ, Goldenberg IF, Limas C. Effect of cardiac transplan-
tation on anti-beta-receptor antibodies in idiopathic dilated
cardiomyopathy. Am J Cardiol 1989;63:1134-7.
8. Jacobs B, Matsuda Y, Deodhar S, Shirey E. Cell-mediated
cytotoxicity to cardiac cells of lymphocytes from patients with
primary myocardial disease. Am J Clin Pathol 1979;72:1-4.
9. Dargie HJ, Goodwin JF. Catecholamines, cardiomyopathies,
and cardiac function. Prog Cardiol 1982;11:93-106.
10. CohnJN, Rector TS. Prognosis of congestive heart failure and
predictors of mortality. Am J Cardiol 1988;62:25A-30A.
11. Gottlieb SS, Kukin ML, Ahern D, Packer M. Prognostic im-
portance of atrial natriuretic peptide in patients wvith chronic
heart failure. J Am Coll Cardiol 1989;13:1534-9. [Published
erratum appears in J Am Coll Cardiol 1989;14:812.]
12. Scholz H. Pharmacological actions of various inotropic
agents. Eur Heart J 1983;4(Suppl A):161-72.
13. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator
therapy on mortality in chronic congestive heart failure.
Results of a Veterans Administration Cooperative Study. N
Engl J Med 1986;314:1547-52.
14. Lee DC-S, Johnson RA, Bingham JB, et al. Heart failure in
outpatients: a randomized trial of digoxin versus placebo.
N Engl J Med 1982;306:699-705.
48 Treatment of Dilated Cardiomyopathy
15. Cantelli I, Vitolo A, Mengoli P, Parchi C, Bracchetti D. Digoxin-
induced haemodynamic changes in congestive heart failure
of differing aetiology: a comparative study. Cuff Ther Res
1984;35:439-54.
16. Greenblatt DJ. Digitalis glycosides. In: Miller RR, Greenblatt
DJ, eds. Drug effects in hospitalized patients: experiences of
the Boston Collaborative Drug Surveillance Program 1966-
1975. New York: John Wiley & Sons, 1976:38-40.
17. Smith TW. Digoxin and congestive heart failure. II: Protago-
nist's viewpoint. J Am Coll Cardiol 1988;12:267-71.
18. The German and Austrian Xamoterol Study Group. Double-
blind placebo-controlled comparison of digoxin and xamoterol
in chronic heart failure. Lancet 1988;1:489-93.
19. The Captopril-Digoxin Multicenter Research Group. Com-
parative effects of therapy with captopril and digoxin in
patients with mild to moderate heart failure. JAMA 1988;259:
539-44.
20. DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant RC,
Wright R. A comparison of oral milrinone, digoxin, and their
combination in the treatment of patients with chronic heart
failure. N Engl J Med 1989;320:677-83.
21. Arnold SB, Byrd RC, Meister W, et al. Long-term digitalis ther-
apy improves left ventricular function in heart failure. N Engl
J Med 1980;303:1443-8.
22. Goldberg LI, McDonald RH Jr, Zimmerman AM. Sodium
diuresis produced by dopamine in patients with congestive
heart failure. N Engl J Med 1963;269:1060-4.
23. Rosenblum R, Tai AR, Lawson D. Dopamine in man: cardio-
renal hemodynamics in normotensive patients with heart
disease. J Pharmacol Exp Ther 1972;183:256-63.
24. Unverferth DV, Leier CV, Magorien RD, et al. Improvement of
human myocardial mitochondria after dobutamine: a quan-
titative ultrastructural study. J Pharmacol Exp Ther 1980;215:
527-32.
25. Liang C-S, Tuttle RR, Hood WB Jr, Gavras H. Conditioning
effects of chronic infusions of dobutamine: comparison with
exercise training. J Clin Invest 1979;64:613-9.
26. Goldstein RA, PassmoreJM. Inotropic therapy for congestive
heart failure. Cardio 1987; June: 47-8,87.
27. Gage J, Rutman H, Lucido D, LeJemtel TH. Additive effects
of dobutamine and amrinone on myocardial contractility and
ventricular performance in patients wvith severe heart failure.
Circulation 1986;74:367-73.
28. Massie B, Bourassa M, DiBianco R, et al. Long-term oral
administration of amrinone for congestive heart failure: lack
of efficacy in a multicenter controlled trial. Circulation 1985;
71:963-71.
29. Katz AM. Cardiomyopathy of overload. A major determinant
of prognosis in congestive heart failure [review]. N EnglJ Med
1990;322:100-10.
30. Salmenpera MT, Falinski WB, Levy JH. Management of con-
gestive heart failure in the postoperative period. Heart
Failure 1990;May/June:98 -107.
31. Hornung RS, Hillis WS. The acute haemodynamic effects of
intravenous enalaprilic acid (MK422) in patients with left
ventricular dysfunction. Br J Clin Pharmacol 1987;23:29-33.
32. The CONSENSUS Trial Study Group. Effects of enalapril on
mortality in severe congestive heart failure. Results of the
Cooperative North Scandinavian Enalapril Survival Study
(CONSENSUS). N Engl J Med 1987;316:1429-35.
33. Kramer B, Topic N, Massie B. Acute and long-term effects
of captopril on exercise cardiac performance and exercise
capacity in congestive heart failure. Br J Clin Pharmacol
1982;14:143S-51S.
34. Mulrow CD, Mulrow JP, Linn WD, Aguilar C, Ramirez G.
Relative efficacy of vasodilator therapy on chronic congestive
heart failure. Implications of randomized trials. JAMA 1988;
259:3422-6.
Volume 18, Number 1, 1991
35. Newman TJ, Maskin CS, Dennick LG, MeyerJH, Hallows BG,
Cooper WH. Effects of captopril on survival in patients with
heart failure. Am J Med 1988;84:140- 4.
36. Webster MWI, Fitzpatrick MA, Nicholls MG, Ikram H, Wells
JE. Effect of enalapril on ventricular arrhythmias in conges-
tive heart failure. Am J Cardiol 1985;56:566-9.
37. Uretsky BF. Pharmacologic therapy for congestive heart
failure: lessons from the 1980s, issues for the 1990s. ACC
Learning Center Highlights 1990;5:11-8.
38. CohnJN, Archibald DG, Ziesche S, et al. Effect of vasodilator
therapy on mortality in chronic congestive heart failure. Results
of a Veterans Administration Cooperative Study. N EnglJ Med
1986;314:1547-52.
39. Chadda K, Goldstein S, Byington R, Curb JD. Effect of pro-
pranolol after acute myocardial infarction in patients with
congestive heart failure. Circulation 1986;73:503-10.
40. Hansteen V, Moinichen E, Lorentsen E, et al. One year's
treatment with propranolol after myocardial infarction: pre-
liminary report of Norwegian multicentre trial. Br MedJ 1982;
284(1):155-60.
41. Anderson JL, Lutz JR, Gilbert EM, et al. A randomized trial
of low-dose beta-blockade therapy for idiopathic dilated
cardiomyopathy. Am J Cardiol 1985;55:471-5.
42. Luu M, Stevenson WG, Stevenson LW, Baron K, Walden J.
Diverse mechanisms of unexpected cardiac arrest in ad-
vanced heart failure. Circulation 1989;80:1675-80.
Taws Heart In-stitutejournal
43. Dargie HJ, ClelandJG, Leckie BJ, Inglis CG, East BW, Ford I.
Relation of arrhythmias and electrolyte abnormalities to sur-
vival in patients with severe chronic heart failure. Circula-
tion 1987;75(Suppl IV):IV-98-107.
44. Cleland JGF, Dargie HJ, Findlay IN, Wilson JT. Clinical,
haemodynamic, and antiarrhythmic effects of long term
treatment with amiodarone of patients in heart failure. Br
Heart J 1987;57:436-45.
45. Winkle RA, Mead RH, Ruder MA, et al. Long-term outcome
with the automatic implantable cardioverter-defibrillator.J Am
Coll Cardiol 1989;13:1353-61.
46. Fisher JD, Kim SG, Mercando AD. Electrical devices for
treatment of arrhythmias [review]. Am J Cardiol 1988;61:
45A-57A.
47. Ciaccheri M, Castelli G, Cecchi F, et al. Lack of correlation
between intracavitary thrombosis detected by cross sectional
echocardiography and systemic emboli in patients with di-
lated cardiomyopathy. Br Heart J 1989;62:26-9
48. Stratton JR, Resnick AD. Increased embolic risk in patients
with left ventricular thrombi. Circulation 1987;75:1004-1 1.
49. Becker BJP, Chatgidakis CB, Van Lingen B. Cardiovascular
collagenosis with parietal endocardial thrombosis: a clinico-
pathologic study of forty cases. Circulation 1953;7:345-56.
50. Fuster V, Gersh BJ, Giuliani ER, Tajik AJ, Brandenburg RO,
Frye RL. The natural history of idiopathic dilated cardiomy-
opathy. Am J Cardiol 1981;47:525-31.
Treatment of Dilated Cardiomyopathy 49